[Federal Register Volume 67, Number 121 (Monday, June 24, 2002)]
[Notices]
[Pages 42600-42608]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-15782]


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DEPARTMENT OF VETERANS AFFAIRS


Diseases Not Associated With Exposure to Certain Herbicide Agents

AGENCY: Department of Veterans Affairs.

ACTION: Notice.

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SUMMARY: As required by law, the Department of Veterans Affairs (VA) 
hereby gives notice that the Secretary of Veterans Affairs, under the 
authority granted by the Agent Orange Act of 1991, has determined that 
a presumption of service connection based on exposure to herbicides 
used in the Republic of Vietnam during the Vietnam Era is not warranted 
for the following conditions: Hepatobiliary cancers, nasal and 
nasopharyngeal cancer, bone cancers, breast cancer, cancers of the 
female reproductive system, urinary bladder cancer, renal cancer, 
testicular cancer, leukemia, reproductive effects (abnormal sperm 
parameters and infertility), Parkinson's disease, chronic persistent 
peripheral neuropathy, lipid and lipoprotein disorders, 
gastrointestinal and digestive disease (other than diabetes mellitus), 
immune system disorders, circulatory disorders, respiratory disorders 
(other than certain respiratory cancers), skin cancer, cognitive and 
neuropsychiatric effects, gastrointestinal tract tumors, brain tumors, 
amyloidosis, and any other condition for which the Secretary has not 
specifically determined a presumption of service connection is 
warranted.

FOR FURTHER INFORMATION CONTACT: John Bisset, Jr., Consultant, 
Regulations Staff, Compensation and Pension Service, Veterans Benefits 
Administration, 810 Vermont Avenue, NW., Washington, DC 20420, 
telephone (202) 273-7213.

SUPPLEMENTARY INFORMATION: Section 3 of the Agent Orange Act of 1991, 
Public Law 102-4, 105 Stat. 11, directed the Secretary to seek to enter 
into an agreement with the National Academy of Sciences (NAS) to review 
and summarize the scientific evidence concerning the association 
between exposure to herbicides used in support of military operations 
in the Republic of Vietnam during the Vietnam Era and each disease 
suspected to be associated with such exposure. Congress mandated that 
NAS determine, to the extent possible: (1) Whether there is a 
statistical association between the suspect diseases and herbicide 
exposure, taking into account the strength of the scientific evidence 
and the appropriateness of the methods used to detect the association; 
(2) the increased risk of disease among individuals exposed to 
herbicides during service in the Republic of Vietnam during the Vietnam 
Era; and (3) whether there is a plausible biological mechanism or other 
evidence of a causal relationship between herbicide exposure and the 
suspect disease. Section 3 of Public Law 102-4 also required that NAS 
submit reports on its activities every two years (as measured from the 
date of the first report) for a ten-year period.
    Section 2 of Public Law 102-4 provides that whenever the Secretary 
determines, based on sound medical and scientific evidence, that a 
positive association (i.e., the credible evidence for the association 
is equal to or outweighs the credible evidence against the association) 
exists between exposure of humans to an herbicide agent (i.e., a 
chemical in an herbicide used in support of the United States and 
allied military operations in the Republic of Vietnam during the 
Vietnam Era) and a disease, the Secretary will publish regulations 
establishing presumptive service connection for that disease. If the 
Secretary determines that a presumption of service connection is not 
warranted, he is to publish a notice of that determination, including 
an explanation of the scientific basis for that determination. The 
Secretary's determination must be based on consideration of the NAS 
reports and all other sound medical and scientific information and 
analysis available to the Secretary.
    Although Public Law 102-4 does not define ``credible,'' it does 
instruct the Secretary to ``take into consideration whether the results 
[of any study] are statistically significant, are capable of 
replication, and withstand peer review.'' Simply comparing the number 
of studies which report a positive relative risk to the number of 
studies which report a negative relative risk for a particular 
condition is not a valid method for determining whether the weight of 
evidence overall supports a finding that there is or is not a positive 
association between herbicide exposure and the subsequent development 
of the particular condition. Because of differences in statistical 
significance, confidence levels, control for confounding factors, bias, 
and other pertinent characteristics, some studies are clearly more 
credible than others, and the Secretary has given the more credible 
studies more weight in evaluating the overall weight of the evidence 
concerning specific diseases.
    NAS issued its initial report, entitled ``Veterans and Agent 
Orange: Health Effects of Herbicides Used in Vietnam,'' (VAO) on July 
27, 1993. The Secretary subsequently determined that a positive 
association exists between exposure to herbicides used in the Republic 
of Vietnam and the subsequent development of Hodgkin's disease, 
porphyria cutanea tarda, multiple myeloma, and certain respiratory 
cancers; and that there was no positive association between herbicide 
exposure and any other condition, other than chloracne, non-Hodgkin's 
lymphoma, and soft-tissue sarcomas, for which presumptions already 
existed. A notice of the diseases that the Secretary determined were 
not associated with exposure to herbicide agents was published on 
January 4, 1994. (See 59 FR 341 (1994).)
    NAS issued its second report, entitled ``Veterans and Agent Orange: 
Update 1996'' (Update 1996), on March 14, 1996. The Secretary 
subsequently determined that a positive association exists between 
exposure to herbicides used in the Republic of Vietnam and the 
subsequent development of prostate cancer and acute and subacute 
peripheral neuropathy in exposed persons. The Secretary further 
determined that there was no positive association between herbicide 
exposure and any other condition, other than those for which 
presumptions already existed. A notice of the diseases that the 
Secretary determined were not associated with exposure to herbicide 
agents was published on August 8, 1996. (See 61 FR 41442 (1996).)
    NAS issued a third report, entitled ``Veterans and Agent Orange: 
Update 1998'' (Update 1998), on February 11, 1999. The focus of this 
updated review was on new scientific studies published since the 
release of Update 1996 and updates of scientific studies previously 
reviewed. After NAS issued Update 1998, the Secretary determined that 
there was no positive association between herbicide exposure and any 
other condition, other than those for which presumptions already 
existed. A notice of the diseases that the Secretary determined were 
not associated with

[[Page 42601]]

exposure to herbicide agents was published on November 2, 1999. (See 64 
FR 59232 (1999).)
    However, after NAS released Update 1998 the National Institute of 
Occupational Safety and Health (NIOSH) published a report that noted an 
association, though not a strong association, between Type 2 diabetes 
and dioxin exposure. The Secretary concluded that the NIOSH study was 
potentially important enough that it warranted a full review by NAS as 
soon as possible, and he directed VA to amend its contract with NAS for 
the third biennial update to require a special report on herbicide 
exposure and Type 2 diabetes.
    In February 2000, before NAS released its report on herbicide 
exposure and Type 2 diabetes, the U.S. Air Force released data from its 
study of participants in operation Ranch Hand (the crews assigned to 
spray Agent Orange from aircraft in Vietnam) (AFHS. 2000a. Air Force 
Health Study: An Epidemiologic Investigation of Health Effects in Air 
Force Personnel Following Exposure to Herbicides. 1997 Follow-up 
Examination Results. Brook AFB, TX: Air Force Research Laboratory. 
AFRL-HE-BR-TR-2000-02.) On April 10, 2000, VA asked NAS to include an 
analysis of the new Ranch Hand data in its report on Type 2 diabetes. 
NAS agreed to do so.
    NAS issued its report, ``Veterans and Agent Orange: Herbicide/
Dioxin Exposure and Type 2 Diabetes'' (VAO: Diabetes) on October 11, 
2000. NAS concluded ``there is limited/suggestive evidence of an 
association between exposure to the herbicides used in Vietnam or the 
contaminant dioxin and Type 2 diabetes.'' NAS based its conclusion on 
the totality of the scientific evidence on this issue, not one 
particular study. (VAO: Diabetes). After considering all of the 
evidence, the Secretary determined that there is a positive association 
between exposure to herbicides and Type 2 diabetes and, therefore, a 
presumption of service connection was warranted. (See 66 FR 2376 
[2001].)
    NAS issued a fourth report, entitled ``Veterans and Agent Orange: 
Update 2000'' (Update 2000), on April 19, 2001. The focus of this 
updated review was on new scientific studies published since the 
release of Update 1998 and updates of scientific studies previously 
reviewed. The Secretary formed a VA task force to review the report and 
pertinent studies and to make recommendations to assist him in 
determining whether a positive association exists between herbicide 
exposure and any condition. The task force has completed that review 
and submitted its recommendations to the Secretary. This notice, 
pursuant to Public Law 102-4, summarizes the scientific data reviewed 
by NAS in its Update 2000 and conveys the Secretary's determination, 
which is based on the cumulative scientific data reported by NAS, that 
there is no positive association between herbicide exposure and 
hepatobiliary cancers, nasal and nasopharyngeal cancer, bone cancers, 
breast cancer, cancers of the female reproductive system, urinary 
bladder cancer, renal cancer, testicular cancer, leukemia, reproductive 
effects (abnormal sperm parameters and infertility), Parkinson's 
disease, chronic persistent peripheral neuropathy, lipid and 
lipoprotein disorders, gastrointestinal and digestive disease (other 
than diabetes mellitus), immune system disorders, circulatory 
disorders, respiratory disorders (other than certain respiratory 
cancers), skin cancer, cognitive and neuropsychiatric effects, 
gastrointestinal tract tumors, brain tumors, amyloidosis, and any other 
condition for which the Secretary has not specifically determined a 
presumption of service connection is warranted.
    NAS, in Update 2000 and a special additional report, assigns 
hepatobiliary cancers, nasal and nasopharyngeal cancer, bone cancers, 
breast cancer, cancers of the female reproductive system, urinary 
bladder cancer, renal cancer, testicular cancer, leukemia, reproductive 
effects (abnormal sperm parameters and infertility), Parkinson's 
disease, chronic persistent peripheral neuropathy, lipid and 
lipoprotein disorders, gastrointestinal and digestive disease (except 
diabetes mellitus), immune system disorders, circulatory disorders, 
respiratory disorders (other than certain respiratory cancers), skin 
cancer, cognitive and neuropsychiatric effects, and amyloidosis to a 
category labeled inadequate/insufficient evidence to determine whether 
an association exists. This is defined as meaning that the available 
studies are of insufficient quality, consistency, or statistical power 
to permit a conclusion regarding the presence or absence of an 
association with herbicide exposure. In Update 2000, NAS assigned 
gastrointestinal tract tumors and brain tumors to a category labeled 
limited or suggestive evidence of no association. This is defined as 
meaning that the available studies are mutually consistent in not 
showing a positive association between exposure to herbicides and the 
outcome at any level of exposure.

Hepatobiliary Cancers

    Hepatobiliary cancers are cancers of the liver and intrahepatic 
bile ducts. There are a variety of known risk factors, including 
chronic infections with hepatitis B and C, exposure to aflatoxin, vinyl 
chloride and polychlorinated biphenyl (PCB) and smoking, that should be 
considered by a credible study.
    NAS noted in VAO and subsequent reports that there were relatively 
few occupational, environmental, or veteran studies of hepatobiliary 
cancer. It also noted that most of the few existing studies addressing 
hepatobiliary cancer contain methodological difficulties such as small 
study size and inadequate control for life-style-related risk factors, 
or do not support an association with herbicide exposure.
    The largest industrial cohort exposed to dioxins is the group of 
5,132 U.S. workers known as the NIOSH cohort. This group was assembled 
from employees of 12 major chemical manufacturers that produced 2,4,5-
trichlorophenol, 2,4,5-T, Silvex, Erbon, Ronnel, and hexachlorophene. 
Workers engaged in production and maintenance were exposed to 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) as a contaminant in these chemicals. 
The first study of mortality through 1987 among these workers 
(Fingerhut et al., 1991, (See 59 FR 341 [1994])) found no elevated risk 
for cancers of the liver or hepatobiliary duct. This cohort has been 
updated through 1993 (Steenland K, Piacitelli L, Deddens J, Fingerhut 
M, Chang LI. 1999. Cancer, heart disease, and diabetes in workers 
exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Journal of the National 
Cancer Institute 91(9): 779-786.). In Update 2000, NAS noted that the 
updated analysis of mortality did not find any elevation in liver 
cancer mortality. Additionally, NAS noted that this study did not 
adjust for life-style factors.
    NAS reported in Update 2000 that a 1998 study of mortality among 
Danish paper mill workers (Rix BA, Villadsen E, Engholm G, Lynge E. 
1998. Hodgkin's disease, pharyngeal cancer, and soft tissue sarcomas in 
Danish paper mill workers. Journal of Occupational and Environmental 
Medicine 40(1):55-62.) did not find any elevation in liver cancer 
mortality.
    NAS noted that follow-up reports of the people environmentally 
exposed to TCDD in Seveso, Italy, (Bertazzi PA, Bernucci I, Brambilla 
G, Consonni D, Pesatori AC. 1998. The Seveso studies on early and long-
term effects of dioxin exposure: a review. Environmental Health 
Perspectives 106 (Suppl 2):625-

[[Page 42602]]

633; Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, 
Zocchetti C, Pesatori AC. 2001. Health effects of dioxin exposure: a 
20-year mortality study. American Journal of Epidemiology, 153(11): 
1031-1044.) did not add any new information concerning hepatobiliary 
cancer. Additionally, NAS noted that these follow-up reports did not 
adjust for life-style factors.
    NAS reported that a recent study of Air Force personnel (AFHS. 
2000b. An Epidemiologic Investigation of Health Effects in Air Force 
Personnel Following Exposure to Herbicides. 1997 Follow-up Examination 
and Results. Reston, VA: Science Application International Corporation. 
F41624-96-C1012.) provides a suggestion of an association between 
herbicide exposure and liver cancer. However, NAS found that, when 
considered with the overall body of evidence, this finding was not 
sufficient to a change its conclusion that there is inadequate or 
insufficient evidence of an association between exposure to herbicides 
used in Vietnam and hepatobiliary cancer.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and hepatobiliary cancer outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

Nasal and Nasopharyngeal Cancer

    Nasal and nasopharyngeal cancers are relatively rare in the United 
States and thus difficult to study epidemiologically. Reported risk 
factors for nasal cancer include occupational exposure to nickel and 
chromium compounds, wood dust, and formaldehyde. Studies of 
nasopharyngeal cancer have reported associations with the consumption 
of salt-preserved foods, cigarette smoking, and Epstein-Barr virus. NAS 
noted in VAO and subsequent reports that there was inadequate or 
insufficient evidence to determine whether an association exists 
between herbicide exposure and nasal and nasopharyngeal cancer.
    NAS reported in Update 2000 that an occupational study (Caplan LS, 
Hall HI, Levine RS, Zhu K. 2000. Preventable risk factors for nasal 
cancer. Annals of Epidemiology 10:186-191.) evaluated exposures among 
cases with nasal cancer identified in population-based cancer 
registries in five metropolitan areas and three states. The cancers 
were a mixed group that included mostly nasopharyngeal carcinomas, some 
sarcomas, and lymphomas. NAS found that this heterogeneity makes 
attribution of nasopharyngeal carcinoma to particular risk factors 
difficult.
    NAS reported that Bertazzi et al., (2001) did not identify any 
nasopharyngeal carcinomas in their population of TCDD-exposed residents 
of Seveso, Italy, and that Ranch Hand participants (AFHS, 2000a) did 
not show an excess risk of nasopharyngeal cancer.
    NAS found that there was no information contained in the research 
reviewed for Update 2000 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides and nasal and nasopharyngeal 
cancer. Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and nasal and nasopharyngeal cancer 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Bone Cancers

    NAS noted that bone cancer is more common in teenagers than adults, 
and, therefore, the incidence among Vietnam veterans is quite low. 
Among the risk factors for adults contracting bone and joint cancer are 
exposure to ionizing radiation from treatment for other cancers and a 
history of certain noncancerous bone diseases. NAS found in VAO and 
subsequent reports that there is inadequate or insufficient information 
to determine whether an association exists between exposure to 
herbicides and bone cancer.
    NAS noted in Update 2000 that Steenland et al.,1999, did not report 
results for bone cancer, and Rix et al., 1998, found only one case of 
bone cancer.
    NAS found that Bertazzi et al., 1998, did not add any new 
information to Bertazzi et al., 1997, (See 64 FR 59232 [1999]), and 
that Bertazzi et al., 2001, did not mention bone cancer mortality. 
Likewise, NAS noted that in AFHS 2000, bone cancer was not reported as 
one of the health outcomes of interest.
    NAS noted little new information to add to the existing sparse 
data, and therefore, found there is inadequate or insufficient evidence 
to determine whether an association exists between exposure to 
herbicides and bone cancer.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and bone cancer outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Breast Cancer

    NAS noted that breast cancer is the single most common cancer among 
women in the United States, excluding certain skin cancers. Breast 
cancer incidence generally increases with age. Risk factors other than 
aging include a personal or family history of breast cancer and certain 
reproductive characteristics; specifically, early onset of menarche, 
late onset of menopause, and either no pregnancies or first full-term 
pregnancy after 30 years of age. NAS noted in VAO and subsequent 
reports that there is inadequate or insufficient information to 
determine whether an association exists between exposure to herbicides 
and breast cancer.
    NAS noted in Update 2000, that Bertazzi et al., 1998, and Bertazzi 
et al., 2001, found no elevations in mortality from breast cancer.
    NAS found that, although there appears to be limited evidence to 
suggest that there is an epidemiologically defined protective effect of 
exposure to TCDD in reducing the overall incidence of breast cancer, 
this should be understood as limited to the narrow context of frequency 
of new disease. NAS noted that the term ``protective'' was used in a 
narrow technical sense of exposure being associated with a reduction in 
risk. The effect is not necessarily a benefit as it remains possible 
that exposure to TCDD and Agent Orange may affect lethality, 
distribution of tissue type, rate of progression, and invasiveness. NAS 
found limited evidence that this may be the case for organochlorine 
exposure in general (Demers A, Ayotte P, Brisson J, Dodin S, Robert J, 
Dewailly E. 2000. Risk and aggressiveness of breast cancer in relation 
to plasma organochlorine concentrations. Cancer Epidemiology, 
Biomarkers and Prevention 9:161-166.), but the data of another study 
(Hoyer AP, Jorgensen T, Brock JW, Grandjean P. 2000. Organochlorine 
exposure and breast cancer survival. Journal of Clinical Epidemiology 
53(3):323-330.) suggest that the effect is very specific in terms of 
compound. NAS stated that it is not known whether compounds relevant to 
Agent Orange exposure have this effect.
    NAS noted that there is a possibility that TCDD exposure could 
adversely affect the natural history of tumors that do arise. NAS cited 
a finding from Demers et al., 2000, that higher organochlorine exposure 
is associated with more invasive and progressive

[[Page 42603]]

disease, once a cancer does develop. NAS noted that Hoyer et al., 2000, 
found that higher levels of one organochlorine were associated with 
poorer prognosis of breast cancer. NAS stated that the relevance to 
women exposed to Agent Orange is uncertain. Importantly, NAS found no 
evidence from which to evaluate the possibility that exposure to 
organochlorine may modify the natural history if exposure takes place 
at certain sensitive periods during the development of breast tissue, 
such as puberty and pregnancy.
    NAS found no information in the research reviewed for Update 2000 
to change the conclusion that there is inadequate or insufficient 
evidence to determine whether an association exists between exposure to 
herbicides and breast cancer. Taking account of the available evidence 
and NAS' analysis, the Secretary has found that the credible evidence 
against an association between herbicide exposure and breast cancer 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Cancers of the Female Reproductive System

    NAS noted that the cancers of the female reproductive system 
include cancers of the cervix, endometrium (also referred to as the 
corpus uteri), and ovaries. Cervical cancers occur more often in 
African-American women than in white women, whereas white women are 
more likely to develop endometrial and ovarian cancers. The incidence 
of endometrial and ovarian cancer also depends on age, with older women 
at greater risk. Human papillomavirus infection is the most important 
risk factor for cervical cancer. Diet, a family history of the disease, 
and breast cancer are among the risk factors for endometrial and 
ovarian cancers. NAS noted in VAO and subsequent reports that there is 
inadequate or insufficient information to determine whether an 
association exists between exposure to herbicides and cancers of the 
female reproductive system.
    NAS stated in Update 2000 that the evidence from the reviewed 
studies is inconclusive because most of the published studies include a 
small number of cases and/or have poor exposure characterization or too 
short a follow-up period.
    NAS noted that Bertazzi et al., 1998 and 2001, found no increases 
in female reproductive cancers.
    NAS found that a case-control study of endometrial cancer in Sweden 
(Weiderpass E, Adami HO, Baron JA, Wicklund-Glynn A, Aune M, Atuma S, 
Persson I. 2000. Organochlorines and endometrial cancer risk. Cancer 
Epidemiology, Biomarkers and Prevention 9:487-493.), after adjustment 
for age and body mass index, reported no pesticides were associated 
with endometrial cancer.
    NAS reported that a study of female Vietnam veterans from Australia 
(Commonwealth Department of Veterans' Affairs (CDVA). 1998b. Morbidity 
of Vietnam Veterans: A Study of the Health of Australia's Vietnam 
Community. Volume 2: Female Vietnam Veterans Survey and Community 
Comparison Outcomes. Canberra: Department of Veterans' Affairs.) found 
an excess of all cancers combined. However, NAS noted that the numbers 
were small, and since the authors did not stratify or adjust for 
marital status, the findings may be confounded.
    NAS found that there was no information contained in the research 
reviewed for Update 2000 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides and cancers of the female 
reproductive system. Taking account of the available evidence and NAS' 
analysis, the Secretary has found that the credible evidence against an 
association between herbicide exposure and cancers of the female 
reproductive system outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.

Urinary Bladder Cancer

    Urinary bladder cancer is the most common of the genitourinary 
tract cancers. Bladder cancer incidence increases greatly with age for 
individuals older than 40. The most important known risk factor for 
bladder cancer is smoking. Occupational exposures to aromatic amines 
(also called arylamines), polycyclic aromatic hydrocarbons (PAHs), and 
certain other organic chemicals used in the rubber, leather, textile, 
paint products, and printing industries are also associated with higher 
incidence of bladder cancer. High-fat diets have been implicated as 
risk factors, along with exposure to the parasite Schistosoma 
haematobium.
    NAS noted in VAO and Update 1996 that there was limited or 
suggestive evidence of no association between exposure to herbicides 
used in Vietnam or the contaminant dioxin and urinary bladder cancer. 
NAS in Update 1998 changed that conclusion to inadequate or 
insufficient information regarding an association.
    NAS noted in Update 2000 that coexposure to TCDD and the known 
bladder carcinogen 4-aminobiphenyl in the Steenland et al., 1999, study 
makes it very difficult to determine whether dioxin exposure affected 
the observed incidence of bladder cancer.
    NAS reported that the overall results concerning bladder cancer 
from Bertazzi et al., 1998, and Bertazzi et al., 2001, were 
statistically indistinguishable from the expected number of bladder 
cancer cases.
    NAS noted that AFHS (2000) combined bladder and kidney cancers for 
analysis. Since both these cancers have a common association with 
smoking but are otherwise etiologically distinct diseases, NAS reported 
that the AFHS results were weakened.
    NAS found no information contained in the research reviewed for 
Update 2000 to change the conclusion that there is inadequate or 
insufficient evidence to determine whether an association exists 
between exposure to herbicides and urinary bladder cancer. Taking 
account of the available evidence and NAS'' analysis, the Secretary has 
found that the credible evidence against an association between 
herbicide exposure and urinary bladder cancer outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Renal Cancer

    Renal cancer is twice as common in men as in women. With the 
exception of Wilm's tumor, which is more likely to occur in children, 
renal cancer is more common in individuals older than 50. Smoking is a 
well-established risk factor for renal cancer. Other potential risk 
factors include diet, weight, and occupational exposure to asbestos and 
cadmium. Firefighters, who are routinely exposed to the decomposition 
of organic substances caused by a rise in temperature, are a known 
higher-risk group.
    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and renal cancer.
    NAS stated in Update 2000 that the results of a study of male Dutch 
production and contract workers (Hooiveld M, Heederik DJ, Kogevinas M, 
Boffetta P, Needham LL, Patterson DG Jr, Bueno de Mesquita HB. 1998. 
Second follow-up of a Dutch cohort occupationally exposed to phenoxy 
herbicides, chlorophenols, and contaminants. American Journal of 
Epidemiology 147(9):891-901.) are limited by the lack of control for 
smoking.
    NAS reported that, because cigarette smoking covaried with the 
indicators of

[[Page 42604]]

herbicide exposure used by AFHS (2000a) researchers, the analysis was 
confounded. NAS noted that the elevated incidence of renal cancer was 
seen in AFHS, 2000a, in the low-dioxin category but not the high-dioxin 
category, which would not be expected if an association existed between 
exposure and renal cancer.
    NAS stated that there is no information contained in the research 
reviewed for Update 2000 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides and renal cancer. Taking account 
of the available evidence and NAS'' analysis, the Secretary has found 
that the credible evidence against an association between herbicide 
exposure and renal cancer outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.

Testicular Cancer

    Testicular cancer is far more likely in men younger than 40 than in 
those who are older. Undescended testicles is a major risk factor for 
testicular cancer. Family history of the disease also appears to be a 
risk factor for testicular cancer.
    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and testicular cancer.
    NAS noted in Update 2000 that, among the studies reviewed, only one 
(Fleming LE, Bean JA, Rudolph M, Hamilton K. 1999b. Cancer incidence in 
a cohort of licensed pesticide applicators in Florida. Journal of 
Occupational and Environmental Medicine 41(4):279-288.) reported a 
statistically significant difference between the observed and expected 
number of cases of testicular cancer. NAS stated that the pesticide 
appliers studied by these researchers were likely exposed to a wide 
variety of chemicals, making it difficult to ascribe any effect to a 
particular compound.
    NAS reported that Bertazzi et al., 1998, did not report testicular 
cancer separately, but instead included it into a category called 
``genitourinary cancers.'' However, NAS noted, no increased risk was 
reported. Bertazzi et al., 2001, similarly did not report an increased 
risk for this category.
    NAS reported that the government of Australia conducted a mail 
survey of male veterans (CDVA, 1998a. Morbidity of Vietnam Veterans: A 
Study of the Health of Australia's Vietnam Veteran Community. Volume 1: 
Male Vietnam Veterans Survey and Community Comparison Outcomes. 
Canberra: Department of Veterans' Affairs.). A follow-up study was 
conducted to medically confirm selected conditions (Australian 
Institute of Health and Welfare (AIHW). 1999. Morbidity of Vietnam 
Veterans: A Study of the Health of Australia's Vietnam Veteran 
Community: Volume 3, Validation Study. Canberra: AIHW.). NAS noted that 
the authors found no elevated risk for testicular cancer.
    Noting that studies with either large numbers of cases or known 
TCDD exposures do not show an increased risk for testicular cancer, NAS 
stated that there is no information contained in the research reviewed 
for Update 2000 to change the conclusion that there is inadequate or 
insufficient evidence to determine whether an association exists 
between exposure to herbicides and testicular cancer. Taking account of 
the available evidence and NAS' analysis, the Secretary has found that 
the credible evidence against an association between herbicide exposure 
and testicular cancer outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.

Leukemia

    Acute lymphocytic leukemia (ALL) is a disease of the young and of 
individuals older than 70, and plays a small role in the age groups 
that characterize most Vietnam veterans. Exposure to high doses of 
ionizing radiation is a known risk factor. Acute myeloid leukemia (AML) 
is the most common leukemia among adults. Risk factors for AML include 
high doses of ionizing radiation, occupational exposure to benzene, and 
some medications used in cancer chemotherapy. Genetic disorders 
including Fanconi's anemia and Down's syndrome are associated with an 
increased risk for AML. Tobacco smoking has been suggested as a risk 
factor.
    Chronic lymphocytic leukemia (CLL) is the most common type of 
leukemia in men. It is largely a disease of individuals older than 40, 
and incidence doubles every 5 years for individuals in the age groups 
that characterize most Vietnam veterans. Some occupational groups, such 
as farmers, appear to have a higher incidence of CLL. A family history 
of the disease and a compromised immune system are additional suspected 
risk factors. Exposure to ionizing radiation does not appear to be 
associated with increased incidence of CLL.
    The incidence of chronic myeloid leukemia (CML) increases with age 
for individuals over 30. For individuals in the age groups that 
characterize most Vietnam Veterans, CML accounts for about one in five 
leukemias. CML is associated with an acquired chromosomal abnormality 
known as the ``Philadelphia chromosome.'' Exposure to high doses of 
ionizing radiation is a known risk factor for CML.
    NAS noted in VAO and subsequent reports that there is inadequate or 
insufficient information to determine whether an association exists 
between exposure to herbicides and leukemia.
    NAS, in Update 2000, reported that Hooiveld et al., 1998, Rix et 
al., 1998, Steenland et al., 1999, showed no increase risk for 
leukemia. NAS stated that CDVA, 1998a and 1998b, validated by AIHW, 
1999, found no increased risk for leukemia.
    NAS stated that the small number of cases found by AFHS (2000a/b) 
led to nonsignificant results.
    NAS reported that there was no information contained in the 
research reviewed for Update 2000 to change the conclusion that there 
is inadequate or insufficient evidence to determine whether as 
association exists between exposure to herbicides and leukemia. Taking 
account of the available evidence and NAS' analysis, the Secretary has 
found that the credible evidence against an association between 
herbicide exposure and leukemia outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.

Reproductive Effects

    Reproductive effects on veterans may include sperm quality and 
infertility.
    NAS noted in VAO and subsequent reports that there is inadequate or 
insufficient information to determine whether an association exists 
between exposure to herbicides and altered sperm parameters or 
infertility.
    NAS, in Update 2000, reported that studies of Danish farmers 
(Larsen SB, Joffe M, Bonde JP. 1998. Time to pregnancy and exposure to 
pesticides in Danish farmers. Occupational and Environmental Medicine 
55(4): 278-283.) and greenhouse workers (Abell A, Juul S, Bonde JP. 
2000. Time to pregnancy among female greenhouse workers. Scandinavian 
Journal of Work, Environment, and Health 26(2):131-136.) lacked 
information on TCDD level as a contaminant of the pesticides 
investigated. NAS also noted that studies limited to couples who 
achieve a pregnancy can be biased, because cases of infertility are 
excluded

[[Page 42605]]

(Sallmen M, Lindbohm ML, Nurminen M. 2000. Paternal exposure to lead 
and infertility. Epidemiology 11(2): 148-152.).
    NAS stated that there is no information in the research reviewed 
for Update 2000 to change the conclusion that there is inadequate or 
insufficient evidence to determine whether an association exists 
between exposure to herbicides and altered sperm parameters or 
infertility.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and reproductive effects in veterans 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Parkinson's Disease

    Because of the increasing concern that a link exists between 
Parkinson's disease (PD) and various chemicals used in herbicides, NAS, 
in VAO and subsequent reports, suggested that as Vietnam veterans move 
into the age groups when PD is more prevalent, attention be given to 
the frequency and character of new cases of PD in exposed versus 
nonexposed individuals.
    NAS, in Update 2000, stated that of the 30 studies summarized, only 
eight provide an estimate of relative risk of PD based on exposure to 
herbicides. Five of these studies found a significant association 
between herbicide exposure and PD (Butterfield et al., 1993 (See 61 FR 
41442 [1996]); Gorrell et al., 1998 (See 64 FR 59232 [1998]); Liou et 
al., 1997 (See 64 FR 59232 [1998]); Seidler et al., 1996 (See 64 FR 
59232 [1998]); Semchuk et al., 1992 (See 61 FR 41442 [1996])). One 
study found no association between herbicide exposure and PD (Taylor 
CA, Saint-Hilaire MH, Cupples LA, Thomas CA, Burchard AE, Feldman RG, 
Myers RH. 1999. Environmental, medical, and family history risk factors 
for Parkinson's disease: a New England-based case control study. 
American Journal of Medical Genetics (Neuropsychiatric Genetics) 88: 
742-749.). The two remaining studies found a negative association 
between herbicide exposure and PD (Kuopio A, Marttila RJ, Helenius H, 
Rinne UK. 1999. Environmental risk factors in Parkinson's disease. 
Movement Disorders 14: 928-939; Stern et al., 1991 (See 61 FR 41442 
[1996])). Based on the totality of the evidence, NAS concluded that 
there remains inadequate or insufficient evidence of an association 
between exposure to herbicides and PD.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and PD outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.

Chronic Persistent Peripheral Neuropathy

    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient evidence of an association between exposure to 
herbicides and chronic persistent peripheral neuropathy. Data from the 
Air Force Health Studies, in a large measure, accounted for this 
conclusion.
    In Update 2000, NAS reported that AFHS, 2000, found five cases of 
peripheral neuropathy in the Ranch Hand ground crew. NAS stated that 
this finding was consistent with the expected prevalence for peripheral 
neuropathy in the general population and prevalence increases with age. 
NAS noted that the development of a peripheral neuropathy associated 
with a toxic exposure begins when the exposure is occurring or shortly 
after cessation of the exposure. Furthermore, the peripheral nervous 
system has the ability to repair itself when the exposure ceases. 
Therefore, NAS stated that it is not biologically plausible that 
peripheral neuropathies found for the first time were caused by an 
exposure to herbicides that occurred 30 years earlier.
    NAS concluded that there remains inadequate or insufficient 
evidence of an association between exposure to herbicides and chronic 
persistent peripheral neuropathy. Taking account of the available 
evidence and NAS' analysis, the Secretary has found that the credible 
evidence against an association between herbicide exposure and chronic 
persistent peripheral neuropathy outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.

Lipid and Lipoprotein Disorders

    Plasma lipid concentrations (notably cholesterol) have been shown 
to predict cardiovascular disease and are considered fundamental to the 
underlying atherosclerotic process. The two major lipids, cholesterol 
and triglycerides, are carried in the blood attached to proteins to 
form lipoproteins. NAS in VAO and subsequent reports found there was 
inadequate or insufficient information to determine whether an 
association exists between exposure to herbicides and lipid and 
lipoprotein disorders.
    NAS, in Update 2000, stated that AFHS, 2000a/b, provided incomplete 
and inconsistent evidence on a possible association between dioxin 
exposure and lipid abnormalities and noted the failure to evaluate the 
role of obesity. NAS noted that there were no other new studies for it 
to evaluate on this subject. NAS concluded that there is inadequate or 
insufficient evidence to determine whether an association exists 
between exposure to herbicides and lipid and lipoprotein disorders.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and lipid and lipoprotein disorders 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Gastrointestinal and Digestive Disease

    Gastrointestinal and digestive disease includes diseases of the 
esophagus, stomach, intestines, rectum, liver, and pancreas. NAS, in 
VAO and subsequent reports, found there was inadequate or insufficient 
information to determine whether an association exists between exposure 
to herbicides and gastrointestinal and digestive disease.
    NAS, in Update 2000, stated that most of the studies reviewed for 
the first time had insufficient numbers of cases to draw confident 
conclusions. NAS noted that one study with a relatively large number of 
observations (Vena J, Boffeta P, Becher H, Benn T, Bueno de Mesquita 
HB, Coggon D, Colin D, Flesch-Janys D, Green L, Kauppinen T, Littorin 
M, Lynge E, Mathews JD, Neuberger M, Pearce N, Pesatori AC, Saracci R, 
Steenland K, Kogevinas M. 1998. Exposure to dioxin and nonneoplastic 
mortality in the expanded IARC international cohort study of phenoxy 
herbicide and chlorophenol production workers and sprayers. 
Environmental Health Perspectives 106 (Suppl. 2): 645-653.) found lower 
digestive system disease and liver cirrhosis mortality among exposed 
workers than unexposed controls.
    NAS reported that studies of Australian veterans (CDVA 1998a and 
1998b) suggested a higher incidence of stomach and duodenal ulcers in 
both men and women, but information was self-reported and the analyses 
were not controlled for confounding influences.
    NAS noted that AFHS, 2000a, found a significantly higher percentage 
of liver disorders among Ranch Hands in the high-dioxin category than 
among comparisons. NAS found that this data was consistent with an 
interpretation of a dose-response relationship, but that

[[Page 42606]]

other explanations were also plausible. NAS noted that the authors of 
AFHS, 2000a/b, are preparing a separate report examining the 
relationship between liver disorders and herbicide exposure in greater 
detail.
    NAS concluded that there was no information contained in the 
research reviewed for Update 2000 to change the conclusion that there 
is inadequate or insufficient evidence to determine whether an 
association exists between exposure to herbicides and gastrointestinal 
and digestive diseases. Taking account of the available evidence and 
NAS' analysis, the Secretary has found that the credible evidence 
against an association between herbicide exposure and gastrointestinal 
and digestive disease outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.

Immune System Disorders

    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and immune system disorders.
    In Update 2000, NAS noted that the immune effects described in 
humans exposed to TCDD have been marginal and have varied from study to 
study. Some studies showed increased risk, others decreased risk, and 
others no effect. Further, workers exposed to high levels of TCDD for 
several years with body burdens at least ten times higher than the 
general population had no significant risk for immune system disorders.
    NAS reported that immune parameters were measured in veterans of 
Operation Ranch Hand (Michalek JE, Ketchum NS, Check IL. 1999a Serum 
dioxin and immunologic response in veterans of Operation Ranch Hand. 
American Journal of Epidemiology 149: 1038-1046; AFHS, 2000a/b). NAS 
noted that there was no evidence of a consistent relationship between 
dioxin exposure and immune system alteration.
    NAS reported in Update 2000 that there is no information contained 
in the research reviewed for this report to change the conclusion that 
there is inadequate or insufficient evidence to determine whether an 
association exists between exposure to herbicides and immune system 
disorders. Taking account of the available evidence and NAS' analysis, 
the Secretary has found that the credible evidence against an 
association between immune system disorders and herbicide exposure 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Circulatory Disorders

    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and circulatory disorders.
    In Update 2000, NAS stated that new studies from occupational 
epidemiology contain the key limitations recognized in Update 1998: 
reliance on mortality as an outcome, the unassessed validity of 
assigned cause of death, and the inability to address potential 
confounding by other causes of cardiovascular and cerebrovascular 
disease.
    NAS reported that the evidence of increased circulatory disease 
mortality exists in the follow-up of the Seveso, Italy, population 
(Bertazzi et al., 2001), but the pattern is somewhat inconsistent 
across levels of exposure and the statistical power of the study 
remains limited, particularly for women.
    NAS reported that the findings on circulatory conditions from AFHS 
2000 tend to be inconsistent and inconclusive. Excess mortality is 
reported for enlisted ground personnel from Operation Ranch Hand, but 
this finding is not supported in subsequent analyses of cardiovascular 
and cerebrovascular morbidity. NAS noted that AFHS 2000 shows no 
dioxin-related increased risk for myocardial infarction and the 
combination of stroke and transient ischemic attack.
    NAS noted that elevated rates of heart disease were reported in the 
Australian veterans studies (CDVA, 1998a and 1998b). However, NAS 
stated that there was some uncertainty in the numbers of cases due to 
possible misreporting.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2000 to change the conclusion that there 
is inadequate or insufficient evidence to determine whether an 
association exists between exposure to herbicides and circulatory 
disorders. Taking account of the available evidence and NAS' analysis, 
the Secretary has found that the credible evidence against an 
association between herbicide exposure and circulatory disorders 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.

Respiratory Disorders

    Cigarette smoking is a major, often overwhelming, confounding 
factor that dominates as a risk for respiratory disorders and may 
obscure weaker risks. NAS noted in VAO and subsequent reports that 
there was inadequate or insufficient information to determine whether 
an association exists between exposure to herbicides and respiratory 
disorders.
    NAS noted in Update 2000 that new evidence (cited below) suggests 
that there may be an increased risk for respiratory disorders among 
individuals exposed to TCDD. However, NAS stated that this association 
is based on small numbers, is not adjusted for smoking, and is not 
internally consistent. Other studies of occupationally exposed subjects 
do not show this association, although some of these studies are large 
enough to have revealed this association if it were present.
    NAS reported that Steenland et al., 1999, showed no risk for 
respiratory disorders. NAS noted that this study was large enough to 
have the statistical power to demonstrate such a risk. Also, NAS found 
that AFHS 2000 showed no increased risk for respiratory disorders.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2000 to change the conclusion that, except 
for respiratory cancers, there is inadequate or insufficient evidence 
to determine whether an association exists between exposure to 
herbicides and respiratory disorders. Taking account of the available 
evidence and NAS' analysis, the Secretary has found that the credible 
evidence against an association between herbicide exposure and 
respiratory disorders other than respiratory cancers outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

Skin Cancer

    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and skin cancer.
    NAS stated that studies reviewed for the first time in Update 2000 
provide additional morbidity data and mortality analyses to account for 
factors that confound the evaluation of melanoma incidence in groups 
with exposure to chemical agents. NAS reported that Bertazzi et al., 
2001, has too few cases of melanoma to be informative. NAS noted that 
CDVA, 1998a and b, and AFHS 2000 provided some new important data. 
However, NAS also reported that AFHS 2000 had too few cases of melanoma 
to be informative. NAS noted that CDVA, 1998a and b, included the use 
of self-reported cases with no validation through medical record 
reviews or other means.

[[Page 42607]]

According to NAS, CDVA, 1998a and b, did not control for confounders 
and used a nonmilitary control group.
    NAS reported that there are relatively few studies that examine 
nonmelanomas and fewer that separate basal and squamous cell 
carcinomas. NAS stated that CDVA, 1998a and 1998b, and AFHS, 2000a/b, 
provide new morbidity data for these outcomes. However, NAS reported 
that the small number of cases in AFHS 2000 limited the results. NAS 
noted that CDVA, 1998a and 1998b, used self-reported cases and failed 
to control for important confounders. Also, NAS noted that the results 
for females were based on a very small number of subjects.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2000 to change the conclusion that there 
is inadequate or insufficient evidence to determine whether an 
association exists between exposure to herbicides and skin cancer. 
Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and skin cancer outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Cognitive and Neuropsychiatric Effects

    NAS noted in VAO and subsequent reports that there was inadequate 
or insufficient information to determine whether an association exists 
between exposure to herbicides and cognitive and neuropsychiatric 
effects.
    NAS noted in Update 2000 that AFHS 2000 found an association 
between dioxin exposure and only one of five disease categories 
studied, ``other'' neuroses, which included more than 100 clinically 
dissimilar classifications of diseases. NAS reported that the 
biological plausibility for such an association is lacking. NAS noted 
that, in cases where verified psychological diagnoses from AFHS 2000 
were combined with verified psychological diagnoses from previous AFHS 
studies, it is not clear whether the past diagnoses were active at the 
time of the AFHS 2000 report. NAS questioned the criteria used for 
these psychological diagnoses. Also, NAS stated that if these other 
neuroses were associated with dioxin exposure, the onset of symptoms of 
specific conditions would have occurred at a much earlier time, when 
they would be more closely related to actual exposure.
    NAS concluded that there is still inadequate or insufficient 
evidence to determine whether an association exists between exposure to 
herbicides and cognitive and neuropsychiatric effects. Taking account 
of the available evidence and NAS' analysis, the Secretary has found 
that the credible evidence against an association between herbicide 
exposure and cognitive and neuropsychiatric effects outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

Gastrointestinal Tract Tumors

    The incidence of stomach, colon, rectal, and pancreatic cancers 
increases with age for individuals between 45 and 59. Other risk 
factors vary for these cancers but always include family history of the 
same form of cancer, certain diseases of the affected organ, and 
dietary factors.
    NAS noted in VAO and subsequent reports that there was limited or 
suggestive evidence of no association between exposure to herbicides 
and gastrointestinal (GI) tract tumors.
    NAS stated in Update 2000 that, with only rare exceptions, studies 
on GI tract cancers and exposure to herbicides in production, from 
agricultural use, from environmental sources, and among veteran 
populations provided no evidence of any increase in risk. NAS noted 
that Steenland et al., 1999, did not report site-specific GI cancers, 
and there was a nonsignificantly elevated excess risk for GI cancers in 
the highest-exposed subgroups. NAS noted that Rix et al., 1998, found 
some nonsignificant elevations of GI cancers, but the possible link 
with dioxin exposure was not well established. NAS noted that Hooiveld 
et al., 1998, found no significant risk of GI cancer. NAS noted that 
Bertazzi et al., 2001, found some statistically excess risks, but these 
were based on relatively small numbers of cases and do not seem to 
occur with any consistency. Also, NAS noted that among studies of 
Vietnam veterans (AFHS, 2000a/b; CDVA, 1998a and 1998b; AIHW, 1999) 
there was no significant evidence of an association between herbicide 
exposure and any GI cancer.
    NAS concluded that there was no new evidence to change the previous 
determination that there is limited or suggestive evidence of no 
association between exposure to herbicides and gastrointestinal tract 
cancer. Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and gastrointestinal tract cancer outweighs 
the credible evidence for such an association, and he has determined 
that a positive association does not exist.

Brain Tumors

    NAS noted in VAO and subsequent reports that there was limited or 
suggestive evidence of no association between exposure to herbicides 
and brain tumors.
    NAS reported in Update 2000 that the studies reviewed for the first 
time found small numbers of cases of brain tumors and no excess risk. 
NAS noted that Hooiveld et al., 1998, found no deaths due to brain 
cancer. NAS noted that Bertazzi et al., 2001, found no new deaths from 
brain cancers. NAS noted that AFHS 2000 reported only one case of brain 
cancer and, consequently, the authors performed no statistical 
analysis.
    NAS concluded that there was no new evidence to change the previous 
determination that there is limited or suggestive evidence of no 
association between exposure to herbicides and brain tumors. Taking 
account of the available evidence and NAS' analysis, the Secretary has 
found that the credible evidence against an association between 
herbicide exposure and brain tumors outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.

Amyloidosis

    Amyloidosis is a group of bone marrow diseases, poorly understood 
and relatively rare, characterized by accumulation of insoluble 
fibrillar proteins (amyloid) in various organs and tissues of the body 
such that vital function is compromised. Systemic amyloidosis is a 
complication that occurs in approximately 15-20 percent of patients 
with multiple myeloma, which is also a bone marrow disease.
    VA asked NAS to address the possible association between exposure 
to herbicides and amyloidosis, a condition not examined in its prior 
reports.
    In Update 2000, NAS identified a single report that addressed 
exposure to the herbicides and amyloidosis. This report (T[oacute]th K, 
Somfai-Relle S, Sug[aacute]r J, Bence J. 1979. Carcinogenicity testing 
of herbicide 2,4,5-trichlorophenoxyethanol containing dioxin and of 
pure dioxin in Swiss mice. Nature 278(5704):548-549.) described the 
results of carcinogenicity tests of the herbicide 2,4,5-
trichlorophenoxyethanol containing dioxin and of pure dioxin in Swiss 
mice. NAS reported that the mice developed amyloidosis secondary to 
skin lesions caused by the chemical exposure. NAS did not identify any 
literature addressing primary (in

[[Page 42608]]

absence of a discernible preceding disease) amyloidosis in animals or 
people exposed to herbicides or dioxin.
    NAS concluded that there is inadequate or insufficient evidence to 
determine whether an association exists between exposure to herbicides 
and amyloidosis. Taking account of the available evidence and NAS' 
analysis, the Secretary has found that the credible evidence against an 
association between herbicide exposure and amyloidosis outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.
    NAS reviewed scientific and medical articles published since the 
publication of its first report as an integral part of the process that 
resulted in ``Veterans and Agent Orange: Update 2000.'' The 
comprehensive review and evaluation of the available literature which 
NAS conducted in conjunction with its report has permitted VA to 
identify all conditions for which the current body of knowledge 
supports a finding of an association with herbicide exposure. 
Accordingly, the Secretary has determined that there is no positive 
association between exposure to herbicides and any other condition for 
which he has not specifically determined that a presumption of service 
connection is warranted.

    Approved: June 11, 2002.
Anthony J. Principi,
Secretary of Veterans Affairs.
[FR Doc. 02-15782 Filed 6-21-02; 8:45 am]
BILLING CODE 8320-01-P