Daily Rules, Proposed Rules, and Notices of the Federal Government
The Agent Orange Act of 1991, Public Law 102-4 (codified in part at 38 U.S.C. 1116), directed the Secretary to seek to enter into an agreement with the National Academy of Sciences (NAS) to conduct a comprehensive review of scientific and medical literature on
Section 2 of Public Law 102-4, codified in pertinent part at 38 U.S.C. 1116(b) and (c), 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.
Although 38 U.S.C. 1116 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.” The Secretary reviews studies that report a positive relative risk and studies that report a negative relative risk of a particular health outcome. He then determines whether the weight of evidence supports a finding that there is or is not a positive association between herbicide exposure and the subsequent health outcome. The Secretary does this by taking into account the statistical significance, capability of replication, and whether that study will withstand peer review. Because of differences in statistical significance, confidence levels, control for confounding factors, bias, and other pertinent characteristics, some studies are more credible than others. The Secretary gives weight to more credible studies in evaluating the overall evidence concerning specific health outcomes.
NAS has issued nine previous biennial reports under the Agent Orange Act. Based on those reports and the requirements of the Agent Orange Act, VA has established presumptions of service connection for 14 categories of disease, which are listed at 38 CFR 3.307(e). Additionally, following each prior NAS report, VA has published a notice explaining the Secretary's determination that presumptions of service connection are not warranted for several diseases discussed in those reports. Those notices are published at: 59 FR 341 (Jan. 4, 1994), 61 FR 41442 (Aug. 8, 1996), 64 FR 59232 (Nov. 2, 1999), 67 FR 42600 (Jun. 4, 2002), 68 FR 27630 (May 30, 2003), 72 FR 32395 (May 20, 2007), 75 FR 32540 (Jun. 8, 2010), and 75 FR 81332 (Dec. 27, 2010). The Secretary's determination that there is not a positive association between herbicide exposure and the diseases addressed in this notice is based upon the prior NAS reports, as discussed in VA's prior
On September 29, 2011, NAS publicly released
Consistent with its prior reviews, NAS concentrated its review on epidemiologic studies to fulfill its charge of assessing whether specific human health effects are associated with exposure to at least one of the herbicides utilized or to a chemical component of herbicides, such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin; referred to as TCDD to represent a single—and the most toxic—congener of the tetrachlorodibenzo-p-dioxins, also commonly referred to as dioxin). NAS also considered controlled laboratory investigations that provided information on whether the association between the chemicals of interest and a given effect is biologically plausible.
The epidemiologic information evaluated in
As in its prior reports, NAS placed each health outcome it reviewed in one of four categories based on the strength of the evidence of association between herbicide exposure and the health outcome. The four categories are: Sufficient Evidence of Association; Limited or Suggestive Evidence of Association; Inadequate or Insufficient Evidence to Determine Whether an Association Exists; and Limited or Suggestive Evidence of No Association. VA has established presumptions of service connection for all diseases NAS placed in the first category and for most of the diseases NAS placed in the second category. This notice explains the basis for VA's determination that presumptions of service connection are not warranted for the remaining diseases discussed in
NAS has defined this category of association to mean that the “evidence suggests an association between exposure to herbicides and the outcome, but a firm conclusion is limited because chance, bias, and confounding could not be ruled out with confidence.”
NAS placed hypertension in the “Limited or Suggestive Evidence of Association” category. Hypertension affects more than 70 million adult Americans and is a major risk factor for coronary artery disease, myocardial infarction, stroke, and heart and renal failure. A recent study of the Framingham cohort (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 2004) showed that in both 55 and 65-year-old participants, the cumulative lifetime risk for the development of hypertension (at or above 140/90 mm Hg, regardless of treatment) was 90%. The lifetime risk statistic is the probability that an individual will develop a disease over a lifetime. Major risk factors are well established and include tobacco use, diet, physical inactivity, obesity, diabetes mellitus, alcohol, and heredity.
In its reports prior to 2006, NAS placed hypertension in the “Inadequate or Insufficient Evidence” category. In
VA has reviewed this additional information in relation to the information in prior NAS reports analyzing studies concerning hypertension. Based on this review, the Secretary has determined that the available evidence presented in
NAS has defined this category of association to mean that available epidemiologic 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 factors, have inadequate exposure assessment, or fail to address latency.
Consistent with its findings in
With respect to the 25 categories of disease considered in its prior reports, NAS found that the studies published since
NAS noted that a follow-up study of residents environmentally exposed to dioxin following an accidental release in Seveso, Italy, found a “barely significant” increased risk of biliary cancer in residents of the moderately-exposed zone, but that no excess was found in the high or low exposure zones. Additionally, two new occupational studies found no statistically significant increased risk of hepatobiliary cancers in exposed workers. NAS concluded that the isolated finding among the moderately-exposed group in the Seveso study did not establish a consistent pattern of risk and that the overall evidence was insufficient to link the chemicals of interest with hepatobiliary cancers.
NAS noted that the Seveso study also found a statistically significant increase in the incidence of breast cancer among female residents of the high exposure zone 10-14 years after the accident. However, NAS also noted that a recent occupational study and a 2008 study of female Vietnam veterans did not support an increased risk of breast cancer mortality in exposed populations. Overall, NAS concluded that the evidence remains inadequate or insufficient to determine whether an association exists.
NAS noted that a study of herbicide production workers reported an “infinitely large” hazard ratio for risk of renal cancer based on eight deaths in the exposed group and none in the control group, but NAS also stated that the moderate size of the cohort limited the study's ability to detect an increase in this relatively rare cancer. Further, the findings of that study were not supported by several other new occupational and environmental studies, which found no increased risk of renal cancer or found moderate but not statistically significant increases. Accordingly, NAS found the evidence overall inadequate or insufficient to determine whether an association exists.
NAS noted that the Seveso follow-up study reported a statistically significant increased incidence of myeloid leukemia in the moderately exposed group but not in the group with the highest exposure. NAS noted that the significance of this finding was limited by concerns about possible misclassification of that type of leukemia and the erratic correlation between intensity of exposure and degree of risk. Further, that finding was not supported by other new occupational and Vietnam Veteran studies, which generally found no increased risk of leukemia in exposed populations.
NAS noted that two new studies reported statistically significant evidence of association between herbicide exposure and chronic obstructive pulmonary disease (COPD). A study of Army Chemical Corps veterans reported a statistically significant excess mortality from COPD. However, NAS found the significance of that finding to be significantly constrained by the inability to fully control for cigarette smoking, the major risk factor for COPD. NAS noted that prior studies of American Vietnam veterans did not find evidence of increased mortality due to noncancerous respiratory conditions. NAS noted that concerns regarding misclassification of COPD on death certificates and misdiagnosis of COPD further limit the conclusion that can be drawn from such mortality data. The other new study found a statistically significant increase in self-reported incidence of emphysema and bronchitis, which are conditions consistent with COPD, among Australian Vietnam veterans. NAS noted that this finding was limited by recall bias and other methodological considerations and expressed general skepticism about the significance of this study's findings due to its low response rate and the study's nearly uniform findings of statistically increased prevalence for nearly 50 health conditions. NAS further noted that prior studies of the full cohort of male Australian Vietnam veterans showed no suggestion of increased
With respect to immune system disorders, NAS noted that the only potentially relevant new study was the above-referenced Australian veteran study, which found that several conditions in which immune function may play a role—including infectious and parasitic diseases, respiratory disorders, and skin disorders—were significantly more prevalent in Australian Vietnam veterans, based on self-reports, than among the general population. For the same reasons discussed above, NAS found the reliance that could be placed on that report to be significantly limited by numerous methodological concerns. Accordingly, NAS found that there was inadequate or insufficient evidence to determine whether an association exists between herbicide exposure and immune system disorders.
In notices following prior NAS reports, cited in section II above, VA has explained the basis for the Secretary's determination that a positive association does not exist between herbicide exposure and the health conditions identified in
Based on the analysis in
NAS has previously concluded that there is limited or suggestive evidence of no association between paternal herbicide exposure and spontaneous abortion. In
Detailed information on NAS' findings may be found at
After careful review of the findings of the 2010 NAS report,
The Secretary of Veterans Affairs, or designee, approved this document and authorized the undersigned to sign and submit the document to the Office of the Federal Register for publication electronically as an official document of the Department of Veterans Affairs. John R. Gingrich, Chief of Staff, Department of Veterans Affairs, approved this document on June 6, 2012, for publication.