[Federal Register Volume 63, Number 217 (Tuesday, November 10, 1998)]
[Proposed Rules]
[Pages 62977-63015]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-30008]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 98P-0683]


Food Labeling: Health Claims; Soy Protein and Coronary Heart 
Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
authorize the use, on food labels and in food labeling, of health 
claims on the association between soy protein and reduced risk of 
coronary heart disease (CHD). FDA is proposing this action in response 
to a petition filed by Protein Technologies International, Inc. (the 
petitioner). The agency has tentatively concluded that, based on the 
totality of publicly available scientific evidence, soy protein 
included in a diet low in saturated fat and cholesterol may reduce the 
risk of CHD.

DATES: Written comments by January 25, 1999.

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: Susan M. Pilch, Center for Food Safety 
and Applied Nutrition (HFS-465), Food and Drug Administration, 200 C 
St. SW., Washington, DC 20204, 202-205-4500.

SUPPLEMENTARY INFORMATION:

I. Background

    On November 8, 1990, the President signed into law the Nutrition 
Labeling and Education Act of 1990 (the 1990 amendments) (Pub. L. 101-
535). This new law amended the Federal Food, Drug, and Cosmetic Act 
(the act) in a 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 
(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 and 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)). These regulations 
became effective on May 8, 1993.
    In response to the 1990 amendments, FDA also conducted an extensive 
review of the evidence on the 10 substance-disease relationships listed 
in the 1990 amendments. As a result of its review, FDA has 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), it authorized a health claim relating diets low in saturated fat 
and cholesterol and high in fruits, vegetables, and grain products that 
contain dietary fiber (particularly soluble fiber) to a reduced risk of 
CHD.
    In the proposed rule entitled ``Health Claims and Label Statements; 
Lipids and Cardiovascular Disease'' (56 FR 60727, November 27, 1991), 
FDA set out the criteria for evaluating evidence on diet and CVD 
relationships. The agency focused on those aspects of the dietary lipid 
and CVD relationship for which the strongest scientific evidence and 
agreement existed. 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 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).
    Based on its review using the stated criteria, and on its 
consideration of comments received in response to the proposed rule 
entitled ``Health Claims; Dietary Fiber and Cardiovascular Disease'' 
(56 FR 60582), FDA concluded that the publicly available scientific 
information supported an association between diets low in saturated fat 
and cholesterol and high in 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 heart disease (58 FR 
2552 at 2572). In the 1993 dietary fiber and CVD final rule, in 
response to a comment regarding the apparent hypocholesterolemic 
properties of specific food fibers, FDA again articulated its criteria 
for evaluating diet and CHD relationships (58 FR 2552 at 2567). FDA 
agreed that

[[Page 62978]]

the effectiveness of naturally occurring fibers in foods in reducing 
the risk of CHD may be documented for specific food products. Further, 
the agency indicated that if manufacturers could document, through 
appropriate studies, that dietary consumption of the soluble fiber in a 
particular food has a beneficial effect on blood lipids predictive of 
CHD risk, they should petition for a health claim for that particular 
product. In response to two petitions that documented such evidence, 
FDA has 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, and 62 FR 8119, February 18, 1998).
    The present rulemaking is in response to a manufacturer's health 
claim petition on the relationship between soy protein and the risk of 
CHD.

II.  Petition for Soy Protein and Reduced Risk of CHD

A. Background

    On May 4, 1998, Protein Technologies International, Inc., submitted 
a health claim petition to FDA requesting that the agency authorize a 
health claim on the relationship between consumption of soy protein and 
the risk of CHD (Refs. 1 and 2). On August 12, 1998, the agency sent 
the petitioner a letter stating that it had completed its initial 
review of the petition, and that the petition would be filed in 
accordance with section 403(r)(4) of the act (21 U.S.C. 343(r)(4)) 
(Ref. 3). In this proposed rule, the agency presents the rationale for 
a health claim on this food-disease relationship as provided for under 
the standard in section 403(r)(3)(B)(i) of the act and Sec. 101.14(c) 
of FDA's regulations.

B. Review of Preliminary Requirements for a Health Claim

1. The Substance Is 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, specifically claims for dietary 
saturated fat and cholesterol and risk of CHD (Sec. 101.75 (21 CFR 
101.75)); fruits, vegetables, and grain products and risk of CHD 
(Sec. 101.77 (21 CFR 101.77)); and soluble fiber from certain foods and 
risk of CHD (Sec. 101.81). 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 
and mortality (Refs. 4 through 6). There are more than 500,000 deaths 
each year for which CHD is an underlying 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) 
per (/) deciliter (dL) and LDL-cholesterol greater than 160 mg/dL) 
(Ref. 7). 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 risk 
factors.
    CHD has a significant effect on health-care costs. In 1985, total 
direct costs related to CHD were estimated at $13 billion, and indirect 
costs from loss of productivity due to illness, disability, and 
premature deaths from this disease were an estimated $36 billion (Ref. 
4). Based on these facts, FDA tentatively 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 Substance Is a Food
    The substance that is the subject of this rulemaking is soy protein 
(Ref. 1). Soy protein is an edible component of the soybean, Glycine 
max. Soybeans are a significant source of low-cost, high-quality 
protein in the human diet.
    Soy protein is used as an ingredient in other foods. It is produced 
from raw whole soybeans by a multistep process that removes the lipid 
and indigestible components to concentrate the protein and increase its 
availability. Depending upon the particular steps used during 
processing, soy protein ingredients may take the form of isolated soy 
protein (ISP), soy protein concentrate (SPC), or soy flour (SF). Each 
of these ingredients may be further processed into texturized soy 
protein or texturized vegetable protein (TVP), used in the manufacture 
of meat and poultry analogs, by thermoplastic extrusion or steam 
texturization to impart structure and shape. In addition to protein, 
these soy protein ingredients contain other naturally occurring soy 
constituents, such as isoflavones, fiber, and saponins. The specific 
processing steps employed determine the extent of retention of such 
naturally occurring constituents in the final product.
    Soy protein is also consumed in the diet as a component of 
traditional fermented and nonfermented soy foods such as tofu, tempeh, 
and miso, in addition to whole soybeans, soynuts, soy milk, soy yogurt, 
and soy cheese. These products contain variable amounts of soy protein 
and other naturally occurring soy constituents depending on the 
specific technologies used in their production.
    Soy protein ingredients (ISP, SPC, and SF) and soy protein-
containing foods may partially replace or be used in addition to animal 
or other vegetable protein sources in the human diet. Therefore, FDA 
has tentatively concluded that the substance satisfies the preliminary 
requirement of Sec. 101.14(b)(3)(i).
3. The Substance Is Safe and Lawful
    The petitioner stated that soy protein ingredients were in common 
use in food before January 1, 1958, and that they are generally 
recognized as safe (GRAS) by self-determination (Ref. 1). Because the 
fractionation procedures used to convert vegetable flours to vegetable 
protein isolates and concentrates were commonplace prior to 1958, the 
petitioner asserted that ISP and SPC can be defined as soy flour 
``subject only to conventional processing as practiced prior to January 
1, 1958.'' The petitioner alluded to statements that it attributed to 
FDA about the GRAS status of soy protein products. (In point of fact, 
however, in one document (35 FR 18530, December 5, 1970), FDA was 
restating a petitioner's grounds for its petition, and in the other 
document (43 FR 30472, July 14, 1978), FDA was stating a condition on 
the vegetable protein products to which the proposed regulation 
applied, and was not itself determining the safety or suitability of 
any product (43 FR 30472 at 30474 to 30475 (comment 10).) The 
petitioner also referred to unidentified statements by the U.S. 
Department of Agriculture, the Association of American Feed Control 
Officials, and the Codex Alimentarius that it asserted support for the 
GRAS status of soy protein products (Ref. 1).
    The petition also addressed some concerns that have been raised 
about the potential risk of consuming soy products: Allergenicity, 
exposure to trypsin inhibitors, reduced bioavailability of minerals, 
and hormonal disturbances.
    As is true for any protein entering the gastrointestinal tract, soy 
protein has the potential to elicit an allergic reaction. Food 
allergies most commonly develop in infants and young children. Although 
the use of heat or hot aqueous ethanol in the processing of soybeans 
destroys the immunochemical reactivity of most of the protein, a small 
number of infants fed soy formula experience allergic reactions to soy 
(Ref. 9). Such sensitization appears to be a manifestation of an 
immature digestive tract and is rarely seen in children more

[[Page 62979]]

than 4 years old or adults. Many children outgrow food allergies (Ref. 
10) and soy and seafood allergies are among those likely to be 
outgrown, in contrast to allergies to milk, egg white, or peanuts.
    Concerns have been raised in the past about exposure to trypsin 
inhibitors contained in soybeans because these compounds had been found 
to stimulate pancreatic hyperplasia and hypertrophy in animals (Ref. 
11). These concerns have been allayed because heat treatment removes 
most of the activity of these proteases (Ref. 12). In addition, recent 
studies have questioned the applicability of the animal models, which 
differ from humans in the type of diet, sensitivity of the pancreas to 
trypsin inhibitors, and the anatomic sites of pancreatic cell 
proliferation (Refs. 12 through 15) and have found low rates of cancer 
in populations with dietary patterns that include soy foods (Ref. 16).
    Soybeans contain phytic acid and dietary fiber, which have well 
documented effects on reducing the bioavailability of divalent 
minerals, and these components are retained in the protein fraction in 
variable amounts depending upon processing. In general, the 
bioavailability of minerals is lower from plant sources than animal 
sources, but soy has not been found to reduce the availability of 
minerals from other dietary sources consumed concurrently (Ref. 17). 
Data on the possible deleterious effects of soy, and particularly its 
phytate content, on mineral balance have been obtained mainly from 
studies of animal models; findings in humans are less consistent and 
suggest that although absorption may be impaired, overall mineral 
balance is not adversely affected (Refs. 13, 18, 19, 20).
    Finally, the possibility of hormonal disturbances from the weakly 
estrogenic-antiestrogenic effects of soy isoflavones has been raised. 
For example, infertility was found in sheep that had consumed clover 
containing isoflavones (Ref. 21); however, studies of soy isoflavones 
in primates showed no effects on male or female reproductive tissue or 
ability (Refs. 22 through 24). Soy isoflavones have been hypothesized 
as a protective factor against breast cancer in populations that 
consume large amounts of soy protein (Ref. 25), and in one controlled 
human trial, a 45-mg/day dose of isoflavones lead to favorable changes 
in menstrual cycle length and hormone levels similar to those seen in 
women treated with tamoxifen (Ref. 26).
    Based on the totality of the evidence and, in particular, its 
common use in food, the agency is not prepared, at this time, to take 
issue with the petitioner's view that the use of soy protein is safe 
and lawful as required in Sec. 101.14(b)(3)(ii). Thus, FDA tentatively 
concludes that the petitioner has provided evidence that satisfies the 
requirement in Sec. 101.14(b)(3)(ii) that use of soy protein at the 
levels necessary to justify a claim is safe and lawful.

III.  Review of Scientific Evidence

A. Basis for Evaluating the Relationship Between Soy Protein and CHD

    The review examined the relationship between soy protein and CHD by 
focusing on the effects of dietary intake of this substance on blood 
lipid 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 
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.
    The Federal Government and others who 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 (inadequate circulation of blood to the heart due to 
narrowing of the arteries) and represent major contributors to CHD (56 
FR 60727 at 60728, 56 FR 60582 at 60583, Refs. 4 through 6). 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. 4 through 6).
    When considering the effect that the diet or components of the diet 
have on blood (or serum) lipids, it is also useful 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 because it is involved in the regulation of 
cholesterol transport out of cells and to the liver, from which it is 
ultimately excreted (Refs. 4 and 8).
    For these reasons, the agency based its evaluation of the 
relationship between consumption of soy protein and CHD primarily on 
changes in blood total and LDL-cholesterol resulting from dietary 
intervention with soy protein-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 
response to the 1990 amendments in deciding on the dietary saturated 
fat and cholesterol and CHD health claim, Sec. 101.75 (56 FR 60727 and 
58 FR 2739); the fruits, vegetables, and grain products and CHD claim, 
Sec. 101.77 (56 FR 60582 and 58 FR 2552); and 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).

B. Review of Scientific Evidence

1. Evidence Considered in Reaching the Decision
    The petitioner submitted scientific studies (Refs. 27 through 66) 
evaluating the relationship between soy protein in the diet and serum 
lipid levels in humans (Refs. 1 and 2). The studies submitted were 
conducted between 1976 and 1998. The petition included tables that 
summarized the outcome of the studies and a summary of the evidence. In 
the approach taken previously in the diet and CVD proposed rules, the 
agency began its review of scientific evidence in support of a 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,'' which is the most recent and comprehensive Federal review of 
the scientific evidence on dietary factors and CVD. In a brief 
discussion of the role of protein in coronary heart disease, the 
Surgeon General's report noted that studies of the substitution of soy 
protein and other vegetable proteins for animal protein in the diets of 
hyperlipidemic patients have shown a marked reduction in serum 
cholesterol levels but only a small change in persons with normal 
cholesterol levels (Ref. 4). Because of the brevity of this 
consideration of soy protein, the agency reviewed all of the studies on 
soy protein submitted by the petitioner, including those published 
prior to 1988.
    The petition also presented some findings from studies that 
employed animal models and from in vitro

[[Page 62980]]

experiments. Human studies are weighted most heavily in the evaluation 
of evidence on a diet and disease relationship; animal model and in 
vitro studies can be considered as supporting evidence but cannot, in 
the absence of human studies, serve as the basis for establishing that 
a diet and disease relationship exists. Such studies may be useful in 
providing information on the mechanism of action of soy protein's 
effects on blood cholesterol levels.
2. Criteria for Selection of Human Studies
    The criteria that the agency used to select the most pertinent 
studies were consistent with those that the agency used to evaluate 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, soy protein intakes; (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 (5), these persons can be 
considered to be adults with blood total cholesterol levels less than 
300 mg/dL. Studies of special population groups, such as adults with 
very high serum cholesterol (mean greater than 300 mg/dL) and children 
with hypercholesterolemia, were considered relative to the nature of 
the support they provided for evidence of effect seen in studies of 
subjects more representative of the general U.S. population.
    In a previous rulemaking (62 FR 28234 at 28238 and 63 FR 8103 at 
8107), the agency concluded that hypercholesterolemic study populations 
are 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. 7). 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. 7). 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. 7). As the leading cause 
of death in this country, CHD is a disease for which the general U.S. 
population is at risk. The risk of dying from CHD is related to serum 
cholesterol levels in a continuous and positive manner, increasing 
slowly for levels between 150 mg/dL and 200 mg/dL and more rapidly when 
the cholesterol level exceeds 200 mg/dL (Ref. 67). The public health 
policy elucidated by the National Cholesterol Education Program (NCEP), 
National Heart, Lung, and Blood Institute, is to extend the benefits of 
cholesterol lowering to the population as a whole by promoting adoption 
of eating patterns that can help lower the blood cholesterol levels of 
most Americans (Ref. 67). A dietary intervention that lowers blood 
cholesterol levels mainly or only in persons with high levels would, 
like an intervention that lowers cholesterol levels across the entire 
population range, cause a shift in the population distribution of blood 
cholesterol levels resulting in a decrease in the mean value for the 
blood cholesterol level in the general population (Ref. 67). The 
anticipated effect of such a shift would be to reduce the morbidity 
from CHD and to produce a continued or accelerated decline in the CHD 
mortality rate in the United States. Accordingly, in this proposal, the 
agency has reviewed and considered the evidence of effects of soy 
protein on serum lipids in hypercholesterolemic subjects.
    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 could not 
provide the primary data.
3. Criteria for Evaluating the Relationship Between Soy Protein and CHD
    Well reasoned approaches for evaluating studies supporting diet/
disease relationships are summarized in the comprehensive report ``Diet 
and Health'' issued by the National Academy of Sciences (Ref. 68) and 
``The Guide to Clinical Preventive Services'' issued by the U.S. 
Preventive Services Task Force (Ref. 69). The criteria articulated in 
these documents provided a starting point for FDA's review of 
individual studies on the relationship between dietary factors and CHD 
in previous rulemakings: In the 1991 proposed rule on lipids and CVD 
(56 FR 60727), in the 1991 proposed rule on dietary fiber and CVD (56 
FR 60582), in the January 1996 proposed rule on whole oats and CHD (61 
FR 296), and in the May 22, 1997, proposed rule on soluble fiber from 
psyllium and CHD (62 FR 28234).
    The criteria that the agency used in evaluating the studies for 
this rulemaking include: (1) Reliability and accuracy of the methods 
used in nutrient intake analysis, including measurements of soy protein 
intake; (2) estimates of intake of saturated fat and cholesterol; (3) 
available information on the soy protein test products and control 
foods; (4) measurement of study endpoints (i.e., measurement of blood 
lipid levels); and (5) general study design characteristics.
    The general study design characteristics for which the agency 
looked included randomization of subjects, appropriateness of controls, 
selection criteria for subjects, attrition rates (including reasons for 
attrition), potential for misclassification of individuals with regard 
to dietary intakes, presence of recall bias and interviewer bias, 
recognition and control of confounding factors (for example, monitoring 
body weight and control of weight loss), appropriateness of statistical 
tests and comparisons, and statistical power of the studies. 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.

C. Review of Human Studies

    FDA conducted a comprehensive review of 41 of 43 human intervention 
studies submitted in the petition and reported in 38 references by the 
petitioner (Refs. 27 through 64). The two studies FDA excluded from 
consideration at the outset (Refs. 32 and 52) were of infants. Of the 
studies reviewed, 27 met the aforementioned criteria for selection 
(Refs. 27, 28, 29, 30 (1 trial), 31, 33, 34, 35, 36, 37, 40 (2 trials), 
42 and 45 (1 trial), 43, 44, 46, 49, 51, 53, 54, 55, 56, 58, 59, 60, 
63, and 64). Of these, the agency gave particular weight to 14 trials 
(Refs. 27, 28, 30 (1 trial), 31, 36, 37 (1 trial), 40 (2 trials), 44, 
49, 51, 54, 58, and 59) that included subjects representative of the 
general U.S. population and that were well controlled, reported intakes 
of saturated fat and cholesterol, and avoided problems associated with 
small sample size, lack of a placebo, and other design problems. These 
studies are summarized in Table 1 at the end of this document and 
discussed in section III.C.1 of this document. Three additional similar 
trials that were included in the review but accorded less weight 
because of issues concerning the populations studied and diets fed 
(Refs. 29, 43, and 53) are also summarized in Table 1 of this document 
and discussed in section III.C.1 of this document. Seven trials in 
adults (Refs. 33, 35, 46,

[[Page 62981]]

55, 56, 60, and 64) and three trials in children (Refs. 34, 42 and 45 
(1 trial), and 63) with type II or familial hypercholesterolemia are 
summarized in Table 2 at the end of this document and discussed in 
section III.C.2 of this document. The fourteen remaining intervention 
trials (Refs. 30 (1 trial), 37 (1 trail), 38, 39 (2 trials), 41, 47, 
48, 50 (2 trials), 57, 61, and 62 (2 trials)) failed to meet the 
inclusion criteria because of small sample size, inadequate period of 
intervention, inadequate characterization of the soy protein tested, 
inadequate information on dietary intake, or lack of data on outcome 
variables. The results of one epidemiological study (Ref. 65) and a 
meta-analysis (Ref. 66) that included a number of the soy protein 
studies submitted in the petition are discussed in sections III.C.3 and 
III.C.4, respectively, of this document.
1. Studies of Adult Subjects Representative of the General U.S. 
Population (Serum Cholesterol <300 mg/dL)
    The agency began its consideration of the data with the 14 well 
controlled and representative studies identified previously (Refs. 27, 
28, 30 (1 trial), 31, 36, 37 (1 trial), 40 (2 trials), 44, 49, 51, 54, 
58, and 59). Several of these studies examined the interaction of 
protein and other components of soy protein sources hypothesized to 
have an impact on lipid-lowering effects (i.e., isoflavones, dietary 
fiber, and soy lipids) (Refs. 31, 28, 27, 51, and 44). Findings with 
respect to soy protein are described in this section, while findings 
regarding the specific influence of soy isoflavones (Refs. 31 and 28) 
are discussed in more detail in section III.C.5 of this document.
    In hypercholesterolemic subjects, Crouse et al. (Ref. 31, 
documented in Ref. 1 with corrections noted in Ref. 2) found that 25 
grams (g) of soy protein from ISP containing 2.5 mg total aglycone 
isoflavones/g protein lowered total (p<0.05) and LDL-cholesterol levels 
(p<0.05) by 4 and 6 percent, respectively, while HDL-cholesterol was 
not altered. Furthermore, in subjects with LDL-cholesterol levels in 
the top half of the study population, serum total and LDL-cholesterol 
were reduced by 9 percent (p<0.03) and 12 percent (p<0.03), 
respectively, by the ISP with 2.5 mg total aglycone isoflavones/g 
protein, and by 8 percent (p<0.03) and 9 percent (p<0.03), 
respectively, by the ISP with 1.6 mg total aglycone isoflavones/g 
protein. HDL-cholesterol concentrations were unchanged. These results 
indicate that soy protein, in a diet low in saturated fat and 
cholesterol, can exert hypocholesterolemic effects but suggest these 
effects may be modulated by the presence of isoflavones.
    In hypercholesterolemic, postmenopausal women, Baum et al. (Ref. 
28) also investigated the impact of soy protein as ISP containing 
different levels of isoflavones. Adjusted mean differences in the 
change from baseline for total serum cholesterol level did not differ 
in the two soy groups and the control group. However, there was a 
statistically significant reduction of 8 to 9 percent in non-HDL (LDL 
plus very low density lipoprotein (VLDL)) cholesterol in both of the 
ISP treatment groups (p<0.05) compared to the control group. HDL-
cholesterol was also significantly increased (p<0.05) in both soy 
groups compared to the control. The level of isoflavones did not affect 
any of the blood lipid levels measured. This study also indicates the 
ability of soy protein provided in a diet low in saturated fat and 
cholesterol to reduce LDL-cholesterol.
    Two studies that examined the effect of soy protein in 
hypercholesterolemic adults consuming low fat diets also evaluated 
whether soy cotyledon fiber had additional lipid-lowering effects. 
Bakhit et al. (Ref. 27) used 25 g protein and 20 g dietary fiber as 
treatment levels while Potter et al. (Ref. 51) used 50 g protein and 20 
g dietary fiber. Soy protein was provided as ISP (Refs. 27 and 51) and 
SF (Ref. 51) incorporated into baked products.
    Bakhit et al. (Ref. 27) studied subjects who had initially been 
screened for eligibility based on plasma total cholesterol 
concentrations greater than 220 mg/dL before starting the study. During 
the baseline dietary period, plasma total cholesterol decreased to 
levels below 220 mg/dL in 10 of the subjects; these subjects did not 
have any further decrease in total or LDL-cholesterol with any of the 
experimental diets. The subjects whose cholesterol remained greater 
than the 220 mg/dL intent-to-treat level did show a statistically 
significant decrease from post-baseline dietary levels for total 
cholesterol, but not for LDL-cholesterol, after consuming ISP. In the 
subset analysis, Bakhit et al. (Ref. 27) found a statistically 
significant decrease in total cholesterol of 7 percent (p<0.05) from 
post-stabilization levels with ingestion of ISP. Addition of soy 
cotyledon fiber to the ISP diet resulted in a statistically significant 
decrease (p<0.05) of 8 percent in total cholesterol. Ingestion of the 
casein plus cellulose control diet produced a nonsignificant decrease 
(p>0.05) in total cholesterol of 3 percent. Differences in LDL- and 
HDL-cholesterol from baseline or control after the two soy diets were 
not statistically significant. In the subset analysis, the additional 
effect of soy fiber on blood cholesterol levels was not significant 
when evaluated by analysis of covariance (p=0.04 for protein effects; 
p=0.07 for fiber effects). This study supports a conclusion that the 
protein and not the fiber component of the soybean is largely 
responsible for effects on blood lipids.
    Potter et al. (Ref. 51) reported a statistically significant 
(p<0.05) decrease in plasma total cholesterol from baseline of 8 
percent with ingestion of diets containing ISP whether soy cotyledon 
fiber or cellulose was also consumed. The 8-percent decrease observed 
in LDL-cholesterol from baseline was statistically significant only 
when the ISP diet also contained soy cotyledon fiber (p<0.05). Total 
and LDL-cholesterol were also significantly (p<0.01) lower with the ISP 
diets compared to the nonfat dry milk-cellulose control diet. No 
statistically significant changes in HDL-cholesterol were observed with 
any of the soy protein diets. Changes from baseline were not 
statistically significant for any of the blood lipids when the diet 
providing soy protein as SF was consumed. However, the difference in 
total cholesterol observed after ingestion of SF was 19 mg/dL lower 
than that on the control diet of nonfat dry milk and cellulose 
(p<0.01). These findings suggest that the principal dietary component 
responsible for the lipid-lowering observed in this study is the soy 
protein fraction, and that soy fiber may have an incremental effect.
    Kurowska et al. (Ref. 44) tested the effects of soy protein and soy 
oil in hypercholesterolemic subjects by adding combinations of ``milk'' 
and desserts to provide a total of 31 g protein from either cow's milk 
or soy milk and 16 g fat from either cow's milk, soybean oil, or whole 
soybean soy milk. The three dietary treatments were cow's milk (2-
percent fat), skim cow's milk (0-percent fat) plus soy oil (16 g), or 
soybean milk. No statistically significant changes from baseline in 
total cholesterol were observed in response to any of the dietary 
treatments. The 4-percent decline in LDL-cholesterol observed with the 
soybean milk diet was not statistically significant. HDL-cholesterol 
was increased 7 percent from baseline (p=0.04) with the whole soybean 
milk treatment. In the subjects with the highest initial LDL-
cholesterol level and LDL/HDL-cholesterol ratio, LDL-cholesterol was 
reduced by 11 percent by the soybean milk diet.

[[Page 62982]]

    Five earlier studies included in Table 1 reported on effects of soy 
protein in hypercholesterolemic subjects.
    In hypercholesterolemic subjects, Goldberg et al. (Ref. 37) 
examined the effects of ISP (99 g of soy protein) incorporated as a 
meat analog or formulated in beverage compared to a control animal 
protein diet consisting of analogous meat products and nonfat dry milk. 
Both diets resulted in statistically significant reductions in serum 
total and LDL-cholesterol levels. With the soy protein diet, total 
cholesterol was decreased by 15 percent (p<0.001) and LDL-cholesterol 
was decreased by 17 percent (p<0.001) from baseline values. Total 
cholesterol was 8 mg/dL lower (p<0.005), and LDL-cholesterol was 10 mg/
dL lower (p<0.05), at the end of the dietary period when soy protein 
was ingested as compared to the animal protein diet. Both the change in 
HDL-cholesterol from the baseline and the difference in HDL-cholesterol 
between the soy and control diets were small and not statistically 
significant.
    Mercer et al. (Ref. 49) tested the effects of approximately 17 g of 
soy protein from ISP as a replacement for 2-percent fat cow's milk in 
subjects with mild to moderate hypercholesterolemia. Total cholesterol 
levels were not significantly different (p>0.05) on the two diets. 
However, among the subjects whose baseline total cholesterol was above 
the 90th percentile, the soy protein diet resulted in a decrease from 
baseline in mean total cholesterol of 4 percent and a level 9 percent 
lower (16 mg/dL; p<0.05) than the level at the end of the cow's milk 
period. There were no statistically significant differences in LDL-
cholesterol and HDL-cholesterol between ISP and cow's milk diets either 
for all subjects or for the subset of subjects with the highest initial 
total cholesterol levels.
    Holmes et al. (Ref. 40) conducted two trials with 
hypercholesterolemic subjects testing SF as a texturized vegetable 
protein product formulated with egg yolk, beef tallow, and cottonseed 
oil to create an analog for lean ground beef. An average of 27 g of soy 
protein was consumed in the partially substituted diet in the first 
trial and 62 g was consumed in the completely substituted diet in the 
second trial. In trial 1, statistically significant changes in total 
cholesterol (p<0.02) and LDL-cholesterol (p<0.05) occurred during the 
initial stabilization period when the control diet was consumed; no 
further changes occurred after the second period during which the 
partially substituted soy diet was consumed. In trial 2, both diets 
significantly lowered mean total cholesterol during the first dietary 
sequence (p<0.05), the animal protein diet by 18 percent and the soy 
diet by 19 percent. Crossing over the diets had no further effect. LDL-
cholesterol levels were not reduced by either diet. HDL-cholesterol 
levels were not significantly affected by diet in either trial. The two 
trials were unique in the source of soy protein and in including 
subjects with type IV hyperlipidemia.
    Shorey et al. (Ref. 54) examined the effects of 57 g of soy protein 
(mean intake) consumed as ISP incorporated both into meat analogs and a 
soy-based beverage in hypercholesterolemic young men. A statistically 
significant (p=0.027) decrease from baseline total cholesterol of 7 
percent was noted in the group consuming the soy protein diet; however, 
these values were 6 mg/dL higher than change from baseline values 
obtained from the control group. HDL-cholesterol also significantly 
(p=0.001) decreased from baseline values by 15 percent. LDL-cholesterol 
was not measured in this study. Although the two diets were well 
matched for saturated fat and cholesterol, interpretation of these 
findings is complicated by the fact that body weight was significantly 
(p<0.004) decreased in both groups of subjects. Subjects who showed a 
significant hypocholesterolemic response on either diet were those who 
substantially reduced their customary protein and fat intakes on the 
experimental diets. In contrast to other studies, subjects in this 
study with lower baseline values experienced more pronounced reductions 
in total cholesterol level.
    Four additional well-controlled studies included in Table 1 of this 
document examined the effects of soy protein in normocholesterolemic 
subjects.
    The study of Carroll et al. (Ref. 30) compared ISP (44 g soy 
protein estimated) incorporated into foods and a soy-based beverage to 
a mixed protein/animal-based diet in healthy young women. Plasma total 
cholesterol was significantly (p<0.05) lower, by 10 mg/dL, when the soy 
protein diet was consumed as compared with the mixed protein diet. 
Neither LDL-cholesterol nor HDL-cholesterol was measured.
    Giovannetti et al. (Ref. 36) examined the effects of ISP (66 to 80 
g of soy protein depending on energy intake) incorporated as meat and 
dairy analogs in healthy young adult women in both high- and low-fat 
diets. On the high-fat diet, serum total cholesterol was 4 mg/dL lower, 
LDL-cholesterol was 6 mg/dL lower, and HDL-cholesterol was 3 mg/dL 
lower after ingestion of the soy protein than after ingestion of the 
mixed protein control. None of the changes in blood lipids reached 
statistical significance. On the low-fat diet, serum total cholesterol 
was 1 mg/dL higher, LDL-cholesterol was 5 mg/dL lower, and HDL-
cholesterol was 2 mg/dL higher after soy protein than after the mixed 
protein control; these differences were not statistically significant. 
The magnitude of reduction in serum total cholesterol with soy protein 
was similar on the high-fat and low-fat diets, 10 percent and 9 
percent, respectively. Substitution of soy protein caused reductions in 
LDL-cholesterol levels during the high-fat diet in 11 of 12 subjects 
and during the low-fat diet in 9 of 12 subjects.
    Van Raaij et al. (Ref. 58) tested the effects of ISP in young 
normocholesterolemic men and women consuming three diets that differed 
in protein composition with 65 percent of the total protein replaced by 
either soy protein (54 g), or casein, or an approximately 2:1 mixture 
of casein (36 g):soy (17 g). In the group consuming the soy protein 
diet, total serum cholesterol and LDL-cholesterol were decreased (-2 
percent and -8 percent, respectively) and HDL-cholesterol increased 
(+10 percent) compared to values at the end of the lead-in period. The 
changes in both LDL-cholesterol and HDL-cholesterol were statistically 
significant (p<0.05). In addition, decreases in LDL-cholesterol were 
significantly (p<0.05) greater with the soy protein diet compared to 
changes with the casein diet. Although weight loss did occur among 
subjects consuming both the soy protein diet (n=9) and the casein diet 
(n=6), when data from the subset without a weight loss of more than 2 
kilograms (kg) were analyzed separately, the same effects of soy 
protein ingestion on blood lipid-lowering were observed. The lipid 
changes in the group that remained on the 2:1 casein:soy diet were not 
statistically significantly different from the casein group, nor were 
changes from the end of the stabilization period significant in this 
group.
    In a trial with both normocholesterolemic and hypercholesterolemic 
subjects, Van Raaij et al. (Ref. 59) tested both ISP and SPC (each 
providing an average of 55 g of soy protein) compared to a casein 
control. Serum total cholesterol was decreased from baseline by 4 
percent and LDL-cholesterol was decreased by 3 percent on the ISP diet. 
These changes were significantly different from those on the SPC diet 
(p<0.05) but not significantly different from those on the casein diet. 
HDL-cholesterol showed a slight but statistically significant

[[Page 62983]]

increase of 2 percent from baseline on the ISP diet, a change that was 
also significantly different from that on the casein diet. When SPC was 
used as the protein source, total cholesterol was not altered, LDL-
cholesterol was increased by 6 percent, and HDL-cholesterol decreased 
by 3 percent compared to baseline. None of these changes in blood 
lipids from baseline or differences between the casein and SPC diets 
was statistically significant. Interpretation of this study is 
complicated by differential weight loss on the experimental diets 
(weight loss was greatest in the casein group) and differential fiber 
intake.
    Three additional studies (Refs. 29, 43, and 53), in which 
interpretation is complicated by design issues such as choice of 
subjects, concerns about weight loss, or uncertainties about other 
components in diets, are also summarized in Table 1 of this document 
and discussed as follows.
    Bosello et al. (Ref. 29) and Jenkins et al. (Ref. 43) both studied 
the hypocholesterolemic effects of soy protein versus casein in the 
context of hypocaloric diets fed to obese persons to achieve 
significant weight reduction. In Bosello et al. (Ref. 29), obese 
subjects (>150 percent of ideal body weight) received 375 kilocalorie 
(kcal)/day initially, followed by an 800 kcal/day diet. During both 
phases, the 375 kcal portion was provided by commercial textured 
protein products that delivered either 27 g protein from casein or 27 g 
protein from soy protein (type of soy protein not given). During the 
second phase, the 375 kcal/day was ``integrated'' with an extra 425 
kcal/day from conventional foods. Mean weight losses for the soy and 
casein groups were 17 and 16 kg, respectively. Total cholesterol and 
LDL-cholesterol in the soy group were both 16 percent lower compared to 
baseline (p<0.01). Compared to the casein group, total cholesterol was 
20 mg/dL lower (p<0.01 ) and LDL-cholesterol was 16 mg/dL lower 
(p<0.01). HDL-cholesterol was decreased in both groups at the end of 
the study; however, only in the casein group was the difference 
statistically significant (p<0.01). Additionally, the decrease in HDL-
cholesterol in the casein group was significantly (p<0.01) greater than 
that observed in the soy protein group.
    Jenkins et al. (Ref. 43) examined the effects of soy protein 
ingestion on serum cholesterol in obese women who were also consuming a 
hypocaloric diet for weight reduction. The three treatments were: A 
control, hypocaloric diet of 1,000 total kcal consumed as conventional 
foods; the same diet with two meals per day replaced by a soy protein 
(18.4 g provided as ISP) liquid formula preparation; or the same diet 
with two meals per day replaced by a milk protein (17.6 g as milk 
protein isolate and nonfat dry milk) liquid formula. An average 2.5 kg 
weight loss per month occurred during the study (p<0.05) across diet 
treatments. Statistically significant decreases from baseline in total 
cholesterol of 10 percent (p<0.05) and in LDL-cholesterol of 17 percent 
(p<0.05) occurred only during the period when the soy protein formula 
was ingested. Changes in HDL-cholesterol were not statistically 
significant. These effects of soy protein were independent of the order 
the soy diet was consumed relative to the conventional hypocaloric 
diet. The levels of total and LDL-cholesterol achieved with ingestion 
of soy protein were, respectively, 10 mg/dL and 8 mg/dL lower with the 
soy protein diet as compared with the casein diet. Neither the 
conventional hypocaloric diet nor the casein formula hypocaloric diet 
resulted in statistically significant decreases in total or LDL-
cholesterol despite weight loss. Calculations of the expected decline 
in serum total cholesterol based on changes in weight, dietary 
cholesterol, and saturated and polyunsaturated fat accurately predicted 
the observed changes in both the hypocaloric diet and milk formula 
groups, but significantly underestimated the decrease observed in the 
soy formula group.
    Sacks et al. (Ref. 53) studied the effects of 27 g of protein 
consumed daily as ISP or casein incorporated into muffins and oatmeal 
in adults who were strict vegetarians. Not unexpectedly, given the very 
low baseline lipid concentrations and very low dietary fat and 
cholesterol intake, no statistically significant changes or differences 
in total cholesterol, LDL-cholesterol or HDL-cholesterol were observed 
from consumption of either soy protein or casein.
    a. Summary--Hypercholesterolemic subjects consuming diets low in 
saturated fat and cholesterol. In five (Refs. 31, 28, 27, 51, and 44) 
of seven (Refs. 31, 28, 27, 51, 44, and 40 (2 trials)) well-controlled 
studies of hypercholesterolemic subjects consuming low saturated fat 
and low cholesterol diets, soy protein intake was associated with 
significant decreases in total and/or LDL-cholesterol levels. Crouse et 
al. (Ref. 31, documented in Ref. 1 with corrections noted in Ref. 2) 
found that soy protein from ISP containing 2.5 mg total aglycone 
isoflavones/g protein statistically significantly lowered total 
(p<0.05) and LDL-cholesterol levels (p<0.05), by 4 and 6 percent, 
respectively, while HDL-cholesterol was not altered. In a subset of 
subjects with LDL-cholesterol levels in the top half of the study 
population, serum total and LDL-cholesterol were reduced by 9 percent 
(p<0.03) and 12 percent (p<0.03), respectively, by the ISP with 2.5 mg 
total aglycone isoflavones/g protein, and by 8 percent (p<0.03) and 9 
percent (p<0.03), respectively, by the ISP with 1.6 mg total aglycone 
isoflavones/g protein. Baum et al. (Ref. 28) found that the adjusted 
mean difference in total serum cholesterol level was not significantly 
(p>0.05) different in the two groups consuming soy as ISP and the 
control group. However, there was a statistically significant reduction 
of 8 to 9 percent in non-HDL (LDL plus VLDL) cholesterol in both of the 
ISP treatment groups (p=0.04) compared to the control group.
    Bakhit et al. (Ref. 27) found, in a subset of subjects whose 
cholesterol remained greater than the 220 mg/dL intent-to-treat level 
after run-in with the baseline diet, a statistically significant 
decrease in total cholesterol of 7 percent (p<0.05) from post-
stabilization levels with ingestion of ISP; addition of soy cotyledon 
fiber to the ISP diet resulted in a significant decrease (p<0.05) of 8 
percent in total cholesterol. Levels of LDL-cholesterol were not 
statistically significantly affected by either soy diet. Potter et al. 
(Ref. 51) reported a statistically significant decrease (p<0.05) from 
baseline in total plasma cholesterol of 8 percent with ingestion of 
diets containing ISP whether soy cotyledon fiber or cellulose was also 
consumed. The 8-percent decrease in LDL-cholesterol from baseline was 
statistically significant only when the ISP diet also contained soy 
cotyledon fiber (p<0.05). Total and LDL-cholesterol were also 
significantly lower (p<0.01) with the ISP diets compared to the nonfat 
dry milk-cellulose diet. Changes from baseline were not statistically 
significant for any of the blood lipids when the diet providing soy 
protein as SF was consumed. However, the difference in total 
cholesterol observed after ingestion of SF was 19 mg/dL lower than that 
on the control diet of nonfat dry milk and cellulose (p<0.01).
    With diets providing either cow's milk (2-percent fat), or skim 
cow's milk (0-percent fat) plus soy oil (16 g), or soybean milk, 
Kurowska et al. (Ref. 44) found no statistically significant changes 
from baseline in total cholesterol and LDL-cholesterol in response to 
any of the dietary treatments. In the subjects with the highest initial 
LDL-cholesterol levels and LDL/HDL-cholesterol ratios, LDL-

[[Page 62984]]

cholesterol was reduced by 11 percent by the soybean milk diet. Holmes 
et al. (Ref. 40) conducted two trials testing SF as a texturized 
vegetable protein product, with averages of 27 and 62 g of soy protein 
consumed, respectively, in the first and the second trial. In trial 1, 
statistically significant changes in total and LDL-cholesterol occurred 
during the stabilization period when the control diet was consumed; no 
further changes occurred after the second dietary period during which 
the partially substituted soy diet was consumed. In trial 2, both diets 
resulted in a statistically significant lowering of total cholesterol 
during the first dietary sequence, the animal protein diet by 18 
percent and the soy diet by 19 percent. Crossing over the diets had no 
further effect. LDL-cholesterol levels were not reduced by either diet. 
These studies were unique in the source of soy protein used and in 
including subjects with type IV hyperlipidemia.
    Levels of HDL-cholesterol were also measured in each of these seven 
studies and were found either to be unchanged (Refs. 31, 27, 51, and 40 
(2 trials)) or to show a slight but statistically significant increase 
(Refs. 28 and 44) in response to consumption of diets containing soy 
protein.
    Levels of soy protein as ISP found to be effective in lowering 
total and LDL-cholesterol levels ranged in these studies from 25 to 50 
g (Refs. 31, 28, 27, and 51). As whole soybean milk, 31 g of soy 
protein lowered LDL-cholesterol only in the subset of subjects with the 
highest initial LDL-cholesterol levels and LDL/HDL-cholesterol levels 
(Ref. 44). Diets providing 50 g of soy protein as SF did not cause 
significant changes from baseline for any of the blood lipids, but the 
decrease in total cholesterol observed after ingestion of SF was 
significantly greater than that on the control diet of nonfat dry milk 
and cellulose (Ref. 51). Diets providing 27 g of soy protein as SF in a 
textured product had no significant effects on blood lipid levels 
compared to a control diet, and a higher level (62 g) significantly 
lowered total cholesterol only in the experimental group fed the soy 
protein diet first (Ref. 40).
    b. Summary--Hypercholesterolemic subjects consuming ``usual'' 
diets. Three studies reported on effects of soy protein in 
hypercholesterolemic subjects consuming ``usual'' diets that were 
generally high in total fat, saturated fat, and cholesterol (Refs. 37, 
49, and 54). Goldberg et al. (Ref. 37) found, on the soy protein diet 
(with 99 g of soy protein as ISP), statistically significant decreases 
from baseline of 15 percent in total cholesterol and 17 percent in LDL-
cholesterol. Total cholesterol was 8 mg/dL lower (p<0.005), and LDL-
cholesterol was 10 mg/dL lower (p<0.05), at the end of the dietary 
period when soy protein was ingested as compared to the animal protein 
diet. Mercer et al. (Ref. 49) found that a diet with approximately 17 g 
of soy protein from ISP did not produce changes in serum cholesterol 
that were significantly different from those of a cow's milk control 
diet. Among subjects whose baseline total cholesterol was above the 
90th percentile, Mercer et al. (Ref. 49) found that the soy protein 
diet resulted in a decrease from baseline in mean total cholesterol of 
4 percent and a level 9 percent lower (16 mg/dL; p<0.05) than the level 
at the end of the cow's milk control period. LDL-cholesterol did not 
differ significantly between ISP and cow's milk diets for all subjects 
or for the subset of subjects with the highest initial total 
cholesterol levels.
    Shorey et al. (Ref. 54) found diets with 57 g of soy protein as ISP 
was associated with a statistically significant decrease from baseline 
in total cholesterol of 7 percent (p=0.027); however, these values were 
6 mg/dL higher than change from baseline values obtained from the 
control group. LDL-cholesterol was not measured in this study. Although 
the two diets were well matched for saturated fat and cholesterol, 
interpretation of these findings is complicated by the fact that body 
weight was significantly decreased in both groups of subjects 
(p<0.004). Subjects who showed a significant hypocholesterolemic 
response on either diet were those who substantially reduced their 
customary protein and fat intakes on the experimental diets. In 
contrast to other studies, subjects in this study with lower baseline 
values experienced more pronounced reductions in total cholesterol 
level.
    HDL-cholesterol was also measured in these three studies. Changes 
were small and not statistically significant in two studies (Refs. 37 
and 49), but HDL-cholesterol was significantly decreased from baseline 
values by 15 percent in one study (Ref. 54). (This latter study had a 
number of anomalous results.)
    Each of these three studies fed soy protein in experimental diets 
as ISP (Refs. 37, 49, and 54). With a diet containing a very high level 
(99 g) of soy protein from this source (Ref. 37), statistically 
significant differences in both total and LDL-cholesterol were 
reported. Results were less consistent with a relatively low level of 
soy protein (17 g) (Ref. 49). An intermediate level of soy protein (57 
g) was found to be ineffective in lowering total cholesterol in the 
study of Shorey et al. (Ref. 54).
    c. Summary--Normocholesterolemic subjects. Five studies examined 
the effects of soy protein in normocholesterolemic subjects (Refs. 30, 
36, 58, 59, and 53). The study of Carroll et al. (Ref. 30) found plasma 
total cholesterol was significantly lower (-10 mg/dL) when a soy 
protein diet (low in saturated fat and cholesterol and providing an 
estimated 44 g soy protein as ISP) was consumed as compared with a 
mixed protein control diet (p<0.05). LDL-cholesterol was not measured. 
Giovannetti et al. (Ref. 36) examined the effects of soy protein as ISP 
(66 to 80 g of soy protein depending on energy intake) in both high- 
and low-fat diets. Changes in total and LDL-cholesterol with the soy 
protein diets were not statistically significantly different from 
changes with the corresponding control diets, regardless of fat 
content. The magnitude of reduction in serum total cholesterol with soy 
protein was similar on the high-fat and low-fat diets, 10 percent and 9 
percent, respectively. Substitution of soy protein caused reductions in 
LDL-cholesterol levels during the high-fat diet in 11 of 12 subjects 
and during the low-fat diet in 9 of 12 subjects.
    Van Raaij et al. (Ref. 58) tested the effects of ISP using three 
diets high in total fat, saturated fat, and cholesterol that differed 
in protein composition with 65 percent of the total protein comprising 
either soy protein (54 g), or casein, or an approximately 2:1 mixture 
of casein (36 g):soy (17 g). In the group consuming the soy protein 
diet, the decrease in total serum cholesterol (-2 percent) was not 
statistically significant, but the decrease in LDL-cholesterol (-8 
percent) was statistically significant (p<0.05). In addition, decreases 
in LDL-cholesterol were significantly greater with the soy protein diet 
compared to changes with the casein diet (p<0.05).
    In a trial with both normocholesterolemic and moderately 
hypercholesterolemic subjects, Van Raaij et al. (Ref. 59) tested both 
ISP and SPC (each providing an average of 55 g of soy protein) compared 
to a casein control in diets high in total fat, saturated fat, and 
cholesterol. Serum total cholesterol was decreased from baseline by 4 
percent and LDL-cholesterol was decreased by 3 percent on the ISP diet. 
These changes were statistically significantly different from those on 
the SPC diet (p<0.05) but not significantly different from those on the 
casein diet. When SPC was used as the protein source, total cholesterol 
was not altered and LDL-cholesterol was increased by 6 percent compared 
to

[[Page 62985]]

baseline. None of these changes in blood lipids from baseline or 
differences between the casein and SPC diets was statistically 
significant. Interpretation of this study is complicated by 
differential weight loss on the experimental diets (weight loss was 
greatest in the casein group) and differential fiber intake.
    Sacks et al. (Ref. 53) studied the effects of 27 g of protein 
consumed daily as ISP or casein incorporated into muffins and oatmeal, 
in diets very low in saturated fat and cholesterol in adults who were 
strict vegetarians. Not unexpectedly, given the very low baseline lipid 
concentrations and very low dietary fat and cholesterol intake, no 
statistically significant changes or differences in total cholesterol 
or LDL-cholesterol or HDL-cholesterol were observed from consumption of 
either soy protein or casein.
    HDL-cholesterol was measured in four of these studies, with 
statistically significant increases associated with soy protein intake 
found in two (Refs. 58 and 59) and no statistically significant changes 
in two (Refs. 36 and 53).
    Effects of soy protein on total and LDL-cholesterol were less 
consistent in normocholesterolemic subjects than in moderately 
hypercholesterolemic subjects. As ISP, 44 g of soy protein was 
effective in statistically significantly lowering total cholesterol in 
one study (Ref. 30), and 54 g statistically significantly lowered LDL-
cholesterol in one study (Ref. 58). With very low initial blood lipid 
levels, the impact of dietary changes appears to be lessened.
    d. Summary--Subjects consuming hypocaloric diets. Bosello et al. 
(Ref. 29) and Jenkins et al. (Ref. 43) both studied the 
hypocholesterolemic effects of soy protein versus casein in the context 
of hypocaloric diets fed to obese persons to achieve significant weight 
reduction. In Bosello et al. (Ref. 29), total cholesterol and LDL-
cholesterol in the soy group (which consumed 27 g of soy protein) were 
both 16 percent lower compared to baseline (p<0.01). Compared to the 
casein control group, total cholesterol was 20 mg/dL lower (p<0.01 ) 
and LDL-cholesterol was 16 mg/dL lower (p<0.01) in the soy protein 
group. Jenkins et al. (Ref. 43) found that statistically significant 
decreases from baseline in total cholesterol of 10 percent (p<0.05) and 
in LDL-cholesterol of 17 percent (p<0.05) occurred only during the 
period when the soy protein formula (which provided 17 g of soy 
protein) was ingested. The levels of total and LDL-cholesterol achieved 
with ingestion of soy protein were, respectively, 10 mg/dL and 8 mg/dL 
lower with the soy protein diet compared with casein diet. Neither the 
conventional hypocaloric diet nor the casein formula hypocaloric diet 
resulted in statistically significant decreases in total or LDL-
cholesterol despite weight loss.
    HDL-cholesterol was decreased in both groups at the end of the 
first study (Ref. 29); however, only the casein group's values were 
significantly (p<0.01) different from baseline. Additionally, the 
decrease in HDL-cholesterol in the casein group was 
significantly(p<0.01) greater than that observed in the soy protein 
group. In the second study (Ref. 43), HDL-cholesterol levels were not 
significantly affected by dietary treatment.
    These two studies (Refs. 29 and 43) demonstrated decreases in both 
total and LDL-cholesterol levels during hypocaloric diets that provided 
relatively low amounts (27 and 17 g, respectively) of soy protein.
2. Studies of Subjects with Type II and Familial Hypercholesterolemia 
(Mean Total Cholesterol Level>300 mg/dL)
    Ten studies (Refs. 33, 35, 46, 55, 56, 60, 64, 34, 42 and 45 (1 
trial), and 63) of subjects with severe (type II or familial) 
hypercholesterolemia (mean total cholesterol level>300 mg/dL) are 
summarized in Table 2 of this document and discussed in section III. 
C.2 of this document. Seven report results in adults (Refs. 33, 35, 46, 
55, 56, 60, and 64) and three in children (Refs. 34, 42 and 45 (1 
trial), and 63).
    a. Studies in adults. Sirtori et al. (Ref. 55) reported a decrease 
of 21 percent in both total (p<0.001) and LDL-cholesterol (p<0.01) with 
soy protein consumption in adults with type II hyperlipoproteinemia. 
Total intake of soy protein, as a textured protein isolate, was not 
given but was approximately 13 percent of kcal or 60 g. The order in 
which the soy protein diet was consumed did not affect the results and 
the changes in total plasma cholesterol level far exceeded those 
expected based on the small differences in ratio of polyunsaturated to 
saturated fat and cholesterol content of the diets. When the control 
diet was fed first, statistically significant changes in total and LDL-
cholesterol were not observed; when it was fed second, total 
cholesterol increased statistically significantly. These investigators 
also reported that addition of 500 mg cholesterol in a small, similar 
study showed that level of dietary cholesterol did not modify the 
cholesterol-lowering effect of soy protein observed.
    Descovich et al. (Ref. 33) examined the effects of soy protein 
replacing animal protein in adults with stable type IIa and IIb 
hypercholesterolemia. Subjects consumed an average of 47 g of soy 
protein in the form of texturized soy protein (from SF) mixed into main 
dishes. During the baseline control period with a lipid-lowering diet, 
plasma total cholesterol decreased 3 percent from baseline levels. When 
soy protein was substituted for animal protein in the second dietary 
period, total cholesterol decreased by 24 percent (p<0.001) at the end 
of the experimental period. All of the subjects demonstrated decreases 
in total cholesterol of at least 10 percent. Upon returning to the 
control diet, plasma total cholesterol increased 7 percent in men and 9 
percent in women. LDL-cholesterol also showed a statistically 
significant decrease, by 31 percent from baseline levels (p<0.001), 
while HDL-cholesterol remained stable over the course of the soy 
protein diet (+0.4 mg/dL for men and +1.0 mg/dL for women).
    Wolfe et al. (Ref. 64) tested the effects of ingesting 47 g of soy 
protein in the form of ISP incorporated into main dishes and a 
beverage, while animal proteins were incorporated into similar main 
dishes and cow's milk was consumed during the mixed protein control 
period. Baseline lipid concentrations were not given; however, mean 
total cholesterol concentrations were 280 mg/dL after the soy protein 
treatment and 321 mg/dL after the control treatment. Thus, compared 
with the control period, serum total cholesterol was 41 mg/dL lower 
with ingestion of soy protein (p<0.05) and LDL-cholesterol was 43 mg/dL 
lower (p<0.05). HDL-cholesterol was similar at the end of the soy 
protein and control dietary periods.
    Sirtori et al. (Ref. 56) conducted a trial that examined the 
effects of complete and partial substitution of soy protein as SF (60 g 
or 30 g of soy protein), in a lecithinated textured vegetable protein, 
for animal protein in adults with type IIa hyperlipoproteinemia. Plasma 
cholesterol levels were not altered during the first control diet 
period. Total plasma cholesterol levels were significantly (p<0.01) 
reduced in both periods of soy protein administration, by 18.6 percent 
when 60 g were consumed and by 13.2 percent when 30 g were consumed. 
Serum cholesterol values returned almost completely to baseline during 
the second control period. Changes in LDL-cholesterol levels were 
superimposable to those of total cholesterol. HDL-cholesterol levels 
tended to increase during the two soy periods and decline to baseline 
levels during the second control period, but these differences were not 
statistically significant.
    Verillo et al. (Ref. 60) compared the effects of substituting 31 g 
of soy protein

[[Page 62986]]

as SF for animal protein versus the addition of 31 g of soy protein as 
SF to animal protein in adults with stable type II 
hypercholesterolemia. Slight, nonsignificant decreases in total and 
LDL-cholesterol levels were reported during the initial control period. 
Among subjects who consumed the soy-substituted diet, serum total 
cholesterol declined significantly (p<0.01) from the end of the 
baseline diet by 35 percent and 23 percent in type IIa and type IIb 
patients, respectively. LDL-cholesterol declined significantly (p<0.01) 
from the end of the baseline diet by 44 percent and 23 percent in type 
IIa and type IIb patients, respectively. HDL-cholesterol increased 8 
percent, but this change did not reach statistical significance. The 
same hypocholesterolemic effects were also seen among subjects who 
consumed the soy-added diet. A comparison of results at the ends of the 
soy periods versus the means of final values of both control periods 
showed differences in serum lipids that were of similar magnitudes, but 
not statistically significantly different. The hypocholesterolemic 
response to soy was significantly related to cholesterol level at entry 
to the study.
    The study of Lovati et al. (Ref. 46) in adults with type II 
hypercholesterolemia provided soy protein as SF, from textured 
vegetable protein, in amounts varying between 70 and 105 g depending 
upon total energy consumed. Plasma total and LDL-cholesterol levels 
both decreased by 16 percent (p<0.01) during the period when soy 
protein diet was ingested compared with levels at the start of the 
experimental period. Changes in these parameters on the control diet 
were negligible. HDL-cholesterol concentrations were not documented but 
were reported to be unchanged on the two diet regimens.
    Gaddi et al. (Ref. 35) examined the effects of replacing animal 
protein and non-soy plant protein with approximately 75 g soy protein 
from SF in a lecithinated textured soy protein, in adults with familial 
hypercholesterolemia. The control diet did not affect plasma lipid 
values during the initial experimental period. After ingestion of the 
soy protein diet, plasma total cholesterol decreased by 21 percent 
(p<0.0l) and LDL-cholesterol decreased by 25 percent (p<0.01) from 
levels measured after the first control diet period. HDL-cholesterol 
levels were unchanged. Plasma total and LDL-cholesterol returned to 
concentrations close to those at baseline following resumption of the 
control diet during the third experimental period.
    b. Studies in children. Gaddi et al. (Ref. 34) studied children 
from 3 to 12 years of age with familial hypercholesterolemia. After a 
baseline dietary period during which subjects consumed a low lipid 
diet, soy protein in the form of SF replaced a portion of the animal 
protein intake. No significant changes in plasma lipids occurred over 
the duration of the baseline dietary period. Plasma total cholesterol 
at the end of the soy protein dietary period was 20 percent lower than 
at the end of the baseline dietary period (p<0.001). LDL-cholesterol 
was 24 percent lower (p<0.01) and HDL-cholesterol level was not 
affected.
    Widhalm et al. (Ref. 63) examined the lipid-lowering effects of 
incorporating ISP (13.5-18 g protein) into food and beverage recipes in 
children with familial hypercholesterolemia. After the soy protein 
dietary periods, plasma total cholesterol was 16 percent lower 
(p<0.005) than baseline levels in the group that consumed the soy 
protein diet before the control diet and 18 percent lower (p<0.001) in 
the group that consumed soy last. LDL-cholesterol was also 
statistically significantly decreased (p<0.001) by 22 percent in the 
first group and 25 percent in the second group. During the control diet 
periods, total and LDL-cholesterol levels were reduced by 8 percent and 
7 percent in the first group and by 12 percent and 13 percent in the 
second group, respectively. HDL-cholesterol was not statistically 
significantly affected by dietary treatment.
    Laurin et al. (Ref. 45) and Jacques et al. (Ref. 42) both reported 
on a test of the lipid-lowering effects of ISP (28 g of soy protein) in 
children, 6 to 12 years of age, with familial hypercholesterolemia. 
Children consumed either a conventional low fat diet with 2-percent 
cow's milk or the same low fat diet with a soy-based beverage made with 
2-percent butterfat substituted for the 2-percent cow's milk. 
Comparisons between the two treatment groups indicated that total and 
LDL-cholesterol levels were not altered. HDL-cholesterol level was 
increased 4 percent (p<0.04) with soy protein compared to cow's milk.
    c. Summary--Subjects with Type II or familial hypercholesterolemia. 
Each of the ten studies of the effects of soy protein in subjects with 
severe (type II or familial) hypercholesterolemia employed diets low in 
saturated fat and cholesterol (Refs. 33, 35, 46, 55, 56, 60, 64, 34, 42 
and 45 (1 trial), and 63), and most subjects had been consuming such a 
therapeutic diet prior to the study. Six of the ten trials were 
conducted by workers from the same group (Refs. 55, 33, 56, 46, 35, and 
34). Most used SF in TVP as the source of soy protein, in amounts 
ranging from 14 to 105 g (Refs. 33, 56, 60, 46, 35, 34, and 63); the 
remainder used ISP as the source of soy protein, in amounts ranging 
from 28 to 60 g (Refs. 55, 64, and 42 and 45 (1 trial)). In all the 
studies conducted in adults (Refs. 33, 35, 46, 55, 56, 60, and 64), 
using both fixed sequence and crossover study designs, large and 
statistically significant decreases in both total and LDL-cholesterol 
levels were observed in response to consumption of diets containing soy 
protein. In the six trials in which they were measured, HDL-cholesterol 
levels were either not statistically significantly affected (Refs. 33, 
64, 60, 46, and 35) or were statistically significantly increased (Ref. 
56).
    In the studies conducted in children with familial 
hypercholesterolemia, two of the three trials demonstrated 
statistically significant decreases from baseline levels in total and 
LDL-cholesterol during the periods when soy protein diets were consumed 
(Refs. 34 and 63). However, interpretation of these findings is 
complicated by uncertainty about the control of intake of other dietary 
constituents, especially saturated fat and cholesterol. In the study 
reported by Laurin et al. and Jacques et al. (Refs. 45 and 42), 
differences in these dietary components were controlled. With diets 
providing 12 percent of kcal from saturated fat and 163 to 180 mg of 
cholesterol, plasma total and LDL-cholesterol levels were not 
statistically significantly different, but the HDL-cholesterol level 
was statistically significantly higher, on the soy diet than on the 
cow's milk diet.
3. Epidemiologic Evidence on Soy Protein and Blood Lipids
    The petitioner also submitted one epidemiologic study by Nagata et 
al. (Ref. 65) that described the relationship between soy product and 
soy protein intake and serum total cholesterol concentrations in 
Japanese men and women. Participants in this study were 1,242 men and 
3,596 women from the Takayama Study, a prospective cohort study on the 
impact of diet and lifestyle on cancer, who attended the annual health 
checkup program between April and October 1992. Data regarding food 
intake were collected by a validated, semiquantitative food frequency 
questionnaire (FFQ). Blood samples were also taken for each subject and 
analyzed for total cholesterol concentrations. Soy products identified 
in the FFQ included tofu (plain, fried, deep-fried, or dried), miso, 
fermented soybeans, soy milk, and boiled soybeans. The estimated amount 
of soy protein consumed from these sources was 8.00  4.95 
g/day for men and 6.88

[[Page 62987]]

 4.06 g/day for women. The authors noted that their FFQ may 
underestimate soy product intake; they also estimated that 4 to 9 g 
additional soy protein may be consumed daily from soy protein added to 
meats and fish pastes that was not accounted for in the FFQ. Thus, 
analyses were presented in terms of relative soy protein intake. Using 
energy-adjusted means for quartiles of soy protein intake, a 
statistically significant negative trend was observed for lower serum 
total cholesterol concentrations with higher levels of soy protein 
intake (p<0.0001 for both men and women). The analysis for men was 
controlled for age, smoking status, and total energy, protein, and fat 
intake. The analysis for women was controlled for age, menopausal 
status, body mass index, and intake of energy and vitamin C. Further 
adjustments for physical activity, coffee and tea consumption, and 
intakes of cholesterol, carbohydrates, fiber, and vitamin E were 
performed and results were not affected. Between the 1st and 4th 
quartiles in men, total cholesterol was lower by 12 mg/dL with a 9.6-g 
increase in soy protein intake. For women, total cholesterol was lower 
by 9 mg/dL with a 7.9-g increase in soy protein intake.
4. Meta-analysis of Studies of Soy Protein and Blood Lipids
    The petitioner presented the results of a 1995 meta-analysis (Ref. 
66) of the effect of soy protein on blood lipids. While the role of 
``research synthesis'' studies, including meta-analyses, is of 
interest, it is as yet unresolved. The appropriateness of such 
analytical techniques to establish diet/health relationships in 
particular is not known. There are on-going efforts to identify 
criteria and critical factors to consider in both conducting and using 
such analyses, but this science is still emerging. Therefore, the meta-
analysis did not weigh heavily within the body of evidence for this 
relationship.
    In summary, Anderson et al. (Ref. 66) pooled data from studies that 
were deemed comparable in methodology in order to perform a meta-
analysis of the effect of soy protein on blood lipids. Of the 37 
publications identified by these investigators that presented data on 
soy protein and lipid changes, 29 met the criteria of using either ISP 
or texturized soy protein as the soy protein source, employing either a 
parallel or crossover design, and providing initial or baseline 
cholesterol values to allow calculation of decreases. These 29 
publications reported the findings from 38 separate trials. Each of 
these publications was included in the petition and was considered for 
review individually by FDA as described previously. Thirty-four of the 
trials were conducted among adults and four among children. Study 
samples included individuals with normal blood cholesterol levels as 
well as those with mildly to severely elevated levels. Twelve of the 
trials were conducted in subjects with familial hypercholesterolemia.
    The specific analytical approach is described in Anderson et al. 
(66). Based on examining the difference from baseline between the soy 
protein and control protein groups, the analysis indicated that soy 
protein consumption statistically significantly decreased total 
cholesterol for the pooled data by 9.3 percent and LDL-cholesterol by 
12.9 percent. HDL-cholesterol was increased by a net of 2.4 percent 
with soy protein ingestion, but this change was not statistically 
significant. This analysis also suggested that the initial level of 
serum total cholesterol was the most important determinant of serum 
lipid response to soy protein. When changes in total and LDL-
cholesterol were examined by quartile of baseline cholesterol 
concentration, a progressively greater magnitude of change was observed 
from the lowest to the highest quartiles. Additional analyses indicated 
that the type and amount of soy protein consumed and type of background 
diet did not substantially influence the results.
    To examine further the effects of the type and amount of soy 
protein, an analysis was performed using changes observed with the soy 
diet alone instead of net changes as the outcome variable. Initial 
serum cholesterol concentration was also the major determinant of 
effects in this model, but statistically significant effects (p=0.02) 
were also obtained for amount of soy protein. This model predicted, 
after adjustment for initial values and other variables, serum total 
cholesterol decreases of 8.9 mg/dL with 25 g/day soy protein, 17.4 mg/
dL with 50 g/day of soy protein, and 26.3 mg/dL with 75 g/day of soy 
protein.
5. Studies of the Role Soy Isoflavones
    Isoflavones are a class of naturally-occurring compounds with weak 
estrogenic/antiestrogenic activities that are present in a wide variety 
of plants. The 12 major isomers of naturally-occurring isoflavones in 
soybeans are genistein, genestin, 6``-O-acetylgenistin, 6``-O-
malonylgenestin, diadzein, diadzin, 6``-O-acetyldiadzin, 6``-O-
malonyldiadzin, glycitein, glycitin, 6``-O-acetylglycitin, and 6``-O-
malonyglycitin. The levels of isoflavones in soybeans are known to vary 
with cultivar and growing conditions. Soy isoflavones are retained to 
variable degrees in soy protein products and soy foods, depending on 
the particular processing techniques used. For example, essentially all 
of the isoflavones in soy protein products can be extracted by alcohol 
washing, and their levels can also be reduced by repeated aqueous 
washings and some texturization techniques. Because of the estrogenic 
activities of the soy isoflavones, they have been hypothesized to 
contribute to the hypocholesterolemic effect of soy protein.
    The petitioner submitted an unpublished study by Crouse et al. 
(Ref. 31, documented in Ref. 1 with corrections noted in Ref. 2) that 
examined the effect of soy protein containing different levels of 
isoflavones in hypercholesterolemic men and women (summarized in Table 
1 of this document). Potential subjects were provided instruction in an 
NCEP Step 1 diet and followed this diet for 1 month. Subjects with 
qualifying serum lipid levels (LDL-cholesterol >140 mg/dL) were given a 
casein drink containing 25 g protein to consume in place of other 
protein in the NCEP Step 1 diet. Subjects compliant with this regimen 
were then randomized into one of five treatment groups and baseline 
blood lipid values were obtained. The treatment groups received 25 g 
protein from ISP prepared from soy with different levels of isoflavones 
(either 1.0, 1.6, or 2.5 mg total aglycone isoflavones/g protein), or 
25 g protein from alcohol-washed ISP that contained essentially no 
isoflavones (0.2 mg total aglycone isoflavones/g protein) or 25 g 
protein from casein (no isoflavones) in beverages for 9 weeks. Dietary 
intake was assessed at baseline and at the end of the study. Diet was 
reported to be stable and comparable between groups throughout the 
study, with 9 percent of energy derived from saturated fat. Body weight 
was also stable, with no differences between groups at baseline or at 
the end of the trial. Results indicated the ISP containing the highest 
level of isoflavones significantly lowered total (p<0.05) and LDL-
cholesterol (p<0.05), by 4 percent and 6 percent, respectively, while 
HDL-cholesterol was not altered (Table 1). Furthermore, in subjects 
with LDL-cholesterol in the top half of the study population, serum 
total and LDL-cholesterol were reduced by 9 percent (p<0.03) and 12 
percent (p<0.03), respectively, by the ISP with the highest isoflavone 
content, and by 8 percent (p<0.03) and 9 percent (p<0.03), respectively 
by the ISP with the second highest isoflavone content, while HDL-
cholesterol concentrations were maintained.

[[Page 62988]]

    Baum et al. (Ref. 28) also investigated the impact in soy protein 
containing different levels of isoflavones on cholesterol lowering and 
examined whether changes in blood lipids were lasting or transient. 
Subjects were moderately hypercholesterolemic women, who were at least 
1 year since last menstrual period, and were not taking medications 
known to alter lipid or bone metabolism. Following a 2-week run-in 
period during which subjects consumed an NCEP Step I diet, subjects 
were randomly assigned to one of three treatment groups consisting of 
40 g protein from either ISP with 1.4 mg total aglycone isoflavones/g 
protein, ISP with 2.3 mg total aglycone isoflavones/g protein, or 
casein/nonfat dry milk for the 24-week treatment period. Although the 
adjusted mean difference in total serum cholesterol level was not 
statistically significantly different in the soy groups and the control 
group, there was a significant reduction of 8 to 9 percent in non-HDL 
(LDL plus VLDL) cholesterol in both of the ISP treatment groups 
(p=0.04) compared to the control group. HDL-cholesterol was also 
significantly increased in both soy groups compared to the control. 
Body weight remained stable, and dietary intake was assessed and was 
reported to be similar among treatment groups although details were not 
reported.
    The petitioner concluded that these two studies (Refs. 31 and 28) 
provided evidence that the hypocholesterolemic effect of soy protein is 
dependent on processing techniques that enable retention of the 
naturally occurring isoflavones in conjunction with the soy protein. As 
additional supportive evidence for this conclusion, the petitioner 
cited studies of the lipid-lowering effects of soy protein with 
naturally occurring isoflavones in nonhuman primates (Refs. 22 and 70). 
In these experiments, the effects of diets including ISP with naturally 
occurring isoflavones compared with those of diets containing either 
casein or alcohol-washed ISP stripped of essentially all naturally 
occurring isoflavones were examined in two species of monkeys. The 
studies demonstrate significant depressions in total and non-HDL (LDL 
plus VLDL) cholesterol levels in response to diets containing 
unextracted ISP as compared with the diets containing casein or 
alcohol-washed ISP. As evidence that soy isoflavones alone, in the 
absence of soy protein, are ineffective in lowering blood lipids, the 
petitioner cited the study of Nestel et al. (Ref. 71). In that study, 
consumption of a tablet containing 80 mg of total aglycone isoflavones 
(mainly genistein and diadzein) had no impact on blood lipid profiles 
in postmenopausal women.
    Although the petitioner suggested, based on the studies of Crouse 
et al. (Ref. 31) and Baum et al. (Ref. 28), that isoflavone content 
exceeding a certain threshold was a useful marker for soy protein that 
would be effective in lowering blood lipid levels, FDA has tentatively 
concluded that the evidence is not sufficient to establish that the 
presence of isoflavones accounts for or is related to the effect on 
blood lipids. The agency notes that there are a variety of methods for 
processing soy that could give rise to variable amounts of naturally-
occurring isoflavones in soy protein products, and this is a possible 
hypothesis for explaining some of the variability in the results of 
human intervention studies. However, with two exceptions (Refs. 31 and 
28), the studies reviewed and described in this document did not 
include concurrent measures of the isoflavone content of the soy 
protein products studied. More importantly, a recent letter to the 
editor from Sirtori et al. (Ref. 72), which was not included in the 
petition, contradicts the conclusions of Crouse et al. (Ref. 31) and 
Baum et al. (Ref. 28). These researchers (Ref. 72) reported that the 
TVP fed in their studies contained essentially no isoflavones and still 
considerable impact on LDL-cholesterol was observed. These studies 
(Refs. 33, 56, 46, 35, and 34) were conducted in subjects with type II 
hypercholesterolemia and all showed large and significant decreases in 
blood total and LDL-cholesterol levels.
    Given the limited number of studies and the contradictory outcomes, 
FDA is not persuaded that the isoflavone component of soy protein is a 
relevant factor to the diet-disease relationship. Rather, FDA 
tentatively concludes that the evidence from a wide range of studies 
using differently processed soy protein is supportive of a relationship 
between soy protein per se and reduced risk of CHD.
6. Summary
    In five (Refs. 31, 28, 27, 51, and 44) of seven (Refs. 31, 28, 27, 
51, 44, and 40 (2 trials)) well-controlled studies of 
hypercholesterolemic subjects consuming low saturated fat and low 
cholesterol diets, soy protein intake was associated with statistically 
significant decreases in total and/or LDL-cholesterol levels, either in 
the entire study populations or subsets of subjects with higher initial 
blood lipid levels. Levels of HDL-cholesterol were found either to be 
unchanged (Refs. 31, 27, 51, and 40 (2 trials)) or slightly but 
statistically significantly increased (Refs. 28 and 44) by consumption 
of diets containing soy protein.
    Levels of soy protein as ISP found to be effective in lowering 
total and LDL-cholesterol levels, in the context of a diet low in 
saturated fat and cholesterol, ranged in these studies from 25 to 50 g 
(Refs. 31, 28, 27, and 51). As whole soybean milk, 31 g of soy protein 
lowered LDL-cholesterol only in the subset of subjects with the highest 
initial LDL-cholesterol levels and LDL/HDL-cholesterol levels (Ref. 
44). Diets providing 50 g of soy protein as SF did not cause 
significant changes from baseline for any of the blood lipids, but the 
decrease in total cholesterol observed after ingestion of SF was 
significantly greater than that on the control diet of nonfat dry milk 
and cellulose (Ref. 51). Diets providing 27 g of soy protein as SF in a 
textured product had no significant effects on blood lipid levels 
compared to a control diet, and a higher level (62 g) significantly 
lowered total cholesterol only in the experimental group fed the soy 
protein diet first (Ref. 40).
    Three intervention studies reported on effects of soy protein in 
hypercholesterolemic subjects consuming ``usual'' diets that were 
generally high in total fat, saturated fat, and cholesterol (Refs. 37, 
49, and 54). In each of these three studies, soy protein was fed in 
experimental diets as ISP (Refs. 37, 49, and 54). With a diet 
containing a very high level (99 g) of soy protein from this source 
(Ref. 37), statistically significant differences in both total and LDL-
cholesterol were reported. Results were less consistent, showing a 
significant decrease in total cholesterol only in subjects with the 
highest baseline levels, with a relatively low level of soy protein (17 
g) (Ref. 49). An intermediate level of soy protein (57 g) was found to 
be ineffective in lowering total cholesterol in the study of Shorey et 
al. (Ref. 54). (This latter study had a number of anomalous results.) 
HDL-cholesterol was also measured in these three studies. Changes were 
small and not statistically significant in two studies (Refs. 37 and 
49), but HDL-cholesterol was statistically significantly decreased from 
baseline values by 15 percent in one study (Ref. 54).
    Five intervention studies examined the effects of soy protein in 
normocholesterolemic subjects (Refs. 30, 36, 58, 59, and 53). Effects 
of soy protein on total and LDL-cholesterol were less consistent in 
normocholesterolemic subjects than in hypercholesterolemic subjects. As 
ISP, 44 g of soy protein was effective in significantly lowering total 
cholesterol in one study (Ref. 30) and 54 g

[[Page 62989]]

significantly lowered LDL-cholesterol in one study (Ref. 58). With very 
low initial blood lipid levels seen in some of these studies, the 
impact of dietary changes is considerably lessened. HDL-cholesterol was 
measured in four of these studies, with statistically significant 
increases associated with soy protein intake found in two (Refs. 58 and 
59) and no statistically significant changes in two (Refs. 36 and 53).
    Two intervention studies (Refs. 29 and 43) examined the 
hypocholesterolemic effects of soy protein versus casein in the context 
of hypocaloric diets fed to obese persons to achieve significant weight 
reduction. These two studies (Refs. 29 and 43) demonstrated large 
decreases in both total and LDL-cholesterol levels during hypocaloric 
diets that provided relatively low amounts (27 and 17 g, respectively) 
of soy protein. HDL-cholesterol was decreased in both soy and casein 
groups at the end of the first study (Ref. 29); however, only the 
casein group's values were significantly different (p<0.01) from 
baseline. Additionally, the decrease in HDL-cholesterol in the casein 
group was significantly greater (p<0.01) than that observed in the soy 
protein group. In the second study (Ref. 43), HDL-cholesterol levels 
were not significantly affected by dietary treatment.
    In all seven intervention studies conducted in adults with type II 
or familial hypercholesterolemia (Refs. 33, 35, 46, 55, 56, 60, and 
64), large and statistically significant decreases in both total and 
LDL-cholesterol levels were observed in response to consumption of 
diets containing soy protein. In the six trials in which they were 
measured, HDL-cholesterol levels were either not statistically 
significantly affected (Refs. 33, 64, 60, 46, and 35) or statistically 
significantly increased (Ref. 56). Each of these studies in adults with 
severe (type II or familial) hypercholesterolemia employed diets low in 
saturated fat and cholesterol (Refs. 33, 35, 46, 55, 56, 60, and 64) 
and most subjects had been consuming such a therapeutic diet prior to 
the study. Most trials used SF in TVP as the source of soy protein, in 
amounts ranging from 31 to 105 g (Refs. 33, 56, 60, 46, and 35); the 
remainder used ISP as the source of soy protein, in amounts ranging 
from 28 to 60 g (Refs. 55 and 64). Two of the three trials conducted in 
children with familial hypercholesterolemia demonstrated significant 
decreases from baseline levels in total and LDL-cholesterol during the 
periods when soy protein diets were consumed (Refs. 34 and 63).
    Evidence from one epidemiologic study (Ref. 65) supported a 
significant negative trend for lower serum total cholesterol 
concentrations with higher levels of soy protein intake (p<0.0001 for 
both men and women). Between the first and fourth quartiles in men 
total cholesterol was lower by12 mg/dL with a 9.6-g increase in soy 
protein intake. For women, total cholesterol was lower by 9 mg/dL with 
a 7.9-g increase in soy protein intake.
    Based on these studies, FDA tentatively finds there is scientific 
evidence for a consistent, clinically significant effect of soy protein 
on blood total and LDL-cholesterol. The hypocholesterolemic effect of 
soy protein is seen in addition to the effects of a low saturated fat 
and low cholesterol diet. The degree of lowering of blood total and 
LDL-cholesterol is consistently and highly dependent on initial levels, 
within and across studies of subjects with normal, moderately elevated, 
and severely elevated blood lipid levels, with persons having higher 
blood lipid levels showing greater effects. Soy protein consistently 
causes only statistically nonsignificant effects or slight elevations 
in HDL-cholesterol levels. The intervention studies suggest that a 
minimum level of approximately 25 g of soy protein is needed to have a 
clinically significant effect on total and LDL-cholesterol levels. 
These conclusions, drawn from the review of the individual, well 
controlled studies, are also supported by the meta-analysis of Anderson 
et al. (66).

IV. Decision To Propose a Health Claim Relating Soy Protein to 
Reduction in Risk of CHD

    The petition provided and FDA reviewed information on pertinent 
human studies that evaluated the effects on serum cholesterol and LDL-
cholesterol levels from dietary intervention with soy protein in 
subjects with normal to elevated serum cholesterol levels.
    FDA tentatively concludes that, based on the totality of publicly 
available scientific evidence, there is significant scientific 
agreement to support the relationship between consumption of soy 
protein included in a diet low in saturated fat and cholesterol and the 
risk of CHD. The strongest evidence for the effect of soy protein on 
the risk of CHD is provided by studies that measured the effect of 
dietary soy protein consumption on the two major risk factors for CHD, 
total and LDL-cholesterol.
    In most intervention trials in subjects with total cholesterol<300 
mg/dL, soy protein was found to reduce total and/or LDL-cholesterol 
levels to a clinically significant degree (Refs. 31, 28, 27, 51, 44, 
37, 49, 30, 58, 29, and 43). Moreover, HDL-cholesterol levels were 
unchanged (Refs. 31, 27, 51, 40, 37, 49, 36, and 53) or slightly 
increased (Refs. 28, 44, 58, and 59). In some cases (Refs. 27, 44, and 
49), decreases in total and LDL-cholesterol were statistically 
significant only in subsets of subjects with the higher initial blood 
lipid levels. Results in normocholesterolemic subjects (Refs. 30, 36, 
58, 59, and 53) were more variable than in hypercholesterolemic 
subjects (31, 28, 27, 51, 44, 40, 37, 49, 54, 29, and 43). The outcome 
of an epidemiologic study (Ref. 65) also supported a relationship 
between higher levels of soy protein intake and lower blood lipid 
levels.
    Most of the studies in subjects with total cholesterol<300 mg/dL 
used low saturated fat and low cholesterol diets (Refs. 31, 28, 27, 51, 
44, 30, 36, 53, 29, and 43), but some used ``usual'' diets (Refs. 37, 
49, 54, 36, 58, and 59). Although soy protein was found to lower blood 
lipid levels in some of the studies using ``usual'' diets, 
hypocholesterolemic effects of soy protein were more consistently 
observed with diets low in saturated fat and cholesterol. In some 
studies (especially those without run-in periods) (Refs. 40 and 54), 
the control low saturated fat and low cholesterol diets induced 
significant decreases in blood lipid levels making it difficult to 
detect any additional effect of soy protein. At the same time, in two 
studies in which soy protein containing hypocaloric diets were compared 
to similar diets without soy (Refs. 29 and 43), only the soy protein 
containing diets induced significant changes in blood lipid levels. 
Given the variability of amounts and forms in which soy protein was 
provided in the diets, the response of blood lipid levels appears 
robust.
    Data from studies of adults with type II and familial forms of 
hypercholesterolemia (and total cholesterol levels in excess of 300 mg/
dL) (Refs. 55, 33, 64, 56, 64, 46, and 35) were more consistent than 
studies in persons with lower blood lipid levels in showing large and 
statistically significant decreases in total and LDL-cholesterol, 
accompanied by no changes or slight increases in HDL-cholesterol 
levels. Nearly all of the subjects in these trials consumed low 
saturated fat and low cholesterol diets during the studies and had 
consumed such diets prior to studies with soy protein.
    Soy protein was tested in a variety of food forms (as soy 
beverages, formulated into meat and dairy product analogs, added to 
soups, or baked into foods, such as muffins and breads) but produced 
fairly consistent results

[[Page 62990]]

regardless of the food form fed and apparent differences in processing 
techniques.
     FDA tentatively concludes, based on the evidence submitted and 
reviewed, that soy protein, included in a diet low in saturated fat and 
cholesterol, can lower blood total and LDL-cholesterol levels, without 
adversely affecting HDL-cholesterol levels. The agency also tentatively 
concludes that the effect is due to soy protein per se and is not 
consistently related to the presence or absence of isoflavones. The 
intervention studies suggest that a minimum level of approximately 25 g 
of soy protein is needed to have a clinically significant effect on 
total and LDL-cholesterol levels.
    Based on the totality of the scientific evidence presented in the 
petition, the agency tentatively concludes that there is significant 
scientific evidence to show that soy protein, included in a diet low in 
saturated fat and cholesterol, will help reduce serum lipids, and that 
such reductions may reduce the risk of CHD. In the majority of clinical 
studies evaluating soy products, total and LDL-cholesterol were the 
lipid fractions shown to be the most affected by soy protein 
intervention. As part of a diet low in saturated fat and cholesterol, 
regular consumption of soy protein, in an amount to provide 25 g/day, 
resulted in reduced total and LDL-cholesterol levels in subjects with 
normal and elevated serum cholesterol levels. As stated in section 
III.A of this document, Federal Government and other reviews 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 (56 FR 60727 at 60728, and Refs. 4 
through 7). Dietary factors that decrease total cholesterol and LDL-
cholesterol will affect the risk of CHD (Refs. 4 through 7).
    Given all of this evidence, the agency is proposing a health claim 
on the relationship between soy protein and reduced risk of CHD.

V. Description and Rationale for Components of Health Claim

A. Relationship Between Soy Protein and CHD and the Significance of the 
Relationship

    Proposed Sec. 101.82(a) describes the relationship between diets 
low in saturated fat and cholesterol containing soy protein and the 
risk of CHD. In proposed Sec. 101.82(a)(1), the agency recounts that 
CHD is the most common and serious form of CVD, and that CHD refers to 
diseases of the heart muscle and supporting blood vessels. The proposed 
section 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 serum lipid 
levels that are associated with borderline high risk. This information 
will assist consumers in understanding the seriousness of CHD.
    In proposed Sec. 101.82(a)(2), the agency recounts that populations 
with a low incidence of CHD tend to have low blood total and LDL-
cholesterol levels. It 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 
authorized health claim for fruits, vegetables, and grain products and 
CHD (Sec. 101.77) and so the agency believes that this information 
provides a basis for a better understanding of the numerous factors 
that contribute to the risk of CHD and the relationship with soy 
protein and diets low in saturated fat and cholesterol.
    Proposed Sec. 101.82(a)(3) states that diets low in saturated fat 
and cholesteral may reduce the risk of CHD. The paragraph further 
states that soy protein, when added to such a diet, may also help 
reduce the risk of CHD.
    Proposed Sec. 101.82(b) describes the significance of the diet-
disease relationship. In proposed Sec. 101.82(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 claim states that early management of 
modifiable risk factors for CHD 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. 4 through 
8).
    In proposed Sec. 101.82(b)(2), the significance of the relationship 
between soy protein and CHD risk factors in context of the total diet 
is discussed. The agency recounts that many Americans' intakes of 
saturated fat and cholesterol exceed recommended levels, and it 
summarizes public health recommendations for the diet (56 FR 60727 at 
60738 and Sec. 101.75(b)(3)). This paragraph also states that 
scientific evidence demonstrates that diets low in saturated fat and 
cholesterol and that contain soy protein are associated with reduced 
blood lipids. FDA tentatively concludes that the latter statement is 
scientifically valid based on the evidence that it has reviewed on this 
nutrient-disease relationship.

B. Nature of the Claim

    In proposed Sec. 101.82(c)(1), FDA is proposing to require that all 
of the general requirements for health claims set out in Sec. 101.14 be 
met. This provision is consistent with the provisions of the other 
specific health claim regulations in 21 CFR part 101, subpart E.
    In proposed Sec. 101.82(c)(2)(i), FDA is proposing to authorize a 
health claim on the relationship between diets that contain soy protein 
and are low in saturated fat and cholesterol and the risk of CHD. The 
agency is proposing to do so based on its review of the scientific 
evidence on this nutrient-disease relationship, which shows that diets 
that contain soy protein and are low in saturated fat and cholesterol 
help to reduce total and LDL-cholesterol levels, especially in 
individuals with elevated blood total cholesterol (Refs. 31, 28, 27, 
51, 44, 37, 49, 30, 58, 29, 43, 55, 33, 64, 56, 64, 46, and 35). 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. 4 through 7).
    Most of the scientific evidence for an effect of soy protein on 
blood lipid levels was provided by studies that used diets low in 
saturated fat and cholesterol. Although soy protein was found to lower 
blood lipid levels in some of the studies using ``usual'' diets (Refs. 
37, 49, and 58), hypocholesterolemic effects of soy protein were more 
consistently observed with diets low in saturated fat and cholesterol.
    Moreover, as stated 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). Dietary estimates for American adults show that the average 
saturated fat intakes of American adults are about 13 percent of 
calories, total fat intakes are about 37 percent of calories, and 
average cholesterol intakes range from 300 to over 400 mg daily for 
adult men and women (56 FR 60727 at 60738). The current intakes of 
saturated fat and total fat are thus well in excess of recommended 
goals of less than 10 percent and 30 percent of calories.

[[Page 62991]]

 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. 4 through 7). The results of several studies showed that daily 
consumption of soy protein lowered total cholesterol and LDL-
cholesterol, and the effects of dietary intake of soy protein were 
evident when the diets were low in saturated fat and cholesterol (Refs. 
31, 28, 27, 51, 44, 30, 29, and 43). Thus, the agency tentatively finds 
that it will be more helpful to Americans' efforts to maintain healthy 
dietary practices if the effect of soy protein on serum lipids is 
characterized in the context of a diet low in saturated fat and 
cholesterol.
    In Sec. 101.82(c)(2)(i)(A), the agency is proposing to require, 
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 (56 FR 60727 at 60740 and 58 FR 2552 at 2573). The 
requirement that the claim use the term ``may'' or ``might'' to relate 
the ability of soy protein to reduce the risk of heart disease is also 
intended to reflect the multifactorial nature of the disease.
    In Sec. 101.82(c)(2)(i)(B), the agency is proposing to require, 
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 (56 FR 60727 at 60740 and 58 FR 2552 at 2573).
    In Sec. 101.82(c)(2)(i)(C), the agency is proposing that the claim 
specify the substance as ``soy protein.'' Based on its review of the 
scientific evidence submitted with the petition, the agency tentatively 
concludes that there is significant scientific agreement that diets low 
in saturated fat and cholesterol that contain soy protein may help to 
reduce blood total and LDL-cholesterol levels, the major modifiable 
risk factors for CHD (Refs. 31, 28, 27, 51, 44, 37, 49, 30, 58, 29, 43, 
55, 33, 64, 56, 64, 46, and 35). As discussed in section III.C.5 of 
this document, FDA did not find persuasive the limited and 
contradictory evidence that soy isoflavones are a relevant factor in 
the diet-disease relationship persuasive. Therefore, FDA has 
tentatively concluded that evidence from a wide range of studies 
supports a relationship between soy protein per se and reduced risk of 
CHD.
    As discussed previously, the agency tentatively finds that for the 
public to understand fully, in the context of the total daily diet, the 
significance of consumption of soy protein 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, in 
Sec. 101.82(c)(2)(i)(D), the agency is proposing to require that the 
claim include the fact that the effect of dietary consumption of soy 
protein on the risk of CHD is evident when it is consumed as part of a 
healthy diet and that, consistent with other authorized health claims, 
the fat component of the diet be specified as ``saturated fat'' and 
``cholesterol.'' Based on its review of the scientific evidence 
submitted with the petition, the agency tentatively concludes that 
there is significant scientific agreement that diets containing soy 
protein and low in saturated fat and cholesterol are associated with 
reduced blood total and LDL-cholesterol levels.
    Proposed Sec. 101.82(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 low in saturated fat and 
cholesterol that contain soy protein. None of the studies that the 
agency reviewed provide a basis for determining the percent reduction 
in risk of CHD likely from consuming diets that contain soy protein and 
are low in saturated fat and cholesterol. Also consistent with other 
authorized claims, proposed Sec. 101.82(c)(2)(i)(F) requires that the 
claim not imply that consumption of diets low in saturated fat and 
cholesterol and that contain soy protein is the only recognized means 
of reducing CHD risk.
    Proposed Sec. 101.82(c)(2)(i)(G) requires that the claim specify 
the daily dietary intake of soy protein 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 Sec. 101.81.
    In the studies showing a statistically significant effect of soy 
protein on total or LDL-cholesterol, the amounts fed ranged from 17 to 
105 g/day (Refs. 31, 28, 27, 51, 44, 37, 49, 30, 58, 29, 43, 55, 33, 
64, 56, 64, 46, and 35). In proposing 25 g/day as an effective daily 
intake of soy protein, the petitioner relied on the meta-analysis by 
Anderson et al. (Ref. 65) and noted that the estimate suggested by the 
meta-analysis was confirmed by the recent study of Crouse et al. (Ref. 
31) that found reductions in total and LDL-cholesterol of 4 and 6 
percent, respectively, with ingestion of 25 g/day of soy protein 
containing high levels of isoflavones.
    FDA notes that, although none of the studies reviewed attempted to 
determine an effective or optimal amount of soy protein, the study by 
Sirtori et al. (Ref. 56) suggests the existence of a dose-response. In 
that study of subjects with type II hypercholesterolemia, total 
cholesterol levels were reduced by 13 and 19 percent, and LDL-
cholesterol levels were reduced by 18 and 23 percent, compared to 
control by ingestion of 30 and 60 g/day of soy protein, respectively. 
With levels of soy protein intake lower than the proposed effective 
amount, findings have been variable. Mercer et al. (Ref. 49) found a 
statistically significant reduction in total cholesterol in response to 
17 g/day of soy protein only in those subjects with high initial 
values. Feeding the same amount (17 g/day) of soy protein in a 
hypocaloric diet, however, Jenkins et al. (Ref. 43) found statistically 
significant reductions of 10 and 17 percent in total and LDL-
cholesterol, respectively. With 25 g/day of soy protein, Bakhit et al. 
(Ref. 27) found a statistically significant reduction in total 
cholesterol (about 8 percent) in subjects with blood cholesterol levels 
greater than 220 mg/dL. Crouse et al. (Ref. 31) found that 25 g of soy 
protein that contained a high level of isoflavones significantly 
lowered total (p<0.05) and LDL-cholesterol (p<0.05), by 4 percent and 6 
percent, respectively. Furthermore, in subjects with LDL-cholesterol in 
the top half of the study population, serum total and LDL-cholesterol 
were reduced by 9 percent (p<0.03) and 12 percent (p<0.03), 
respectively, by soy protein with the highest isoflavone content, and 
by 8 percent (p<0.03) and 9 percent (p<0.03), respectively, by soy 
protein with the second highest isoflavone content. Although Holmes et 
al. (Ref. 40) did not find statistically significant changes in blood 
lipids with 27 g of soy protein, using 28 g of soy protein in a 
hypocaloric diet, Bosello et al. (Ref. 29) observed decreases of 16 
percent from baseline in both total and LDL-cholesterol (p<0.01). With 
31 g of soy protein, Kurowska et al. (Ref. 44) found an 11-percent 
reduction in LDL-cholesterol in subjects with the highest initial LDL-
cholesterol levels and LDL/HDL-cholesterol ratios. As a substitution or 
as an addition, Verillo et al. (Ref. 60) found 31 g of soy protein 
produced large (>20 percent) reductions in both total and LDL-
cholesterol in subjects with type II hypercholesterolemia.
    Based on these data that support a dose-response and that show 
clinically significant reductions in total and LDL-

[[Page 62992]]

cholesterol with soy protein ingestion in the range of 17 to 31 g/day, 
and recognizing that the hypocholesterolemic effects of soy protein are 
highly dependent on initial blood lipid levels, the agency has 
tentatively accepted that 25 g/day represents a reasonable effective 
amount of soy protein. In addition, an amount of 25 g/day of soy 
protein represents half of the Reference Daily Intake (RDI) of 50 g for 
protein and is a reasonable level of consumption in the context of the 
total daily diet. Thus, FDA tentatively concludes that the amount of 
soy protein associated with reduction in total and LDL-cholesterol 
levels and, thus, with reduced risk of CHD is 25 g or more of soy 
protein per day. The agency is asking for comments on this tentative 
determination.

C. Nature of the Substance

    Proposed Sec. 101.82(c)(2)(ii)(A) indicates that soy protein from 
the legume seed Glycine max is the substance that is the subject of 
this claim.
    Proposed Sec. 101.82(c)(2)(ii) (B) sets out FDA's tentative 
decision that soy protein when evaluated for compliance purposes by the 
agency will be measured using the Association of Official Analytical 
Chemists International (AOAC) official method of analysis No. 988.10.
    The petitioner proposed that measurement of total soy isoflavones 
be used as a marker for the content of soy protein in foods and as an 
indicator of the effectiveness of soy protein products in reducing 
blood cholesterol. As discussed in section C.III.5 of this document, 
FDA disagrees with the petitioner's conclusions regarding the 
significance of soy isoflavones with respect to the observed 
hypocholesterolemic effects of soy protein. Accordingly, FDA finds the 
proposed methodology to assess isoflavones irrelevant. The AOAC method 
that FDA is proposing instead is an enzyme-linked immunosorbant assay 
that detects soy protein in raw and heat-processed meat products. With 
this assay, samples are compared to standard commercial soy protein and 
appropriate blanks. The method is described as semi-quantitative, but 
it can be quantitative when the nature of the soy protein in the 
samples is known and the assay is calibrated accordingly. The sample 
extraction procedure, which involves preparation of an acetone powder, 
has been shown to be appropriate for a complex food matrix (meat). FDA 
believes, therefore, that this assay should also be suitable for other 
food matrices. FDA is requesting comments on the suitability of this 
method for assuring that foods bearing the health claim contain 
qualifying levels of soy protein.

D. Nature of the Food

    Proposed Sec. 101.82(c)(2)(iii)(A) requires that the food bearing 
the health claim contain at least 6.25 g of soy protein per reference 
amount customarily consumed (RACC) of the food product.
    Using 25 g of soy protein as the qualifying amount for a CHD claim, 
the petitioner suggested that a single serving of a soy protein-
containing product (i.e., 1 RACC) should provide 1/4 of this amount 
(based on 4 servings a day). Thus, a soy protein-containing product 
would have to contain at least 6.25 g soy protein (1/4 x 25 g) per 
RACC. The petitioner stated that this approach is reasonable because it 
would permit a wide variety of low fat, soy protein containing products 
to bear the health claim. The petitioner provided a list of products on 
the market that currently meet the proposed requirements and a list of 
products that could be modified to meet them (Ref. 1, Appendix V).
    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 (baked goods, tofu, 
soy beverages and shakes, meat analogs), the agency has tentatively 
concluded that the assumption of 4 servings/d of soy protein containing 
foods is reasonable. Therefore, the agency tentatively finds that use 
of the qualifying criterion set forth in the petition for this proposed 
rule is appropriate and is proposing this level in this document. The 
qualifying level of protein, 6.25 g/RACC, exceeds the amount required 
for a food to qualify as a ``good source'' of protein, i.e., 10 percent 
of the RDI of 50 g or 5 g/RACC).
    In Sec. 101.82(c)(2)(iii)(B), the agency is proposing, consistent 
with other authorized heart disease health claims, that foods bearing 
the health claim meet requirements for ``low saturated fat,'' ``low 
cholesterol,'' and ``low fat.'' In the preamble to the final rule on 
fruits, vegetables, and grain products and heart disease (Sec. 101.77, 
58 FR 2552 at 2572), the agency stated that populations with diets rich 
in these low saturated fat and low cholesterol foods experience many 
health advantages, including lower rates of heart disease. In the 
preamble to the proposed rule on dietary lipids and heart disease (56 
FR 60727 at 60739), the agency stated that while total fat is not 
directly linked to increased risk of CHD, it may have significant 
indirect effects. Foods that are low in total fat facilitate reductions 
in intakes of saturated fat and cholesterol to recommended levels. 
Therefore, the agency tentatively concludes that proposed 
Sec. 101.82(c)(2)(iii)(B) sets forth an appropriate requirement for 
food to be eligible to bear the soy protein and CHD claim.

E. Optional Information

    FDA is proposing in Sec. 101.82(d)(1) that the claim may state that 
the development of heart disease depends on many factors and, 
consistent with authorized CHD health claims, may list the risk factors 
for heart disease that are listed in Secs. 101.75(d)(1), 101.77(d)(1), 
and 101.81(d)(1). The agency is also proposing, in response to the 
petition, that the claim may provide additional information about the 
benefits of exercise and body weight management. This additional 
information can provide a context that is useful for an understanding 
of the relationship between soy protein and heart disease, but 
manufacturers should be cautioned that it should not be presented in a 
way that is misleading to the consumer.
    In proposed Sec. 101.82(d)(2), consistent with Secs. 101.75(d)(2), 
101.77(d)(2), and 101.81(d)(2), FDA is providing that the claim may 
state that the relationship between a diet high in soy protein and 
reduced risk of heart disease is through the intermediate link of 
``blood cholesterol'' or ``blood total cholesterol'' and ``LDL- 
cholesterol.'' The relationship between soy protein and reduced blood 
total cholesterol and LDL-cholesterol is supported by the scientific 
evidence presented in this proposal.
    In Sec. 101.82(d)(3), the agency is proposing that, consistent with 
Secs. 101.75(d)(3), 101.77(d)(3), and 101.81(d)(3), the claim may 
include information from Sec. 101.82(a) and (b). These paragraphs 
summarize information regarding the relationship between diets high in 
soy protein 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 high in soy protein can play to help reduce 
the risk of CHD.
    The agency is proposing that the claim may include any of the 
optional information authorized to be included in Secs. 101.75(d)(5), 
(d)(6), and (d)(7), 101.77(d)(5), (d)(6), and (d)(7), and 101.81(d)(5), 
(d)(6), and (d)(7). The health claim may state that diets high in soy 
protein and low in saturated fat and cholesterol are part of a dietary 
pattern

[[Page 62993]]

that is consistent with dietary guidelines for Americans. The claim may 
state that individuals with elevated serum lipids should consult their 
physicians for medical advice and treatment and may include information 
on the prevalence of CHD in the United States. The intent of this 
information is to provide consumers with information that will help 
them understand the seriousness of CHD in the United States and to help 
them understand that diets high in soy protein are consistent with 
dietary guidelines.

F. Model Health Claims

    In proposed Sec. 101.82(e), FDA is providing model health claims to 
illustrate the requirements of new Sec. 101.82. FDA emphasizes that 
these model health claims are illustrative only. These model claims 
illustrate the required, and some of the optional, elements of the 
proposed rule. If the agency authorizes a claim about the relationship 
between soy protein and CHD, manufacturers will be free to design their 
own claim so long as it is consistent with Sec. 101.82(c).
    In Secs. 101.82(e)(1) and (e)(2), the model claim illustrates all 
of the required elements of the proposed health claim. The claim states 
``25 grams of soy protein a day, as part of a diet low in saturated fat 
and cholesterol, may reduce the risk of heart disease. A serving of 
[name of food] supplies ---------- grams of soy protein.'' or ``Diets 
low in saturated fat and cholesterol that include 25 grams of soy 
protein may reduce the risk of heart disease. One serving of [name of 
food] provides ---------- grams of soy protein.''

VI. 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.

VII. Analysis of Impacts

A. Cost-Benefit Analysis

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866. Executive Order 12866 directs Federal 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). According to Executive Order 12866, a regulatory action is 
``economically 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 considered 
``significant'' under Executive Order 12866 if it raises novel legal or 
policy issues. FDA finds that this proposed rule is neither an 
economically significant nor a significant regulatory action as defined 
by Executive Order 12866.
    In addition, in accordance with the Small Business Regulatory 
Enforcement Fairness Act (5 U.S.C. 801(a)(1)(A)(ii)), the Administrator 
of the Office of Information and Regulatory Affairs of the Office and 
Management and Budget (the Administrator) has determined that this 
proposed rule is not a major rule for the purpose of congressional 
review. A major rule for this purpose is defined in 5 U.S.C. 804(2) as 
one that the Administrator has determined has resulted or is likely to 
result in: (1) An annual effect on the economy of $100,000,000 or more; 
or (2) a major increase in costs for prices for consumers, individual 
industries, Federal, State, or local government agencies, or geographic 
regions; or (3) significant adverse effects on competition, employment, 
investment, productivity, innovation, or on the ability of U.S.-based 
enterprises to compete with foreign-based enterprises in domestic or 
export markets.
    This proposed rule will give firms the option of making certain 
label claims involving soy protein. No costs will be generated by this 
proposed rule because it will not require any labels to be changed or 
any product to be reformulated. Firms will only relabel or reformulate 
products if the benefits to those firms outweigh the costs. Social 
benefits may be generated by this proposed rule because the value some 
consumers place on the information provided in these claims may be 
greater than the cost to industry of making these claims. In general, 
consumers may value this type of information because it will enable 
them to eat a healthier diet. Consumers may value this type of 
information presented on product labels, in particular, because it 
would obviate the need to consult other sources of information and 
because it may reassure consumers who are aware of the role of FDA in 
regulating health claims on product labels that the information is 
truthful, not misleading, and scientifically valid.
    Consumer valuation of this information will reflect the value that 
consumers place on reducing the likelihood of CHD and the perceived 
usefulness of this information for reducing the likelihood of CHD. 
However, consumers may either underestimate or overestimate the 
usefulness of this information in reducing the likelihood of CHD. 
Therefore, another metric for valuing the social benefits of this 
proposed rule is the health care costs avoided by the reduction in CHD-
related disease and disability made possible by this proposed rule. If 
consumers were aware of these health care costs and had an accurate 
notion of the likelihood that such costs could be avoided by using the 
information provided in the claims allowed by this proposed rule, then 
consumer valuation of this information would be at least as great as 
the value of any health care costs avoided. The value of the 
information might be greater because some consumers might value the 
information but might not choose to modify their behavior so as to 
reduce the likelihood of CHD.
    In general terms, the relevant regulatory options available to FDA 
are as follows: (1) Allow this claim to be made under a broader set of 
conditions than those specified in this proposed rule (e.g., with fewer 
required elements in the claim, or with a lower level of soy protein in 
a serving of food), and (2) allow this claim to be made under a more 
restricted set of conditions than those specified in this rule (e.g., 
more required elements or higher levels of soy protein). Neither of 
these alternatives would generate net costs because, like the proposed 
action, firms would only relabel or reformulate products if the 
benefits to those firms outweigh the costs. These options would 
generate higher benefits than the proposed action if allowing this 
claim to be made under either a broader set of conditions or more 
restricted set of conditions than the proposed conditions would provide 
consumers with more valuable information (that would nonetheless be 
truthful, not misleading, and scientifically valid) or would make 
possible a greater reduction in health care costs than would the 
proposed action. FDA tentatively believes that no alternative 
conditions exist that would render the net benefits of this proposed 
rule greater than the proposed conditions. In particular, FDA believes 
that the information proposed to be required in a health claim about 
the relationship between soy protein and CHD is the minimum necessary 
for the claim to be truthful, not misleading, and

[[Page 62994]]

scientifically valid, thereby maximizing the likelihood that qualifying 
foods will be labeled with the claim and that consumers will be able to 
use the information. Similarly, FDA believes that the amount of soy 
protein proposed to be required for a food bearing this claim will 
allow both the claim to appear on a significant number of foods and 
consumers who use the claim, in the aggregate, to benefit from the use 
of soy protein in their diet. However, FDA requests comments and 
supporting information on any modifications of the conditions under 
which this claim is allowed that would increase the net benefits of 
this proposed rule.

B. Small Entity Analysis

    FDA has examined the impacts of this proposed rule under the 
Regulatory Flexibility Act (5 U.S.C. 601-612). The Regulatory 
Flexibility Act requires Federal agencies to consider alternatives that 
would minimize the economic impact of their regulations on small 
businesses and other small entities. No costs will be generated by this 
proposed rule because it will not require any labels to be changed, or 
any product to be reformulated. Therefore, small businesses will only 
relabel or reformulate products if the benefits (e.g., increased sales 
of their products) to those small businesses outweigh the costs. 
Accordingly, under the Regulatory Flexibility Act) (5 U.S.C. 605(b)), 
the Commissioner of Food and Drugs certifies that this proposed rule, 
if issued, will not have a significant economic impact on a substantial 
number of small entities.

VIII. Paperwork Reduction Act

    FDA tentatively concludes that the labeling requirements proposed 
in this document 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 proposed food labeling health claim on the 
association between soy protein and coronary heart disease would be 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)).

IX. Effective Date

     FDA is proposing to make these regulations effective upon 
publication in the Federal Register of a final rule based upon this 
proposal.

X. Comments

    Interested persons may, on or before January 25, 1999, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. 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 office above 
between 9 a.m. and 4 p.m., Monday through Friday.

XI. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Protein Technologies International, Inc., ``Health Claim 
Petition,'' (CP1, vol. 1-3), May 4, 1998.
    2. Protein Technologies International, Inc., ``Addendum to Health 
Claim Petition,'' (CPI, vol. 4) August 10, 1998.
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of Hyperlipidemic Individuals,'' Atherosclerosis, 36:379-387, 1980.
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    42. Jacques, H., D. Laurin, S. Moorjani, F. H. Steinke, C. Gagne, 
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    44. Kurowska, E. M., J. Jordan, J. D. Spence, S. Wetmore, L. A. 
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American Journal of Clinical Nutrition, 54:98-103, 1991.
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Vaccarino, M. Marchi, G. Gaddi, and C. R. Sirtori, ``Soybean Protein 
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    47. Meinertz, H., O. Faergeman, K. Nilausen, M. J. Chapman, S. 
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Clinical Nutrition, 65:166-167, 1997.

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, it is 
proposed that 21 CFR part 101 be 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. New Sec. 101.82 is added to subpart E to read as follows:


Sec. 101.82   Health claims: Soy protein and risk of coronary heart 
disease (CHD).

      (a) Relationship between diets that are low in saturated fat and 
cholesterol and that include soy protein and the risk of CHD. (1) 
Cardiovascular disease means diseases of the heart and circulatory 
system. 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 CHD. 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 total 
cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18 mmol/L) 
and 130 to 159 mg/dL (3.36 to 4.11 mmol/L) of LDL-cholesterol. 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.

[[Page 62997]]

     (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 low in saturated 
fat and cholesterol may reduce the risk of CHD. Other evidence 
demonstrates that the addition of soy protein to a diet that is low in 
saturated fat and cholesterol may also help to reduce the risk of CHD.
    (b) Significance of the relationship between diets that are low in 
saturated fat and cholesterol and that include soy protein 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) 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 
lower blood total and LDL-cholesterol levels. Soy protein, when 
included in a low saturated fat and cholesterol diet, also helps to 
lower blood total and LDL-cholesterol levels.
     (c) Requirements. (1) All requirements set forth in Sec. 101.14 
shall be met.
    (2) Specific requirements--(i) Nature of the claim. A health claim 
associating diets that are low in saturated fat and cholesterol and 
that include soy protein 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 diets that are low in saturated fat and 
cholesterol and that include soy protein ``may'' or ``might'' reduce 
the risk of heart disease;
    (B) In specifying the disease, the claim uses the following terms: 
``heart disease'' or ``coronary heart disease'';
    (C) In specifying the substance, the claim uses the term ``soy 
protein'';
    (D) In specifying the fat component, the claim uses the terms 
``saturated fat'' and ``cholesterol'';
     (E) The claim does not attribute any degree of risk reduction for 
CHD to diets that are low in saturated fat and cholesterol and that 
include soy protein;
    (F) The claim does not imply that consumption of diets that are low 
in saturated fat and cholesterol and that include soy protein is the 
only recognized means of achieving a reduced risk of CHD; and
    (G) The claim specifies the daily dietary intake of soy protein 
that is necessary to reduce the risk of coronary heart disease and the 
contribution one serving of the product makes to the specified daily 
dietary intake level. The daily dietary intake level of soy protein 
that has been associated with reduced risk of coronary heart disease is 
25 grams (g) or more per day of soy protein.
    (ii) Nature of the substance. (A) Soy protein from the legume seed 
Glycine max.
    (B) FDA will measure soy protein by method No. 988.10 from the 
``Official Methods of Analysis of the Association of Official 
Analytical Chemists International,'' 16th Ed. (1995), which is 
incorporated by reference in accordance with 5 U.S.C. 522(a) and 1 CFR 
part 51. Copies may be obtained from the Association of Official 
Analytical Chemists International, 481 North Frederick Ave., suite 500, 
Gaithersburg, MD 20877-2504, or 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;
    (iii) Nature of the Food Eligible to Bear the Claim. (A) The food 
product shall contain at least 6.25 g of soy protein reference amount 
customarily consumed of the food product;
    (B) The food shall meet the nutrient content requirements in 
Sec. 101.62 for a ``low saturated fat,'' ``low cholesterol,'' and ``low 
fat'' food.
     (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 are low in saturated fat and cholesterol and that include 
soy protein 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 
are low in saturated fat and cholesterol and that include soy protein 
and CHD and the significance of the relationship;
     (4) The claim may state that a diet low in saturated fat and 
cholesterol that includes soy protein is 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);
     (5) 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;
    (6) 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,'' USDA and DHHS, GPO;
     (e) Model health claim. The following model health claims may be 
used in food labeling to describe the relationship between diets that 
are low in saturated fat and cholesterol and that include soy protein 
and reduced risk of heart disease:
    (1) 25 grams of soy protein a day, as part of a diet low in 
saturated fat and cholesterol, may reduce the risk of heart disease. A 
serving of [name of food] supplies -------------- grams of soy protein.
     (2) Diets low in saturated fat and cholesterol that include 25 
grams of soy protein may reduce the risk of heart disease. One serving 
of [name of food] provides ---------------- grams of soy protein.

    Dated: November 2, 1998.
William B. Schultz,
Deputy Commissioner for Policy.

[FR Doc. 98-30008 Filed 11-9-98; 8:45 am]
BILLING CODE 4160-01-F

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[FR Doc. 98-30008 Filed 11-9-98; 8:45 am]
BILLING CODE 4160-01-C