[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