[Federal Register Volume 61, Number 154 (Thursday, August 8, 1996)]
[Proposed Rules]
[Pages 41368-41371]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-20196]


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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]
BILLING CODE 8320-01-P