[Federal Register Volume 65, Number 175 (Friday, September 8, 2000)]
[Rules and Regulations]
[Pages 54686-54739]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-22892]



[[Page 54685]]

-----------------------------------------------------------------------

Part III





Department of Health and Human Services





-----------------------------------------------------------------------



Food and Drug Administration



-----------------------------------------------------------------------



21 CFR Part 101



Food Labeling: Health Claims; Plant Sterol/Stanol Esters and Coronary 
Heart Disease; Interim Final Rule

  Federal Register / Vol. 65, No. 175 / Friday, September 8, 2000 / 
Rules and Regulations  

[[Page 54686]]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket Nos. 00P-1275 and 00P-1276]


Food Labeling: Health Claims; Plant Sterol/Stanol Esters and 
Coronary Heart Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Interim final rule.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is authorizing the use, 
on food labels and in food labeling, of health claims on the 
association between plant sterol/stanol esters and reduced risk of 
coronary heart disease (CHD). FDA is taking this action in response to 
a petition filed by Lipton (plant sterol esters petitioner) and a 
petition filed by McNeil Consumer Healthcare (plant stanol esters 
petitioner). Based on the totality of publicly available evidence, the 
agency has concluded that plant sterol/stanol esters may reduce the 
risk of CHD.

DATES: This rule is effective September 8, 2000. Submit written 
comments by November 22, 2000. The Director of the Office of the 
Federal Register approves the incorporation by reference in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51 of certain publications in 21 
CFR 101.83(c)(2)(ii)(A)(2) and (c)(2)(ii)(B)(2), as of September 8, 
2000.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Sharon A. Ross, Center for Food Safety 
and Applied Nutrition (HFS-832), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-205-5343.

SUPPLEMENTARY INFORMATION:

I. Background

    The President signed into law, on November 8, 1990, the Nutrition 
Labeling and Education Act of 1990 (the 1990 amendments) (Public Law 
101-535). This new law amended the Federal Food, Drug, and Cosmetic Act 
(the act) in number of important ways. One of the most notable aspects 
of the 1990 amendments was that they provided procedures whereby FDA is 
to regulate health claims on food labels and in food labeling.
    In the Federal Register of January 6, 1993 (58 FR 2478), FDA issued 
a final rule that implemented the health claim provisions of the act 
for conventional foods (hereinafter referred to as the 1993 health 
claims final rule). In that final rule, FDA adopted Sec. 101.14 (21 CFR 
101.14), which sets out the rules for the authorization of health 
claims by regulation and prescribes general requirements for the use of 
health claims. Additionally, Sec. 101.70 (21 CFR 101.70) establishes a 
process for petitioning the agency to authorize health claims about a 
substance-disease relationship (Sec. 101.70(a)) and sets out the types 
of information that any such petition must include (Sec. 101.70(d)). On 
January 4, 1994 (59 FR 395), FDA issued a final rule applying the 
requirements of Secs. 101.14 and 101.70 to health claims for dietary 
supplements.
    FDA also conducted an extensive review of the evidence on 10 
substance-disease relationships listed in the 1990 amendments. As a 
result of its review, FDA authorized claims for 8 of these 10 
relationships, one of which focused on the relationship between dietary 
saturated fat and cholesterol and reduced risk of CHD. CHD is the most 
common, most frequently reported, and most serious form of 
cardiovascular disease (CVD) (58 FR 2739, January 6, 1993). Further, 
while the agency denied the use on food labeling of health claims 
relating dietary fiber to reduced risk of CVD (58 FR 2552, January 6, 
1993), it authorized a health claim relating fiber-containing fruits, 
vegetables, and grain products to a reduced risk of CHD.
    In the proposed rule entitled ``Health Claims and Label Statements; 
Lipids and Cardiovascular Disease'' (56 FR 60727 at 60727, 60728, and 
60732, November 27, 1991), FDA set out the criteria for evaluating 
evidence on diet and CVD relationships, including the relationship 
between diet and CHD. FDA noted that, because of the public health 
importance of CHD, identification of ``modifiable'' risk factors for 
CHD had been the subject of considerable research and public policy 
attention. The agency also noted that there is general agreement that 
elevated blood cholesterol levels are one of the major modifiable risk 
factors in the development of CHD. FDA cited Federal Government and 
other reviews that concluded that there is substantial epidemiologic 
and clinical evidence that high blood levels of total and low density 
lipoprotein (LDL) cholesterol are a cause of atherosclerosis 
(inadequate blood circulation due to narrowing of the arteries) and 
represent major contributors to CHD. Further, factors that decrease 
total blood cholesterol and LDL cholesterol will also decrease the risk 
of CHD. FDA concluded that it is generally accepted that blood total 
and LDL cholesterol levels are major risk factors for CHD, and that 
dietary factors affecting blood cholesterol levels affect the risk of 
CHD. High intakes of dietary saturated fat and, to a lesser degree, of 
dietary cholesterol are consistently associated with elevated blood 
cholesterol levels. FDA concluded that the publicly available data 
supported an association between diets low in saturated fat and 
cholesterol and reduced risk of CHD (58 FR 2739 at 2751).
    The agency has authorized other health claims for reducing the risk 
of CHD using the aforementioned criteria. In the final rule entitled 
``Health Claims; Dietary Fiber and Cardiovascular Disease'' (58 FR 
2552), FDA concluded that the publicly available scientific information 
supported an association between fruits, vegetables, and grain products 
(i.e., foods that are low in saturated fat and cholesterol and that are 
good sources of dietary fiber) and reduced risk of CHD through the 
intermediate link of blood cholesterol (58 FR 2552 at 2572) (codified 
at Sec. 101.77)). In response to two petitions documenting that dietary 
consumption of soluble fiber from beta-glucan from oat products and 
psyllium seed husk significantly reduced blood cholesterol levels, FDA 
authorized health claims for soluble fiber from certain foods and 
reduced risk of CHD in Sec. 101.81 (21 CFR 101.81) (62 FR 3584 at 3600, 
January 23, 1997, and amended at 62 FR 15343 at 15344, March 31, 1997, 
pertaining to beta-glucan from oat products, and 63 FR 8103 at 8119, 
February 18, 1998 pertaining to psyllium seed husk). More recently, FDA 
authorized a health claim for soy protein and reduced risk of CHD in 
Sec. 101.82 (21 CFR 101.82) (64 FR 57700, October 26, 1999). In the 
final rule authorizing the claim, the agency concluded, based on the 
totality of publicly available scientific evidence, that there is 
significant scientific agreement that soy protein, included at a level 
of 25 grams (g) per day (d) in a diet low in saturated fat and 
cholesterol, can help reduce total and LDL cholesterol levels, and that 
such reductions may reduce the risk of CHD (64 FR 57700 at 57713). The 
dietary fiber and CVD (56 FR 60582 at 60583 and 60587, November 27, 
1991), soluble fiber from beta-glucan from oat products and CHD (61 FR 
296 at 298, January 4, 1996), soluble fiber from psyllium seed husk and 
CHD (62 FR 28234 at 28236 and 28237, May 22, 1997), and soy protein and 
CHD (63 FR 62977 at 62979 and 62980, November 10, 1998) health claim 
reviews in the proposed rules were conducted in accordance with the

[[Page 54687]]

1991 criteria for evaluating the evidence between diet and CHD (56 FR 
60727 at 60727, 60728, and 60732.
    The present rulemaking is in response to two health claim 
petitions. One health claim petition concerns the relationship between 
plant sterol esters and the risk of CHD, and the other concerns the 
relationship between plant stanol esters and the risk of CHD. Although 
the plant sterol esters petition characterizes the petitioned substance 
as vegetable oil sterol esters, FDA believes it is more accurately 
characterized as plant sterol esters. The petition states that 
vegetable oil sterol esters consist of esterified plant sterols (Ref. 
1, page 3). The petition also mentions that canola oil is one of the 
oils used as a source for the sterol component of vegetable oil sterol 
esters (Ref. 1, page 82). Canola oil is derived from a seed (rapeseed). 
Although seeds are clearly part of the plant kingdom, they are not 
ordinarily thought of as vegetables. Therefore, FDA is concerned that 
the term ``vegetable oil sterol esters'' may not be understood to cover 
esterified sterols from sources like canola oil. Accordingly, the 
agency is using the term ``plant sterol esters'' throughout this 
document. For purposes of this rule, plant sterol esters and plant 
stanol esters will be referred to collectively as ``plant sterol/stanol 
esters.''

II. Petitions for Plant Sterol/Stanol Esters and Reduced Risk of 
CHD

A. Background

    Lipton submitted a health claim petition to FDA on February 1, 
2000, requesting that the agency authorize a health claim on the 
relationship between consumption of certain plant sterol ester-
containing foods and the risk of CHD (Refs.1 through 4). Specifically, 
Lipton requested that spreads and dressings for salad\1\ containing at 
least 1.6 grams of plant sterol esters per reference amount customarily 
consumed be authorized to bear a health claim about reduced risk of 
CHD. On May 11, 2000, the agency sent this petitioner a letter stating 
that FDA had decided to file the petition for further review (Ref. 5). 
On June 26, 2000, Lipton submitted a request asking FDA to exercise its 
authority under section 403(r)(7) of the act (21 U.S.C. 343(r)(7)) to 
make any proposed regulation for its petitioned health claim effective 
upon publication, pending consideration of public comment and 
publication of a final rule (Ref. 6). If the agency does not act, by 
either denying the petition or issuing a proposed regulation to 
authorize the health claim, within 90 days of the date of filing, the 
petition is deemed to be denied unless an extension is mutually agreed 
upon by the agency and the petitioner (section 403(r)(4)(a)(i) of the 
act and 21 CFR 101.70(j)(3)(iii)). On August 2, 2000, FDA and the plant 
sterol ester petitioner agreed to an extension of 30 days, until 
September 6, 2000 (Ref. 7).
---------------------------------------------------------------------------

    \1\ The agency is using the term ``dressings for salad'' 
throughout this document in lieu of the term ``salad dressing'' used 
by the petitioners because the standard of identity for ``salad 
dressing'' in Sec. 169.150 (21 CFR 164.150) refers to a limited 
class of dressings for salad, i.e., those that contain egg yolk and 
meet certain other specifications. ``Salad dressing'' as defined in 
Sec. 169.150 does not include a number of common types of dressings 
for salad, such as Italian dressing.
---------------------------------------------------------------------------

    On February 15, 2000, McNeil Consumer Healthcare submitted a health 
claim petition to FDA requesting that the agency authorize a health 
claim on the relationship between consumption of plant stanol ester-
containing foods and dietary supplements and the risk of CHD (Refs. 8 
through 14). On May 25, 2000, the agency sent this petitioner a letter 
stating that FDA had decided to file the petition for further review 
(Ref. 15). On June 14, 2000, McNeil Consumer Healthcare submitted a 
request asking FDA to exercise its authority under section 403(r)(7) of 
the act to make any proposed regulation for its petitioned health claim 
effective upon publication, pending consideration of public comment and 
publication of a final rule (Ref. 16). On July 17, 2000, FDA and the 
plant stanol ester petitioner agreed to an extension of the deadline to 
publish a proposed regulation until September 6, 2000 (Ref. 17).
    In this interim final rule, the agency concludes that a health 
claim about plant sterol/stanol esters and reduced risk of CHD should 
be authorized under the standard in section 403(r)(3)(B)(i) of the act 
and Sec. 101.14(c) of FDA's regulations and should be made effective 
upon publication under section 403(r)(7) of the act, pending 
consideration of public comment and publication of a final regulation. 
The agency is requesting comments on this interim final rule. Firms 
should be aware that a final rule on this health claim may differ from 
this interim final rule and that they would be required to revise their 
labels to conform to any changes adopted in the final rule.

B. Review of Preliminary Requirements for a Health Claim

1. The Substances Are Associated With a Disease for Which the U.S. 
Population Is at Risk
    Several previous rules establish that CHD is a disease for which 
the U.S. population is at risk. These include rules authorizing claims 
for dietary saturated fat and cholesterol and risk of CHD Sec. 101.75 
(21 CFR 101.75)); fiber-containing fruits, vegetables, and grain 
products and risk of CHD (Sec. 101.77); soluble fiber from certain 
foods and risk of CHD (Sec. 101.81); and soy protein and risk of CHD 
(Sec. 101.82). FDA stated in these rules that CHD remains a major 
public health problem and the number one cause of death in the United 
States. Despite the decline in deaths from CHD over the past 30 years, 
this disease is still exacting a tremendous toll in morbidity (illness 
and disability) and mortality (premature deaths) (Refs. 18 through 20). 
There are more than 500,000 deaths each year for which CHD is the 
primary cause, and another 250,000 deaths for which CHD is a 
contributing cause. About 20 percent of adults (male and female; black 
and white) ages 20 to 74 years have blood total cholesterol (or serum 
cholesterol) levels in the ``high risk'' category (total cholesterol 
greater than (>) 240 milligrams (mg) / deciliter (dL) and LDL 
cholesterol > 160mg/dL) (Ref. 21). Another 31 percent have ``borderline 
high'' cholesterol levels (total cholesterol between 200 and 239 mg/dL 
and LDL cholesterol between 130 and 159 mg/dL) in combination with two 
or more other risk factors for CHD.
    CHD has a significant effect on health care costs. In 1999, total 
direct costs related to CHD were estimated at $53.1 billion, and 
indirect costs from loss of productivity due to illness, disability, 
and premature deaths from this disease were an estimated $46.7 billion 
(Ref. 22). Based on these facts, FDA concludes that, as required in 
Sec. 101.14(b)(1), CHD is a disease for which the U.S. population is at 
risk.
2. The Substances Are Food
    The substances that are the subject of this interim final rule are 
plant sterol esters and plant stanol esters (Refs. 1 through 4 and 8 
through 14).
    a. Plant sterol esters. The substance that is the subject of the 
plant sterol ester petition is a mixture of plant sterols esterified to 
food-grade fatty acids. The sterols are primarily (beta-sitosterol, 
campesterol, and stigmasterol and are extracted from plant sources 
(Ref. 1, page 6). Plant sterols occur widely throughout the plant 
kingdom

[[Page 54688]]

and are present in many edible fruits, vegetables, nuts, seeds, 
cereals, and legumes (Refs. 23 and 24). The plant sterols in foods may 
occur as either the free sterol or esterified with a fatty acid.
    Several studies have estimated dietary plant sterol intake. From a 
population in the Los Angeles area, Nair et al. (Ref. 25) found that 
plant sterol (beta-sitosterol and stigmasterol) intake ranged from 77.9 
mg/d in the general population to 343.6 mg/d in lacto-ovo vegetarians. 
The 1991 British diet was estimated to contain about 158 mg/d of 
sterols (beta-sitosterol, stigmasterol, and campesterol) (Ref. 26). 
Scandinavian vegetarians consume, on average, 513 mg/d and 
nonvegetarians 398 mg/d (Ref. 27). Plant sterol intake in the Japanese 
diet has been estimated at 373 mg/d (Ref. 28). In an analysis of diets 
of participants in the Seven Countries Study, deVries et al. (Ref. 29) 
found plant sterol intake (sitosterol, stigmasterol and campesterol) to 
range from 170 mg/d among U.S. railroad workers to 358 mg/d in Corfu, 
Greece. In a review, Ling and Jones (Ref. 30) estimated average U.S. 
intake at 250 mg/d; it was speculated that this level was doubled among 
vegetarians. Thus, plant sterols are a constituent of the diet for 
Americans and other population groups.
    According to the plant sterol ester petitioner, the solubility of 
free sterols in oil is only 2 percent, but the solubility of sterol 
esters in oil exceeds 20 percent (Ref. 1, pages 14 and 99). Therefore, 
the free plant sterols are esterified with fatty acids from sunflower 
to improve solubility. The petitioner also notes that improved 
solubility of plant sterols creates a palatable product and is 
associated with more uniform distribution in the product and in the 
gastrointestinal tract (Ref. 1, page 14). In vegetable oils, typically 
between 25 and 80 percent of the sterol is in the ester form (Refs. 31 
through 34). One gram of plant sterols is equivalent to about 1.6 g of 
plant sterol esters (Refs. 35 and 36).
    Under Sec. 101.14(b)(3)(i), the substance that is the subject of a 
health claim must contribute taste, aroma, or nutritive value, or any 
other technical effect listed in Sec. 170.3(o) (21 CFR 170.3(o)), to 
the food and must retain that attribute when consumed at the levels 
that are necessary to justify a claim. Plant sterol esters do not 
contribute taste, aroma, or any other technical effect listed in 
Sec. 170.3(o), and thus the plant sterol esters must contribute 
nutritive value to meet the requirement in Sec. 101.14(b)(3)(i).
    The term `nutritive value' is defined in Sec. 101.14(a)(3) as 
``value in sustaining human existence by such processes as promoting 
growth, replacing loss of essential nutrients, or providing energy.'' 
In the proposed rule entitled ``Labeling; General Requirements for 
Health Claims for Food'' (56 FR 60537, November 27, 1991), FDA proposed 
this definition and explained its interpretation of nutritive value in 
the context of whether a substance is a food and thus appropriately the 
subject of a health claim (56 FR 60537 at 60542). The agency indicated 
that the definition was formulated based on the common meaning of the 
words that make up the term ``nutritive value.'' The agency also added 
that use of the phrase ``such processes as'' in the definition of 
nutritive value was intended to provide a measure of flexibility that 
the agency believed would be necessary in evaluating future petitions. 
In the final rule adopting the proposed definition, the agency noted 
that the evaluation of the nutritive value of substances would be done 
on a case-by-case basis to best ensure that the definition retains its 
intended flexibility (58 FR 2478 at 2488). In a subsequent final rule 
on health claims for dietary supplements (59 FR 395 at 407), FDA 
further explained that nutritive value ``includes assisting in the 
efficient functioning of classical nutritional processes and of other 
metabolic processes necessary for the normal maintenance of human 
existence.''
    The scientific evidence suggests that the cholesterol-lowering 
effect of plant sterol esters is achieved through an effect on the 
digestive process (Ref. 1, pages 62 through 64). The digestive process 
is one of the metabolic processes necessary for the normal maintenance 
of human existence. Therefore, the agency concludes that the 
preliminary requirement of Sec. 101.14(b)(3)(i) is satisfied.
    b. Plant stanol esters. The substance that is the subject of the 
plant stanol ester petition is a mixture of plant stanols esterified to 
food-grade fatty acids. The stanols are primarily sitostanol and 
campestanol and may be derived from hydrogenated plant sterol mixtures 
or extracted from plant sources (Ref. 8, page 18). Sitostanol and 
campestanol occur naturally in small quantities in the lipid fractions 
of cereal grains such as wheat, rye, and corn (Refs. 37 through 39) and 
in vegetable oils such as corn and olive oil (Refs. 40 and 41). The 
average western diet provides 20 to 50 mg of plant stanols daily (Ref. 
42).
    According to the plant stanol ester petitioner, esterification of 
free stanols with fatty acids renders plant stanols readily soluble in 
foods and makes an effective vehicle for delivery of plant stanols to 
the small intestine (Ref. 8, page 9). One gram of wood-derived plant 
stanols is equivalent to about 1.7 g of plant stanol esters (Ref. 43), 
and 1 g of vegetable oil plant stanols is equivalent to about 1.8 g of 
plant stanol esters (Ref. 43).
    As discussed in section II.B.2.a of this document, the substance 
that is the subject of a health claim must contribute taste, aroma, or 
nutritive value, or any other technical effect listed in Sec. 170.3(o), 
to the food and must retain that attribute when consumed at levels that 
are necessary to justify a claim (Sec. 101.14(b)(3)(i)). Plant stanol 
esters do not contribute taste, aroma or any other technical effect 
listed in Sec. 170.3(o) and thus must contribute nutritive value to 
meet the requirement in Sec. 101.14(b)(3)(i). The term ``nutritive 
value'' is defined in Sec. 101.14(a)(3) as ``value in sustaining human 
existence by such processes as promoting growth, replacing loss of 
essential nutrients, or providing energy.''
    The scientific evidence suggests that the cholesterol-lowering 
effect of plant stanol esters is achieved through an effect on the 
digestive process (Ref. 8, pages 11 through 12). As discussed in 
section II.B.2.a of this document and in the final rule on health 
claims for dietary supplements (59 FR 395 at 407), nutritive value 
includes assisting in the efficient functioning of classical 
nutritional processes and of other metabolic processes necessary for 
the normal maintenance of human existence, such as digestive processes. 
Therefore, the agency concludes that the preliminary requirement of 
Sec. 101.14(b)(3)(i) is satisfied.
3. The Substances Are Safe and Lawful
    a. Plant sterol esters. The plant sterol ester petitioner asserts 
that plant sterol esters are generally recognized as safe (GRAS) for 
certain uses. In a submission dated January 11, 1999, the petitioner 
informed FDA of its conclusion that plant sterol esters are GRAS for 
use in vegetable oil spreads at levels up to 20 percent (corresponding 
to 1.6 g of plant sterol esters per serving) to supplement the 
nutritive value of the spread, and to help structure the fat phase and 
reduce the fat and water content of the spread. The January 11, 1999, 
submission included the supporting data on which this conclusion was 
based. FDA responded to this submission in a letter dated April 30, 
1999 (Ref. 44). In its response, the agency stated, ``Based on its 
evaluation, the agency has no questions at this time regarding Lipton's 
conclusion that vegetable oil sterol esters are GRAS under the intended 
conditions of use. Furthermore, FDA is not aware of any scientific 
evidence that

[[Page 54689]]

vegetable oil sterol esters would be harmful. The agency has not, 
however, made its own determination regarding the GRAS status of the 
subject use of vegetable oil sterol esters'' (Ref. 44). In a letter 
dated September 24, 1999, the petitioner informed FDA of an additional 
use of plant sterol esters in dressings for salad (Ref. 45). The letter 
contained additional safety information to support the new use.
    The agency notes that authorization of a health claim for a 
substance should not be interpreted as affirmation that the substance 
is GRAS. A review of Lipton's January 11, 1999, submission and of its 
September 24, 1999, letter to the agency, however, reveals significant 
evidence supporting the safety of the use of plant sterol esters at the 
levels necessary to justify a health claim. Moreover, FDA is not aware 
of any evidence that provides a basis to reject the petitioner's 
position that the use of plant sterol esters in spreads and dressings 
for salad up to 1.6 g/serving is safe and lawful. As discussed in 
section V.B of this document, the level of plant sterol esters 
necessary to justify a claim is 1.3 g per day. Therefore, FDA concludes 
that the petitioner has satisfied the requirement of 
Sec. 101.14(b)(3)(ii) to demonstrate that the use of plant sterol 
esters in spreads and dressings for salad at the levels necessary to 
justify a claim is safe and lawful.
    b. Plant stanol esters. Under the health claim petition process, 
FDA evaluates whether the substance is ``safe and lawful'' under the 
applicable food safety provisions of the act (Sec. 101.14(b)(3)(ii)). 
For conventional foods, this evaluation involves considering whether 
the ingredient that is the source of the substance is GRAS, listed as a 
food additive, or authorized by a prior sanction issued by FDA (see 
Sec. 101.70(f)). Dietary ingredients in dietary supplements, however, 
are not subject to the food additive provisions of the act (see section 
201(s)(6) of the act (21 U.S.C. 321(s)(6)). Rather, they are subject to 
the new dietary ingredient provisions in section 413 of the act (21 
U.S.C. 350b) and the adulteration provisions in section 402 of the act 
(21 U.S.C. 342). The term ``dietary ingredient'' is defined in section 
201(ff)(1) of the act and includes vitamins; minerals; herbs and other 
botanicals; dietary substances for use by man to supplement the diet by 
increasing the total daily intake; and concentrates, metabolites, 
constituents, extracts, and combinations of the preceding ingredients.
    A ``new dietary ingredient'' is a dietary ingredient that was not 
marketed in the United States before October 15, 1994 (section 413(c) 
of the act). If a dietary supplement contains a new dietary ingredient 
that has not been present in the food supply as an article used for 
food in a form in which the food has not been chemically altered, 
section 413(a)(2) of the act requires the manufacturer or distributor 
of the supplement to submit to FDA, at least 75 days before the dietary 
ingredient is introduced or delivered for introduction into interstate 
commerce, information that is the basis on which the manufacturer or 
distributor has concluded that a dietary supplement containing such new 
dietary ingredient will reasonably be expected to be safe. FDA reviews 
this information to determine whether it provides an adequate basis for 
such a conclusion. Under section 413(a)(2) of the act, there must be a 
history of use or other evidence of safety establishing that the 
dietary ingredient, when used under the conditions recommended or 
suggested in the labeling of the dietary supplement, will reasonably be 
expected to be safe. If FDA believes that this requirement has not been 
met, the agency responds to the notification within 75 days from the 
date of its receipt. Otherwise, no response is sent. If a new dietary 
ingredient notification has been submitted and a history of use or 
other evidence of safety exists that establishes a reasonable 
expectation of safety, the new dietary ingredient may be lawfully 
marketed in dietary supplements 75 days after the notification is 
submitted.
    As previously noted, the plant stanol ester petitioner requested 
authorization to make a health claim about plant stanol esters and the 
risk of CHD in the labeling of both conventional foods and dietary 
supplements. Because the standards under which the safety and legality 
of conventional foods and dietary supplements are evaluated differ, the 
agency is discussing these two proposed uses separately.
    i. Conventional foods. The plant stanol ester petitioner asserts 
that plant stanol esters are GRAS. In a submission dated February 18, 
1999, the petitioner informed FDA of its conclusion that plant stanol 
esters are GRAS for use as a nutrient in spreads at a level of 1.7g of 
plant stanol esters per serving of spread. The February 18, 1999, 
submission included the supporting data on which this conclusion was 
based. FDA responded to this submission in a letter dated May 17, 1999 
(Ref. 46). In its response, the agency stated, ``Based on its 
evaluation, the agency has no questions at this time regarding McNeil's 
conclusion that plant stanol esters are GRAS under the intended 
conditions of use. Furthermore, FDA is not aware of any scientific 
evidence that plant stanol esters would be harmful. The agency has not, 
however, made its own determination regarding the GRAS status of the 
subject use of plant stanol esters'' (Ref. 46). The petitioner's GRAS 
determination applies to plant stanol esters whose stanol components 
are prepared by the hydrogenation of commercially available plant 
sterol blends, which are obtained as distillates from vegetable oils or 
as byproducts of the kraft paper pulping process (Ref. 46). In letters 
dated July 21, 1999, and October 13, 1999, the petitioner informed FDA 
of additional uses of plant stanol esters in dressings for salad and 
snack bars (Refs. 47 and 48).
    The agency notes that authorization of a health claim for a 
substance should not be interpreted as affirmation that the substance 
is GRAS. A review of McNeil's February 18, 1999, submission, however, 
reveals significant evidence supporting the safety of the use of plant 
stanol esters at the levels necessary to justify a health claim. 
Moreover, FDA is not aware of any evidence that provides a basis to 
reject the petitioner's position that the use of plant stanol esters in 
spreads, dressings for salad, snack bars, and other foods is safe and 
lawful. FDA therefore concludes that the petitioner has satisfied the 
requirement of Sec. 101.14(b)(3)(ii) to demonstrate that the use of 
plant stanol esters in conventional foods at the levels necessary to 
justify a claim is safe and lawful.
    ii. Dietary supplements. The petitioner submitted a new dietary 
ingredient notification for plant stanol esters on August 19, 1999.\2\ 
The new dietary ingredient notification contained several papers that 
reported the results of studies conducted in humans to test 
hypocholesterolemic effects of plant stanol esters as well as a 
reference to the plant stanol ester petitioner's GRAS submission of 
February 18, 1999, and the agency's response to this submission in a 
letter dated May 17, 1999 (Ref. 46). In FDA's judgment, the studies 
submitted in the plant stanol esters new dietary ingredient 
notification and GRAS submission appeared to provide an adequate basis 
that a dietary

[[Page 54690]]

supplement containing plant stanol esters would reasonably be expected 
to be safe. Therefore, the agency did not respond to the new dietary 
ingredient notification. Because the safety standard in section 
413(a)(2) of the act has been met and the new dietary ingredient 
notification was submitted more than 75 days ago, plant stanol esters 
may now be lawfully marketed as dietary ingredients in dietary 
supplements. Therefore, FDA concludes that the petitioner has satisfied 
the requirement of Sec. 101.14(b)(3)(ii) to demonstrate that the use of 
plant stanol esters in dietary supplements at the levels necessary to 
justify a claim is safe and lawful.
---------------------------------------------------------------------------

    \2\ The notification states that McNeil does not believeplant 
stanol esters to be a new dietary ingredient requiring submission of 
a premarket notification, but that McNeil is voluntarily submitting 
the information that would be required as part of such a 
notification ``for the purpose of providing the Food and Drug 
Administration with advance notice concerning its dietary 
ingredient'' (Ref. 49).
---------------------------------------------------------------------------

III. Review of Scientific Evidence of the Substance-Disease 
Relationship

A. Basis for Evaluating the Relationship Between Plant Sterol/Stanol 
Esters and CHD

    FDA's review examined the relationship between plant sterol/stanol 
esters and CHD by focusing on the effects of dietary intake of this 
substance on blood cholesterol levels and on the risk of developing 
CHD. In the 1991 lipids-CVD and dietary fiber-CVD health claim 
proposals, the agency set forth the scientific basis for the 
relationship between dietary substances and CVD (56 FR 60727 at 60728 
and 56 FR 60582 at 60583). In those documents, the agency stated that 
there are many risk factors that contribute to the development of CVD, 
and specifically CHD, one of the most serious forms of CVD and among 
the leading causes of death and disability. The agency also stated that 
there is general agreement that elevated blood cholesterol levels are 
one of the major modifiable risk factors in the development of CVD and, 
more specifically, CHD.
    Several Federal agencies and scientific bodies that have reviewed 
the matter have concluded that there is substantial epidemiologic 
evidence that high blood levels of total cholesterol and LDL 
cholesterol are a cause of atherosclerosis and represent major 
contributors to CHD (56 FR 60727 at 60728, 56 FR 60582 at 60583, Refs. 
18 through 20). Factors that decrease total cholesterol and LDL 
cholesterol will also tend to decrease the risk of CHD. High-intakes of 
saturated fat and, to a lesser degree, of dietary cholesterol are 
associated with elevated blood total and LDL cholesterol levels (56 FR 
60727 at 60728). Thus, it is generally accepted that blood total 
cholesterol and LDL cholesterol levels can influence the risk of 
developing CHD, and, therefore, that dietary factors affecting these 
blood cholesterol levels affect the risk of CHD (Refs. 18 through 20).
    When considering the effect that the diet or components of the diet 
have on blood (or serum) lipids, it is important to consider the effect 
that these factors may have on blood levels of high density lipoprotein 
(HDL) cholesterol. HDL cholesterol appears to have a protective effect 
against CHD because it is involved in the regulation of cholesterol 
transport out of cells and to the liver, from which it is ultimately 
excreted (Refs. 18 and 50).
    For these reasons, the agency based its evaluation of the 
relationship between consumption of plant sterol/stanol esters and the 
risk of CHD primarily on changes in blood total and LDL cholesterol 
resulting from dietary intervention with plant sterol/stanol ester-
containing products. A secondary consideration was that beneficial 
changes in total and LDL cholesterol should not be accompanied by 
potentially adverse changes in HDL cholesterol. This focus is 
consistent with that used by the agency in deciding on the dietary 
saturated fat and cholesterol and CHD health claim, Sec. 101.75 (56 FR 
60727 and 58 FR 2739); the fiber-containing fruits, vegetables, and 
grain products and CHD claim, Sec. 101.77 (56 FR 60582 and 58 FR 2552); 
the soluble fiber from certain foods and CHD claim, Sec. 101.81 (61 FR 
296, 62 FR 3584, 62 FR 28234, and 63 FR 8119) and the soy protein and 
CHD claim, Sec. 101.82 (63 FR 62977 and 64 FR 57700).

B. Review of Scientific Evidence

1. Evidence Considered in Reaching the Decision
    a. Plant sterol esters and CHD. The plant sterol esters petitioner 
submitted 15 scientific studies (Refs. 51 through 60, 61 and 62 (1 
study), 63 and 64 (1 study), and 65 through 67) evaluating the 
relationship between plant sterol esters or plant sterols and blood 
cholesterol levels in humans. The studies submitted were conducted 
between 1953 and 2000. The petition included tables that summarized the 
outcome of each of the studies and a summary of the evidence.
    The plant sterol ester petitioner states that since plant sterol 
esters are hydrolyzed to free sterols and fatty acids in the 
gastrointestinal tract (see Refs. 68 through 70), and free sterols are 
the active moiety of plant sterol esters (see Refs. 69 and 71), the 
literature on free plant sterols has a direct bearing on this petition 
(Ref. 1, page 14). The agency agrees that the active moiety of the 
plant sterol ester is the plant sterol and has concluded that studies 
of the effectiveness of free plant sterols in blood cholesterol 
reduction are relevant to the evaluation of the evidence in the plant 
sterol esters petition. Accordingly, FDA included such studies in its 
evaluation of the relationship between plant sterol esters and reduced 
risk of CHD if they met the study selection criteria specified in 
section III.B.2 of this document.
    In several previous diet and CHD health claim rulemakings, the 
agency began its review of scientific evidence in support of the health 
claim by considering those studies that were published since 1988, the 
date of publication of the ``Surgeon General's Report on Nutrition and 
Health'' (Ref. 18), which is the most recent and comprehensive Federal 
review of the scientific evidence on dietary factors and CHD. That 
approach was not possible in this instance, however, as the ``Surgeon 
General's Report on Nutrition and Health'' does not discuss the effects 
of dietary plant sterols or plant sterol esters on blood cholesterol or 
CHD. A discussion of the role of dietary sterols in CHD does appear in 
another roughly contemporaneous source, the National Academy Press 
publication ``Diet and Health: Implications for Reducing Chronic 
Disease Risk'' (Ref. 19), which was issued in 1989. That publication 
states:
    Long ago, plant sterols (beta-sitosterol and related compounds) 
were found to prevent absorption of dietary cholesterol (Best et al., 
1955; Farquhar and Sokolow, 1958; Farquhar et al., 1956; Lees et al., 
1977; Peterson et al., 1959), apparently by blocking absorption of 
cholesterol in the intestine (Davis, 1955; Grundy and Mok, 1977; 
Jandacek et al., 1977; Mattson et al., 1977). More recent reports 
indicate that these compounds may be more effective in small doses than 
previously believed (Mattson et al., 1982).
    This discussion highlights the previous and current emphasis of 
research on the topic. Investigations in the 1950's reported the 
effects of plant sterols on cholesterol absorption using animal models 
and in a few human studies; work in the 1970's examined beta-sitosterol 
in the form of a drug product to lower cholesterol in humans. In fact, 
beta-sitosterol is approved for use as a drug to lower cholesterol 
(Refs. 72 and 73). More recent research has focused on smaller amounts 
of plant sterols that are solubilized as fatty acid esters of plant 
sterols in food products. The agency considers the older research to be 
of little relevance to the petitioned health claim because it concerned 
forms and amounts of the substance different from those that are the 
subject of the

[[Page 54691]]

petition. Therefore, FDA included in its review only those studies 
published from 1982 (the date the National Academy Press publication 
refers to for the more recent research reports (Ref. 19)) to the 
present among those submitted by the petitioner (Refs. 51, 52, 57, 58, 
61 and 62 (1 study), 63 and 64 (1 study), 65, and 67). In addition to 
eight studies submitted by the petitioner, FDA also considered two 
other studies (Refs. 74 and 75) concerning the effects of plant sterol 
esters on blood cholesterol. These two studies were identified by a 
literature search (Ref. 76) performed to verify that the totality of 
publicly available scientific evidence had been submitted to the 
agency.
    In addition to the human studies previously discussed, the plant 
sterol esters petition also presented some findings from studies that 
employed animal models. Human studies are weighted most heavily in the 
evaluation of evidence on a diet and disease relationship; animal model 
studies can be considered as supporting evidence but cannot serve as 
the sole basis for establishing that a diet and disease relationship 
exists. Because there were enough well-controlled studies in humans to 
evaluate the relationship between plant sterol esters and CHD, FDA did 
not closely review the studies in animals.
    b. Plant stanol esters and CHD. The plant stanol ester petitioner 
submitted 21 scientific studies (Refs. 63 and 64 (1 study), and 67, 77 
through 80, 81 and 82 (1 study), and 83 through 96) evaluating the 
relationship between plant stanol esters or plant stanols and blood 
cholesterol levels in humans. The studies submitted were conducted 
between 1993 and 2000. The petition included tables that summarized the 
outcome of each of the studies and a summary of the evidence.
    Stanol esters are hydrolyzed in the gastrointestinal tract to fatty 
acids and free stanols, and investigators believe there is 
physiological equivalence of free stanols and stanol esters in 
affecting blood cholesterol concentrations. Accordingly, the agency 
concludes that studies of the effectiveness of free plant stanols in 
blood cholesterol reduction are relevant to the evaluation of the 
relationship between plant stanol esters and reduced risk of CHD when 
such studies meet the study selection criteria specified in section 
III.B.2 of this document.
    In several previous diet and CHD health claim rulemakings, the 
agency began its review of scientific evidence in support of the health 
claim by considering those studies that were published since 1988, the 
date of publication of the ``Surgeon General's Report on Nutrition and 
Health'' (Ref. 18), which is the most recent and comprehensive Federal 
review of the scientific evidence on dietary factors and CHD. The 
``Surgeon General's Report on Nutrition and Health,'' however, did not 
discuss the effects of dietary plant stanol esters on blood cholesterol 
or CHD. Although a discussion of the role of dietary sterols in CHD 
appears in the 1989 National Academy Press publication ``Diet and 
Health: Implications for Reducing Chronic Disease Risk,'' there is no 
mention of plant stanol esters in this publication (Ref. 19). In fact, 
research on the cholesterol-lowering capacity of plant stanol esters 
has been a recent development. The agency used 1992 as a starting point 
for its scientific evaluation, because this is the year that the 
earliest study evaluating the effects of plant stanol esters on blood 
cholesterol was published. The agency included in its review 24 studies 
published from 1992 to present that were submitted by the petitioner or 
otherwise identified (Refs. 58, 63 and 64 (1 study), 67, 74, 77 through 
80, 81 and 82 (1 study), and 83 through 97). Of these, 21 studies 
(Refs. 63 and 64 (1 study), 67, 77 through 80, 81 and 82 (1 study), and 
83 through 96) were submitted by the petitioner. Two studies (Refs. 74 
and 97) were identified by a literature search (Ref. 76) performed to 
verify that the totality of publicly available scientific evidence had 
been submitted to the agency. In addition, one recently published study 
that was submitted in the plant sterol esters petition included 
administration of plant stanol esters (Ref. 58). This study was 
included in the plant stanol ester review.
    In addition to the published studies previously discussed, the 
plant stanol ester petitioner submitted a summary of 10 unpublished 
studies (Ref. 8, pages 59 through 69). The unpublished studies did not 
weigh heavily in the agency's review because health claims are 
authorized based on the totality of publicly available scientific 
evidence (see section 403(r)(3)(B)(i) of the act and Sec. 101.14(c)) 
and because the summaries of these studies lacked sufficient detail on 
study design and methodologies.
2. Criteria for Selection of Human Studies on Plant Sterol/Stanol 
Esters and CHD
    The criteria that the agency used to select the most pertinent 
studies in both health claim petitions were consistent with those that 
the agency used in evaluating the relationship between other substances 
and CHD. These criteria were that the studies: (1) Present data and 
adequate descriptions of the study design and methods; (2) be available 
in English; (3) include estimates of, or enough information to 
estimate, intakes of plant sterols or stanols and their esters; (4) 
include direct measurement of blood total cholesterol and other blood 
lipids related to CHD; and (5) be conducted in persons who represent 
the general U.S. population. In the case of criterion (5), these 
persons can be considered to be adults with blood total cholesterol 
levels less than 300 mg/dL, as explained below.
    In a previous rulemaking (62 FR 28234 at 28238 and 63 FR 8103 at 
8107), the agency concluded that hypercholesterolemic study populations 
were relevant to the general population because, based on data from the 
National Health and Nutrition Examination Surveys (NHANES) III, the 
prevalence of individuals with elevated blood cholesterol (i.e., 200 
mg/dL or greater) is high, i.e., approximately 51 percent of adults 
(Ref. 21). The proportion of adults having moderately elevated blood 
cholesterol levels (i.e., between 200 and 239 mg/dL) was estimated to 
be approximately 31 percent, and the proportion of adults with high 
blood cholesterol levels (240 mg/dL or greater) was estimated to be 
approximately 20 percent (Ref. 21). It is also estimated that 52 
million Americans 20 years of age and older would be candidates for 
dietary intervention to lower blood cholesterol (Ref. 21). As the 
leading cause of death in this country, CHD is a disease for which the 
general U.S. population is at risk. Since more than half of American 
adults have mildly to moderately elevated blood cholesterol levels, FDA 
considers studies in these populations to be representative of a large 
segment of the general population. Accordingly, in this rule, the 
agency has reviewed and considered the evidence of effects of plant 
sterol/stanol esters on blood cholesterol in mildly and moderately 
hypercholesterolemic subjects as well as subjects with cholesterol 
levels in the normal range.
    In selecting human studies for review, the agency excluded studies 
that were published in abstract form because they lacked sufficient 
detail on study design and methodologies, and because they lacked 
necessary primary data. Studies using special population groups, such 
as adults with very high serum cholesterol (mean greater than 300 mg/
dL), children with hypercholesterolemia, and persons who had already 
experienced a myocardial infarction (heart attack) or

[[Page 54692]]

who had a diagnosis of noninsulin dependent diabetes mellitus, were 
also excluded because of questions about their relevance to the general 
U.S. population.
3. Criteria for Evaluating the Relationship Between Plant Sterol/Stanol 
Esters and CHD
    The evaluation of study design, protocol, measurement, and 
statistical issues for individual studies serves as the starting point 
from which FDA determines the overall strengths and weaknesses of the 
data and assesses the weight of the evidence. FDA's ``Guidance for 
Industry: Significant Scientific Agreement in the Review of Health 
Claims for Conventional Foods and Dietary Supplements'' articulates the 
agency's approach to evaluating studies supporting diet/disease 
relationships (Ref. 98). The criteria that the agency used in 
evaluating the studies for this rulemaking include: (1) Adequacy and 
clarity of the design (e.g., was the methodology used in the study 
clearly described and appropriate for answering the questions posed by 
the study?); (2) population studied (e.g., was the sample size large 
enough to provide sufficient statistical power to detect a significant 
effect?); (3) assessment of intervention or exposure and outcomes 
(e.g., was the dietary intervention or exposure well defined and 
appropriately measured?); and (4) statistical methods (e.g., were 
appropriate statistical analyses applied to the data?).
    The general study design characteristics for which the agency 
looked included selection criteria for subjects, appropriateness of 
controls, randomization of subjects, blinding, statistical power of the 
studies, presence of recall bias and interviewer bias, attrition rates 
(including reasons for attrition), potential for misclassification of 
individuals with regard to dietary intakes, recognition and control of 
confounding factors (for example, monitoring body weight and control of 
weight loss), and appropriateness of statistical tests and comparisons. 
The agency considered whether the intervention studies that it 
evaluated had been of long enough duration, greater than or equal to 3 
weeks duration, to ensure reasonable stabilization of blood lipids.
    As discussed above, dietary saturated fat and cholesterol affect 
blood cholesterol levels (Refs. 19 and 20). Previous reviews by FDA and 
other scientific bodies have generally concluded that, in persons with 
relatively higher baseline levels of blood cholesterol, responses to 
dietary intervention tend to be of a larger magnitude than is seen in 
persons with more normal blood cholesterol levels (56 FR 60582 at 60587 
and Refs. 19 and 20). To take into account these factors, FDA 
separately evaluated studies on mildly to moderately 
hypercholesterolemic individuals (persons with elevated blood total 
cholesterol levels of 200 to 300 mg/dL) and studies on 
normocholesterolemic individuals (persons with blood total cholesterol 
levels in the normal range ( 200 mg/dL)). FDA also separately evaluated 
studies in which the effects of plant sterol/stanol esters were 
evaluated as part of a ``typical'' American diet (approximately 37 
percent of calories from fat, 13 percent of calories from saturated 
fat, and more than 300 mg of cholesterol daily) and studies in which 
the test protocols incorporated a dietary regimen that limits fat 
intake such as the National Heart, Lung, and Blood Institute's National 
Cholesterol Education Program Step I Diet (intake of 8 to 10 percent of 
total calories from saturated fat, 30 percent or less of calories from 
total fat, and cholesterol less than 300 mg/d) (Ref. 99).

C. Review of Human Studies

1. Studies Evaluating the Effects of Plant Sterol Esters on Blood 
Cholesterol
    As discussed in section III. B.1.a of this document, FDA reviewed 
10 human clinical studies on plant sterol esters or other plant sterols 
(Refs. 51, 52, 57, 58, 61 and 62 (1 study), 63 and 64 (1 study), 65, 
67, and 74 and 75). Of these, nine met the selection criteria listed in 
section III.B.2 of this document (Refs. 51, 57, 58, 61 and 62 (1 
study), 63 and 64 (1 study), 65, 67 and 74 and 75). These studies are 
summarized in table 1 at the end of this document and discussed below. 
The remaining study (Ref. 52) failed to meet the inclusion criteria 
because the population studied (children with familial 
hypercholesterolemia) was not representative of the general U.S. 
population. As supporting evidence, the results of one research 
synthesis study (Ref. 100) that included a number of the plant sterol 
ester studies submitted in the petition are discussed in section 
III.C.1.d of this document.
    Studies typically report the amount of free plant sterol consumed 
rather than the amount of plant sterol ester administered. Where 
possible, we report both the amount of plant sterol ester and the 
equivalent free sterol.
    (a) Hypercholesterolemics (serum cholesterol  300 mg/dL): low 
saturated fat and cholesterol diets. One study was submitted as a draft 
in the plant sterol esters petition because it has been submitted for 
publication, but has not yet been published other than in abstract form 
(Ref. 62). FDA reviewed this study but considers the results 
preliminary until a full report of the study has been published. The 
preliminary results in this study (Refs. 61 and 62 (1 study)) showed a 
cholesterol-reducing effect of plant sterol esters in 
hypercholesterolemic subjects who consumed soybean oil sterol esters as 
part of a low saturated fat and low cholesterol diet. In this study, 
224 men and women with mild-to-moderate hypercholesterolemia instructed 
to follow a National Cholesterol Education Program Step I diet were 
randomly assigned to one of three groups: (1) control reduced-fat 
spread, (2) reduced-fat spread containing 1.76 g/d of plant sterol 
esters (1.1 g/d free plant sterols) (low intake group), or (3) reduced-
fat spread containing 3.52 g/d of plant sterol esters (2.2 g/d free 
plant sterols) (high-intake test group). All subjects consumed 14 g/d 
of spread in two 7 g servings/day, with food. Subjects in the low- and 
high-intake groups who consumed ``80 percent of scheduled servings had 
decreases in serum total cholesterol of 5.2 and 6.6 percent, and LDL 
cholesterol of 7.6 and 8.1 percent, respectively, versus control 
(p0.001). The difference between the two test groups with regard to 
serum total and LDL cholesterol levels was not statistically 
significant. HDL cholesterol responses did not differ among the groups. 
These preliminary results indicate that a plant sterol ester-containing 
reduced-fat spread, in a diet low in saturated fat and cholesterol, can 
reduce cholesterol.
    (b) Hypercholesterolemics (serum cholesterol  300 mg/dL): 
``typical'' or ``usual'' diets. Four studies (Refs. 57, 58, 67, and 74) 
show a relationship between consumption of plant sterols and reduced 
blood cholesterol in hypercholesterolemic subjects consuming diets 
within the range of a typical American diet. A fifth study (Refs. 63 
and 64 (1 study)) shows inconclusive results.
    Jones et al. (Ref. 58) conducted a controlled feeding crossover 
study in which diets were based on a fixed-food North American diet 
formulated to meet Canadian recommended nutrient intakes. This study 
reported significantly lower plasma total cholesterol (9.1 percent, p  
0.005) and LDL cholesterol (13.2 percent, p  0.02) in male subjects 
consuming 2.94 g/d vegetable oil sterol esters (1.84 g/d free plant 
sterols delivered in 23 g of margarine each day; daily margarine doses 
were divided into three equal

[[Page 54693]]

portions and added to each meal) for 21 days compared to 21 days on 
control margarine. Plasma HDL cholesterol did not differ across groups 
and there was no significant weight change shown by the subjects while 
consuming any of the margarine mixtures.
    Hendriks et al. (Ref. 57) reported the effects of feeding three 
different levels of vegetable oil sterol esters (1.33, 2.58, and 5.18 
g/d corresponding to 0.83, 1.61, and 3.24 g/d free plant sterols, 
respectively) incorporated in spreads (25 g/d of spread replaced an 
equivalent amount of the spread(s) habitually used; one-half was 
consumed at lunch, one-half at dinner) in apparently healthy 
normocholesterolemic and mildly hypercholesterolemic subjects using a 
randomized, double-blind placebo-controlled balanced incomplete Latin 
square design with five treatments and four periods. The vegetable oil 
sterols were esterified to sunflower oil and the degree of 
esterification was 82 percent. Blood total and LDL cholesterol levels 
were reduced compared to the control spread (p 0.001) after 3.5 weeks. 
Blood total cholesterol decreased by 4.9, 5.9, and 6.8 percent for 
daily consumption of 1.33, 2.58, and 5.18 g/d plant sterol esters, 
respectively. For LDL cholesterol these decreases were 6.7, 8.5, and 
9.9 percent. No significant differences in cholesterol-lowering effect 
between the three levels of plant sterol esters could be detected. 
There were no effects on HDL cholesterol. The subjects' body weight 
differed after daily consumption of 2.58 and 5.18 g plant sterol esters 
by 0.3 kilogram (kg) (p  0.01), but this small difference in body 
weight probably did not affect the study findings.
    Another study by Jones et al. (Ref. 74) investigated the effects of 
a mixture of plant sterols and plant stanols. The plant stanol compound 
sitostanol made up about 20 percent of the mixture by weight. The 
remaining sterol component of the mixture was composed mostly of the 
plant sterols sitosterol and campesterol from tall oil (derived from 
pine wood). The investigators evaluated the cholesterol-lowering 
properties of this nonesterified plant sterol/stanol mixture in a 
controlled feeding regimen based on a ``prudent,'' fixed-food North 
American diet formulated to meet Canadian recommended nutrient intakes. 
Thirty-two hypercholesterolemic men were fed either a diet of prepared 
foods alone or the same diet plus 1.7 g per d of the plant sterol/
stanol mixture (in 30 g/d of margarine, consumed during 3 meals) for 30 
days in a parallel study design. The plant sterol/stanol mixture had no 
statistically significant effect on plasma total cholesterol 
concentrations. However, LDL cholesterol concentrations on day 30 had 
decreased by 8.9 percent (p  0.01) and 24.4 percent (p  0.001) with the 
control and plant sterol/stanol-enriched diets, respectively. On day 
30, LDL cholesterol concentrations were significantly lower (p  0.05) 
by 15.5 percent in the group consuming the plant sterol/stanol mixture 
compared to the control group. HDL cholesterol concentrations did not 
change significantly during the study.
    Weststrate and Meijer (Ref. 67) evaluated the effects of different 
plant sterols on plasma total and LDL cholesterol in 
normocholesterolemic and mildly hypercholesterolemic subjects consuming 
their usual diets with the addition of a test or placebo margarine. A 
randomized double-blind placebo-controlled balanced incomplete Latin 
square design with five treatments and four periods of 3.5 weeks was 
utilized to compare the effect of margarines (30 g/d) with added sterol 
esters from soybean oil (4.8 g/d; 3 g/d free plant sterol), sheanut oil 
(2.9 g/d) or ricebran oil (1.6 g/d) or with plant stanol esters (4.6 g/
d; 2.7 g/d free plant stanols) to a placebo margarine. The sterol 
esters from soybean oil were mainly esters from sitosterol, 
campesterol, and stigmasterol. Plasma total and LDL cholesterol 
concentrations were significantly reduced, by 8.3 and 13.0 percent (p  
0.05), respectively, compared to control, in the soybean oil sterol 
ester margarine group. Similar reductions were reported in the plant 
stanol ester margarine group (see discussion of this study in section 
III. C.2.b of this document). Sterols from sheanut oil and rice bran 
oil did not have a significant effect on cholesterol levels. No effects 
on HDL cholesterol concentrations were reported in either the control 
or any of the test groups. The cholesterol-lowering effects of 
ingestion of plant sterol/stanol esters on blood cholesterol did not 
differ between normocholesterolemic and mildly hypercholesterolemic 
subjects. The authors concluded that both the margarine with plant 
stanol esters and the margarine with sterol esters from soybean oil 
were effective in lowering blood total and LDL cholesterol levels 
without affecting HDL cholesterol concentrations. The authors further 
suggested that incorporating such substances in edible fat-containing 
products may substantially reduce the risk of cardiovascular disease in 
the population.
    Two reports of apparently the same study (Refs. 63 and 64) gave 
inconclusive results regarding the relationship between plant sterol 
consumption and blood cholesterol levels. Interpretation of this study 
is complicated by design issues such as concerns about sample size and 
level of plant sterol administered, but both reports are discussed here 
and summarized in table 1 of this document because they provide 
information to assist in determining the minimum level of plant sterol 
esters necessary to provide a health benefit.
    Miettinen and Vanhanen (Refs. 63 and 64 (1 study)) reported the 
effect of small amounts of sitosterol (700 mg/d free sterols) and 
sitostanol (700 mg/d free stanols) dissolved in 50 g rapeseed oil (RSO) 
mayonnaise on serum cholesterol in 31 subjects with 
hypercholesterolemia for 9 weeks. Subjects did not change their diets 
except for replacing 50 g/d of dietary fat with the 50 g/d of RSO 
mayonnaise. It appears that these authors later conducted another 9-
week phase of the study using sitostanol esters (1.36 g/d plant stanol 
esters or 800 mg/d free stanols) dissolved in 50 g RSO mayonnaise. The 
results of this later phase were reported in the Miettinen reference 
(Ref. 63), together with the earlier results. The Vanhanen reference 
(Ref. 64) reports only the earlier results for sitosterol and 
sitostanol. The Vanhanen reference (Ref. 64) reports reduced serum 
total cholesterol concentrations (8.5 percent) during the RSO 
mayonnaise run-in period (stabilization period before the intervention 
begins) compared to values before the run-in period when combining all 
subjects. Continuation of RSO mayonnaise in the RSO mayonnaise control 
group (n=8) during the experimental period had no further effect on 
blood cholesterol (Refs. 63 and 64). (``N'' refers to the number of 
subjects.) Neither sitosterol (n=9) nor sitostanol (n=7) significantly 
altered serum total cholesterol or LDL cholesterol concentrations 
compared to the RSO control group (n=8) during the experimental period 
(Refs. 63 and 64). Sitostanol ester (n=7), however, significantly 
reduced serum total and LDL cholesterol levels compared to the RSO 
control group (Ref. 63). Furthermore, serum total cholesterol was 
significantly reduced by 4 percent (p  0.05) during the experimental 
period in an analysis, which compared the combined plant sterol/stanol 
groups (sitostanol, sitosterol, and sitostanol ester groups; n=23) to 
the RSO control group (n=8) (Ref. 63). HDL cholesterol did not change 
in the plant sterol group compared to the RSO control group (Ref. 63).
    The agency notes that it is difficult to decipher from the 
descriptions in these

[[Page 54694]]

reports the amount of plant sterol that was consumed and the level of 
cholesterol-lowering that was observed. For the sitosterol group, as an 
example, the method section states that 722 mg/d of sitosterol was 
added to the RSO mayonnaise, yet the abstract mentions that the RSO 
mayonnaise contained an additional 625 mg/d of sitosterol (Ref. 64). 
The results section of the Miettinen reference (Ref. 63) notes that in 
the combined plant sterol/stanol groups, total and LDL cholesterol 
levels were slightly but significantly decreased up to 4 percent, yet 
the abstract states that serum total cholesterol was reduced by about 5 
percent in the combined plant sterol/stanol groups. Therefore, FDA 
considers the results in these reports inconclusive because of 
inconsistencies in the descriptions of methods and results.
    (c) Normocholesterolemics: ``typical'' or ``usual'' diets. The 
results of three studies (Refs. 51, 65, and 75) support a cholesterol-
lowering effect of plant sterols in subjects with normal cholesterol 
values.
    Ayesh et al. (Ref. 51), in a controlled feeding study, reported 
significantly lower serum total cholesterol (18 percent, p  0.0001) and 
LDL cholesterol (23 percent, p  0.0001) in subjects consuming 13.8 g/d 
vegetable oil sterol esters (8.6 g/d free plant sterols delivered in 40 
g of margarine each day consumed with breakfast and dinner under 
supervision) for 21 days in males and 28 days in females, compared to 
subjects consuming a control margarine. These results were calculated 
as the difference from baseline to days 21 for male and 28 for female; 
analysis of covariance was adjusted for gender. There was no 
significant difference in effect on HDL cholesterol between control and 
plant sterol groups.
    In a double-blind crossover study, Sierksma et al. (Ref. 75) showed 
that daily consumption of 25 g of a spread enriched with free soybean 
oil sterols (0.8 g/d) for 3 weeks lowered plasma total and LDL 
cholesterol concentrations respectively by 3.8 percent (p  0.05) and 6 
percent (p  0.05) compared with a placebo spread. No effect on plasma 
HDL cholesterol was found. Subjects followed their usual diets, except 
that they replaced their usual spread with the test or placebo spread. 
The investigators also tested sheanut-oil sterols (3.3 g/d) in 25 g of 
spread and found that the sheanut-oil spread did not lower plasma total 
and LDL cholesterol levels. The sheanut-oil sterols were primarily 
phenolic acid esters of 4,4-dimethyl sterols, whereas the soybean-oil 
product contained 4-desmethyl sterols (the class of sterols containing 
no methyl group at the carbon 4 atom). The structure of 4-desmethyl 
sterols is more similar to cholesterol than the structure of 4,4-
dimethyl sterols. The investigators stated that soybean-oil sterol 
structural similarity to cholesterol may offer increased competition 
with cholesterol for incorporation in mixed micelles, the most likely 
mechanism for the blood cholesterol-lowering action of plant sterols.
    Pelletier et al. (Ref. 65) reported reductions in blood total 
cholesterol (10 percent, p  0.001) and LDL cholesterol (15 percent, p  
0.001), compared to a control period, in subjects consuming 740 mg/d of 
soybean oil sterols (nonesterified) in 50 g/d of butter for 4 weeks. 
These results were obtained in a crossover experiment in 12 
normocholesterolemic men consuming a controlled, but ``normal'' diet. 
The total fat intake as a percent of energy was 36.4 percent during 
both the control and the plant sterol-feeding period. The cholesterol 
intake during the control period was 436 mg/d; it was 410 mg/d during 
the plant sterol-feeding period. The diets were designed to have a 
plant sterol to cholesterol ratio of 2.0, which has repeatedly been 
shown to affect cholesterol levels in various animal models. There was 
no significant difference in effect on HDL cholesterol between control 
and plant sterol groups.
    (d) Other studies: research synthesis study. FDA considered the 
results of a March 25, 2000, research synthesis study by Law (Ref. 100) 
of the effect of plant sterols and stanols on serum cholesterol 
concentrations. While evaluation of research synthesis studies, 
including meta-analyses, is of interest, the appropriateness of such 
analytical techniques in establishing substance/disease relationships 
has not been determined. There are ongoing efforts to identify criteria 
and critical factors to consider in both conducting and using such 
analyses, but standardization of this methodology is still emerging. 
Therefore, this research synthesis study was considered as supporting 
evidence but did not weigh heavily within the body of evidence on the 
relationship between plant sterol/stanol esters and CHD.
    Law performed a research synthesis analysis of the effect of plant 
sterols and stanols on serum cholesterol concentrations by pooling data 
from randomized trials identified by a Medline search using the term 
``plant sterols.'' Law obtained additional data for analysis from other 
studies cited in papers and review articles. A total of 14 studies that 
employed either a parallel or crossover design were incorporated in the 
analysis, consisting of 20 dose comparisons of either plant sterols or 
plant stanols to a control vehicle. The data described the effects on 
serum LDL cholesterol concentrations obtained from using spreads (or in 
some cases, mayonnaise, olive oil, or butter) with and without added 
plant sterols or stanols. Studies that included children with familial 
hypercholesterolemia were excluded from the research synthesis 
analysis. Law included in the research synthesis analysis study 
populations with severe hypercholesterolemia (mean serum total 
cholesterol greater than 300 mg/dL) and study populations with previous 
myocardial infarction or noninsulin dependent diabetes mellitus, as 
well as study populations with mildly and moderately 
hypercholesterolemic and/or normal cholesterol concentrations.
    Based on the placebo-adjusted reduction in serum LDL cholesterol, 
the analysis indicated that 2 g of plant sterol (equivalent to 3.2 g/d 
of plant sterol esters) or plant stanol (equivalent to 3.4 g/d of plant 
stanol esters) added to a daily intake of spread (or mayonnaise, olive 
oil, or butter) reduces serum concentrations of LDL cholesterol by an 
average of 20.9 mg/dL (0.54 millimole per liter (mmol/l)) in people 
aged 50 to 59 (p=0.005), 16.6 mg/dL (0.43 mmol/l) in those aged 40 to 
49 (p=0.005), and 12.8 mg/dL (0.33 mmol/l) in those aged 30 to 39 
(p=0.005). The results indicated that the reduction in the 
concentration of LDL cholesterol at each dose is significantly greater 
in older people versus younger people. The reductions in blood total 
cholesterol concentrations were similar to the LDL cholesterol 
reductions and there was little change in serum concentrations of HDL 
cholesterol. The results of this analysis also suggested that doses 
greater than about 2 g of plant sterol (3.2 g/d of plant sterol esters) 
or stanol (3.4 g/d of plant stanol esters) per day would not result in 
further reduction in LDL cholesterol (Ref. 100).
    Observational studies and randomized trials concerning the 
relationship between serum cholesterol and the risk of heart disease 
(Ref. 101) indicate that for people aged 50 to 59, a reduction in LDL 
cholesterol of about 19.4 mg/dL (0.5 mmol/l) translates into a 25 
percent reduction in the risk of heart disease after about 2 years. 
Studies administering plant sterols and stanols have demonstrated the 
potential to provide this protection. According to Law, the 
cholesterol-lowering capacity of plant sterols and stanols is even 
larger than the effect that could be expected to occur if people ate 
less animal fat (or saturated fat) (Ref. 100).

[[Page 54695]]

    (e) Summary. In one preliminary report of hypercholesterolemic 
subjects consuming a low saturated fat and low cholesterol diet (Refs. 
61 and 62 (1 study)), plant sterol ester intake was associated with 
statistically significant decreases in serum total and LDL cholesterol 
levels. Levels of HDL cholesterol did not change during plant sterol 
consumption compared to controls. Levels of plant sterol ester found to 
be effective in lowering serum total and LDL cholesterol levels, in the 
context of a diet low in saturated fat and cholesterol, were reported 
to be 1.76 and 3.52 g/d (1.1 and 2.2 g/d of free plant sterol) (Refs. 
61 and 62 (1 study)).
    In four (Refs. 57, 58, 67, and 74) of five (Refs. 57, 58, 67, 74, 
and 63 and 64 (1 study)) studies of hypercholesterolemic subjects 
consuming ``usual'' diets that were generally high in total fat, 
saturated fat and cholesterol, plant sterol intake was associated with 
statistically significant decreases in blood total and/or LDL 
cholesterol levels. Levels of HDL cholesterol were found to be 
unchanged by consumption of diets containing plant sterol (Refs. 57, 
58, 67, 74, and 63 and 64 (1 study)). Levels of plant sterol ester 
found to be effective in lowering blood total and/or LDL cholesterol 
levels, in the context of a usual diet, ranged in these studies from 
1.33 (Ref. 57) to 5.18 g/d (Ref. 57) (equivalent to 0.83 to 3.24 g/d of 
free plant sterol).
    The results of one study in hypercholesterolemic subjects consuming 
``usual'' diets (Refs. 63 and 64 (1 study)) are inconclusive; this may 
be due to lack of statistical power (e.g., sample size too small to 
detect the hypothesized difference between groups) or too low a dose of 
plant sterols to provide an effect. As previously discussed, the 
descriptions of methods and results also were inconsistent and 
difficult to interpret. These investigators report no effect of 700 mg/
d of plant sterol (equivalent to 1.12 g/d of plant sterol esters) on 
blood cholesterol levels. However, when the results of three test 
groups (700 mg/d plant sterol, 700 mg/d plant stanol, 1.36 mg/d plant 
stanol ester) were pooled and compared to a control group, a 
statistically significant effect on reducing serum total cholesterol 
emerged, perhaps because the increased number of subjects in this 
pooled analysis artificially increased the ability to detect a 
difference.
    In three of three studies (Refs. 51, 65, and 75) of healthy adults 
with normal blood cholesterol levels consuming a ``usual'' diet, plant 
sterol intake was associated with statistically significant decreases 
in both blood total and LDL cholesterol levels. HDL cholesterol levels 
were not significantly affected by plant sterol intake. Levels of plant 
sterol found to be effective in lowering blood total and LDL 
cholesterol ranged in these studies from 0.74 (Ref. 65) to 8.6 g/d 
(equivalent to 1.2 to 13.8 g/d of plant sterol esters) (Ref. 51).
    Based on these studies, FDA finds there is scientific evidence for 
a consistent, clinically significant effect of plant sterol esters on 
blood total and LDL cholesterol. The cholesterol-lowering effect of 
plant sterol esters is consistent in both mildly and moderately 
hypercholesterolemic populations and in populations with normal 
cholesterol concentrations. The cholesterol-lowering effect of plant 
sterol esters has been reported in addition to the effects of a low 
saturated fat and low cholesterol diet. It has been consistently 
reported that plant sterols do not affect HDL cholesterol levels. These 
conclusions are drawn from the review of the well controlled clinical 
studies and are supported by the research synthesis study of Law (Ref. 
100).
2. Studies Evaluating the Effects of Plant Stanol Esters on Blood 
Cholesterol
    As discussed in section III.B.1.b of this document, FDA reviewed 24 
studies (Refs. 58, 63 and 64 (1 study), 67, 74, 77 through 80, 81 and 
82 (1 study), and 83 through 97) on plant stanols, including both free 
and esterified forms. Of these, 15 met the selection criteria listed in 
section III.B.2. of this document (Refs. 58, 63 and 64 (1 study), 67, 
74, 77, 78, 80, 81 and 82 (1 study), 88 through 92, 94, and 97). These 
studies are summarized in table 2 at the end of this document and 
discussed below. The nine remaining studies (Refs. 79, 83 through 87, 
93, 95, and 96) failed to meet the selection criteria because of 
insufficient information to evaluate the design and method of the study 
or because the populations studied were not considered representative 
of the general U.S. adult population. For example, some of the studies 
were performed in children with type II or familial 
hypercholesterolemia; others used adult subjects with mean serum total 
cholesterol levels > 300 mg/dL or subjects with preexisting disease 
(e.g., diabetes). As supporting evidence, the results of a community 
intervention study (Ref. 102) and a research synthesis study (Ref. 100) 
that included a number of the plant stanol ester studies submitted in 
the petition are discussed in section III.C.2.d of this document.
    Studies typically report the amount of free plant stanol consumed, 
rather than the levels of stanol esters administered. Where possible, 
we report both the amount of plant stanol ester and the equivalent free 
stanol.
    (a) Hypercholesterolemics (serum cholesterol  300 mg/dL): low 
saturated fat and cholesterol diets. Two studies (Refs. 77 and 80) 
showed a relationship between consumption of plant stanol esters and 
reduced blood cholesterol in hypercholesterolemic subjects who consumed 
plant stanol esters as part of a low saturated fat and low cholesterol 
diet.
    Andersson et al. (Ref. 80) randomized subjects to receive one of 
three test diets: Either a low fat margarine containing 3.4 g/d plant 
stanol esters (2 g/d of plant stanols) with a controlled, low saturated 
fat, low cholesterol diet; a control low fat margarine containing no 
plant stanol esters with a controlled, low saturated fat, low 
cholesterol diet; or to continue their normal diet with the addition of 
the margarine containing 3.4 g/d plant stanol esters (2 g/d of plant 
stanols). Serum total and LDL cholesterol were reduced in all three 
groups after 8 weeks. The group consuming the margarine containing 
plant stanol esters with the low saturated fat, low cholesterol diet 
showed 12 percent (p  0.0035) and 15 percent (p  0.0158) reductions in 
serum total and LDL cholesterol levels, respectively, compared to the 
group that consumed a control low fat margarine with a controlled, low 
saturated fat, low cholesterol diet. The serum total and LDL 
cholesterol reductions were reported to be 4 percent (p  0.0059) and 6 
percent (p  0.0034), respectively, for the group consuming the 
margarine containing plant stanol esters with the low saturated fat, 
low cholesterol diet compared to the group consuming the margarine 
containing plant stanol esters with a normal diet. Although a normal 
diet and control margarine group was not included, this study suggests 
that 3.4 g/d of plant stanol esters in conjunction with a normal or 
controlled, low saturated fat, low cholesterol diet can significantly 
lower serum cholesterol levels. There was no change in HDL cholesterol 
levels in the normal diet, plant stanol ester margarine group. The 
study results suggest that the reduction in serum cholesterol levels is 
significantly greater when the plant stanol esters are consumed as part 
of a diet low in saturated fat and cholesterol. HDL cholesterol was 
decreased, however, in subjects in both low saturated fat, low 
cholesterol diet groups, and this result was statistically significant 
in the group that consumed the plant stanol ester margarine in 
conjunction with this diet.

[[Page 54696]]

    Hallikainen et al. (Ref. 77) randomly assigned 55 mildly 
hypercholesterolemic subjects, after a 4-week high fat diet (36 to 38 
percent of energy from fat), to one of three low fat margarine groups: 
a 3.9 g/d (2.31 g/d of free plant stanols) wood stanol ester-containing 
margarine, a 3.9 g/d (2.16 g/d of free plant stanols) vegetable oil 
stanol ester-containing margarine, or a control margarine group. The 
groups consumed the margarines for 8 weeks as part of a diet resembling 
that of the National Heart, Lung, and Blood Institute's National 
Cholesterol Education Program Step II diet (a diet in which saturated 
fat intake is less than 7 percent of calories and cholesterol is less 
than 200 mg/d) (Ref. 99). During the experimental period, the serum 
total cholesterol reduction was significantly greater in the wood 
stanol ester-containing margarine (10.6 percent, p  0.001) and 
vegetable oil stanol ester-containing margarine (8.1 percent, p  0.05) 
groups than in the control group, but no significant differences were 
found between the wood stanol ester-containing margarine and vegetable 
oil stanol ester-containing margarine groups. The LDL cholesterol 
reduction was significantly greater in the wood stanol ester-containing 
margarine (13.7 percent p  0.01) group than in the control group. For 
the vegetable oil stanol ester-containing margarine group, the LDL 
cholesterol reduction was 8.6 percent greater than in the control, but 
the difference was not statistically significant (p= 0.072). However, 
there were no significant differences reported between the wood stanol 
ester-containing margarine and vegetable oil stanol ester-containing 
margarine groups for LDL cholesterol. HDL cholesterol concentrations 
did not change during the study. The authors state, ``* * * that plant 
stanols can reduce serum cholesterol concentrations, even in 
conjunction with a markedly low dietary cholesterol intake, indicates 
that plant stanols must inhibit not only the absorption of dietary 
cholesterol but also that of biliary cholesterol.''
    The results of another study (Ref. 97) did not show a relationship 
between consumption of plant stanols and blood cholesterol in 
hypercholesterolemic subjects who consumed plant stanols as part of a 
low saturated fat and low cholesterol diet. In this study, Denke (Ref. 
97) tested the cholesterol-lowering effects of dietary supplementation 
with plant stanols (3 g/d suspended in safflower oil and packed into 
gelatin capsules) in 33 men with moderate hypercholesterolemia who were 
consuming a Step 1 diet. Plant stanol consumption did not significantly 
lower plasma total cholesterol or LDL cholesterol compared with the 
Step 1 diet alone. HDL cholesterol levels were also unchanged. The 
authors state that although previous reports suggested that low dose 
plant stanol consumption is an effective means of reducing plasma 
cholesterol concentrations, its effectiveness may be attenuated when 
the diet is low in cholesterol. The agency notes that, unlike several 
of the studies submitted with the petition, this study was not a 
randomized, placebo-controlled, double-blind study, but rather a fixed 
sequence design. One result of this design was that during the plant 
stanol dietary supplement phase the subjects consumed an additional 12 
g of fat that they did not consume in other phases because each dietary 
supplement contained 1g of safflower oil and subjects were instructed 
to consume 4 capsules per meal (subjects were to consume a total of 12 
capsules (3000 mg) in three divided doses during three meals). The 
agency does not give as much weight to this study as it does the 
studies in which subjects were randomly assigned to placebo or plant 
stanol arms of a study with all else being equal among the 
participants.
    (b) Hypercholesterolemics (serum cholesterol  300 mg/dL): 
``typical'' or ``usual'' diets. Eight studies (Refs. 63 and 64 (1 
study), 67, 78, 81 and 82 (1 study), 88 through 90, and 94) show a 
relationship between consumption of plant stanols and reduced blood 
total and LDL cholesterol in hypercholesterolemic subjects consuming 
diets within the range of a typical American diet. Two studies (Refs. 
58 and 74) show a relationship between consumption of plant stanols and 
reduced LDL cholesterol, but not blood total cholesterol, in the same 
category of subjects consuming diets within the range of a typical 
American diet.
    Hallikainen et al. (Ref. 88) conducted a single-blind, crossover 
study in which 22 hypercholesterolemic subjects consumed margarine 
containing four different doses of plant stanol esters, including 1.4, 
2.7, 4.1, and 5.4 g/d (0.8, 1.6, 2.4, and 3.2 g/d of free plant 
stanols) for 4 weeks each. These test margarine phases were compared to 
a control margarine phase, also 4 weeks long. All subjects followed the 
same standardized diet throughout the study, and the order of the 
margarine phases was randomized. Serum total cholesterol concentration 
decreased (calculated in reference to control) by 2.8 percent for the 
1.4 g/d dose (p=0.384), 6.8 percent for the 2.7 g/d dose (p 0.001), 
10.3 percent for the 4.1 g/d dose (p0.001) and 11.3 percent (p 0.001) 
for the 5.4 g/d dose of plant stanol esters. The respective decreases 
for LDL cholesterol were 1.7 percent (p=0.892), 5.6 percent (p 0.05), 
9.7 percent (p0.001) and 10.4 percent (p0.001). Although decreases were 
numerically greater with 4.1 and 5.4 g doses than with the 2.7 g dose, 
these differences were not statistically significant (p=0.054-0.516). 
This study demonstrates that at least 2.7 g/d of plant stanol esters 
can significantly reduce both serum total cholesterol and LDL 
cholesterol levels by at least 5.6 percent compared to control. No 
statistically significant changes in HDL cholesterol were observed with 
any of the plant stanol ester margarines.
    Gylling and Miettinen (Ref. 78) reported the serum cholesterol-
lowering effects of feeding different campestanol/sitostanol mixtures 
in margarine or butter in 23 postmenopausal women using a double-blind 
crossover design. The participants were randomly allocated to study 
periods where they consumed 25 g/d of plant stanol-containing rapeseed 
oil margarine with either 5.4 g sitostanol ester-rich (3.18 g of free 
plant stanols; wood-derived plant stanol esters with a campestanol to 
sitostanol ratio 1:11) plant stanol esters or 5.7 g campestanol ester-
rich (3.16 g of free plant stanols; vegetable oil-derived plant stanol 
esters with a campestanol to sitostanol ratio 1:2) plant stanol esters. 
After 6 weeks, subjects consumed the other margarine for an additional 
6 weeks. Following an 8 week home diet wash-out period, 21 of the 
subjects were randomly assigned to consume either 25 g of butter or 4.1 
g/d plant stanol esters (2.43 g/d of free plant stanols with a 
campestanol to sitostanol ratio 1:1) in 25 g of butter for an 
additional 5 weeks. Throughout the study, subjects consumed their usual 
diets, except that they were instructed to substitute the 25 g/d of 
butter or margarine consumed as part of the study for 25 g of their 
normal daily fat intake. Both the wood and vegetable stanol ester 
margarines lowered serum total cholesterol by 4 and 6 percent, 
respectively, compared to baseline (p  0.05 for both). LDL cholesterol 
was reduced by 8 and 10 percent with the wood and vegetable stanol 
ester margarines, respectively, versus baseline (p  0.05 for both). 
Furthermore, HDL cholesterol was increased by 6 and 5 percent (p  0.05) 
with the wood and vegetable stanol ester margarines, respectively, 
versus baseline, so the LDL/HDL cholesterol ratio was reduced by 15 
percent (p 

[[Page 54697]]

0.05 for both). The two plant stanol mixtures in margarine appeared 
equally effective in reducing serum cholesterol. Butter alone increased 
serum total and LDL cholesterol by 4 percent (p  0.05 for total 
cholesterol, not statistically significant for LDL cholesterol). 
Although the plant stanol ester butter did not significantly reduce 
serum total and LDL cholesterol compared to baseline, the plant stanol 
ester butter was found to decrease serum total cholesterol by 8 percent 
and LDL cholesterol by 12 percent (p  0.05 for both) compared to butter 
alone. There was no significant change in HDL cholesterol between the 
two butter groups. The study reported that plant stanol esters are able 
to decrease serum total and LDL cholesterol in a saturated environment, 
i.e., when plant stanol ester is consumed in butter, a high saturated-
fat food, and compared to the effects of butter without plant stanol 
esters. The observation that the plant stanol ester butter did not 
reduce blood cholesterol levels compared to baseline suggests that 
plant stanol esters do not completely counteract the impact of a high 
saturated-fat diet on blood cholesterol levels.
    Nguyen et al. (Ref. 90) examined the blood cholesterol-lowering 
effects in subjects consuming either a European spread containing 5.1 
g/d plant stanol esters (3 g/d free plant stanols), a U.S.-reformulated 
spread containing 5.1 g/d plant stanol esters (3 g/d free plant 
stanols), a U.S.-reformulated spread containing 3.4 g/d plant stanol 
esters (2 g/d of free plant stanols), or a U.S.-reformulated spread 
without plant stanol esters for 8 weeks. The subjects consumed a total 
of 24 g of spread in three 8 g servings a day, but made no other 
dietary changes. Serum total cholesterol (p  0.001) and LDL cholesterol 
(p 0.02) levels were significantly reduced in all three test groups 
compared with the placebo group at all time points during the 
ingredient phase. The U.S. spread containing 5.1 g/d plant stanol 
esters lowered serum total and LDL cholesterol by 6.4 and 10.1 percent, 
respectively, when compared to baseline (p 0.001). Subjects consuming 
the 5.1 g/d plant stanol esters European spread achieved a 4.7 percent 
reduction in serum total cholesterol and a 5.2 percent reduction in LDL 
cholesterol compared to baseline (p  0.001). The 3.4 g/d plant stanol 
ester U.S. spread group showed a 4.1 percent reduction in both serum 
total and LDL cholesterol levels compared to baseline (p  0.001). HDL 
cholesterol levels were unchanged throughout the study.
    Weststrate and Meijer (Ref. 67) evaluated the effects of different 
plant sterols and stanols on plasma total and LDL cholesterol in 
normocholesterolemic and mildly hypercholesterolemic subjects. The 
subjects consumed their usual diets with the addition of a test or 
placebo margarine. A randomized double-blind placebo-controlled 
balanced incomplete Latin square design with five treatments and four 
periods of 3.5 weeks was utilized to compare the effect of margarines 
(30 g/d) with added plant stanol esters (4.6 g/d; 2.7 g/d free plant 
stanols), or with added plant sterol esters from sheanut oil (2.9 g/d), 
ricebran oil (1.6 g/d), or soybean oil (4.8 g/d; 3 g/d free plant 
sterol) to a placebo margarine. Plasma total and LDL cholesterol 
concentrations were significantly reduced by 7.3 and 13.0 percent (p  
0.05), respectively, compared to control, in the plant stanol ester 
margarine group. Similar reductions were reported in the soybean oil 
sterol ester margarine group (see discussion of this study in section 
III.C.1.b of this document). No effect on HDL cholesterol 
concentrations was reported during the study.
    In a long term study conducted in Finland (Ref. 89), 153 mildly 
hypercholesterolemic subjects were instructed to consume 24 g/d of 
canola oil margarine or the same margarine with added plant stanol 
esters for a targeted consumption of 5.1 g/d plant stanol esters (3 g/d 
free plant stanols), without other dietary changes. At the end of 6 
months, those consuming plant stanol esters were randomly assigned 
either to continue the test margarine with a targeted intake of 5.1 g/d 
plant stanol esters or to switch to a targeted intake of 3.4 g/d plant 
stanol esters (2 g/d free plant stanols) for an additional 6 months. 
The control group also continued for another 6 months. Based on 
measured margarine consumption, average plant stanol ester intakes were 
4.4 g/d (in the 5.1 g/d target group) and 3.1 g/d (in the 3.4 g/d 
target group). The mean 1 year reduction in serum total cholesterol was 
10.2 percent in the 4.4 g/d plant stanol ester group, as compared with 
an increase of 0.1 percent in the control group. The difference in the 
change in serum total cholesterol concentration between the two groups 
was -24 mg/dL (p  0.01). The respective reductions in LDL cholesterol 
were 14.1 percent in the 4.4 g/d plant stanol ester group and 1.1 
percent in the control group. The differences in the change in LDL 
cholesterol concentration between the two groups was -21 mg/dL (p  
0.001). Significant reductions in serum total and LDL cholesterol were 
also reported after consuming plant stanol esters for 6 months. Unlike 
the group consuming 4.4 g/d of plant stanol esters for 12 months, where 
continued reductions in serum total and LDL cholesterol were observed 
from 6 to 12 months, the reduction in plant stanol ester intake to 3.1 
g/d at 6 months was not followed by any further decrease in the serum 
total and LDL cholesterol concentrations. Serum HDL cholesterol 
concentrations were not affected by plant stanol esters.
    Vanhanen et al. (Ref. 94) reported the hypocholesterolemic effects 
of 1.36 g/d of plant stanol esters (800 mg/d of free plant stanols) in 
RSO mayonnaise for 9 weeks followed by 6 weeks of consumption of 3.4 g/
d of plant stanol esters (2 g/d of free plant stanols) in RSO 
mayonnaise compared to a group receiving RSO mayonnaise alone. Subjects 
consumed their usual diets, except that they were instructed to 
substitute the RSO mayonnaise for 50 g/d of their normal daily fat 
intake. After 9 weeks of consumption of the lower dose plant stanol 
ester mayonnaise, the changes in serum levels of total and LDL 
cholesterol were -4.1 percent (p  0.05) and -10.3 percent (not 
statistically significant), respectively, as compared to the control. 
Greater reductions in both serum total and LDL cholesterol were 
observed after consumption of 3.4 g/d of plant stanol esters for an 
additional 6 weeks (p  0.05). The changes in serum levels of total and 
LDL cholesterol were -9.3 percent and -15.2 percent, respectively, for 
subjects consuming 3.4 g/d of plant stanol esters as compared to 
control. Plant stanol ester consumption in RSO mayonnaise did not 
change HDL cholesterol levels compared to control RSO mayonnaise.
    Blomqvist et al. (Ref. 81) and Vanhanen et al. (Ref. 82) separately 
reported the results of another study showing plasma cholesterol-
lowering effects of plant stanol esters dissolved in RSO mayonnaise. 
After subjects replaced 50 g of their daily fat intake by 50 g of RSO 
mayonnaise for 4 weeks, they were randomized into two groups, one that 
continued with the original RSO mayonnaise (control group) and the 
other with RSO mayonnaise in which 5.8 g of plant stanol ester was 
dissolved (3.4 g/d of free plant stanols in 50 g of mayonnaise 
preparation). After 6 weeks on the plant stanol ester-enriched diet, 
plasma total and LDL cholesterol were reduced from 225  27 
(control group) to 2-  34 mg/dL (plant stanol ester group) 
(p  0.001) and from 134  18 (control group) to 124 
 32 mg/dL (plant stanol ester) (p 0.01), respectively (Ref. 
81). In the report by

[[Page 54698]]

Blomqvist (Ref. 81), HDL cholesterol was reported to be significantly 
lower in the plant stanol ester group compared to the control group. 
Using the same data, with the exception that the number of control 
subjects utilized in the analysis was 33 rather than 32 as in the 
Blomqvist report, HDL cholesterol was reported to be unchanged in the 
report by Vanhanen (Ref. 82). The agency does not give as much weight 
to this study because the two reports lacked sufficient detail on the 
reason for the varying number of control subjects.
    Two reports of apparently the same study (Refs. 63 and 64) gave 
inconclusive results regarding the relationship between plant stanol 
ester consumption and blood cholesterol levels. Interpretation of this 
study is complicated by design issues such as concerns about sample 
size and level of plant sterol/stanol administered, but both reports 
are discussed here and summarized in table 2 of this document because 
they provide information to assist in determining the minimum level of 
plant stanol esters necessary to provide a health benefit.
    Miettinen and Vanhanen (Refs. 63 and 64 (1 study)) reported the 
effect of small amounts of sitosterol (700 mg/d free sterols) and 
sitostanol (700 mg/d free stanols) dissolved in 50 g RSO mayonnaise on 
serum cholesterol in 31 subjects with hypercholesterolemia for 9 weeks. 
Subjects did not change their diets except for replacing 50 g/d of 
dietary fat with the 50 g/d of RSO mayonnaise. It appears that these 
authors later conducted another 9-week phase of the study using 
sitostanol esters (1.36 g/d plant stanol esters or 800 mg/d free 
stanols) dissolved in 50 g RSO mayonnaise. The results of this later 
phase were reported in the Miettinen reference (Ref. 63), together with 
the earlier results. The Vanhanen reference (Ref. 64) reports only the 
earlier results for sitosterol and sitostanol. The Vanhanen reference 
(Ref. 64) reports reduced serum total cholesterol (8.5 percent) 
concentrations during the RSO mayonnaise run-in period compared to 
values before the run-in period when combining all subjects. 
Continuation of RSO mayonnaise in the RSO mayonnaise control group 
(n=8) during the experimental period had no further effect on blood 
cholesterol (Refs. 63 and 64). Free sitostanol (n=7) did not 
significantly alter serum total cholesterol or LDL cholesterol compared 
to the RSO control group during the experimental period (Refs. 63 and 
64). HDL cholesterol also did not change in the free sitostanol group 
(Ref. 63). Serum total and LDL cholesterol were significantly reduced 
in the sitostanol ester group (n=7), however (Ref. 63). The mean change 
in serum total cholesterol from baseline was -7.4 mg/dL in the 
sitostanol ester group, compared to +4.6 mg/dL in the control group (p 
0.05). The mean change in LDL cholesterol from baseline was -7.7 mg/dL 
in the sitostanol ester group compared to +3.1 mg/dL in the control 
group (p  0.05). A statistically significant increase in HDL 
cholesterol from baseline, however, was reported in the sitostanol 
ester-treated group (Ref. 63).
    The agency notes that it is difficult to decipher from the 
descriptions in these reports the amount of plant stanol ester that was 
consumed and the level of cholesterol-lowering that was observed. For 
the sitostanol ester group, as an example, the experimental design 
section states that 800 mg/d of sitostanol transesterified with RSO 
fatty acids was added to the RSO mayonnaise, yet table 1 of this 
document shows that the amount of sitostanol ester in the RSO 
mayonnaise was 830 mg (Ref. 63). Since the conversion factor to obtain 
the stanol ester equivalent of a given amount of free stanol is 1.7, 
the amounts of sitostanol and sitostanol ester given in the 
experimental design section and table 1 cannot both be correct. Based 
on information in the results section of the Miettinen reference (Ref. 
63), serum total cholesterol reduction in the sitostanol ester group 
can be calculated to be approximately 18 percent as compared to 
control, yet the abstract of the Vanhanen reference mentions that 
sitostanol ester reduced serum total cholesterol by 7 percent (Ref. 
63). Therefore, FDA considers the results in these reports inconclusive 
because of inconsistencies in the descriptions of methods and results.
    Two studies (Refs. 58 and 74) show a relationship between 
consumption of plant stanols and reduced LDL cholesterol, but not blood 
total cholesterol, in subjects consuming a diet within the range of a 
typical American diet, although the diet was a controlled feeding 
regimen formulated to meet Canadian recommended nutrient intakes.
    Jones et al. (Ref. 58) reported the effects of consuming 2.94 g/d 
of plant sterol esters in 23 g of margarine, 3.31 g/d of plant stanol 
esters in 23 g of margarine (1.84 g/d free plant stanols; daily 
margarine doses were divided into three equal portions and added to 
each meal) and 23 g/d of control margarine for 21 days each, using a 
controlled feeding crossover study design. During the experimental 
period, subjects consumed a fixed-food North American diet formulated 
to meet Canadian recommended nutrient intakes. The results from 
consumption of the plant sterol ester margarine are discussed in 
section III.C.1.b of this document. Plasma LDL cholesterol levels were 
reduced by 6.4 percent (p  0.02) in the plant stanol ester group 
compared to the control group. Plasma total cholesterol was not 
significantly reduced in the plant stanol ester group. Plasma HDL 
cholesterol did not differ across groups, and there was no significant 
weight change shown by the subjects while consuming any of the 
margarine mixtures.
    Jones et al. (Ref. 74) evaluated the effects of a mixture of plant 
stanols and plant sterols. The plant stanol compound sitostanol made up 
about 20 percent of the mixture by weight. The remaining sterol 
component of the mixture was mostly composed of the plant sterols 
sitosterol and campesterol. These investigators evaluated the 
cholesterol-lowering properties of this nonesterified plant sterol/
stanol mixture in a controlled feeding regimen based on a ``prudent,'' 
fixed-food North American diet formulated to meet Canadian recommended 
nutrient intakes. Thirty-two hypercholesterolemic men were fed either a 
diet of prepared foods alone or the same diet plus 1.7 g/d of the plant 
sterol/stanol mixture (in 30 g/d of margarine, consumed during 3 meals) 
for 30 days in a parallel study design. The plant sterol/stanol mixture 
had no statistically significant effect on plasma total cholesterol 
concentrations. However, LDL cholesterol concentrations on day 30 had 
decreased by 8.9 percent (p  0.01) and 24.4 percent (p  0.001) with the 
control and plant sterol/stanol-enriched diets, respectively. On day 
30, LDL cholesterol concentrations were significantly lower (p  0.05) 
by 15.5 percent in the group consuming the plant sterol/stanol mixture 
compared to the control group. HDL cholesterol concentrations did not 
change significantly during the study.
    (c) Normocholesterolemics: ``typical'' or ``usual'' diets. Two 
studies (Refs. 91 and 92) show a relationship between consumption of 
plant stanols and reduced blood cholesterol in subjects with normal 
cholesterol concentrations consuming a typical American diet.
    Plat and Mensink (Ref. 92) examined the effects of two plant stanol 
ester preparations in healthy subjects with normal serum cholesterol 
levels. During a 4 week run-in period, 112 subjects consumed a rapeseed 
oil margarine (20 g/d) and shortening (10 g/d). For the next 8 weeks, 
42 subjects continued with these products, while the other

[[Page 54699]]

subjects received margarine (20 g/d) and shortening (10 g/d) with a 
vegetable oil-based stanol ester mixture (6.8 g/d plant stanol esters 
or 3.8 g/d free plant stanols) or pine wood-based stanol ester mixture 
(6.8 g/d plant stanol ester or 4 g/d plant stanol). Subjects did not 
change their diets except for replacing 30 g/d of dietary fat with the 
30 g/d of test margarine and shortening. In the vegetable oil plant 
stanol ester group, the mean change in serum total cholesterol from 
baseline was -16.6 mg/dL, compared to -1.6 mg/dL in the control group 
(p  0.001). In the pine wood stanol ester group, the mean change in 
serum total cholesterol from baseline was -16.3 mg/dL compared to -1.6 
mg/dL in the control group (p  0.001). Compared to consumption of a 
control margarine and shortening, consumption of 6.8 g/d of vegetable 
oil-based stanol esters lowered LDL cholesterol by 14.6  
8.0 percent (p  0.001). Consumption of 6.8 g/d of the pine wood-based 
stanol esters showed a comparable decrease of 12.8  11.2 
percent (p  0.001) in comparison to control margarine consumption. 
Decreases in LDL cholesterol were not significantly different between 
the two experimental groups (p= 0.793). Serum HDL cholesterol did not 
change during the study.
    Niinikoski et al. (Ref. 91) randomly assigned 24 subjects with 
normal serum cholesterol levels to use either a plant stanol ester 
margarine (5.1 g/d plant stanol esters; 3 g/d of free plant stanols) or 
ordinary rapeseed oil margarine (control) for 5 weeks. Subjects 
followed their normal diets, except for substituting the test or 
control margarine for normal dietary fat intake. During the study 
period the mean plus/minus standard deviation for serum total 
cholesterol decreased more in the plant stanol ester spread group (-31 
plus/minus 19.4) compared to the ordinary rapeseed oil spread group (-
11.6 plus/minus 19.4) (p  0.05). Serum non-HDL (LDL plus very low 
density lipoprotein) cholesterol also decreased more in the plant 
stanol ester group (-31 plus/minus 23) compared to the control group (-
11.6 plus/minus 19.4) (p  0.05), but the plant stanol ester spread did 
not influence HDL cholesterol concentration (p= 0.71 between groups).
    (d) Other studies: research synthesis study. As discussed in 
section III.C.1.d of this document, the agency considered the results 
of a March 25, 2000, research synthesis study (Ref. 100) of the effect 
of plant sterols and plant stanols on serum cholesterol concentrations 
as supporting evidence on the relationship between plant sterol/stanol 
esters and CHD. In this research synthesis study, the combined effect 
of plant sterols and stanols on serum cholesterol concentrations was 
analyzed by pooling data from 14 randomized trials that employed either 
a parallel or crossover design, consisting of 20 dose comparisons of 
either plant sterols or plant stanols to a control vehicle. The data 
described the effects on serum LDL cholesterol concentrations obtained 
from using spreads (or, in some cases, mayonnaise, olive oil, or 
butter) with and without added plant sterols or stanols.
    Based on the placebo-adjusted reduction in serum LDL cholesterol, 
the analysis indicated that 2 g of plant sterol (equivalent to 3.2 g/d 
of plant sterol esters) or plant stanol (equivalent to 3.4 g/d of plant 
stanol esters) added to a daily intake of spread (or mayonnaise, olive 
oil, or butter) reduces serum concentrations of LDL cholesterol by an 
average of 20.9 mg/dL in people aged 50 to 59 (p=0.005), 16.6 mg/dL in 
those aged 40 to 49 (p=0.005), and 12.8 mg/dL in those aged 30 to 39 
(p=0.005). The results indicated that the reduction in the 
concentration of LDL cholesterol at each dose is significantly greater 
in older people versus younger people. Reductions in blood total 
cholesterol concentrations were similar to the LDL cholesterol 
reductions and there was little change in serum concentrations of HDL 
cholesterol. The results of this analysis also suggested that doses 
greater than about 2 g of plant sterol (3.2 g/d of plant sterol esters) 
or stanol (3.4 g/d of plant stanol esters) per day would not result in 
further reduction in LDL cholesterol.
    Observational studies and randomized trials concerning the 
relationship between serum cholesterol and the risk of heart disease 
(Ref. 101) indicate that for people aged 50 to 59, a reduction in LDL 
cholesterol of about 19.4 mg/dL (0.5 mmol/l) translates into a 25 
percent reduction in the risk of heart disease after about 2 years. 
Studies administering plant sterols and stanols have demonstrated the 
potential to provide this protection. According to Law, the 
cholesterol-lowering capacity of plant sterols and stanols is even 
larger than the effect that could be expected to occur if people ate 
less animal fat (or saturated fat) (Ref. 100).
Community Intervention Study
    The plant stanol ester petitioner also submitted a community 
intervention study by Puska et al. (Ref. 102) that described the 
relationship between consumption of plant stanol ester-containing 
margarine and serum total cholesterol concentrations in North Karelia, 
Finland. FDA considered this study as supporting evidence for the 
relationship between plant stanol esters and CHD. In the early 1970's, 
Finland had the highest cardiovascular-related mortality in the world. 
Since 1972, active prevention programs carried out in the framework of 
the North Karelia Project have reduced these high rates. A central 
target of these programs was promotion of dietary changes to reduce 
population cholesterol levels. In spite of great success in the 1970's 
and 1980's, cholesterol levels at the end of the 1980's remained, by 
international standards, relatively high in North Karelia, especially 
in rural areas. The Village Cholesterol Competition was introduced as 
an innovative method to promote further cholesterol reduction in the 
population. Puska et al. (Ref. 102) describe two competitions (1991 and 
1997) in which serum cholesterol values of subjects ages 20 to 70 years 
in participating villages were measured twice during a 2 month period. 
The village with the greatest mean reduction in serum cholesterol was 
awarded a monetary prize. The 1991 competition is not relevant to this 
interim rule because plant stanol ester-containing spreads were not 
available at the time. However, the 1997 competition is relevant 
because plant stanol ester-containing spreads had become available and, 
as discussed below, were consumed by a significant number of 
participants. Subjects were asked to complete a questionnaire about 
demographic factors, risk factors, dietary changes, and physical 
activity. The questionnaire included specific questions on changes in 
use of milk, fat spreads, fat used for baking, and food preparation. 
Participating villages were responsible for arranging intervention 
activities and blood cholesterol measurements.
    Sixteen villages, with a total of 1,333 participants, were included 
in the results. There were 8 weeks between the initial and final blood 
cholesterol measurements. Approximately 24 percent of the participants 
changed their fat spread on bread to recommended alternatives (e.g., 
from butter to margarine), but 57 percent did not make any changes in 
their choice of spread. Use of plant stanol ester-containing spread 
increased nearly fivefold, whereas use of butter, butter-vegetable oil 
mixture and normal vegetable margarine use declined. Approximately 200 
participants began to use plant stanol ester spread during the 
competition as their fat spread on bread.
    The winning village had an average serum total cholesterol 
reduction of 16 percent (p  0.001). Results for each village were 
calculated as the mean percent reduction in individual

[[Page 54700]]

cholesterol levels. The mean reduction in serum total cholesterol of 
all participating villages was 9 percent (p  0.001). In 14 of 16 
villages, the reduction between the initial and final blood cholesterol 
measurements was statistically significant (p  0.05). The investigators 
observed that the greater the self-reported daily use of the plant 
stanol ester spread, the greater the serum cholesterol reduction. 
Furthermore, of those who reported using more than 5 teaspoonfuls per 
day of plant stanol ester-containing spread, an average serum total 
cholesterol reduction of 21.3 percent was achieved.
    (e) Summary. In two (Refs. 77 and 80) of three (Refs. 77, 80, and 
97) studies of hypercholesterolemic subjects consuming low saturated 
fat and low cholesterol diets, plant stanol ester intake was associated 
with statistically significant decreases in total and LDL cholesterol 
levels when compared to a control group. Levels of HDL cholesterol were 
found to be unchanged (Refs. 77, 80, and 97).
    Levels of plant stanol esters found to be effective in lowering 
total and LDL cholesterol levels, in the context of a diet low in 
saturated fat and cholesterol, were 3.4 g (Ref. 80) and 3.9 g (Ref. 77) 
(equivalent to 2 and 2.31 g of free plant stanols, respectively). Other 
results from one of these studies (Ref. 77) reported a statistically 
significant effect of 3.9 g/d of vegetable oil stanol esters (2.16 g/d 
of free plant stanols) on blood total cholesterol, but not LDL 
cholesterol. Dietary supplementation with 3 g of plant stanols per day 
(equivalent to 5.1 g/d of plant stanol esters) to hypercholesterolemic 
subjects consuming a low saturated fat and low cholesterol diet (Ref. 
97) did not significantly lower plasma total or LDL cholesterol.
    In 10 of 10 studies of hypercholesterolemic subjects consuming 
``usual'' diets (Refs. 58, 63 and 64 (1 study), 67, 74, 78, 81 and 82 
(1 study), 88 through 90, and 94), plant stanol ester intake was 
associated with statistically significant decreases in blood total and/
or LDL cholesterol levels. In seven (Refs. 58, 67, 74, 88 through 90, 
and 94) of these ten studies, HDL cholesterol levels were not 
significantly affected by plant stanol dietary treatment. In 2 studies 
(Refs. 63 and 64 (1 study) and 78) of the 10 studies, plant stanol 
esters were reported to increase the levels of HDL cholesterol from 
baseline levels. Two separate published reports of another study (Refs. 
81 and 82) were inconsistent in their description of effects on HDL 
cholesterol. One publication (Ref. 81) reported HDL cholesterol to be 
significantly lower in the plant stanol ester group compared to a 
control group, but the other publication reported that the difference 
in HDL cholesterol between the two groups was not significant (Ref. 
82). This incongruity may be due to the difference in the number of 
control subjects utilized in the analysis between the two publications. 
The agency notes that the majority of studies do not report a 
statistically significant change in HDL cholesterol in the plant stanol 
ester groups compared to the control groups.
    Levels of plant stanol esters found to be effective in lowering 
total and/or LDL cholesterol levels in hypercholesterolemic subjects 
consuming a ``usual'' diet ranged from 1.36 to 5.8 g/d (equivalent to 
0.8 to 3.4 g/d of free plant stanols) (Refs. 58, 63 and 64 (1 study), 
67, 74, 78, 81 and 82 (1 study), 88 through 90, and 94). In the study 
by Hallikainen et al. (Ref. 88), 1.4 g/d plant stanol ester (0.8 g/d of 
free plant stanol) did not significantly reduce serum cholesterol 
levels, but intakes of 2.7, 4.1, and 5.4 g/d of plant stanol esters 
(1.6, 2.4, and 3.2 g/d of free plant stanols, respectively) were found 
to significantly reduce both serum total and LDL cholesterol levels. In 
another of the 10 studies described above (Ref. 94), subjects consuming 
a higher dose (3.4 g/d, equivalent to 2 g/d of free plant stanols) of 
plant stanol esters showed statistically significant reductions in both 
blood total and LDL cholesterol, but a lower dose of plant stanol 
esters (1.36 g/d, equivalent to 0.8 g/d of free plant stanols) showed 
reductions in blood total, but not in LDL cholesterol. The results of 
the study by Miettinen and Vanhanen (Refs. 63 and 64) are inconclusive. 
This may be due to lack of statistical power (e.g., sample size too 
small to detect the hypothesized difference between groups) or too low 
a dose of plant stanols to provide an effect. As previously discussed, 
the descriptions of methods and results also were inconsistent and 
difficult to interpret. Although these investigators reported (Ref. 63) 
a statistically significant effect of 1.36 g/d plant stanol esters 
(equivalent to 0.8 g/d of free plant stanols) on reducing serum total 
and LDL cholesterol compared to a control group, there was no effect of 
700 mg/d of the free plant stanols (equivalent to 1.19 g/d of plant 
stanol esters) on blood cholesterol levels.
    Two studies (Refs. 91 and 92) examined the effects of plant stanol 
esters in healthy adults with normal cholesterol levels consuming a 
``usual'' diet. Both of these studies demonstrated significant 
decreases in blood total and LDL cholesterol or non-HDL cholesterol 
levels when compared to controls. Levels of plant stanol esters found 
to be effective were 6.8 g/d (vegetable oil stanol esters; 3.8 g/d of 
free plant stanols) (Ref. 92), 6.8 g/d (pine wood stanol esters; 4 g/d 
of free plant stanols) (Ref. 92), and 5.1 g/d (source unreported; 
approximately 3 g/d of free plant stanols) (Ref. 91). HDL cholesterol 
levels were not significantly affected by plant stanol consumption in 
these reports.
    Based on these studies, FDA finds there is scientific evidence for 
a consistent, clinically significant effect of plant stanol esters on 
blood total and LDL cholesterol. The cholesterol-lowering effect of 
plant stanol esters is consistent in both mildly and moderately 
hypercholesterolemic populations and in populations with normal 
cholesterol concentrations. The cholesterol-lowering effect of plant 
stanol esters has been reported in addition to the effects of a low 
saturated fat and low cholesterol diet. Most studies also report that 
plant stanols do not affect HDL cholesterol levels. These conclusions 
are drawn from the review of the well controlled clinical studies and 
are supported by the research synthesis study of Law (Ref. 100) and the 
community intervention trial of Puska et al. (Ref. 102).

IV. Decision to Authorize a Health Claim Relating Plant Sterol/
Stanol Esters to Reduction in Risk of CHD

A. Relationship Between Plant Sterol Esters and CHD

    The plant sterol esters petition provided information on pertinent 
human studies that evaluated the effects on serum total cholesterol and 
LDL cholesterol levels from dietary intervention with plant sterols or 
plant sterol esters in subjects with normal to mildly or moderately 
elevated serum cholesterol levels. FDA reviewed the information in the 
petition as well as other pertinent studies identified by the agency's 
literature search.
    FDA concludes that, based on the totality of publicly available 
scientific evidence, there is significant scientific agreement to 
support a relationship between consumption of plant sterol esters and 
the risk of CHD. The evidence that plant sterol esters affect the risk 
of CHD is provided by studies that measured the effect of plant sterol 
ester consumption on the two major risk factors for CHD, serum total 
and LDL cholesterol.
    In most intervention trials in subjects with mildly to moderately 
elevated cholesterol levels (total cholesterol 300 mg/dL), plant sterol 
esters were found to

[[Page 54701]]

reduce blood total and/or LDL cholesterol levels to a significant 
degree (Refs. 57, 58, 61 and 62 (1 study), 67, and 74). Moreover, HDL 
cholesterol levels were unchanged (Refs. 57, 58, 61 and 62 (1 study), 
67, and 74). Results in normocholesterolemic subjects (Refs. 51, 65, 
and 75) were similar to the results in mildly to moderately 
hypercholesterolemic subjects.
    Most of the studies in subjects with mildly to moderately elevated 
cholesterol levels used ``usual'' diets in either a controlled feeding 
(Refs. 58 and 74) or free-living (Refs. 57, 63 and 64 (1 study), and 
67) situation, but one study used a low saturated fat, low cholesterol 
diet during the study (Refs. 61 and 62 (1 study)). All three of the 
studies in subjects with normal blood cholesterol levels used ``usual'' 
diets in either a controlled feeding (Refs. 51 and 65) or free-living 
(Ref. 75) situation. Plant sterol esters have been reported to lower 
blood cholesterol levels in subjects with mildly to moderately elevated 
cholesterol consuming either a ``usual'' diet or low saturated fat, low 
cholesterol diet and in subjects with normal blood cholesterol levels 
consuming ``usual'' diets. Therefore, the evidence suggests that the 
blood cholesterol-lowering response occurs regardless of the type of 
background diet subjects consume.
    Plant sterols (esterified or free) were tested in either a spread, 
margarine, or butter carrier and produced fairly consistent results 
regardless of the food carrier and apparent differences in processing 
techniques. Given the variability of amounts and of food carriers in 
which plant sterols and plant sterol esters were provided in the diets 
studied, the response of blood cholesterol levels to plant sterols 
appears to be consistent and substantial, except for plant sterols from 
sheanut oil and ricebran oil (Refs. 67 and 75).
    Based on the totality of the publicly available scientific 
evidence, the agency concludes that there is significant scientific 
agreement that plant sterol esters from certain sources will help 
reduce serum cholesterol and that such reductions may reduce the risk 
of CHD. Section 101.83(c)(2)(ii)(A)(1) (discussed in section V.C of 
this document) specifies the plant sterol esters that have been 
demonstrated to have a relationship to the risk of CHD. In the majority 
of clinical studies evaluating plant sterols or plant sterol esters, 
blood total and LDL cholesterol were the lipid fractions shown to be 
the most affected by plant sterol intervention. As discussed in section 
I of this document, reviews by Federal agencies and other scientific 
bodies have concluded that there is substantial epidemiologic and 
clinical evidence that high blood levels of total cholesterol and LDL 
cholesterol represent major contributors to CHD and that dietary 
factors that decrease blood total cholesterol and LDL cholesterol will 
affect the risk of CHD (56 FR 60727 at 60728, and Refs. 18 through 21).
    Given all of this evidence, the agency is authorizing a health 
claim on the relationship between plant sterol esters and reduced risk 
of CHD.

B. Relationship Between Plant Stanol Esters and CHD

    The plant stanol esters petition provided information on pertinent 
human studies that evaluated the effects on serum total cholesterol and 
LDL cholesterol levels from dietary intervention with plant stanols or 
plant stanol esters in subjects with normal to mildly or moderately 
elevated serum cholesterol levels. FDA reviewed the information in the 
plant stanol esters petition as well as other pertinent studies from 
the plant sterol esters petition and from the studies identified by the 
agency's literature search.
    FDA concludes that, based on the totality of publicly available 
scientific evidence, there is significant scientific agreement to 
support a relationship between consumption of plant stanol esters and 
the risk of CHD. The evidence that plant stanol esters affect the risk 
of CHD is provided by studies that measured the effect of plant stanol 
ester consumption on the two major risk factors for CHD, serum total 
and LDL cholesterol.
    In most intervention trials in subjects with mildly to moderately 
elevated cholesterol levels (total cholesterol 300 mg/dL), plant stanol 
esters were found to reduce blood total and/or LDL cholesterol levels 
to a significant degree (Refs. 58, 63 and 64 (1 study), 67, 74, 77, 78, 
80, 81 and 82 (1 study), 88 through 90, and 94). Moreover, HDL 
cholesterol levels were unchanged in most intervention studies (Refs. 
58, 67, 74, 77, 80, 88 through 90, and 94). Results in 
normocholesterolemic subjects (Refs. 91 and 92) were similar to the 
results in mildly to moderately hypercholesterolemic subjects.
    Most of the studies in subjects with mildly to moderately elevated 
cholesterol levels used ``usual'' diets in either a controlled feeding 
(Refs. 58 and 74) or free-living (Refs. 63 and 64 (1 study), 67, 78, 81 
and 82 (1 study), 88 through 90, and 94) situation, but three studies 
used a low saturated fat, low cholesterol diet during the study (Refs. 
77, 80 and 97). Both of the studies in subjects with normal blood 
cholesterol levels (Refs. 91 and 92) used ``usual'' diets in a free-
living situation. Plant stanol esters have been reported to lower blood 
cholesterol levels in subjects with mildly to moderately elevated 
cholesterol consuming either a ``usual'' diet or low saturated fat, low 
cholesterol diet and in subjects with normal blood cholesterol levels 
consuming ``usual'' diets. Therefore, the evidence suggests that the 
blood cholesterol-lowering response occurs regardless of the type of 
background diet subjects consume.
    Plant stanol esters were tested in either a spread, margarine, 
butter, mayonnaise or shortening carrier and produced fairly consistent 
results regardless of the food carrier and apparent differences in 
processing techniques. Given the variability of amounts and food 
carriers in which plant stanol esters were provided in the diets 
studied, the response of blood cholesterol levels appears to be 
consistent and substantial.
    Based on the totality of the publicly available scientific 
evidence, the agency concludes that there is significant scientific 
agreement that plant stanol esters will help reduce blood cholesterol 
and that such reductions may reduce the risk of CHD. Section 
101.83(c)(2)(ii)(B)(1) (discussed in section V.C of this document) 
specifies the plant stanol esters that have been demonstrated to have a 
relationship to the risk of CHD. In the majority of clinical studies 
evaluating plant stanol esters, blood total and LDL cholesterol were 
the lipid fractions shown to be the most affected by plant stanol 
intervention. As discussed in section I of this document, reviews by 
Federal agencies and other scientific bodies have concluded that there 
is substantial epidemiologic and clinical evidence that high blood 
levels of total cholesterol and LDL cholesterol represent major 
contributors to CHD and that dietary factors that decrease blood total 
cholesterol and LDL cholesterol will affect the risk of CHD (56 FR 
60727 at 60728, and Refs. 18 through 21).
    Given all of this evidence, the agency is authorizing a health 
claim on the relationship between plant stanol esters and reduced risk 
of CHD.

V. Description and Rationale for Components of Health Claim

A. Relationship Between Plant Sterol/Stanol Esters and CHD and the 
Significance of the Relationship

    New section 101.83(a) describes the relationship between diets 
containing plant sterol/stanol esters and the risk of CHD. In 
Sec. 101.83(a)(1), the agency recounts that CHD is the most common and 
serious form of CVD, and that CHD

[[Page 54702]]

refers to diseases of the heart muscle and supporting blood vessels. 
This paragraph also notes that high blood total and LDL cholesterol 
levels are associated with increased risk of developing CHD and 
identifies the levels of total cholesterol and LDL cholesterol that 
would put an individual at high risk of developing CHD, as well as 
those blood cholesterol levels that are associated with borderline high 
risk. This information will assist consumers in understanding the 
seriousness of CHD.
    In Sec. 101.83(a)(2), the agency recounts that populations with a 
low incidence of CHD tend to have low blood total and LDL cholesterol 
levels. This paragraph states that these populations also tend to have 
dietary patterns that are low in total fat, saturated fat, and 
cholesterol, and high in plant foods that contain fiber and other 
components. This information is consistent with that provided in the 
regulations authorizing health claims for fiber-containing fruits, 
vegetables, and grain products and CHD (Sec. 101.77), soluble fiber 
from certain foods and CHD (Sec. 101.81), and soy protein and CHD 
(Sec. 101.82). The agency believes that this information provides a 
basis for a better understanding of the numerous factors that 
contribute to the risk of CHD, including the relationship of plant 
sterol/stanol esters and diets low in saturated fat and cholesterol to 
the risk of CHD.
    Section 101.83(a)(3) states that diets that include plant sterol/
stanol esters may reduce the risk of CHD.
    Section 101.83(b) describes the significance of the diet-disease 
relationship. In Sec. 101.83(b)(1), the agency recounts that CHD 
remains a major public health concern in the United States because the 
disease accounts for more deaths than any other disease or group of 
diseases. The regulation states that early management of modifiable CHD 
risk factors, such as high blood total and LDL cholesterol levels, is a 
major public health goal that can assist in reducing the risk of CHD. 
This information is consistent with the evidence that lowering blood 
total and LDL cholesterol levels reduces the risk of CHD (56 FR 60727, 
58 FR 2739, and Refs. 18 through 21 and 50). Section 101.83(b)(2) 
states that including plant sterol/stanol esters in the diet helps to 
lower blood total and LDL cholesterol levels. FDA concludes that this 
statement is scientifically valid based on the evidence that it has 
reviewed on this diet-disease relationship.

B. Nature of the Claim

    In new Sec. 101.83(c)(1), FDA is providing that the general 
requirements for health claims in Sec. 101.14 must be met, except that 
the disqualifying level for total fat per 50 g in Sec. 101.14(a)(4) 
does not apply to spreads and dressings for salad, and the minimum 
nutrient contribution requirement in Sec. 101.14(e)(6) does not apply 
to dressings for salad. FDA has decided to except these plant sterol/
stanol ester products from the specified requirements in 
Sec. 101.14(a)(4) and (e)(6) because it has determined that permitting 
the health claim on such products will help consumers develop a dietary 
approach that will result in significantly lower blood cholesterol 
levels and an accompanying reduction in the risk of heart disease. The 
basis for this decision is discussed in more detail in section V.D of 
this document. The agency is requesting comments on this decision.
    In Sec. 101.83(c)(2)(i), FDA is authorizing a health claim on the 
relationship between diets that contain plant sterol/stanol esters and 
the risk of CHD. The agency is authorizing this health claim based on 
its review of the scientific evidence on this substance-disease 
relationship, which shows that diets that contain plant sterol/stanol 
esters help to reduce total and LDL cholesterol (Refs. 51, 57, 58, 61 
and 62 (1 study), 63 and 64 (1 study), 65, 67, 74, 75, 77, 78, 80, 81 
and 82 (1 study), 88 through 92, and 94). This result is significant 
for the risk of heart disease because elevated levels of total and LDL 
cholesterol are associated with increased risk of CHD (Refs. 18 through 
21).
    In Sec. 101.83(c)(2)(i)(A), FDA is requiring, consistent with other 
health claims to reduce the risk of CHD, that the claim state that 
plant sterol/stanol esters should be consumed as part of a diet low in 
saturated fat and cholesterol. The agency acknowledges that most of the 
scientific evidence for an effect of plant sterol/stanol esters on 
blood cholesterol levels was provided by studies that used ``usual'' 
diets (Refs. 51, 57, 58, 63 and 64 (1 study), 65, 67, 74, 75, 78, 81 
and 82 (1 study), 88 through 92, and 94). Some studies used low fat, 
low cholesterol diets and also found a cholesterol-lowering effect of 
plant sterol/stanol esters (Refs. 61 and 62 (1 study), 77, and 80). The 
results were consistent across studies, regardless of the background 
diet used. However, not all studies reported whether reductions in 
cholesterol were achieved as compared to baseline. The results of one 
study that investigated the effects of plant stanol esters added to 
butter (Ref. 78) suggest that plant stanol esters may not be able to 
fully counteract the impact of a high saturated fat diet on blood 
cholesterol levels. In that study, plant stanol esters added to butter 
significantly reduced both serum total cholesterol and LDL cholesterol 
compared to control (butter alone), but there was no significant 
reduction in either serum total or LDL cholesterol compared to 
baseline. Since there must be a cholesterol reduction compared to 
baseline in order for risk of CHD to decrease, it would be misleading 
for the claim to imply that plant sterol/stanol esters affect the risk 
of CHD regardless of diet, when that may not be the case.
    In addition, as more fully discussed in section V.A of this 
document, CHD is a major public health concern in the United States, 
and the totality of the scientific evidence provides strong and 
consistent support that diets high in saturated fat and cholesterol are 
associated with elevated levels of blood total and LDL cholesterol and, 
thus, CHD (56 FR 60727 at 60737). The majority of Americans consume 
amounts of total fat and saturated fat that exceed the recommendations 
made in the Dietary Guidelines for Americans (Ref. 103). For example, 
from 1994 to 1996 only about one-third of Americans age 2 and older 
consumed no more than 30 percent of calories from total fat and only 
about one-third consumed less than 10 percent calories from saturated 
fat (Ref. 104). Dietary guidelines from both government and private 
scientific bodies conclude that the majority of the American population 
would benefit from decreased consumption of dietary saturated fat and 
cholesterol (Refs. 18 through 21). Thus, the agency finds that it will 
be more helpful to Americans' efforts to maintain healthy dietary 
practices if claims about the effect of plant sterol/stanol esters on 
the risk of CHD also recommend a diet low in saturated fat and 
cholesterol.
    Moreover, the agency finds that for the public to understand fully, 
in the context of the total daily diet, the significance of consumption 
of plant sterol/stanol esters on the risk of CHD (see section 
403(r)(3)(B)(iii) of the act), information about the total diet must be 
included as part of the claim. Therefore, the agency believes the plant 
sterol/stanol-containing food product bearing the health claim should 
provide information on consuming plant sterol/stanol esters in the 
context of a healthy diet. In fact, as evidenced by the requirement in 
section 403(r)(3)(B)(iii) of the act that health claims be stated so 
that the public may understand the significance of the information in 
the context of ``a total daily diet,'' Congress intended FDA to 
consider the role of substances in food in a way that will enhance the 
chances of consumers constructing diets that are balanced and

[[Page 54703]]

healthful overall (Ref. 105). Therefore, the agency finds that the 
health claim that is the subject of this interim rule should be 
consistent with the Dietary Guidelines for Americans, 2000 (Ref. 103) 
guideline for fat and saturated fat intake, which states, ``Choose a 
diet that is low in saturated fat and cholesterol and moderate in total 
fat.''
    In Sec. 101.83(c)(2)(i)(B), the agency is requiring, consistent 
with other health claims, that the relationship be qualified with the 
terms ``may'' or ``might.'' These terms are used to make clear that not 
all persons can necessarily expect to benefit from these dietary 
changes (see 56 FR 60727 at 60740 and 58 FR 2552 at 2573) or to 
experience the same degree of blood cholesterol reduction. The 
requirement that the claim use the term ``may'' or ``might'' to relate 
the ability of plant sterol/stanol esters to reduce the risk of CHD is 
also intended to reflect the multifactorial nature of the disease.
    In Sec. 101.83(c)(2)(i)(C), the agency is requiring, consistent 
with other authorized health claims, that the terms ``coronary heart 
disease'' or ``heart disease'' be used in specifying the disease. These 
terms are commonly used in dietary guidance materials, and therefore 
they should be readily understandable to the consumer (see 56 FR 60727 
at 60740 and 58 FR 2552 at 2573).
    In Sec. 101.83(c)(2)(i)(D), the agency is requiring that the claim 
specify the substance as ``plant sterol esters'' or ``plant stanol 
esters,'' except that if the sole source of plant sterols or stanols is 
vegetable oil, the claim may use the term ``vegetable oil sterol 
esters'' or ``vegetable oil stanol esters,'' as appropriate.
    Section 101.83(c)(2)(i)(E), consistent with other authorized health 
claims, requires that the claim not attribute any degree of risk 
reduction of CHD to consumption of diets that contain plant sterol/
stanol esters. Also consistent with other authorized claims, 
Sec. 101.83(c)(2)(i)(F) requires that the claim not imply that 
consumption of diets that contain plant sterol/stanol esters is the 
only recognized means of reducing CHD risk.
    Investigators have estimated the size of the reduction in risk of 
heart disease produced by a given reduction in blood cholesterol 
concentration according to age and the time needed to attain the full 
reduction in risk (Ref. 101), but these data are population estimates 
and do not reflect individual risk reduction potential. Moreover, 
population risk reduction estimates from plant sterol/stanol ester 
consumption cannot be determined because the data do not reveal a 
consistent level of blood cholesterol reduction for a given plant 
sterol/stanol ester intake level. Therefore, the plant sterol/stanol 
ester studies that the agency reviewed do not provide a basis for 
determining the percent reduction in risk of CHD likely to be realized 
from consuming plant sterol/stanol esters, and therefore claims of a 
particular degree of risk reduction would be misleading.
    Section 101.83(c)(2)(i)(G) requires that the claim specify the 
daily dietary intake of plant sterol or stanol esters needed to reduce 
the risk of CHD and the contribution one serving of the product makes 
to achieving the specified daily dietary intake. This requirement is 
consistent with requirements set forth in Secs. 101.81 and 101.82.
    Section 101.83(c)(2)(i)(G)(1) specifies the daily dietary intake of 
plant sterol esters needed to reduce the risk of CHD.
    In the studies the agency reviewed that show a statistically 
significant effect of plant sterols on total and LDL cholesterol, the 
amounts fed ranged from 0.74 to 8.6 g/d of free plant sterols, which is 
equivalent to approximately 1.2 to 13.8 g/d of plant sterol esters 
(Refs. 51, 57, 58, 61 and 62 (1 study), 65, 67, and 75). (Without the 
high outlier of 8.6 g/d of free plant sterol ester consumed in one 
study (Ref. 51), the range is 0.74 g/d to 3.24 g/d of free plant 
sterols (Refs. 57, 58, 61 and 62 (1 study), 65, 67, and 75.)) In 
proposing 1 g/d of free plant sterols (1.6 g/d plant sterol esters) as 
the daily dietary intake level associated with reduced risk of CHD, the 
plant sterol ester petitioner asserted (Ref. 1, page 41) that intakes 
above 1 g/d have consistently been shown to lower blood total and LDL 
cholesterol, citing the studies by Maki et al. (Refs. 61 and 62 (1 
study), Hendriks et al. (Ref. 57), and Weststrate and Meijer (Ref. 67), 
but that intakes below this level have not. As support for the latter 
statement, the petitioner cited the reports by Miettinen and Vanhanen 
(Refs. 63 and 64 (1 study)), which found no statistically significant 
blood cholesterol reduction from consumption of 0.7 of plant sterols 
(equivalent to 1.12 g/d of plant sterol esters).
    Although the agency agrees with the plant sterol ester petitioner 
that free plant sterol consumption of greater than 1 g/d (1.6 g/d of 
plant sterol esters) has consistently been shown to lower total and LDL 
cholesterol levels (Refs. 51, 57, 58, 61 and 62 (1 study), and 67), the 
agency reviewed the studies to determine whether there is a lower level 
at which consumption of plant sterols has consistently shown 
cholesterol-lowering effects. There were three studies (Refs. 57, 65, 
and 75) that found a statistically significant reduction in cholesterol 
with free plant sterol consumption less than 1 g/d. Hendriks et al. 
(Ref. 57) reported the effects of feeding three different levels of 
plant sterol esters, including 1.33 g/d (equivalent to 0.83 g/d free 
plant sterols). At that intake level, blood total cholesterol decreased 
by 4.9 percent (p 0.001), and LDL cholesterol decreased by 6.7 percent 
(p 0.001), compared to a control spread. Sierksma et al (Ref. 75) 
reported that daily consumption of 0.8 g/d of free soybean oil sterols 
lowered plasma total and LDL cholesterol concentrations by 3.8 percent 
(p  0.05) and 6 percent (p  0.05), respectively, compared to a control 
spread. Pelletier et al. (Ref. 65) reported a 10 percent reduction in 
blood total cholesterol (p  0.001) and a 15 percent reduction in LDL 
cholesterol (p  0.001), compared to a control group, in subjects 
consuming 0.74 g/d of soybean sterols (nonesterified) in 50 g/d of 
butter for 4 weeks.
    For the purpose of setting the daily dietary intake level to be 
used in the plant sterol esters and risk of CHD health claim, the 
agency is placing greater emphasis on studies that incorporated plant 
sterol esters into foods that will be permitted to bear the claim. 
Therefore, the study by Pelletier et al. (Ref. 65), in which 0.74 g/d 
of free plant sterols were incorporated into butter, rather than a 
vegetable-based spread, is less relevant in determining a useful daily 
intake level. (Butter would not be able to bear the claim because it 
exceeds the disqualifying levels for cholesterol and saturated fat on a 
50 gram basis.) The daily intake level utilized in the study by 
Pelletier et al. (Ref. 65) is also very close to that used in the study 
by Miettinen and Vanhanen (Refs. 63 and 64 (1 study)) which found that 
0.7 g/d of free plant sterols did not result in statistically 
significant reductions of blood total and LDL cholesterol. For the 
purpose of setting a daily intake level, FDA therefore focused instead 
on the intakes consumed in the Sierksma et al. report (Ref. 75), 0.8 g/
d of free plant sterols (equivalent to 1.3 g/d of plant sterol esters), 
and the Hendriks et al. report (Ref. 57), 0.83 g/d of free plant 
sterols (1.33 g/d of plant sterol esters). These two intake levels are 
almost identical, and both resulted in statistically significant 
reductions in blood total and LDL cholesterol. As previously noted, all 
other studies with higher intakes of plant sterols also resulted in 
statistically significant reductions of both blood total and LDL 
cholesterol (Refs. 51, 57,

[[Page 54704]]

58, 61 and 62 (1 study), and 67). The agency therefore finds that 
consumption of at least 0.8 g/d of free plant sterols, or 1.3 g/d of 
plant sterol esters, has consistently been shown to lower blood total 
and LDL cholesterol. Accordingly, FDA is providing in 
Sec. 101.83(c)(2)(i)(G)(1) that the daily intake of plant sterol esters 
associated with reduced risk of CHD is 1.3 g or more of plant sterol 
esters per day. The agency is asking for comments on this 
determination.
    Section 101.83(c)(2)(i)(G)(2) specifies the daily dietary intake of 
plant stanol esters needed to reduce the risk of CHD. In the studies 
the agency reviewed that show a statistically significant effect of 
plant stanols on blood total and LDL cholesterol, the amounts fed 
ranged from 0.8 to 4 g/d of free plant stanols, which is equivalent to 
approximately 1.36 to 6.8 g/d of plant stanol esters (Refs. 63 and 64 
(1 study), 67, 77, 78, 80, 81 and 82 (1 study), 88 through 92, and 94). 
In proposing 3.4 g/d of plant stanol esters (2 g/d free plant stanols) 
as the daily dietary intake level associated with reduced risk of CHD, 
the plant stanol ester petitioner asserted (Ref. 6, page 12) that 
intakes of at least 3.4 g/d of plant stanol esters have been shown to 
significantly reduce blood total and LDL cholesterol, citing the 
studies by Miettinen et al. (Ref. 89) and Nguyen (Ref. 90).
    Although the agency agrees with the plant stanol ester petitioner 
that plant stanol ester consumption of approximately 3.4 g/d has been 
shown to significantly lower total and LDL cholesterol levels in 
several studies (Refs. 80, 89, 90, and 94), FDA notes that two other 
studies (Refs. 77 and 97) with an intake level of plant stanol esters 
greater than 3.4 g/d did not report significant reductions in blood 
total and LDL cholesterol levels. The study by Denke (Ref. 97) did not 
find reductions in either total or LDL cholesterol after consumption of 
a total daily intake of 3 g/d of free plant stanols (equivalent to 5.1 
g/d of plant stanol esters). Unlike most of the other studies that the 
agency reviewed, however, the Denke study (Ref. 97) was not a 
randomized, placebo-controlled, double-blind study, but rather a fixed 
sequence design. One result of this design was that during the plant 
stanol dietary supplement phase the subjects consumed an additional 12 
g of fat that they did not consume in other phases; this makes 
comparisons between phases difficult, and therefore FDA gives less 
weight to this study.
    In a report by Hallikainen et al. (Ref. 77), total cholesterol, but 
not LDL cholesterol, was significantly reduced after consumption of 3.9 
g/d plant stanol esters from a vegetable oil source; this same study 
reported statistically significant reductions in both blood total and 
LDL cholesterol from a daily intake of 3.9 g/d of plant stanol esters 
from a wood-derived source. After evaluating the relative effectiveness 
of the vegetable oil and wood-derived plant stanol esters, however, the 
authors of this study concluded that the cholesterol-lowering effects 
of plant stanol esters from these two sources did not differ 
significantly. Pointing out that there were no significant differences 
in absolute or percentage changes in cholesterol concentrations between 
the vegetable oil and wood-derived plant stanol ester groups and that 
the percentage reduction in LDL cholesterol for the vegetable oil 
stanol esters compared to control was ``almost significant'' (p = 
0.072) , these authors concluded that both wood-derived stanol esters 
and vegetable oil stanol esters reduce serum cholesterol concentrations 
``with apparently equal efficacy.'' Another study supports this 
conclusion. Plat et al. (Ref. 92) compared the reductions in blood 
total and LDL cholesterol in subjects who consumed 6.8 g/d of wood-
derived stanol esters with the blood total and LDL cholesterol 
reductions in subjects who consumed an equal amount of vegetable oil 
stanol esters. Again, no statistically significant differences were 
found; in numerical terms, the cholesterol reductions associated with 
the vegetable oil stanol esters were slightly greater.
    In light of the strong evidence (four studies) that 3.4 g/d of 
plant stanol esters significantly lowers both total and LDL 
cholesterol, FDA concludes that intakes of 3.4 g/d or more of plant 
stanol esters can be expected to significantly lower both total and LDL 
cholesterol. As explained above, the agency is giving less weight to 
the Denke study (Ref. 97), in which the intake of plant stanols was 
equivalent to 5.1 g/d of plant stanol esters, than to the four studies 
at the 3.4 g/d intake (Refs. 80, 89, 90, and 94) because of a weakness 
in the design of the Denke study. Although the failure of the 
Hallikainen study (Ref. 77) to show a statistically significant 
reduction in LDL cholesterol at 3.9 g/d of vegetable oil stanol esters 
raises a question about whether the source of the plant stanol esters 
affects the daily intake level necessary to achieve a benefit, it 
appears that this was an anomalous result, as explained above. Two 
studies (Refs. 77 and 92) have concluded that plant stanol esters from 
vegetable oil and plant stanol esters from wood sources have equal 
effectiveness in lowering both total and LDL cholesterol.
    FDA also reviewed the studies to determine whether there is a level 
lower than 3.4 g/d at which consumption of plant stanol esters has 
consistently shown cholesterol-lowering effects. The lowest level at 
which a study found statistically significant reductions in both total 
and LDL cholesterol was 1.36 g/d of plant stanol esters (Refs. 63 and 
64 (1 study)). However, another study at the same level reported a 
statistically significant reduction in serum total but not LDL 
cholesterol (Ref. 58). Further, a study by Hallikainen et al. (Ref. 88) 
at a slightly higher level reported that 1.4 g/d of plant stanol esters 
did not significantly reduce serum total or LDL cholesterol levels. The 
same study (Ref. 88) reported that 2.7 g/d of plant stanol ester 
significantly reduced serum total and LDL cholesterol levels. However, 
Jones et al. (Ref. 58) found significant LDL cholesterol, but not total 
cholesterol, reductions with intake of 3.31 g/d plant stanol esters 
(Ref. 58). Thus, the agency was unable to find an intake level lower 
than 3.4 g/d that consistently showed cholesterol-lowering effects for 
both total and LDL cholesterol.
    Except as previously noted for the studies by Denke (Ref. 97) and 
Hallikainen (Ref. 77), all the studies with intakes of 3.4 g/d or more 
of plant stanol esters resulted in statistically significant reductions 
of both total and LDL cholesterol levels (Refs. 67, 77, 78, 80, 81 and 
82 (1 study), 88 through 92, and 94). The agency agrees with the 
petitioner that a total daily intake of at least 3.4 g/d of plant 
stanol esters (equivalent to 2 g/d of free plant stanols) represents an 
amount that has been shown to be effective in reducing blood 
cholesterol. Accordingly, FDA is providing in 
Sec. 101.83(c)(2)(i)(G)(2) that the daily intake of plant stanol esters 
associated with reduced risk of CHD is 3.4 g or more of plant stanol 
esters per day. The agency is asking for comments on this 
determination.
    In Sec. 101.83(c)(2)(i)(H), FDA is requiring the claim to state 
that the daily dietary intake of plant sterol/stanol esters should be 
consumed in two servings eaten at different times. In the studies 
showing a statistically significant effect of plant sterols or plant 
sterol esters on blood total and LDL cholesterol levels, subjects were 
provided with and instructed to consume the daily intake of plant 
sterols or plant sterol esters in two (Refs. 51, 57, 61 and 62 (1 
study), and 67) or three (Refs. 58 and 74) servings at different times 
of the day, or subjects were provided with the plant sterol-

[[Page 54705]]

containing food and asked to replace from 25 to 50 g of their typical 
dietary fat intake with an equal amount of the test food over the 
course of the day's dietary intake, usually during meals (Refs. 63 and 
64 (1 study), 65, and 75). The agency concludes that, to be consistent 
with the conditions of the studies on which the claim is based, the 
daily intake of plant sterol esters should be consumed in at least two 
servings eaten at different times during the day with other foods. For 
the reasons given in section V.D.1.a of this document, FDA is 
specifying two servings as the target number of servings.
    Similarly, in the studies showing a statistically significant 
effect of plant stanols or plant stanol esters on blood total and LDL 
cholesterol levels, subjects were provided with and instructed to 
consume the daily intake of plant stanols or plant stanol esters in two 
(Ref. 67) or three (Refs. 58, 74, 80, and 88 through 92) servings at 
different times of the day, or subjects were provided with the plant 
stanol-containing food and asked to replace from 25 to 50 g of their 
typical dietary fat intake with an equal amount of the test food over 
the course of the day's dietary intake, usually during meals (Refs. 63 
and 64 (1 study), 77, 78, 81 and 82 (1 study), and 94). The agency 
concludes that, to be consistent with the conditions of the studies on 
which the claim is based, the daily intake of plant stanol esters 
should be consumed in at least two servings eaten at different times 
during the day with other foods. For the reasons given in section 
V.D.1.b of this document, FDA is specifying two servings as the target 
number of servings.

C. Nature of the Substance

    Section 101.83(c)(2)(ii)(A)(1) specifies the plant sterol esters 
that have been demonstrated to have a relationship to the risk of CHD. 
Plant sterols can be classified on structural and biosynthetical 
grounds into 4-desmethyl sterols, 4-monomethyl sterols, and 4,4-
dimethyl sterols. Plant sterols of the 4-desmethyl sterol class are the 
plant sterols that have demonstrated the blood cholesterol-lowering 
effect (Refs. 51, 57, 58, 63 and 64 (1 study), 65, 67, and 75). The 
major 4-desmethyl sterols are beta-sitosterol, campesterol and 
stigmasterol (Ref. 106).
    Most of the studies that the agency reviewed used vegetable oil 
sterols, particularly those derived from soybean oil, as the source of 
beta-sitosterol, campesterol, and stigmasterol. These three 4-desmethyl 
sterols are also the predominant sterols in corn and canola oil. 
According to the plant sterol ester petitioner, the typical sterol 
composition of plant sterol esters is as follows: beta-sitosterol 
contributes from 30 to 65 percent (by weight) of the sterols, 
campesterol contributes from 10 to 40 percent of the sterols, and 
stigmasterol contributes from 6 to 30 percent of the sterols, with 
other sterols making up no more than 9 percent of the total (Ref. 1, 
appendix E). The composition of the vegetable oils used as sterol 
sources in most of the studies that demonstrated a cholesterol-lowering 
effect was similar (Refs. 51, 57, 58, 65, 67, and 75).
    Ricebran oil and sheanut oil principally contain the methylated 
sterols of the 4,4-dimethyl sterol class. Studies investigating the 
effects of sterols from ricebran oil and sheanut oil on blood 
cholesterol levels have not found a cholesterol-lowering effect (Refs. 
67 and 75). The structure of the 4-desmethyl sterols is more similar to 
cholesterol than the structure of 4,4-dimethyl sterols. Because of this 
structural similarity, it has been suggested that the 4-desmethyl 
sterols may offer more opportunity for competition with cholesterol for 
incorporation into mixed micelles, one of the putative mechanisms for 
the blood cholesterol-lowering action of sterols (Ref. 75).
    In studies that found a significant effect on blood cholesterol 
levels and reported the sterol composition of the plant sterol esters 
tested, the total amount of the major 4-desmethyl sterols (beta-
sitosterol, campesterol and stigmasterol) provided to the subjects 
during the experimental period ranged from 76 to 98 percent (Refs. 51, 
57, 58, 65, 67, and 75), with only 1 study at 76 percent (Ref. 65). The 
rest of the studies clustered toward the high end of the range, between 
89 to 98 percent (Refs. 51, 57, 58, 67, and 75). The agency believes 
there are a number of likely sources of variability in the sterol 
composition of the plant sterol ester mixtures, including variability 
in analytical determinations, processing, seasonal changes, and variety 
of the crop used. FDA does not have data on the extent of variability 
in sterol composition but has concluded that it is necessary to provide 
for some such variability. Given the distribution of the sterol 
composition percentages in the studies that showed significant effects 
on blood cholesterol levels and the possible variability of plant 
sterols in the finished product, FDA has decided to require that the 
combined percentage of beta-sitosterol, campesterol, and stigmasterol 
in the plant sterol component of plant sterol esters be 80 percent or 
higher as a condition of eligibility to bear the health claim. The 
agency requests comments on the variability of the level of beta-
sitosterol, campesterol, and stigmasterol in plant sterols, 
particularly with respect to the variability of these levels in the 
plant sterol component of plant sterol ester products used in studies 
that reported significant cholesterol-lowering effects.
    The agency is specifying that only edible oils may be used as the 
source oils for plant sterols. The agency is also specifying that food-
grade fatty acids must be used to esterify the plant sterols. Although 
the agency is not specifying further the type of fatty acid, such as 
chain length and degree of unsaturation, FDA expects that the fatty 
acids will primarily be monounsaturated or polyunsaturated fatty acids 
to avoid increases in saturated fatty acid content of the final food 
products.
    Section 101.83(c)(2)(ii)(A)(1) provides that the plant sterol 
substance that is the subject of the health claim for reduced risk of 
CHD is plant sterol esters prepared by esterifying a mixture of plant 
sterols from edible oils with food-grade fatty acids. Consistent with 
information in the petition and the sterol composition of test 
substances used in the studies that showed a cholesterol-lowering 
effect, Sec. 101.83(c)(2)(ii)(A)(1) further provides that the plant 
sterol mixture shall contain at least 80 percent beta-sitosterol, 
campesterol, and stigmasterol (combined weight). The agency is 
requesting comments on these requirements.
    Section 101.83(c)(2)(ii)(A)(2) sets out FDA's decision that plant 
sterol esters, when evaluated for compliance purposes by the agency, 
will be measured by a method that is based upon a standard triglyceride 
or cholesterol determination that uses sample saponification followed 
by hexane extraction and includes an internal standard. The extract is 
analyzed by gas chromatography. The method, found in appendix F of the 
plant sterol esters petition (Ref. 1) and titled, ``Determination of 
the Sterol Content in Margarines, Halvarines, Dressings, Fat Blends and 
Sterol Fatty Acid Ester Concentrates By Capillary Gas Chromatography,'' 
developed by Unilever United States, Inc., dated February 1, 2000, 
describes a gas chromatographic procedure for determination of the 
total sterol content in margarines, halvarines (low fat spreads), 
dressings, fats or fat blends and in sterol ester concentrates. The 
method is designed for total sterol levels of approximately 10 percent 
in margarines, fat and fat blends, 8 percent

[[Page 54706]]

in halvarines, from 3 to 10 percent in dressings, and approximately 60 
percent in sterol ester concentrates. An internal standard is added for 
quantification. The sample is saponified and the unsaponifiable portion 
is extracted with heptane. The extract is then analyzed by gas 
chromatography using a nonpolar stationary phase capillary column with 
beta-cholestanol as an internal standard. The petitioner has submitted 
data that demonstrate the precision and inter-analyst reproducibility 
of the method (Ref. 1, appendix F). Specific sterols have been 
identified based on gas chromatography/mass spectrometry (GC/MS) 
analysis and comparison of data in the mass spectral library of the 
National Institute of Standards and Technology (NIST) (Ref. 4). The 
method has neither been subjected to validation through the Association 
of Official Analytical Chemist's (AOAC's) collaborative study or peer-
verified method validation procedures, nor is it published in the open 
literature. FDA is requesting comments on the suitability of the plant 
sterol ester petitioner's method for assuring that foods bearing the 
health claim contain the qualifying levels of plant sterol esters. In 
this document, FDA is incorporating the plant sterol ester petitioner's 
method by reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 
51. Copies of the method may be obtained from the Center for Food 
Safety and Applied Nutrition's Office of Nutritional Products, 
Labeling, and Dietary Supplements, Division of Nutrition Science and 
Policy, 200 C St. SW., rm. 2831, Washington, DC 20204, and may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
200 C St. SW., rm. 3321, Washington, DC, or at the Office of the 
Federal Register, 800 North Capital St. NW., suite 700, Washington, DC.
    Section 101.83(c)(2)(ii)(B)(1) specifies the plant stanol esters 
that have been demonstrated to have a relationship to the risk of CHD. 
Sitostanol and campestanol, the saturated (at the 5 position) 
derivatives of beta-sitosterol, campesterol, and stigmasterol, are the 
plant stanols that have demonstrated the blood cholesterol-lowering 
effect (Refs. 58, 63 and 64 (1 study), 67, 77, 78, 81 and 82 (1 study), 
88 through 92, and 94). Like the sterols from which they derive, 
sitostanol and campestanol are in the 4-desmethyl sterol class, and as 
such are similar in structure to cholesterol. Sitostanol is formed by 
the hydrogenation of beta-sitosterol, and also by the complete 
hydrogenation of stigmasterol (stigmasterol has two double bonds that 
are saturated during the hydrogenation process, whereas sitostanol has 
one double bond that is saturated during the hydrogenation process). 
Campestanol is formed by the hydrogenation of campesterol.
    Most of the studies that the agency reviewed used vegetable oil 
stanols or wood-derived plant stanols as the source of sitostanol and 
campestanol. According to the plant stanol ester petitioner, the 
stanols in plant stanol esters are derived from hydrogenated plant 
sterol mixtures or extracted from plant sources (Ref. 8, page 18). In 
studies that found a significant effect on blood cholesterol levels and 
reported the stanol composition of the plant stanol esters tested, the 
combined percentage of sitostanol and campestanol ranged from 64 to 100 
percent by weight (Refs. 58, 63 and 64 (1 study), 67, 77, 78, 88, 90, 
and 92), with only one study at 64 percent (Refs. 63 and 64 (1 study). 
The rest of the studies clustered toward the high end of the range, 
between 89 and 100 percent (Refs. 58, 67, 77, 78, 88, 90, and 92).
    The agency believes there are a number of likely sources of 
variability in the stanol composition of the plant stanol ester 
mixtures, including variability in analytical determinations, 
processing, seasonal changes, and variety of the crop used. FDA does 
not have data on the extent of variability in stanol composition but 
has concluded that it is necessary to provide for some such 
variability. Given the distribution of the stanol composition 
percentages in the studies that showed significant effects on blood 
cholesterol levels and the possible variability of plant stanols in the 
finished product, FDA has decided to require that the combined 
percentage of sitostanol and campestanol in the plant stanol component 
of plant stanol esters be 80 percent or higher as a condition of 
eligibility to bear the health claim. The agency requests comments on 
the variability of the level of sitostanol and campestanol in plant 
stanols, particularly with respect to the variability of these levels 
in the plant stanol component of plant stanol ester products used in 
studies that reported significant cholesterol-lowering effects.
    The agency is specifying the source material for plant stanols, 
which may be either plant-derived oils or wood. The plant stanol ester 
petitioner's GRAS determination, and consequently the agency's safe and 
lawful conclusion in section II.B.3.b.i of this document, apply only to 
plant stanols derived from edible oils or from byproducts of the kraft 
paper pulping process (Ref. 46). Therefore, FDA is providing that 
plant-derived oils used as the source for plant stanols must be edible 
oils. If wood is used as the source material, the plant stanols must be 
derived from byproducts of the kraft paper pulping process. The agency 
is also specifying that food-grade fatty acids must be used to esterify 
the plant stanols. Although the agency is not specifying further the 
type of fatty acid, such as chain length and degree of unsaturation, 
FDA expects that the fatty acids will primarily be monounsaturated or 
polyunsaturated fatty acids to avoid increases in saturated fatty acid 
content of the final food products.
    Section 101.83(c)(2)(ii)(B)(1) provides that the plant stanol 
substance that is the subject of the health claim for reduced risk of 
CHD is plant stanol esters prepared by esterifying a mixture of plant 
stanols derived from edible oils or byproducts of the kraft paper 
pulping process with food-grade fatty acids. Consistent with the stanol 
composition of test substances used in the studies that showed a 
cholesterol-lowering effect, Sec. 101.83(c)(2)(ii)(B)(1) further 
provides that the plant stanol mixture shall contain at least 80 
percent sitostanol and campestanol (combined weight). The agency is 
requesting comments on these requirements.
    Section 101.83(c)(2)(ii)(B)(2) sets out FDA's decision that plant 
stanol esters, when evaluated for compliance purposes by the agency, 
will be measured using a standard cholesterol determination that uses 
sample saponification, followed by heptane extraction, derivatization 
to trimethylsilyl ethers and analyzed by gas chromatography.
    The plant stanol ester petition (Refs. 8, 11, and 14) provided the 
following four analytical methods developed by McNeil Consumer 
Healthcare dated February 15, 2000, for use in different food matrices. 
The method titled ``Determination of Stanols and Sterols in 
Benecol \3\ Tub Spread'' describes a procedure for 
determination of stanols and sterols in tub spreads containing 6 to 18 
percent stanol esters. The primary analytes are sitostanol, 
campestanol, sitosterol and campesterol. Samples are saponified 
directly with alcoholic potassium hydroxide. Stanols and sterols remain 
in the unsaponified fraction and are extracted with hexane. The 
extracted stanols and sterols are then derivatized to trimethylsilyl 
ethers and analyzed by gas chromatography. The internal standard 
utilized is cholestanol.
---------------------------------------------------------------------------

    \3\ Benecol'' is the plant stanol ester petitioner's 
brand of plant stanol ester-containing food products.

---------------------------------------------------------------------------

[[Page 54707]]

    The method titled ``Determination of Stanols and Sterols in Benecol 
Snack Bars'' is suitable for the determination of stanols and sterols 
in snack bars containing 2.5 to 7.5 percent stanol esters. The method 
titled ``Determination of Stanols and Sterols in Benecol 
Dressing'' is suitable for determination of stanols and sterols in 
dressing for salad containing 3 to 8 percent stanol esters. Both the 
dressing for salad and snack bar procedures are similar to that 
described above for Benecol tub spread.
    The method titled ``Determination of Stanols and Sterols in 
Benecol Softgels'' describes a procedure for determination of 
stanols and sterols in softgels (gelatin capsules with liquid center) 
containing from 464 to 696 nanograms of stanol esters. The primary 
analytes are sitostanol, campestanol, sitosterol and campesterol. 
Stanol ester centers are washed from the gelatin shell and directly 
saponified with alcoholic potassium hydroxide. Stanols and sterols 
remain in the unsaponified fraction and are extracted with hexane. The 
extracted stanols and sterols are then derivatized to trimethylsilyl 
ethers and analyzed by gas chromatography. The internal standard 
utilized is cholestanol.
    The methods described above separate the major plant stanols in 
food products from their sterol derivatives. The petitioner has 
submitted data that show that these analytical methods are linear over 
a specified range, accurate, precise and reproducible (Refs. 8, 11, and 
13). Gas chromatography/mass spectrometry studies were used to confirm 
the identity of the major stanols (Ref. 14). The data obtained from GC/
MS studies with the plant stanol ester raw material and with chemical 
standards were compared with published spectra and confirmed the purity 
and identity of the major stanols, sitostanol and campestanol. The 
method has neither been subjected to validation through the AOAC's 
collaborative study or peer-verified method validation procedures, nor 
is it published in the open literature. FDA is requesting comments on 
the suitability of the plant stanol ester petitioner's methods for 
assuring that foods bearing the health claim contain the qualifying 
levels of plant stanol esters. In this document, FDA is incorporating 
the plant stanol ester petitioner's methods by reference in accordance 
with 5 U.S.C. 552(a) and 1 CFR part 51. Copies of the methods may be 
obtained from the Center for Food Safety and Applied Nutrition's Office 
of Nutritional Products, Labeling, and Dietary Supplements, Division of 
Nutrition Science and Policy, 200 C St. SW., rm. 2831, Washington, DC 
20204, or may be examined at the Center for Food Safety and Applied 
Nutrition's Library, 200 C St. SW., rm. 3321, Washington, DC, and at 
the Office of the Federal Register, 800 North Capital St. NW., suite 
700, Washington, DC.

D. Nature of the Food Eligible to Bear the Claim

1. Eligible Types of Foods and Qualifying Level of Plant Sterol/Stanol 
Esters Per Serving
    a. Plant sterol esters. Section 101.83(c)(2)(iii)(A)(1) provides 
that the types of foods eligible to bear the plant sterol esters and 
risk of CHD health claim are spreads and dressings for salad. Section 
101.83(c)(2)(iii)(A)(1) requires that any food bearing the health claim 
contain at least 0.65 g of plant sterol esters per reference amount 
customarily consumed (RACC) (i.e., per standardized serving). See 
Sec. 101.12 for an explanation of how RACC's are determined and a list 
of RACC's for commonly consumed foods. As discussed in section V.B of 
this document, the daily dietary intake level of plant sterol esters 
that has been associated with reduced risk of CHD is approximately 1.3 
g or more per day.
    The petitioner suggested that the qualifying level for foods to 
bear a health claim be 1.6 g per RACC, the same as the target daily 
intake level associated with reduced risk of CHD. The petitioner stated 
that the RACC's for spreads and dressings for salad, 1 and 2 
tablespoons (tbsp), respectively, are similar to the mean daily intakes 
of spreads and dressings for salad identified in the U.S. Department of 
Agriculture (USDA) 1994/96 Continuing Surveys of Food Intakes by 
Individuals (Ref. 1, appendix G), which were 11.4 and 40 g/d, 
respectively. The petitioner reasoned that the qualifying level per 
RACC should be the same as the target daily intake level to assure that 
people who consume only one serving a day of spread or dressings will 
still be able to obtain the health benefits of the target daily intake 
level.
    Although FDA recognizes that, based on the plant sterol ester 
petitioner's data, U.S. mean consumption for users of such products is 
only one serving of spread or dressing for salad a day, the agency is 
persuaded by the evidence from the studies supporting the claim that 
the daily amount should be consumed in at least two servings eaten at 
different times (see discussion of Sec. 101.83(c)(2)(i)(H) in section 
V.B of this document).
    The agency has generally made the assumption that a daily food 
consumption pattern includes three meals and a snack (see 58 FR 2302 at 
2379, January 6, 1993). Because of the wide variety of types of foods 
that could contain qualifying levels of soy protein in the soy protein/
CHD health claim (Sec. 101.82) or soluble fiber in the soluble fiber/
CHD health claim (Sec. 101.81), the agency concluded that the 
assumption of four servings/day of such foods was reasonable. 
Therefore, the daily qualifying level for soluble fiber substances and 
soy protein foods was based on consumption of four servings/day of such 
products. In contrast, however, there is not a wide variety of foods 
that contain plant sterol esters in significant quantities, and 
therefore the agency believes that it would be difficult for many 
consumers to eat four servings a day of such foods. The agency also has 
concluded that a recommendation for four servings of plant sterol 
ester-containing foods per day would not be an appropriate dietary 
recommendation because such foods are necessarily fat-based.
    FDA believes that a recommendation for plant sterol-containing 
products to be consumed over two servings per day is reasonable in 
light of the composition of these products (i.e., their fat content) 
and the limited number of available products. Therefore, the agency is 
requiring that a food bearing a health claim for plant sterol esters 
and risk of CHD contain at least 0.65 g of plant sterol esters per 
reference amount customarily consumed (1.3 g divided by two servings 
per day). The agency is requesting comments on this decision.
    The plant sterol ester petitioner requested that the claim be 
permitted for spreads and dressings for salad. The petitioner did not 
request authorization to use the health claim in the labeling of any 
other type of conventional food nor in the labeling of dietary 
supplements. The agency concluded in section II.B.3.a that the 
petitioner satisfied the requirement of Sec. 101.14(b)(3)(ii) to 
demonstrate that the use of plant sterol esters in spreads and 
dressings for salad at the levels necessary to justify a claim is safe 
and lawful. Furthermore, the petitioner submitted analytical methods 
for measurement of plant sterol esters in spreads and dressings for 
salad. Therefore, the agency is providing that the foods eligible to 
bear the health claim are spreads and dressings for salad. If comments 
on this interim final rule submit supporting data establishing that the 
use of plant sterol esters in other food products is safe and lawful 
and provide a validated analytical method that permits accurate 
determination of the amount of plant

[[Page 54708]]

sterol esters in these foods, FDA will consider broadening the 
categories of foods eligible to bear the claim in the final rule.
    b. Plant stanol esters. Section 101.83(c)(2)(iii)(A)(2) provides 
that the types of foods eligible to bear the plant stanol esters and 
risk of CHD health claim are spreads, dressing for salad, snack bars, 
and dietary supplements in softgel form. Section 
101.83(c)(2)(iii)(A)(2) requires that any food bearing the health claim 
contain at least 1.7 g of plant stanol esters per reference amount 
customarily consumed. As discussed in section V.B of this document, the 
daily dietary intake level of plant stanol esters that has been 
associated with reduced risk of CHD is 3.4 g or more per day.
    The plant stanol ester petitioner suggested that the qualifying 
level for foods to bear a health claim be 0.85 g per RACC. The 
petitioner explained that this level was derived by dividing the target 
daily intake level of 3.4 g plant stanol esters by four daily servings.
    As discussed in section V.B of this document, analysis of the 
studies supporting the claim has persuaded FDA that the daily intake of 
plant stanol esters should be consumed in at least two servings eaten 
at different times. Moreover, as with plant sterol esters (see section 
V.D.1.a of this document), FDA believes that two servings of plant 
stanol esters per day is a more appropriate baseline than four. There 
is not a wide variety of foods that contain plant stanol esters in 
significant quantities, and therefore it would be difficult for many 
consumers to eat four servings a day of such foods. The agency also has 
concluded that a recommendation for four servings of plant sterol 
ester-containing foods per day would not be an appropriate dietary 
recommendation because such foods, like foods containing plant sterol 
esters, are necessarily fat-based.
    As with plant sterol esters, the agency believes that a 
recommendation for the daily intake of plant stanol esters to be 
consumed over two servings per day is reasonable in light of the 
composition of products containing plant stanol esters (i.e., their fat 
content) and the limited number of available products. Therefore, the 
agency is requiring that a food bearing a health claim for plant stanol 
esters and risk of CHD contain at least 1.7 g of plant stanol esters 
per reference amount customarily consumed (3.4 g divided by two 
servings per day). The agency is requesting comments on this decision.
    The plant stanol ester petitioner requested that the claim be 
authorized for use on conventional foods and dietary supplements. The 
agency concluded in section II.B.3.b of this document that the 
petitioner satisfied the requirement of Sec. 101.14(b)(3)(ii) to 
demonstrate that the use of plant stanol esters in conventional foods 
or dietary supplements at the levels necessary to justify the claim is 
safe and lawful. The petitioner also submitted analytical methods for 
measurement of plant stanol esters in spreads, dressings for salad, 
snack bars, and dietary supplements in softgel (gelatin capsules with 
liquid center) form; however, the petitioner did not submit an 
analytical method suitable for measurement of plant stanol esters in 
other foods. Without such a method, FDA would have no way to verify 
that foods bearing the health claim contain the qualifying level of 
plant stanol esters per RACC, and false claims could be made that would 
mislead consumers. Therefore, the agency concludes that only foods for 
which a suitable method is available should be authorized to bear the 
health claim. Accordingly, FDA is providing that the foods eligible to 
bear the health claim are spreads, dressings for salad, snack bars, and 
dietary supplements in softgel form. If comments on this interim final 
rule provide a validated analytical method that permits accurate 
determination of the amount of plant stanol esters in other foods, FDA 
will consider broadening the categories of foods eligible to bear the 
claim in the final rule.
2. Fat Content Requirements
    a. Low fat. In Sec. 101.83(c)(2)(iii)(B), the agency is requiring, 
consistent with other authorized heart disease health claims, that 
foods bearing the health claim meet the requirements for ``low 
saturated fat'' and ``low cholesterol'' (see Sec. 101.62(c)(2) and 
(d)(2) (21 CFR 101.62(c)(2) and (d)(2)). As discussed elsewhere in this 
document and in the preamble to the final rule on fiber-containing 
fruits, vegetables, and grain products and CHD (58 FR 2552 at 2573), 
the scientific evidence linking diets low in saturated fat and 
cholesterol to reduced risk of CHD is strong. Therefore, FDA has 
consistently required foods that make claims about reducing the risk of 
CHD to be low in saturated fat and cholesterol.
    With few exceptions, as noted below, FDA has also required that 
foods bearing the previously authorized CHD health claims meet the 
requirements for ``low fat'' (see Sec. 101.62(b)(2)). In the dietary 
lipid and CVD proposed rule, FDA proposed that in order for a food to 
bear the health claim, the food must meet the requirements for a 
``low'' claim relative to total fat content (56 FR 60727 at 60739). The 
agency noted that, while total fat is not directly related to increased 
risk for CHD, it may have significant indirect effects. The agency 
mentioned that low fat diets facilitate reductions in the intake of 
saturated fat and cholesterol to recommended levels. Furthermore, the 
agency noted that obesity is a major risk factor for CHD, and dietary 
fats, which have more than twice as many calories per gram as proteins 
and carbohydrates, are major contributors to total calorie intakes. For 
many adults, maintenance of desirable body weight is more readily 
achieved with moderation of intake of total fat. The agency also 
concluded that this approach would be most consistent with the U.S. 
Dietary Guidelines, 4th edition (Ref. 107) and other dietary guidance 
that recommended diets low in saturated fat, total fat, and 
cholesterol. In the dietary saturated fat and cholesterol and CHD final 
rule (58 FR 2739 at 2742), FDA required most foods bearing the claim to 
meet the requirements for ``low fat,'' but allowed for the exception 
that fish and game meats could instead meet the less demanding 
requirements for ``extra lean,'' because these foods are appropriately 
included in a diet low in fat, saturated fat, and cholesterol. The 
agency also waived the requirement for ``low fat'' on products 
consisting of or derived from whole soybeans in the soy protein final 
rule (64 FR 57700 at 57718), as long as those products contained no 
additional fat not derived from the soybeans. FDA noted that products 
derived from whole soybeans are useful sources of soy protein that, 
like fish and game meats that are ``extra lean,'' can be appropriately 
incorporated in a diet that is low in fat, saturated fat, and 
cholesterol.
    The recently distributed Dietary Guidelines for Americans, 2000 
(Ref. 103) modify the previous guideline for total fat intake. The new 
guideline states, ``Choose a diet that is low in saturated fat and 
cholesterol and moderate in total fat.'' This new guideline also 
states, ``Some kinds of fat, especially saturated fats, increase the 
risk for coronary heart disease by raising the blood cholesterol. In 
contrast, unsaturated fats (found mainly in vegetable oils) do not 
increase blood cholesterol.'' This modification in the dietary 
guidelines, from the recommendation to choose a diet low in total fat 
in the 4th edition of the U.S. Dietary Guidelines (Ref. 107) to the 
recommendation to choose a diet moderate in total fat in the Dietary 
Guidelines for Americans, 2000 (Ref. 103) is based on current 
scientific

[[Page 54709]]

evidence of the role of diet in CHD, which does not support assigning 
first priority to a diet low in total fat (Ref. 108). The agency's 
reliance on dietary guidelines in this rulemaking and in previous 
health claim regulations is based on provisions of the 1990 amendments 
that direct FDA to issue health claim regulations that take into 
account the role of the nutrients in food in a way that will enhance 
the chances of consumers maintaining healthy dietary practices (see 
section 403(r)(3)(A) and (r)(3)(B) of the act (21 U.S.C. 343(r)(3)(A) 
and (r)(3)(B)), along with legislative history that mentions the role 
of health claims in encouraging Americans to eat balanced, healthful 
diets that meet federal government recommendations (Ref. 105).
    The agency finds that not imposing a ``low fat'' requirement is 
consistent with the emphasis in the new Dietary Guidelines for 
Americans, 2000 (Ref. 103) on diets moderate in total fat. Inasmuch as 
fats are currently the only technically feasible carriers of plant 
sterol/stanol esters, requiring foods bearing the health claim to be 
``low fat'' would greatly limit the number of foods that could use this 
health claim. Such a requirement would lessen the public health 
benefits of the rule. On the other hand, there are a number of foods, 
such as spreads and dressings for salad, that can be formulated to 
contain plant stanol or sterol esters while still qualifying as ``low 
saturated fat'' and ``low cholesterol.'' Given the strength of the 
evidence supporting the cholesterol-lowering effects of plant sterol/
stanol esters, the agency is requiring that foods bearing this health 
claim meet the nutrient content requirements in Sec. 101.62 for ``low 
saturated fat'' and ``low cholesterol,'' but not the requirements for 
``low fat.''
    b. Disqualifying levels. The plant sterol ester and plant stanol 
ester petitioners requested an exception for certain food products from 
the disqualifying nutrient level for total fat per 50 g of food in the 
general health claim regulations (Sec. 101.14(a)(4)). The plant sterol 
ester petitioner requested an exception for spreads and dressings for 
salad, and the plant stanol ester petitioner requested an exception for 
all foods with small serving sizes (less than or equal to 2 tbsp or 30 
g per RACC). Section 403(r)(3)(A)(ii) of the act provides that a health 
claim may only be made for a food that:

    does not contain, as determined by the Secretary by regulation, 
any nutrient in an amount which increases to persons in the general 
population the risk of a disease or health-related condition which 
is diet related, taking into account the significance of the food in 
the total daily diet, except that the Secretary may by regulation 
permit such a claim based on a finding that such a claim would 
assist consumers in maintaining healthy dietary practices and based 
on a requirement that the label contain a disclosure * * *.

    Accordingly, if FDA finds that such a claim will assist consumers 
in maintaining healthy dietary practices, the agency may issue a 
regulation permitting the claim, provided that the regulation requires 
the label of foods that bear the claim to identify the nutrient that 
exceeds the disqualifying level. The general requirements for health 
claims, Sec. 101.14(a)(4) and (e)(3), implement this provision of the 
act. Section 101.14(a)(4) defines the disqualifying levels of total 
fat, saturated fat, cholesterol, and sodium for different types of 
foods. The disqualifying level for total fat is 13 g per RACC, per 
labeled serving size, and, for foods with a RACC of 30 g or less or 2 
tbsp or less (i.e., foods with a small serving size), per 50 g. All 
three criteria apply; i.e., if a food with a small serving size 
contains more than 13 g of total fat per 50 g, it is considered to 
exceed the disqualifying level for total fat even if it contains less 
than 13 g of total fat per RACC and per labeled serving size. Section 
101.14(e)(3) provides that the nutrient content of foods that bear a 
health claim must be within the disqualifying levels in 
Sec. 101.14(a)(4), unless: (1) FDA has established alternative 
disqualifying levels in the regulation authorizing the claim; or (2) 
FDA has permitted the claim based on a finding that it will assist 
consumers in maintaining healthy dietary practices, and the label of 
foods bearing the claim bears the required disclosure statement about 
the nutrient that exceeds the disqualifying level.
    FDA first considered the plant sterol ester petitioner's request 
for an exception limited to spreads and dressings for salad. As noted 
above, foods with reference amounts of 30 g or 2 tbsp or less must 
contain no more than 13 g of total fat per 50 g of food product to 
avoid disqualification (Sec. 101.14(a)(4)). Reference amounts 
customarily consumed for spreads and dressings for salad are 1 tbsp and 
30 g, respectively. Many spreads and dressings for salad contain total 
fat levels above the 13 g total fat per 50 g food disqualifying level. 
Spreads and dressings for salad, however, are appropriate vehicles for 
plant sterol/stanol esters because such substances are soluble in these 
fat-based foods.
    In the proposed rule entitled ``Food Labeling: Nutrient Content 
Claims, General Principles; Health Claims, General Requirements and 
Other Specific Requirements for Individual Health Claims'' (60 FR 
66206, December 21, 1995; hereinafter the 1995 proposed rule), the 
agency proposed four factors as being important to a decision as to 
whether to grant an exception from a disqualifying level (60 FR 66206 
at 66222). The agency applied these four factors in its consideration 
of whether to grant an exception from the per 50 g disqualifying level 
of total fat for spreads and dressings for salad.
    The first factor is whether the disease that is the subject of the 
petition is of such public health significance, and the role of the 
diet so critical, that the use of a disqualifying level is not 
appropriate. CHD is of the highest public health significance, and the 
role of the diet is critical to reducing the risk of CHD. The National 
Heart, Lung and Blood Institute in its report, ``Morbidity and 
Mortality: 1998 Chartbook on Cardiovascular, Lung and Blood Diseases,'' 
published in 1998, estimated that the prevalence of CHD in the United 
States was 12 million (Ref. 109). Furthermore, it was estimated that 
2,130,000 hospitalizations and 9,941,000 visits to physicians' offices 
were the result of CHD in the United States in 1995 (Ref. 109). CHD is 
the leading cause of premature, permanent disability in the U.S. labor 
force, accounting for 19 percent of disability allowances by the Social 
Security Administration. CHD has a significant effect on U.S. health 
care costs. For 1999, total direct costs related to CHD were estimated 
at $53.1 billion and indirect costs from lost productivity associated 
with morbidity (illness and disability) and mortality (premature 
deaths) at $46.7 billion (Ref. 22). The agency notes that since plant 
sterol/stanol esters have been shown to significantly reduce blood 
cholesterol levels, and thereby help reduce the risk of CHD, an 
exception from the disqualifying level appears appropriate when 
considering the disease that is the subject of the claim.
    The second factor is whether, absent an exception from the 
disqualifying levels, the availability of foods that qualify for a 
health claim would be adequate to address the public health concern 
that is the subject of the health claim. If only a limited number of 
food products qualify to bear the claim because of the disqualifying 
levels, the agency would consider providing an exception. Without an 
exception from the disqualifying level for total fat, all currently 
marketed spreads and dressings for salad containing plant sterol/stanol 
esters would be ineligible to bear the health claim, and the number

[[Page 54710]]

of foods eligible for this health claim would be limited to such an 
extent that the public health value of the claim would be undermined. 
The agency therefore concludes that the second factor also supports 
granting an exception.
    The third factor in the 1995 proposed rule was whether there is 
``evidence that the population to which the health claim is targeted is 
not at risk for the disease or health-related condition associated with 
the disqualifying nutrient'' (60 FR 66206 at 66222). The agency stated 
that the current disqualifying nutrients--total fat, saturated fat, 
cholesterol and sodium--are associated with diseases or health-related 
conditions that pose risks to the general population, but that there 
may be some categories of foods that are targeted to specific 
subpopulations that are not at particular risk for the disease or 
health-related condition associated with the disqualifying nutrient 
(toddlers, for example). Because the target population for this health 
claim is the general population, not a specific subpopulation that is 
not at risk for CHD, FDA concludes that the third factor does not weigh 
in favor of granting an exception from the disqualifying levels for 
total fat.
    The final factor is whether there are any other public health 
reasons for providing for disclosure of the total fat level rather than 
disqualification. In this regard, the agency notes that the scientific 
evidence indicates that plant sterol/stanol esters could contribute 
significantly to reducing the risk of CHD in the United States. As 
reviewed in section III.C of this document, a number of well controlled 
randomized trials have found that plant sterol/stanol esters reduce 
cholesterol levels in amounts that can be easily consumed by the 
average adult when incorporated into spreads or dressings for salad. 
The agency has determined that permitting the health claim on plant 
sterol/stanol ester-containing spreads and dressings for salad will 
help consumers develop a dietary approach that will result in 
significantly lower cholesterol levels and an accompanying reduction in 
the risk of heart disease.
    Another public health reason for providing for disclosure of the 
total fat level rather than disqualification concerns the change in 
expert opinion on total fat intake, the risk of CHD, and general 
health. Although diets high in saturated fat and cholesterol are 
implicated in CHD, current scientific evidence does not indicate that 
diets high in unsaturated fat are associated with CHD (Refs. 103 and 
108). Furthermore, the 2000 Dietary Guidelines Advisory Committee 
concluded that the scientific evidence on dietary fat and health 
supports assigning first priority to reducing saturated fat and 
cholesterol intake, not total fat intake (Ref. 108). In fact, the new 
guideline for fat intake in the Dietary Guidelines for Americans, 2000 
(Ref. 103) states, ``Choose a diet that is low in saturated fat and 
cholesterol and moderate in total fat.''
    Based on the agency's analysis of the four factors identified in 
the 1995 proposed rule (60 FR 66206 at 66222) and consistent with the 
new Dietary Guidelines for Americans, 2000 (Ref. 103), the agency has 
determined that, despite the fact that spreads and dressings for salad 
that contain plant stanol/sterol esters may also contain a 
disqualifying level of total fat per 50 g, a health claim for plant 
sterol/stanol esters on such foods will assist consumers in maintaining 
healthy dietary practices. Therefore, the agency is providing in 
Sec. 101.83(c)(2)(iii)(C) a limited exception to the per 50 g 
disqualifying nutrient level for total fat in Sec. 101.14(a)(4) for 
spreads and dressings for salad that contain plant sterol/stanol 
esters. The agency is requesting comment on this decision. All foods 
bearing the health claim for plant sterol/stanol esters and risk of CHD 
must, however, meet the requirements for ``low saturated fat'' and 
``low cholesterol'' (see Sec. 101.83(c)(2)(iii)(B)). Likewise, all 
foods bearing the claim must meet the 13 g limit for total fat per RACC 
and per labeled serving size.
    In accordance with Sec. 101.14(e)(3), FDA is also providing that 
spreads and dressings for salad that take advantage of the exception to 
the disqualifying level must bear a disclosure statement that complies 
with Sec. 101.13(h) (21 CFR 101.13(h)). This statement must identify 
the disqualifying nutrient and refer the consumer to more information 
about the nutrient, as follows: ``See nutrition information for fat 
content.'' This statement must be included on the label of spreads and 
dressings for salad that bear a health claim for plant sterol/stanol 
esters and risk of CHD and that contain more than 13 g of total fat per 
50 g of product. Requirements for the format and placement of the 
disclosure statement are found in Sec. 101.13(h)(4).
    FDA considered the plant stanol ester petitioner's request that the 
exception to the disqualifying level for total fat per 50 g apply to 
all foods with small serving sizes. The agency has decided not to grant 
this request. There is a wide variety of foods that are consumed in 
small serving sizes, and the agency is not aware of any public health 
rationale that would justify applying the exception to all possible 
foods that are consumed in small serving sizes. Nor did the plant 
stanol ester petitioner provide such a rationale. The petitioner first 
argued generally that the benefits of cholesterol reduction through 
consumption of plant stanol esters would outweigh any negative dietary 
consequences of consuming foods that would not qualify for the health 
claim absent an exception from the disqualifying level for total fat 
(Ref. 8, page 25). The petitioner then argued more specifically that 
foods containing plant stanol esters replace other fat-containing foods 
in the diet (Ref. 8, page 25): ``Benecol foods are promoted as foods to 
be used in place of other similar foods. In the case of spreads, for 
example, Benecol spreads can be used as an alternative to butter, 
margarine or other spreads and, therefore, will not increase the 
overall level of fat in the diet while providing the cholesterol-
lowering benefits of plant stanol esters.''
    This rationale would not apply to all foods with small serving 
sizes, however, because not all such foods are used in place of other 
foods. This rationale provided by the petitioner applies to spreads and 
dressings for salad, but not necessarily to other foods with small 
serving sizes. FDA also does not agree that the health benefits of 
plant stanol esters outweigh the negative consequences of consuming 
high fat foods to such an extent that an unlimited exception to the 
disqualifying level for total fat should be permitted for all foods 
with small serving sizes. The agency further concludes that such a 
broad exception is not necessary because the availability of spreads 
and dressings for salad that qualify for the health claim will be 
sufficient so that consumers will be able to eat a sufficient quantity 
of plant sterol/stanol esters to receive the cholesterol-lowering 
benefits those substances provide. It is also likely that there are 
other types of foods that can be formulated to fall within the limits 
for total fat in Sec. 101.14(a)(4).
    Despite FDA's reluctance to grant broad exceptions to the 
disqualifying levels, the agency is willing to consider additional 
exceptions on a limited, case-by-case basis. Manufacturers of products 
other than spreads and dressings for salad that exceed the 
disqualifying level of total fat may submit comments with supporting 
information or petition the agency for an exception from 
disqualification in accordance with Sec. 101.14(e)(3) if they wish to 
make the health claim that is the subject of this interim final rule.

[[Page 54711]]

3. Minimum Nutrient Contribution Requirement
    The plant sterol ester and plant stanol ester petitioners requested 
an exception for certain food products containing plant sterol/stanol 
esters from the minimum nutrient contribution requirement in the 
general health claim regulations (Sec. 101.14(e)(6)). The plant sterol 
ester petitioner requested an exception for dressings for salad, and 
the plant stanol ester petitioner requested a general exception for all 
foods. Section 101.14(e)(6) specifies that conventional foods bearing a 
health claim must contain 10 percent or more of the Reference Daily 
Intake or the Daily Reference Value for vitamin A, vitamin C, iron, 
calcium, protein, or fiber per reference amount customarily consumed 
before any nutrient addition, except as otherwise provided in 
individual regulations authorizing particular health claims. Dietary 
supplements are not subject to this requirement. As explained in the 
1993 health claims final rule (58 FR 2478), FDA concluded that such a 
requirement is necessary to ensure that the value of health claims will 
not be trivialized or compromised by their use on foods of little or no 
nutritional value (58 FR 2478 at 2521). FDA adopted this requirement in 
response to Congress' intent that health claims be used to help 
Americans maintain a balanced and healthful diet (Ref. 105) (58 FR 2478 
at 2489 and 2521).
    The agency concludes that, with respect to dressings for salad, the 
minimum nutrient content requirements of Sec. 101.14(e)(6), while 
important, are outweighed by the public health importance of 
communicating the cholesterol-lowering benefits from consumption of 
plant sterol/stanol esters. The agency believes that the value of 
health claims will not be trivialized or compromised by their use on 
dressings for salad because dressings for salad often are consumed with 
foods rich in nutrients and fiber. Salads, for example, are usually 
rich in vegetables that provide important nutrients at significant 
levels, e.g., tomatoes--vitamins A and C; carrots--vitamin A; spinach--
vitamin A and calcium.
    In recognition of the usefulness of plant sterol/stanol esters in 
reducing blood cholesterol and the nutritional value of salad, FDA has 
determined that there is sufficient public health evidence to support 
providing an exception from Sec. 101.14(e)(6) for plant sterol/stanol 
ester-containing dressings for salad. However, the agency has decided 
not to grant the plant stanol ester petitioner's request for a general 
exception from the minimum nutrient content requirement. The basis for 
the plant stanol ester petitioner's request for such an exception is 
that the cholesterol-lowering benefits of plant stanol ester-containing 
foods do not depend upon the presence of 10 percent or more of the 
Reference Daily Intake or the Daily Reference Value for vitamin A, 
vitamin C, iron, calcium, protein, or fiber. The agency, however, 
concludes that this rationale is not sufficient to justify an exception 
for all possible foods that would require an exception from the minimum 
nutrient contribution requirement in order to use the health claim. FDA 
believes that case-by-case consideration of the justification for an 
exception is necessary to ensure that the goals of the minimum nutrient 
contribution requirement are not undermined.
    Accordingly, in Sec. 101.83(c)(2)(iii)(D), the agency is providing 
that dressings for salad bearing the health claim are excepted from the 
minimum nutrient requirement of Sec. 101.14(e)(6), but that other foods 
must comply with this requirement to be eligible to bear a health claim 
about plant sterol/stanol esters and the risk of CHD. The agency is 
requesting comment on this decision.
    Manufacturers of foods that do not meet the minimum nutrient 
contribution requirement may submit comments with supporting 
information or petition the agency to request an exception from this 
requirement if they wish to use the health claim that is the subject of 
this interim final rule.

E. Optional Information

    FDA is providing in Sec. 101.83(d)(1) that the claim may state that 
the development of heart disease depends on many factors and, 
consistent with other authorized CHD health claims, may list the risk 
factors for heart disease. The risk factors are those currently listed 
in Secs. 101.75(d)(1), 101.77(d)(1), 101.81(d)(1), and 101.82(d)(1). 
The claim may also provide additional information about the benefits of 
exercise and management of body weight to help lower the risk of heart 
disease.
    In Sec. 101.83(d)(2), consistent with Secs. 101.75(d)(2), 
101.77(d)(2), 101.81(d)(2), and 101.82(d)(2), FDA is providing that the 
claim may state that the relationship between diets that include plant 
sterol/stanol esters and reduced risk of heart disease is through the 
intermediate link of ``blood cholesterol'' or ``blood total 
cholesterol'' and ``LDL cholesterol.'' The relationship between plant 
sterol/stanol esters and reduced blood total cholesterol and LDL 
cholesterol is supported by the scientific evidence summarized in this 
interim final rule.
    In Sec. 101.83(d)(3), the agency is providing that, consistent with 
Secs. 101.75(d)(3), 101.77(d)(3), 101.81(d)(3), and 101.82(d)(3), the 
claim may include information from Sec. 101.83(a) and (b). These 
paragraphs summarize information about the relationship between diets 
that include plant sterol/stanol esters and the risk of CHD and about 
the significance of that relationship. This information helps to convey 
the seriousness of CHD and the role that a diet that includes plant 
sterol/stanol esters can play to help reduce the risk of CHD.
    In Sec. 101.83(d)(4), the agency is providing that the claim may 
include information on the relationship between saturated fat and 
cholesterol in the diet and the risk of CHD. This information helps to 
convey the importance of keeping saturated fat and cholesterol intake 
low to reduce the risk of CHD.
    In Sec. 101.83(d)(5), the agency is providing that the claim may 
state that diets that include plant sterol/stanol esters and are low in 
saturated fat and cholesterol are part of a dietary pattern that is 
consistent with current dietary guidelines for Americans.
    In Sec. 101.83(d)(6), the agency is providing that the claim may 
state that individuals with elevated blood total and LDL cholesterol 
should consult their physicians for medical advice and treatment. If 
the claim defines high or normal blood total and LDL cholesterol 
levels, then the claim shall state that individuals with high blood 
cholesterol should consult their physicians for medical advice and 
treatment.
    In Sec. 101.83(d)(7), the agency is providing that the claim may 
include information on the number of people in the United States who 
have heart disease. The sources of this information shall be 
identified, and it shall be current information from the National 
Center for Health Statistics, the National Institutes of Health, or 
``Nutrition and Your Health: Dietary Guidelines for Americans, 2000,'' 
USDA and Department of Health and Human Services (DHHS), Government 
Printing Office (GPO) (Ref. 103).
    The optional information provided in Sec. 101.83(d)(4) through 
(d)(7) is consistent with optional information set forth in 
Secs. 101.75, 101.77, 101.81, and 101.82. The intent of this 
information is to help consumers understand the seriousness of CHD in 
the United States and the role of diets that include plant sterol/
stanol esters and are low in saturated fat and cholesterol in reducing 
the risk of CHD.

[[Page 54712]]

F. Model Health Claims

    In Sec. 101.83(e), FDA is providing model health claims to 
illustrate the requirements of Sec. 101.83. FDA emphasizes that these 
model health claims are illustrative only. These model claims 
illustrate the required, and some of the optional, elements of the 
interim final rule. Because the agency is authorizing a claim about the 
relationship between plant sterol/stanol esters and CHD, not approving 
specific claim wording, manufacturers will be free to design their own 
claim so long as it is consistent with Sec. 101.83(c) and (d).
    In Sec. 101.83(e)(1)(i) and (e)(1)(ii), the model claims illustrate 
all of the required elements of the health claim for plant sterol 
esters. The first claim states, ``Foods containing at least 0.65 grams 
per serving of plant sterol esters, eaten twice a day with meals for a 
daily total intake of at least 1.3 grams, as part of a diet low in 
saturated fat and cholesterol, may reduce the risk of heart disease. A 
serving of [name of the food] supplies grams of vegetable oil sterol 
esters.'' The second claim states, ``Diets low in saturated fat and 
cholesterol that include two servings of foods that provide a daily 
total of at least 1.3 grams of vegetable oil sterol esters in two meals 
may reduce the risk of heart disease. A serving of [name of the food] 
supplies grams of vegetable oil sterol esters.''
    In Sec. 101.83(e)(2)(i) and (e)(2)(ii), the model claims illustrate 
all of the required elements of the health claim for plant stanol 
esters. The first claim states, ``Foods containing at least 1.7 grams 
per serving of plant stanol esters, eaten twice a day with meals for a 
total daily intake of at least 3.4 grams, as part of a diet low in 
saturated fat and cholesterol, may reduce the risk of heart disease. A 
serving of [name of the food] supplies grams of plant stanol esters.'' 
The second claim states, ``Diets low in saturated fat and cholesterol 
that include two servings of foods that provide a daily total of at 
least 3.4 grams of vegetable oil stanol esters in two meals may reduce 
the risk of heart disease. A serving of [name of the food supplies 
grams of vegetable oil stanol esters.''
    The plant stanol ester petitioner proposed three model health 
claims that included the following statements, respectively: ``5 g of 
plant stanol esters per day is more effective in reducing cholesterol 
and may further reduce the risk of heart disease,'' ``5 g plant stanol 
esters may be more beneficial in reducing the risk of heart disease,'' 
and ``5 g plant stanol esters per day has been shown to further lower 
LDL (bad) cholesterol and may further reduce the risk of heart 
disease.'' The agency reviewed the scientific evidence to determine 
whether the data supported these statements, starting with four studies 
(Refs. 88 through 90, and 94) that reported the blood cholesterol-
lowering effects from two or more consumption levels of plant stanol 
esters.
    Hallikainen et al. (Ref. 88) conducted a single-blind, crossover 
study in which 22 hypercholesterolemic subjects consumed margarine 
containing four different doses of plant stanol esters, including 1.4, 
2.7, 4.1, and 5.4 g/d (0.8, 1.6, 2.4, and 3.2 g/d of free plant 
stanols), for 4 weeks each. These test margarine phases were compared 
to a control margarine phase, also 4 weeks long. Serum total 
cholesterol concentration decreased (calculated in reference to 
control) by 2.8 percent (p=0.384), 6.8 percent (p 0.001), 10.3 percent 
(p0.001) and 11.3 percent (p 0.001) by doses from 1.4 to 5.4 g plant 
stanol esters. The respective decreases for LDL cholesterol were 1.7 
percent (p=0.892), 5.6 percent ( 0.05), 9.7 percent (p0.001) and 10.4 
percent (p0.001). Although serum total and LDL cholesterol decreases 
were numerically greater with the 4.1 and 5.4 g doses than with the 2.7 
g dose, these differences were not statistically significant (p=0.054-
0.516).
    Nguyen et al. (Ref. 90) examined the blood cholesterol-lowering 
effects in subjects consuming either a U.S.-reformulated spread 
containing 5.1 g/d plant stanol esters (3 g/d free plant stanols), a 
U.S.-reformulated spread containing 3.4 g per d plant stanol esters (2 
g/d of free plant stanols), or a U.S.-reformulated spread without plant 
stanol esters for 8 weeks. Serum total cholesterol (p  0.001) and LDL 
cholesterol (p 0.02) levels were significantly reduced in the 5.1 and 
3.4 g/d plant stanol ester groups compared with the placebo group. The 
U.S. spread containing 5.1 g/d plant stanol esters lowered serum total 
and LDL cholesterol by 6.4 and 10.1 percent, respectively, when 
compared to baseline (p 0.001). The 3.4 g/d plant stanol ester U.S. 
spread group showed a 4.1 percent reduction in both serum total and LDL 
cholesterol levels compared to baselinese 105 (p  0.001). The reduction 
in the LDL cholesterol level was found to be significantly greater in 
the 5.1 g/d plant stanol ester group compared to the 3.4 g/d plant 
stanol ester group (p  0.001). The authors did not report a statistical 
analysis comparing serum total cholesterol concentrations between the 
two consumption levels of plant stanol esters.
    Miettinen et al. (Ref. 89) instructed 153 mildly 
hypercholesterolemic subjects to consume 24 g/d of canola oil margarine 
or the same margarine with added plant stanol esters for a targeted 
consumption of 5.1 g/d plant stanol esters (3 g/d free plant stanols), 
without other dietary changes. At the end of 6 months, those consuming 
plant stanol esters were randomly assigned either to continue the test 
margarine with a targeted intake of 5.1 g/d plant stanol esters or to 
switch to a targeted intake of 3.4 g/d plant stanol esters (2 g/d free 
plant stanols) for an additional 6 months. Based on measured margarine 
consumption, average plant stanol ester intakes were 4.4 g/d (in the 
5.1 g/d target group) and 3.1 g/d (in the 3.4 g/d target group). 
Significant reductions in serum total and LDL cholesterol were reported 
after consuming 4.4 or 3.1 g/d of plant stanol esters compared to the 
control group (p  0.01). Moreover, a statistically significant 
difference was observed between the 6th and 12th months in the serum 
total cholesterol (p= 0.047) and LDL cholesterol (p= 0.017) curves 
between the 4.4 and 3.1 g/d plant stanol ester groups, representing a 
greater serum total cholesterol and LDL cholesterol reduction in the 
4.4 g/d plant stanol ester group compared to the 3.1 g/d plant stanol 
ester group. The authors state, however, ``Despite the finding that the 
decreasing trends between the 6th and 12th months in the total and LDL 
cholesterol concentrations in the group consuming 2.6 g of sitostanol 
were slightly different from the increasing trends in the group 
consuming 1.8 g, for practical purposes the two doses produced similar 
cholesterol-lowering effects.''
    Vanhanen et al. (Ref. 94) reported the hypocholesterolemic effects 
of 1.36 g/d of plant stanol esters (800 mg/d of free plant stanols) RSO 
mayonnaise for 9 weeks followed by 6 weeks of consumption of 3.4 g/d of 
plant stanol esters (2 g/d of free plant stanols) in RSO mayonnaise 
compared to a group receiving RSO mayonnaise alone. After 9 weeks of 
consumption of the lower dose (1.36 g/d) plant stanol ester mayonnaise, 
the changes in serum levels of total and LDL cholesterol were -4.1 
percent (p  0.05) and -10.3 percent (not statistically significant), 
respectively, as compared to the control. Greater reductions in both 
serum total and LDL cholesterol were observed after consumption of 3.4 
g/d of plant stanol esters for an additional 6 weeks (p  0.05). The 
changes in serum levels of total and LDL cholesterol were -9.3 percent 
and -15.2 percent,

[[Page 54713]]

respectively, for subjects consuming 3.4 g/d of plant stanol esters as 
compared to control. These investigators commented:

    [T]he reductions in the serum cholesterol level by SaE 
[sitostanol ester] were dose-dependent, indicating that the low 
dose, less than 1 g of sitostanol/day, reduced LDL-cholesterol 
insufficiently (8.5%). Accordingly, the higher dose, about 2 g/d, 
appears to be large enough for a reasonable (about 15%) lowering of 
serum LDL cholesterol. Preliminary studies with even higher doses, 3 
g/d, does not appear to increase the cholesterol-lowering effect, 
even though cholesterol absorption efficiency decreases by almost 
two-thirds in men with non-insulin-dependent diabetes mellitus at 
least * * *.

    In only one (Ref. 90) of the four studies (Refs. 88 through 90, and 
94) described above did the investigators report a statistically 
significant greater reduction in blood total and LDL cholesterol from 
consumption of 5 g or more of plant stanol ester compared to a lower 
consumption level of plant stanol ester. Another study (Ref. 88) found 
no statistically significant difference between the cholesterol-
lowering effects of 5.4 g/d plant stanol esters and two lower intake 
levels (2.7 and 4.1 g/d). The remaining two studies (Refs. 89 and 94) 
involved maximum intakes of less than 5 g/d, but in both studies the 
authors expressed the opinion that higher intakes did not appear to 
increase the cholesterol-lowering effect for practical purposes. In 
addition to these multiple-dose studies, FDA reviewed six single-dose 
studies (Refs. 67, 77, 78, 81 and 82 (1 study), 91, and 92) that 
reported statistically significant blood cholesterol-lowering effects 
from daily intake levels greater than 3.4 g/d of plant stanol esters. 
The agency compared these studies to the studies that found 
statistically significant blood cholesterol-lowering effects at intakes 
of plant stanol esters at or close to the 3.4 g/d level. Considering 
all the studies described above that reported the cholesterol-lowering 
effectiveness of total daily intake levels greater than 3.4 g/d of 
plant stanol esters (Refs. 67, 77, 78, 81 and 82 (1 study), 88 through 
92, and 94), the blood cholesterol-lowering effect for total 
cholesterol ranged from 7.1 percent from 5.8 g/d of plant stanol esters 
(Refs. 81 and 82 (1 study)) to 11.3 percent from 5.4 g/d of plant 
stanol esters (Ref. 88), and for LDL cholesterol the range was from 7.5 
percent from 5.8 g/d of plant stanol esters (Refs. 81 and 82 (1 study)) 
to 15 percent from 4.4 g/d of plant stanol esters (Ref. 89). These 
cholesterol-lowering results are similar to those observed in studies 
that utilized a daily total intake at or close to 3.4 g/d of plant 
stanol esters (Refs. 58, 80, 89, 90, and 94). In these lower daily 
intake studies, the blood total cholesterol reduction ranged from 9.3 
percent (Ref. 94) to 12 percent (Ref. 80) for 3.4 g/d of plant stanol 
esters. Similarly, for LDL cholesterol the reductions associated with 
these lower daily intake levels ranged from 6.4 percent for 3.31 g/d of 
plant stanol esters (Ref. 58) to 15 percent for 3.4 g/d of plant stanol 
esters (Refs. 80 and 94). Thus, comparison of the blood cholesterol-
lowering ranges between the higher and the lower daily intake levels of 
plant stanol esters suggests that there is no increased benefit from 
daily intake levels greater than 3.4 g/d.
    Furthermore, the results of a research synthesis analysis (Ref. 
100) suggest that intakes greater than about 3.4 g/d of plant stanol 
esters (2 g/d of plant stanol) would not result in further reduction in 
LDL cholesterol. This analysis found that a continuous dose response 
exists up to the 3.4 g/d level, but at higher daily intake levels of 
plant stanol esters, no further reduction in LDL cholesterol was 
apparent. Another recent analysis of the dose responsiveness to plant 
stanol esters, using a compilation of data from published studies, 
indicates a curvilinear dose response for both blood total and LDL 
cholesterol, with a clear leveling-off at an intake of about 3.74 g/d 
plant stanol esters (2.2 g/d free plant stanols) (Ref. 110).
    The agency therefore concludes that the weight of the evidence does 
not support the comparative claims requested by the plant stanol esters 
petitioner and that such claims would be misleading to consumers. 
Therefore, FDA is not including the petitioner's requested comparative 
claims in the model health claims in Sec. 101.83 and is not authorizing 
the plant sterol/stanol esters and risk of CHD health claim to include 
any statements claiming that 5 g per day of plant stanol esters is more 
effective than 3.4 g per day of plant stanol esters in reducing blood 
total or LDL cholesterol or in reducing the risk of heart disease.

VI. Issuance of an Interim Final Rule, Immediate Effective Date, 
and Opportunity for Public Comment

    FDA is issuing this rule as an interim final rule, effective 
immediately, with an opportunity for public comment. Section 403(r)(7) 
of the act authorizes FDA (by delegation from the Secretary of Health 
and Human Services (the Secretary)) to make proposed regulations issued 
under section 403(r) of the act effective upon publication pending 
consideration of public comment and publication of a final regulation, 
if the agency determines that such action is necessary for public 
health reasons. This authority enables the Secretary to act promptly on 
petitions that provide information that is necessary to: (1) Enable 
consumers to develop and maintain healthy dietary practices, (2) enable 
consumers to be informed promptly and effectively of important new 
knowledge regarding nutritional and health benefits of food, or (3) 
ensure that scientifically sound nutritional and health information is 
provided to consumers as soon as possible. Proposed regulations made 
effective upon publication under this authority are deemed to be final 
agency action for purposes of judicial review. The legislative history 
indicates that such regulations should be issued as interim final rules 
(H. Conf. Rept. No. 105-399, at 98 (1997)).
    Both the plant sterol ester petitioner and the plant stanol ester 
petitioner have submitted requests for the agency to consider making 
any proposed regulation on the petitioned health claims effective upon 
publication in an interim final rule (Refs. 6 and 16).
    The plant stanol ester petitioner's request states that all three 
of the criteria in section 403(r)(7)(A) of the act are met:

    As the petition makes clear, regular consumption of plant stanol 
esters as part of a healthy dietary pattern provides substantial 
health benefits. The health claim will, for the first time, provide 
consumers with important health information on the package label 
regarding the role of plant stanol esters in lowering cholesterol 
and reducing the risk of heart disease--information which should be 
made available to consumers at the earliest possible time. The 
health claim will provide consumers with scientifically sound 
information on the nutritional and health benefits of foods 
containing plant stanol ester, and will enable consumers to develop 
and maintain healthy dietary practices that include the 
incorporation of plant stanol esters into their diets.

    The plant sterol ester petitioner's request also states that all 
three of the criteria in section 403(r)(7)(A) of the act are met, and 
its rationale for meeting the criteria is similar to that of the plant 
stanol ester petitioner. The plant sterol ester petitioner also points 
out that if firms are required to wait until publication of a final 
rule to use the petitioned health claim, consumers will likely not read 
it on labeling until May 2001 or later. The petitioner further states, 
if FDA permits the claim to be used upon publication of the proposed 
rule, however, the claim could appear on labeling almost a year 
earlier, providing a significant period of time during which consumers 
could

[[Page 54714]]

effectively use the information to make healthier dietary choices.
    The agency has considered the requests to make any proposed rule 
for plant sterol/stanol esters and CHD effective upon publication and 
concurs that the standard in section 403(r)(7)(A) of the act is met. 
The agency agrees with the plant sterol ester and plant stanol ester 
petitioners that authorizing the health claim immediately will help 
consumers develop and maintain healthy dietary practices. As discussed 
above, FDA has concluded that there is significant scientific agreement 
that plant sterol/stanol esters reduce blood total and LDL cholesterol 
levels. The reported reductions in blood total and LDL cholesterol 
levels are significant and may have a profound impact on population 
risk of CHD if consumption of plant stanol esters becomes widespread. 
The agency has determined that issuance of an interim final rule is 
necessary to enable consumers to be informed promptly and effectively 
of this important new knowledge regarding the nutritional and health 
benefits of plant sterol/stanol esters. The agency has also determined 
that issuance of an interim final rule is necessary to ensure that 
scientifically sound nutritional and health information is provided to 
consumers as soon as possible.
    FDA invites public comment on this interim final rule. The agency 
will consider modifications to this interim final rule based on 
comments made during the comment period. Interested persons may submit 
to the Dockets Management Branch (address above) written comments 
regarding this interim final rule by November 22, 2000. Two copies of 
any comments are to be submitted, except that individuals may submit 
one copy. Comments are to be identified with the docket number found in 
brackets in the heading of this document. Received comments may be seen 
in the Dockets Management Branch between 9 a.m. and 4 p.m., Monday 
through Friday.
    These regulations are effective September 8, 2000. The agency will 
address comments and confirm or amend the interim rule in a final rule.

VII. Environmental Impact

    The agency has determined under 21 CFR 25.30(k) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VIII. Analysis of Economic Impacts

A. Benefit-Cost Analysis

    FDA has examined the economic implications of this interim final 
rule as required by Executive Order 12866. Executive Order 12866 
directs agencies to assess all costs and benefits of available 
regulatory alternatives and, when regulation is necessary, to select 
regulatory approaches that maximize net benefits (including potential 
economic, environmental, public health and safety, and other 
advantages; distributive impacts; and equity). Executive Order 12866 
classifies a rule as significant if it meets any one of a number of 
specified conditions, including having an annual effect on the economy 
of $100 million or adversely affecting in a material way a sector of 
the economy, competition, or jobs. A regulation is also considered a 
significant regulatory action if it raises novel legal or policy 
issues. FDA has determined that this interim final rule is not a 
significant regulatory action as defined by Executive Order 12866.
    The authorization of health claims about the relationship between 
plant sterol/stanol esters and coronary heart disease leads to costs 
and benefits only to those food manufacturers who choose to use the 
claim. This interim final rule would not require that any labels be 
redesigned or that any products be reformulated. Therefore, this rule 
will not generate any direct compliance costs. No firm will choose to 
bear the cost of redesigning labels unless it believes that the claim 
will lead to increased sales of its product sufficient to justify that 
cost. The benefit of this rule is to provide new information in the 
market regarding the relationship between plant sterol/stanol esters 
and the risk of coronary heart disease. FDA authorization for this 
health claim will provide consumers with the assurance that this 
information is truthful, not misleading, and scientifically valid.

B. Small Entity Analysis

    FDA has examined the economic implications of this interim final 
rule as required by the Regulatory Flexibility Act (5 U.S.C. 601-612). 
If a rule has a significant economic impact on a substantial number of 
small entities, the Regulatory Flexibility Act requires the agency to 
analyze regulatory options that would minimize the economic impact of 
the rule on small entities.
    As previously explained, this interim final rule will not generate 
any direct compliance costs. Small businesses will incur costs only if 
they choose to take advantage of the marketing opportunity presented by 
this interim final rule. No small entity, however, will choose to bear 
the cost of redesigning labels unless it believes that the claim will 
lead to increased sales of its product sufficient to justify those 
costs.
    Accordingly, FDA certifies that this interim final rule will not 
have a significant economic impact on a substantial number of small 
entities. Therefore, under the Regulatory Flexibility Act, no further 
analysis is required.

C. Unfunded Mandates Reform Act of 1995

    Title II of the Unfunded Mandates Reform Act of 1995 (Public Law 
104-4) requires cost-benefit and other analyses before any rulemaking 
if the rule would include a ``Federal mandate that may result in the 
expenditure by State, local, and tribal governments, in the aggregate, 
or by the private sector, of $100,000,000 or more (adjusted annually 
for inflation) in any 1 year.'' FDA has determined that this interim 
final rule does not constitute a significant regulatory action under 
the Unfunded Mandates Reform Act.

IX. Paperwork Reduction Act

    FDA concludes that the labeling provisions of this interim final 
rule are not subject to review by the Office of Management and Budget 
because they do not constitute a ``collection of information'' under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). Rather, the 
food labeling health claim on the association between plant sterol/
stanol esters and coronary heart disease is a ``public disclosure of 
information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public'' (5 CFR 
1320.3(c)(2)).

X. Federalism

    FDA has analyzed this interim final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the rule does not contain policies that have substantial direct effects 
on the states, on the relationship between the National Government and 
the States, or on the distribution of power and responsibilities among 
the various levels of government. Accordingly, the agency has concluded 
that the interim final rule does not contain policies that have 
federalism implications as defined in the order and consequently, a 
federalism summary impact statement is not required.

XI. References

    The following references have been placed on display in the Dockets

[[Page 54715]]

Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Lipton, ``Petition for Health Claim--Vegetable Oil Sterol 
Esters and Coronary Heart Disease,'' Item CP1, Docket 00P-1275, 
Dockets Management Branch, February 1, 2000.
    2. Letter from Daniel R. Dwyer, Kleinfeld, Kaplan and Becker, to 
Sharon A. Ross, FDA, Item MT1, Docket 00P-1275, Dockets Management 
Branch, March 31, 2000.
    3. Letter from Daniel R. Dwyer, Kleinfeld, Kaplan and Becker, to 
Sharon A. Ross, FDA, Item MT2, Docket 00P-1275, Dockets Management 
Branch, May 3, 2000.
    4. Letter from Daniel R. Dwyer, Kleinfeld, Kaplan and Becker, to 
Lynn A. Larsen, FDA, June 30, 2000.
    5. Letter from Lynn A. Larsen, FDA, to Nancy Schnell, Lipton, 
May 11, 2000.
    6. Letter from Daniel R. Dwyer, Kleinfeld, Kaplan and Becker, to 
Lynn A. Larsen, FDA, June 26, 2000.
    7. Letter from Nancy L. Schnell, Lipton, to Christine J. Lewis, 
FDA, August 2, 2000.
    8. McNeil Consumer Healthcare, ``Petition for Health Claim--
Plant Stanol Esters and Coronary Heart Disease,'' Item CP1, Docket 
00P-1276, Dockets Management Branch, February 15, 2000.
    9. Letter from G. A. Leveille, McNeil Consumer Healthcare, to 
Sharon Ross, FDA, Item MM2, Docket 00P-1276, Dockets Management 
Branch, February 28, 2000.
    10. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Sharon Ross, FDA, Item MM3, Docket 00P-1276, Dockets Management 
Branch, March 21, 2000.
    11. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Sharon Ross, FDA, Item MM4, Docket 00P-1276, Dockets Management 
Branch, April 3, 2000.
    12. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Sharon Ross, FDA, Item MM5, Docket 00P-1276, Dockets Management 
Branch, May 1, 2000.
    13. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Sharon A. Ross, FDA, June 23, 2000.
    14. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Lynn Larsen, FDA, July 18, 2000.
    15. Letter from Lynn A. Larsen, FDA, to Dr. Gilbert A. Leveille, 
McNeil Consumer Healthcare, May 25, 2000.
    16. Letter from Mark A. Sievers, Johnson & Johnson (parent 
company to McNeil Consumer Healthcare), to Lynn A. Larsen, FDA, June 
14, 2000.
    17. Letter from Gilbert A. Leveille, McNeil Consumer Healthcare, 
to Lynn Larsen, FDA, July 17, 2000.
    18. U.S. Department of Health and Human Services, Public Health 
Service, The Surgeon General's Report on Nutrition and Health, 
Washington, DC: U.S. Government Printing Office, 1988, pp. 83-137.
    19. Food and Nutrition Board, National Academy of Sciences, Diet 
and Health: Implications for Reducing Chronic Disease Risk, 
Washington, DC: National Academy Press, 1989, pp. 291-309 and 529-
547.
    20. U.S. Department of Health and Human Services, Public Health 
Service, and National Institutes of Health, National Cholesterol 
Education Program: Population Panel Report, NIH Publication No. 90-
3046, Bethesda, MD, November 1990, pp. 1-40.
    21. Sempos, C. T., J. I. Cleeman, M. D. Carroll, C. L. Johnson, 
P. S. Bachorik, D. J. Gordon, V. L. Burt, R. R. Briefel, C. D. 
Brown, K. Lippel, and B. M. Rifkind, ``Prevalence of High Blood 
Cholesterol Among U.S. Adults. An Update Based on Guidelines From 
the Second Report of the National Cholesterol Education Program 
Adult Treatment Panel,'' Journal of the American Medical 
Association, vol. 269, pp. 3009-3014, 1993.
    22. American Heart Association, 1999 Heart and Stroke 
Statistical Update, Dallas, TX: American Heart Association, 1998.
    23. Weihrauch, J. L., and J. M. Gardner, ``Sterol Content of 
Foods of Plant Origin,'' Journal of the American Dietetic 
Association, vol. 73, pp. 39-47, 1978.
    24. U.S. Department of Agriculture, Agricultural Research 
Service, ``USDA Nutrient Database for Standard Reference, Release 
12,'' Nutrient Data Laboratory Home Page (www.nal.usda.gov/fnic/foodcomp), 1998.
    25. Nair, P. P., N. Turjman, G. Kessie, B. Calkins, G. T. 
Goodman, H. Davidovitz, and G. Nimmagadda, ``Diet, Nutrition Intake, 
and Metabolism in Populations at High and Low Risk for Colon Cancer. 
Dietary Cholesterol, Beta-Sitosterol, and Stigmasterol,'' American 
Journal of Clinical Nutrition, vol. 440, pp. 927-930, 1984.
    26. Morton, G. M., S. M. Lee, D. H. Buss, and P. Lawrence, 
``Intakes and Major Dietary Sources of Cholesterol and Phytosterols 
in the British Diet,'' Journal of Human Nutrition and Dietetics, 
vol. 8, pp. 429-440, 1995.
    27. Miettinen, T. A., and A. Tarpila, ``Fecal Beta-sitosterol in 
Patients with Diverticular Disease of the Colon and in 
Vegetarians,'' Scandinavian Journal of Gastroenterology, vol. 13, 
pp. 573-576, 1978.
    28. Hirai K., C. Shimazu, R. Takezoe, and Y. Ozek, 
``Cholesterol, Phytosterol and Polyunsaturated Fatty Acid Levels in 
1982 and 1957 Japanese Diets,'' Journal of Nutritional Science and 
Vitaminology, vol. 32, pp. 363-372, 1986.
    29. deVries, J. H. M., A. Jansen, D. Kromhout, P. van de 
Bovenkamp, W. A. van Staveren, R. P. Mensink, and M. D. Katan, ``The 
Fatty Acid and Sterol Content of Food Composites of Middle-Aged Men 
in Seven Countries,'' Journal of Food Composition and Analysis, vol. 
10, pp. 115-141, 1997.
    30. Ling, W. H., and P. J. H. Jones, ``Dietary Phytosterols: A 
Review of Metabolism, Benefits, and Side Effects,'' Life Sciences, 
vol. 57, pp. 195-206, 1995.
    31. Johansson, A., ``The Content and Composition of Sterols and 
Sterol Esters in Sunflower and Poppy Seed Oils,'' Lipids, vol. 14, 
pp. 285-291, 1979.
    32. Johansson, A., and L. A. Appelqvist, ``The Content and 
Composition of Sterols and Sterol Esters in Low Erucic Acid 
Rapeseed,'' Lipids, vol. 13, pp. 658-665, 1978.
    33. Johansson, A., and I. Hoffman, ``The Effect of Processing on 
the Content and Composition of Free Sterols and Sterolesters in 
Soybean Oil,'' Journal of the American Oil Chemists Society, vol. 
56, pp. 886-889, 1979.
    34. Kochhar, S. P., ``Influence of Processing on Sterols of 
Edible Vegetable Oils,'' Progress In Lipid Research, vol. 22, pp. 
161-188, 1983.
    35. Hepburn, P. A., S. A. Horner, and M. Smith, ``Safety 
Evaluation of Phytosterol Esters. Part 2. Subchronic 90-Day Oral 
Toxicity Study on Phytosterol Esters--A Novel Functional Food,'' 
Food and Chemical Toxicology, vol. 37, pp. 521-532, 1999.
    36. Waalkens-Berendsen, D. H., A. P. M. Wolterbeek, M. V. W. 
Wunands, M. Richold, and P. A. Hepburn, ``Safety Evaluation of 
Phytosterol Esters. Part 3. Two-Generation Reproduction Study in 
Rats with Phytosterol Esters--A Novel Functional Food,'' Food and 
Chemical Toxicology, vol. 37, pp. 683-696, 1999.
    37. Barnes, P. J., ``Non-Saponifiable Lipids in Cereals,'' in 
Lipids in Cereal Technology, London: Academic, 1983, pp. 33-55.
    38. Dutta, P. C., and L. A. Appelqvist, ``Saturated Sterols 
(Stanols) in Unhydrogenated and Hydrogenated Edible Vegetable Oils 
and in Cereal Lipids,'' Journal of the Science of Food and 
Agriculture, vol. 71, pp. 383-391, 1996.
    39. MacMurray, T. A., and W. R. Morrison, ``Composition of 
Wheat-Flour Lipids,'' Journal of the Science of Food and 
Agriculture, vol. 21, pp. 520-528, 1970.
    40. Schuhmann, P., and R. Schneller, ``Method for Qualitative 
and Quantitative Determination of Phytosterols in Vegetable Oils 
Using LC-GC Off-Line,'' Mitt. Gebiete Lebensm. Hyg., vol. 87, pp. 
708-715, 1996 (translation from German).
    41. Boskou, D., ``Olive Oil Composition,'' in Olive Oil 
Chemistry and Technology, Ed. D. Boskou, Champaign, IL: AOCS, pp. 
52-83, 1996.
    42. Cater, N. B., and S. M. Grundy, ``Lowering Serum Cholesterol 
with Plant Sterols and Stanols: Historical Perspectives,'' in 
Postgraduate Medicine a Special Report: New Developments in the 
Dietary Management of High Cholesterol, Ed. T. T. Nguyen, 
Minneapolis, MN: McGraw-Hill, November 1998, pp. 6-14.
    43. Turnbull, D., M. H. Whittaker, V. H. Frankos, and D. Jonker, 
``13-Week Oral Toxicity Study with Stanol Esters in Rats,'' 
Regulatory Toxicology and Pharmacology, vol. 29, pp. 216-226, 1999.
    44. Letter from Alan M. Rulis, FDA, to Daniel R. Dwyer, 
Kleinfeld, Kaplan and Becker, April 30, 1999.
    45. Letter from Daniel R. Dwyer, Kleinfeld, Kaplan and Becker, 
to George H. Pauli, FDA, September 24, 1999.
    46. Letter from Alan M. Rulis, FDA, to Vivian A. Chester, and 
Edward B. Nelson, McNeil Consumer Healthcare, May 17, 1999.
    47. Letter from John C. Young, McNeil Consumer Healthcare, to 
Alan Rulis, FDA, July 21, 1999.
    48. Letter from John C. Young, McNeil Consumer Healthcare, to 
Alan Rulis, FDA, October 13, 1999.
    49. McNeil Consumer Healthcare, ``New Dietary Ingredient 
Notification--Plant Stanol Esters,'' Docket 95S-0316, Dockets 
Management Branch, August 19, 1999.
    50. Ross, R., ``Atherosclerosis,'' in Cecil Textbook of 
Medicine, Eds. J. B. Wyndaarden, L. H. Smith, and J. C. Bennett, 
Philadelphia: Harcourt Brace Jovanevich, Inc., 1992, p. 293.

[[Page 54716]]

    51. Ayesh, R., J. A. Weststrate, P. N. Drewitt, and P. A. 
Hepburn, ``Safety Evaluation of Phytosterol Esters. Part 5. Faecal 
Short-Chain Fatty Acid and Microflora Content, Faecal Bacterial 
Enzyme Activity and Serum Female Sex Hormones in Healthy 
Normolipidaemic Volunteers Consuming a Controlled Diet Either With 
or Without a Phytosterol Ester-Enriched Margarine,'' Food and 
Chemical Toxicology, vol. 31, pp. 1127-1138, 1999.
    52. Becker, M., D. Staab, and K. Von Bergmann, ``Treatment of 
Severe Familial Hypercholesterolemia in Childhood with Sitosterol 
and Sitostanol,'' Journal of Pediatrics, vol. 122, pp. 292-296, 
1993.
    53. Beveridge, J. M. R., E. F. Connel, G. A. Mayer, and H. L. 
Haust, ``Plant Sterols, Degree of Saturation, and 
Hypocholesterolemic Action of Certain Fats,'' Canadian Journal of 
Biochemistry and Physiology, vol. 36, pp. 895-911, 1958.
    54. Beveridge, J. M. R., H. L. Haust, and W. F. Connell, 
``Magnitude of the Hypocholesterolemic Effect of Dietary Sitosterol 
in Man,'' Journal of Nutrition, vol. 83, pp. 119-122, 1964.
    55. Briones, E. R., D. Steiger, P. J. Palumbo, and B. A. Kottke, 
``Primary Hypercholesterolemia: Effect of Treatment on Serum Lipids, 
Lipoprotein Fractions, Cholesterol Absorption, Sterol Balance and 
Platelet Aggregation,'' Mayo Clinic Proceedings, vol. 59, pp. 51-
257, 1984.
    56. Farquhar, J. W., R. E. Smith, and M. E. Dempsey, ``The 
Effect of Beta-Sitosterol on the Serum Lipids of Young Men with 
Arteriosclerotic Heart Disease,'' Circulation, vol. 14, pp. 77-82, 
1956.
    57. Hendriks, H. F. J., J. A. Weststrate, T. van Vliet, and G. 
W. Meijer, ``Spreads Enriched with Three Different Levels of 
Vegetable Oil Sterols and the Degree of Cholesterol Lowering in 
Normocholesterolaemic and Mildly Hypercholesterolaemic Subjects,'' 
European Journal of Clinical Nutrition, vol. 53, pp. 319-27, 1999.
    58. Jones, P. J., M. Raeini-Sarjaz, F. Y. Ntanios, C. A. 
Vanstone, J. Y. Feng, and W. E. Parsons, ``Modulation of Plasma 
Lipid Levels and Cholesterol Kinetics By Phytosterol Versus 
Phytostanol Esters,'' Journal of Lipid Research, vol. 41, No. 5, pp. 
697-705, 2000.
    59. Kudchodkar, B. J., L. Horlick, and H. S. Sodhi, ``Effects of 
Plant Sterols on Cholesterol Metabolism in Man,'' Atherosclerosis, 
vol. 28, pp. 239-248, 1976.
    60. Lees, A. M., H. Y. I. Mok, R. S. Lees, M. A. MsCluskey, and 
S. M. Grundy, ``Plant Sterols as Cholesterol-Lowering Agents: 
Clinical Trials in Patients with Hypercholesteremia and Studies of 
Sterol Balance,'' Atheroscelrosis, vol. 28, pp. 325-338, 1977.
    61. Maki, K. C., M. H. Davidson, D. M. Unporowicz, E. Shafer, M. 
R. Dicklin, K. A. Ingram, S. Chen, J. R. McNamara, B. W. Gebhart, 
and W. C. Franke, ``Lipid Responses to Plant Stero--Enriched 
Reduced--Fat Spreads Incorporated into an NCEP Step 1 Diet,'' 
Submitted to American Journal of Clinical Nutrition, 1999.
    62. Maki, K. C., M. H. Davidson, D. Umporowicz, E. J. Schaefer, 
M. R. Dicklin, K. A. Ingram, S. Chen, B. Gebhart, and W. C. Franke, 
``Lipid Responses to Plant Sterol-Enriched Reduced--Fat Spreads 
Incorporated into a Step 1 Diet,'' Circulation, vol. 100, No. 18, 
Supplement I, p. I-115 (abstract), November 1999.
    63. Miettinen, T. A., and H. T. Vanhanen, ``Dietary Sitostanol 
Related Absorption, Synthesis and Serum Level of Cholesterol in 
Different Apolipoprotein E Phenotypes,'' Atheroscelrosis, vol. 105, 
pp. 217-226, 1994.
    64. Vanhanen, H. T., and T. A. Miettinen, ``Effects of 
Unsaturated and Saturated Dietary Plant Sterols on their Serum 
Contents,'' Clinica Chimica Acta; International Journal of Clinical 
Chemistry; vol. 205, pp. 97-107, 1992.
    65. Pelletier, X., S. Belbraouet, D. Mirabel, F. Mordet, J. L. 
Perrin, X. Pages, and G. Derby, ``A Diet Moderately Enriched in 
Phytosterols Lowers Plasma Cholesterol Concentrations in 
Normocholesterolemic Humans,'' Annals of Nutrition and Metabolism, 
vol. 39, pp. 291-295, 1995.
    66. Pollak, O. J., ``Reduction of Blood Cholesterol in Man,'' 
Circulation, vol. 7, pp. 702-706, 1953.
    67. Weststrate, J. A., and G. W. Meijer, ``Plant Sterol-Enriched 
Margarines and Reduction of Plasma Total- and LDL-Cholesterol 
Concentrations in Normocholesterolaemic and Mildly 
Hypercholesterolaemic Subjects,'' European Journal of Clinical 
Nutrition, vol. 52, pp. 334-343, 1998.
    68. Best, M. M., and C. H. Duncan, ``Effects of the 
Esterification of Supplemental Cholesterol and Sitosterol in the 
Rat,'' Journal of Nutrition, vol. 65, pp. 169-181, 1958.
    69. Mattson, F. H., R. A. Volpenhein, and B. A. Erickson, 
``Effect of Plant Sterol Esters on Absorption of Dietary 
Cholesterol,'' Journal of Nutrition, vol. 107, pp. 1139-1146, 1977.
    70. Swell, L., H. Field, and C. R. Treadwell, ``Sterol 
Specificity of Pancreatic Cholesterol Esterase,'' Proceedings of the 
Society for Experimental Biology and Medicine, vol. 87, pp. 216-218, 
1954.
    71. Mattson, F. H., S. M. Grundy, and J. R. Crouse, ``Optimizing 
the Effect of Plant Sterols on Cholesterol Absorption in Man,'' 
American Journal of Clinical Nutrition, vol. 35, pp. 697-700, 1982.
    72. Kritchevsky, D.,``Phytosterols,'' Advances in Experimental 
Medicine and Biology, vol. 427, pp. 235-243, 1997.
    73. Pollak, O. J., ``Effect of Plant Sterols on Serum Lipids and 
Atherosclerosis,'' Pharmacology and Therapeutics, vol. 31, pp. 177-
208, 1985.
    74. Jones P. J., F. Y. Ntanios, M. Raeini-Sarjaz, and C. A. 
Vanstone, ``Cholesterol-Lowering Efficacy of a Sitostanol-Containing 
Phytosterol Mixture with a Prudent Diet in Hyperlipidemic Men,'' 
American Journal of Clinical Nutrition, vol. 69, No. 6, pp. 1144-50, 
1999.
    75. Sierksma, A., J. A. Weststrate, and G. W. Meijer,``Spreads 
Enriched with Plant Sterols, Either Esterified 4,4-Dimethylsterols 
or Free 4-Desmethylsterols, and Plasma Total- and LDL-Cholesterol 
Concentrations,'' British Journal of Nutrition, vol. 82, No. 4, pp. 
273-82, 1999.
    76. ICF Consulting, ``Literature Search Results for Work 
Assignment 00-12 (Human Health Effects of Phytosterols on Serum 
Lipids or Heart Disease),'' prepared under FDA Contract No. 223-96-
2302, Washington, DC, FDA, DHHS, April 10, 2000.
    77. Hallikainen, M. A, and M. I. J. Uusitupa, ``Effects of 2 
Low-Fat Stanol Ester-Containing Margarines on Serum Cholesterol 
Concentrations as Part of a Low-Fat Diet in Hypercholesterolemic 
Subjects,'' American Journal of Clinical Nutrition, vol. 69, pp. 
403-410, 1999.
    78. Gylling, H., and T. A. Miettinen, ``Cholesterol Reduction by 
Different Plant Stanol Mixtures and with Variable Fat Intake,'' 
Metabolism, vol. 48, pp. 575-580, 1999.
    79. Gylling, H., and T. A. Miettinen, ``Serum Cholesterol and 
Cholesterol and Lipoprotein Metabolism in Hypercholesterolaemic 
NIDDM Patients Before and During Sitostanol Ester-Margarine 
Treatment,'' Diabetologia, vol. 37, pp. 773-780, 1994.
    80. Andersson, A., B. KarlstroAE4m, R. Mohsen, and B. Vessby, 
``Cholesterol-Lowering Effects of a Stanol Ester-Containing Low-Fat 
Margarine Used in Conjunction with a Strict Lipid-Lowering Diet,'' 
European Heart Journal Supplements, vol. 1 (Suppl S), pp. S80-S90, 
1999.
    81. Blomqvist, S. M., M. Jauhiainen, A. van Tol, M. HyvoAE4nen, 
I. Torstila, H. T. Vanhanen, T. A. Miettinen, and C. Ehnholm, 
``Effect of Sitostanol Ester on Composition and Size Distribution of 
Low- and High-Density Lipoprotein,'' Nutrition, Metabolism and 
Cardiovascular Diseases, vol. 3, pp. 158-164, 1993.
    82. Vanhanen, H. T., S. Blomqvist, C. Ehnholm, M. Hyvonen, M. 
Jauhiainen, I. Torstila, and T. A. Miettinen, ``Serum Cholesterol, 
Cholesterol Precursors, and Plant Sterols in Hypercholesterolemic 
Subjects with Different apoE Phenotypes During Dietary Sitostanol 
Ester Treatment,'' Journal of Lipid Research, vol. 34, pp. 1535-
1544, 1993.
    83. Gylling, H., and T. A. Miettinen, ``The Effect of 
Cholesterol Absorption Inhibition on Low Density Lipoprote in 
Cholesterol Level,'' Atherosclerosis, vol. 117, pp. 305-308, 1995.
    84. Gylling, H., and T. A. Miettinen, ``Effects of Inhibiting 
Cholesterol Absorption and Synthesis on Cholesterol and Lipoprotein 
Metabolism in Hypercholesterolemic Non-Insulin-Dependent Diabetic 
Men,'' Journal of Lipid Research, vol. 37, pp. 1776-1785, 1996.
    85. Gylling, H, and T. A. Miettinen, ``Sitostanol Ester Added to 
Long-Term Simvastatin Treatment of Coronary Patients with Low and 
High Basal Cholesterol Absorption,'' Journal of the American College 
of Cardioliogy, vol. 31, Issue 2, Supplement 1, p. 281A (abstract), 
February 1998.
    86. Gylling, H., R. Radhakrishnan, and T. A. Miettinen, 
``Reduction of Serum Cholesterol in Postmenopausal Women with 
Previous Myocardial Infarction and Cholesterol Malabsorption Induced 
by Dietary Sitostanol Ester Margarine: Women and Dietary 
Sitostanol,'' Circulation, vol. 96, pp. 4226-4231, 1997.

[[Page 54717]]

    87. Gylling, H., M. A. Siimes, and T. A. Miettinen, ``Sitostanol 
Ester Margarine in Dietary Treatment of Children with Familial 
Hypercholesterolemia,'' Journal of Lipid Research, vol. 36, pp. 
1807-1812, 1995.
    88. Hallikainen, M. A., E. S. Sarkkinen, and M. I. J. Uusitupa, 
``Plant Stanol Esters Affect Serum Cholesterol Concentrations of 
Hypercholesterolemic Men and Women in a Dose-Dependent Manner,'' 
Journal of Nutrition, vol. 130, pp. 767-776, 2000.
    89. Miettinen, T. A., P. Puska, H. Gylling, H. Vanhanen, and E. 
Vartiainen, ``Reduction of Serum Cholesterol with Sitostanol-Ester 
Margarine in a Mildly Hypercholesterolemic Population,'' New England 
Journal of Medicine, vol. 333, pp. 1308-1312, 1995.
    90. Nguyen, T. T., L. C. Dale, K. von Bergmann, and I. T. 
Croghan, ``Cholesterol Lowering Effect of Stanol-Ester in a U.S. 
Population of Mildly Hypercholesterolemic Men and Women,'' Mayo 
Clinic Proceedings, vol. 74, pp. 1198-1206, 1999.
    91. Niinikoski, H., J. Viikari, and T. Palmu, ``Cholesterol-
Lowering Effect and Sensory Properties of Sitostanol Ester Margarine 
in Normocholesterolemic Adults,'' Scandinavian Journal of Nutrition, 
vol. 41, pp. 9-12, 1997.
    92. Plat, J., and R. P. Mensink, ``Vegetable Oil Based Versus 
Wood Based Stanol Ester Mixtures: Effects on Serum Lipids and 
Hemostatic Factors in Non-Hypercholesterolemic Subjects,'' 
Atherosclerosis, vol. 148, pp. 101-112, 2000.
    93. Vanhanen, H., ``Cholesterol Malabsorption Caused by 
Sitostanol Ester Feeding and Neomycin in Pravastatin-Treated 
Hypercholesterolaemic Patients,'' European Journal of Clinical 
Pharmacology, vol. 47, pp. 169-176, 1994.
    94. Vanhanen, H. T., J. Kajander, H. Lehtovirta, and T. A. 
Miettinen, ``Serum Levels, Absorption Efficiency, Faecal Elimination 
and Synthesis of Cholesterol During Increasing Doses of Dietary 
Sitostanol Esters in Hypercholesterolaemic Subjects,'' Clinical 
Science, vol. 87, pp. 61-67, 1994.
    95. Vuorio, A. F., H. Gylling, H. Turtola, K. Kontula, and T. A. 
Miettinen, ``Sitostanol Ester Spread Without and With Simvastatin in 
Dietary Treatment of Families Heterozygous of Familial 
Hypercholesterolemia North Karelia Deletion,'' Circulation, vol. 98, 
Supplement I, p. I-533 (abstract), 1998.
    96. Williams, C. L., M. C. Bollella, B. A. Strobino, L. Boccia, 
and L. Campanaro, ``Plant Stanol Ester and Bran Fiber in Childhood: 
Effects on Lipids, Stool Weight and Stool Frequency in Preschool 
Children,'' Journal of the American College of Nutrition, vol. 18, 
pp. 572-581, 1999.
    97. Denke, M. A., ``Lack of Efficacy of Low-Dose Sitostanol 
Therapy as an Adjunct to a Cholesterol-Lowering Diet in Men with 
Moderate Hypercholesterolemia,'' American Journal of Clinical 
Nutrition, vol. 61, No. 2, pp. 392-6, February 1995.
    98. U.S. Department of Health and Human Services, Food and Drug 
Administration, ``Guidance for Industry: Significant Scientific 
Agreement in the Review of Health Claims for Conventional Foods and 
Dietary Supplements; Availability (Docket No. 99D-5424),'' Federal 
Register, vol. 64, No. 245, p. 71794, December 22, 1999.
    99. National Cholesterol Education Program, Second Report of the 
Expert Panel on Detection, Evaluation, and Treatment of High Blood 
Cholesterol in Adults (Adult Treatment Panell II), NIH Publication 
No. 93-3-5, Rockville, MD: US Department of Health and Human 
Services, National Institutes of Health, September 1993.
    100. Law, M., ``Plant Sterol and Stanol Margarines in Health,'' 
British Medical Journal, vol. 320, pp. 861-864, 2000.
    101. Law, M. R., M. J. Wald, and S. G. Thompson, ``By How Much 
and How Quickly Does a Reduction in Serum Cholesterol Concentrations 
Lower Risk of Ischaemic Heart Disease,'' British Medical Journal, 
vol. 308, pp. 367-373, 1994.
    102. Puska, P., M. IsokaAE4aAE4ntaAE4, V. Korpelainen, and E. 
Vartiainen, ``Village Competition as an Innovative Method for 
Lowering Population Cholesterol,'' in Postgraduate Medicine A 
Special Report: New Developments in the Dietary Management of High 
Cholesterol, Ed. T. T. Nguyen, Minneapolis, MN: McGraw-Hill, 
November 1998, pp. 44-53.
    103. U.S. Department of Agriculture and U.S. Department of 
Health and Human Services. Nutrition and Your Health: Dietary 
Guidelines for Americans, 2000, 5th ed., Home and Garden Bulletin 
No. 232, 2000.
    104. National Center for Health Statistics, Healthy People 2000 
Review, 1998-99, Hyattsville, Maryland: Public Health Service, 1999, 
p. 41.
    105. House of Representatives, Committee on Energy and Commerce, 
``Nutrition Labeling and Education Act of 1990,'' H. Rept. 101-538, 
June 13, 1990.
    106. Piironen, V., D. G. Lindsay, T. A. Miettinen, J. Toivo, and 
A. Lampi, ``Plant Sterols: Biosynthesis, Biological Function and 
their Importance to Human Nutrition,'' Journal of the Science of 
Food and Agriculture, vol. 80, pp. 939-966, 2000.
    107. U.S. Department of Agriculture and U.S. Department of 
Health and Human Services, Nutrition and Your Health: Dietary 
Guideline for Americans, 4th ed., Home and Garden Bulletin No. 232, 
1995.
    108. Report of the Dietary Guidelines Advisory Committee on 
Dietary Guidelines for Americans, 2000, to the Secretary of Health 
and Human Services and the Secretary of Agriculture, June 2000 
(http://www.ars.usda.gov/dgac).
    109. National Heart, Lung, and Blood Institute, Morbidity & 
Mortality: 1998 Chartbook on Cardiovascular, Lung and Blood 
Diseases, Rockville, MD: US Department of Health and Human Services, 
National Institutes of Health, 1998.
    110. Wester, I., ``Dose Responsiveness to Plant Stanol Esters,'' 
European Heart Journal Supplements, vol. 1 (Supplement S), pp. S104-
S108, 1999.

List of Subjects in 21 CFR Part 101

    Food labeling, Incorporation by reference, Nutrition, Reporting and 
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
101 is amended as follows:

PART 101--FOOD LABELING

    1. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: 15 U.S.C. 1453, 1454, 1455, 21 U.S.C. 321, 331, 342, 
343, 348, 371.


    2. Section 101.83 is added to subpart E to read as follows:


Sec. 101.83  Health claims: plant sterol/stanol esters and risk of 
coronary heart disease (CHD).

    (a) Relationship between diets that include plant sterol/stanol 
esters and the risk of CHD. (1) Cardiovascular disease means diseases 
of the heart and circulatory system. Coronary heart disease (CHD) is 
one of the most common and serious forms of cardiovascular disease and 
refers to diseases of the heart muscle and supporting blood vessels. 
High blood total cholesterol and low density lipoprotein (LDL) 
cholesterol levels are associated with increased risk of developing 
coronary heart disease. High CHD rates occur among people with high 
total cholesterol levels of 240 milligrams per deciliter (mg/dL) (6.21 
millimole per liter (mmol/l)) or above and LDL cholesterol levels of 
160 mg/dL ( 4.13 mmol/l) or above. Borderline high risk blood 
cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18 mmol/l) 
for total cholesterol, and 130 to 159 mg/dL (3.36 to 4.11 mmol/l) of 
LDL cholesterol.
    (2) Populations with a low incidence of CHD tend to have relatively 
low blood total cholesterol and LDL cholesterol levels. These 
populations also tend to have dietary patterns that are not only low in 
total fat, especially saturated fat and cholesterol, but are also 
relatively high in plant foods that contain dietary fiber and other 
components.
    (3) Scientific evidence demonstrates that diets that include plant 
sterol/stanol esters may reduce the risk of CHD.
    (b) Significance of the relationship between diets that include 
plant sterol/stanol esters and the risk of CHD. (1) CHD is a major 
public health concern in the United States. It accounts for more deaths 
than any other disease or group of diseases. Early management of risk 
factors for CHD is a major public health goal that can assist in 
reducing risk of CHD. High blood total and LDL cholesterol are major 
modifiable risk factors in the development of CHD.
    (2) The scientific evidence establishes that including plant 
sterol/stanol esters in the diet helps to lower blood total and LDL 
cholesterol levels.
    (c) Requirements--(1) General. All requirements set forth in 
Sec. 101.14 shall

[[Page 54718]]

be met, except Sec. 101.14(a)(4) with respect to the disqualifying 
level for total fat per 50 grams (g) in dressings for salad and spreads 
and Sec. 101.14(e)(6) with respect to dressings for salad.
    (2) Specific requirements--(i) Nature of the claim. A health claim 
associating diets that include plant sterol/stanol esters with reduced 
risk of heart disease may be made on the label or labeling of a food 
described in paragraph (c)(2)(iii) of this section, provided that:
    (A) The claim states that plant sterol/stanol esters should be 
consumed as part of a diet low in saturated fat and cholesterol;
    (B) The claim states that diets that include plant sterol/stanol 
esters ``may'' or ``might'' reduce the risk of heart disease;
    (C) In specifying the disease, the claim uses the following terms: 
``heart disease'' or ``coronary heart disease'';
    (D) In specifying the substance, the claim uses the term ``plant 
sterol esters'' or ``plant stanol esters,'' except that if the sole 
source of the plant sterols or stanols is vegetable oil, the claim may 
use the term ``vegetable oil sterol esters'' or ``vegetable oil stanol 
esters'';
    (E) The claim does not attribute any degree of risk reduction for 
CHD to diets that include plant sterol/stanol esters;
    (F) The claim does not imply that consumption of diets that include 
plant sterol/stanol esters is the only recognized means of achieving a 
reduced risk of CHD; and
    (G) The claim specifies the daily dietary intake of plant sterol or 
stanol esters that is necessary to reduce the risk of CHD and the 
contribution one serving of the product makes to the specified daily 
dietary intake level. Daily dietary intake levels of plant sterol and 
stanol esters that have been associated with reduced risk of are:
    (1) 1.3 g or more per day of plant sterol esters.
    (2) 3.4 g or more per day of plant stanol esters.
    (H) The claim specifies that the daily dietary intake of plant 
sterol or stanol esters should be consumed in two servings eaten at 
different times of the day with other foods.
    (ii) Nature of the substance--(A) Plant sterol esters. (1) Plant 
sterol esters prepared by esterifying a mixture of plant sterols from 
edible oils with food-grade fatty acids. The plant sterol mixture shall 
contain at least 80 percent beta-sitosterol, campesterol, and 
stigmasterol (combined weight).
    (2) FDA will measure plant sterol esters by the method entitled 
``Determination of the Sterol Content in Margarines, Halvarines, 
Dressings, Fat Blends and Sterol Fatty Acid Ester Concentrates by 
Capillary Gas Chromatography,'' developed by Unilever United States, 
Inc., dated February 1, 2000, the method, which is incorporated by 
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51, may be 
obtained from the Center for Food Safety and Applied Nutrition, Office 
of Nutritional Products, Labeling, and Dietary Supplements, Division of 
Nutrition Science and Policy, 200 C St. SW., rm. 2831, Washington, DC 
20204, and may be examined at the Center for Food Safety and Applied 
Nutrition's Library, 200 C St. SW., rm. 3321, Washington, DC, or at the 
Office of the Federal Register, 800 North Capitol St. NW., suite 700, 
Washington, DC.
    (B) Plant stanol esters. (1) Plant stanol esters prepared by 
esterifying a mixture of plant stanols derived from edible oils or 
byproducts of the kraft paper pulping process with food-grade fatty 
acids. The plant stanol mixture shall contain at least 80 percent 
sitostanol and campestanol (combined weight).
    (2) FDA will measure plant stanol esters by the following methods 
developed by McNeil Consumer Heathcare dated February 15, 2000: 
``Determination of Stanols and Sterols in Benecol Tub Spread''; 
``Determination of Stanols and Sterols in Benecol Dressing''; 
``Determination of Stanols and Sterols in Benecol Snack Bars''; or 
``Determination of Stanols and Sterols in Benecol Softgels.'' These 
methods are incorporated by reference in accordance with 5 U.S.C. 
552(a) and 1 CFR part 51. Copies may be obtained from the Center for 
Food Safety and Applied Nutrition, Office of Nutritional Products, 
Labeling, and Dietary Supplements, Division of Nutrition Science and 
Policy, 200 C St., SW., rm. 2831, Washington, DC, 20204, or may be 
examined at the Center for Food Safety and Applied Nutrition's Library, 
200 C St., SW., rm. 3321, Washington, DC, and at the Office of the 
Federal Register, 800 North Capitol St. NW., suite 700, Washington, DC.
    (iii) Nature of the food eligible to bear the claim. (A) The food 
product shall contain:
    (1) At least 0.65 g of plant sterol esters that comply with 
paragraph (c)(2)(ii)(A)(1) of this section per reference amount 
customarily consumed of the food products eligible to bear the health 
claim, specifically spreads and dressings for salad, or
    (2) At least 1.7 g of plant stanol esters that comply with 
paragraph (c)(2)(ii)(B)(1) of this section per reference amount 
customarily consumed of the food products eligible to bear the health 
claim, specifically spreads, dressings for salad, snack bars, and 
dietary supplements in softgel form.
    (B) The food shall meet the nutrient content requirements in 
Sec. 101.62 for a ``low saturated fat'' and ``low cholesterol'' food; 
and
    (C) The food must meet the limit for total fat in 
Sec. 101.14(a)(4), except that spreads and dressings for salad are not 
required to meet the limit for total fat per 50 g if the label of the 
food bears a disclosure statement that complies with Sec. 101.13(h); 
and
    (D) The food must meet the minimum nutrient contribution 
requirement in Sec. 101.14(e)(6) unless it is a dressing for salad.
    (d) Optional information. (1) The claim may state that the 
development of heart disease depends on many factors and may identify 
one or more of the following risk factors for heart disease about which 
there is general scientific agreement: A family history of CHD; 
elevated blood total and LDL cholesterol; excess body weight; high 
blood pressure; cigarette smoking; diabetes; and physical inactivity. 
The claim may also provide additional information about the benefits of 
exercise and management of body weight to help lower the risk of heart 
disease.
    (2) The claim may state that the relationship between intake of 
diets that include plant sterol/stanol esters and reduced risk of heart 
disease is through the intermediate link of ``blood cholesterol'' or 
``blood total and LDL cholesterol.''
    (3) The claim may include information from paragraphs (a) and (b) 
of this section, which summarize the relationship between diets that 
include plant sterol/stanol esters and the risk of CHD and the 
significance of the relationship.
    (4) The claim may include information from the following paragraph 
on the relationship between saturated fat and cholesterol in the diet 
and the risk of CHD: The scientific evidence establishes that diets 
high in saturated fat and cholesterol are associated with increased 
levels of blood total and LDL cholesterol and, thus, with increased 
risk of CHD. Intakes of saturated fat exceed recommended levels in the 
diets of many people in the United States. One of the major public 
health recommendations relative to CHD risk is to consume less than 10 
percent of calories from saturated fat and an average of 30 percent or 
less of total calories from all fat. Recommended daily cholesterol 
intakes are 300 mg or less per day. Scientific evidence demonstrates 
that diets low in saturated fat and cholesterol are associated with

[[Page 54719]]

lower blood total and LDL cholesterol levels.
    (5) The claim may state that diets that include plant sterol or 
stanol esters and are low in saturated fat and cholesterol are 
consistent with ``Nutrition and Your Health: Dietary Guidelines for 
Americans,'' U.S. Department of Agriculture (USDA) and Department of 
Health and Human Services (DHHS), Government Printing Office (GPO).
    (6) The claim may state that individuals with elevated blood total 
and LDL cholesterol should consult their physicians for medical advice 
and treatment. If the claim defines high or normal blood total and LDL 
cholesterol levels, then the claim shall state that individuals with 
high blood cholesterol should consult their physicians for medical 
advice and treatment.
    (7) The claim may include information on the number of people in 
the United States who have heart disease. The sources of this 
information shall be identified, and it shall be current information 
from the National Center for Health Statistics, the National Institutes 
of Health, or ``Nutrition and Your Health: Dietary Guidelines for 
Americans,'' U.S. Department of Agriculture (USDA) and Department of 
Health and Human Services (DHHS), Government Printing Office (GPO).
    (e) Model health claim. The following model health claims may be 
used in food labeling to describe the relationship between diets that 
include plant sterol or stanol esters and reduced risk of heart 
disease:
    (1) For plant sterol esters: (i) Foods containing at least 0.65 g 
per serving of plant sterol esters, eaten twice a day with meals for a 
daily total intake of at least 1.3 g, as part of a diet low in 
saturated fat and cholesterol, may reduce the risk of heart disease. A 
serving of [name of the food] supplies grams of vegetable oil sterol 
esters.
    (ii) Diets low in saturated fat and cholesterol that include two 
servings of foods that provide a daily total of at least 1.3 g of 
vegetable oil sterol esters in two meals may reduce the risk of heart 
disease. A serving of [name of the food] supplies grams of vegetable 
oil sterol esters.
    (2) For plant stanol esters: (i) Foods containing at least 1.7 g 
per serving of plant stanol esters, eaten twice a day with meals for a 
total daily intake of at least 3.4 g, as part of a diet low in 
saturated fat and cholesterol, may reduce the risk of heart disease. A 
serving of [name of the food] supplies grams of plant stanol esters.
    (ii) Diets low in saturated fat and cholesterol that include two 
servings of foods that provide a daily total of at least 3.4 g of 
vegetable oil stanol esters in two meals may reduce the risk of heart 
disease. A serving of [name of the food] supplies grams of vegetable 
oil stanol esters.

    Dated: August 30, 2000.
Margaret Dotzel,
Associate Commissioner for Policy.
    Tables 1 and 2 to Preamble:
    Note: These tables will not appear in the Code of Federal 
Regulations.

[[Page 54720]]



                                                                        Table 1.--Plant Sterol Esters and CHD (Studies are listed in reverse chronological order)
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
           Study                          Design                           Population             Vegetable oil sterols: dose/form              Duration                       Dietary intakes                       Results
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Jones PJ, 2000  (Ref. 58)   Randomized                         N=15 (M) hypercholesterolemic      (1)Control;                       Run-in period NR; 21 days         Subjects consumed a fixed intake  Percent change in cholesterol
                              double-blind                      subjects; plasma total            (2) Phytosterol esters 2.94 g/d    duration on each phase:           North American solid foods diet   compared to control at day 21:
                              crossover                         cholesterol concentrations         (1.84 g/d free);                  margarine control, phytosterol    in a controlled feeding          Total-C
                              balanced Latin square design.     ranging from 232 mg/dL to 387 mg/ (3) Phytostanol esters 3.13 g/d    ester margarine, and              situation; diets formulated to     phytosterol esters: -
                                                                dL.                                (1.84 g/d free)                   phytostanol ester margarine;      meet Canadian recommended         9.1
                                                               Means at day 0:                      --in 23 g of margarine           each phase followed by a 5-week   nutrient intakes.                  phytostanol esters: -5.5
                                                                 (1) Control group 2509 mg/dL                      meals).                                                            Total fat (% TE): 35                phytosterol esters: -13.2*
                                                                 (2) Phytosterol ester group:     Sterol source: vegetable oil.                                       Saturated fat (% TE): 10            phytostanol esters: -6.4*
                                                                2477 mg/dL                                                                                Cholesterol (mg/d): NR            HDL-C
                                                                 (3) Phytostanol ester group                                                                                                              phytosterol esters: 0
                                                                2477 mg/dL                                                                                                                    phytostanol esters: 0
                                                                                                                                                                                                        P  0.005, *P 0.02,
                                                                                                                                                                                                         relative to control
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Maki KC, submitted for      Randomized, double-blind, three-   N= 224 randomized; N= 193          (1) Control;                      4 week run-in period, followed    Run-in diet: NCEP Step I diet     Percent change in cholesterol at
 publication (Refs. 61 and   arm parallel controlled study.     completed study (M/F) (control    (2) Low phytosterol esters (PSE)   by 5 week treatment period.       and a conventional 50% fat        end of 5 weeks, relative to
 62)                                                            N= 83; low PSE N= 75; high PSE     group: 1.76 g/d (1.1 g/d free);                                     spread; background diet: NCEP     control:
                                                                N= 35) mild to moderate           (3) High phytosterol esters                                          Step I diet and a reduced-fat    Total-C
                                                                hypercholesterolemics (mean        group: 3.52 g/d (2.2 g/d free)                                      (40%) spread.                      low PSE group: -5.2%*
                                                                baseline total cholesterol: 240   --in 14 g/d of reduced fat (40%)                                    Dietary intake, end of study:       high PSE group: -6.6%*
                                                                mg/dL).                            spread (two 7 g servings/d,                                        Total Fat (% TE)                  LDL-C
                                                                                                   with food).                                                          control: 29.50.8      low PSE group: -7.6%*
                                                                                                  Sterol source: soybean oil.                                           low PSE: 29.10.9      high PSE group: -8.1%*
                                                                                                                                                                        high PSE: 28.81.4   HDL-C
                                                                                                                                                                      Saturated Fat (%TE)                 low PSE group: 0.8%
                                                                                                                                                                        control: 9.10.4       high PSE group: 1.6%
                                                                                                                                                                        low PSE: 8.60.4     *P 0.001
                                                                                                                                                                        high PSE: 9.10.6
                                                                                                                                                                      Cholesterol (mg/d)
                                                                                                                                                                        control: 18213
                                                                                                                                                                        low PSE: 20316
                                                                                                                                                                        high PSE: 19419
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54721]]

 
Ayesh R, 1999 (Ref. 51)     Randomized placebo-controlled      N=21 (10 M/ 11F) healthy           (1) Control;                      Run-in duration: 21 days M and    Controlled diet based on a        Percent change in cholesterol at
                             dietary study.                     population; inclusion criteria    (2) Phytosterol ester              28 days F; treatment duration:    typical British diet; breakfast   end of 21/28 days, relative to
                                                                at baseline for total serum       13.8 g/d (8.6 g/d free)            21 days M and 28 days F.          and dinner consumed under         control:
                                                                cholesterol concentration: 158    --in 40 g/d of margarine;                                            supervision, but lunch and       Total-C: -18%*
                                                                to 255 mg/dL (mean 18725 mg/dL).                   dinner under supervision.                                           consumed unsupervised outside    HDL-C: -7%
                                                                                                  Sterol source: vegetable oil.                                        the unit.                        *(P0.0001)
                                                                                                                                                                      Dietary intake during study:
                                                                                                                                                                        Total fat (% TE): 40%
                                                                                                                                                                        Saturated fat (% TE): NR
                                                                                                                                                                        Cholesterol (mg/day): 460
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Hendriks HFJ, 1999 (Ref.    Randomized, double-blind,          N= 100 (42 M/ 58 F), but 80        (1) Butter (control);             No run-in period; each subject    Consumption of habitual Dutch     Percent change in cholesterol at
 57)                         crossover, balanced incomplete     subjects for each spread          (2) Spread (control);              consumed 4 spreads for a period   diet (self-selected diets on      end of 3.5 weeks, relative to
                             Latin square design; 5 spreads,    (incomplete Latin square design=  (3) Plant sterol ester 1.33 g/d    of 3.5 weeks each; wash-out       study).                           control spread:
                             4 periods.                         5 spreads in four periods);        (0.83 g/d free);                  period NR.                       Dietary intake, end of study:     Total-C
                                                                normochol-esterolemic and mildly  (4) Plant sterol ester 2.58 g/d                                     Total fat (% TE)                    1.33 g/d PSE: -4.9*
                                                                cholesterolemic volunteers;        (1.61 g/d free);                                                     control:33.95.6       2.58 g/d PSE: -5.9*
                                                                inclusion criteria at baseline    (5) Plant sterol ester 5.18 g/d                                       1.33 g/d PSE: 32.95.2                        LDL-C
                                                                concentration:  290 mg/dL         --in 25 g/d of spread (or                                             2.58 g/d PSE: 33.35.5                          2.58 g/d PSE: -8.5*
                                                                mean 19738 mg/dL,      equivalent amount of the                                             5.18 g/d PSE: 33.95.5                        HDL-C
                                                                                                   2\ at lunch, \1/2\ at dinner.                                      Saturated fat (% TE)                1.33 g/d PSE: -0.3
                                                                                                  Sterol source: soybean and other                                      control: 13.52.9      2.58 g/d PSE: -1.3
                                                                                                   vegetable oil.                                                       1.33 g/d PSE: 13.42.5                        *(P  0.0001)
                                                                                                                                                                        2.58 g/d PSE: 13.32.7
                                                                                                                                                                        5.18 g/d PSE: 13.52.86
                                                                                                                                                                      Cholesterol (mg/d)
                                                                                                                                                                        control: 24558.5
                                                                                                                                                                        1.33 g/d PSE: 24568.6
                                                                                                                                                                        2.58 g/d PSE: 24861
                                                                                                                                                                        5.18 g/d PSE: 26163
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54722]]

 
Jones PJH, 1999 (Ref. 74)   Randomized double-blind placebo-   N=32 (M) hypercholesterolemic      (1) Control;                      No run-in period; experimental    Controlled feeding regimen for    Day 30 cholesterol (mg/dL):
                             controlled, parallel study.        subjects (N= 16 control group,    (2) Sitostanol-containing          period: 30 days; 20 days          all subjects; a `prudent,'       Total-C
                                                                N=16 phytosterol group);           phytosterols (20% sitostanol,     followup after experimental       fixed-food North American diet     control: 23656
                                                                inclusion criteria serum total     remaining plant sterols are       period.                           formulated to meet Canadian        sitostanol-containing
                                                                cholesterol concentrations         sitosterol, campesterol) 1.7 g/                                     recommended nutrient intakes.     phytosterols: 21036
                                                                between 252 to 387 mg/dL; mean     d                                                                  Dietary intake during study:      LDL-C
                                                                cholesterol at baseline, mg/dL:   --in 30 g/d of margarine                                              Total fat (% TE): 35%             control: 17652
                                                                control group 263.5    consumed during 3 meals;                                             Saturated fat (% TE): 11%         sitostanol-containing
                                                                50, phytosterol group 260.5        sterols/stanols not esterified.                                      Cholesterol (mg/d): NR           phytosterols: 13036
                                                                 44.5.                Sterol source: tall oil (derived                                                                        (p  0.05 relative to control
                                                                                                   from pine wood).                                                                                      group)
                                                                                                                                                                                                        HDL-C
                                                                                                                                                                                                          control: 237
                                                                                                                                                                                                          sitostanol-containing
                                                                                                                                                                                                         phytosterols: 267
                                                                                                                                                                                                        Day 0 to day 30, percent change:
                                                                                                                                                                                                        LDL-C
                                                                                                                                                                                                          control: -8.9%, P  0.01
                                                                                                                                                                                                          sitostanol-containing
                                                                                                                                                                                                         phytosterols: -24.4%, P 0.001
                                                                                                                                                                                                          sitostanol-containing
                                                                                                                                                                                                         phytosterols:
                                                                                                                                                                                                          -15.5%, P 0.05, relative to
                                                                                                                                                                                                         control
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54723]]

 
Sierksma A, 1999 (Ref. 75)  Balanced, double-blind crossover   N=76, 75, or 74 healthy            (1) Control (Flora spread);       Run-in period: 1 week on control  Volunteers maintained normal      Cholesterol (mg/dL):
                             design.                            volunteers (39 M/37 F); baseline  (2) Soybean sterols: 0.8 g/d       spread; experimental period: 3    dietary patterns during study;     mean (95% CI)
                                                                plasma total cholesterol levels    (non-esterified);                 weeks each experimental period,   spreads were meant to replace    Total-C
                                                                310 mg/dL.                        (3) Sheanut oil sterols            9 weeks total; no wash-out        all or part of the volunteers'     control: 196 (193, 199)
                                                                                                   (esterified): 3.3 g/d             period (balanced design with      habitual spread or butter used     soybean sterols: 188 (186,
                                                                                                  --in 25 g /d spread.               period by group random            for spreading, but not to be      191)*
                                                                                                  Sterol source: soybean oil or      allocation).                      used for baking or frying.         sheanut sterols: 194 (191,
                                                                                                   sheanut oil.                                                       Dietary intake during study:       197)
                                                                                                                                                                      Total fat (% TE)                  LDL-C
                                                                                                                                                                        control: 38.3                     control: 122 (119, 124)
                                                                                                                                                                        soybean sterols: 38.3             soybean sterols: 114 (112,
                                                                                                                                                                        sheanut sterols: 38.4            116)*
                                                                                                                                                                      Saturated fat (% TE)                sheanut sterols: 119 (116,
                                                                                                                                                                        control: 13.9                    122)
                                                                                                                                                                        soybean sterols: 13.8           HDL-C
                                                                                                                                                                        sheanut sterols: 14.3*            control: 50 (49, 50)
                                                                                                                                                                      Cholesterol (mg/d)                  soybean sterols: 50 (49, 51)
                                                                                                                                                                        control: 246                      sheanut sterols: 50 (49, 51)
                                                                                                                                                                        soybean sterols: 247            P  0.05, relative to control
                                                                                                                                                                        sheanut sterols: 242            Percent change, relative to
                                                                                                                                                                      *P  0.05                           control:
                                                                                                                                                                                                        Total-C
                                                                                                                                                                                                          soybean sterols: -3.8%*
                                                                                                                                                                                                        LDL-C
                                                                                                                                                                                                          soybean sterols: -6%*
                                                                                                                                                                                                        HDL-C: 0
                                                                                                                                                                                                        * P  0.05
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54724]]

 
Weststrate JA, 1998 (Ref.   Randomized double-blind            N= 95 (100 enrolled= 50 M/ 50 F)   (1) Control (Flora spread);       Run-in of 5 days; each subject    Volunteers were requested to      Percent change in cholesterol at
 67)                         crossover, balanced incomplete     but approximately 80 subjects     (2) Plant stanol esters 4.6 g/d    consumed 4 margarines for a       retain their normal dietary       the end of 3.5 weeks, relative
                             Latin square design with 5         for each margarine (incomplete     (2.7 g/d free);                   period of 3.5 weeks each; wash-   pattern.                          to control spread:
                             margarines, 4 periods of 3.5       Latin square design= 5            (3) Soybean sterol esters 4.8 g/   out period between experimental  Dietary intake during study:      Total-C
                             weeks.                             margarines in four periods);       d (3 g/d free);                   periods- NR.                     Total fat (% TE)                    plant stanol esters: -7.3*
                                                                normocholesterolemic and mildly   (4) Ricebran sterols 1.6 g/d                                          control: 42                       soybean sterol esters: -8.3*
                                                                hyperchol-esterolemic subjects;   (5) Sheanut sterols 2.9 g/d;                                          plant stanol esters: 41.8         ricebran sterols: -1.1
                                                                inclusion criteria at baseline    --in 30 g/d of margarine,                                             soybean sterol esters: 41.5       sheanut sterols: -0.7
                                                                for total plasma cholesterol       consumption at lunch and                                             ricebran sterols: 41.4          LDL-C
                                                                concentration:  310 mg/dL          dinner; margarine replaced                                           sheanut sterols: 41.3             plant stanol esters: -13*
                                                                (baseline total cholesterol:       margarines habitually used.                                        Saturated fat (%TE)                 soybean sterol esters: -13*
                                                                mean 20741 mg/dL).    Sterol source: soybean, ricebran                                      control: 15.9                     ricebran sterols: -1.5
                                                                                                   and sheanut.                                                         plant stanol esters: 16.2         sheanut sterols: -0.9
                                                                                                                                                                        soybean sterol esters: 15.3     HDL-C
                                                                                                                                                                        ricebran sterols: 15.4            plant stanol esters: 0.1
                                                                                                                                                                        sheanut sterols: 16.9             soybean sterol esters: 0.6
                                                                                                                                                                      Cholesterol (mg/d)                  ricebran sterols: -1.3
                                                                                                                                                                        control: 233;                     sheanut sterols: -1.2
                                                                                                                                                                        plant stanol esters: 243        *P 0.05
                                                                                                                                                                        soybean sterol esters: 226
                                                                                                                                                                        ricebran sterols: 233
                                                                                                                                                                        sheanut sterols: 227
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Pelletier X, 1995 (Ref.     Randomized, crossover design       N= 12 normolipidic healthy men     (1) Group 1: 4 weeks normal diet  1 week run-in period and two      Subjects on a controlled diet,    Percent change in cholesterol at
 65)                         (blinding NR).                     (baseline cholesterol levels       followed by 4 weeks plant         experimental periods of 4 weeks   but diet is a ``normal'' diet.    end of 4 weeks, plant sterol-
                                                                NR).                               sterol-enriched diet 0.740 g/d;   each; wash-out period NR.        Dietary intake, during study:      enriched butter relative to
                                                                                                  (2) Group 2: 4 weeks plant                                          Total fat (% TE)                   control butter:
                                                                                                   sterol-enriched diet 0.740 g/d                                       Period 1: 36.47.1   Total-C
                                                                                                   followed by 4 weeks normal diet                                      Period 2: 36.46.9     -10%*
                                                                                                  --in 50 g/d of butter; plant                                        Saturated fat (% TE)              LDL-C
                                                                                                   sterols are not esterified.                                          Control: NR                       -15%*
                                                                                                  Sterol source: soybean oil.                                           Plant Sterol: NR                HDL-C
                                                                                                                                                                      Cholesterol (mg/d)                  +4.6%
                                                                                                                                                                      Control: 436                      P  0.001
                                                                                                                                                                        Plant Sterol: 410
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54725]]

 
Miettinen, TA, 1994 (Ref.   Randomized, placebo-controlled,    N= 31 (22 M/ 9 F) (control N= 8;   (1) Rapeseed oil (RSO) control;   6 week run-in period; 9 week      No diet changes other than        Change in cholesterol from end
 63) (same as or partial     double-blind study.                sitosterol N= 9; sitostanol N=    (2) Sitosterol 0.7 g/d;            study period.                     replacing 50 g of typical daily   of run-in period to end of 9
 study of Vanhanen HT,                                          7; sitostanol ester N= 7);        (3) Sitostanol 0.7 g/d;                                              fat by 50 g of RSO mayonnaise.    week study period (mg/dL):
 1992 (Ref. 64))                                                hypercholesterolemic subjects;    (4) Sitostanol ester 1.36 g/d                                       Dietary intake at end of study    Total-C
                                                                inclusion criteria at baseline     (0.8 g/d free)                                                      for all subjects:                  RSO control: +4.64.3
                                                                concentration: >232 mg/dL.        Sterol source: NR.                                                    1149                  sitosterol: -7.75.0
                                                                                                                                                                        12.40.7%              sitostanol: -0.45.4
                                                                                                                                                                        32628                 sitostanol ester: -7.43.1
                                                                                                                                                                                                        LDL-C
                                                                                                                                                                                                          RSO control: +3.14.3
                                                                                                                                                                                                          sitosterol: -7.04.3
                                                                                                                                                                                                          sitostanol: -1.24.6
                                                                                                                                                                                                          sitostanol ester: -7.73.1*
                                                                                                                                                                                                        HDL-C
                                                                                                                                                                                                          RSO control: +2.31.2
                                                                                                                                                                                                          sitosterol: +0.001.5
                                                                                                                                                                                                          sitostanol: +2.31.5
                                                                                                                                                                                                          sitostanol ester: +2.30.8*
                                                                                                                                                                                                        *P  0.05, relative to run-in
                                                                                                                                                                                                        P  0.05, relative to RSO
                                                                                                                                                                                                         control
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Vanhanen HT, 1992 (Ref.     Placebo-controlled, randomized,     N=24 (M and F) (control group n=  (1) Rapeseed oil control;         6 week run-in on rapeseed oil     On average 50 g of visible        Percent change in cholesterol at
 64) (same as or partial     double-blind study.                8; sitosterol group n= 9;         (2) Sitosterol: 0.625 or 0.722 g/  spread; 9 week period.            dietary fat as butter,            end of 9 week study period,
 study of Miettinen TA,                                         sitostanol group n=7)              d;                                                                  margarine, milk fat, sausages     relative to control:
 1994 (Ref. 63))                                                hypercholesterolemic individuals  (3) Sitostanol:0.630 g/d                                             and cheeses was replaced by the  Total-C
                                                                (serum cholesterol> 232 mg/dL).   --in 50 g/d of rapeseed oil                                          fat spread.                        sitosterol group: -7.6 (NS)
                                                                                                   mayonnaise; plant sterols/                                         Dietary intake during study:        sitostanol group: -9.7 (NS)
                                                                                                   stanols are not esterified.                                          Total fat: NR                   Cholesterol at end of study (mg/
                                                                                                  Sterol source: rapeseed oil.                                          Saturated fat: NR                dL):
                                                                                                                                                                        Cholesterol: NR                 Total-C
                                                                                                                                                                                                          control: 23910
                                                                                                                                                                                                          sitosterol group: 22113
                                                                                                                                                                                                          sitostanol group: 2169
                                                                                                                                                                                                        all NS
                                                                                                                                                                                                        LDL-C: NR
                                                                                                                                                                                                        HDL-C: NR
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


[[Page 54726]]

    Table 1. Plant Sterol Esters and CHD-continued
    Acronyms and Abbreviations Used in Table
    d  day
    d  deciliter
    CI  confidence interval
    F  female
    g  gram
    HDL-C  serum high density lipoprotein cholesterol level
    LDL-C  serum low in density lipoprotein cholesterol level
    M  male
    mg  miligram
    N  number
    NCEP  National Cholesterol Education Program
    NR  not reported
    NS  not statistically significant
    %   percent
    P   probability of type 1 error
    PSE  phytosterol ester
    TE  total energy
    Total-C  serum total cholesterol level
    RSO  rapseed oil (or canola oil)
    X  times

[[Page 54727]]



                                                    Table 2.--Plant Stanol Esters and CHD (studies are listed in reverse chronological order)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
       Study                   Design                     Population            Plant stanol: dose/form              Duration                 Dietary intakes                  Results
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Hallikainen MA,     Randomized single-blind,     N= 22 (M/F)                  (1) Control;                 Run-in duration: 1 week      Subjects followed a          Cholesterol after test (mg/
 2000 (Ref. 88)     crossover design (dose-       hypercholesterolemic        (2) Plant stanol esters       period; 5 test periods of    standardized background      dL):
                     dependent study).            subjects; inclusion         1.4 g/d, (0.8 g/d free);      4 weeks each; no washout     diet throughout the study.  Total-C
                                                  criteria: serum total       (3) Plant stanol esters       between periods.            Dietary intake during          control: 25240
                                                  ranging from 193.5 to 329   (4) Plant stanol esters                                   Total fat (% TE)               1.4 g/d: 24545
                                                  266 50 mg/dL).              (5) Plant stanol esters                                    minus>4.9                     2.7 g/d: 23538*
                                                                              --in 25 g of margarine                                     minus>4.9                     4.1 g/d: 22536*
                                                                               portions with meals.                                      minus>4.3                     5.4 g/d: 22330*
                                                                              All subjects followed the                                  minus>5.4                   LDL-C
                                                                               same dosage order; the                                     5.4 g/d: 33.54.2                    minus>37
                                                                               randomly determined as                                   Saturated fat (% TE)           1.4 g/d: 16839
                                                                               (control) and 0.8 g/d.                                    minus>2.2                     2.7 g/d: 16134
                                                                                                                                         minus>1.9                     4.1 g/d: 15329*
                                                                                                                                         minus>1.3                     5.4 g/d: 15127*
                                                                                                                                         minus>2.1                   HDL-C
                                                                                                                                          5.4 g/d: 9.312
                                                                                                                                         minus>2.2                     1.4 g/d: 5812
                                                                                                                                        Cholesterol (mg/d)             2.7 g/d: 5912
                                                                                                                                          control: 158                 4.1 g/d: 5814
                                                                                                                                          1.4 g/d: 179                 5.4 g/d: 5812
                                                                                                                                          2.7 g/d: 155               Percent change, relative to
                                                                                                                                          4.1 g/d: 153                control:
                                                                                                                                          5.4 g/d: 177               Total-C
                                                                                                                                                                       1.4 g/d: -2.8%
                                                                                                                                                                       2.7 g/d: -6.8% *
                                                                                                                                                                       4.1 g/d: -10.3% *
                                                                                                                                                                       5.4 g/d: -11.3% *
                                                                                                                                                                     LDL-C
                                                                                                                                                                       1.4 g/d: -1.7%
                                                                                                                                                                       2.7 g/d: -5.6%
                                                                                                                                                                       4.1 g/d: -9.7% *
                                                                                                                                                                       5.4 g/d: -10.4% *
                                                                                                                                                                     *P 20 0.001 or
                                                                                                                                                                      P  0.05 vs control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Jones PJ, 2000      Randomized double-blind      N=15 (M)                     (1)Control;                  Run-in period NR; 21 days    Subjects consumed a fixed    Percent change in
 (Ref. 58)           crossover balanced Latin     hypercholesterolemic        (2) Phytosterol esters2.94    duration on each phase:      intake North American        cholesterol from control
                     square design.               subjects; plasma total       g/d (1.84 g/d free);         margarine control,           solid foods diet in a        at day 21:
                                                  cholesterol concentrations  (3) Phytostanol esters3.31    phytosterol ester            controlled feeding          Total-C
                                                  ranging from 232 mg/dL to    g/d (1.84 g/d free)          margarine, and phytostanol   situation; diets              phytosterol esters: -9.1
                                                  387 mg/dL.                  --in 23 g of margarine        ester margarine; each        formulated to meet            phytostanol esters: -5.5
                                                 Means at day 0:               (margarine consumed 3X/d     phase followed by a 5-week   Canadian recommended        LDL-C
                                                 (1) Control group 2509 mg/dL               Stanol source: vegetable                                  Dietary intake during         *
                                                 (2) Phytosterol ester         oil.                                                      study:                        phytostanol esters: -6.4*
                                                  group: 2477 mg/                                                           Total fat (% TE): 35         HDL-C
                                                  dL                                                                                    Saturated fat (% TE): 10       phytosterol esters: 0
                                                 (3) Phytostanol ester group                                                            Cholesterol (mg/d): NR         phytostanol esters: 0
                                                  2477 mg/dL                                                                                             P 0.005, *P 0.02, relative
                                                                                                                                                                      to control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54728]]

 
Plat J, 2000 (Ref.  Randomized double-blind,     N= 112 (41 M/71 F) non-      (1) Control;                 Run-in duration: 4 weeks;    Subjects consumed usual      Change in cholesterol from
 92)                 placebo-controlled study.    hypercholesterolemic        (2) Pine wood stanol esters   experimental period: 8       habitual diet with the       run-in to experimental
                                                  subjects (control N= 42,     6.8 g/d (4 g/d free);        weeks.                       exception that 30 g of       period (mg/dL):
                                                  pine wood stanol esters N=  (3) Vegetable oil stanol                                   test margarine and          Total-C
                                                  34, vegetable oil stanol     esters 6.8 g/d (3.8 g/d                                   shortening replaced 30 g      control: -1.615.5
                                                 criteria: serum total        --in 20 g of rapeseed oil                                 Dietary intake during          wood stanol esters: -
                                                  cholesterol concentrations   margarine plus 10 g of                                    study:                       16.315.1*
                                                   252 mg/dL.                  rapeseed oil shortening                                  Total fat (% TE)               vegetable stanol esters:
                                                                               per day.                                                   control: 39.210.8*
                                                                              Stanol source: pine wood                                   minus>4.2                   LDL-C
                                                                               based or vegetable oil.                                    wood stanol esters:          control: -2.33.8          minus>14.3
                                                                                                                                          vegetable stanol esters:     wood stanol esters: -
                                                                                                                                         40.14.1          15.913.9*
                                                                                                                                        Saturated fat (% TE)           vegetable stanol esters:
                                                                                                                                          control: 14.310.1*
                                                                                                                                         minus>2.0                   HDL-C
                                                                                                                                          wood stanol esters:          control: 0.41.6          minus>6.2
                                                                                                                                          vegetable stanol esters:     wood stanol esters:
                                                                                                                                         13.62.2          0.45.0
                                                                                                                                        Cholesterol (mg/d)             vegetable stanol esters:
                                                                                                                                          control: 221.5              0.04.3
                                                                                                                                          wood stanol esters: 238.5  Percent change, relative to
                                                                                                                                          vegetable stanol esters:    control:
                                                                                                                                         239.5                       Total-C
                                                                                                                                                                       wood stanol esters: -
                                                                                                                                                                      8.17.5%*
                                                                                                                                                                       vegetable stanol esters:
                                                                                                                                                                      8.6 5.1%*
                                                                                                                                                                     LDL-C
                                                                                                                                                                       wood stanol esters: -
                                                                                                                                                                      12.811.2%*
                                                                                                                                                                       vegetable stanol esters:
                                                                                                                                                                      14.6 8.0%*
                                                                                                                                                                     * P  0.001 relative to
                                                                                                                                                                      control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54729]]

 
Andersson A, 1999   Randomized double-blind      N= 61 (28 M/33 F)            (1) Controlled lipid-        Run-in period: 4 weeks;      Subjects consumed either     Percent change in
 (Ref. 80)           study.                       moderately                   lowering diet (test diet)    experimental period: 8       usual diet (control diet)    cholesterol from baseline:
                                                  hypercholesterolemic         + low fat margarine          weeks.                       or controlled feeding       Total-C
                                                  subjects                     (control margarine);                                       lipid lowering diet (test    test diet+control
                                                 ((1) test diet+control       (2) Controlled lipid-                                      diet) during study.          margarine: -8*
                                                  margarine: N= 21             lowering diet (test diet)                                Calculated /food analysis      test diet+test margarine:
                                                 (2) test diet+test            + a low fat 3.4 g/d stanol                                nutrient composition of      -15*
                                                  margarine: N= 19             ester (2g/d free)-                                        test diet:                    control diet+test
                                                 (3) usual diet+test           containing margarine (test                                 Total fat (%TE): 35         margarine: -9*
                                                  margarine: N= 21);           margarine);                                                Saturated fat (%TE): 8     LDL-C
                                                  inclusion criteria: serum   (3) Usual diet (control                                     Cholesterol(mg/d): 171       test diet+control
                                                  total cholesterol levels     diet)+ a low fat 3.4 g/d                                 Estimated (dietary records)   margarine: -12*
                                                  at screening >194 mg/dL;     stanol ester (2g/d free)-                                 nutrient composition of       test diet+test margarine:
                                                  mean serum cholesterol at    containing margarine (test                                control diet:                -19*
                                                  baseline: 26444; exclusion         --in 25 g/d (use 3X per                                    31.84.6          margarine: -12*
                                                  criteria: serum              day) of low fat (40% fat)                                  Saturated fat (%TE):       HDL-C
                                                  cholesterol > 330 mg/dL at   margarine made from low                                   11.92.2           test diet+control
                                                  screening.                   erucic acid rapeseed                                       Cholesterol (mg/d):         margarine: -4
                                                                               (canola) oil.                                             279104            test diet+test margarine:
                                                                              Stanol source: NR.                                                                      -7 
                                                                                                                                                                       control diet+test
                                                                                                                                                                      margarine: 0
                                                                                                                                                                     *P  0.0001; P
                                                                                                                                                                      0.0005, relative to
                                                                                                                                                                      baseline
                                                                                                                                                                     Percent change (P value)
                                                                                                                                                                      for differences between
                                                                                                                                                                      test diet+test margarine
                                                                                                                                                                      relative to test
                                                                                                                                                                      diet+control margarine:
                                                                                                                                                                     Total-C: -12% (P  -0.0035)
                                                                                                                                                                     LDL-C: -15% (P  -0.0158)
                                                                                                                                                                     HDL-C: 0% (P  0.1226)
                                                                                                                                                                     Percent change (P value)
                                                                                                                                                                      for differences between
                                                                                                                                                                      test diet+test margarine
                                                                                                                                                                      relative to usual diet+
                                                                                                                                                                      test margarine:
                                                                                                                                                                     Total-C: -4% (P  0.0059)
                                                                                                                                                                     LDL-C: -6% (P  0.0034)
                                                                                                                                                                     HDL-C: -6% (P  0.0-3)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54730]]

 
Gylling H, 1999     Margarine study: randomized  N=23 during margarine        (1) Sitostanol ester         Run-in period: 1 week; the   Subjects were advised to     Cholesterol at end of
 (Ref. 78)           double-blind crossover       period, N= 21 during         margarine 5.4 g/d (3.18 g/   margarine interventions      replace 25 g of their        period (mg/dL):
                     study; after the margarine   butter period; moderately    day free) (wood oil);        lasted 6 weeks, the butter   normal dietary fat with     Total-C
                     period the same women were   hypercholesterolemic        (2) Campestanol ester         interventions lasted 5       stanol ester margarine or     run-in home diet:
                     randomized to the Butter     postmenopausal women;        margarine 5.7 g/d (3.16 g/   weeks; a washout period of   butter with or without       2356
                     study, which is a            inclusion criteria: serum    d free) (vegetable oil);     8 weeks separated the        stanol esters.                sitostanol ester
                     randomized double-blind       cholesterol between 213    (3) Butter control;            margarine and butter       Dietary intake during         margarine: 2247*
                                                                               4.1 g/d (2.43 g/d free)                                  Total fat (g/d)                campestanol ester
                                                                               (wood oil)                                                 margarine period: 936                      minus>7*
                                                                               butter.                                                    butter period: 976                      minus>8*
                                                                               vegetable oil.                                           Saturated fat                  sitostanol ester butter:
                                                                                                                                          margarine period: NR        2287 
                                                                                                                                          butter period: NR          LDL-C
                                                                                                                                        Cholesterol (mg/d)             run-in home diet:
                                                                                                                                          margarine period:           1545
                                                                                                                                         26219             sitostanol ester
                                                                                                                                          butter period: 32319                     minus>5*
                                                                                                                                                                       campestanol ester
                                                                                                                                                                      margarine: 1397*
                                                                                                                                                                       butter control: 1617
                                                                                                                                                                       sitostanol ester butter:
                                                                                                                                                                      1436
                                                                                                                                                                     HDL-C
                                                                                                                                                                       run-in home diet: 603.5
                                                                                                                                                                       sitostanol ester
                                                                                                                                                                      margarine: 634*
                                                                                                                                                                       campestanol ester
                                                                                                                                                                      margarine: 633*
                                                                                                                                                                       butter control: 634*
                                                                                                                                                                       sitostanol ester butter:
                                                                                                                                                                      634
                                                                                                                                                                     Percent change from butter
                                                                                                                                                                      control:
                                                                                                                                                                     Total-C
                                                                                                                                                                       sitostanol ester butter:
                                                                                                                                                                      8%
                                                                                                                                                                     LDL-C
                                                                                                                                                                       sitostanol ester butter:
                                                                                                                                                                      12%
                                                                                                                                                                     *Significantly different
                                                                                                                                                                      from run-in home diet, P
                                                                                                                                                                      0.05;
                                                                                                                                                                     Significantly
                                                                                                                                                                      different from butter, P
                                                                                                                                                                      0.05
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54731]]

 
Hallikainen MA,     Randomized double-blind,     N= 55 (M/F);                 (1) Control margarine;       Run-in period: 4 week;       Subjects consumed the        Change in cholesterol from
 1999 (Ref. 77)      placebo-controlled,          hypercholesterolemic        (2) WSEM 3.9 g/d (2.31 g/d    experimental period: 8       margarines as part of a      week 0 to week 8 (mg/dL):
                     parallel study.              subjects                     free);                       weeks.                       diet resembling that of     Total-C
                                                 ((1)control margarine N= 6   (3) VOSEM 3.9 g/d (2.16 g/d                                the National Cholesterol      control: -18.619
                                                 (2) wood stanol ester-       --in 25 g low-erucic acid                                  II diet.                      WSEM: -46.823.6*
                                                  (WSEM) N= 8 M, 10 F,         35% fat) margarine per                                    study:                        VOSEM: -3822.8
                                                  ester-containing margarine  Stanol source: wood or                                      control: 26.53.1                     control: -17.43.3   minus>22.8
                                                  total cholesterol                                                                       VOSEM: 25.617
                                                  concentrations between 2-                                                              minus>3.9                     VOSEM: -3119.4
                                                  cholesterol at baseline,                                                                control: 7.31.6                     control: 0.41.4    minus>5.8
                                                  minus>25                                                                                VOSEM: 6.81.7    WSEM: -1.26.6
                                                 WSEM group 2467
                                                  minus>29; VOSEM group                                                                   control: 135               Percent change, relative to
                                                  23831.                                                                      WSEM: 164                   control:
                                                                                                                                          VOSEM: 139                 Total-C
                                                                                                                                                                       WSEM: -10.6%*
                                                                                                                                                                       VOSEM: -8.1%
                                                                                                                                                                     LDL-C
                                                                                                                                                                       WSEM: 13.7%
                                                                                                                                                                       VOSEM: 8.6%
                                                                                                                                                                     Significantly different
                                                                                                                                                                      from control group: *P
                                                                                                                                                                      0.001, P  0.05,
                                                                                                                                                                     P  0.01
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Jones PJH, 1999     Randomized double-blind      N=32(M)                      (1) Control;                 No run-in period;            Controlled feeding regimen   Day 30 cholesterol (mg/dL):
 (Ref. 74)           placebo-controlled,         hypercholesterolemic         (2) Sitostanol-containing     experimental period: 30      for all subjects, a         Total-C
                     parallel study.              subjects (N= 16 control      phytosterols (20%            days; 20 days followup       `prudent,' fixed-food         control: 23656
                                                  group); inclusion criteria   plant sterols are                                         formulated to meet            sitostanol-containing
                                                  serum total cholesterol      sitosterol, campesterol)                                  Canadian recommended         phytosterols: 21036
                                                  to 387 mg/dL; mean          --in 30 g/d of margarine                                  Dietary intake during        LDL-C
                                                  cholesterol at baseline,     consumed during 3 meals;                                  study:                        control: 17652
                                                  263.550,         esterified.                                                Saturated fat (% TE): 11%    sitostanol-containing
                                                  phytosterol group 260.5     Sterol source: tall oil                                     Cholesterol (mg/d): NR      phytosterols: 13044.5.            (derived from pine wood)                                                               minus>36
                                                                                                                                                                     (p  0.05 relative to
                                                                                                                                                                      control group)
                                                                                                                                                                     HDL-C
                                                                                                                                                                       control: 237
                                                                                                                                                                       sitostanol-containing
                                                                                                                                                                      phytosterols: 267
                                                                                                                                                                     Day 0 to day 30 (% change):
                                                                                                                                                                     LDL-C
                                                                                                                                                                       control: -8.9%, P  0.01
                                                                                                                                                                       sitostanol-containing
                                                                                                                                                                      phytosterols: -24.4%, P
                                                                                                                                                                      0.001
                                                                                                                                                                       sitostanol-containing
                                                                                                                                                                      phytosterols:
                                                                                                                                                                       -15.5%, P 0.05, relative
                                                                                                                                                                      to control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54732]]

 
Nguyen TT, 1999     Multicenter, randomized      N= 298 (51% M/ 49% F)        (1) Control: US              Run-in period: 4 weeks;      Usual dietary habits         Percent change in
 (Ref. 90)           double-blind, placebo-       mildly                       reformulation of vegetable   experimental period: 8       maintained, but some         cholesterol from baseline
                     controlled parallel study.   hypercholesterolemic         oil spread;                  weeks.                       subjects on a NCEP Step I    to week 8:
                                                  subjects;                    (2) EU 3G: 5.1 g/d stanol                                 diet, so background diets   Total-C
                                                 ((1) control N= 76, (2) EU    esters (3g/d free)                                        varied, but diet            control: 0.5*
                                                  3G N=74, (3) US 3G N= 71,    European formulation of                                   composition reported not    EU 3G: -4.7*
                                                  (4) US 2G N= 77);            vegetable oil spread;                                     to differ among the four    US 3G: -6.4*
                                                 inclusion criteria serum     (3) US 3G: 5.1 g/d stanol                                  groups.                     US 2G: -4.1*
                                                  total cholesterol            esters (3 g/d free) US                                   Dietary intake during        LDL-C
                                                  concentrations between 200   reformulation of vegetable                                study:                      control: 0.1*
                                                  to 280 mg/dL; mean           oil spread;                                              Total fat (% TE): 32.8       EU 3G: -5.2*
                                                  baseline total              (4) US 2G: 3.4 g/d stanol                                  (6.8)                       US 3G: -10.1*
                                                  cholesterol: 23320 mg/dL.              reformulation of vegetable                                (3.0)                       HDL-C
                                                                               oil spread                                               Cholesterol (mg/d): 234      control: 2.0
                                                                              --in 24 g/d spread (three 8                                (147)                       EU 3G: 0.0
                                                                               g servings a day).                                                                    US 3G: 0.0
                                                                              Stanol source: wood.                                                                   US 2G: 0.0
                                                                                                                                                                     *P  0.001, relative to
                                                                                                                                                                      baseline
                                                                                                                                                                     Total-C (P  0.001) and LDL-
                                                                                                                                                                      C (P 0.02) levels were
                                                                                                                                                                      significantly reduced in
                                                                                                                                                                      all 3 active-ingredient
                                                                                                                                                                      groups compared with the
                                                                                                                                                                      placebo group at all time
                                                                                                                                                                      points during the
                                                                                                                                                                      ingredient phase. (see
                                                                                                                                                                      figures in paper for
                                                                                                                                                                      values)
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54733]]

 
Weststrate JA,      Randomized double-blind      N= 95 (100 enrolled= 50 M/   (1) Control (Flora spread);  Run-in of 5 days; each       Volunteers were requested    Percent change in
 1998 (Ref. 67)      crossover balanced           50 F) but approximately 80  (2) Plant stanol esters 4.6   subject consumed 4           to retain their normal       cholesterol at end of 3.5
                     incomplete Latin square      subjects for each            g/d (2.7 g/d free);          margarines for a period of   dietary pattern.             weeks, relative to
                     design with 5 margarines,    margarine (incomplete       (3) Soybean sterol esters     3.5 weeks each; wash-out    Dietary intake during         control:
                     4 periods of 3.5 weeks.      Latin square design= 5       4.8 g/d (3 g/d free);        period between               study:                      Total-C
                                                  margarines in four          (4) Ricebran sterols 1.6 g/   experimental periods- NR.   Total fat (% TE)               plant stanol esters: -
                                                  periods);                    d free;                                                    control: 42                 7.3*
                                                  normocholesterolemic and    (5) Sheanut sterols 2.9 g/d                                 plant stanol esters: 41.8    soybean sterol esters: -
                                                  mildly hyperchol-            free                                                       soybean sterol esters:      8.3*
                                                  esterolemic subjects;       --in 30 g/d of margarine,                                  41.5                          ricebran sterols: -1.1
                                                  inclusion criteria at        consumption at lunch and                                   ricebran sterols: 41.4       sheanut sterols: -0.7
                                                  baseline for total plasma    dinner; margarines                                         sheanut sterols: 41.3      LDL-C
                                                  cholesterol concentration:   replaced margarines                                      Saturated fat (%TE)            plant stanol esters: -13*
                                                   310 mg/dL (baseline total   habitually used.                                           control: 15.9                soybean sterol esters: -
                                                  cholesterol: mean 207       Stanol source: wood.                                        plant stanol esters: 16.2   13*
                                                  41mg/dL).                                                                   soybean sterol esters:       ricebran sterols: -1.5
                                                                                                                                         15.3                          sheanut sterols: -0.9
                                                                                                                                          ricebran sterols: 15.4     HDL-C
                                                                                                                                          sheanut sterols: 16.9        plant stanol esters: 0.1
                                                                                                                                        Cholesterol (mg/d)             soybean sterol esters:
                                                                                                                                          control: 233                0.6
                                                                                                                                          plant stanol esters: 243     ricebran sterols: -1.3
                                                                                                                                          soybean sterol esters:       sheanut sterols: -1.2
                                                                                                                                         226                         *P 0.05
                                                                                                                                          ricebran sterols: 233
                                                                                                                                          sheanut sterols: 227
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Niinikoski H, 1997  Randomized double-blind,     N=24 (M/F)                   (1) Control;                 No run-in period;            Subjects were advised to     Cholesterol change from
 (Ref. 91)           placebo-controlled study.    normocholesterolemic        (2) Sitostanol ester 5.1 g/   experimental period: 5       replace normal dietary fat   baseline to 5 weeks (mg/
                                                  subjects (N=12 (4 M/8 F)     d (3 g/d free);              weeks.                       for 5 weeks with the study   dL):
                                                  control, N=12 (4 M/8 F)     --in 24 g of a RSO based                                   margarine; the amount and   Total-C
                                                  sitostanol ester);           margarine to be used on                                   quality of ingested fat     control: -11.619.4
                                                  cholesterol: 19738.7 mg/dL.            portions over the day.                                   Dietary intake during         minus>19.4*
                                                                              Stanol source: NR.                                         study:                      Non-HDL-C
                                                                                                                                        Total fat: NR                control: -11.619.4
                                                                                                                                        Cholesterol: NR              sitostanol ester: -3123*
                                                                                                                                                                     HDL-C
                                                                                                                                                                     control: -1.5 6.6
                                                                                                                                                                     sitostanol ester: -2.34.6
                                                                                                                                                                     *P 0.05, relative to
                                                                                                                                                                      control

[[Page 54734]]

 
Denke MA., 1995     Fixed sequence design with   N= 33 (M) moderate           (1) Control (Step 1 Diet     1 month run-in on Step I     Subjects were instructed to  Cholesterol, at end of each
 (Ref. 97)           three sequential             hypercholesterolemic         alone);                      Diet; experimental           follow a cholesterol-        period (mg/dL):
                     experimental periods.        subjects; total             (2) Plant stanol 3 g/d +      periods: 3 months in         lowering diet in which      Total-C
                                                  cholesterol concentration    Step 1 Diet;                 duration; washout period:    dietary cholesterol was     control: 23929
                                                  after run-in period:        (3) Washout (Step 1 Diet      1 month.                     restricted to  200 mg/d     plant stanol + Step I Diet:
                                                  23929.           alone)                                                    (Step I Diet).              23831
                                                                              --plant stanol was                                        Dietary intake (self-        washout: 24429
                                                                               suspended in safflower oil                                reported intake):           LDL-C
                                                                               and packed into gelatin                                  Total fat (%TE): 30          control: 17526
                                                                               capsules, each capsule                                   Saturated fatty acids        plant stanol + Step I Diet:
                                                                               containing 250 mg                                         (%TE): 10                   17231
                                                                               sitostanol and 1 g of                                    Cholesterol (mg/d): 188      washout: 18130
                                                                               safflower oil; subjects                                                               HDL-C
                                                                               instructed to consume 4                                                               control: 3911
                                                                               capsules per meal                                                                     plant stanol + Step I Diet:
                                                                               (subjects were to consume                                                             4112
                                                                               a total of 12 capsules (3                                                             washout: 3911
                                                                               g) in three divided doses                                                             NS differences between any
                                                                               during three meals); plant                                                             period.
                                                                               stanols not esterified.
                                                                              Stanol source: tall oil.
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54735]]

 
Miettinen TA, 1995  Randomized double-blind,     N= 153 (42% M/ 58% F) (N=    (1) Control margarine;       Run-in period: 6 weeks;      During the study subjects    Cholesterol concentration
 (Ref. 89)           placebo-controlled study.    51 control margarine,       (2) Sitostanol ester 5.1 g/   experimental period: 1       were advised to replace 24   at 1 year (mg/dL):
                                                  N=102 test margarine) mild   d (3 g/d free) for 1 year;   year; after 6 months the     g per day of their normal   Total-C
                                                  hypercholesterolemic        (3) Sitostanol ester 5.1 g/   sitostanol-ester group was   dietary fat with a          control: 2374
                                                  subjects; inclusion          d (3 g/d free) for 6         randomly reassigned either   margarine containing RSO,   4.4 g/d stanol ester:
                                                  criteria: serum              months, followed by          to continue their intake     according to careful         2104*
                                                  cholesterol concentration    sitostanol ester 3.4 g/d     of 4.4 g/d of sitostanol     instructions from a         3.1 g/d stanol ester:
                                                  216 mg/dL.       (2 g/d free) for next 6      ester (N= 51) or to reduce   qualified nurse, otherwise   2144*
                                                                               months                       their intake to 3.1 g/d      typical ad libitum diet     LDL-C
                                                                              --in 24 g/d margarine.        (N= 51); subjects were not   during study.               control: 1574
                                                                              Actual intake of sitostanol   informed of this change in  Dietary intake during        4.4 g/d stanol ester:
                                                                               ester                        sitostanol ester intake.     study:                       1343*
                                                                              for 5.1 g/d: 4.4 g/d                                      Total fat (%TE)              3.1 g/d stanol ester:
                                                                              for 3.4 g/d: 3.1 g/d.                                     control: 34.93*
                                                                              Stanol source: wood.                                       minus>0.9                   HDL-C
                                                                                                                                        4.4 g/d stanol ester:        control: 542
                                                                                                                                         35.70.8         4.4 g/d stanol ester:
                                                                                                                                        3.1g/d stanol ester:          531
                                                                                                                                         34.80.9         3.1 g/d stanol ester:
                                                                                                                                        Saturated fat (%TE)           582
                                                                                                                                        control: 13.90.5                    baseline
                                                                                                                                        4.4 g/d stanol ester:        Mean change after 1 year
                                                                                                                                         14.40.4          (mg/dL):
                                                                                                                                        3.1 g/d stanol ester:        Total-C
                                                                                                                                         14.30.7         control: -1
                                                                                                                                        Cholesterol (mg/d)           4.4 g/d stanol ester: -25*
                                                                                                                                        control: 31427   (difference -24 (95% CI: -
                                                                                                                                        4.4 g/d stanol ester:         17 to -32))
                                                                                                                                         34037           LDL-C
                                                                                                                                        3.1 g/d stanol ester:        control: -3
                                                                                                                                         30820           4.4 g/d stanol ester: -24*
                                                                                                                                                                     (difference -21 (95% CI: -
                                                                                                                                                                      14 to -29))
                                                                                                                                                                     HDL-C
                                                                                                                                                                     control: 0.0
                                                                                                                                                                     4.4 g/d stanol ester: 0.4
                                                                                                                                                                     *P  0.001, relative to
                                                                                                                                                                      control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54736]]

 
Miettinen, T A,     Randomized placebo-          N= 31 (22 M/ 9 F) (control   (1) RSO control;             6 week run-in period; 9      No diet changes other than   Change in cholesterol from
 1994 (Ref. 63)      controlled, double-blind     N= 8; sitosterol N= 9;      (2) Sitosterol 0.7 g/d;       week study period.           replacing 50 g of typical    end of run-in period to
 (same as or         study.                       sitostanol N= 7;            (3) Sitostanol 0.7 g/d;                                    daily fat by 50 g of RSO     end of 9 week study period
 partial study of                                 sitostanol ester N= 7);     (4) Sitostanol ester 1.36 g/                               mayonnaise.                  (mg/dL):
 Vanhanen HT, 1992                                hypercholesterolemic         d (0.8 g/d free)                                         Dietary intake at end of     Total-C
 (Ref. 64))                                       subjects; inclusion         --in 50 g/d of RSO                                         study for all subjects:     RSO control: 4.64.3
                                                  total serum cholesterol     Stanol source: NR.                                        1149             sitosterol: -7.7 232 mg/                                                              Saturated fat (% of total     minus>5.0
                                                  dL.                                                                                    fat)                        sitostanol: -0.40.7%          minus>5.4
                                                                                                                                        Cholesterol (mg/d)           sitostanol ester: -7.428             minus>3.1
                                                                                                                                                                     LDL-C
                                                                                                                                                                     RSO control: 3.14.3
                                                                                                                                                                     sitosterol: -7.04.3
                                                                                                                                                                     sitostanol: -1.24.6
                                                                                                                                                                     sitostanol ester: -7.73.1*
                                                                                                                                                                     HDL-C
                                                                                                                                                                     RSO control: 2.31.2
                                                                                                                                                                     sitosterol: 0.001.5
                                                                                                                                                                     sitostanol: 2.31.5
                                                                                                                                                                     sitostanol ester: 2.30.8*
                                                                                                                                                                     *P  0.05, relative to run-
                                                                                                                                                                      in
                                                                                                                                                                     P  0.05, relative
                                                                                                                                                                      to RSO control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54737]]

 
Vanhanen HT, 1994   Randomized double-blind,     N= 15 (11M/ 4 F) mildly      (1) Control (RSO             Run-in period: 6 weeks;      Subjects replaced 50 g of    Cholesterol change from
 (Ref. 94)           placebo-controlled study.    hypercholesterolemic         mayonnaise);                 experimental period: 15      their usual dietary fat by   baseline (mg/dL):
                                                  subjects (N= 8 control      (2) Sitostanol ester 1.36 g/  weeks; lower dose            50 g of RSO mayonnaise,     Total-C
                                                  group,                       d (0.8 g/d free);            sitostanol for 9 weeks,      otherwise usual diet.       control: 55
                                                 N= 7 sitostanol group);      (3) Sitostanol ester 3.4 g/   followed by higher dose     Dietary intake during run-   1.36 g/d: -7.43.1
                                                  selection criteria > 232    --in 50 g/d of RSO                                         similar to the              control: 8.15.4
                                                  mg/dL.                       mayonnaise.                                               experimental period):       3.4 g/d: -11.2
                                                                              Stanol source: NR.                                        Total fat (g/d):               3.5*
                                                                                                                                          control group: 124         LDL-C
                                                                                                                                          sitostanol group: 118      control: 3.14.6
                                                                                                                                        Saturated fat:               1.36 g/d: -7.73.1*
                                                                                                                                          sitostanol group: NR       control: 5.85.4
                                                                                                                                        Cholesterol (mg/day):        3.4 g/d: -15.12.7*
                                                                                                                                          sitostanol group: 265      HDL-C
                                                                                                                                                                     control: 2.31.2
                                                                                                                                                                     1.36 g/d: 2.30.8
                                                                                                                                                                     control: 0.81.9
                                                                                                                                                                     3.4 g/d: 2.71.5
                                                                                                                                                                     Percent change, relative to
                                                                                                                                                                      control:
                                                                                                                                                                     Total-C
                                                                                                                                                                     1.36 g/d: -4.1%
                                                                                                                                                                     3.4 g/d: -9.3%
                                                                                                                                                                     TLDL-C
                                                                                                                                                                     1.36 g/d: -10.3%
                                                                                                                                                                     3.4 g/d: -15.2%
                                                                                                                                                                     HDL-C
                                                                                                                                                                     1.36 g/d: 0.5%
                                                                                                                                                                     3.4 g/d: 0%
                                                                                                                                                                     *P  0.05, relative to
                                                                                                                                                                      baseline
                                                                                                                                                                     P  0.05, relative to
                                                                                                                                                                      control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Blomqvist SM, 1993  Randomized double-blind,     N= 67 (47 M/ 20 F)           (1) Control (RSO             Run-in period: 4 weeks;      Subjects replaced 50 g of    Cholesterol after 6 weeks
 (Ref. 81)           placebo-controlled study.    moderately                   mayonnaise);                 experimental period: 6       daily fat intake with 50 g   (mg/dL):
(same as Vanhanen                                 hypercholesterolemic        (2) Sitostanol ester 5.8 g/   weeks.                       of RSO mayonnaise; a        Total-C
 HT, 1993 (Ref.                                   subjects (N= 66 in           d (3.4 g/d free)                                          second 7-day diet record    control: 22527
 82))                                              Tables: control N=32;      --in 50 g RSO mayonnaise.                                  performed during the        sitostanol ester: 2-34*
                                                  plasma cholesterol                                                                     indicated that diet         LDL-C
                                                  concentration at baseline:                                                             composition was similar to  control: 13418
                                                  246  33 mg/dL.                                                                 that during the run-in      sitostanol ester: 12432
                                                                                                                                        Dietary intake during the    HDL-C
                                                                                                                                         standardization period      control: 5311
                                                                                                                                         (run-in):                   sitostanol ester: 5112*
                                                                                                                                        Saturated fat (% TE): 12     P  0.01; * P
                                                                                                                                        Cholesterol (mg/d): 270       0.001, relative to control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 54738]]

 
Vanhanen HT, 1993   PRandomized double-blind,    N= 67 (47 M/ 20 F)           (1) Control (RSO             Run-in period: 4 weeks;      Subjects replaced 50 g of    Cholesterol change from
 (Ref. 82)           placebo-controlled study.    moderately                   mayonnaise);                 experimental period: 6       daily fat intake with 50 g   baseline period, mg/dL
 (same as                                         hypercholesterolemic        (2) Sitostanol ester 5.8 g/   weeks.                       of RSO mayonnaise; a         (cholesterol concentration
 Blomqvist SM,                                    subjects; (control N=33;     d (3.4 g/d free)                                          second 7-day diet record     at 6 weeks in mg/dL):
 1993 (Ref. 81))                                  sitostanol ester N=34);     --in 50 g RSO mayonnaise.                                  performed during the        Total-C
                                                  serum cholesterol           Stanol source: NR.                                         experimental period         control: -2.7 232                                                               indicated that diet          minus>2.3 (225)
                                                  mg/dL.                                                                                 composition was similar to  itostanol ester: -17.02.3* (2-)
                                                                                                                                         period.                     LDL-C
                                                                                                                                        Dietary intake during the    control: -1.52.7 (142)
                                                                                                                                         (run-in):                   sitostanol ester: -
                                                                                                                                        Total fat (% TE): 37          14.32.3* (130)
                                                                                                                                        Saturated fat (% TE): 12     HDL-C
                                                                                                                                        Cholesterol (mg/d): 270      control: -1.20.8 (53)
                                                                                                                                                                     sitostanol ester: -1.20.8 (52)
                                                                                                                                                                     *P  0.05, relative to
                                                                                                                                                                      control
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Vanhanen HT, 1992   Placebo-controlled,           N=24 (M and F) (control     (1) RSO control;             6 week run-in on RSO         On average 50 g of visible   Percent change in
 (Ref. 64) (same     randomized double blind      group N= 8; sitosterol      (2) Sitosterol: 0.625 or      spread; 9 week period.       dietary fat as butter,       cholesterol at end of 9
 as or partial       study.                       group N= 9; sitostanol       0.722 g/d;                                                margarine, milk fat,         week study period,
 study of                                         group N=7)                  (3) Sitostanol: 0.630 g/d                                  sausages and cheeses was     relative to control:
 Miettinen, TA,                                   hypercholesterolemic        --in 50 g/d of RSO                                         replaced by the fat         Total-C
 1994 (Ref. 63))                                  individuals (serum           mayonnaise; plant sterols/                                spread.                     sitosterol group: -7.6(NS)
                                                  cholesterol > 232 mg/dL).    stanols are not                                          Dietary intake during        sitostanol group: -9.7(NS)
                                                                               esterified.                                               study:                      At end of study (mg/dL):
                                                                              Stanol source: rapeseed                                   Total fat: NR                Total-C
                                                                               oil.                                                     Saturated fat: NR            control: 23910
                                                                                                                                        Cholesterol: NR              sitosterol group: 22113
                                                                                                                                                                     sitostanol group: 2169
                                                                                                                                                                     all NS
                                                                                                                                                                     LDL-C: NR
                                                                                                                                                                     HDL-C: NR
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


[[Page 54739]]

Table 2.--Plant Stanol Esters and CHD--continued

    Acronyms and Abbreviations Used in Table
    d  day
    dl  deciliter
    CI  confidence interval
    EU  European
    EU 3G  European, 3 grams
    F  female
    g  gram
    HDL-C  serum high density lipoprotein cholesterol level
    LDL-C  serum low density lipoprotein cholesterol level
    M  male
    mg  milligram
    N  number
    NCEP  National Cholesterol Education Program
    NR  not reported
    NS  not statistically significant
    %  percent
    P  probability of type I error
    TE  total energy
    Total-C serum   total cholesterol level
    RSO  rapeseed oil (or canola oil)
    US  United States
    US 2G  United States, 2 grams
    US 3G  United States, 3 grams
    VOSEM  vegetable oil stanol ester-containing margarine
    WSEM  wood stanol ester-containing margarine
    X  times

[FR Doc. 00-22892 Filed 9-5-00; 8:45 am]
BILLING CODE 4160-01-F