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1 Introduction F rom 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped to conceal opposition forces, to destroy crops that enemy forces might depend on, and to clear tall grasses and bushes from the perimeters of US base camps and outlying fire-support bases. Mixtures of 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophen- oxyacetic acid (2,4,5-T), picloram, and cacodylic acid made up the bulk of the herbicides sprayed. The herbicide mixtures used were named according to the colors of identification bands painted on the storage drums; one of the main chemical mixtures sprayed was Agent Orange (a 50:50 mixture of 2,4-D and 2,4,5-T). At the time of the spraying, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, one form of dioxin) was an unintended contaminant formed in the pro- duction of 2,4,5-T and was present in Agent Orange and some other formula- tions sprayed in Vietnam. In 1991, because of continuing uncertainty about the long-term health ef- fects on Vietnam veterans of the herbicides sprayed, Congress passed Public Law (PL) 102-4, the Agent Orange Act of 1991. That legislation directed the secretary of veterans affairs to ask the National Academy of Sciences (NAS) to perform a comprehensive evaluation of scientific and medical information re- garding the health effects of exposure to Agent Orange, other herbicides used in Vietnam, and the various chemical components of those herbicides, including TCDD. The secretary was also to ask NAS to conduct an update at least every 2 years for 10 years from the date of the first report to review newly available literature and draw conclusions from the overall evidence. In response to the request, the Institute of Medicine (IOM) convened a committee, whose conclusions were published in 1994 in Veterans and Agent 9

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10 VETERANS AND AGENT ORANGE Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO). The work of later committees resulted in the publication of biennial updates (Update 1996, Update 1998, Update 2000, and Update 2002) and focused reports reviewing the scientific evidence regarding type 2 (non-insulin- dependent) diabetes (Type 2 Diabetes) and acute myelogenous leukemia in chil- dren (Acute Myelogenous Leukemia). VAO (IOM, 1994) concluded that there is "limited/suggestive" evidence of an association between exposure to at least one of the chemicals of interest (2,4- D, 2,4,5-T and its contaminant TCDD, picloram, and cacodylic acid) and respi- ratory cancer (of lung and bronchus, larynx, and trachea). That conclusion was reaffirmed in Update 1996 (IOM, 1996), Update 1998 (IOM, 1999), Update 2000 (IOM, 2001), and Update 2002 (IOM, 2003). The Department of Veterans Affairs (VA), on the basis of the findings of VAO and its own review of the literature, published a notice in the Federal Register in February 1994, stating that there is "a positive association between exposure to herbicides used in the Republic of Vietnam and the subsequent development of respiratory cancers" (Federal Register, 1994). The VA further found that "the weight of the available evidence indicates that chemically- induced respiratory cancers manifest within a definitive period following expo- sure, after which there is little effect from the exposure" (Federal Register, 1994). That Federal Register notice discusses data on chemically-induced respiratory cancers in Ontario steel-plant workers (Finkelstein et al., 1991), people exposed as a result of a trichlorophenol-process accident in West Virginia (Zack and Suskind, 1980), and workers exposed to TCDD after a 1953 accident in a factory in Germany (Zober et al., 1990). The VA therefore proposed, as part of its rule, that respiratory cancer "be presumed service connected only if it is manifest within 30 years after exposure" (Federal Register, 1994). The Veterans Education and Benefits Expansion Act of 2001, PL 107-103, removed the 30-year presumptive period for respiratory cancer and mandated that the secretary of veterans affairs ask the National Academy of Sciences (NAS) to review "available scientific literature on the effects of exposure to an herbi- cide agent containing dioxin on the development of respiratory cancers in hu- mans." And to review "whether it is possible to identify a period of time after exposure to herbicides after which a presumption of service-connection" for the disease would not be warranted. CHARGE TO THE COMMITTEE In response to the VA request, IOM extended the service of the Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides that was responsible for Update 2002 to address the question of presumptive period and respiratory cancer. The charge to the committee was to review and evaluate the evidence regarding the period between cessation of exposure to the

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INTRODUCTION 11 chemicals used in Vietnam (2,4-D, 2,4,5-T and its contaminant TCDD, cacodylic acid, and picloram) and the occurrence of respiratory cancer. COMMITTEE'S APPROACH TO THE CHARGE To meet its charge, the committee conducted literature searches to identify relevant research. As discussed earlier, the committee had concluded in Update 2002 that there is "limited/suggestive" evidence of an association between at least one of the chemicals of interest and respiratory cancer. For the current report, the committee did not reevaluate that conclusion; rather, it focused on articles that provide information on the time course of exposure and develop- ment of disease. In addition to the data on the chemicals of interest, the commit- tee briefly reviewed what is known regarding the latent period of respiratory cancer after exposure to other physical and chemical agents. And, although it is not possible to extrapolate directly from animal bioassays to human cancers with respect to the timing of carcinogenesis, the committee reviewed data from ex- perimental animal and in vitro studies that could provide insight into the mecha- nisms by which the chemicals might lead to cancer. PREVIOUS CONCLUSION REGARDING RESPIRATORY CANCER Update 2002 (IOM, 2003) concluded that evidence remained "limited/sug- gestive" regarding an association between exposure to at least one of the chemi- cals of interest (2,4-D, 2,4,5-T and its contaminant TCDD, picloram, or ca- codylic acid) and respiratory cancer (of the lung and bronchus, larynx, and trachea). A health outcome is classified as being "limited/suggestive" if the evi- dence is suggestive of an association between herbicides and the outcome but is limited because chance, bias, and confounding could not be ruled out with confi- dence. For example, at least one high-quality study shows a positive association, but the results of other studies are inconsistent. Uncertainty is introduced by the absence of data on smoking, occupational exposures, and other confounding factors in available studies. Animal studies support the plausibility of the asso- ciation and a role of TCDD as a promoter. EVALUATIONS OF LATENCY BY PREVIOUS COMMITTEES The question of the latent period between exposure to the chemicals of interest and respiratory cancer was first addressed by the IOM committee in Update 1996. That report reviewed results on the timing of exposure in relation to respiratory cancer and prostate cancer. For respiratory cancer (as well as pros- tate cancer), the reports of some potentially informative studies did not include latency, and no latent period could be estimated. Update 1998 reviewed the literature relevant to latency that was published

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12 VETERANS AND AGENT ORANGE after Update 1996. With respect to respiratory cancer, it discussed evidence from the National Institute for Occupational Safety and Health study of chemical work- ers (Fingerhut et al., 1991), studies of environmental exposures after an indus- trial accident in Seveso, Italy (Bertazzi et al., 1989a,b; 1997), a study of Finnish herbicide appliers (Asp et al., 1994), occupational studies on a cohort compiled by the International Agency for Research on Cancer (Kogevinas et al., 1997) and a study on a subset of the cohort (Becher et al., 1996), studies of Vietnam veter- ans who were involved in the aerial spraying of the herbicides (the Ranch Hands) (Michalek et al., 1998), and studies of Australian Vietnam veterans (Crane et al., 1997). The Update 1998 committee's conclusion was that "the evidence sug- gests that if respiratory cancer does result from exposure to the herbicides used in Vietnam, the greatest relative risk for lung cancer may be in the first decade after exposure, but until further follow-up has been carried out for some of the cohorts, it will not be possible to put an upper limit on the length of time these herbicides could exert their effect" (IOM, 1999). When Update 2000 was being prepared, the new data on latency were not sufficient to warrant a reexamination of the latent period. In light of the request for the present report, the Update 2002 committee did not review latency. ORGANIZATION OF THIS REPORT The remainder of this report is organized into three chapters. Chapter 2 discusses the committee's use of the terms latency and presumptive period and the factors that can affect those periods, and briefly discusses chemicals that are known to be associated with respiratory cancer and confounders and cofactors that are especially pertinent to respiratory cancer. Epidemiology studies of the chemicals of interest that provide information on latency are discussed in Chap- ter 3. Chapter 4 presents the committee's overall conclusions on the period be- tween exposure to the chemicals of interest and the development of respiratory cancer. It also describes how those conclusions are related to the period during which a respiratory cancer could be presumed to have been caused by exposures incurred during service in Vietnam. REFERENCES Asp S, Riihimaki V, Hernberg S, Pukkala E. 1994. Mortality and cancer morbidity of Finnish chlo- rophenoxy herbicide applicators: an 18-year prospective follow-up. American Journal of Indus- trial Medicine 26:243253. Becher H, Flesch-Janys D, Kauppinen T, Kogevinas M, Steindorf K, Manz A, Wahrendorf J. 1996. Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins. Cancer Causes and Control 7(3):312321. Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989a. Mortality in an area contaminated by TCDD following an industrial incident. Medicina Del Lavoro 80:316 329.

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INTRODUCTION 13 Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Sanarico M, Radice L. 1989b. Ten-year mor- tality study of the population involved in the Seveso incident in 1976. American Journal of Epidemiology 129:11871200. Bertazzi PA, Zochetti C, Guercilena S, Consonni D, Tironi A, Landi MT, Pesatori AC. 1997. Dioxin exposure and cancer risk: a 15-year mortality study after the "Seveso accident." Epidemiology 8(6):646652. Crane PJ, Barnard DL, Horsley KW, Adena MA. 1997. Mortality of Vietnam veterans: the veteran cohort study. A report of the 1996 retrospective cohort study of Australian Vietnam veterans. Canberra: Department of Veterans' Affairs. Federal Register. 1994. Disease Associated with Exposure to Certain Herbicide Agents (Multiple Myeloma and Respiratory Cancers). Proposed Rule (38 CFR Part 3, RIN 2900-AG73), Febru- ary 3. Fingerhut MA, Halperin WE, Marlow DA, Piacitelli LA, Honchar PA, Sweeney MH, Greife AL, Dill PA, Steenland K, Suruda AJ. 1991. Cancer mortality in workers exposed to 2,3,7,8-tetra- chlorodibenzo-p-dioxin. New England Journal of Medicine 324:212218. Finkelstein MM, Boulard M, Wilk N. 1991. Increased risk of lung cancer in the melting department of a second Ontario steel manufacturer. American Journal of Industrial Medicine 19(2):183 194. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. IOM. 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press. IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2001. Veterans and Agent Orange: Update 2000. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. Kogevinas M, Becher H, Benn T, Bertazzi PA, Boffetta P, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Fingerhut M, Green L, Kauppinen T, Littorin M, Lynge E, Mathews JD, Neuberger M, Pearce N, Saracci R. 1997. Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. American Journal of Epidemiology 145(12):10611075. Michalek JE, Ketchum NS, Akhtar FZ. 1998. Postservice mortality of U.S. Air Force veterans occupationally exposed to herbicides in Vietnam: 15-year follow-up. American Journal of Epi- demiology 148(8):786792. Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to tetrachlorodibenzo- dioxin in a trichlorophenol process accident. Journal of Occupational Medicine 22:1114. Zober A, Messerer P, Huber P. 1990. Thirty-four-year mortality follow-up of BASF employees exposed to 2,3,7,8-TCDD after the 1953 accident. International Archives of Occupational and Environmental Health 62:139157.