[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]
=======================================================================
-----------------------------------------------------------------------
DEPARTMENT OF VETERANS AFFAIRS
Disease 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, 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