[Federal Register Volume 61, Number 154 (Thursday, August 8, 1996)]
[Notices]
[Pages 41442-41449]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-20197]
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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: Hepatobiliary cancers, nasal/
nasopharyngeal cancer, bone cancer, female reproductive cancers, breast
cancer, renal cancer, testicular cancer, leukemia, abnormal sperm
parameters and infertility, cognitive and neuropsychiatric disorders,
motor/coordination dysfunction, chronic peripheral nervous system
disorders, metabolic and digestive disorders, immune system disorders,
circulatory disorders, respiratory disorders (other than certain
respiratory cancers), 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, 810 Vermont Avenue, NW., Washington, DC 20420,
telephone (202) 273-7230.
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 provides that whenever the Secretary
determines, based on sound medical and scientific evidence, that a
positive association (i.e., the credible evidence for the association
is equal to or outweighs the credible evidence against the association)
exists between exposure of humans to an herbicide agent (i.e., a
chemical in an herbicide used in support of the United States and
allied military operations in the Republic of Vietnam during the
Vietnam era) and a disease, the Secretary will publish regulations
establishing presumptive service connection for that disease. If the
Secretary determines that a presumption of service connection is not
warranted, he is to publish a notice of that determination, including
an explanation of the scientific basis for that determination. The
Secretary's determination must be based on consideration of the NAS
reports and all other sound medical and scientific information and
analysis available to the Secretary.
Although Pub. L. 102-4 does not define ``credible,'' it does
instruct the Secretary to ``take into consideration whether the results
[of any study] are statistically significant, are capable of
replication, and withstand peer review.'' Simply comparing the number
of studies which report a positive relative risk to the number of
studies which report a negative relative risk for a particular
condition is not a valid method for determining whether the weight of
evidence overall supports a finding that there is or is not a positive
association between herbicide exposure and the subsequent development
of the particular condition. Because of differences in statistical
significance, confidence levels, control for confounding factors, and
other pertinent
[[Page 41443]]
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,'' 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 341-46).
NAS issued a second report, entitled ``Veterans and Agent Orange:
Update 1996,'' on March 14, 1996. The focus of this updated review was
on new scientific studies published since the release of the first
report and updates of scientific studies previously reviewed.
The day that NAS issued its second report, the Secretary announced
the formation of a VA task force to review the report and pertinent
studies and to make recommendations to assist the Secretary in
determining whether a positive association exists between herbicide
exposure and any condition. That review has been completed, and the
task force's recommendations were submitted to the Secretary. This
notice, pursuant to Pub. L. 102-4, conveys the Secretary's
determination that there is no positive association between herbicide
exposure and hepatobiliary cancers, nasal/nasopharyngeal cancer, bone
cancer, female reproductive cancers, breast cancer, renal cancer,
testicular cancer, leukemia, abnormal sperm parameters and infertility,
cognitive and neuropsychiatric disorders, motor/coordination
dysfunction, chronic peripheral nervous system disorders, metabolic and
digestive disorders, immune system disorders, circulatory disorders,
respiratory disorders (other than certain respiratory cancers), 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.
NAS, in its 1996 report, assigns hepatobiliary cancers, nasal/
nasopharyngeal cancer, bone cancer, female reproductive cancers, breast
cancer, renal cancer, testicular cancer, leukemia, abnormal sperm
parameters and infertility, cognitive and neuropsychiatric disorders,
motor/coordination dysfunction, chronic peripheral nervous system
disorders, metabolic and digestive disorders, immune system disorders,
circulatory disorders, respiratory disorders (other than certain
respiratory cancers), and skin cancer 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 strength to permit a conclusion
regarding the presence or absence of an association with herbicide
exposure.
Hepatobiliary cancers are cancers of the liver and bile duct. There
are a variety of risk factors, including hepatitis B and C, alcohol
abuse, cirrhosis, exposure to polychlorinated biphenyl (PCB), and
smoking, that should be considered by a credible study. NAS, in its
1993 report, found the relevant studies to be few, and to have not
adequately controlled for these risk factors. One large case-control
study showed a positive relationship between herbicide exposure and the
subsequent development of hepatobiliary cancer; however, most other
credible studies of similar size indicated no relationship. A large
occupational study and a study of farmers found no relationship. See 59
FR 343 for study citations.
NAS noted in its 1996 report that an association between dioxin and
liver cancer is biologically plausible, in view of evidence that very
high exposures to similar compounds which interact with the Ah receptor
(an intracellular protein) increase liver cancer risk. However, NAS
concluded in that report that the available evidence is inadequate to
determine whether an association exists between exposure to herbicides
or dioxin and the incurrence of hepatobiliary cancer. The evidence of
biologic plausibility may lend credibility to the evidence for an
association between herbicide exposure and liver cancer, but does not
itself provide significant evidence of such an association. A case-
control study of North Vietnamese veterans (Cordier S., Le T.B., Verger
P., Bard D., Le C.D., Larouge B., Dazza M.C., Houng T.Q., Abenhaim L.,
1993. Viral infections and chemical exposures as risk factors for
hepatocellular carcinoma in Vietnam. International Journal of Cancer
55:196-201) found a significantly increased risk of hepatobiliary
cancer (odds ratio (OR) = 8.8, confidence interval (CI) 1.9-41) based
on Vietnam service generally. However, investigation of those who had
direct contact with aerial sprayings of herbicides yielded a much
smaller and nonsignificant OR = 1.3. Also, NAS noted that the value of
that study was limited because most cancer cases were diagnosed on
clinical or biochemical grounds and were not confirmed histologically.
NAS, in its 1996 report, noted that there are few occupational,
environmental, or veterans' studies of liver cancer, and most of these
are small in size and were not controlled for other risk factors. For
example, one small occupational study of workers with potential
exposure to TCDD and 4-aminobiphenyl (Collins J.J., Strauss M.E.,
Levinskas G.J., Connor P.C., 1993. The mortality experience of workers
exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a trichlorophenal
process accident. Epidemiology 4:7-13) showed a slight, but not
statistically significant, increased risk for hepatobiliary cancer;
however, it did not control for exposure to 4-aminobiphenyl. A large
study of herbicide applicators in Finland (Asp S., Riihimaki V.,
Hernberg S., Pukkala E., 1994. Mortality and cancer morbidity in
Finnish chlorophenoxy herbicide applicators: an 18-year prospective
follow-up. American Journal of Industrial Medicine 26:243-253) found no
increased risk of hepatobiliary cancer. A study of farmers in 23 states
(Blair A., Mustafa D., Heineman E.F., 1993. Cancer and other causes of
death among male and female farmers from twenty-three states. American
Journal of Industrial Medicine 23:729-742) found no increase in
proportionate cancer mortality for liver cancer. In summary, most
studies that address hepatobiliary cancers suffer from methodological
problems or do not reflect an association. 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.
NAS noted in its 1993 report an association between nasal cancers
and occupational exposure to nickel and 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-
[[Page 41444]]
preserved foods. Most studies showed inconclusive results, and often
did not control for known confounding variables. Pharmacokinetic
studies indicate that dioxin accumulates in the nasopharyngeal areas of
animals. Two epidemiological studies and one case-control study showed
increased risk associated with herbicide exposure; however, two of
those studies were statistically insignificant and the small size of
the three studies limits their value in detecting an association. (See
59 FR 345 for study citations.) One study (Wiklund K., 1983. Swedish
agricultural workers: a group with a decreased risk of cancer. Cancer
51:566-568) found a decreased risk of nasal cancer in Swedish
agricultural workers. A study of Vietnam veterans (Centers for Disease
Control, 1990. The association of selected cancers with service in the
U.S. military in Vietnam. III. Hodgkin's disease, nasal cancer,
nasopharyngeal cancer, and primary liver cancer. The Selected Cancers
Cooperative Study Group. Archives of Internal Medicine 150:2495-2505)
found no association between nasal/nasopharyngeal cancers and Vietnam
service. NAS noted in its 1996 report that the scientific evidence
concerning an association between herbicide exposure and nasopharyngeal
cancer continues to be too sparse to make a definitive conclusion
regarding the association of nasal/nasopharyngeal cancers with
herbicide exposure. An 18-year follow-up of Finnish herbicide
applicators (Asp et al., 1994) showed a small, statistically
insignificant increased risk and a decreased mortality risk for cancers
of the nasopharynx and larynx. Moreover, that study presented little
data and combined cancers of the nasopharynx and larynx into a single
category, which diminishes its importance regarding the relationship
between herbicide exposure and nasopharyngeal cancers. An environmental
study based on a follow-up of the Seveso, Italy, population (Bertazzi
A., Pesatori A.C., Consonni D., Tironi A., Landi M.T., Zocchetti C.,
1993. Cancer incidence in a population accidentally exposed to 2,3,7,8-
tetrachlorodibenzo-para-dioxin. Epidemiology 4:398-406) found a
statistically insignificant increased risk for cancer of the nose and
nasal cavity among women in the least-contaminated area and found no
cases among men in the same area (although 1.5 were expected) and no
cases in the most-contaminated areas. Accordingly, the Secretary has
found that the credible evidence against an association between nasal/
nasopharyngeal 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 in the
1993 NAS report. Because of the rarity of bone cancers, most studies
were too small to detect a significant risk. There was not a consistent
finding of bone cancer in exposed groups; a number of studies showed no
association, and the few studies that demonstrated a positive
relationship were small and had large confidence intervals. The small
size of the studies and the statistical limitations compromised their
credibility. (See 59 FR 343 for study citations.) NAS noted in its 1996
report only two new studies that considered bone cancers. Both studies
(Collins et al., 1993 and Blair et al., 1993) found nonsignificant
increases in mortality rates due to bone cancers. Methodologic problems
did not permit NAS to reach a conclusion regarding the presence or
absence of an association between bone cancers and exposure to
herbicides. 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 in its 1993 report
included those of the breast, ovaries, and uterus (including the cervix
and endometrium). The data related to women and herbicide exposure were
extremely limited because few of the studies included women. Most of
the breast cancer studies showed no association. Two studies, both of
which failed to control for reproductive histories and had
methodological problems, showed a nonsignificant risk for breast
cancer. (See 59 FR 343 for study citations.) Because of the public
health significance of breast cancer, NAS, in its 1996 report,
considered breast cancer separately from the other reproductive
cancers. The data relating exposure to herbicides to breast cancer are
sparse. In its 1996 report, NAS reviewed four recently published
studies (Bertazzi et al., 1993; Blair et al., 1993; Kogevinas M.,
Saracci R., Winkelman R., Johnson E.S., Bertazzi P.A., Bueno de
Mesquita B.H., Kauppinen T., Littorin M., Lynge E., Neuberger M., 1993.
Cancer incidence and mortality in women occupationally exposed to
chlorophenoxy herbicides, chlorophenols, and dioxins. Cancer Causes and
Control 4:547-553; and Dalager M.S., Kang H.K., Thomas T.L., 1995.
Cancer mortality patterns among women who served in the military: The
Vietnam experience. Journal of Occupational and Environmental Medicine
37:298-305) that showed no increased risk for breast cancer. NAS noted
that it was unclear whether the female members of those cohorts had
substantial chemical exposure. Accordingly, 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.
-In the 1993 report, NAS identified only one small case-control
study which found an association with ovarian cancer, but the
confidence intervals were very large. See 59 FR 343 for study citation.
The larger occupational and farm worker studies generally showed no
increased risk for ovarian or uterine cancers. (See, e.g., Ronco G.,
Costa G., Lynge E., 1992. Cancer risk among Danish and Italian farmers.
British Journal of Industrial Medicine 49:220-225; and 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., Winkelmann R., 1991. Cancer
mortality in workers exposed to chlorophenoxy herbicides and
chlorophenols. Lancet 338:1027-1032.) The 1993 NAS report identified
three studies (Saracci et al., 1991; Ronco et al., 1992; and Wiklund,
1983) showing no increased risk for uterine cancer (including cancers
of the cervix and endometrium). One study (Lynge E., 1985. A follow-up
study of cancer incidence among workers in manufacture of phenoxy
herbicides in Denmark. British Journal of Cancer 52:259-270) showed a
slightly increased risk for cervical cancer and no increased risk for
endometrial cancer. In its 1996 report, NAS reviewed a follow-up study
of the Seveso population (Bertazzi et al., 1993) which found no
significant increased risk of ovarian or uterine cancer. A study of 701
women occupationally exposed to chlorophenoxy herbicides,
chlorophenols, and dioxins (Kogevinas et al., 1993) found one death
from each of the following types of cancer: cervical (standardized
mortality rate (SMR)=80), uterine nonspecified (SMR=192), and ovarian
(SMR=74). However, no confidence intervals were cited. One study (Lynge
E., 1993. Cancer in phenoxy herbicide manufacturing workers in Denmark,
1947-87--an update. Cancer Causes and Control 4:261-272) found a
statistically significant increase in cervical cancer
[[Page 41445]]
among employees of two Danish phenoxy herbicide manufacturing
facilities, based on seven cases (standardized incidence rate
(SIR)=3.2, CI 1.3-6.6). A study of farmers in 23 states (Blair et al.,
1993) found no increase in the proportionate cancer mortality ratio
(PCMR) for cervical cancer in white female farmers, but found a
significantly increased PCMR in nonwhite female farmers. The Blair
study did not correlate the increased PCMR to herbicide exposure and
NAS noted that the increased mortality may reflect risks associated
with factors other than herbicide exposure. A study of female Vietnam
veterans (Dalager et al., 1995) showed a nonsignificant increased risk
of uterine cancer. Although the studies cited in the 1996 NAS report
provide some evidence of an association between herbicide exposure and
cervical cancer, there continues to be a number of significant studies
showing no association between herbicide exposure and either ovarian or
uterine cancers (including cervical and endometrial cancers).
Considering the entire evidence, the Secretary has found that the
credible evidence against an association between herbicide exposure and
ovarian and uterine cancers outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
NAS found in its 1993 report that the leather industry, asbestos,
cadmium, petroleum products, analgesics, smoking, and obesity are
associated with renal cancers. Studies of renal cancers in relation to
herbicide exposure have generally produced inconclusive results because
of failure to adequately control for these confounding factors. Only
one study of agricultural and forest workers showed a significantly
increased risk of death from renal cancers; however, the preponderance
of studies, including the two largest, showed either no relationship
with renal cancers or increased risk which was not significant. (See 59
FR 343 for study citations.) In its 1996 report, NAS reviewed two new
studies (Blair et al., 1993; and Visintainer P.F., Barone M., McGee H.,
Peterson E.L., 1995. Proportionate mortality study of Vietnam-era
veterans of Michigan. Journal of Occupational and Environmental
Medicine 37:423-428) that showed increased risk for renal cancer that
was not significant. A third cohort study (Bertazzi et al., 1993)
demonstrated no increased risk of renal cancer in highly exposed
individuals. One case-control study (Mellengaard R., Engholm G.,
McLaughlin J.K., Olsen J.H., 1994. Occupational risk factors for renal-
cell carcinoma in Denmark. Scandinavian Journal of Work, Environment,
and Health 20:160-165) showed increased risk for renal cancer; however,
the results were considered highly uncertain because of the wide
confidence limits. Accordingly, the Secretary has found that the
credible evidence against an association between renal cancer and
herbicide exposure outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
NAS, in its 1993 report, identified the major risk factors for
testicular cancer as undescended testis and other factors, such as
genetic abnormalities, infections, etc., which produce atrophy and
dysfunction. Occupational and environmental studies found either no
association between herbicide exposure and testicular cancer, or
increased risk which was not significant. (See 59 FR 343 for study
citations.) In its 1996 report, NAS reviewed three new studies (Blair
et al., 1993; Bertazzi et al., 1993; and Bullman T.A., Watanabe K.K.,
Kang H.K., 1994. Risk of testicular cancer associated with surrogate
measures of Agent Orange exposure among Vietnam veterans on the Agent
Orange Registry. Annals of Epidemiology 4:11-16) that produced results
generally consistent with the 1993 findings, i.e., either no
association with testicular cancer, or increased risk which was 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.
NAS, in its 1993 report, found that the potential evidence for an
association between herbicide exposure and leukemia came from studies
of farmers and residents of Seveso, Italy. When farmers were stratified
by suspected herbicide exposure, the incidence of leukemia was
generally not elevated, and in some cases elevation appeared to be due
to factors other than herbicide exposure. Those studies generally did
not adequately control for other significant confounding exposures. 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. (See 59 FR 343-44 for study citations.) In its 1996
report, NAS reviewed seven new studies (Kogevinas et al., 1993; Asp et
al., 1994; Blair et al., 1993; Bertazzi et al., 1993; Visintainer et
al., 1995; Semenciw R.M., Morrison H.I., Morrison D., Mao Y., 1994.
Leukemia mortality and farming in the prairie provinces of Canada.
Canadian Journal of Public Health 85:208-211; and Dean G., 1994. Deaths
from primary brain cancers, lymphatic and haematopoietic cancers in
agricultural workers in the Republic of Ireland. Journal of
Epidemiology and Community Health 48:364-368). Six of these studies
showed no association between herbicide exposure and leukemia or a
nonsignificant elevated risk. Blair et al. (1993), a mortality study of
farmers, showed a significantly increased PCMR for leukemia. The Blair
study, however, did not correlate the increased PCMR to suspected
herbicide exposure and did not control for other confounding factors.
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.
Infertility 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. The 1993 NAS report found no
occupational or environmental studies that examined herbicide exposure
and infertility, and veteran studies did not support an association
between herbicide exposure and infertility. There are several
components of male fertility, including sperm parameters and
reproductive hormones. The common parameters used to evaluate toxic
effects to sperm are number, motility, structure, and morphology. NAS
found in its 1993 report that many chemicals have been implicated in
interfering with motility and sperm structure. One occupational study
and one study of Vietnam veterans found no association with decreased
sperm count. Another study of Vietnam veterans found lower sperm
concentrations and reduced sperm motility, but suggested these outcomes
may be associated with the Vietnam experience rather than exposure to
herbicides. NAS did not cite any studies concerning male reproductive
hormone levels in its 1993 report. (See 59 FR 344 for study citations.)
NAS, in its 1996 report, reviewed one occupational study (Egeland G.M.,
Sweeney M.H., Fingerhut M.A., Wille K.K., Schnorr T.M., Halperin W.E.,
1994. Total serum testosterone and gonadotropins in workers exposed to
dioxin. American Journal of Epidemiology 139:272-281 and Egeland G.M.,
Sweeney M.H.,
[[Page 41446]]
Fingerhut M.A., Wille K.K., Schnorr T.M., Halperin W.E., 1995. Reply to
letter to the editor. American Journal of Epidemiology 141:477-478);
and, although it suggested an association between TCDD exposure and
changes in male reproductive hormones, there were a number of
methodologic concerns that did not permit definitive conclusions to be
drawn. NAS noted that the hormonal changes were subtle, and it is not
known whether they would have any implications for reproductive
failure. 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.
NAS found in its 1993 report that the studies of cognitive and
neuropsychiatric disorders were 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, those studies lacked credibility in
assessing the relationship of herbicide exposure to these conditions.
The 1996 NAS report reviewed one study (Peper M., Klett M., Frentzel-
Beyme R., Heller W.D., 1993. Neuropsychological effects of chronic
exposure to environmental dioxins and furans. Environmental Research
60:124-135) that found multiple neuropsychological changes; however,
the significance of these findings is uncertain because of the small
number of subjects, possible selection bias, the lack of an external
control group, and the low estimated amount of exposure. Another
reviewed study of a large sample of Vietnam veterans (Decoufle P.,
Holmgreen P., Boyle C.A., Stroup N.E., 1992. Self-reported health
status of Vietnam veterans in relation to perceived exposure to
herbicides and combat. American Journal of Epidemiology 135:312-323)
found reports of psychological dysfunction correlated with self-reports
of combat exposure and level of herbicide exposure. Without
confirmation of the subject reports, the significance of these results
is in doubt. Because of methodological problems with the preceding
studies and two other reviewed studies (Zober A., Ott M.G., Messerer
P., 1994. Morbidity follow up study of BASF employees exposed to
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after a 1953 chemical
reactor incident. Occupational and Environmental Medicine 51:469-486;
and Visintainer et al., 1995), there continues to be no credible
evidence for an association between herbicide exposure and cognitive
disorders or neuropsychiatric effects. Accordingly, the Secretary has
determined that a positive association does not exist.
NAS indicated in its 1993 report that it had found no significant
studies available to analyze whether an association exists between
herbicide exposure and motor/coordination dysfunction. NAS, in its 1996
report, reported finding no new studies directly addressing this topic.
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.
Chronic peripheral nervous system disorders (chronic peripheral
neuropathy) can be induced by many common medical and environmental
disorders unrelated to herbicide exposure, such as alcoholism,
diabetes, and exposure to other toxic chemicals. NAS, in its 1993
report, stated that many case reports suggested that acute or subacute
(transient) peripheral neuropathy can develop with exposure to dioxin,
but that the most rigorously conducted studies argued against a
relationship between dioxin or herbicides and chronic peripheral
neuropathy. NAS's first report stated that, as a group, the studies on
peripheral neuropathy suffered from various methodologic defects, such
as not applying consistent methods to define a comparison group,
determine exposure, evaluate clinical deficits, use standard
definitions of peripheral neuropathy, or eliminate confounding
variables. Occupational studies that 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. (See 59
FR 343 for study citations.)
NAS, in its 1996 report, assigned acute and subacute peripheral
neuropathy to the category labeled limited/suggestive evidence of an
association with herbicide exposure, 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.
However, NAS continued to assign chronic peripheral neuropathy to the
category labeled inadequate/insufficient evidence to determine whether
an association exists. Two case studies (Todd R.L., 1962. A case of
2,4-D intoxication. Journal of the Iowa Medical Society 52:663-664; and
Berkley M.C., Magee K.R., 1963. Neuropathy following exposure to a
dimethylamine salt of 2,4-D. Archives of Internal Medicine 111:133-134)
reported development of peripheral neuropathies within days of exposure
to 2,4-D followed by gradual recovery over a period of months. Studies
of the Seveso, Italy, accident (Boeri R., Bordo B., Crenna P.,
Filippini G., Massetto M., Zecchini A., 1978. Preliminary results of a
neurological investigation of the population exposed to TCDD in the
Seveso region. Rivista di Patologia Nervosa e Mentale 9:111-128;
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 Science 320:311-320; and
Filippini G., Bordo B., Crenna P., 1981. Relationship between clinical
and electrophysiological findings and indicators of heavy exposure to
2,3,7,8-tetrachlorodibenzo-p-dioxin. Scandinavian Journal of Work,
Environment, and Health 7:257-262) suggested that peripheral nerve
problems were more prevalent in the exposed group. Filippini et al.
(1981) demonstrated that those individuals with clinical signs of
significant exposure (chloracne or elevated liver enzymes) showed a
risk ratio of 2.8. Two subsequent follow-up studies (Barbieri S.,
Pirovano C., Scarbato G., Tarchini P., Zappa A., Maranzana M., 1988.
Long-term effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the
peripheral nervous system. Clinical and neurophysiological controlled
study on subjects with chloracne from the Seveso area.
Neuroepidemiology 7:29-37; and Assennato G., Cervino D., Emmett E.A.,
Longo G., Merlo F., 1989. Follow-up of subjects who developed chloracne
following TCDD exposure at Seveso. American Journal of Industrial
Medicine 16:119-125) showed no increased frequency of peripheral
neuropathy several years after the accident among the highly exposed
group. Environmental studies and case reports suggest that the
development of peripheral neuropathy can follow high levels of exposure
to herbicides, and that peripheral neuropathy associated with herbicide
exposure will manifest very soon after exposure. The trend to recovery
in the individual cases
[[Page 41447]]
reported and the negative findings of many long-term follow up studies
of peripheral neuropathy (e.g., Zober et al., 1994) suggest that, if a
neuropathy develops, it resolves with time. Their findings are
consistent with others who found no evidence of increased occurrence of
chronic persistent peripheral neuropathy after TCDD exposure. Although
the Secretary has found a positive association between herbicide
exposure and acute and subacute peripheral neuropathy, considering all
of the evidence, he has found that the credible evidence against an
association between chronic nervous system disorders and herbicide
exposure outweighs the credible evidence for such an association, and
he has determined that a positive association does not exist.
Metabolic and digestive disorders include diabetes mellitus,
hepatic enzyme abnormality, lipid abnormalities, and ulcers. Although
NAS found no biological basis to suspect an association between
herbicide exposure and diabetes in its 1993 report, abnormal glucose
tolerance tests were reported in three studies. While this suggested
such an association, the evidence was inconclusive and its credibility
was questionable because an abnormal glucose tolerance test is not an
absolute indicator of diabetes and none of the studies allowed for the
confounding role of obesity. Two other studies found no association,
and a number of studies showed no increased death rates from diabetes.
Two 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 did not control for the
confounding variables of obesity and genetic factors, and no medical
significance of the modest and variable increases was demonstrated. The
risk of gastric ulcers in exposed populations was not sufficiently
studied to establish an association with herbicide exposure. Only one
study indicated any increase, and in that study it was 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. (See 59 FR 344-45 for study citations.) In its 1996
report, NAS reviewed two studies of workers at a BASF plant who had
been potentially exposed to TCDD and other chemicals in a plant
accident in 1953 (Ott M.G., Zober A., Germann C., 1994. Laboratory
results for selected target organs in 138 individuals occupationally
exposed to TCDD. Chemosphere 29:2423-2437; and Zober et al., 1994) for
any relationship between herbicide exposure and diabetes. Ott et al.
(1994) showed a marginal elevation in fasting serum glucose levels, but
did not control for obesity. Zober et al. (1994) demonstrated no
increase in diabetes with chloracne severity or TCDD levels, and the
study did not control for obesity. A third study, involving employees
of six chemical factories in Germany (Von Benner A., Edler L., Mayer
K., Zober A., 1994. ``Dioxin'' investigation program of the chemical
industry professional association. Arbeitsmedizin Sozialmedizin
Praventivmedizin 29:11-16) showed no correlation between serum TCDD
levels and blood glucose levels. In its 1996 report, NAS reviewed the
same three studies (Ott et al., 1994; Zober et al., 1994; and Von
Benner et al., 1994) when considering the relationship between
herbicide exposure and hepatic enzyme abnormalities. The noted
increases in abnormal liver function tests or the frequency of chronic
liver disease were confounded by the lack of control for alcohol abuse.
Zober, et al. (1994) found a nonsignificant increase in liver disease
among individuals exposed to dioxin, and Von Benner, et al. (1994)
found no correlation between serum dioxin levels and abnormalities in
liver function tests. One new study was reviewed in the 1996 NAS report
concerning any association between herbicide exposure and lipid
abnormalities (Ott et al., 1994) and showed no substantial differences
between the exposed and reference groups. The only new study reviewed
in the 1996 NAS report concerning any relationship between ulcers and
exposure to herbicides (Zober et al., 1994) showed no increases in the
frequency of ulcers. Accordingly, the Secretary has found that the
credible evidence against an association between metabolic and
digestive disorders and herbicide exposure outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
NAS found, in its 1993 report, that the available data dealt with
two categories of immune system disorders: immune modulation and
autoimmunity. Many immune parameters were studied; however, few showed
a relationship to herbicide exposure. Most studies addressed such a
wide range of immune parameters that it was likely that at least some
of the positive results were due to chance alone. Other studies found
no relationship between immune system disorders and herbicide exposure.
(See 59 FR 345 for study citations.) NAS noted in its 1996 report that
no new studies of heightened susceptibility to infectious disease or
new studies that investigated the association of autoimmune disease
with exposure to herbicides have been identified. However, some new
information has been published regarding the effects of TCDD on
immunological parameters in laboratory measurements. The new studies
(Ott et al., 1994; Von Benner et al., 1994; Jansing P.J., Korff R.,
1994. Blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin and gamma-
globulins in a follow-up investigation of employees with chloracne.
Journal of Dermatological Science 8:91-95; Svenson B.G., Hallberg T.,
Nilsson A., Schutz A., Hagmar L., 1994. Parameters of immunological
competence in subjects with high consumption of fish contaminated with
persistent organochlorine compounds. International Archives of
Occupational and Environmental Health 65:351-358; Neubert R., Maskow
L., Webb J., Jacob-Muller U., Nogueira A.C., Delgado I., Helge H.,
Neubert D., 1993. Chlorinated dibenzo-p-dioxins and dibenzofurans and
the human immune system. 1. Blood cell receptors in volunteers with
moderately increased body burdens. Life Sciences 53:1995-2006; and
Neubert R., Maskow L., Delgado I., Helge H., Neubert D., 1994.
Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune
system. 2. In vitro proliferation of lymphocytes from workers with
quantified moderately increased body burdens. Life Sciences 56:421-436)
reviewed such a wide range of immune parameters that it is likely that
at least some of the abnormal laboratory tests were due to chance. In
addition, these studies failed to show a relationship between
laboratory abnormalities and development of disease in the populations
studied. 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.
NAS noted in its 1993 report that most occupational studies
concerning circulatory disorders showed no increased mortality or
morbidity after herbicide exposure. The studies of the residents of
Seveso, Italy, showed some increased risk of mortality in the first
five-year follow-up; however, those studies had a number of technical
problems: They were not specific to
[[Page 41448]]
circulatory disease and did not control for the confounding variables
of smoking, diabetes, and hypertension. Certain of the veteran studies
suggested that any increase in heart disease may be associated with the
Vietnam experience rather than herbicide exposure, and most of those
studies did not adjust for confounding variables. (See 59 FR 345 for
study citations.) NAS reviewed one study (Zober et al., 1994) in its
1996 report that showed no increase in the frequency of heart disease.
Another study (Von Benner, et al., 1994) found possible correlations
for elevated systolic blood pressure; however, this relationship was
difficult to evaluate because age and body-mass index also had a
significant effect. An analysis (Wolfe W.H., Michalek J.E., Miner J.C.,
Roegner R. H., Grubbs W.D., Lustik M.B., Brockman A.S., Henderson S.C.,
Williams D.E., 1992. The air force health study: An epidemiologic
investigation of health effects in Air Force personnel following
exposure to herbicides, serum dioxin analysis of 1987 examination
results. Chemosphere 25:213-216) of the data from an Air Force study
(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. 9 vols. Brooks AFB, TX:
USAF School of Aerospace Medicine) provides some potentially
significant evidence for an association with dioxin exposure, since the
results were derived from the first large-scale study of dose-response
relationships. However, this study did not control for the confounding
factor of diabetes. There was a significant increased risk of essential
hypertension for the participants with a high-level of dioxin exposure.
However, the reverse analysis of participants suffering from
hypertension did not show an association with dioxin, suggesting lack
of dose-response relationships. Accordingly, the Secretary has found
that the credible evidence against an association between circulatory
disorders and herbicide exposure outweighs the credible evidence for
such an association, and he has determined that a positive association
does not exist.
In its 1993 report, NAS examined studies that covered a wide
variety of respiratory disorders (e.g., chronic bronchitis, asthma,
pleurisy, pneumonia, and tuberculosis), other than respiratory cancers.
Studies of individuals exposed in occupational settings revealed no
increase in mortality from respiratory disease. Environmental exposure
studies similarly showed no significant differences in mortality due to
respiratory disease. Mortality studies of Vietnam veterans generally
found no increased risk. Morbidity data were generally difficult to
evaluate because of methodological problems and because studies focused
on symptoms, lung function tests and x-ray interpretation rather than
disease. One occupational study showed no excess morbidity; another
occupational study found increased symptomatology of respiratory
disease, but did not adequately control for the confounding factor of
age. (See 59 FR 345 for study citations.) NAS, in its 1996 report,
reviewed three new studies (Zober et al., 1994; Garry V.F., Kelly J.T.,
Sprafka J.M., Edwards S., Griffith J., 1994. Survey of health and use
characterization of pesticide appliers in Minnesota. Archives of
Environmental Health 49:337-343; and Senthilselvan A., McDuffie H.H.,
Dosman J.A., 1992. Association of asthma with use of pesticides:
results of a cross-sectional survey of farmers. American Review of
Respiratory Diseases 146:884-887), all of which found no significant
increase in respiratory disease associated with herbicide exposure.
Accordingly, the Secretary has found that the credible evidence against
an association between respiratory disorders (other than certain
respiratory cancers) and herbicide exposure outweighs the credible
evidence for such an association, and he has determined that a positive
association does not exist.
NAS, in its 1993 report, assigned skin cancer to a category labeled
limited/suggestive evidence of no association with herbicide exposure.
This is 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. There were many credible studies that showed no association
or a negative association with herbicide exposure. (See Chapter 8 of
NAS's first report.) The 1996 NAS report reviewed one new study (Lynge,
1993) that did find an excess risk of skin cancer. However, another new
study (Bertazzi et al., 1993) found no increased risk of skin cancer.
Three other new studies (Asp et al., 1994; Collins et al., 1993; and
Bueno de Mesquita H.B., Doornbos G., Van der Kuip D.A., Kogevinas M.,
Winkelmann R., 1993. Occupational exposure to phenoxy herbicides and
chlorophenols and cancer mortality in the Netherlands. American Journal
of Industrial Medicine 23:289-300) were too small to have sufficient
statistical power to give definitive results. A mortality study of
farmers in 23 states utilizing occupational information from death
certificates (Blair et al., 1993) found an increased PCMR for skin
cancer in white male farmers. The Blair study, however, did not
correlate the increased PCMR to suspected herbicide exposure and did
not control for other confounding factors. NAS felt that these studies,
while not providing suggestive evidence of an association with
herbicide exposure, undermined the evidence of no association discussed
in its first report, and thus warranted changing skin cancer from the
``limited/suggestive evidence of no association'' category to the
``inadequate/insufficient evidence to determine whether an association
exists'' category. Based on the available evidence, the Secretary has
found that the credible evidence against an association between skin
cancer and herbicide exposure outweighs the credible evidence for such
an association, and he has determined that a positive association does
not exist.
NAS, in its 1996 report (as it had in its 1993 report), also
reviewed the current literature with respect to possible associations
between herbicide exposure and various reproductive effects, i.e.,
spontaneous abortion, spina bifida, birth defects (other than spina
bifida), neonatal/infant deaths and stillbirths, low birthweights, and
childhood cancer in offspring. Compensation of a veteran or a veteran's
child for these effects is beyond VA's authority (See title 38, U.S.C.)
and would require enabling legislation.
NAS, in its 1996 report, assigns three diseases or categories of
diseases to a category labeled limited/suggestive evidence of no
association with herbicide exposure, which it defined in the same
manner as in the 1993 NAS report (see above). The conditions include
gastrointestinal tumors (stomach cancer, pancreatic cancer, colon
cancer, and rectal cancer), bladder cancer, and brain tumors. There
were many credible studies (see the 1996 NAS report, Chapter 7)
concerning all of these conditions that showed no association or a
negative association with herbicide exposure. Accordingly, the
Secretary has found that the credible evidence against an association
between gastrointestinal tumors (stomach cancer, pancreatic cancer,
colon cancer, and rectal cancer), bladder cancer, and brain tumors and
herbicide exposure outweighs the credible evidence for such an
association, and he has
[[Page 41449]]
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 1996.'' In our
judgment, 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: July 8, 1996.
Jesse Brown,
Secretary of Veterans Affairs.
[FR Doc. 96-20197 Filed 8-7-96; 8:45 am]
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