[Federal Register Volume 68, Number 97 (Tuesday, May 20, 2003)]
[Notices]
[Pages 27630-27641]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-12593]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF VETERANS AFFAIRS


Diseases Not Associated With Exposure to Certain Herbicide Agents

AGENCY: Department of Veterans Affairs.

ACTION: Notice.

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

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 and the Veterans 
Education and Benefits Expansion Act of 2001, 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, nasopharyngeal cancer, 
bone and joint cancer, breast cancer, cancers of the female 
reproductive system, urinary bladder cancer, renal cancer, testicular 
cancer, leukemia (other than chronic lymphocytic leukemia (CLL)), 
abnormal sperm parameters and infertility, Parkinson's disease and 
parkinsonism, amyotrophic lateral sclerosis (ALS), chronic persistent 
peripheral neuropathy, lipid and lipoprotein disorders, 
gastrointestinal and digestive disease, immune system disorders, 
circulatory disorders, respiratory disorders (other than certain 
respiratory cancers), skin cancer, cognitive and neuropsychiatric 
effects, gastrointestinal tract tumors, brain tumors, light chain-
associated (AL) amyloidosis, endometriosis, adverse effects on thyroid 
homeostasis, and any other condition for which the Secretary has not 
specifically determined a presumption of service connection is 
warranted.

FOR FURTHER INFORMATION CONTACT: Cheryl Konieczny, Consultant, 
Regulations Staff, Compensation and Pension Service, Veterans Benefits 
Administration, 810 Vermont Avenue, NW, Washington, DC 20420, telephone 
(202) 273-6779.

SUPPLEMENTARY INFORMATION: Section 3 of the Agent Orange Act of 1991, 
Pub. L. 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 Pub. L. 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 Pub. L. 102-4, codified in pertinent part at 38 U.S.C. 
1116(b) and (c), 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.
    Section 2 of the Agent Orange Act of 1991 provided that the 
Secretary's authority and duties under that section would expire 10 
years after the first day of the fiscal year in which NAS transmitted 
its first report to VA. The first NAS report was transmitted to VA in 
July 1993, during the fiscal year that began on October 1, 1992. 
Accordingly, VA's authority under section 2 of the Agent Orange Act of 
1991 expired on September 30, 2002. In December 2001, however, Congress 
enacted the Veterans Education and Benefits Expansion Act of 2001, 
Public Law 107-103. Section 201(d) of that Act extended VA's authority 
under 38 U.S.C. 1116(b)-(d) through September 30, 2015.
    Although 38 U.S.C. 1116 does not define ``credible,'' it does 
instruct the Secretary to ``take into consideration whether the results 
[of any study] are

[[Page 27631]]

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 exposure to herbicide agents was published on 
November 2, 1999. (See 64 FR 59232 [1999].)
    At VA's request, NAS issued a special interim 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. After NAS issued Update 2000, 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 exposure to herbicide agents was published on June 
24, 2002 (See 67 FR 42600-608).
    NAS issued its fifth report, entitled ``Veterans and Agent Orange: 
Update 2002'' (Update 2002) on January 23, 2003. The focus of this 
updated review was on new scientific studies published since the 
release of Update 2000, and to review the studies previously reviewed 
along with the newest scientific evidence. The Secretary subsequently 
determined that a positive association exists between exposure to 
herbicides used in the Republic of Vietnam and the subsequent 
development of chronic lymphocytic leukemia (CLL) in exposed persons. A 
proposed rule to establish a presumption of service connection for CLL 
was published in the Federal Register of March 26, 2003 (See 68 FR 
14567). The Secretary also determined that there is no positive 
association between herbicide exposure and hepatobiliary cancers, 
nasopharyngeal cancer, bone and joint cancer, breast cancer, cancers of 
the female reproductive system, urinary bladder cancer, renal cancer, 
testicular cancer, leukemia (other than CLL), abnormal sperm parameters 
and infertility, Parkinson's disease and parkinsonism, amyotrophic 
lateral sclerosis (ALS), chronic persistent peripheral neuropathy, 
lipid and lipoprotein disorders, gastrointestinal and digestive disease 
including liver toxicity, immune system disorders, circulatory 
disorders, respiratory disorders (other than certain respiratory 
cancers), skin cancer, cognitive and neuropsychiatric effects, 
gastrointestinal tract tumors, brain tumors, AL amyloidosis, 
endometriosis, adverse effects on thyroid homeostasis, and any other 
condition for which the Secretary has not specifically determined a 
presumption of service connection is warranted. This notice, pursuant 
to 38 U.S.C. 1116(c)(1)(B), summarizes the scientific data reviewed by 
NAS in its Update 2002, and conveys the Secretary's determination 
regarding no positive association between herbicide exposure and the 
above-cited conditions.
    NAS, in Update 2002, assigns hepatobiliary cancers, nasopharyngeal 
cancer, bone and joint cancer, breast cancer, cancers of the female 
reproductive system, urinary bladder cancer, renal cancer, testicular 
cancer, leukemia (other than CLL), abnormal sperm parameters and 
infertility, Parkinson's disease and parkinsonism, chronic persistent 
peripheral neuropathy, lipid and lipoprotein disorders, 
gastrointestinal and digestive disease, immune system disorders, 
circulatory disorders, respiratory disorders (other than certain 
respiratory cancers), skin cancer, cognitive and neuropsychiatric 
effects, AL amyloidosis, endometriosis, and adverse effects on thyroid 
homeostasis 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 2002, 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

[[Page 27632]]

herbicides and the outcome at any level of exposure.
    The Secretary's determinations regarding individual diseases are 
based on all available evidence in Update 2002 and prior NAS reports. 
This notice generally states specific information only with respect to 
significant additional studies that were first reviewed by NAS in 
Update 2002. Information regarding additional relevant studies has 
previously been stated in VA's prior notices following earlier NAS 
reports, and will not be repeated here.

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 or 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.
    An environmental study of the residents of Chapaevsk, Russia, an 
industrial community with documented contamination by dioxins and other 
chemicals of the food and water supply, revealed a higher incidence of 
liver cancer than in Russia as a whole or the Samara region of Russia, 
in which Chapaevsk is located, although no information was provided on 
exposed cases or estimated relative risk for morbidity. (Revich B, 
Aksel E, Ushakova T, Ivanova I, Zuchenko N, Lyuev N, Brodsky B, Sotsov 
Y. 2001. Dioxin exposure and public health in Chapaevsk, Russia. 
Chemosphere 43:951-966) In Update 2002, NAS determined that this study 
cannot be taken as strong evidence for an association between dioxins 
and liver cancer because the study failed to adjust for confounding by 
socioeconomic, lifestyle, comorbidity and other factors, and because of 
the likelihood of multiple exposures and concerns regarding the study 
design.
    NAS found that there was no information contained in the research 
reviewed for Update 2002 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides 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.

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.
    An environmental study of the residents of Chapaevsk, Russia, 
revealed a higher incidence of pharyngeal cancer in females than in 
Russia as a whole, although no information was provided on exposed 
cases or estimated relative risk for morbidity. (Revich et al., 2001.) 
Male residents of Chapaevsk did not show a higher incidence of 
pharyngeal cancer. NAS reported, in Update 2002, that the usefulness of 
these data is restricted because of factors such as lack of adjustment 
for confounding, the likelihood of multiple exposures, concern 
regarding the study design, and the absence of information on the 
completeness and accuracy of cancer incidence data.
    NAS found that there was no information contained in the research 
reviewed for Update 2002 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides 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 nasopharyngeal cancer outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

Bone and Joint Cancer

    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.
    An environmental study of the residents of Chapaevsk, Russia, 
revealed seven deaths in male residents and seven deaths in female 
residents due to cancer of the bones or soft tissues. (Revich et al., 
2001.) In Update 2002, NAS reported that these results cannot be taken 
as evidence for an association between bone cancer and dioxins, because 
cancers of the bone and soft tissue were combined in the analysis. 
Further, the increased risk for death due to bone cancer and soft-
tissue cancer combined was not statistically significant.
    NAS found that there was no information contained in the research 
reviewed for Update 2002 to change the conclusion that there is 
inadequate or insufficient evidence to determine whether an association 
exists between exposure to herbicides and bone and joint 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 and joint 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 second most common cancer among 
women in the United States. 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 age 30. 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.
    In its prior reports, NAS reviewed several studies finding no 
increased risk of breast cancer associated with herbicide exposure or 
Vietnam service, and possibly even showing a limited protective effect 
for new incidence of breast cancer

[[Page 27633]]

    NAS reviewed a number of new studies for Update 2002. A follow up 
to an occupational study reviewed in Update 2000 published results on 
the reproducibility of the self-reported data on farm exposures to 
potentially hazardous agents such as pesticides. (Duell EJ, Millikan 
RC, Savitz DA, Schell MJ, Newman B, Tse CJ, Sandler DP. 2001. 
Reproducibility of reported farming activities and pesticide use among 
breast cancer cases and controls: A comparison of two modes of data 
collection. Annals of Epidemiology 11(3):178-185) It was found that the 
farming-exposure information was generally reproducible, which provided 
some assurance that the prior conclusion of no overall excess risk of 
breast cancer was not due to measurement error in the exposure 
assessment.
    An environmental study of the joint effects of all congeners of 
polychlorinated biphenyls (PCBs) (Holford TR, Zheng T, Mayne ST, Zahm 
SH, Tessari JD, Boyle P. 2000. Joint effects of nine polychlorinated 
biphenyl (PCB) congeners on breast cancer risk. International Journal 
of Epidemiology 29 (6):975-82) showed that total PCB was not 
significantly associated with breast cancer risk. NAS noted, however, 
that significant protective effects were detected for potential 
antiestrogens and a dioxin-like congener. This study was consistent 
with results of previously reported studies. General population 
controls were not used, which limited the external validity of the 
results.
    The relationship between the relatively high dioxin concentrations 
in Chapaevsk, Russia and breast cancer incidence and related mortality 
was studied in Revich et al. (2001). The incidence rate of female 
breast cancer, age-adjusted to the Russian standard population, was 
higher in Chapaevsk in all age groups than in Russia and the Samara 
region. NAS noted that the lack of adjustment for such risk factors as 
family size, breastfeeding, alcohol use, body-mass index and fat 
consumption was one of the main weakness of this study.
    Two environmental studies provided evidence of a relationship 
between the development of breast cancer and increased concentrations 
of PCB congeners that have dioxin-like activity. (Aronson KJ, Miller 
AB, Woolcott CG, Sterns EE, McCready DR, Lickley LA, Fish EB, Hiraki 
GY, Holloway C, Ross T, Hanna WM, SenGupta SK, Weber J-P. 2000. Breast 
adipose tissue concentrations of polychlorinated biphenyls and other 
organochlorines and breast cancer risk. Cancer Epidemiology, Biomarkers 
and Prevention 9(1):53-63; Demers A, Ayotte P, Brisson J, Dodin S, 
Robert J, Dewailly E. 2002. Plasma concentrations of polychlorinated 
biphenyls and the risk of breast cancer: A congener-specific analysis. 
American Journal of Epidemiology 155(7):629-635) NAS noted that the 
external validity of one of the studies (Aronson et al.) was limited by 
the lack of general-population controls. NAS found that the other study 
(Demers et al.) was well conducted and appears to have used appropriate 
statistical methods. NAS also noted, however, that PCB cogeners also 
have non-dioxin-like components, and that the observed effects may be 
attributable to those components.
    Another study found further evidence of increased breast cancer 
risk associated with increased serum TCDD. (Warner M, Eskenazi B, 
Mocarelli P, Gerthoux PM, Samuels S, Needham L, Patterson D, Brambilla 
P. Serum dioxin concentrations and breast cancer risk in the Seveso 
Women's Health Study. Environmental Health Perspectives 2002; 110(7) 
625-628) NAS found that this study adjusted for risk factors and was 
apparently free from potential bias. NAS also noted, however, that the 
findings were potentially limited because they were based on only 15 
cases.
    In a Vietnam veteran study that included 4,140 female Vietnam 
veterans and 4,140 veteran controls that did not service in Vietnam, it 
was concluded that Vietnam veterans did not experience a significantly 
higher prevalence of breast cancer. (Kang HK, Mahan CM, Lee KY, Magee 
CA, Selvin S. 2000. Prevalence of gynecologic cancers among female 
Vietnam veterans. Journal of Occupational & Environmental Medicine 
42(11):1121-1127.) Although the prevalence of breast cancer was higher 
in female Vietnam veterans than in non-Vietnam veterans, the difference 
was not considered statistically significant. This study, also, was 
considered by NAS to be well designed, have adequate power, and be 
highly relevant for the assessment of the effect of Agent Orange and 
other herbicides on breast cancer risk in Vietnam veterans. NAS also 
noted, however, that the study's usefulness may be limited because 
questions on exposure focused on the Vietnam experience as a whole 
instead of on exposures to Agent Orange, other herbicides or their 
contaminants.
    NAS concluded that there is still inadequate or insufficient 
evidence to determine whether there is an association between exposure 
to herbicides and breast cancer.
    As noted above, studies reviewed in prior NAS reports predominately 
showed no association between breast cancer and herbicide exposure, or 
possibly a limited protective association. The additional evidence 
reviewed in Update 2002 includes evidence consistent with those prior 
studies, as well as some studies providing evidence of an association, 
subject to the limitations discussed above.
    Taking account of the available evidence and NAS's 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.
    In Update 2002, NAS reported that the environmental study involving 
Chapaevsk, Russia (Revich et al., 2001) appeared to show an increased 
risk of cervical cancer, but noted that the number of cases on which 
the rates were calculated was not provided and may have been small, and 
further noted that the potential for confounding by socioeconomic 
factors was not addressed.
    NAS noted that the Kang et al. (2000) environmental study on 
gynecologic cancers among female Vietnam veterans provided some 
evidence that service in Vietnam does not substantially increase the 
risk of uterine, ovarian or cervical cancer, but the report made no 
attempt to examine exposures to herbicides or TCDD in Vietnam.
    NAS found that no strong studies addressing female reproductive 
cancers

[[Page 27634]]

in relation to herbicides or their contaminants had been conducted 
since Update 2000. They concluded that there was no information 
contained in the research reviewed for Update 2002 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 over 
40 years. 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. Exposure 
to inorganic arsenic is also a risk factor for bladder cancer, and 
cacodylic acid is a metabolite of inorganic arsenic. The data remain 
insufficient to conclude that studies of inorganic arsenic exposure are 
directly relevant to exposure to cacodylic acid. Therefore, NAS did not 
consider the literature on inorganic arsenic.
    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, beginning with Update 1998, changed that conclusion to inadequate 
or insufficient information regarding an association.
    In Update 2002, NAS reviewed an updated occupational study of 
mortality in Dow chemical workers potentially exposed to herbicides 
(Burns CJ, Beard KK, Cartmill JB. 2001. Mortality in chemical workers 
potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-
1994: an update. Occupational and Environmental Medicine 58(1):24-30), 
which found no increased risk of mortality due to bladder cancer.
    NAS also reviewed Revich et al. (2001), in which an increase in 
age-adjusted bladder cancer incidence was shown in Chapaevsk compared 
to the Samara Region of the Russian Republic. NAS noted, however, that 
the study did not control for occupation and smoking history, and there 
was no information on the number of cases included in the analysis or 
the completeness of surveillance for cancer in Chapaevsk and the Samara 
region.
    In Update 2002, NAS concluded that there is no evidence to support 
changing the ``inadequate or insufficient'' categorization for 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 over age 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.
    In Update 2002, NAS reviewed an updated occupational study of 
mortality in Dow chemical workers potentially exposed to herbicides 
(Burns et al., 2001), which concluded that there was no evidence of an 
association between exposure to 2,4-D and mortality due to renal 
cancer. NAS noted that this study has low precision due to the small 
number of deaths from renal cancer.
    NAS also reviewed the results of Revich et al. (2001), which found 
age-adjusted incidence of renal cancer to be similar between Chapaevsk 
and the Samara region. Incidence rates of renal cancer in all of Russia 
was slightly lower. However, NAS noted that no information was given on 
the number of cases in the calculation of those incidence rates or the 
stability of those rates in previous years, and does not consider 
confounders other than age.
    NAS stated that there is no information contained in the research 
reviewed for Update 2002 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.
    In Update 2002, NAS reviewed an update of an occupational study of 
mortality in chemical workers at Dow Chemical Company (Burns et al., 
2001). One death from testicular cancer was identified among 1,517 male 
Dow employees. The study concluded that there is no significant risk of 
testicular cancer in this cohort. NAS concluded that the updated study 
analysis provided no evidence to suggest that chronic herbicide 
exposure increases the risk of 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 (Other than chronic lymphocytic leukemia (CLL))

    There are four primary types of leukemia: The acute and chronic 
forms of lymphocytic leukemia and the acute and chronic forms of 
myeloid (or granulocytic) 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

[[Page 27635]]

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.
    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 that abnormality.
    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. Because CLL, the most 
common form of leukemia, shares many traits with lymphomas, NAS 
reviewed it separately from the other leukemias in Update 2002.
    In Update 2002, NAS reviewed one new occupational study (Burns et 
al., (2001)) which reported data on a cohort male workers involved in 
the manufacture or formulation of 2,4-D. Mortality from leukemia in the 
entire cohort was similar to rates in all U.S. males. Similar results 
were obtained in an analysis based on a 20-year induction period. In 
the comparison with nonexposed workers, an excess in lymphopoietic 
mortality was noted in workers with high-cumulative-dose exposure to 
2,4-D. NAS noted, however, that at least some of the deaths may have 
been due to Hodgkin's disease or multiple myeloma.
    In another occupational study, cancer incidence and mortality were 
assessed in a cohort of 504 forestry workers in Sweden who were 
characterized by presence or absence of exposure to phenoxy herbicides 
in 1954-1967 (Thorn A, Gustavsson P, Sadigh J, Westerlund-Hannerstrand 
B, Hogstedt C 2000. Mortality and cancer incidence among Swedish 
lumberjacks exposed to phenoxy herbicides. Occupational and 
Environmental Medicine 57:718-720). No cases of leukemia occurred in 
the exposed members of this cohort.
    In an environmental study, Revich et al. (2001) analyzed data on 
cancer incidence and mortality in Chapaevsk, Russia. Mortality due to 
leukemia during the years 1995-1998 was compared with mortality in the 
Samara region as a whole. Age-adjusted incidences during 1998 were 
reported for leukemia and lymphoma combined. The rates in Chapaevsk 
were lower than in the Samara region in men but higher in women. NAS 
noted a number of weaknesses contained in this study, including failure 
to report the actual number of cases, failure to calculate confidence 
intervals, and lack of adjustment for factors other than age.
    NAS found no compelling or consistent evidence of an association 
with exposure to herbicides contained in the new reports reviewed for 
Update 2002 to change the conclusion that there is inadequate or 
insufficient evidence to determine whether as association exists 
between exposure to herbicides and leukemia (other than CLL).
    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 (other than CLL) outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.

Abnormal Sperm Parameters 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.
    In Update 2002, NAS reviewed the results of an environmental study 
which assessed whether exposure to heavy metals, PCBs, volatile organic 
compounds, and polycyclic aromatic hydrocarbons is related to early 
reproductive effects. (Staessen JA, Nawrot T, Hond ED, Thijs L, Fagard 
R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, 
Van Hecke E, Verschaeve L, Vlietinck R, Roels HA. 2001. Renal function, 
cytogenetic measurements, and sexual development in adolescents in 
relation to environmental pollutants: a feasibility study of 
biomarkers. Lancet 357(9269):1660-1669. [Comment in Lancet 2001. 
358(9295):1816-1817.]) The study compared 100 17-year-old lifetime 
residents of two highly exposed suburbs of Antwerp, Belgium, with 100 
17-year-old lifetime residents of a rural control community. 
Concentrations of several environmental agents, including dioxin-like 
compounds in serum samples, were found to be higher in the two suburban 
locations than in the control community, after adjustment for sex, 
body-mass index (BMI), weeks of breastfeeding, parental social class, 
and dietary fat intake. NAS noted that the results indicate that 
children in the two suburban locations experienced substantial and 
statistically significant delays in sexual maturation and lower 
testicular volume. NAS further noted that the results of this study 
support a potential effect on male reproductive capacity, but that the 
implication for Vietnam veterans remains unclear, inasmuch as most 
veterans were past their pubertal development during their tours of 
duty.
    NAS also discussed a review of medical literature (Fig[aacute]-
Talamance I, Traina ME, Urbani E. 2001. Occupational exposures to 
metals, solvents, and pesticides: recent evidence on male reproductive 
effects and biological markers. Occupational Medicine 51(3): 174-88.), 
the authors of which concluded that there is insufficient evidence to 
conclude that the use of pesticides leads to significantly higher risk 
to human reproduction.
    NAS stated that there is no information in the research reviewed 
for Update 2002 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 and Parkinsonism

    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 noted in VAO and subsequent reports that there is inadequate or 
insufficient information to determine whether an association exists 
between exposure to herbicides and PD.
    In Update 2002, NAS reviewed an occupational study in which 238 
subjects exposed to pesticides in an occupational setting and 72 
nonexposed controls were examined for the presence of parkinsonism. 
(Engel LS, Checkoway H, Keifer MC, Seixas NS, Longstreth WT, Scott KC, 
Hudnell K, Anger WK, Camicioli R. 2001. Parkinsonism and occupational 
exposure to pesticides.

[[Page 27636]]

Occupational and Environmental Medicine 58:582-589.) NAS stated that 
the overall results of this study are similar to those of many other 
studies reviewed in Update 2000, in which an association with many 
years of occupational exposure is associated with parkinsonism but no 
association is found with any individual pesticide or class of 
pesticides.
    NAS also reviewed a prospective cohort study with 30 years of 
follow up on 7,986 Japanese-American men (Honolulu Heart Program) who 
worked on sugar cane and pineapple plantations in Hawaii to determine 
whether working on a plantation or exposure to pesticides is associated 
with an increased risk of PD. (Petrovich et al. (2002, in press).) The 
study showed that as the duration of work increased, pesticide exposure 
increased significantly. NAS stated that even though age-adjusted 
incidence of PD increased with increasing pesticide exposure, the trend 
was not significant. Those with over 20 years of plantation work had 
twice the risk of PD of those with no plantation work. With 10 years of 
plantation work or less, there was no increase in risk of PD, but a 
significant trend of increased risk occurred with further years of 
exposure.
    NAS noted that an association of PD with exposure to 2,4-D, 2,4,5-
T, or TCDD is not reported in any of the studies.
    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.

Amyotrophic Lateral Sclerosis (ALS)

    ALS is a progressive motor neuron disease with adult onset that 
presents with muscle atrophy, weaknesses, and fasciculations. The 
incidence of ALS peaks between the ages of 55 to 75 years. Known risk 
factors for ALS are age and a family history of ALS. Interest in the 
role of occupational or environmental exposure originated in cases of 
motor neuron disease associated with exposure to heavy metals, chemical 
plants, animal carcasses, heavy manual labor, work with electricity, 
pneumatic tools, work in the plastic industry, and work as a truck 
driver.
    In Update 2002, NAS summarized the results of five epidemiologic 
studies of pesticide exposure and ALS. One study found the association 
between pesticides and ALS was not statistically significant but was 
positive. (Deapen DM, Henderson BE. 1986. A case-control study of 
amyotrophic lateral sclerosis. American Journal of Epidemiology 
123:790-799.) In another study, no statistically significant 
associations were found between ALS and several risk factors, including 
agricultural chemicals and organic solvents, although there was a 
positive association between ALS and agricultural chemicals. 
(Savettieri G, Salemi G, Arcara A, Cassata M. Castiglione MG, Fierro B. 
1991. A case-control study of amyotrophic lateral sclerosis. 
Neuroepidemiology 10:242-245.)
    A case-control epidemiologic study in Scotland of 103 ALS cases 
from a Scottish motor neuron disease register and 103 age- and sex-
matched controls identified risk factors for development of the 
disease. (Chancellor AM, Slattery JM, Fraser H. 1993. Risk factors for 
motor neuron disease: A case-control study based on patients from the 
Scottish motor neuron disease register. Journal of Neurology, 
Neurosurgery, and Psychiatry 56:1200-1206.) Significant differences 
with increased exposure in cases were found for occupational exposure 
to lead and ``solvent/chemicals.'' NAS noted that occupational 
pesticide exposure was not significantly different but did have a 
positive association.
    The results of a mortality study of male employees of the Dow 
Chemical Company (Burns et al., 2001) showed three deaths due to ALS. 
The study found a significantly increased relative risk of death due to 
ALS. All three died more than 20 years after their first exposure; 
duration of employment was 1.3, 1.8, and 12.5 years.
    A population-based case-control epidemiologic study was conducted 
to examine the relationship between ALS and occupational exposures to 
metals, solvents, and agricultural chemicals. (McGuire V, Longstreth 
WT, Nelson LM, Koepsell TD, Checkoway H. Morgan MS, van Belle G. 1997. 
Occupational exposure and amyotrophic lateral sclerosis: A population-
based case-control study. American Journal of Epidemiology 145:1076-
1088.) Exposure to metals and solvents was not associated with ALS. 
Association between exposure to agricultural chemicals and ALS was 
observed in men. Exposure to specific agricultural chemicals, such as 
herbicides, did not pose a significantly increased risk of ALS. Excess 
exposure to agricultural chemicals from accidents or spills was 
associated with ALS, but this accounted for six cases and only three 
controls. NAS noted that the careful attention to exposure assessment 
in this study makes the association between agricultural chemicals and 
ALS intriguing, but that there are few exposed subjects and further 
studies are needed.
    NAS concluded that there is inadequate or insufficient evidence of 
an association between exposure to herbicides and motor neuron disease 
or ALS.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and ALS 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.
    A publication relating serum TCDD and peripheral neuropathy from 
the 1982, 1985, 1987, 1992, and 1997 examinations of the Ranch Hand 
study found significantly increased risk of peripheral neuropathy among 
Ranch Hand veterans in the high-exposure category in 1997. (Michalek 
JE, Akhtar FZ, Arezzo JC, Garabrant DH, Albers JW. 2001. Serum dioxin 
and peripheral neuropathy in veterans of operation ranch hand. 
Neurotoxicology 22:479-490.) NAS noted a major problem in the 
interpretation of TCDD effects on the peripheral nerves in light of the 
presence of diabetes and preclinical diabetes in the majority of the 
cases identified. NAS also noted that the cases of probable and 
possible peripheral neuropathy were identified for the first time in 
1992 and 1997, with prior examinations being normal. NAS determined 
that these findings weakened the ability to implicate TCDD exposure as 
the etiologic agent given that the peripheral nerve is known to repair 
itself after cessation of exposure or after diminution of the body 
burden of the responsible toxicant.
    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

[[Page 27637]]

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 (notably cholesterol) concentrations have been shown 
to predict cardiovascular disease and are considered fundamental to the 
underlying atherosclerotic process. The two major types of 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.
    An occupational study of 92 workers at a municipal waste 
incinerator in Japan included measures of serum polychlorinated 
dibenzo-p-dioxins (PCDD) and self-reported history of a number of 
diseases and health-related conditions. (Kitamura K, Kikuchi Y, 
Watanabe S, et al. Health effects of chronic exposure to 
polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and 
coplanar PCB (Co-PCB) of municipal waste incinerator workers. Journal 
of Epidemiology 2000;10:262-270.) Eight of the 92 subjects reported 
having been diagnosed with high cholesterol.
    NAS noted that this study's contribution to the literature is 
limited for a number of reasons: the study is cross-sectional, so there 
is no opportunity to establish that the exposure clearly preceded the 
outcome; the sample is small; the exposure is an aggregate measure of 
PCDD (with TCDD as only one component); and the measure of high 
cholesterol is based solely on self-report. NAS stated that, because of 
those limitations, the study does not change the inconclusive status of 
the epidemiologic evidence on the relationship between exposure to 
herbicides and high serum lipids.
    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, Including Liver Toxicity

    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, including 
liver toxicity.
    An occupational study reported on two cases of heavy TCDD 
intoxication, and presented a 2-year follow-up. (Geusau A, Abraham K, 
Geissler K, Sator MO, Stingl G. Tschachler E. 2001. Severe 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD) intoxication: clinical and 
laboratory effects. Environmental Health Perspectives 109(8):865-869.) 
One patient, a 30-year-old woman, presented with chloracne and had the 
highest TCDD concentration ever recorded in a human. The other patient 
was a 27-year-old woman who worked in the same room as the first 
patient. Both patients experienced gastrointestinal symptoms, including 
nausea, vomiting, epigastric pain, and loss of appetite, which lasted 
about 4 months. Liver function studies were within the normal limits, 
except for one value in the first patient of alkaline phosphatase at 
1.5 times the upper limit of normal. Apart from the chloracne and 
gastrointestinal symptoms, few clinical signs or symptoms were observed 
in the acute phase of the intoxication.
    In a report evaluating hepatic abnormalities in Vietnam veterans of 
Operation Ranch Hand, the authors examined exposure to TCDD and the 
prevalence of liver disease and hepatomegaly through March 1993 in 
relation to tests of liver function at the 1992 physical examination. 
(Michalek JE, Ketchum NS, Longnecker MP. 2001. Serum dioxin and hepatic 
abnormalities in veterans of Operation Ranch Hand. Annals of 
Epidemiology 11(5):304-311.) Hepatomegaly among veterans in the high-
exposure category was slightly higher than that in nonexposed veterans 
in the comparison category. The prevalence of nonspecific liver 
disorders increased across categories of TCDD exposure and among Ranch 
Hands in the high-exposure category. The study authors and NAS noted 
that the significance of those findings may be limited because 
heightened levels of the enzyme GGT, an abnormality sometimes reported 
in association with TCDD exposure, may also be caused by alcohol 
consumption, and the mean GGT in the high-exposure group was 
significantly increased among veterans with history of light to 
moderate drinking. The authors concluded that evidence of clinically 
significant liver disease was limited to the increase in hepatomegaly, 
and that the increased GGT could have been due to confounding.
    NAS stated that the evaluation of the effects of herbicide exposure 
on noncancer gastrointestinal ailments is very difficult, due to 
limitations of medical history and physical examination in diagnosing 
such ailments and the strong interdependence between individual 
characteristics of a person and the body burden of TCDD.
    NAS concluded that there was no information contained in the 
research reviewed for Update 2002 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

    The immune system is responsible for protecting the body against 
invasion by infectious microorganisms. 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.
    No relevant occupational, environmental, or Vietnam-veteran studies 
were published subsequent to Update 2000.
    NAS concluded that there was no information reviewed for Update 
2002 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

[[Page 27638]]

insufficient information to determine whether an association exists 
between exposure to herbicides and circulatory disorders.
    In Update 2002, NAS noted that there is growing evidence that 
exposure to inorganic arsenic is a risk factor for cardiovascular 
disease, and cacodylic acid (DMA) is a metabolite of inorganic arsenic. 
However, the data remain insufficient to conclude that studies of 
inorganic arsenic exposure are directly relevant to exposure to 
cacodylic acid. Therefore, the literature on inorganic arsenic was not 
considered by NAS.
    NAS reviewed an occupational study of mortality in male workers at 
a Dow chemical plant (Burns et al., 2001). NAS stated that mortality 
due to circulatory conditions among the workers was similar to that 
experienced by U.S. white males in general. NAS noted that mortality 
analyses of other occupational cohorts have tended to find 
cardiovascular effects among the more highly exposed workers, but that 
a dose-specific analysis of the data on this outcome was not reported.
    A cross-sectional occupational study was conducted in 1998 to 
assess the association between serum PCDD and a variety of health 
conditions in a sample of workers employed at a municipal waste 
incinerator in Japan (Kitamura et al., 2000). Fourteen of the 92 
workers participating in the study reported a history of hypertension. 
No information was provided on the date of this diagnosis relative to 
dates of employment at the plant. The coefficients for the categories 
of PCDD were reported as not statistically significant, but the values 
of the coefficients and their standard errors were not given.
    In an environmental study, a survey was administered to 727 adult 
residents of farming households and 262 residents of nonfarming 
households. (Masley ML, Semchuk KM, Senthilselvan A, at al. Health and 
environment of rural families: results of a community canvass survey in 
the Prairie Ecosystem Study. Journal of Agricultural Safety and Health 
2000;6:103-115.) The survey included questions about the use of 
pesticides and fertilizers and a number of health conditions and 
symptoms that might be associated with agricultural exposures. 
Physician-diagnosed hypertension and heart disease were reported by 154 
and 44 survey respondents, respectively. Neither condition was 
associated with residing on a farm. No information was provided on the 
validity of measurement of the self-reported health conditions, and the 
report did not examine more specific associations with pesticide or 
fertilizer use.
    NAS noted that neither Kitamura et al. (2000) nor Masley et al. 
(2000) provided data on validation from medical records or direct 
measurement of blood pressure, that some misclassification is likely 
(with false negatives being more common than false positives), and that 
both studies used nonspecific assessment of exposure. NAS further noted 
the possibility that the null findings on hypertension in these studies 
reflect the influence of misclassification that led to bias toward the 
null.
    Mortality from cardiovascular diseases was examined by Revich et 
al. (2001) in their study of multiple health outcomes among the 
residents of Chapaevsk. The authors reported that mortality from 
cardiovascular diseases in men was 1.14 times greater than the 
mortality rate for Russia as a whole, and that the difference in 
mortality was especially pronounced in men 30 to 49 years old. The 
authors also noted, however, that trends in mortality were directly 
related to trends in unemployment, which NAS noted suggests the 
simultaneous effects of other aspects of the environment in the area.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2002 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

    The major risk factor for both acute and chronic respiratory 
disorders is cigarette smoking. Cigarette smoking is a major 
confounding factor in interpreting the literature on risk factors for 
respiratory disease. 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 nonmalignant 
respiratory disorders.
    In Update 2002, NAS reviewed an occupational study of a cohort of 
male employees of the Dow Chemical Company (Burns et al., 2001). No 
excess mortality from nonmalignant respiratory disorders was 
demonstrated.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2002 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 discussed the 
evidence concerning two categories of skin cancer: Melanoma and 
nonmelanoma (basal-cell and squamous-cell).
    In Update 2002, NAS reviewed an occupational study of mortality in 
a cohort of male Dow Chemical Company workers (Burns et al., 2001). No 
deaths due to skin cancer of any type were reported in the study.
    NAS also reviewed an occupational study which analyzed cancer 
incidence and mortality in a cohort of forestry workers in Sweden 
(Thorn et al., 2000). The observed frequency of cancer was compared 
with expected values on the basis of data on the population of Sweden. 
One case of melanocytic skin cancer was recorded in an exposed female 
worker. Nonmelanocytic skin cancer was diagnosed in one exposed 
foreman, and in three nonexposed workers. The report found increased 
risks for both types of skin cancer, but the findings were not 
statistically significant and were limited by the small number of 
cases.
    An environmental study analyzed cancer incidence and mortality in 
Chapaevsk, Russia (Revich et al., 2001). Mortality data were not 
reported for skin cancer. The age-adjusted incidence of melanoma in 
Chapaevsk relative to the Samara region during 1998 was somewhat lower 
in men but notably higher in women. The age-adjusted incidence of skin 
cancers other than melanoma was similar in men and somewhat higher in 
women. NAS noted that the number of cases was not given, hypothesis 
testing and interval

[[Page 27639]]

estimation were not performed, and no confounding factors were 
considered besides age. NAS noted that the lack of complete information 
prevented conclusions based on the study.
    NAS stated that the new studies add little information on the 
association between exposure to herbicides and the incidence of skin 
cancer.
    NAS concluded that there is no information contained in the 
research reviewed for Update 2002 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.
    Results of a Vietnam veteran study of cognitive functioning from an 
Air Force Health Study (AFHS) examination in 1982 were reviewed by NAS 
in Update 2002. (Barrett DH, Morris RD, Akhtar FZ, Michalek JE. 2001. 
Serum dioxin and cognitive functioning among veterans of operation 
ranch hand. Neurotoxicology 22:491-502.) NAS noted that cognitive 
functioning in the Ranch Hand veterans evaluated with about 33 measures 
assessed through a variety of tests found eight significant group 
differences that did not support a dose-effect relationship with TCDD; 
that is, worse performance was seen in the background or low-TCDD 
groups. Ranch Hand veterans with the highest TCDD exposure had 
significantly lower scores on Logical Memory (Wechsler Memory Scale 
Form 1 (WMS)). NAS stated that finding could be attributed to chance 
alone and was not in agreement with other administered tests of verbal 
memory. NAS further stated that overall, the significant weaknesses in 
the study design, analyses, and interpretation of the results in the 
examination of serum TCDD and cognitive functioning in the Ranch Hand 
veterans prevent an association between exposure and neuropsychologic 
effects from being established.
    In Update 2002, NAS reviewed a 30-year follow-up occupational study 
of 13 men in Czechoslovakia with TCDD exposure during the production of 
2,4,5-T. (Pelclova D, Fenclova Z, Dlaskova Z, Urban P, Lukas E, 
Prochazka B, Rappe C. 2001. Biochemical, neuropsychological, and 
neurological abnormalities following 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) exposure. Archives of Environmental Health 56:493-500.) 
TCDD was correlated significantly with the memory quotient from WMS, 
the verbal IQ from the Wechsler Adult Intelligence Scale-Revised (WAIS-
R), and the Benton test of visual memory. Age-corrected norms were used 
to determine abnormal performance. Education did not affect the 
results, but no demographic data on education were presented. Ten of 13 
subjects drank alcohol daily, but this was not taken into account in 
the analyses. NAS reported that the low-voltage electroencephalogram 
with increased beta activity seen in 7 subjects could be related to the 
daily alcohol consumption. NAS further noted that it is not possible to 
determine the relationship between TCDD and cognitive functioning 
without attention to confounding.
    An environmental study (Gauthier E, Fortier I, Courchesne F, Pepin 
P, Mortimer J, Gauvreau D. 2001. Environmental pesticide exposure as a 
risk factor for Alzheimer's disease: A case-control study. 
Environmental Research Section A 86:37-45) found that long-term 
exposure to herbicides and insecticides was not significantly related 
to the development of Alzheimer's disease. Occupational exposure to 
neurotoxic substances, including pesticides, was also not significantly 
related to Alzheimer's disease.
    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 years old. 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.
    An occupational study (Burns et al., 2001) of mortality of male 
employees of the Dow Chemical Company found fewer deaths than expected 
from all malignant neoplasms and specifically cancers of the digestive 
organs and peritoneum.
    An environmental study of residents of Chapaevsk, Russia (Revich et 
al., 2001) showed a higher incidence of colon cancer in males than 
Russia as a whole or the Samara region of Russia. Female residents of 
Chapaevsk did not have a higher incidence. However, female residents of 
Chapaevsk did have a higher incidence of stomach cancer than Russia or 
Samara. Male residents of Chapaevsk had a lower incidence of stomach 
cancer than Russia, but higher than Samara. Both male and female 
residents of Chapaevsk had a lower incidence of rectal cancer than 
Russia or Samara. NAS stated that, because of the lack of adjustment 
for confounding, the likelihood of multiple exposures, the absence of 
information on the completeness and accuracy of cancer diagnoses, and 
the ecologic study design, this study provides little evidence for 
associations with gastrointestinal cancers.
    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

    Exposure to ionizing radiation is an established risk factor for 
brain cancer. Several other potential factors have been examined, but 
most brain cancers are not associated with any known risk factors. 
Brain cancer occurs relatively infrequently.
    NAS noted in VAO and subsequent reports that there was limited or 
suggestive evidence of no association between exposure to herbicides 
and brain tumors.
    Two occupational studies published since Update 2000 were reviewed 
by

[[Page 27640]]

NAS in Update 2002. Both studies (Burns et al., 2001; Thorn et al., 
2000) demonstrated no excess mortality from brain cancer. NAS noted, 
however, that both studies were small and had limited power to detect 
an increase in an uncommon outcome.
    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.

AL Amyloidosis

    Amyloidosis refers to a group of diseases in which insoluble 
fibrillar proteins (amyloid) accumulate in tissues to a point that 
causes organs to malfunction. NAS reviewed AL amyloidosis (also 
sometimes referred to as primary amyloidosis), in which the light chain 
of immunoglobulin molecules is the aberrant protein. AL amyloidosis is 
the most common form of amyloidosis in the United States.
    NAS in Update 2000 found there was inadequate or insufficient 
information to determine whether an association exists between exposure 
to herbicides and AL amyloidosis.
    No relevant occupational, environmental, or Vietnam-veteran studies 
have been published since Update 2000.
    NAS concluded that there is no information to change the conclusion 
that there is inadequate or insufficient evidence to determine whether 
an association exists between exposure to herbicides and AL 
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.

Endometriosis

    NAS reviewed endometriosis for the first time in Update 2002.
    Endometrium is the tissue that lines the inside of the uterus. In 
endometriosis, endometrium is found outside the uterus, usually in 
other parts of the reproductive system, the abdomen, or the tissues 
near the reproductive organs, and results in inflammation, internal 
bleeding, and degeneration of blood and tissue which can cause 
scarring, pain, infertility, adhesions, and intestinal problems. The 
cause of endometriosis is unknown.
    Suspicion that TCDD is involved in the etiology of endometriosis 
began after the observation that the incidence of endometriosis was 
higher in monkeys treated with low doses of TCDD than in control 
monkeys.
    In Update 2002, NAS reviewed a study which analyzed blood TCDD 
concentrations in 79 women who were being evaluated for infertility, 44 
of whom were diagnosed with endometriosis by laparoscopy. (Mayani A, 
Barel S, Soback S, and Almagor M. 1997. Dioxin concentration in women 
with endometriosis. Human Reproduction. 12:373-375.) Eight of the 44 
women with endometriosis were positive for TCDD compared with one of 
the 35 controls. NAS noted that the number of subjects in this study is 
small, the ethnic distribution differed, and the limit of TCDD 
detection was not clear. Although the study reported an increased risk, 
the confidence interval was very wide and the finding was not 
statistically significant.
    Another study assessed whether TCDD toxic equivalents (TEQs) in 
serum are associated with endometriosis in an infertile population of 
women who enrolled in fertility treatment. (Pauwels A, Schepens PJ, 
D'Hooghe T, Delbeke L, Dhont M, Brouwer A, Weyler J. 2001. The risk of 
endometriosis and exposure to dioxins and polychlorinated biphenyls: A 
case-control study of infertile women. Human Reproduction. 16:2050-5.) 
The case-control study evaluated 42 women with endometriosis and 27 
controls without endometriosis, but with infertility related to other 
causes. The authors reported no association between median total TEQs 
and endometriosis in infertile women.
    NAS concluded that there is inadequate or insufficient evidence to 
determine whether an association exists between exposure to herbicides 
and endometriosis.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and endometriosis outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.

Thyroid Homeostasis

    NAS reviewed the thyrotoxic potential of herbicides for the first 
time in Update 2002.
    The thyroid gland secretes hormones (T4 and T3) which stimulate 
metabolic rate. Secretion of T4 and T3 is under the control of thyroid-
stimulating hormone (TSH), which is secreted by the anterior pituitary 
gland. The thyroid also secretes calcitonin, a hormone that controls 
calcium concentration in the blood and storage of calcium in bones. 
Chemical-induced alterations in thyroid homeostasis can adversely 
affect the development of many organ systems, including the nervous and 
reproductive systems. Most adverse effects are caused by lack of 
thyroid hormone alone rather than by increases in TSH. TCDD affects the 
concentrations of thyroid hormones; the effects appear to be species-
dependent and may reflect both the dose and the duration of exposure. 
TCDD influences the metabolism of thyroid hormones and TSH. Studies of 
environmental exposure have emphasized thyroid alterations in prenatal 
and early childhood development rather than in adults.
    One environmental study reviewed by NAS evaluated 38 mother-infant 
pairs, selected for normal birth weight and no complications. (Pluim 
HJ, Koppe JG, Olie K, Vd Slikke JW, Kok JH, Vulsma T, Van Tijn D, De 
Vijlder JJ. 1992. Effects of dioxins on thyroid function in newborn 
babies. Lancet. 339:1303.) In cord blood, the concentrations of total 
T4 and thyroxine-binding globulin (TBG) were suggestively higher in the 
high exposure group, but no other measurements approached significance. 
At 1 week, total T4 and the ratio of total T4 to TBG were significantly 
greater in the high-exposure than the low-exposure group, and the same 
was true at 11 weeks. TSH concentrations were also significantly higher 
at 11 weeks. When only infants who were breastfed for the full 11 weeks 
were considered, only the ratio of total T4 to TBG remained 
significantly different. In a subset of the births for which values 
were obtained in both the cord and 1-week samples, the increases in 
total T4 and in TBG were substantially higher in the high-exposure 
group. NAS stated that concerns about those results are related to the 
size of the study sample and the loss of nearly one-fourth of the 
maternal-blood samples and five of the cord-blood samples for all 
thyroid measurements. Several more samples were insufficient for some 
of the analyses.
    A larger study of 105 mother-infant pairs conducted similar 
analyses. (Koopman-Esseboom C, Morse DC, Weisglas-Kuperus N, 
Lutkeschipholt IJ, Van der Paauw CG, Tuinstra LG, Brouwer A, Sauer PJ. 
1994. Effects of dioxins and polychlorinated biphenyls

[[Page 27641]]

on thyroid hormone status of pregnant women and their infants. 
Pediatric Research. 36:468-73.) TEQ correlated negatively with maternal 
pregnancy total T3 and maternal postdelivery total T3 and total T4; 
similar associations were seen for planar PCB TEQ and total PCB and 
TEQ, and the associations with total T3 were also observed for 
nonplanar PCB TEQ. In addition, all four TEQ measurements correlated 
positively with infant 2-week TSH, and all except the nonplanar PCB TEQ 
were positively associated with the infant 3-month TSH.
    Another environmental study examined PCB concentrations in breast-
milk specimens, without adjustment for lipids, in relation to thyroid 
hormones in cord serum in a population with background exposure. 
(Longnecker MP, Gladen BC, Patterson DG, Rogan WJ. 2000. 
Polychlorinated biphenyl (PCB) exposure in relation to thyroid hormone 
levels in neonates. Epidemiology 11:249-254.) They found little 
evidence of an association, although the direction of the coefficient 
for TSH in multiple-regression analysis was consistent with findings in 
other studies: increases in TSH with increases in PCBs. NAS stated that 
because non-dioxin-like PCBs are the most abundant, and PCBs are 
contaminated with furans, this study is not very informative for the 
effects of TCDD or the herbicides used in Vietnam.
    Another environmental study examined TCDD-exposed workers at two 
plants who were engaged in the production of 2,4,5-T or one of its 
derivatives. (Calvert GM, Sweeney MH, Deddens J, Wall DK. 1999. 
Evaluation of diabetes mellitus, serum glucose, and thyroid function 
among United States workers exposed to 2,3,7,8-tetrachlorodibenzo-p-
dioxin. Occupational and Environmental Medicine 56(4):270-276.) 
Referents were residents in the neighborhood of each worker, matched by 
age, race, and sex. Serum specimens were analyzed for TCDD, total T4, 
TSH, and thyroid hormone binding resin, and the free T4 index was 
calculated. The results showed that workers had a significantly higher 
adjusted mean free T4 index than referents, and the highest index was 
among those with the highest half-life extrapolated TCDD, but a clear 
dose-response relationship was not observed.
    A Vietnam veteran study examined thyroid-hormone status in the AFHS 
cohort. (Pavuk M, Schecter AJ, Akhtar FZ, Michalek JE. Serum 2,3,7,8-
Tetrachlorodibenzo-p-dioxin (TCDD) Levels and Thyroid Function in Air 
Force Veterans of the Vietnam War (in press).) At each of the 1982, 
1985, 1987, 1992, and 1997 examinations, there was a trend toward an 
increasing concentration of TSH, which was not accompanied by changes 
in circulating T4 or in the percentage uptake of T3 (measured only in 
the earlier years). In a repeated-measures linear regression adjusted 
for age, race, and military occupation, the low-exposure and high-
exposure Ranch Hands had TSH significantly higher than the comparison 
population. There was no evidence of changes in clinical thyroid 
disease. The percentage with abnormally high TSH was higher at each 
examination in the high-exposure group than in the comparison 
population, but these findings were not very precise.
    After reviewing the relevant literature, NAS stated that although 
some effects on thyroid homeostasis have been observed, mainly in the 
perinatal period (the period shortly before and after birth), the 
functional importance of those changes is unclear because adaptive 
capacity may be adequate to accommodate them. NAS noted that the AFHS 
study demonstrated biologic changes in TSH levels, but without any 
accompanying effect on the health of the Ranch Hand veterans. NAS 
further stated that the evidence indicates that both infants and Ranch 
Hand personnel were able to adapt to the changes that may have been 
induced by higher body burdens of TCDD.
    NAS concluded that there is inadequate or insufficient evidence to 
determine whether an association exists between exposure to herbicides 
and adverse effects on thyroid homeostasis.
    Taking account of the available evidence and NAS' analysis, the 
Secretary has found that the credible evidence against an association 
between herbicide exposure and adverse effects on thyroid homeostasis 
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 2002.'' 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: May 8, 2003.
Anthony J. Principi,
Secretary of Veterans Affairs.
[FR Doc. 03-12593 Filed 5-19-03; 8:45 am]
BILLING CODE 8320-01-P