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Veterans and Agent Orange: Herbicide/Dioxin Exposure and Acute Myelogenous Leukemia in the Children of Vietnam Veterans EXECUTIVE SUMMARY In 2001, in response to a request by the U.S. Department of Veterans Affairs (DVA), the Institute of Medicine (IOM) called together a committee to conduct a review of the scientific evidence regarding the association between exposure to dioxin1 and other chemical compounds in herbicides used in Vietnam and acute myelogenous leukemia in the offspring of Vietnam veterans. The committee was asked to determine, to the extent that available data permitted meaningful deter- minations: (1) whether a statistical association with herbicide exposure exists, taking into account the strength of the scientific evidence and the appropriate- ness of the statistical and epidemiologic methods used to detect the association; (2) the increased risk of the disease associated with exposure to herbicides during Vietnam service; (3) whether there is a plausible biological mechanism or other evidence of a causal relationship between herbicide exposure and the disease. The work performed by the committee adheres to the format of a set of studies performed by the IOM at the behest of DVA under Public Law 102-4, the 12,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as TCDD or âdioxin,â was an uninten- tional contaminant of one of the herbicides used in Vietnam. 1
2 VETERANS AND AGENT ORANGE âAgent Orange Act of 1991.â The conclusions in this report are based on cumu- lative evidence from the scientific literature reviewed in these studiesâVeterans and Agent Orange: Health Effects of Herbicides Used in Vietnam; Veterans and Agent Orange: Update 1996; Veterans and Agent Orange: Update 1998; Veterans and Agent Orange: Update 2000âand information published or identified through October 18, 2001, the date the deliberations of the Update 2000 committee were completed. Strength of Evidence in Epidemiologic Studies Based on the scientific evidence reviewed in this report, the committee finds there is inadequate or insufficient evidence to determine if an association exists between exposure to the herbicides used in Vietnam or their contami- nants and acute myelogenous leukemia (AML) in the children of Vietnam veterans. This is a change in classification from the recent Veterans and Agent Orange: Update 2000 report, which found limited/suggestive evidence for such an association. The Update 2000 report committee primarily based its findings on three studies. Oneâa report on AML incidence in the children of Australian veterans of Vietnam (AIHW, 2000)âwas later found to have contained an error that led its authors to incorrectly conclude that these children faced a significantly greater risk of AML than the general population. The revised analysis found that while AML incidence was somewhat elevated, it was within the range that might be expected in the community (AIHW, 2001). A second study of U.S. veterans found that paternal self-reported service in Vietnam or Cambodia was associated with an elevated risk of AML in offspring after adjusting for some potentially confounding lifestyle and sociodemographic factors (Wen et al., 2000). The third study found that occupational use of pesti- cides by either the mother or the father, as reported in detailed interviews, was associated with an elevated risk (Buckley et al., 1989). However, because of a high correlation among exposures in the three periods studied (before, during, and after pregnancy), it was not possible to determine whether exposure uniquely prior to the pregnancy was associated with increased risk of AML in the children. This is an important consideration because the wartime exposure of male veterans to herbicides would have occurred prior to conception. For female veterans, it could have occurred during early pregnancy. Two other analyses not previously reviewed in a Veterans and Agent Orange series report were also evaluated by the committee: a paper on cancer morbidity in the children of agricultural workers in Norway (Kristensen et al., 1996) and an unpublished extension of an interview study of childhood cancers in Germany (Meinert et al., 2000) presented at an October 2001 IOM workshop by co- investigator Dr. Joachim Schüz. These provided the committee with little addi- tional information due to the relatively small numbers of exposed cases and lack
HERBICIDE/DIOXIN EXPOSURE AND ACUTE MYELOGENOUS LEUKEMIA 3 of data on exposures to specific substances. The German study did have a general measure of paternal exposure prior to conception and found no association with AML in offspring. None of the other studies of childhood cancer outcomes reviewed in Veterans and Agent Orange reports provides explicit information specific to the evaluation of AML in the offspring of exposed individuals. Considered together, the corrected data from the AIHW report, the other newly reviewed research results, and the information from previously reviewed studies no longer meet the definition for âlimited/suggestive evidenceââevidence suggestive of an association but limited because chance, bias, and confounding could not be ruled out with confidence. Risk of Acute Myelogenous Leukemia Among the Children of Vietnam Veterans Presently available data allow for the possibility of an increased risk of AML in the children of Vietnam veterans. Studies of both U.S. and Australian veterans reported a slightly elevated incidence of the disease in offspring.2 However, for the reasons detailed in this report, the committee believes that these studies and the other available information constitute inadequate/insufficient evidence to determine whether an association does or does not exist. As a consequence, there is also inadequate/insufficient information to assess the risk to veteransâ children. Biologic Plausibility Studies reviewed in earlier Veterans and Agent Orange series reports suggest that the reproductive systems of adult male laboratory animals are relatively insensitive to TCDD. Effects on testes and accessory organ weights, testicular morphology, spermatogenesis, and fertility were observed in many species, including rats, mice, guinea pigs, marmosets, monkeys, and chickens, but gener- ally occurred only at doses that caused overt toxicity. Animal studies reviewed in Update 1998 did not observe paternally mediated developmental effects in the offspring of mice exposed to mixtures of the herbicides used in Vietnam, except at levels that also caused paternal toxicity. The committee is not aware of any information published since the release of Update 2000 that bears on the issue of the biologic plausibility of an association between paternal exposure to the herbi- cides used in Vietnam (or dioxin) and AML in offspring. 2The report Veterans and Agent Orange: Update 2000 indicated that there was insufficient or inadequate evidence to determine whether an association exists between exposure to the herbicides used in Vietnam and leukemia in adults. AML was not addressed as a separate disease outcome in this report, due to the lack of data on this outcome in exposed adults.