[Federal Register Volume 59, Number 2 (Tuesday, January 4, 1994)]
[Notices]
[Pages 341-346]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-73]


[[Page Unknown]]

[Federal Register: January 4, 1994]


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DEPARTMENT OF VETERANS AFFAIRS

 

Disease 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: Prostate cancer, peripheral neuropathy, 
hepatobiliary cancers, bone cancers, female reproductive cancers, renal 
cancers, testicular cancer, leukemia, abnormal sperm parameters and 
infertility, cognitive and neuropsychiatric disorders, motor/
coordination dysfunction, metabolic and digestive disorders, immune 
system disorders, circulatory disorders, respiratory disorders (other 
than lung cancer), nasal/nasopharyngeal cancer, skin cancer, 
gastrointestinal tumors, bladder cancer, brain tumors, 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, Department of Veterans Affairs, 810 Vermont Avenue, 
NW., Washington, DC 20420, (202) 233-3005.

SUPPLEMENTARY INFORMATION: Section 3 of the Agent Orange Act of 1991, 
Public Law 102-4, 105 Stat. 11 (1991), directed the Secretary to enter 
into an agreement with the National Academy of Sciences (NAS) to review 
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 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 will publish a notice of that determination, which 
includes an explanation of the scientific basis for that determination.
    Although Public Law 102-4 does not define ``credible'', it does 
instruct the Secretary to ``take into consideration whether the results 
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, etc., some studies 
are clearly more credible than others, and the Secretary has given them 
more weight in evaluating the overall credibility of the evidence 
concerning specific diseases.
    After reviewing approximately 6,420 abstracts of scientific or 
medical articles and selecting approximately 230 epidemiologic studies 
for detailed analysis, consulting with outside experts, and conducting 
public hearings, NAS issued a report, entitled ``Veterans and Agent 
Orange: Health Effects of Herbicides Used in Vietnam'', on July 27, 
1993. The Secretary announced that same day that he had concluded that 
a positive association exists between exposure to herbicides used in 
the Republic of Vietnam and the subsequent development of Hodgkin's 
disease and porphyria cutanea tarda. Proposed regulations were 
published in the Federal Register on September 28, 1993 (See 58 FR 
50528-30). The Secretary also announced that VA would review the 
remaining findings in the NAS report to determine whether a positive 
association exists between herbicide exposure and any other conditions. 
That review has been completed and this notice, pursuant to Public Law 
102-4, conveys the Secretary's determination that there is no positive 
association between herbicide exposure and prostate cancer, peripheral 
neuropathy, hepatobiliary cancers, bone cancers, female reproductive 
cancers, renal cancers, testicular cancer, leukemia, abnormal sperm 
parameters and infertility, cognitive and neuropsychiatric disorders, 
motor/coordination dysfunction, metabolic and digestive disorders, 
immune system disorders, circulatory disorders, respiratory disorders 
(other than lung cancer), nasal/nasopharyngeal cancer, skin cancer, 
gastrointestinal tumors, bladder cancer, brain tumors, and any other 
condition for which the Secretary has not specifically determined a 
presumption of service connection is warranted.
    The NAS report assigns prostate cancer to a category labeled 
limited/suggestive evidence of an association, which it defined as 
meaning there is evidence suggestive of an association between 
herbicide exposure and a particular health outcome, but that evidence 
is limited because chance, bias, and confounding could not be ruled out 
with confidence. Prostate cancer is a very common male genitourinary 
cancer which shows marked increased prevalence with age. There are 
statistically significant occupational studies which show no 
association between prostate cancer and herbicide exposure (e.g., 
Fingerhut M.A., Halperin W.E., Marlow D.A., Piacitelli L.A., Honchar 
P.A., Sweeney M.H., Greife A.L., Dill P.A., Steenland K., Suruda A.J. 
1991. Cancer mortality in workers exposed to 2,3,7,8-
tetrachlorodibenzo-p-dioxin. New England Journal of Medicine 324:212-
218; Manz A., Berger J., Dwyer J.H., Flesch-Janys D., Nagel S., 
Waltsgott H. 1991. Cancer mortality among workers in chemical plant 
contaminated with dioxin. Lancet 338:959-964; Saracci R., Kogevinas M., 
Bertazzi P.A., Bueno De Mesquita B.H., Coggon D., Green L.M., Kauppinen 
T., L'Abbe K.A., Littorin M., Lynge E., Mathews J.D., Neuberger M., 
Osman J., Pearce N., Winkelman R. 1991. Cancer mortality in workers 
exposed to chlorophenoxy herbicides and chlorophenois. Lancet 338:1027-
1032). Some occupational studies have shown a slight elevated risk for 
prostate cancer among farm and forestry workers (e.g., Burmeister L.F., 
1981. Cancer mortality in Iowa farmers: 1971-1978. Journal of the 
National Cancer Institute 66:461-464; Alavanja M.C., Merkle S., Teske 
J. Eaton B., Reed B. 1989. Mortality among forest and soil 
conservationists. Archives of Environmental Health 44:94-101); however, 
only one study concerning a small sub-set of farmers (Morrison H., 
Savitz, D., Semenciw R., Hulka B., Mao Y., Morison D., Wigle D. 1993. 
Farming and prostate cancer mortality. American Journal of Epidemiology 
137:270-280) associated the increased risk of prostate cancer among 
farmers specifically with herbicide exposure. The Morrison study is so 
recent that it it too early to determine whether its results will be 
replicated by other research. Accordingly, the Secretary has found that 
the credible evidence against an association between prostate cancer 
and herbicide exposure outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.
    The NAS report assigns peripheral neuropathy, hepatobiliary 
cancers, bone cancers, female reproductive cancers, renal cancers, 
testicular cancer, leukemia, abnormal sperm parameters and infertility, 
cognitive and neuropsychiatric disorders, motor/coordination 
dysfunction, metabolic and digestive disorders, immune system 
disorders, circulatory disorders, respiratory disorders (other than 
lung cancer), and nasal/nasopharyngeal cancer to a category labeled 
inadequate/insufficient evidence to determine whether an association 
exists, which is defined as meaning that the available studies are of 
insufficient quality, consistency, or statistical strength to permit a 
conclusion regarding the presence or absence of an association with 
herbicide exposure.
    Peripheral neuropathy can be induced by many common medical and 
environmental disorders unrelated to herbicide exposure, such as aging, 
alcoholism, diabetes, and exposure to other toxic chemicals. The last 
time VA considered this issue, it determined, after receiving the 
advice of the Veterans' Advisory Committee on Environmental Hazards, 
that there was sufficient evidence to meet the requirements for a 
``significant statistical association,'' the standard in effect at that 
time, between exposure to herbicides containing dioxin and the 
subsequent development of peripheral neuropathy under certain 
circumstances (See 57 FR 2236-38). That conclusion, however, relied 
heavily on case reports, which are anecdotal and have no statistical 
significant, and occupational studies such as Singer and colleagues 
(1982) (Singer R., Moses M., Valciukas J., Lilis R., Selikoff I.J., 
1982. Nerve conduction velocity studies of workers employed in the 
manufacture of phenoxy herbicides. Environmental Research 29:297-311) 
whose credibility is compromised because they did not apply consistent 
methods to define a comparison group, determine exposure, evaluate 
clinical deficits, use standard definitions of peripheral neuropathy, 
or eliminate confounding variables. The Singer study, for example, 
excluded individuals with excessive alcohol consumption from the 
controls but not from the subjects of the study. Other occupational 
studies, such as Suskind and Herzberg (1984) (Suskind R.R., Hertzberg 
V.S., 1984. Human health effects of 2,4,5-T and its toxic contaminants. 
Journal of the American Medical Association 251:2372-2380), which did 
not have those methodological problems, showed no difference in the 
incidence of peripheral neuropathy for workers exposed to herbicides 
and workers not so exposed. Accordingly, the Secretary has found that 
the credible evidence against an association between peripheral 
neuropathy and herbicide exposure outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.
    Hepatobiliary cancers are cancers of the liver and bile duct. There 
are a variety of risk factors that should be considered by a credible 
study, including hepatitis B and C, alcohol abuse, cirrhosis, exposure 
to polychlorinated biphenyl (PCB), and smoking. The relevant studies 
are few, and have not adequately controlled for these risk factors. A 
Swedish case control study (Hardell L., Bengtsson N.O., Jonsson U., 
Eriksson S., Larsson L.G., 1984. Aetiological aspects on primary liver 
cancer with special regard to alcohol, organic solvents and acute 
intermittent porphyria: an epidemiological investigation. British 
Journal of Cancer 50:389-397) showed a relationship between herbicide 
exposure and the subsequent development of hepatobiliary cancer; 
however, other studies of similar size (Ronco G, Costa G., Lynge E., 
1992. Cancer risk among Danish and Italian farmers. British Journal of 
Industrial Medicine 49:220-225; Wiklund K., 1983. Swedish agricultural 
workers: a group with a decreased risk of cancer. Cancer 51:566-568) 
indicated no relationship. A large occupational study (Fingerhut et 
al., 1991) and a study of farmers in Denmark and Italy (Ronco et al., 
1992) found no relationship. Accordingly, the Secretary has found that 
the credible evidence against an association between hepatobiliary 
cancer and herbicide exposure outweighs the credible evidence for such 
an association, and he has determined that a positive association does 
not exist.
    Bone cancers were considered together with joint cancers by NAS. 
Because of the rarity of bone cancers, most studies have been too small 
to detect a significant risk. There has not been a consistent finding 
of bone cancer in exposed groups; the preponderance of studies show no 
association, and the few studies that demonstrate a positive 
relationship (Fingerhut et al., 1991; Breslin P., Kang H., Lee y., Burt 
V., Shepard B.M., 1988. Proportionate mortality study of U.S. Army and 
U.S. Marine Corps veterans of the Vietnam War. Journal of Occupational 
Medicine 30:412-419) are small and have large confidence intervals 
which include one. The small size of the studies and the confidence 
limitations compromise their significance. Accordingly, the Secretary 
has found that the credible evidence against an association between 
bone cancers and herbicide exposure outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.
    Female reproductive cancers reviewed by NAS include those of the 
breast, uterus, cervix, ovary, and other genital malignancies. The data 
related to women and herbicide exposure is extremely limited because 
few of the studies included women. A large number of the breast cancer 
studies showed no association. Two studies (Thomas T.L., Kang H., 
Dalager N., 1991. Mortality among women Vietnam veterans, 1973-1987. 
American Journal of Epidemiology 134:973-980; Manz et al., 1991) showed 
an increased risk for breast cancer which was not significant since 
both studies failed to control for reproductive histories and had 
methodological problems. Only one small case control study (Donna A., 
Betta P-G., Robutti F., Crosignani P., Berrino F., Bellingeri D., 1984. 
Ovarian mesothelial tumors and herbicides: a case control study. 
Carcinogenesis 5:941-942) showed an association with ovarian cancer, 
but the confidence intervals were very wide. The larger occupational 
and farm worker studies all showed significantly lower mortality ratios 
than expected. Likewise, studies of exposures generally found less 
uterine and cervical cancer than expected. Accordingly, the Secretary 
has found that the credible evidence against an association between 
female reproductive cancers and herbicide exposure outweighs the 
credible evidence for such an association, and he has determined that a 
positive association does not exist.
    The leather industry, asbestos, cadmium, petroleum products, 
analgesics, smoking, and obesity have been associated with renal 
cancers. Studies of renal cancer have generally produced inconclusive 
results, in some cases because of failure to adequately control for 
these confounding factors. Only one study of agricultural and forest 
workers (Alavanja et al., 1989) showed a significantly increased risk 
of death from renal cancers; however, the preponderance of studies, 
including the two largest (Wiklund, 1983; Burmeister, 1981), showed 
either no relationship with renal cancers or increased risk which was 
not significant. Accordingly, the Secretary has found that the credible 
evidence against an association between renal cancers and herbicide 
exposure outweighs the credible evidence for such an association, and 
he has determined that a positive association does not exist.
    Major risk factors for testicular cancer are undescended testis and 
other factors, such as genetic abnormalities, infections, etc., which 
produce atrophy and dysfunction. In general, occupational studies 
(Ronco et al., 1992; Wiklund, 1983) have shown no association between 
herbicide exposure and testicular cancer. Occupational and 
environmental studies have found either no association or increased 
risk which was not significant. Studies concerning Vietnam veterans 
were inconsistent, and in those that found increased risk, that risk 
was generally not significant. Accordingly, the Secretary has found 
that the credible evidence against an association between testicular 
cancer and herbicide exposure outweighs the credible evidence for such 
an association, and he has determined that a positive association does 
not exist.
    Potential evidence for an association between herbicide exposure 
and leukemia comes primarily from studies of farmers (Ronco et al., 
1992; Wigle D.T., Semenciw R.B., Wilkins K., Riedel D., Ritter L., 
Morrison H.I., Mao Y., 1990. Mortality study of Canadian male farm 
operators: non-Hodgkin's lymphoma mortality and agricultural practices 
in Saskatchewan. Journal of the National Cancer Institute 82:575-582) 
and residents of Seveso, Italy (Bertazzi P.A., Zocchetti C., Pesatori 
A.C., Guercilena S., Sanarico M., Radice L., 1989b. Ten-year mortality 
study of the population involved in the Seveso incident in 1976. 
American Journal of Epidemiology 129:1187-1200; Bertazzi P.A., 
Zocchetti C., Pesatori A.C., Guercilena S., Consonni D., Tironi A., 
Landi M.T., 1992. Mortality of a young population after accidental 
exposure to 2,3,7,8-tetrachlorodibenzodioxin. International Journal of 
Epidemiology 21:118-123). The studies of farmers did not control for 
other confounding exposures (Brownson R.C., Reif J.S., Chang J.C., 
Davis J.R., 1989. Cancer risk among Missouri farmers. Cancer 64:2381-
2385.; Brown L.M., Blair A., Gibson R., Everett G.D., Cantor K.P., 
Schuman L.M., Burmeister L.F., Van Lier S.F., Dick F. 1990. Pesticide 
exposures and other agricultural risk factors for leukemia among men in 
Iowa and Minnesota. Cancer Research 50:6585-6591). When farmers were 
stratified by suspected herbicide exposure, the incidence of leukemia 
was generally not elevated. Any elevation appeared to be due to factors 
other than herbicide exposure, e.g., risk was higher among chicken 
farmers than wheat farmers (Alavanja M.C., Blair A, Merkle S., Teske J. 
Eaton B., 1988. Mortality among agricultural extension agents. American 
Journal of Industrial Medicine 14:167-176). The suggestive evidence of 
increased risk concerning Seveso, Italy was not significant because of 
the small number of actual cases in which leukemia was found. Since 
none of the studies demonstrated a dose-response for any subtype of 
leukemia, it is not possible to attribute leukemia to herbicide 
exposure. Accordingly, the Secretary has found that the credible 
evidence against an association between leukemia and herbicide exposure 
outweighs the credible evidence for such an association, and he has 
determined that a positive association does not exist.
    The common parameters used to evaluate toxic effects to sperm are 
number, motility, structure, and morphology. Many chemicals have been 
implicated in interfering with motility and sperm structure (Wyrobek 
A.J., Gordon L.A., Burkhart J.G., Francis M.W., Kapp R.W., Letz G., 
Malling H.V., Topham J.C., Whorton M.D., 1983. An evaluation of human 
sperm as indicators of chemically induced alterations of spermatogenic 
function. A report of the U.S. Environmental Protection Agency Gene-Tox 
Program. Mutation Research 115:73-148). One occupational study (Lerda 
D., Rizzi R., 1991. Study of reproductive function in persons 
occupationally exposed to 2,4-dichlorophenoxyacetic acid (2,4-D). 
Mutation Research 262:47-50) and one study of Vietnam veterans (Air 
Force Health Study (AFHS), 1992. An Epidemiologic Investigation of 
Health Effects in Air Force Personnel Following Exposure to Herbicides. 
Reproductive Outcomes. Brooks AFB: USAF School of Aerospace Medicine. 
AL-TR-992-0900 602 pp.) found no association with decreased sperm 
count. Another study of Vietnam veterans (Centers for Disease Control 
(CDC), 1989. Comparison of Serum Levels of 2,3,7,8-Tetrachlorodibenzo-
p-dioxin with Indirect Estimates of Agent Orange Exposure Among Vietnam 
Veterans: Final Report. Atlanta: U.S. Department of Health and Human 
Services) found lower sperm concentration and reduced sperm motility, 
but suggested these outcomes may be associated with the Vietnam 
experience rather than exposure to herbicides. Infertility usually 
incorporates two concepts: the inability to conceive and the inability 
to produce live children. Most studies do not take into account the 
desire for children, contraceptive practices, and other factors 
influencing fertility. NAS found no occupational or environmental 
studies examining herbicide exposure and infertility, and veteran 
studies (Field B., Kerr C., 1988. Reproductive behavior and consistent 
patterns of abnormality in offspring of Vietnam veterans. Journal of 
Medical Genetics 25:819-826; AFHS, 1992; Centers for Disease Control 
(CDC), 1988. Health status of Vietnam veterans. III. Reproductive 
outcomes and child health. Journal of the American Medical Association 
259:2715-2717) do not support an association between herbicide exposure 
and infertility. Accordingly, the Secretary has found that the credible 
evidence against an association between abnormal sperm parameters and 
infertility and herbicide exposure outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.
    Studies of cognitive and neuropsychiatric disorders are beset by a 
number of methodologic problems, including exposure measures, the wide 
variety of ``standardized'' test instruments used, and the inability to 
detect or correct for other influences on test results such as 
emotional state, non-neurologic disease, metabolic conditions, fatigue, 
medications, or style of the examiner. Because of their failure to 
adequately control for these confounding factors, these studies lack 
credibility in assessing the relationship of herbicide exposure to 
these conditions. Accordingly, the Secretary has found that there is no 
credible evidence for an association between cognitive and 
neuropsychiatric disorders and herbicide exposure, and he has 
determined that a positive association does not exist.
    There were no significant studies available to analyze whether an 
association exists between herbicide exposure and motor/coordination 
dysfunction. Accordingly, the Secretary has found that there is no 
credible evidence for an association between motor/coordination 
dysfunction and herbicide exposure, and he has determined that a 
positive association does not exist.
    Metabolic and digestive disorders (diabetes mellitus, hepatic 
enzyme abnormality, lipid abnormalities, and ulcers) were also 
categorized by NAS as health outcomes with inadequate/insufficient 
evidence to determine whether an association exists. Although NAS found 
no biologic basis to suspect an association between herbicide exposure 
and diabetes, abnormal glucose tolerance tests have been reported in 
three studies (Sweeney M.H., Fingerhut M.A., Arezzo J.C., Hornung R.W., 
Connally L.B. In press. Peripheral neuropathy after occupational 
exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).; Air Force 
Health Study. 1991. An Epidemiologic Investigation of Health Effects in 
Air Force Personnel Following Exposure to Herbicides. Serum Dioxin 
Analysis of 1987 Examination Results. Brooks AFB, TX: USAF School of 
Aerospace Medicine. 9 vols.; Pazderova-Vejlupkova J., Lukas E., Nemcova 
M., Pickova J., Jirasek L., 1991. The development and prognosis of 
chronic intoxication by tetrachlorodibenzo-p-dioxin in men. Archives of 
Environmental Health 36:5-11). While this suggests such an association, 
the evidence is inconclusive and its credibility is questionable 
because an abnormal glucose tolerance test is not an absolute indicator 
of diabetes and none of these studies allowed for the confounding role 
of obesity. Two other studies found no association (Moses M., Lilis R., 
Crow K.D., Thornton J., Fischbein A., Anderson H.A., Selikoff I.J., 
1984. Health status of workers with past exposure to 2,3,7,8-
tetrachlorodibenzo-p-dioxin in the manufacture of 2,4,5-
trichlorophenoxyacetic acid: Comparison of findings with and without 
chloracne. American Journal of Industrial Medicine 5:161-182; Suskind 
and Hertzberg, 1984), and a number of studies have shown no increased 
death rates from diabetes (Bertazzi et al., 1989; Cook R.R., Bond G.G., 
Olson R.A., Ott M.G., 1987. Update of the mortality experience of 
workers exposed to chlorinated dioxins. Chemosphere 16:2111-2116; 
Henneberger P.K., Ferris B.G. Jr., Monson R.R., 1989. Mortality among 
pulp and paper workers in Berlin, New Hampshire. British Journal of 
Industrial Medicine 46:658-664). Accordingly, the Secretary has found 
that the credible evidence against an association between diabetes and 
herbicide exposure outweighs the credible evidence for such an 
association, and he has determined that a positive associations does 
not exist.
    The studies related to hepatic enzyme abnormality did not 
demonstrate an association with liver disease, and confounding factors 
(alcohol abuse, cirrhosis, hepatitis, and other toxic chemicals) were 
not ruled out. Studies showing lipid abnormalities do not control for 
the confounding variables of obesity and genetic factors, and no 
medical significance of the modest and variable increases has been 
demonstrated. The risk of gastric ulcers in exposed populations has not 
been sufficiently studied to establish an association with herbicide 
exposure. Only one study (Suskind and Hertzberg, 1984) indicates any 
increase, and in that study it is difficult to rule out the many 
factors (e.g., alcoholism, non-steroidal anti-inflammatory drugs, and 
H. pylori infection) known to be associated with ulcers. Accordingly, 
the Secretary has found that there is no credible evidence for an 
association between metabolic and digestive disorders (other than 
diabetes) and herbicide exposure, and he has determined that a positive 
association does not exist.
    The available data deal with two categories of immune system 
disorders: immune modulation and autoimmunity. Many immune parameters 
have been studied; however, few show a relationship to herbicide 
exposure. Most studies address such a wide range of immune parameters 
that it is likely that at least some of the positive results are due to 
chance alone, which undermines the credibility of those studies. 
Furthermore, the clinical meaning, i.e., the relationship of immune 
disorders to disease, is unclear. Other studies (e.g., Pocchiari F., 
Silano V., Zampieri A., 1979. Human health effects from accidental 
release of tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Annals 
of the New York Academy of Sciences 320:311-320; Ghezzi I., Cannatelli 
P., Assennato G., Merlo F., Mocarelli P., Brambilla P., Sicurello F., 
1982. Potential 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure of Seveso 
decontamination workers. A controlled prospective study. Scandinavian 
Journal of Work, Environment, and Health 8:176-179) found no 
relationship between immune system disorders and herbicide exposure. 
Accordingly, 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.
    Most occupational studies concerning circulatory disorders (e.g., 
Moses et al., 1984; Suskind and Hertzberg, 1984) showed no increased 
mortality or morbidity from circulatory disorders after herbicide 
exposure. The studies of the residents of Seveso, Italy (Bertazzi, 
P.A., Zocchetti C., Pesatori A.C., Guercilena S., Sanarico M., Radice 
L., 1989a. Mortality in an area contaminated by TCDD following an 
industrial incident. Medicina Del Lavoro 80:316-329; Bertazzi et al., 
1989b) showed some increased risk of mortality in the first five year 
follow-up; however, these studies had a number of technical problems: 
they were not specific to circulatory disease and did not control for 
the confounding variables of smoking, diabetes, and hypertension. 
Veteran studies (e.g., CDC, 1988) have suggested that any increase in 
heart disease may be associated with the Vietnam experience rather than 
herbicide exposure, and most of these studies did not adjust for 
confounding variables. Accordingly, the Secretary has found that the 
credible evidence against an association between circulatory diseases 
and herbicide exposure outweighs the credible evidence for such an 
association, and he has determined that a positive association does not 
exist.
    NAS examined studies that covered a wide variety of respiratory 
disorders (e.g., chronic bronchitis, asthma, pleurisy, pneumonia, and 
tuberculosis), other than respiratory cancer. Studies of individuals 
exposed in occupational settings revealed no increase in mortality from 
respiratory disease (Coggon D., Pannett B., Winter P., 1991. Mortality 
and incidence of cancer at four factories making phenoxy herbicides. 
British Journal of Industrial Medicine 48:173-178; Blair A., 1983. Lung 
cancer and other causes of death among licensed pesticide applicators. 
Journal of the National Cancer Institute 71:31-37; Alavanja et al., 
1989; Coggon D., Pannett B., Winter P.D., Acheson E.D., Bonsall J., 
1986. Mortality of workers exposed to 2-methyl--chlorophenoxyacetic 
acid. Scandinavian Journal of Work, Environment, and Health 12:448-
454). Environmental exposure studies similarly showed no significant 
differences in mortality due to respiratory disease (Bertazzi et al., 
1989a,b). Also, mortality studies of Vietnam veterans generally found 
no increased risk.
    Morbidity data are generally difficult to evaluate because of 
methodological problems and because studies focused on symptoms, lung 
function tests and x-ray interpretation rather than disease (e.g., 
Calvert et al., 1991; Pollei S., Mettler F.A. Jr., Kelsey C.A., Walters 
M.R., White R.E., 1986. Follow-up chest radiographs in Vietnam 
veterans: Are they useful? Radiology 161:101-102). One occupational 
study (Calvert G.M., Sweeney M.H., Morris J.A., Fingerhut M.A., Hornung 
R.W., Halperin W.E., 1991. Evaluation of chronic bronchitis, chronic 
obstructive pulmonary disease, and ventilatory function among workers 
exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. American Review of 
Respiratory Disease 144:1302-1306) showed no excess morbidity; another 
occupational study (Suskind and Hertzberg, 1984) found increased 
symptomatology of respiratory disease, but did not adequately control 
for the confounding factor of age. Accordingly, the Secretary has found 
that the credible evidence against an association between respiratory 
disorders and herbicide exposure outweighs the credible evidence for 
such an association, and he has determined that a positive association 
does not exist.
    NAS noted an association between nasal cancers and occupational 
exposure to nickel and to chromates. Exposure to wood dust is also a 
risk factor for nasal cancers; smoking and exposure to formaldehyde may 
increase the risk associated with wood dust. There is also evidence 
that leather workers have an increased risk for nasal cancers, and that 
there is an association between chronic nasal diseases and consumption 
of salt-preserved foods. Most studies (e.g., Wiklund, 1983; Ronco et 
al., 1992) showed inconclusive results, and often did not control for 
confounding variables. Two other epidemiological studies based on the 
same three cases (Saracci et al., 1991; Coggon D., Pannett B., Winter 
P.D., Acheson E.D., Bonsall J., 1986. Mortality of workers exposed to 2 
methyl-4-chlorophenoxyacetic acid. Scandinavian Journal of Work, 
Environment, and Health 12:448-454) and one case-control study (Hardell 
L., Johansson B., Axelson O., 1982. Epidemiological study of nasal and 
nasopharyngeal cancer and their relation to phenoxy acid or 
chlorophenol exposure. American Journal of Industrial Medicine 3:247-
257) showed increased risk associated with herbicide exposure; however, 
that risk was not statistically significant, which diminishes the 
importance of these studies. Accordingly, the Secretary has found that 
the credible evidence against an association between nasal/
nasopharyngeal cancers and herbicide exposure outweighs the credible 
evidence for such an association, and he has determined that a positive 
association does not exist.
    NAS also reviewed the literature with respect to possible 
associations between herbicide exposure and various reproductive 
effects, i.e., spontaneous abortion, birth defects, neonatal infant 
deaths and stillbirths, low birth weight, and childhood cancers in 
offspring. These reproductive effects were categorized by NAS as health 
outcomes with inadequate/insufficient evidence to determine whether an 
association exists because the studies were of inadequate statistical 
power for specific birth defects, contained a limited sample size, and/
or failed to exclude bias and chance. It should be noted that to 
compensate a veteran for these conditions is beyond VA's authority (See 
title 38, U.S.C.) and would require enabling legislation.
    NAS assigns four diseases or categories of diseases to a category 
labeled limited/suggestive evidence of no association with herbicide 
exposure which it defined as meaning that several adequate studies, 
covering the full range of levels of exposure that humans are known to 
encounter, are mutually consistent in not showing a positive 
association between herbicide exposure and the particular health 
outcome at any level of exposure. The conditions include skin cancer, 
gastrointestinal tumors (stomach cancer, pancreatic cancer, colon 
cancer, and rectal cancer), bladder cancer, and brain tumors. There 
were many credible studies (See NAS Report, Chapter 8) concerning all 
of these conditions that showed no association or a negative 
association with herbicide exposure. Accordingly, the Secretary has 
found that there is no credible evidence for an association between 
skin cancer, gastrointestinal tumors (stomach cancer, pancreatic 
cancer, colon cancer, and rectal cancer), bladder cancer, and brain 
tumors and herbicide exposure, and he has determined that a positive 
association does not exist.
    NAS reviewed approximately 6,420 abstracts of scientific or medical 
articles as an integral part of the process that resulted in its 
report, entitled ``Veterans and Agent Orange: Health Effects of 
Herbicides Used in Vietnam.'' From these articles, approximately 230 
epidemiologic studies, including studies of people exposed to 
herbicides in occupational and environmental settings as well as 
studies of Vietnam veterans, were chosen for detailed review and 
analysis. In our judgment, the comprehensive review and evaluation of 
the available literature which NAS conducted in conjunction with its 
report has permitted us 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.

    Dated: December 22, 1993.
Jesse Brown,
Secretary of Veterans Affairs.
[FR Doc. 94-73 Filed 1-3-94; 8:45 am]
BILLING CODE 8320-01-M