[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]
BILLING CODE 8320-01-P