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Executive Summary F rom 1962 to 1971, US military forces sprayed herbicides over Vietnam to strip the thick jungle canopy that helped 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 majority of the herbicides sprayed. Agent Orange was 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 from the production of 2,4,5-T and was present in Agent Orange and some other formulations 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 102-4, the Agent Orange Act of 1991. That legislation directed the secre- tary of veterans affairs to ask the National Academy of Sciences (NAS) to per- form a comprehensive evaluation of scientific and medical information regard- ing 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 that NAS conduct updates 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) of NAS con- vened a committee, whose conclusions IOM published in 1994 in Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (hereafter referred to as VAO). The work of later committees resulted in the publication of biennial 1
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2 VETERANS AND AGENT ORANGE updates (Update 1996, Update 1998, Update 2000, and Update 2002) and of 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 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 respiratory cancer. That conclusion was reaffirmed in Update 1996, Update 1998, Update 2000, and Update 2002. The Department of Veterans Affairs (VA), on the basis of the findings of VAO and its own review of the available literature, published a notice in the Federal Register on February 3, 1994, stating that there is "a positive association between exposure to herbicides used in the Republic of Vietnam and the subse- quent development of respiratory cancers." The VA further found that "the weight of the available evidence indicates that chemically-induced respiratory cancers manifest within a definitive period following exposure, after which there is little effect from the exposure," and proposed, as part of its rule, that respira- tory cancer will be presumed service connected only if it is manifest within 30 years after exposure. In the Veterans Education and Benefits Expansion Act of 2001, Public Law 107-103, Congress removed the 30-year presumptive period for respiratory can- cer and mandated that the secretary of veterans affairs ask NAS to conduct a study. That study was to review "available scientific literature on the effects of exposure to an herbicide agent containing dioxin on the development of respira- tory cancers in humans." And to review "whether it is possible to identify a period of time after exposure to herbicides after which a presumption of service- connection" of respiratory cancer would not be warranted. The question of the latent period between exposure to the chemicals of interest and the time frame for manifestation of increased respiratory cancer risk was addressed in Update 1996 and Update 1998. Update 1996 reviewed pub- lished results on the timing of exposure in relation to several cancers, including respiratory cancer. For respiratory cancer, the reports of some potentially infor- mative studies did not include latency results, and no latent period could be estimated. On the basis of several subsequent studies that did address that issue, 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." CHARGE TO THE COMMITTEE In response to the request from the VA, IOM extended the service of the Committee to Review the Health Effects in Vietnam Veterans of Exposure to
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EXECUTIVE SUMMARY 3 Herbicides that was responsible for Update 2002 to address the question of presumptive period and respiratory cancer. The charge to the committee was to undertake a review and evaluation of the evidence regarding the period between cessation of exposure to herbicides used in Vietnam and their contaminants (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 The committee 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 (of lung and bronchus, larynx, and trachea). For the present report, the committee did not reevaluate that conclusion. Rather, its literature review focused on articles that provide information on the time course of expo- sure and the development of respiratory cancer. In addition to the data on the chemicals of interest, the committee briefly reviewed what is known about the latent period of respiratory cancer after exposure to some other physical and chemical agents. Although it is difficult to extrapolate timeframes from animal bioassays to human cancers, the committee reviewed data from experimental animal and in vitro studies that could provide insight into the mechanisms by which the chemicals might lead to cancer and the toxicokinetics (absorption, distribution, metabolism and elimination) of the chemicals. On the basis of the available epidemiologic and toxicologic data, the committee considered TCDD to be the main chemical of concern for respiratory cancer and therefore focused on the toxicokinetic and mechanistic data related to TCDD. When discussing how long the effects of exposure in Vietnam might last, the committee found it important to differentiate between the actual latent period (time from disease induction to disease detection), the latent period typically measured in epidemiologic studies (time from beginning of exposure to disease detection), and what can be referred to as the presumptive period (time from cessation of exposure to disease detection). It is important to note that the latent period measured is typically a range representing the latencies of all individuals. Given the congressional mandate to review "whether it is possible to identify a period of time after which a presumption of service-connection" of respiratory cancer would not be warranted, the presumptive period is the primary concern of this committee. EPIDEMIOLOGIC EVIDENCE If there is a causal association between TCDD exposure and respiratory cancer, the literature suggests that the risk can be increased beginning as early as 6 years after exposure, but it is less clear on how long the effect lasts. In a study of industrial workers exposed to TCDD conducted by the National Institute for Occupational Safety and Health (NIOSH), risks were most increased 20 years or
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4 VETERANS AND AGENT ORANGE more after exposure began, even for those with only 14 years of exposure (that is, 1619 years after exposure ended). In a study conducted by the International Agency for Research on Cancer, the standardized mortality ratio (SMR) in work- ers exposed to TCDD or higher chlorinated dioxins dropped to 1.0 1019 years after first exposure and rose to 1.2 20 years or more after first exposure (95% confidence interval [95% CI], 1.01.4), but no analyses are presented by years since last exposure. Studies have been conducted on a cohort exposed environ- mentally to TCDD after an accident at a chemical plant in Seveso, Italy. The 15- year follow-up of the Seveso cohort did not provide any data on lung cancer1 latency, but the most recent follow-up showed a modest increase in the risk estimate 15-20 years after exposure. A study of Australian Vietnam veterans showed increased lung cancer mortality in the first decade after the start of their military service, but that finding is based on a small number of deaths. The most recent study of the Ranch Hands (Air Force personnel responsible for aerial spraying of Agent Orange) showed an SMR of 1.3 for 20 years or more of latency. The committee also found evidence in the NIOSH study that the time be- tween exposure and the detection of respiratory cancer depends on the magni- tude of exposure. If latency depends on the level of exposure, the pattern of time between exposure and detection would not necessarily be expected to be the same in all studies, nor would the pattern of risk over time since exposure be expected to be the same for Vietnam veterans as it was for those exposed in manufacturing plants or through accidental environmental releases of the same chemicals. In summary, a number of studies have examined latency by stratifying on time since first exposure. In those analyses, some studies suggest increased risk of respiratory cancer within 10 years of exposure, others indicated increased risk 1520 years after exposure began, and still others report risks that remained elevated 20 or more years beyond initial exposure. No analyses examined the risks in relation to the presumptive period, so there is no empirical evidence regarding how long this would be for TCDD. In many of the studies, however, there is no indication that risks return to background levels during the entire length of the follow-up. 1The committee's conclusions are for respiratory cancer (of the lung, bronchus, larynx, and tra- chea). Some epidemiology studies look at respiratory cancer together; others separate those cancers into subtypes (for example, lung cancer, tracheal cancer). When discussing the epidemiology studies, the committee refers to the designation used by the study author.
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EXECUTIVE SUMMARY 5 OTHER EVIDENCE Toxicokinetic Data TCDD readily crosses cell membranes and accumulates in lipid-rich organs. Estimates of the half-life of TCDD in humans have been consistent in confirm- ing 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 consideration in evaluating cessation of exposure and the presumptive period. Mobilization of TCDD stored in lipid-rich organs can result in continued exposure of target organs after exter- nal exposure has ended. Although exposure to herbicides in Vietnam was time- limited, potential elevated exposure of target organs could occur until serum TCDD in a Vietnam veteran reached the background value. Therefore, the per- sistence of an elevated body burden of TCDD could increase the duration of exposure of target organs, during which induction of disease may occur at any time, thereby lengthening the presumptive period (i.e., the interval between ex- ternal exposure cessation and disease detection) from the cessation of external TCDD exposure in Vietnam to the detection of respiratory cancer. Mechanistic Data To mechanistically model and evaluate the carcinogenic properties of a chemical, the multistage-carcinogenesis approach is often used: a chemical might initiate, promote, or alter the progression of a neoplasm. Latent periods and presumptive periods for different chemicals will depend on differences in the mechanisms by which the 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. Therefore, latencies may be short or long from the time of initial exposure be- cause effects on the carcinogenic process may occur at any time during the period when the body burden is increased and at multiple stages of the carcino- genic process. All available experimental evidence indicates that TCDD acts as a promoter by multiple pathways in the regulation of cell proliferation and differ- entiation. Given the tumor-promoting potential of TCDD and its persistence, latency might be altered by TCDD's acting as a promoter whenever the body burden of TCDD is increased. Data on Other Respiratory Carcinogens Although no epidemiologic studies have evaluated the presumptive period for TCDD and respiratory cancer, a substantial body of literature explores issues of timing of exposure and respiratory cancer for other respiratory carcinogens, including gamma rays, radon daughters, smoking, arsenic, and asbestos. Most of
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6 VETERANS AND AGENT ORANGE the data on those agents indicate that the risk of respiratory cancer remains increased for many decades after exposure has ended. For example, lung cancer risk posed by exposure to arsenic or radon remained increased in Chinese tin miners for more than 50 years after exposure ended. Time courses cannot be directly extrapolated from other chemicals to TCDD, but the available data indi- cate that in many instances respiratory cancer can be associated with a chemical exposure that occurred many decades earlier. UNCERTAINTY To assess the presumptive period between cessation of exposure and a given health outcome in a particular group, such as Vietnam veterans, it must be estab- lished that the exposure in question is associated with the outcome, and then how long the risk of the health outcome remains increased after cessation of exposure must be evaluated. The overall uncertainty in the estimate of the presumptive period includes uncertainty in the association and uncertainty in the time course. Update 2002 concluded that evidence remains "limited/suggestive" that there is an association between exposure to at least one of the chemicals of interest and respiratory cancer. As is evident from the categorization of the evidence as "lim- ited/suggestive", uncertainty remains with regard to the association between the exposures of interest and respiratory cancer. For the chemicals 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 of data on smoking, occupational expo- sures, and other confounding factors in published studies. However, some con- fidence in the lack of confounding by smoking and other exposures comes from evidence that smoking is not a confounder in large-scale occupational studies with internal comparisons; although smoking patterns differ between white- collar and blue-collar workers, there are not large variations in smoking rates within industrial cohorts. The presence of animal data that support the plausibil- ity of an association between TCDD and respiratory cancer--with studies indi- cating that TCDD can act as a promoter of respiratory cancer--also increases the committee's confidence in its conclusion of "limited/suggestive" evidence of an association between the exposure and respiratory cancer. With respect to determining the time course of exposure and disease detec- tion, errors in the assignment or timing of exposure could increase uncertainty in the estimates. Other aspects of epidemiologic studies that might affect the pre- sumptive period include whether a study evaluates cancer incidence or cancer mortality, whether competing mortality is affecting the results of a study, and whether a substantial subgroup in the population is genetically susceptible or has acquired a susceptibility to respiratory cancer. There is also the possibility that coexposure to effect modifiers alters the presumptive period. Although other exposures, such as smoking and other chemicals, could potentially modify the
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EXECUTIVE SUMMARY 7 effects of TCDD on respiratory cancer, there is no evidence of such a modifica- tion in the epidemiologic studies reviewed. The greatest uncertainty with respect to the presumptive period for TCDD and respiratory cancer, however, comes from the lack of data on the time be- tween cessation of exposure and manifestation of respiratory cancer in the epide- miologic literature. Such data are needed to provide an accurate estimate of the presumptive period. COMMITTEE'S CONCLUSIONS ON PRESUMPTIVE PERIOD There are few data on the latent period and no data on the presumptive period for TCDD and respiratory cancer. The available data on latency suggest that an increased risk of respiratory cancer occurs within 10 years of exposure. In many of the studies, the risk of respiratory cancer is still increased at the end of the follow-up period, or until at least 20 or 25 years after exposure began. The main question for the committee is whether it is possible to put an upper limit on the length of time that TCDD can exert its effect and, if so, what that limit would be--that is, the presumptive period. Because there are no epidemio- logic data on the length of time after exposure to TCDD ceases during which an increase in respiratory cancer is associated with that exposure, the committee cannot determine a period beyond which occurrence of respiratory cancer could no longer be presumed to be related to exposure to TCDD (that is, no upper limits on the latency or presumptive period could be determined). However, given the long latent period seen in epidemiologic studies (risks remaining in- creased up to 25 years after exposure), the persistence of TCDD in the body, and the fact that the risk of respiratory cancer posed by some other agents remains increased for many decades after exposure has ended (50 years or more follow- ing cessation of exposure), the committee concludes that the effects of TCDD on respiratory cancer could last many decades.
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Representative terms from entire chapter: