Agent Orange Link to AML in Vietnam Veteransʼ Children Remains Complex & Elusive

WASHINGTON, DC—It is a tantalizing and troubling finding: The association between the chemical herbicide Agent Orange and an elevated risk of acute myelogenous leukemia (AML) in the children of veterans who fought in Vietnam. The link has proved to be highly complex, and scientific efforts to pin it down have not been conclusive. At issue is whether the children of Vietnam veterans exposed to Agent Orange who develop AML should receive a coverage benefit from the US Department of Veterans Affairs. A committee of the Institute of Medicine (IOM) held a workshop here this fall to hear more data on the elusive link. A new report from the IOM on the topic is expected early this year. Beginning in 1962, US servicemen sprayed Agent Orange and other defoliants over parts of South Vietnam and Cambodia. Such spraying was halted in 1970 after a report concluded that one of the primary chemicals used in Agent Orange could cause birth defects in laboratory animals. Exposure to Agent Orange or other chemicals used in the Vietnam War has been linked to an increased risk of poor pregnancy outcomes, including birth defects and spontaneous abortions. Earlier scientific findings have shown “sufficient” evidence of a link between chemical exposure and the development of soft-tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, and chloracne (an acne-like eruption of comedones, cysts, and pustules) in veterans. In addition, studies continue to offer “limited or suggestive” evidence of an association between exposure and Type II diabetes (which is moving closer to becoming a covered benefit), respiratory cancers, prostate cancer, and multiple myeloma—as well as spina bifida in veterans' children. Last April the IOM committee released a comprehensive Congressionally mandated report supported by the VA that bolstered the possibility of an association between chemicals used in herbicides during the Vietnam war and AML in veterans' children, but stopped short of establishing a direct, conclusive connection. Previous IOM reports had found “inadequate or insufficient” evidence to determine whether a link existed for AML or other cancers in Vietnam veterans' children. “New research does suggest that some kind of connection exists between AML in children and their fathers' military service in Vietnam or Cambodia,” Committee Chairman Irva Hertz-Picciotto, PhD, Professor of Epidemiology at the University of North Carolina, said in April. The IOM committee Dr. Hertz-Picciotto chairs has been conducting a review of the scientific evidence on the statistical associations between diseases and exposure to chemical compounds in herbicides used in Vietnam. On the strength of that report, Secretary of Veterans Affairs Anthony J. Principi announced the day after the report was released that he would ask Congress to pass legislation to provide benefits to affected pediatric AML patients. The VA has no authority to provide any monetary benefits to these veterans' children with AML unless Congress authorizes it. Errors in Study But less than a month after Mr. Principi announced that he would seek legislation to provide coverage—on May 16, 2001—Australian researchers (whose work was integral to the findings in the April IOM report)—announced that they had discovered errors in their study. After correcting for errors, the Australian data no longer showed a link between exposed Australian Vietnam veterans and AML in their children. In the face of flawed data, Mr. Principi then signed a contract with IOM to revisit and take a second look at evidence linking AML to Agent Orange exposure in veterans during the Vietnam War. “I hope that Agent Orange does not cause the children of Vietnam veterans to develop this dreadful disease,” he said. “If the scientific evidence shows a link, I will support creating benefits for these children of Vietnam veterans. But, first, I believe we must ensure that we are basing our commitments upon sound scientific evidence.” At the workshop this fall, the most persuasive new scientific evidence linking paternal military service in Vietnam or Cambodia to an increased risk of AML in their children was presented by Xiao-Ou Shu, MD, PhD, Associate Professor in the Division of General Internal Medicine at the Center for Health Services Research at Vanderbilt University Medical Center. Dr. Shu and her colleagues analyzed data from three case-control studies conducted by the Children's Cancer Group (CCG) from 1983 to 1993. The CCG is a cooperative clinical trials group with approximately 100 centers in the United States, Canada, and Australia. Data from a total of 605 cases of AML in children age 18 years or younger and 2,117 ALL cases in children age 14 years or younger were included. Paternal military history and other exposure data were obtained for 2,343 matched case-control sets, including 1,805 ALL and 528 AML cases. Paternal military service in general was not associated with an increased risk of leukemia in veterans' offspring, said Dr. Shu. However, “a small, but significant, increase in the risk for AML” was seen among the children of veterans who had served in Vietnam or Cambodia after adjustment for paternal education, race, income, smoking, x-ray exposure, and marijuana use. “The risk was predominantly present in children diagnosed before the age of two,” said Dr. Shu. The risk was more evident for the children of men who reported two or more tours in Vietnam or Cambodia, she added. Military service in Vietnam or Cambodia was not related to the risk for ALL in veterans' offspring. Was there something unique about veterans' exposures in Vietnam, or is paternal pesticide exposure per se associated with an increased risk of AML in offspring? German data presented at the IOM workshop by Joachim Schuz, PhD, Professor at the Institute for Medical Biometrics, Epidemiology and Informatics at the University of Mainz, did not find an association between paternal pesticide exposure and an increased risk of AML in children prior to conception. Dr. Schuz studied farmers, gardeners, truck drivers, office workers, and painters. A previous study done by the Children's Study Group, however, found that self-reported paternal pesticide exposures of more than 1,000 days were associated with a 2.7-fold increased risk of fathering a child who developed AML. Vietnam Veterans of America (VVA), which is Congressionally chartered, is calling for additional studies to probe the link between paternal chemical exposure in Vietnam veterans and AML in their offspring. VVA National President George C. Duggins has called on the VA to fund additional Agent Orange research, based on the IOM's April 2001 report. He said the finding of an increased risk of AML should provide the impetus for the VA to fund a large-scale study or a series of epidemiological studies of Vietnam veterans and their children. Meanwhile, in a related development, the Leukemia & Lymphoma Society is urging Congress to provide more funding for blood cancer research and education. New Bill A new bill, the Hematological Cancer Research Investment and Education Act of 2001 (HR 2629)—which also has a Senate version—would establish the Joe Moakley Research Excellence Program, honoring the late Massachusetts Congressman, a 30-year member of the House who died of leukemia in February 2001. It would also authorize funding for the Geraldine Ferraro Cancer Education Program, honoring Ms. Ferraro, a former member of Congress and a 1984 vice presidential candidate, who was recently diagnosed with myeloma.

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