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HERBICIDE/DIOXIN EXPOSURE AND ACUTE MYELOGENOUS LEUKEMIA 21 They are Kristensen and colleaguesâ 1996 paper on cancer morbidity in the children of agricultural workers in Norway, and an unpublished extension of the Meinert et al. (2000) case-control interview study of childhood cancers in Germany presented to the committee at an October 2001 IOM workshop by co-investigator Dr. Joachim Schüz. These provide little additional information, however, because of the relatively small numbers of exposed cases (12 and 6, respectively) and lack of data on exposures to specific substances. Previous analyses of the German study found an association (OR = 1.5, 1.1â2.2) between preconceptional paternal exposure and all childhood leukemia combined. No association (OR = 0.9, 0.3â2.4) was observed when the analysis was restricted to AML alone. Two studies reviewed in Update 1996 of cancers among subjects aged 0â19 living in the area surrounding Seveso, Italyâsite of a 1976 industrial accident that released dioxin into the environmentâwere also examined (Bertazzi et al., 1992; Pesatori et al., 1993). However, since all 3 AML cases in this cohort were in individuals born prior to the accident, these data were not relevant to the issue of paternal exposures prior to conception. While other studies reviewed in earlier Veterans and Agent Orange series reports address leukemia incidence in the children of individuals exposed to herbicides or dioxin, none provide specific information concerning AML. CONCLUSIONS The committee assessed the association between paternal herbicide or dioxin exposure and acute myelogenous leukemia in offspring. The assessment included studies reviewed in previous Veterans and Agent Orange reports and newly identified or published reports. Strength of Evidence in Epidemiologic Studies Based on the scientific evidence reviewed above, 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 contaminants 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 asso- ciation. The Update 2000 committee had based its findings in part on a study of AML incidence in the children of Australian veterans of Vietnam (AIHW, 2000) that was later found to have contained an error. The error led the studyâs authors to incorrectly conclude that these children faced a significantly greater risk of AML than the general population. A revised analysis found that while AML incidence was somewhat elevated in the cohort, it was within the range that might be expected in the community (AIHW, 2001).
22 VETERANS AND AGENT ORANGE In reaching this finding, the committee took into account the other studies that had figured prominently in the previous decision. These included a case- control study of AML conducted by the Childrenâs Cancer Group (Wen et al., 2000) in which self-reported service in Vietnam or Cambodia was associated with an elevated risk after adjusting for numerous potentially confounding life- style and sociodemographic factors; it also considered a study that had played a lesser role in the previous committee decision that showed an association of childhood AML with paternal occupational exposure to herbicides/pesticides before, during, or after gestation (Buckley et al., 1989). The committee also considered newly identified information on a cohort from Norway (Kristensen et al., 1996), and an unpublished extension of a study of childhood cancers in Germany (Meinert et al., 2000), presented at an October 2001 IOM workshop by co-investigator Dr. Joachim Schüz. Taken together, these studies constitute inadequate or insufficient evidence to determine whether an association exists between childhood AML and the herbicides used in Vietnam or their contaminants; that is, they are of insufficient quality, consistency, or statistical power to permit a conclusion regarding the presence or absence of an association. 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. (Wen et al., 2000) and Australian (AIHW, 2001) veterans reported a slightly elevated risk of the disease in offspring. 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. There is thus also inadequate/insufficient information to assess the risk to veter- ansâ children. Biologic Plausibility Toxicologic 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 because high doses are required to elicit effects. VAO reported that effects on testes and accessory organ weights, testicular morphology, spermatogenesis, and fertility had been observed in many species, including rats, mice, guinea pigs, marmosets, monkeys, and chickens, but gener- ally occurred only at doses that caused overt toxicity. Two animal studies reviewed in Update 1998 investigated developmental effects following paternal exposure to the chemicals of interest. No paternally mediated effects were observed in the offspring of mice exposed to a mixture of
