Diseases Not Associated With Exposure to Certain Herbicide Agents

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

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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

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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

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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

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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

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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]

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