[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