Diseases Associated With Exposure to Certain Herbicide Agents (Prostate Cancer and Acute and Subacute Peripheral Neuropathy)

DEPARTMENT OF VETERANS AFFAIRS

38 CFR Part 3

RIN 2900-AI35

Diseases Associated With Exposure to Certain Herbicide Agents

(Prostate Cancer and Acute and Subacute Peripheral Neuropathy)

AGENCY: Department of Veterans Affairs.

ACTION: Proposed rule.

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SUMMARY: The Department of Veterans Affairs (VA) is proposing to amend

its adjudication regulations concerning presumptive service connection

for certain diseases for which there is no record of the disease during

service. This proposed amendment is necessary to implement a decision

of the Secretary of Veterans Affairs under the authority granted by the

Agent Orange Act of 1991 that there is a positive association between

exposure to herbicides used in the Republic of Vietnam during the

Vietnam era and the subsequent development of prostate cancer and acute

and subacute peripheral neuropathy. The intended effect of this

proposed amendment is to establish presumptive service connection for

those conditions based on herbicide exposure.

DATES: Comments must be received on or before September 9, 1996.

ADDRESSES: Mail or hand deliver written comments to: Director, Office

of Regulations Management (02D), Department of Veterans Affairs, 810

Vermont Avenue, NW, Room 1154, Washington DC 20420. Comments should

indicate that they are in response to ``RIN 2900-AI35.'' All written

comments will be available for public inspection at the above address

in the Office of Regulations Management, Room 1158, between the hours

of 8 a.m. and 4:30 p.m., Monday through Friday (except holidays).

FOR FURTHER INFORMATION CONTACT: John Bisset, Jr., Consultant,

Regulations Staff, Compensation and Pension Service, Veterans Benefits

Administration, 810 Vermont Avenue, NW., Washington, DC 20420,

telephone (202) 273-7230.

SUPPLEMENTARY INFORMATION: Section 3 of the Agent Orange Act of 1991,

Pub. L. 102-4, 105 Stat. 11, directed the Secretary to seek to enter

into an agreement with the National Academy of Sciences (NAS) to review

and summarize the scientific evidence concerning the association

between exposure to herbicides used in support of military operations

in the Republic of Vietnam during the Vietnam era and each disease

suspected to be associated with such exposure. Congress mandated that

NAS determine, to the extent possible: (1) Whether there is a

statistical association between the suspect diseases and herbicide

exposure, taking into account the strength of the scientific evidence

and the appropriateness of the methods used to detect the association;

(2) the increased risk of disease among individuals exposed to

herbicides during service in the Republic of Vietnam during the Vietnam

era; and (3) whether there is a plausible biological mechanism or other

evidence of a causal relationship between herbicide exposure and the

suspect disease. Section 3 of Pub. L. 102-4 also required that NAS

submit reports on its activities every two years (as measured from the

date of the first report) for a ten-year period.

Section 1116(b) of 38 U.S.C., which was added by Pub. L. 102-4,

provides that whenever the Secretary determines, based on sound medical

and scientific evidence, that a positive association exists between

exposure of humans to a herbicide agent (i.e., a chemical in a

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. An association is

considered ``positive'' if the credible evidence for the association is

equal to or outweighs the credible evidence against the association. In

making that determination, the Secretary is to consider the reports

received from NAS as well as all other available sound medical and

scientific information and analyses.

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 positive

associations exist 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. Final regulations were published in the Federal Register on

February 3, 1994 (See 59 FR 5106-07) and June 9, 1994 (See 59 FR 29723-

24) creating presumptions of service connection for these conditions

based on herbicide exposure. Presumptions already existed for

chloracne, non-Hodgkin's lymphoma and soft tissue sarcomas.

After reviewing the latest scientific studies and conducting a

public meeting, NAS issued a second report, entitled ``Veterans and

Agent Orange: Update 1996,'' on March 14, 1996. On the same day, the

Secretary announced that VA would review the findings in that second

NAS report and pertinent studies to determine whether a positive

association exists between herbicide exposure and any condition for

which the Secretary has not specifically determined a presumption of

service connection is warranted. That review has been completed and the

Secretary has concluded that positive associations exist for prostate

cancer and acute and subacute peripheral neuropathy.

Prostate cancer is a very common male genitourinary cancer which

shows marked increased prevalence with age. The 1993 NAS report

assigned prostate cancer to a category labeled limited/suggestive

evidence of an association. This is 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. There

were statistically significant occupational studies which showed no

association between prostate cancer and herbicide

[[Page 41369]]

exposure (Ronco G., Costa G., Lynge E., 1992. Cancer risk among Danish

and Italian farmers. British Journal of Industrial Medicine 49:220-225;

and Wiklund K., 1983. Swedish agricultural workers: A group with

decreased risk of cancer. Cancer 51:566-568). Some occupational studies

showed a slight, elevated risk for prostate cancer among farm and

forestry workers; a cohort study of farmers found the risk of prostate

cancer among farmers increased with the magnitude of potential

herbicide exposure. (See 59 FR 342 for study citations.) Upon a review

of the evidence then available, the Secretary determined that the

credible evidence against an association between prostate cancer and

herbicide exposure outweighed the credible evidence for such an

association, and he determined that a positive association did not

exist.

In its 1996 report NAS, after a thorough review of previously and

newly available scientific literature, also assigned prostate cancer to

the category labeled limited/suggestive evidence of an association with

herbicide exposure, which it defined in the same manner as in the 1993

NAS report (See above). The 1996 NAS report noted several new

occupational studies and veteran studies. One large study (Blair A.,

Mustafa D., Heineman E.F., 1993. Cancer and other causes of death among

male and female farmers from twenty-three states. American Journal of

Industrial Medicine 23:729-742) found a statistically significant,

slightly increased proportionate cancer mortality ratio (PCMR) for

prostate cancer among farmers in 22 of 23 states. Another cancer

mortality study (Bueno de Mesquita H.B., Doornbos G., Van der Kuip

D.A., Kogevinas M., Winkelmann R., 1993. Occupational exposure to

phenoxy herbicides and chlorophenols and cancer mortality in the

Netherlands. American Journal of Industrial Medicine 23:289-300)

evaluated employees of two Dutch companies which produced chlorophenoxy

herbicides. Mortality rates from prostate cancer were increased among

the exposed men in this study (standardized mortality rate (SMR) = 2.6,

confidence interval (CI) 0.5-7.7), although the results were not

statistically significant. A mortality study of chemical workers

exposed to an accidental release of TCDD in 1949 (Collins J.J., Strauss

M.E., Levinskas G.J., Connor P.C., 1993. The mortality experience of

workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin in a

trichlorophenol process accident. Epidemiology 4:7-13) found an

increased risk of prostate cancer death in the exposed workers when

compared to the rates in the local population, although, again, the

results were not statistically significant. One recent study of Finnish

herbicide workers with a median total duration of exposure of six weeks

showed no increased risk of death from prostate cancer (Asp S.,

Riihimaki V., Hernberg S., Pukkala E., 1994. Mortality and cancer

morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year

prospective follow-up. American Journal of Industrial Medicine 26:243-

253). Cancer incidence rates after TCDD exposure in the Seveso, Italy,

cohort were re-evaluated (Bertazzi A., Pesatori A.C., Consonni D.,

Tironi A., Landi M.T., Zocchetti C., 1993. Cancer incidence in a

population accidentally exposed to 2,3,7,8-tetrachlorodibenzo-para-

dioxin. Epidemiology 4:398-406). The cancer risk in the more highly

exposed zones was previously reported to be slightly increased

(relative risk (RR) = 1.4, CI 0.5-3.9), although not to a statistically

significant degree, (Pesatori A.C., Consonni D., Tironi A., Landi M.T.,

Zocchetti C., Bertazzi P.A., 1992. Cancer morbidity in Seveso area,

1976-1986. Chemosphere 25:209-212), but an updated study of the less

exposed areas failed to show an increased risk (Bertazzi et al., 1993).

A proportionate mortality study of Michigan Vietnam veterans

(Visintainer P.F., Barone M., McGee H., Peterson E.L., 1995.

Proportionate mortality study of Vietnam-era veterans of Michigan.

Journal of Occupational and Environmental Medicine 37:423-428), showed

a nonsignificant, slightly increased rate of death due to genital

cancers. Prostate cancer rates were not reported separately in this

study.

The large cohort study of Canadian farmers (Morrison et al., 1993)

had been previously reviewed by the 1993 NAS report. Although this

study found a decreased risk of prostate cancer for the entire cohort,

when the cohort was divided into subsets based on suspected herbicide

exposure, the study found an increased risk of prostate cancer among

those considered most likely to have been exposed (based on amount of

herbicides used on the subjects' farms and the lack of hired help or

customary expenses for assisting in work). In addition, the study

reported an increasing risk with increasing numbers of acres sprayed.

Subsequent to the 1993 report, the authors published a letter to the

editor containing a reanalysis of their data which supported the

findings of an increased risk of prostate cancer and the previously

reported dose-response relationship with herbicide exposure (Morrison

et al., 1994. (Letter to the editor). American Journal of Epidemiology

140:1058-1059). Most of the other occupational and environmental

studies indicate some elevation in risk of prostate cancer. Considering

all of the evidence, the Secretary has determined that the credible

evidence for an association is equal to or outweighs the credible

evidence against an association and, therefore, there is a positive

association between herbicide exposure and prostate cancer.

Accordingly, we are proposing to amend 38 CFR 3.309(e) to establish a

presumption of service connection based on herbicide exposure for

prostate cancer that manifests itself to a degree of 10 percent at any

time after exposure. This amendment is proposed to be effective the

date of publication of the final rule, in accordance with 38 U.S.C.

1116(c)(2).

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. The 1993

NAS report assigned peripheral neuropathy to a category labeled

inadequate/insufficient evidence to determine whether an association

exists, which was defined as meaning that the available studies were of

insufficient quality, consistency, or statistical strength to permit a

conclusion regarding the presence or absence of an association with

herbicide exposure. NAS stated that many case reports suggested that

acute or subacute 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. Accordingly, the

Secretary determined that the credible evidence against an association

between peripheral neuropathy and herbicide exposure outweighed the

credible evidence for such an association, and he determined that a

positive association did not exist. (See 59 FR 343 for study

citations.) The Secretary asked, however, that NAS reconsider in detail

the relationship

[[Page 41370]]

between exposure to herbicides and the development of acute and

subacute effects of peripheral neuropathy in the next report.

The 1996 NAS report assigned acute and subacute peripheral

neuropathy to the category labeled limited/suggestive evidence of an

association with herbicide exposure. However, the 1996 NAS report

continued to assign chronic peripheral neuropathy to the category

labeled inadequate/insufficient evidence to determine whether an

association exists. In response to VA's request to conduct a detailed

reconsideration of the relationship between herbicide exposure and the

subsequent development of acute and subacute peripheral neuropathy, the

1996 NAS report noted that the methodology used to establish

associations between suspected causal agents and persistent chronic

peripheral neuropathy relies on epidemiological studies with adequate

controls. Such studies can rarely be set in motion with sufficient

speed to assess relationships between unexpected chemical exposure and

the development of acute or subacute peripheral neuropathy. Because of

the transient nature of the conditions, documenting signs and symptoms

in association with documented exposures can be difficult to accomplish

in a systematic manner. Consequently, greater reliance must be placed

on case and less well controlled studies.

Two case studies (Todd R.L., 1962. A case of 2,4-D intoxication.

Journal of the Iowa Medical Society 52:663-664; and Berkley M.C., Magee

K.R., 1963. Neuropathy following exposure to a dimethylamine salt of

2,4-D. Archives of Internal Medicine 111:133-134) reported development

of peripheral neuropathies within days of exposure to 2,4-D followed by

gradual recovery over a period of months. Studies of the Seveso, Italy

accident (Boeri R., Bordo B., Crenna P., Filippini G., Massetto M.,

Zecchini A., 1978. Preliminary results of a neurological investigation

of the population exposed to TCDD in the Seveso region. Rivista di

Patologia Nervosa e Mentale 9:111-128; Pocchiari F., Silano V.,

Zampieri A., 1979. Human health effects from accidental release of

tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy. Annals of the New

York Academy of Science 320:311-320; and Filippini G., Bordo B., Crenna

P., 1981. Relationship between clinical and electrophysiological

findings and indicators of heavy exposure to 2,3,7,8-

tetrachlorodibenzo-p-dioxin. Scandinavian Journal of Work, Environment,

and Health 7:257-262) suggested that peripheral nerve problems were

more prevalent in the exposed group. Filippini et al. (1981)

demonstrated that those individuals with clinical signs of significant

exposure (chloracne or elevated liver enzymes) showed a risk ratio of

2.8. Two subsequent follow-up studies (Barbieri S., Pirovano C.,

Scarbato G., Tarchini P., Zappa A., Maranzana M., 1988. Long-term

effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the peripheral

nervous system. Clinical and neurophysiological controlled study on

subjects with chloracne from the Seveso area. Neuroepidemiology 7:29-

37; and Assennato G., Cervino D., Emmett E.A., Longo G., Merlo F.,

1989. Follow-up of subjects who developed chloracne following TCDD

exposure at Seveso. American Journal of Industrial Medicine 16:119-125)

showed no increased frequency of peripheral neuropathy several years

after the accident among the highly exposed group. Environmental

studies and case reports suggest that the development of peripheral

neuropathy can follow high levels of exposure to herbicides, and that

peripheral neuropathy associated with herbicide exposure will manifest

very soon after exposure. The trend to recovery in the individual cases

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. Considering all of the evidence, the Secretary has

determined that the credible evidence for an association is equal to or

outweighs the credible evidence against an association and, therefore,

there is a positive association between herbicide exposure and acute

and subacute peripheral neuropathy that manifests within one year of

exposure.

Since the available evidence indicates that herbicide-related acute

and subacute peripheral neuropathy develops shortly after exposure, in

our judgment a manifestation period of one year following exposure will

allow VA to identify all peripheral neuropathies that are associated

with herbicide exposure. We are proposing to define the term ``acute

and subacute peripheral neuropathy'' to mean transient peripheral

neuropathy that appears within weeks or months of exposure to an

herbicide agent and resolves within two years of the date of onset.

Most of the toxic diseases of nerve develop subacutely over weeks or

months (``Principles of Neurology'' Raymond D. Adams, M.D., and Maurice

Victor, M.D., fifth ed., 1993). As the 1996 NAS report indicates,

neuropathies associated with herbicide exposure are transient and

resolve over several months. In our judgment, requiring that peripheral

neuropathy resolve within two years of onset is, therefore, a

reasonable method to differentiate transient peripheral neuropathies,

for which the Secretary has found a positive association with herbicide

exposure, from chronic peripheral neuropathies, for which he has found

no such association. We are proposing to amend 38 CFR 3.307(a) and

3.309(e) to establish a presumption of service connection for acute and

subacute peripheral neuropathy becoming manifest within one year

following exposure to herbicide agents. This amendment is proposed to

be effective the date of publication of the final rule, in accordance

with 38 U.S.C. 1116(c)(2).

The six-year benefit cost for prostate cancer based on herbicide

exposure is $65.3 million, with an administrative cost of $959,000.

Additionally, the medical care cost over six years is $38 million.

Prostate cancer is a male genitourinary cancer that shows marked

increased prevalence with age. Accordingly, costs beyond the six-year

period would likely be substantially higher.

For the purposes of this rulemaking, ``acute and subacute

peripheral neuropathy'' means transient peripheral neuropathy that

appears within weeks or months of exposure to an herbicide agent and

resolves within two years of the date of onset. Consequently, there are

no benefit costs associated with this condition.

The Secretary hereby certifies that these regulatory amendments

will not have a significant economic impact on a substantial number of

small entities as they are defined in the Regulatory Flexibility Act

(RFA), 5 U.S.C. 601-612. The reason for this certification is that

these amendments would not directly affect any small entities. Only

claimants for VA benefits could be directly affected. Therefore,

pursuant to 5 U.S.C. 605(b), these amendments are exempt from the

initial and final regulatory flexibility analysis requirements of

sections 603 and 604.

The Secretary has determined that it is not feasible to allow the

60-day comment period referred to in section 6(a)(1) of Executive Order

12866 because a comment period of that length would prevent VA from

complying with the statutory requirement to publish a final rule within

90 days of publication of the proposed rule imposed by 38 U.S.C.

1116(c)(2).

The Catalog of Federal Domestic Assistance program numbers are

64.109 and 64.110.

[[Page 41371]]

List of Subjects in 38 CFR Part 3

Administrative practice and procedure, Claims, Disability benefits,

Health care, Pensions, Veterans, Vietnam.

Approved: July 8, 1996.

Jesse Brown,

Secretary of Veterans Affairs.

For the reasons set forth in the preamble, 38 CFR part 3 is

proposed to be amended as follows:

PART 3--ADJUDICATION

Subpart A--Pension, Compensation, and Dependency and Indemnity

Compensation

1. The authority citation for Part 3, subpart A continues to read

as follows:

Authority: 38 U.S.C. 501(a), unless otherwise noted.

Sec. 3.307 [Amended]

2. In Sec. 3.307, paragraph (a)(6)(ii) is amended by removing

``chloracne and'' and adding, in its place, ``chloracne,''; and by

adding ``tarda, and acute and subacute peripheral neuropathy''

immediately following ``cutanea''.

Sec. 3.309 [Amended]

3. In Sec. 3.309, paragraph (e), the listing of diseases is amended

by adding ``Acute and subacute peripheral neuropathy'' between ``Non-

Hodgkin's lymphoma'' and ``Porphyria cutanea tarda''; by adding

``Prostate cancer'' between ``Porphyria cutanea tarda'' and

``Respiratory cancers (cancer of the lung, bronchus, larynx, or

trachea)''.

4. Section 3.309, paragraph (e) is further amended by redesignating

the Note as ``Note 1:''; and by adding ``Note 2:'' to read as follows:

Sec. 3.309 Disease subject to presumptive service connection.

* * * * *

(e) * * *

Note 2: For purposes of this section, the term acute and

subacute peripheral neuropathy means transient peripheral neuropathy

that appears within weeks or months of exposure to an herbicide

agent and resolves within two years of the date of onset.

[FR Doc. 96-20196 Filed 8-7-96; 8:45 am]

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