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4 Conclusions T his chapter summarizes the data that are available for estimating the pre- sumptive period for respiratory cancer after exposure in Vietnam and the uncertainties that are inherent in the estimation, and it presents the over- all conclusions of the committee on the latent period and the presumptive period. DATA FOR ESTIMATION OF PRESUMPTIVE PERIOD As discussed in Chapter 2, the main chemical used in Vietnam that is of concern for respiratory cancer is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin). The committee considered four types of data to evaluate the presump- tive period, the period between cessation of exposure to TCDD and respiratory cancer: toxicokinetic data, mechanistic data, epidemiologic data, and data on the presumptive period for other respiratory carcinogens. Toxicokinetic Data TCDD is a highly hydrophobic chemical that readily crosses cell mem- branes and accumulates in lipid-rich organs. Mobilization of TCDD that accu- mulates in those organs results in continued target organ exposure after external exposure has ended. Estimates of the half-life of TCDD in humans have been consistent in confirming that TCDD is highly persistent in the body, with a half- life averaging about 7.5 years. That long half-life must be taken into consider- ation in determining cessation of exposure and the presumptive period. Although external exposure to herbicides in Vietnam was time-limited, elevated TCDD body burden could remain for many years after service in Vietnam. That pro- 51

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52 VETERANS AND AGENT ORANGE longed elevation of body burden might result in respiratory cancers being linked to exposures in Vietnam at a later date than would be expected if the end of service in Vietnam was considered when TCDD could no longer have an effect. That is, the prolonged elevation of body burden would, in effect, lengthen the presumptive period for TCDD because the duration of the ongoing potential exposure of target organs from the elevated body burden is part of the presump- tive period. Mechanistic Data To model and evaluate the carcinogenic properties of a chemical mechanis- tically, the multistage-carcinogenesis approach is often used (Pitot, 1986; Barrett, 1993). A chemical might initiate, promote, or alter the progression of a neo- plasm. Latent periods and presumptive periods for different chemicals depend on differences in the mechanisms by which chemicals act, that is, on whether they are initiators or promoters. Furthermore, carcinogenic chemicals that are relatively persistent in the body may initiate or promote the carcinogenic process over a long period. In that case, latency may be either short or long from the time of initial exposure because it is possible that effects on the carcinogenic process may occur whenever body burden is increased and at multiple stages of the carcinogenic process. TCDD is a known carcinogen in rats and mice and is considered to be a carcinogen in humans. All the available evidence indicates that it acts as a pro- moter by multiple pathways in the regulation of cell proliferation and differentia- tion (IOM, 2003). Given the tumor-promoting potential of TCDD and its persis- tence, it is possible that, as indicated above, the latent and presumptive periods could be altered because promotion of cells initiated by other chemicals after external exposure to TCDD has ended could occur whenever body burden is increased. Epidemiologic Data Studies have examined latency by stratifying on time since first exposure and through the simplest approaches described in Chapter 2. Some of the data suggest that an increased risk of respiratory cancer occurs within 10 years of first exposure. No analyses have examined the presumptive period for TCDD, that is, the time between termination of exposure and end of an association with respira- tory cancer. Therefore, there is no clear indication of the presumptive period, and no upper limit on that period could be determined. Many of the studies also lack an indication that the risk returns to the background value for the entire length of follow-up; some increase in risk remains for 20 or 25 years, or more, after exposure began. Most of the studies, however, have not followed the cohort

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CONCLUSIONS 53 beyond 30 years, leaving no data with which to determine a latent or presump- tive period beyond that time frame. Data on Other Respiratory Carcinogens No epidemiologic studies have evaluated the time between cessation of ex- posure to TCDD and occurrence of respiratory cancer, but there is a substantial body of literature on timing of exposure and respiratory cancer for other carcino- gens. Chapter 2 briefly reviews data on gamma rays, radon daughters, smoking, arsenic, and asbestos. Most of the data on those agents indicate that the risk of respiratory cancer remains increased for many decades after the end of exposure. For example, lung cancer risk posed by exposure to arsenic or radon remains increased in Chinese tin miners for more than 50 years after the end of exposure (Hazelton et al., 2001). Time courses cannot be directly extrapolated from other chemicals to TCDD, but those data do indicate that in many instances respiratory cancer can be associated with a chemical exposure that occurred many decades earlier. UNCERTAINTY There are two steps in the assessment of the presumptive period between an exposure and a given health outcome in a particular group, such as Vietnam veterans. The first step is to establish that the exposure in question is associated with the outcome, and the second is to evaluate how long the risk of the outcome remains increased after the cessation of the exposure. The overall uncertainty in the estimate of the presumptive period includes uncertainty in the association and uncertainty in the time course. The Update 2002 committee concluded that evidence remains limited but suggestive that there is an association between exposure to at least one of the chemicals of interest (2,4-dichlorophenoxyacetic acid, 2,4,5-trichlorophenoxy- acetic acid and its contaminant TCDD, picloram, and cacodylic acid) and respi- ratory cancer (cancer of the lung and bronchus, larynx, and trachea) (IOM, 2003). As is evident from the categorization of the evidence as limited/suggestive, un- certainty remains with regard to the association between the exposure of inter- est and respiratory cancer. Uncertainty can be introduced by the statistical error and potential biases that characterize any epidemiologic study. As discussed in Update 2002 (IOM, 2003) and in Chapter 1 of the present report, for the chemi- cals of interest and respiratory cancer uncertainty in the strength of the evidence of an association and in whether the association is causal is a consequence of the absence, in available studies, of data on smoking, occupational exposure, and other confounding factors. As discussed in Chapter 2, however, the likelihood of confounding by smoking in studies that include internal comparisons (that is, that calculate relative risks rather than standardized mortality ratios) might be

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54 VETERANS AND AGENT ORANGE low. Studies have shown that in large-scale occupational studies that conduct internal comparisons, smoking is not a confounder because there are not large variations in smoking within industrial cohorts (Bang and Kim, 2001). Studies that rely on standardized mortality ratios could be confounded. Animal data that support the plausibility of an association between TCDD and respiratory cancer--studies indicate that TCDD can act as a promoter for lung cancer--also increase the committee's confidence in its conclusion of limited/suggestive evidence of an association between the exposure and respira- tory cancer. As mentioned above, there is also uncertainty in the time course of exposure and disease detection. Various statistical modeling techniques have been devel- oped to evaluate latent periods and presumptive periods. Each model has limita- tions and is only as good as the available input data. The limitations of the various models must be kept in mind in evaluating the uncertainty surrounding a presumptive period. In estimating a latent period or presumptive period from epidemiologic data, errors in the assignment or timing of exposures could in- crease uncertainty. Other aspects of epidemiologic studies that might affect the presumptive period are whether a study evaluates cancer incidence or cancer mortality, whether competing mortality is affecting the results of a study, and whether there is a substantial population group that is genetically susceptible or has acquired a susceptibility to respiratory cancer. There is also the possibility that coexposure to effect modifiers has altered the presumptive period. As dis- cussed in Chapter 2, other exposures, such as to smoking and other chemicals, can potentially modify the effects of TCDD on respiratory cancer; but no studies appear to have evaluated the impact of smoking on the latent or presumptive period associated with TCDD. The greatest source of uncertainty with respect to the presumptive period for TCDD and respiratory cancer, however, is the lack of data on the time between cessation of exposure and the manifestation of respira- tory cancer in the epidemiologic literature. Such data are needed to provide an accurate estimate of the presumptive period. Data on latency in epidemiology studies provide a framework for the consideration of presumptive period, but are not sufficient for drawing quantitative conclusions regarding the length of that period. The relationship between cumulative or peak dose in TCDD carcinogen- esis is unknown, and the relative importance of the first or any specific window of exposures remains unclear because information from epidemiologic studies has not been sufficient to disentangle them. For any given individual who devel- ops respiratory cancer, the exact exposures that contributed to the pathogenesis of that cancer are unknown. The conclusions that the committee can draw, on the basis of the available data, are discussed below.

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CONCLUSIONS 55 COMMITTEE'S CONCLUSIONS ON LATENT PERIOD AND PRESUMPTIVE PERIOD Earlier Institute of Medicine reports on veterans and Agent Orange have looked at the question of the latent period between exposure to TCDD and respi- ratory cancer (IOM, 1996, 1999). The committees responsible for those reports concluded that no latent period could be estimated. Specifically, Update 1998 concluded that "the evidence suggests 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", that is, the presumptive period (IOM, 1999). There are still few data on the latent period and no data on the presumptive period for TCDD and respiratory cancer. The available data on latency still suggest that an increased risk of respiratory cancer may occur within 10 years of exposure. The data also indicate that risk may remain elevated into at least the third decade after initiation of exposure. The main question to the committee is whether it is possible to put an upper limit on the length of time that TCDD could exert its effect and, if so, what that limit would be. That is, the committee has tried to evaluate the presumptive period for exposure to the herbicides used in Vietnam and their contaminant TCDD and respiratory cancer. Because no epidemiologic studies have examined the time between cessation of exposure and the occurrence of respiratory cancer, the committee cannot determine a period beyond which the occurrence of respi- ratory cancer could no longer be presumed to be related to exposure to TCDD. However, given the long latent period seen in epidemiologic studies (increased risk remaining 20 or 25 years after first exposure), the persistence of TCDD in the body, the promoting activity of TCDD, and the fact that respiratory cancer risk posed by some other agents remains increased for many decades after expo- sure has ended (at least 50 years after cessation of exposure), the committee concludes that the risk of respiratory cancer posed by exposure to TCDD could last many decades. REFERENCES Bang KM, Kim JH. 2001. Prevalence of cigarette smoking by occupation and industry in the United States. American Journal of Industrial Medicine 40(3):233239. Barrett JC. 1993. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ- mental Health Perspectives 100:920. Hazelton WD, Luebeck EG, Heidenreich WF, Moolgavkar SH. 2001. Analysis of a historical cohort of Chinese tin miners with arsenic, radon, cigarette smoke, and pipe smoke exposures using the biologically based two-stage clonal expansion model. Radiation Research 156:7894. IOM (Institute of Medicine). 1996. Veterans and Agent Orange: Update 1996. Washington, DC: National Academy Press.

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56 VETERANS AND AGENT ORANGE IOM. 1999. Veterans and Agent Orange: Update 1998. Washington, DC: National Academy Press. IOM. 2003. Veterans and Agent Orange: Update 2002. Washington, DC: The National Academies Press. Pitot HC. 1986. The molecular determinants of carcinogenesis. Symposium on Fundamental Cancer Research 39:187196.