[Federal Register Volume 64, Number 211 (Tuesday, November 2, 1999)]
[Notices]
[Pages 59232-59243]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-28579]
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DEPARTMENT OF VETERANS AFFAIRS
Diseases 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, breast cancer, female reproductive
cancers, urinary bladder cancer, renal cancer, testicular cancer,
leukemia, abnormal sperm parameters and infertility, motor/coordination
dysfunction, chronic peripheral nervous system disorders, metabolic and
digestive disorders (other than diabetes mellitus), immune system
disorders, circulatory disorders, respiratory disorders (other than
certain respiratory cancers), skin cancer, cognitive and
neuropsychiatric effects, gastrointestinal tumors, 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: Donald England, Chief, Regulations
Staff, Compensation and Pension Service, Veterans Benefits
Administration, 810 Vermont Avenue, NW., Washington, DC 20420,
telephone (202) 273-7210.
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
[[Page 59233]]
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, bias,
and other pertinent characteristics, some studies are clearly more
credible than others, and the Secretary has given the more credible
studies more weight in evaluating the overall weight of the evidence
concerning specific diseases.
NAS issued its initial report, entitled ``Veterans and Agent
Orange: Health Effects of Herbicides Used in Vietnam,'' (VAO) on July
27, 1993. The Secretary subsequently determined that a positive
association exists between exposure to herbicides used in the Republic
of Vietnam and the subsequent development of Hodgkin's disease,
porphyria cutanea tarda, multiple myeloma, and certain respiratory
cancers; and that there was no positive association between herbicide
exposure and any other condition, other than chloracne, non-Hodgkin's
lymphoma, and soft-tissue sarcomas, for which presumptions already
existed. A notice of the diseases that the Secretary determined were
not associated with exposure to herbicide agents was published on
January 4, 1994 (See 59 FR 341-46).
NAS issued its second report, entitled ``Veterans and Agent Orange:
Update 1996'' (Update 1996), on March 14, 1996. The Secretary
subsequently determined that a positive association exists between
exposure to herbicides used in the Republic of Vietnam and the
subsequent development of prostate cancer and acute and subacute
peripheral neuropathy in exposed persons. The Secretary further
determined that there was no positive association between herbicide
exposure and any other condition, other than those for which
presumptions already existed. A notice of the diseases that the
Secretary determined were not associated with exposure to herbicide
agents was published on August 8, 1996 (See 61 FR 41442-49).
NAS issued a third report, entitled ``Veterans and Agent Orange:
Update 1998'' (Update 1998), on February 11, 1999. The focus of this
updated review was on new scientific studies published since the
release of Update 1996 and updates of scientific studies previously
reviewed.
Shortly after NAS issued Update 1998, the Secretary formed a VA
task force to review the report and pertinent studies and to make
recommendations to assist him in determining whether a positive
association exists between herbicide exposure and any condition. The
task force has completed that review and submitted its recommendations
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, breast cancer, female reproductive cancers,
urinary bladder cancer, renal cancer, testicular cancer, leukemia,
abnormal sperm parameters and infertility, motor/coordination
dysfunction, chronic peripheral nervous system disorders, metabolic and
digestive disorders (other than diabetes mellitus), immune system
disorders, circulatory disorders, respiratory disorders (other than
certain respiratory cancers), skin cancer, cognitive and
neuropsychiatric effects, gastrointestinal tumors, brain tumors, and
any other condition for which the Secretary has not specifically
determined a presumption of service connection is warranted.
This notice also conveys the Secretary's determination that a new
study concerning the possible association between exposure to
herbicides and diabetes mellitus that was published since NAS completed
Update 1998, is potentially significant. The Secretary has requested,
and the NAS is currently reviewing that new study and will determine
whether a positive association exists between herbicide exposure and
diabetes mellitus after their review.
NAS, in Update 1998, assigns hepatobiliary cancers, nasal/
nasopharyngeal cancer, bone cancer, breast cancer, female reproductive
cancers, urinary bladder cancer, renal cancer, testicular cancer,
leukemia, abnormal sperm parameters and infertility, motor/coordination
dysfunction, chronic peripheral nervous system disorders, metabolic and
digestive disorders (including diabetes mellitus), 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 power to permit a
conclusion regarding the presence or absence of an association with
herbicide exposure.
Hepatobiliary Cancers
Hepatobiliary cancers are cancers of the liver and intrahepatic
bile ducts. There are a variety of known risk
[[Page 59234]]
factors, including chronic infections with hepatitis B and C, exposure
to aflatoxin, vinyl chloride and polychlorinated biphenyl (PCB) and
smoking, that should be considered by a credible study. NAS, in VAO,
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 Update 1996 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. NAS, in
Update 1996, again 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 et al., 1993) 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
et al., 1994) found no increased risk of hepatobiliary cancer. A study
of farmers in 23 states (Blair et al., 1993) found no increase in
proportionate cancer mortality for liver cancer. In summary, most
studies that addressed hepatobiliary cancers suffered from
methodological problems or did not reflect an association. See 61 FR
41443 for study citations.
NAS, in Update 1998, again assigned hepatobiliary cancer to the
category ``inadequate/insufficient evidence to determine whether an
association exists.'' The IARC study (Kogevinas M, Becher H, Benn T,
Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D,
Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Lettorin M, Lynge E,
Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in
workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An
expanded and updated international cohort study. American Journal of
Epidemiology 145(12): 1061-1075.) noted no excess of death from
hepatobiliary cancer among a group of all workers exposed to phenoxy
herbicides or chlorophenol, although those exposed to TCDD or higher
chlorinated dioxins had a higher risk (SMR=0.87, CI 0.45-1.52) than
those not exposed (SMR=0.41, CI 0.09-1.22). However, this study did not
include a detailed analysis by exposure variables (such as duration and
time since first exposure), and did not distinguish heavily exposed
workers from those with minor exposures. A study of 2,479 male workers
in German facilities that produced phenoxy herbicides and chlorophenols
(Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz
A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed
to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3): 312-
21.) showed only one death due to hepatobiliary cancer (SMR=1.2, CI 0-
6.9); this was in one of the groups with presumed lower TCDD exposure.
Observed and expected deaths due to liver cancer among a cohort of rice
growers in northern Italy between 1957 and 1992 (Gambini GF, Mantovani
C, Pira E, Piolatto PG, Negri E. 1997. Cancer mortality among rice
growers in Novara Province, Northern Italy. American Journal of
Industrial Medicine 31(4); 435-441.) did not differ significantly from
national rates (SMR=1.3, CI 0.5-2.6). This small study is limited by
its crude exposure assessment and uncertainty in establishing degree of
exposure. A 15-year follow-up of the exposed population of Seveso,
Italy (Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A,
Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: A 15-year
mortality study after the ``Seveso Accident.'' Epidemiology 8(6): 646-
652) showed nonsignificant decreases in liver cancer in all exposure
groups except for women in group B, where a nonsignificant elevation
was seen (3 cases for an SMR=1.3, CI 0.3-3.8). A study of two cohorts
of Swedish fishermen, distinguished by the types of fish in their diets
and the presumed levels of PCB, PCDD, and PCDF in the fish (Svennson
BG, Mikoczy Z, Stromberg U, Hagmar L. 1995. Mortality and cancer
incidence among Swedish fishermen with a high dietary intake of
persistent organochlorine compounds. Scandinavian Journal of Work,
Environment, and Health 21(2): 106-115.), showed nonsignificantly
decreased mortality from liver cancer in both groups. The group
presumed to have higher exposure had a nonsignificantly increased
incidence of the disease compared to national Swedish rates (SIR=1.31,
CI 0.48-2.85), while the less exposed group had a nonsignificantly
decreased incidence. A particular weakness of this study is the lack of
data to support the differences in reported blood levels of dioxin-like
compounds for each group. A study of male Australian Vietnam veterans
(Crane PJ, Horsley KD, Adena MA. 1997a. Mortality of Vietnam veterans:
the veteran cohort study: A report of the 1996 retrospective cohort
study of Australian Vietnam veterans, Canberra; Department of Veterans
Affairs.) reported a statistically significant excess of all cancer
deaths among the 2,067 deaths recorded from 1980 to 1994 but observed
no excess of mortality from liver cancer (SMR=0.6, CI 0.3-1.2).
However, among the weaknesses of this study are the possible under
ascertainment of death, and the uncertain quality of assessing such
risk factors as smoking, alcohol, and herbicide and dioxin exposure.
Crane's subsequent study of mortality among Australian National Service
Vietnam veterans reported similar findings for hepatobiliary cancer
(Crane PJ, Horsley KD, Adena MA. 1997b. Mortality of Vietnam veterans:
the national servicemen comparison. A report of the 1996 retrospective
cohort study of Australian Vietnam veterans. Canberra; Department of
Veterans Affairs.).
Most of the few existing studies addressing hepatobiliary cancer
contain methodological difficulties such as small study size and
inadequate control for life-style-related risk factors, or do not
support an association with herbicide exposure. 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.
Nasal/Nasopharyngeal Cancer
NAS noted that exposure to nickel, chromates, wood dust and
formaldehyde are risk factors for nasal cancers. Smoking, exposure to
salt-preserved foods, and Epstein-Barr virus may increase the risk of
nasopharyngeal cancer.
In VAO, NAS found studies of nasal and nasopharyngeal cancers very
limited. Most studies showed
[[Page 59235]]
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. One study (Wiklund K., 1983) found a
decreased risk of nasal cancer in Swedish agricultural workers. A study
of Vietnam veterans (Centers for Disease Control, 1990) found no
association between nasal/nasopharyngeal cancers and Vietnam service.
(See 59 FR 345 for study citations.)
NAS noted in Update 1996 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 et al., 1993) 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. (See 61 FR 41443-44 for study
citations.)
In Update 1998, NAS stated that scientific evidence of an
association with herbicide exposure continues to be too sparse to make
a definitive statement. The IARC study (Kogevinas et al., 1997) has
brought together almost all of the phenoxy herbicide production workers
in 36 cohorts for a joint analysis. That combined cohort study showed
no effect of phenoxy herbicide exposure on oral cavity or pharyngeal
cancers (RR=1.1, CI 0.7-1.6). There were three deaths from cancer of
the nose and nasal sinuses, but none in the TCDD-exposed group (RR=1.6,
CI 0.3-4.7). Crane et al, (1997a) found no deaths from either nasal or
nasopharyngeal cancer in Australian Vietnam veterans during 1964-1979,
with 0.8 expected. For the period 1980-1994, there were two deaths due
to nasal and two due to nasopharyngeal cancers, with 1.7 and 3.9
expected, respectively. Crane's companion study comparing Australian
Vietnam veterans with military personnel who did not serve there showed
one death due to nasopharyngeal cancer in each group between 1982-1994,
and only one death due to nasal cancer, which occurred in the
comparison population (Crane et al., 1997b). NAS found that the
scientific evidence of the association between herbicide exposure and
nasopharyngeal cancer continues to be too sparse to make a definitive
statement.
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
Bone cancers were considered together with joint cancers in VAO.
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 Update 1996 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. (See 61 FR 41444 for study
citations.)
In Update 1998, NAS reports that there is minimal new information
regarding bone cancer and that few data existed before. A study of the
IARC combined occupational cohorts (Kogevinas et al., 1997) found five
cases of bone cancer for all workers (SMR=1.2, CI 0.4-2.8). The SMR in
those exposed to TCDD was lower (1.1) than in those not exposed (1.4).
A study of 770 pentachlorophenol workers reported no deaths from bone
cancer (Ramlow JM, Spadacene JW, Hoag SR, Stafford BA, Cartmill JB,
Lerner PJ. 1996. Mortality in a cohort of pentachlorophenol
manufacturing workers, 1940-1989. American Journal of Industrial
Medicine 30(2): 180-194.). A study of rice growers in northern Italy
(Gambini et al., 1997) identified only one death, and a study of 26,000
Canadian sawmill workers presumptively exposed to dioxin-contaminated
chlorophenate reported five bone cancer deaths (SMR=1.3, CI 0.5-2.7)
(Hertzmann C, Teschke K, Ostry A, Hershler R, Dimich-Ward H, Kelly S,
Spinelli JJ, Gallagher RP, McBride M, Marion SA. 1997. Mortality and
cancer incidence among sawmill workers exposed to chlorophenate wood
preservatives. American Journal of Public Health 87(1): 71-79.). A
follow-up of individuals exposed as a result of the 1976 industrial
accident in Seveso, Italy, found 2 deaths in men (SMR=0.5) in the
lowest exposure zone and 7 deaths in women in the lowest exposure zone
(SMR=2.4) (Bertazzi et al., 1997). Clapp's update of his study of
Massachusetts Vietnam veterans reports 4 cases of bone cancer (OR=0.9,
CI 0.1-11.3) (Clapp RW. 1997. Update of cancer surveillance of veterans
in Massachusetts, USA. International Journal of Epidemiology 26(3):
679-681.). Other Vietnam veteran studies did not report bone cancer
results. After reviewing all available evidence, 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.
Breast Cancer and Female Reproductive Cancers
The data related to women and herbicide exposure have been
extremely limited because few of the studies have included women.
Cohorts reviewed in occupational studies have included few exposed
female workers.
Female reproductive cancers reviewed by NAS in VAO included those
of the breast, ovaries, and uterus (including the cervix and
endometrium). Because of the public health significance of breast
cancer, NAS, in Update 1996, considered breast cancer separately from
the other reproductive cancers. In Update 1998, NAS again addresses
breast cancer separately from the other cancers.
Breast Cancer
Risk factors for breast cancer include age, race, personal or
family history of breast cancer and reproductive history. The data
relating exposure to herbicides to breast cancer are sparse. In VAO,
NAS found that most of the breast cancer studies showed no association.
Two studies, both of which failed to
[[Page 59236]]
control for reproductive histories and had methodological problems,
showed a nonsignificant risk for breast cancer. (See 59 FR 343 for
study citations.)
In Update 1996, NAS reviewed four recently published studies
(Bertazzi et al., 1993; Blair et al., 1993; Kogevinas et al., 1993, and
Dalager et al., 1995) 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. (See 61 FR 41444 for study
citations.)
NAS found few new published studies on breast cancer since Update
1996. The IARC study (Kogevinas et al., 1997) found a nonsignificant
increased risk of breast cancer in males, as well as a significant
increased risk in one cohort of women from Germany with substantial
exposure to TCDD or higher chlorinated dioxins. Data from Australian
Vietnam veterans (Crane et al., 1997a) also indicated an elevation of
male breast cancer (SMR=5.5, 95% CI 1.1-16.1). The findings of
increased risk for males are notable because breast cancer in males is
rare. On the other hand, the 15-year follow-up of the Seveso population
(Bertazzi et al., 1997) indicates no excess of breast cancer, and even
suggests a possible protective effect of TCDD exposure (RR less than
1.0). TCDD also appears to exert a protective effect on the incidence
of mammary tumors in experimental animals. Taken together, the data
continue to be inconclusive. 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.
Female Reproductive Cancers (Ovaries, Uterus, Cervix, Endometrium)
In VAO, NAS identified only one small case-control study which
found an association with ovarian cancer, but the confidence intervals
were very large. The larger occupational and farm worker studies
generally showed no increased risk for ovarian or uterine cancers. VAO
identified three studies showing no increased risk for uterine cancer
(including cancers of the cervix and endometrium). One study showed a
slightly increased risk for cervical cancer and no increased risk for
endometrial cancer. (See 59 FR 343 for study citations.)
In Update 1996, NAS reviewed a follow-up study of the Seveso
population which found no significant increased risk of ovarian or
uterine cancer. A study of 701 women occupationally exposed to
chlorophenoxy herbicides, chlorophenols and dioxins found one death
from each of the following types of cancer: cervical (SMR=80), uterine
nonspecified (SMR=192), and ovarian (SMR=74). One study found a
statistically significant increase in cervical cancer among employees
of two Danish phenoxy herbicide manufacturing facilities, based on
seven cases (SIR=3.2, CI 1.3-6.6). A study of farmers in 23 states
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. This 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 showed a
nonsignificant increased risk of uterine cancer. Although the studies
cited in Update 1996 provided some evidence of an association between
herbicide exposure and cervical cancer, there continued to be a number
of significant studies showing no association between herbicide
exposure and either ovarian or uterine cancers (including cervical and
endometrial cancers). (See 61 FR 4144-45 for study citations.)
In Update 1998, NAS reviewed two new studies. A 15-year follow-up
of more than 20,000 exposed women in the Seveso population (Bertazzi et
al., 1997) provides no evidence that TCDD is associated with deaths
from either uterine or ovarian cancer. Deaths from uterine cancer were
lower than expected in the two zones with the highest exposures, and
the deaths from ovarian cancer were 1 and 0, respectively, where 0.4
and 2.7, respectively, were expected. In one zone with a lower exposure
(but still greater than those not exposed to the accident), 27 uterine
cancer deaths were observed, where 23.7 were expected (RR=1.1, 95% CI
0.8-1.7). The RR for ovarian cancer in this zone was 1.0 (CI 0.6-1.6).
However, it may still be too early for tumors related to exposure to
have come to clinical attention. In the IARC study (Kogevinas et al.,
1997), no deaths from cancer of the uterine cervix or the ovary were
observed among women exposed to TCDD or higher chlorinated dioxins. An
SMR of 3.41 was observed for cancer of the endometrium and uterus based
on three cases with exposure to TCDD or higher chlorinated dioxins. Two
of these cases occurred in the cohort that included most of the TCDD-
exposed female production workers. NAS concluded that despite some
strong associations with ovarian and uterine cancers, the evidence
remains inconclusive, largely because most of the published studies
have only a small number of cases, poor exposure characterization, or
too short a follow-up period. 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.
Urinary Bladder Cancer
Smoking is the most important risk factor for cancer of the urinary
bladder. However, exposure to aromatic amines, high fat diet and
schistosoma hematobium infection have also been implicated. In VAO and
Update 1996, NAS assigned urinary bladder cancer to a category labeled
limited/suggestive evidence of no association with herbicide exposure.
This category 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. One study found a small excess of
mortality in chemical production workers exposed to TCDD. There were
many other credible studies that produced inconclusive results. (For
study citations, see pages 515-17 of the 1993 report and pages 225-27
of the 1996 report.)
In Update 1998, NAS, on the basis of all epidemiologic evidence,
felt that urinary bladder cancer should now be assigned to the category
``inadequate/insufficient evidence to determine whether an association
exists.'' The risk ratios (RR) in some of the largest cohorts tended to
be greater than 1, weakening the prior conclusion that there was
positive evidence of no relationship. The IARC study found an SMR of
1.0 (CI 0.7-1.5) for all workers, and an SMR of 1.4 (CI 0.9-2.1) among
workers exposed to TCDD or higher chlorinated dioxins (Kogevinas et
al., 1997). A follow-up of BASF employees (Ott MG, Zober A. 1996. Cause
specific mortality and cancer incidence among employees exposed to
2,3,7,8-TCDD after a 1953 reactor accident. Occupational and
Environmental Medicine 53(9): 606-612.) found two deaths from a total
of five cases (SIR=1.4, CI 0.4-3.2), but they were described as due to
``bladder or kidney'' cancer. A cohort of Swedish fisherman with
presumed elevated-exposure (Svensson et al., 1995) showed
[[Page 59237]]
an SIR of 0.7 (CI 0.4-1.3), while a comparison cohort showed an SIR of
0.9 (CI 0.7-1.1). SMRs for the two cohorts were 1.3 (CI 0.4-3.1) and
1.0 (CI 0.6-1.6), respectively. Other new occupational and
environmental studies showed results around the null (Hertzman et al.,
1997; Gambini et al., 1997; and Bertazzi et al., 1997). Among Vietnam
veteran studies, a study of the mortality experience of Australian
veterans relative to military personnel who did not serve in Vietnam
reported a statistically significant RR of 0.6 based on one death among
Vietnam veterans and two in the comparison group (Crane et al., 1997b).
An update of a study of Massachusetts veterans (Clapp, 1997) found an
OR of 0.6 (CI 0.2-1.3) based on 80 cases.
On the basis of its review of new studies, NAS found that there is
no evidence that exposure to herbicides alone is related to bladder
cancer. Exposure to TCDD in combination with other known bladder
carcinogens made it difficult to isolate any additional effect of
herbicides. Considering the entire evidence, the Secretary has found
that the credible evidence against an association between herbicide
exposure and urinary bladder cancer outweighs the credible evidence for
such an association, and he has determined that a positive association
does not exist.
Renal Cancer
NAS found in VAO 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 they
failed 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 Update 1996, NAS reviewed two new studies (Blair et al., 1993;
and Visintainer et al., 1995) 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 Danish case-control study (Mellengaard et al., 1994)
showed increased risk for renal cancer; however, the results were
considered highly uncertain because of the wide confidence limits. (See
61 FR 41445 for study citations.)
In Update 1998, NAS found that the most important new study was
that of the IARC cohorts (Kogevinas et al., 1997). This study reported
26 cases of kidney cancer (SMR=1.6; CI 1.1-2.4) for workers exposed to
TCDD, and an SMR of 1.1 (CI 0.7-1.6) for all workers exposed to any
phenoxy herbicide or chlorophenol. However, the study provided no trend
analysis by duration of exposure or time since exposure. Clapp's update
on Massachusetts Vietnam veterans (Clapp, 1997) reported an OR of 1.0
(CI 0.4-2.3). A study comparing all Australian Vietnam veterans to the
male Australian population reported SMR=1.2 (CI 0.8-1.9) (Crane et al.,
1997a). Another study of Australian Vietnam veterans compared with
military personnel who did not serve in the conflict reported a
statistically significant RR of 3.9 based on three deaths among Vietnam
veterans and one in the comparison population between 1982 and 1984
(Crane et al., 1997b). However, this study did not have exposure
information. Other studies reviewed by NAS produced equivocal results.
NAS concluded that of the literature published since Update 1996, only
the IARC study points to a possible association between herbicide
exposure and renal cancer, but that, due to its marginal significance,
lack of trend data, and heterogeneity of the cohorts, it was not strong
enough to outweigh the equivocal results of the other studies.
Therefore, on the basis of all available evidence, 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.
Testicular Cancer
In VAO, NAS 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 Update 1996, NAS
reviewed three new studies that produced results generally consistent
with the 1993 findings, i.e., either no association with testicular
cancer, or increased risk which was not significant. (See FR 61 41445
for study citations.)
In Update 1998, NAS found minimal new information on this rare
cancer based on a review of 10 new studies (Kogevinas et al., 1997;
Ramlow et al., 1996; Hertzman et al., 1997; Bertazzi et al., 1997;
Zhong Y, Raffnsson V. 1996. Cancer incidence among Icelandic pesticide
users. International Journal of Epidemiology 25(6): 1117-1124; Dalager
NA, Kang HK. 1997. Mortality among Army Chemical Corps Vietnam
veterans. American Journal of Industrial Medicine 31(6): 719-726;
Watanabe KK, Kang HK. 1996. Mortality patterns among Vietnam veterans:
a 24-year retrospective analysis. Journal of Occupational and
Environmental Medicine 38(3): 272-278; Crane et al., 1997a; Crane et
al., 1997b; and Clapp 1997). NAS felt that what new information there
is provides little evidence of a connection between testicular cancer
and herbicide exposure. Several studies of military working dogs showed
abnormal testicular pathology and a moderate excess of seminomas in
dogs that had worked in Vietnam. However, NAS did not feel that these
studies carried great weight in the absence of exposure data and
without observed excesses in human populations. 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.
Leukemia
In VAO, NAS found evidence for a possible association between
herbicide exposure and leukemia 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 Update 1996, NAS reviewed seven new studies. Six of these
studies showed no association between herbicide exposure and leukemia
or a nonsignificant elevated risk. One study, a mortality study of
farmers, showed a significantly increased PCMR for leukemia but did not
correlate the increased PCMR to suspected herbicide exposure and did
not control for other confounding factors. (See 61 FR 41445 for study
citations.)
In Update 1998, NAS again found that, generally, the evidence of an
[[Page 59238]]
association of leukemia with herbicide exposure came from studies of
agricultural workers and a small subset of the Seveso cohort. A
population-based case-control study of farm workers in northeastern
Italy (Amadori D, Nanni O, Falcini F, Saragoni A, Tison V, Callea A,
Scarpi E, Ricci M, Riva N, Buiatti E. 1995. Chronic lymphocytic
leukaemias and non-Hodgkin's lymphomas by histological type in farming-
animal breeding workers: a population case-control study based on job
titles. Occupational and Environmental Medicine 52(6): 374-379.) found
a high risk among farmers who are also involved in animal breeding
(OR=1.8, 95% CI 1.2-2.6). However, analysis of the population broken
down by the more frequent occupational categories showed no
significantly high risk in any occupation. A survey of total and site-
specific cancer incidence in male and female adults from 1959 to 1987
(Waterhouse D, Carman WJ, Schottenfeld D, Gridley G, McLean S. 1996.
Cancer incidence in the rural community of Tecumseh, Michigan: A
pattern of increased lymphopoietic neoplasms. Cancer 77(4): 763-770.),
as compared with site-specific cancer incidence rates reported by the
Connecticut tumor registry, showed a significantly increased incidence
of non-Hodgkin's lymphoma, Hodgkin's disease, and chronic lymphocytic
leukemia. A nested case-control study of this group, using risk factor
information documented prior to diagnosis, found that the RR of a
family history of lymphoma, leukemia, or multiple myeloma was
significantly increased among patients with lymphoproliferative
neoplasms (OR=3.8, CI 1.5-9.8; p=.005). The follow-up of the Seveso
population (Bertazzi et al., 1997) also suggested an increased risk,
but the results were based on very limited data from one small subset
of the whole cohort. Other studies, including occupational studies
(Kogevinas et al., 1997; Ramlow et al., 1996), a study of agricultural
workers (Gambini et al., 1997), and studies of Vietnam veterans
(Dalager and Kang, 1997; Crane et al., 1997b), showed no increased risk
or increases or decreases that were not significant.
An association of leukemia with herbicide exposure is biologically
plausible, and the histological similarity of chronic lymphocytic
leukemia with non-Hodgkin's lymphoma also suggests an association.
Nonetheless, the overall evidence is too slight to warrant assigning
leukemia to a higher category. 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.
Abnormal Sperm Parameters and Infertility
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. VAO 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 VAO 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 VAO. (See 59
FR 344 for study citations.)
In Update 1996, NAS reviewed one occupational study. 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.
In Update 1998, NAS reviewed two new studies that evaluated
hormone, semen quality, and fertility endpoints in relation to
potential dioxin exposure. The Ranch Hand study (Henriksen GL, Michalek
JE, Swaby JA, Rahe AJ. 1996. Serum dioxin, testosterone, and
gonadotropins in veterans of Operation Ranch Hand. Epidemiology 7(4):
352-357.) reported a relatively small decrease in testosterone in
relation to increased dioxin level. A study of British Columbia sawmill
workers (Heacock H, Hogg R, Marion SA, Hershler R, Teschke K, Dimich-
Ward H, Demers P, Kelly S, Ostry A, Hertzman C. 1998. Fertility among a
cohort of male sawmill workers exposed to chlorophenate fungicides.
Epidemiology 9(1): 56-60.) found reduced fertility rates among exposed
workers but could not consistently attribute this to chlorophenate
exposure. NAS again determined that uncertainty remained due to
methodologic limitations of some existing studies.
NAS also reviewed the related fertility endpoint of altered sex
ratio as a result of dioxin/herbicide exposure. One study of a small
part of the Seveso population (Mocarelli P, Brambilla P, Gerthoux PM,
Patterson DG Jr, Needham LL. 1996. Change in sex ratio with exposure to
dioxin. Lancet 348(9024): 409.) suggested an altered ratio of male to
female children, but other studies did not support that finding (Garry
VF, Schreinemachers D, Harkins ME, Griffith J. 1996b. Pesticide
appliers, biocides, and birth defects in rural Minnesota. Environmental
Health Perspectives 104(4): 394-399; Heacock et al., 1998). NAS
concluded that experimental animal evidence and further mechanistic
data were needed to evaluate the relationship between sex ratio and
exposure to dioxin or herbicides.
Accordingly, on the basis of all available evidence, 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.
Motor/Coordination Dysfunction
NAS indicated in VAO that it had found no significant studies
available to analyze whether an association exists between herbicide
exposure and motor/coordination dysfunction. In Update 1996, NAS
reported finding no new studies directly addressing this topic. In
Update 1998, NAS reported that it was not aware of new studies relating
directly to 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 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. In VAO, NAS stated
that many case
[[Page 59239]]
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. VAO 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.)
In Update 1996, NAS 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 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 suggested that peripheral nerve problems were more prevalent
in the exposed group. One of these studies 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 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 reported and the negative findings of many
long-term follow up studies of peripheral neuropathy 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. (See 61
FR 41446-47 for study citations.)
In Update 1998, NAS stated that no new information had appeared
since Update 1996 to alter its previous conclusions on chronic
persistent peripheral neuropathy. Where peripheral neuropathy is due to
a toxic exposure (such as to herbicides), it is characterized by acute
onset and subsequent resolution of the neuropathy after exposure to the
toxin is terminated. It would not be expected to appear for the first
time many years after exposure. Although the Secretary has previously
found a positive association between herbicide exposure and such acute
and subacute (transient) 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
Metabolic and digestive disorders covered in this notice include
hepatic enzyme abnormality, lipid abnormalities, and ulcers. In VAO,
NAS found that two studies related to hepatic enzyme abnormality did
not demonstrate an association with liver disease, and that 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 Update 1996, NAS reviewed the same studies 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. One study found a nonsignificant increase in
liver disease among individuals exposed to dioxin, and another found no
correlation between serum dioxin levels and abnormalities in liver
function tests. One new study was reviewed in Update 1996 concerning an
association between herbicide exposure and lipid abnormalities that
showed no substantial differences between the exposed and reference
groups. The only new study reviewed in Update 1996 concerning a
relationship between ulcers and exposure to herbicides showed no
increases in the frequency of ulcers. (See 61 FR 41447 for study
citations.)
The two major lipids are cholesterol and triglycerides. They are
carried in the blood attached to proteins to form lipoproteins.
Lipoproteins are classed according to their density: very low density
lipoprotein (VLDL); intermediate-density lipoprotein (IDL); low-density
lipoprotein (LDL, the so-called ``bad'' cholesterol particle); and
high-density lipoprotein (HDL, the ``good cholesterol'' particle).
Lipid concentrations play a major role in determining an individual's
susceptibility to cardiovascular disease. Disorders of lipoprotein
metabolism are usually characterized by abnormally high or low
concentrations of lipoproteins. A number of factors may influence these
concentrations. For example, when assessing the effects of herbicide
exposure, obesity must be controlled for because it is a primary
determinant of both triglyceride and TCDD concentrations.
The majority of new studies reviewed by NAS in Update 1998 do not
suggest any effects in lipid or lipoprotein concentrations as a result
of exposure to herbicide agents. A study of 641 Australian Vietnam
veterans (O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M,
Ffrench M, Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996b. The
Australian Vietnam Veterans Health Study: II. Self-reported health of
veterans compared with the Australian population. International Journal
of Epidemiology 25(2): 319-330.), did find an increased frequency of
elevated cholesterol compared to that expected from national Australian
data (RR=3.0, 95% CI 1.3-4.7), but the health problems of these
veterans were self-reported, and the data are difficult to assess with
any degree of certainty. A follow-up of the Ranch Hand study
participants (Air Force Health Study (AFHS). 1996. An epidemiologic
Investigation of Health Effects in Air Force Personnel Following
Exposure to Herbicides. Mortality Update 1996. Brooks AFB, TX:
Epidemiologic Research Division. Armstrong Laboratory. AL/AO-TR-1996-
0068. 31 pp.) showed essentially no differences in the prevalence of
high triglyceride
[[Page 59240]]
levels, low HDL concentrations, or high ratios of total cholesterol to
HDL cholesterol between the Ranch Handers and the comparison group.
Other studies (Calvert et al., 1996; Ott and Zober, 1996) similarly
indicate a negative or at best a weak association for prevalence of any
abnormal lipid or lipoprotein concentrations.
In Update 1998, NAS reviewed a few credible studies reporting some
increase in gastrointestinal disease possibly associated with exposure
to herbicide agents. A mortality study of a cohort of workers exposed
to pentachlorophenol (Ramlow et al., 1996) showed a slight increase in
overall digestive system disease. Increases were higher for gastric and
duodenal ulcer specifically (SMR 3.6, CI 1.2-8.3; 15-year latency SMR
5.6, CI 1.8-13.0). Higher rates of digestive disease generally were
seen in those exposed to higher PCP levels, but a significant decrease
in the risk for ulcer was found at higher levels of exposure. Liver
cirrhosis increased significantly with level of exposure, but
alcoholism played a role in some of these cases and cannot, therefore,
be discounted in the rest. In a study of the self-reported health
status of Australian veterans (O'Toole et al., 1996b), data indicated
that the veterans reported ulcer and other digestive disease more
frequently than did the control group. In these instances, however, the
authors suggested that psychological stress due to combat may have been
a causative factor and implied that high alcohol consumption played a
role. Two studies of American Vietnam veterans (AFHS, 1996; Dalager and
Kang, 1997) reported an increased incidence of digestive disease,
particularly cirrhosis or other liver disease. Lack of data about
alcohol consumption, however, makes this information difficult to
assess. Other studies provide no evidence of an association of
digestive system disease with exposure to herbicide agents. Some
studies, in fact, suggest no association (e.g., Bullman TA, Kang HK.
1996. The risk of suicide among wounded Vietnam veterans. American
Journal of Public Health 86(5): 662-667.), which observed a significant
decrease in deaths due to digestive disease among Vietnam veterans who
had been hospitalized for wounds suffered in Vietnam.
After considering all evidence available, 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.
Diabetes Mellitus
In both VAO and Update 1996, NAS placed metabolic and digestive
disorders (including diabetes mellitus) in the category labeled
``Inadequate/Insufficient Evidence to Determine Whether an Association
Exists.'' According to NAS, this means that the available studies are
of insufficient quality, consistency, or statistical power to permit a
conclusion regarding the presence or absence of an association. For
example, studies fail to control for confounding, have inadequate
exposure assessments, or fail to address latency.
In Update 1998, NAS reviewed several new studies, including the
1997 report from the Ranch Hand study (Henrikson GL, Ketchum NS,
Michalek JE, Swaby JA. 1997. Serum dioxin and diabetes mellitus in
veterans of operation Ranch Hand. Epidemiology 8:252-258), that
addressed the issue of diabetes mellitus. Based on the evidence
reported in these and the previously reviewed studies, NAS again
concluded that there is inadequate/insufficient evidence to determine
whether an association exists between herbicide or dioxin exposure and
increased risk of diabetes. However, since NAS released Update 1998 the
National Institute of Occupational Safety and Health (NIOSH) published
a report that detects an association, though not a strong association
between diabetes and dioxin exposure. The study does suggest a dose
response relationship because of excess cases of diabetes found in
workers having the highest serum-lipid levels of dioxin (Calvert GM,
Sweeney MH, Deddens J, Wall DK. 1999. Evaluation of Diabetes Mellitus,
Serum Glucose and Thyroid Function Among U.S. Workers Exposed to
2,3,7,8 tetrachlorodibenzo-p-dioxin. Occupational and Environmental
Medicine 56:270-276). The Secretary has concluded that the NIOSH study
is potentially important enough that it warrants a full review by NAS
as soon as possible, and he has directed VA to amend its contract with
NAS for the third biennial update to require a special report on
herbicide exposure and diabetes, as a separate deliverable, within
approximately six months. The Secretary will make a determination as to
whether there is an association between herbicide exposure and diabetes
mellitus after NAS has reviewed the NIOSH report.
Immune System Disorders
In VAO, NAS found 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 Update 1996 that no new studies of heightened
susceptibility to infectious disease or new studies that investigated
the association of autoimmune disease with exposure to herbicides had
been identified. However, some new information had been published
regarding the effects of TCDD on immunological parameters in laboratory
measurements. The new studies 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. (See 61 FR 41447 for study
citations.)
In Update 1998, NAS reviewed two new studies relating to the
incidence of infectious diseases in American Vietnam veterans and two
new studies of Australian Vietnam veterans. A proportionate mortality
study of Vietnam veterans (Visintainer PF, Barone M, McGee H, Peterson
EL. 1995. Proportionate mortality study of Vietnam-era veterans of
Michigan. Journal of Occupational and Environmental Medicine 37(4):
423-428) studied a cohort of 377,028 veterans who are on the Michigan
Department of Management and Budget's Vietnam-Era Bonus List. Vietnam
veterans compared with non-Vietnam veterans had a slightly elevated
proportionate mortality ratio from infectious and parasitic diseases
(PMR=1.6, CI 1.2-2.1, N=56). The study, however, did not distinguish
Vietnam veterans exposed to Agent Orange from those with no known
exposure. Watanabe and Kang (1995) (Watanabe KK, Kang HK. 1995.
Military service in Vietnam and the risk of death from trauma and
selected cancers. Annals of Epidemiology 5(5): 407-12.) found a
nonsignificant increased risk for infectious diseases in Vietnam
Marines compared with non-Vietnam Marines (RR=2.8; CI 0.8-10.3). The
studies of Australian Vietnam veterans did not show any increase in
mortality due to infectious or parasitic diseases (Crane et al.,
1997a,b). NAS concluded that no evidence is available to associate
defects in the immune response with Agent Orange exposure.
[[Page 59241]]
NAS also discussed several studies concerning exposure to
halogenated aromatic hydrocarbons and shifts in lymphocyte
subpopulations. It concluded on the basis of these studies that there
is inadequate or insufficient evidence to determine whether an
association exists between exposure to herbicides and immune
suppression or autoimmunity.
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.
Circulatory Disorders
NAS noted in VAO 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 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 in Update 1996 that showed no increase in
the frequency of heart disease. Another study 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 of the data from an Air
Force study provided 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. (See 61 FR 41447-48 for study citations.)
In Update 1998 NAS found sporadic reports of increased circulatory
disease potentially related to exposure to herbicides or TCDD. A study
of cancer and circulatory system mortality among 1,189 male workers in
a chemical plant in Hamburg, Germany (Flesch-Janys D, Berger J, Gurn P,
Manz A, Nagel S, Waltsgott H, Dwyer JH. 1995. Exposure to
polychlorinated dioxins and furans (PCDD/F) and mortality in a cohort
of workers from a herbicide-producing plant in Hamburg, Federal
Republic of Germany. American Journal of Epidemiology 142(11): 1165-
1175.) found overall circulatory system disease mortality to be
elevated among exposed workers. Results were dose-dependent; the RR
among those exposed to the highest estimated levels of TCDD was 2.0
(95% CI 1.2-3.3). The increased risk appeared to be restricted to
ischemic heart disease (IHD). Information was not available for
confounding factors related to IHD, but the authors reasoned that the
use of an unexposed referent population combined with the strong dose-
response relationship argued against attributing the results to
confounding factors. They also noted that the smoking rates and
socioeconomic status of both cohorts appeared to be similar. In a
simple random sample of Australian Army Vietnam veterans on self-
reported health status (O'Toole et al., 1996b), hypertension and other
circulatory system disease were reported significantly more frequently
by veterans. However, there was no significant association with combat
exposure, and veterans were more likely to be current or former smokers
and to report high alcohol consumption. The ongoing study of Ranch Hand
veterans (AFHS, 1996), observed a significant increase of circulatory
disorders among ground troops (SMR 1.5, CI 1.0-2.2), with nearly half
of the increase due to atherosclerotic heart disease (SMR 1.4, CI 0.8-
2.1). However, data on smoking and alcohol use were not available.
Most studies, however, noted decreases in incidence of circulatory
disorders, or at best, nonsignificant increases among exposed
individuals. NAS found inconsistent results across the studies
reviewed. Interpretation of individual studies was generally limited by
a lack of information on cigarette smoking, obesity, serum lipid
levels, presence of diabetes, and other risk factors. Accordingly,
after reviewing all available evidence, 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.
Respiratory Disorders
In VAO, NAS examined studies that covered a wide variety of
respiratory disorders other than respiratory cancers (e.g., chronic
bronchitis, asthma, pleurisy, pneumonia, and tuberculosis). 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.)
In Update 1996, NAS reviewed three new studies, all of which found
no significant increase in respiratory disease associated with
herbicide exposure. (See 61 FR 41448 for study citations.)
In Update 1998, NAS reviewed evidence from several new occupational
and veteran studies (Becher et al., 1996; Svensson et al., 1995; Ott
and Zober, 1996; Ramlow et al. 1996; Kogevinas et al., 1997; Bullman
TA, Kang HK. 1996. The risk of suicide among wounded Vietnam veterans.
American Journal of Public Health 86(5): 662-667; O'Toole et al.,
1996b; Watanabe and Kang, 1996; Dalager and Kang, 1997; Crane et al.,
1997a; Crane et al., 1997b; and the ongoing study of Ranch Hand
veterans, AFHS, 1996). O'Toole et al., 1996b showed the strongest
association between exposure and respiratory disease. Although there
was no significant increase in overall respiratory system disease among
veterans, hay fever, bronchitis, emphysema, and other respiratory
disease were significantly elevated compared to the general population.
However, these conditions were not related to an index of combat
exposure, and the veterans were more likely to have smoked at some
point in their lives than the general population. Although, in general,
there were sporadic reports of increased respiratory disease
potentially related to exposure to herbicides or dioxin, the results
were inconsistent across the studies. In addition, interpretation of
individual studies was generally limited by a lack
[[Page 59242]]
of information on cigarette smoking. 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.
Skin Cancer
In VAO, NAS 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
VAO.)
Update 1996 reviewed one new study (Lynge, 1993) that did find an
excess risk of skin cancer. However, another new study found no
increased risk of skin cancer. Three other new studies 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 found an increased PCMR for skin
cancer in white male farmers. This 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. (See 61 FR 41448 for study citations.)
In Update 1998, NAS discussed malignant melanoma separately from
squamous and basal cell carcinomas because of the different biologic
behaviors and risk factors for these cancers.
Melanoma
Two new studies showed a statistically significant increase in
melanoma mortality, but the data are not particularly strong. A study
of U.S. Marine and Army veterans (Watanabe and Kang, 1996) found an
increased risk of skin cancers only among Marine veterans (PMR=1.3, CI
1.0-1.6). Army veterans showed no increased risk in comparison to any
of the control groups. This study made no distinction between melanoma
and other skin cancers. A study of Australian Vietnam veterans (Crane
et al., 1997a) showed an increased risk when compared to the Australian
population, but no increased risk when the comparison group was non-
Vietnam veterans (Crane et al., 1997b). None of these studies
controlled for exposure to sunlight, the greatest risk-factor for
malignant melanoma. A study of Swedish fishermen (Svensson et al.,
1995) reported no elevated incidence of melanoma and found a decreased
risk of death from the disease compared to the general Swedish
population. Other new studies and updates of previous studies found
either no increased risk or only a slightly elevated increase that was
not considered significant (Bertazzi et al., 1997; Kogevinas et al.,
1997; Hertzmann et al., 1997; Dalager and Kang, 1997; Clapp, 1997). NAS
did not feel that the evidence warranted altering its prior
determination that there was inadequate or insufficient evidence of an
association between exposure to herbicide agents and the subsequent
development of malignant melanoma.
Basal Cell and Squamous Cell Carcinomas
The most compelling study reviewed by NAS was a Canadian community
case-control study (Gallagher RP, Bajdik CD, Fincham S, Hill GB, Keefe
AR, Coldman A, McLean DI, 1996. Chemical exposures, medical history,
and risk of squamous and basal cell carcinoma of the skin. Cancer
Epidemiology, Biomarkers and Prevention 5(6): 419-424.), which found an
increased risk for squamous cell carcinoma, but not basal cell
carcinoma, in individuals exposed to herbicides (OR=1.5, CI 1.0-2.3).
The risk increased with increasing lifetime exposure. However, neither
control for confounders nor assessment of exposure were adequate.
Moreover, the findings in this study are in conflict with the earlier
findings in the Ranch Hand study (Wolfe WH, Michalek JE, Miner JC, Rahe
A, Silva J, Thomas WF, Grubbs WD, Lustik MB, Karrison TG, Roegner RH,
Williams DE, 1990. Health status of Air Force veterans occupationally
exposed to herbicides in Vietnam. I. Physical health. Journal of the
American Medical Association 264: 1824-1831.) of an increased incidence
of basal cell carcinoma, but not squamous cell carcinoma. The study of
Swedish fishermen (Svensson et al., 1995) showed a statistically
significant increase in the incidence of such cancers (RR=2.3, CI 1.4-
3.5) among the fishermen who ate more of the fish potentially
containing higher levels of organochlorine compounds. However, this
study provided no measurements of the levels of TCDD or arsenic in
either fish or fishermen. Other studies reviewed by NAS generally
reported no statistically significant increases of basal cell or
squamous cell carcinomas in exposed groups. Again, NAS did not feel
that the evidence warranted altering its prior determination that there
was inadequate or insufficient evidence of an association between
exposure to herbicide agents and the subsequent development of basal
cell and squamous cell carcinomas.
Accordingly, based on all available evidence, the Secretary has
found that the credible evidence against an association between these
skin cancers (malignant melanoma, basal cell carcinoma, and squamous
cell carcinoma) and herbicide exposure outweighs the credible evidence
for such an association, and he has determined that a positive
association does not exist.
Cognitive and Neuropsychiatric Effects
NAS found in VAO 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.
Update 1996 reviewed one study 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 study of a large sample of
Vietnam veterans 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, there continued to be
no credible evidence for an association between herbicide exposure and
cognitive disorders or neuropsychiatric
[[Page 59243]]
effects. (See 61 FR 41446 for study citations.)
In Update 1998, NAS briefly discussed a report from Australia
(O'Toole BI, Marshall RP, Grayson DA, Schureck RJ, Dobson M, Ffrench M,
Pulvertaft B, Meldrum L, Bolton J, Vennard J. 1996c. The Australian
Vietnam Veterans Health Study: III. Psychological health of Australian
Vietnam veterans and its relationship to combat. International Journal
of Epidemiology 25(2): 331-340.) that analyzed the self-reported
psychiatric states of Vietnam veterans as determined 20-25 years after
the war. This study found higher prevalences of alcohol abuse or
dependence, PTSD, and social and simple phobias among Vietnam veterans
than among the civilian population. However, there was no attempt to
relate these behavioral disorders to herbicide exposure. NAS stated it
was unaware of other new studies that provide any further evidence of
an association between herbicide exposure and cognitive or
neuropsychiatric disorders. Therefore, based on available evidence, the
Secretary continues to find that the credible evidence against an
association between cognitive or neuropsychiatric disorders and
herbicide exposure outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
Reproductive Effects in Male Veterans
In Update 1998 NAS, as it had in VAO and Update 1996, reviewed the
current literature with respect to possible associations between
herbicide exposure and various reproductive effects, i.e., spontaneous
abortion, spina bifida and other birth defects, neonatal/infant deaths
and stillbirths, low birth weights, and childhood cancer in offspring.
NAS continued to find limited/suggestive evidence of an association of
spina bifida with exposure to herbicides. For other reproductive
outcomes, while the evidence suggests that an association is
biologically plausible, various factors complicate reaching more
definitive conclusions. (See Chapter 9 of the 1998 NAS report for
additional information.)
Except in the case of spina bifida, compensation of a veteran or a
veteran's child for these effects is beyond VA's statutory authority
(title 38, United States Code) and would require enabling legislation.
In 1996, Sec. 421 of Public Law 104-204, as amended by Sec. 404 of
Public Law 105-114, gave VA the authority that the Secretary had
requested to provide benefits for spina bifida in the natural children
of individuals who had served in Vietnam during the period from January
9, 1962, through May 7, 1975. (See 38 U.S.C., Chapter 18.)
Gastrointestinal Tumors and Brain Tumors
In Update 1998 NAS, as it had in VAO and Update 1996, assigned
gastrointestinal tumors (stomach cancer, pancreatic cancer, colon
cancer, and rectal cancer) and brain tumors to the category labeled
limited/suggestive evidence of no association with herbicide exposure.
This category 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. NAS reviewed several new credible
studies (see the 1998 NAS report, Chapter 7) concerning all of these
conditions that generally showed no association or a negative
association with herbicide exposure. One study of workers exposed to
TCDD in 1953 at a BASF plant in Germany (Ott and Zober, 1996) did
report a statistically significant positive association of both death
and incidence of digestive cancer. However, one of the cases of
reported digestive cancer was actually primary liver cancer. If this
had been classified as hepatobiliary cancer, the reported association
probably would have been weaker. Accordingly, on the basis of all
evidence available, the Secretary has found that the credible evidence
against an association between gastrointestinal tumors (stomach cancer,
pancreatic cancer, colon cancer, and rectal cancer) and brain tumors
and herbicide exposure outweighs the credible evidence for such an
association, and he has determined that a positive association does not
exist.
NAS reviewed scientific and medical articles published since the
publication of its first report as an integral part of the process that
resulted in ``Veterans and Agent Orange: Update 1998.'' 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: October 26, 1999.
Togo D. West, Jr.,
Secretary of Veterans Affairs.
[FR Doc. 99-28579 Filed 11-1-99; 8:45 am]
BILLING CODE 8320-01-P
