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2 Evaluation of Latent and Presumptive Periods A s discussed in Chapter 1, the committee is charged with evaluating the presumptive period between exposure to the herbicides used in Vietnam and their contaminants on the one hand, and risk of respiratory cancer on the other, and with determining whether it is possible to identify a time after cessation of exposure to those compounds beyond which a presumption of ser- vice connection for respiratory cancer could not be warranted. Many issues must be taken into consideration in evaluating the period over which a disease can be presumed to be associated with a given exposure. This chapter discusses those issues. It begins by defining concepts of latent period and presumptive period and then discusses factors that can affect the latent period. A discussion of issues to consider in evaluating latent period and presumptive period in epidemiology studies and of statistical methods to use in their analysis follows. Finally, the chapter discusses the time course of respiratory cancer after exposure to chemi- cals known to be associated with it, and how coexposure to the chemicals might affect the presumptive period for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and respiratory cancer. LATENT PERIOD VS PRESUMPTIVE PERIOD When quantifying the relationship between a chemical exposure and a dis- ease, epidemiologists are interested in the rate of disease among exposed people (that is, people exposed to concentrations of the chemical greater than back- ground exposure) compared with the rate expected if people had not been ex- posed (that is, people exposed only to a background concentration). They are interested in either the relative rate or the excess rate of disease as the measure of 14

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 15 comparison. Because cancer can take a long time to develop (years or even decades), an analysis of the effects of an exposure must take into account the latent period, a complex concept that can be defined as the time between an exposure and the occurrence of disease related to it. Depending on the circum- stances, determining the length of the latent period can be simple or complex. The discussion below begins with a simple example of a latent period and progresses to complex examples. The latent period is simplest in the scenario illustrated in Figure 2-1a: an exposure occurs at a single time, and a disease has a relatively quick onset, as in a sudden outbreak of acute illness in a fixed population with common exposure to contaminated food, water, or air. For instance, if mayonnaise at the church picnic was contaminated with salmonellae and many picnickers became acutely ill with diarrhea and vomiting 13 days later, the latent period would be 13 days and would correspond to the incubation period (the time during which the microorganisms multiplied). As is evident from the range of days, the latent period can vary even in such simple cases. Factors that affect the length of latency--such as age, health status, and genetic susceptibility--are discussed later. Because of the variation of the latent period within an exposed popula- tion--which results in different "latencies" that depend on the various factors involved--epidemiologists usually express latency as a range of intervals be- tween exposure and disease onset. The latent period is more difficult to identify when an exposure occurs over an extended period, not at just one time. An example is cigarette-smoking. Expo- sure to smoke usually does not occur at a single time, but over many years. Therefore, it is difficult to know exactly when the exposure caused the cancer. Typically, the latent period is measured from the time of first exposure, that is, when a person began smoking. Evidence that early exposure is most important in determining the risk of respiratory cancer makes such a measurement of latency valid. But there is also evidence that duration of smoking contributes to overall risk, with increasing duration causing greater elevation in risk. To evaluate the period over which a disease can be presumed to be associ- ated with a given exposure, time since start of exposure and time since cessation of exposure need to be determined. For exposures of short duration, times since start and cessation of exposure are often easy to define; this situation holds for environmental exposures in industrial accidents, particularly if an exposure in- volves chemicals that do not remain in the environment or are quickly eliminated from the body. If the exposure is protracted, like the exposure of pesticide appliers who repeatedly apply pesticides or of production workers employed for months or years, time since exposure is more difficult to quantify because there may have been many individual incidents of exposure. It is also important to distinguish between cessation of external exposure and cessation of exposure of the target organs from persistent elevation of TCDD body burden. Some chemicals, including TCDD and many other chlorinated

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16 VETERANS AND AGENT ORANGE herbicides, are retained in some body tissues for a long time (even decades), so target organ exposure continues even after external exposure ceases. Even a brief external exposure, such as that which occurred in Seveso, Italy (Bertazzi et al., 1989a,b; 1997), can involve protracted exposure of many organs. This more- complex scenario is illustrated in Figure 2-1b. In that scenario, disease induc- tion, the point at which initiation of the disease occurs (note that the disease might not be apparent or detectable at this point), might even occur after external exposure ceases. Given the difficulty in establishing the true latent period in studies in which exposure is protracted, several surrogate measures of latency are often estimated. In epidemiologic studies, they can include the time between first exposure and the time of peak relative risks compared with those among the nonexposed, the time between cessation of exposure and the point when disease rates increase above those among the nonexposed, and the time after cessation of exposure when disease rates fall back to those among the nonexposed. It is the third interval that is of interest to this committee. The committee's charge is to assess the length of time after cessation of exposure beyond which respiratory cancer could no longer presumably have been caused by the exposure--the "presump- tive period" for respiratory cancer and exposure to TCDD. The relationship between exposure and chronic diseases can be viewed as a multistage process (see Figure 2-1c) (Checkoway et al., 1990). First, exposure of sufficient duration or intensity begins a disease process. The time between first exposure and the occurrence of the initial steps towards the disease (that is, disease induction) can be called the induction period; this is illustrated in Figure 2-1c as the time from A to B. The induction period can depend on the dose and on other cofactors, such as genetic susceptibility, overall health, and diet. Sec- ond, the manifestation of the disease process (when the disease is detected or observed, which could be when symptoms appear, or when subclinical tests indicate positive evidence of early disease) occurs some time after the induction period. The time between induction and disease manifestation (from B to D in Figure 2-1c) is the true, biologic latent period. In practice, however, it is difficult to distinguish the induction period from the latent period. Unless there is a pre- cursor lesion, which serves as a marker, the disease process usually has begun before the disease is manifest. Therefore, in epidemiologic studies, B (disease induction) in Figure 2-1c is not observed and is usually unknowable, and the entire period between first exposure and disease manifestation is often referred to as the latent period. Hence, in the remainder of this report, we will refer to this period, from first exposure to disease manifestation (the time from A to D in Figure 2-1c) as the latent period, and data shown in Chapter 3 have been based on this definition of latency. The period of concern to the Department of Veterans Affairs, referred to as the presumptive period, is the time from cessation of external exposure to dis- ease manifestation (from C1 to D in Figure 2-1c); termination of service in Viet-

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 17 a) External Exposure Latent Period Disease Detection A D Time b) External External Body Burden Disease Disease Exposure Exposure Reaches Induction Detection Begins Ends Background A B C1 C2 D Body Burden Time True Latent Period c) Induction Period Unrelated Exposure Presumptive Period External Disease External Disease Exposure Induction Exposure Detection Begins Ends A B C1 D True Latent Period FIGURE 2-1 Schematic time courses for exposure and manifestation of disease. a) Sim- ple model of single, acute exposure to chemical with short half-life in body and no accumulation. b) More complex model of accumulation of chemical in body. c) Model of onset of disease process (modified from Checkoway et al., 1990). Unrelated exposure refers to continued exposure that is not related to the induction of the disease. Although the figure depicts disease induction (B) as occurring prior to the end of external exposure, disease induction can occur at any point (during or after exposure) before disease detec- tion. Note that the latent period depicted in a) through c) is the true latent period, that is, the time from disease induction to disease detection. Typically that period is difficult to determine, therefore, the time between first exposure and the time of elevated relative risk is used as a surrogate measure for the true latent period in epidemiologic studies.

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18 VETERANS AND AGENT ORANGE nam is a surrogate for cessation of external exposure. Disease induction by a chemical (B in Figure 2-1c), however, may or may not precede cessation of exposure (C1 in Figure 2-1c). It is possible that B, the effective exposure, could occur at any point during the external exposure (time A to C1 in Figure 2-1c) or at any point after the end of the external exposure at which the body burden is still above background concentration (between C1 and C2 in Figure 2-1b). If the manifestation of disease is contingent on exposures incurred near the end of the exposure period, the induction period might not end until some time after expo- sure ends. It should also be noted that the period from B (disease induction) to D (disease manifestation) is influenced by many factors besides the biology of the disease or the aggressiveness of tumor development, such as access to care, quality of screening, health-care use, comorbidity, and tolerance of symptoms. The period from B to D can also depend on the exposure that initiated the disease process; for instance, the characteristics of the exposure can affect progression of a tumor or the speed at which cells proliferate. In the case of TCDD, addi- tional exposure may affect tumor growth and hence latency. Finally, in light of the persistence indicated by the long half-life of TCDD, it is necessary to visual- ize the various periods with the more complex exposure scenario presented in Figure 2-1b, where point C1 represents the end of external exposure, but the period from C1 to C2 represents the time it takes until exposure declines to that among the general population (who did not receive the high exposure from A to C1). During the period from C1 to C2, the body burden remains high, and expo- sures of organs may contribute to any stage in the disease process. Thus, point B may actually occur around the time of C2. The preceding paragraphs have discussed latency as it may occur in a single individual. Earlier in this chapter, it was pointed out that latency in a population is a range representing the latencies in all the individuals. The range occurs because of variability in the induction period and in the interval from disease induction to diagnosis. When exposure is protracted, the exposures that are rel- evant to disease in a particular person are generally unknown, and this adds uncertainty to variability. These phenomena apply to the period between cessa- tion of exposure (whether external or from elevated body burdens) and disease detection. To ensure that any veteran who develops respiratory cancer that could be ascribed to exposures incurred during service in Vietnam is taken into ac- count, the presumptive period must be the maximal interval between cessation of exposure and detection of disease ascribable to that exposure. FACTORS THAT AFFECT TIME COURSE OF DISEASE Chemical Persistence and Duration of Exposure Previous Veterans and Agent Orange (VAO) reports have concluded that there is "limited/suggestive" evidence of an association between respiratory can-

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 19 cer and exposure to Agent Orange. Epidemiologic studies suggest that risk is related to dose. In this report, the committee evaluates whether there is evidence of a presumptive period after which risk has decreased to the level among those with background exposure. It is also important to determine how that presump- tive period might be related to exposure history and to the dose to which the respiratory system is exposed. To assess the relationship between body burden and the presumptive period, it is important to know the initial exposure and the initial internal concentration, the course of exposure over time, the duration of exposure, the persistence of the chemical, and, on the basis of those, the cumulative body burden at any time. The routes and rates of uptake, tissue distribution, and transformation of a toxi- cant, and its elimination from the body determine the amounts of a particular chemical that potentially reach and persist in organs or cells, thereby influencing the toxicity and the frequency of genetic changes or nongenetic carcinogenic events in those organs or cells. The known toxicokinetic behavior of a chemical of interest is central in reconstructing exposure history. On the basis of the literature reviewed in the Veterans and Agent Orange series, the chemical in herbicides sprayed in Vietnam that is of greatest concern with respect to respiratory cancer is TCDD (IOM, 2003). The distribution of TCDD and other chlorodibenzo-p-dioxin congeners has been examined exten- sively in animal models and to a smaller extent in humans throughout the last 2 decades. The toxicokinetic behavior of TCDD has been discussed in greater detail in VAO and updates up to the most recent, Update 2002 (IOM, 2003). As summarized in Update 2002, TCDD is distributed to all compartments of the body, although the distribution is not uniform and the proportions accumulated differ from organ to organ. Properties of the chemical, properties of the organs and cells, and the route of exposure affect partitioning, absorption, and accumu- lation. The concentration of chemical in a given organ or tissue depends on the dose to which one is exposed and on the absorption, lipid content, and metabo- lism in the organ of concern. In addition, accumulation in one organ can be influenced by processes in other organs. TCDD is a highly hydrophobic chemical that, like other hydrophobic chemi- cals, readily crosses cell membranes and accumulates in lipid-rich organs. Lipid content is a major factor in the accumulation of TCDD in different organs and in the body as a whole. Biologic processes, especially metabolism, are less well characterized for humans than for animals. It is clear, however, that chemical stored or sequestered internally will be mobilized to maintain an equilibrium between the blood and lipid-rich organs, constituting a source of the chemical for other organs. Target organ exposure to a chemical may persist long after increased exposure from external sources has ceased. At any given time, the combination of tissue concentrations and blood concentrations represents the body burden. In practice, blood concentrations are used as a surrogate for body burden, particularly for quantifying TCDD, for which blood concentrations are

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20 VETERANS AND AGENT ORANGE standardized to lipid concentrations. Blood concentrations over time determine the cumulative exposure of organs, including the lung. Estimates of the half-life of TCDD in humans have been derived from long- term studies of blood concentrations in Vietnam veterans and other exposed populations. Studies have consistently confirmed that TCDD is highly persistent in the body, with a half-life in humans averaging about 7.5 years. However, as discussed in Update 2002, recent data now indicate that elimination of TCDD is biphasic; a faster phase occurs very early, and the curve of this elimination may be much steeper in people who are highly exposed. Variation in half-life has been demonstrated to be associated with a number of variables, including body- mass index (BMI), weight, initial dose, time after exposure, and age (IOM, 2003). Differing half-lives of the biphasic elimination of TCDD might complicate the back-extrapolation from serum measurements to body burden after initial expo- sure but might not greatly affect the determination of cumulative dose resulting from persistence or continuing exposure. Determination of cumulative dose re- quires multiple body-burden measurements. The timing of those measurements combined with the nonlinearity in elimination could cause errors in extrapolation to initial peaks (times when exposures were highest) and hence affect the esti- mate of cumulative dose. As outlined above, because TCDD and chlorinated herbicides are retained in some body tissues for a long time (such as decades), target organ exposure continues after external exposure ceases. Thus, even an acute external exposure can result in protracted exposure throughout the body. One can think epidemio- logically of the effect of exposure in the past as the change in risk today that is ascribable to prolonged exposure of target organs; tissue concentrations may decline slowly, and blood concentrations may be maintained over time by redis- tribution from one or more storage sites. Determining at what point a past exposure no longer influences disease induction, or what might be considered the period during which an exposure could be presumed to be associated with a disease requires knowledge of both the beginning and the end of the exposure. In the case of chemicals that are rapidly eliminated from the body, it is reasonable to assume that exposure ends with the termination of contact (for example, the end of a work shift for occupa- tional exposures). In the case of TCDD, as with any chemical that can be stored in the body, a person's exposure can be said to continue as the chemical is released from compartments in the body where it is stored. This continuing elevation in body burden increases the overall duration of exposure of the target organs until the body burden, measured as serum concentration, declines to the background value, that is, until it is indistinguishable from the concentrations in populations that have not had an unusual external exposure. Although external exposure to herbicides in Vietnam had a finite duration, the presumptive period (i.e., the interval between external exposure cessation and disease detection) for respiratory cancer due to increased TCDD concentra-

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 21 tion after service in Vietnam will be extended by virtue of the prolonged eleva- tion in the body burden of TCDD as reflected in the serum concentration. Fol- lowing that logic, "last exposure" or "end of exposure" would not occur until serum TCDD in Vietnam veterans reaches the background value (C2 in Figure 2-1b). It is also known that loss of weight or body fat, whether intentional or through inanition or cachexia, releases stores of TCDD from adipose tissue. For those reasons, serum concentration at any given time, although correlated with persistent exposure from body burden and external sources combined, does not necessarily reflect the pattern of concentrations through time; consequently, a single measurement cannot reflect overall dose over time, which might be the relevant measurement for risk assessment related to the persistent TCDD. Mechanism of Carcinogenicity The multistage carcinogenesis model is often used to evaluate the carcino- genic properties of a chemical by a mechanistic approach (Barrett, 1993; Pitot, 1986). According to that model, a chemical might initiate, promote, or alter the progression of a neoplasm. A chemical that initiates the neoplastic process might do so in a single exposure. Initiation involves a heritable change in the genome of a normal cell whereby it becomes an "initiated" cell. Chemicals that promote the clonal expansion of initiated cells into a histologically visible population are defined as promoters. Promotion might require multiple exposures for a given duration. Often, the first end product of tumor promotion is a benign cellular lesion that is reversible. In progression, initiated cells undergo further changes and expansion into a tissue mass that may progress irreversibly to malignancy. Some chemicals may act specifically in the progression phase of carcinogenesis (Barrett and Wiseman, 1987). For example, an animal can be treated with a chemical that induces initiated cells in the mammary gland; later exposure to another chemical may promote development, clonal expansion, and progression of those cells into a cancer. Multistage models have also been used in experi- mental animals for the development of pulmonary cancers; such models use N- nitrosodimethylamine or urethan as initiators of the tumors (Beebe et al., 1995; Blakley et al., 1992). Multistage models of carcinogenesis recognize that alterations of multiple independent genes (either by direct or epigenetic actions) are involved in the carcinogenic process (Barrett, 1993). The altered expression of proto-oncogenes can result in positive proliferative signals, and the modulation of tumor- suppressor genes can block the neoplastic growth of cells (Boyd and Barrett, 1991). Chemicals can influence the gene expression of important regulators of clonal expansion and cell proliferation that affect not only induction of neopla- sia but also time to full tumor development. Latent periods for different chemicals depend on differences in the mecha- nisms by which the chemicals act, that is, on their contribution to the initiation

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22 VETERANS AND AGENT ORANGE and promotion phase. They also vary within a population because of individual differences in the biochemical pathways (some of which are induced by such chemicals as TCDD) that regulate the kinetics and metabolism of the chemicals and in the stages of the carcinogenic process at which exposure occurs. Carcino- genic chemicals that are relatively persistent in the body may initiate or promote the carcinogenic process over a long period. In such cases, latency can vary and may be short or long from the time of initial exposure. For example, substantial individual differences in latency might be observed for persistent tumor promot- ers, such as TCDD, depending on the time of the exposure relative to the time of exposure to the initiating chemicals or events (for example, mutations). For chemicals with relatively short half-lives, such as 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), initiation or promotion might be expected to occur only during a very short period when the body burden is high. As mentioned earlier, however, the latent period may also be affected by individual differences in biochemical and biologic pathways that affect the carcinogenic process. Such differences generally are based on genetic polymorphisms that affect the function or expression of proto-oncogenes and tumor-suppressor genes or affect biochemical pathways that regulate cellular differentiation and proliferation, including signaling processes that regulate the cell cycle. The relative expression of those pathways is also likely to be tissue- specific. Furthermore, the relative activities of processes that repair mutated DNA and of processes, such as immune surveillance mechanisms, that are responsible for removal of cancerous cells may vary individually and affect not only the ability to develop a tumor but the latent period. Such processes may be consider- ably less efficient in older people or in people who have compromised health status and potentially can lead to shorter average latent periods. Metabolism of a chemical may affect the carcinogenic process, as well as the latent period for tumor development. If a chemical requires metabolism to an active intermediate for initiation of a tumorigenic process, tissue-, cell-, and age- specific characteristics of its metabolism may determine the relative amounts of active carcinogen present. That may be more important for chemicals to which there is protracted exposure or that are persistent. In such cases, changes in metabolic processes that occur with changes in health status, coexposure to other chemicals (such as therapeutic drugs or chemicals in cigarette smoke), and aging could affect the amount of the active metabolite produced at any particular time during the exposure period and alter the apparent timing of disease induction or detection. The amounts of carcinogenic metabolites of most chemicals usually depend on dose. At low doses, metabolism by metabolizing enzymes may effi- ciently limit the accumulation of carcinogenic metabolites; at higher doses, meta- bolic processes may be overwhelmed and this can result in a greater abundance of active metabolites. Such properties may be responsible for suggestions that dose-response relationships for many carcinogens are nonlinear and have thresh-

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 23 olds. If clearance of active compounds is also affected, apparent latency might be altered. CARCINOGENICITY OF TCDD Research has been conducted with the herbicides sprayed in Vietnam and with TCDD to investigate the mechanisms by which they might induce respira- tory cancer. Most of the experimental data on respiratory cancer are for TCDD, not the herbicides themselves. Therefore, TCDD is the focus of this discussion, however, herbicides are also discussed below. Development of cancer in experimental animals usually depends on the dose of and duration of exposure to a chemical. Cancers can develop during the expo- sure period (for example, during the 2 years of dosing in lifetime-exposure stud- ies in rodents) or at some distant time (latency) after a non-lifetime-exposure regimen. To determine whether a chemical is carcinogenic, under some proto- cols laboratory rodents are exposed to incremental doses of a chemical for a lifetime and monitored for the development of cancer. To assess latency, animals are exposed to a carcinogen for a defined duration and then observed for the rest of their life. TCDD is a known carcinogen in rats and mice and is considered to be a carcinogen in humans. There is no evidence to indicate that TCDD is genotoxic. All the available evidence indicates that it acts as a promoter through multiple pathways in the regulation of cell proliferation and differentiation.1 In addition, TCDD is known to alter the relative levels of enzymes that metabolize other chemicals to genotoxic metabolites. Liver tumors have been consistently ob- served in animals after TCDD treatment, and increases in skin cancer, lung can- cer, and thyroid and adrenal cancers have been seen in some studies. Decreases in uterine, pancreatic, pituitary, mammary, and adrenal cancers have also been seen, but most of these decreases occurred only at high doses and were associ- ated with decreases in body-weight gain; the decrease in mammary tumors was seen in only one study (see IOM, 2003 for review). TCDD has been assessed for tumor-promoting activity in a mouse-lung model. Lung tumors were statistically significantly increased in mice initiated with N-nitrosodimethylamine (NDMA) when promoted with low doses of TCDD (Beebe et al., 1995), but not higher doses, which may have caused pulmonary toxicity. The study lasted 52 weeks. It was suggested that the TCDD-elicited induction of cytochrome P4501A1 in the same model system is correlated with and possibly causally involved in the promotion of tumors (Anderson et al., 1The term "initiator" and "promoter" are used in this report to describe the observed behavior of agents in the classical two-stage carcinogenesis model. The committee notes, however, that TCDD can be carcinogenic in rats in the absence of other known exposures (Kociba et al., 1978).

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24 VETERANS AND AGENT ORANGE 1991). In another study with the NDMA model, it was determined that TCDD might promote tumors by contributing to the down-regulation of the K-ras proto- oncogene and the stimulation of raf-1 (Ramakrishna et al., 2002). Lung lesions were evaluated in rats treated with TCDD for 14, 30, or 60 weeks (Tritscher et al., 2000); a statistically significant increase in alveolar-bronchiolar metaplasia was observed in the rats treated for 60 weeks but not in those treated for 30 weeks and observed for another 30 weeks, and this suggested that the develop- ment of lesions in this model system required the longer duration of exposure or perhaps a higher cumulative exposure to TCDD. Despite extensive research in this area, the mechanism underlying TCDD's carcinogenicity remains unknown. Although TCDD is the main chemical of interest for respiratory cancer, it is important to consider the herbicides used in Vietnam and their possible role in respiratory cancer. Cacodylic acid was present in an herbicide used in Vietnam. Cacodylic acid is dimethylarsinic acid (DMA), which is also a metabolite of inorganic arsenic in humans. As discussed elsewhere (see US EPA, 2004), inor- ganic arsenic has been associated with lung cancer and other cancers in occupa- tional settings and in studies of individuals exposed to elevated arsenic in drink- ing water (NRC, 2001), and is classified as "known to be a human carcinogen" by the National Toxicology Program (NTP, 2002). Inorganic arsenic has not been shown to be able to induce tumors in laboratory animals, but exposure of rodents to high concentrations of DMA increased bladder tumors in male Fischer 344 rats (Wei et al., 1999) and pulomary tumors in A/J mice (Hayashi et al., 1998). DMA has also been shown to promote urinary, bladder, kidney, liver, and thyroid tumors in rats and lung tumors in mice (see Kenyon and Hughes, 2001 for review). In a recent study, however, pulmonary neoplasms did not develop in rats exposed to DMA at up to 200 ppm in drinking water for 104 weeks (Wei et al., 2002). Therefore, DMA does not appear to be a potent pulmonary carcinogen in those strains of rats and mice. Furthermore, the mechanism of DMA-induced neoplasia is unknown. Finally, although DMA is formed in humans after expo- sure to inorganic arsenic, it has not been established and cannot be inferred that the effects seen after that exposure occur after exposure to cacodylic acid. Epidemiology studies of agricultural workers and chemical-industry work- ers exposed occupationally to those chemicals have been conducted, but it is difficult in many of those studies to determine which chemical (e.g., 2,4-D, 2,4,5-T or its contaminant TCDD, or other pesticides or chemicals) underlies any effects seen. Those studies are discussed in the Veterans and Agent Orange reports (see IOM, 2003). Any of those studies that are relevant to the presump- tive or latent periods and respiratory cancer are discussed in Chapter 3 of this report. There is no strong evidence of tumorigenic potential of 2,4-D, 2,4,5-T, or picloram in laboratory animals or cell-system assays (see IOM, 2001;2003, for reviews). As discussed in VAO (IOM, 1994) and reviewed in Update 2002 (IOM, 2003), three studies have looked at the carcinogenicity of picloram, of which two were negative and one had equivocal results for which a contaminant

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 29 Exponential-Decay Model This method is a variant of the bilinear model discussed above. The impor- tant difference is that it fits a straight-line latency-weight function up to the inflection point but fits an exponential decay curve afterward. The method al- lows for the fact that the exposure agent of interest (such as TCDD) may be retained in the body and slowly released internally. In such scenarios, the expo- nential decay curve is affected by the number of years required for the effect to be reduced by one-half, the so-called half-life (Langholz et al., 1999). Spline-Based Model This method fits piecewise polynomials within a series of time-window intervals and then smoothly joins the piecewise curves by putting appropriate continuity constraints on the estimation process. The resulting latency curve is called a spline. Hauptmann et al. (2000) discuss the details of the method. It has also been applied to the Colorado Plateau uranium-miner data on radon expo- sures (Hauptmann et al., 2001). Mechanistic Models Unlike the various empirical models discussed above, mechanistically based statistical models assess latency under an assumed theory of carcinogenesis, such as the Armitage-Doll multistage model (Armitage and Doll, 1961) or the Moolgavkar-Knudsen two-stage model (Moolgavkar and Venzon, 1979). If the assumed model of carcinogenesis is correct, mechanistic models provide a pow- erful means for dealing with exposure-time-response relationships. Implications of Model Choice Methods for addressing how long it takes to detect an increase in disease risk after exposure and how long the effects of exposure last are discussed below. Time After Exposure to Detect Increase in Disease Risk To determine how long it takes after an exposure (either initial exposure or cessation of exposure) to detect an increase in disease (that is, latency), one must examine the pattern of relative risk over time, looking for the earliest detection of an increase in risk in an exposed population relative to a nonexposed compari- son group. For protracted exposure, it is customary to examine relative risk by time since first exposure because the earliest detectable increase in relative risk may be a manifestation of the earliest exposure. In fact, relative risk related to

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30 VETERANS AND AGENT ORANGE specific times since first exposure is often the only measure of latency reported in studies of protracted exposure to herbicides. The critical data items required are the date of first exposure of each subject and the dates of diagnosis of relevant outcomes. With that information, an inves- tigator can determine the contribution of each subject's time-since-first-exposure to the latent period for the study population. If full exposure histories are avail- able, more sophisticated analyses are possible; to account adequately for dose and duration, a full exposure history is needed. With that information, an investi- gator can determine the contribution from each subject in each exposure cat- egory. Several studies provide excellent examples of how a full exposure his- tory, based on employment histories or some combination of external or internal measurements, can be used in a detailed analysis of latency and other time- related factors. One such study is the Colorado Plateau uranium-miner cohort described and analyzed in detail by Langholz et al. (1999). In that study, bilinear and exponential decay models of latency are evaluated, as well as how to fit those models to various types of data. Duration of Effects of Exposure Relative risk related to specific intervals of time since last exposure are used to address the question of how long the effect of an exposure lasts. The pattern of relative risk is examined for the latest indication that the relative risk is greater than 1. The critical data items required for addressing the question are the dates of each start and stop of exposure and the intensity of exposure. Those are needed to classify subjects' time spent in each time-since-first-exposure category. Again, if full exposure histories are available, more sophisticated analyses (for example, time-windows analyses) are possible. However, if the critical issue is time since last exposure, multiple starts and stops present greater complexity in assignment of dose. Data on last exposure before an event are used to determine how long an effect can persist. Comparison of Methods In addressing how long it takes after an exposure to detect an increase in disease risk, the earliest indication of an increase in relative risk is difficult to measure and will be refined as more data are collected. Latent period varies among individuals, so risk in a population changes continuously rather than suddenly jumping from "normal" to "above normal". The simpler stratified and piecewise-constant models may not be able to depict that reality. In contrast, the bilinear and spline-based models allow greater flexibility in accounting for the continuity in the latency-weight function and may yield a more realistic picture of the underlying exposure-time-response relationship.

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 31 Mechanistic models constitute a more structured way of handling the under- lying process and could be informative if the presumed model of carcinogenesis is reasonable. Actual changes in relative risk probably would occur earlier than indicated by the analysis; but because of limitations in study designs, such changes might not be detectable. In other words, the degree to which an in- creased risk is statistically detectable depends on the size of the particular dataset, on the magnitude of the background risk (which in turn depends on the age distribution of study subjects), and on the magnitude of the increase in risk (which in turn depends on exposure, variation in susceptibility, length of follow- up, and distribution of latent periods among the exposed population). It should be noted that if the latent periods are highly variable among individuals, analysis by time since first exposure may be insensitive because an increase in risk will appear slight and occur gradually. In addition, if the effect of time since first exposure is modified by intensity of exposure or age at exposure, these other factors would have to be accounted for in the analysis. For example, latency might be longer after a small exposure than after a larger one, in which case a study that examined only time since first exposure might encounter greater vari- ability in latency and hence have less ability to assess how long it takes to observe an effect of exposure. Such effect modification would also limit the degree to which results of one study can be generalized to a different population or to another exposure scenario. If exposure is protracted, time since last exposure must be analyzed in the proper time-dependent fashion to address how long the effect of an exposure lasts (Clayton and Hills, 1993). Adjustment for age is also necessary. To achieve adequate power and precision, a study must use a sufficient number of subjects with a long period since cessation of exposure. If exposure has been protracted, much longer follow-up is needed to determine the presumptive period than the latent period. Latency and Interpretation of Epidemiologic Literature Measurement Error Measurement error in assignment of exposure or timing of exposure could increase observed variation in latent period or presumptive period. If extended elevation of body burden after external exposure ceases was not explicitly taken into account in the analysis, the resulting error would be considered an error in measurement. Mortality and Incidence Studies for Examining Latency A chemical with carcinogenic activity may increase the chance of cancer, or it may accelerate development of cancer so that it occurs at an earlier age than it

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32 VETERANS AND AGENT ORANGE otherwise would have. The agent may also influence the likelihood that a cancer will result in death, or it may shorten the time between occurrence of the cancer and death caused by it. Which of those processes occurs may depend not only on the agent but also on the site of cancer. For example, lung cancer tends to be fatal in a very high percentage of cases, and death usually comes swiftly. For lung cancer, therefore, a study of mortality is unlikely to provide different results from a study of incidence. In a contrasting example, prostate cancer is fatal in a fairly small proportion of cases; incidence is 5 times higher, or more, than mor- tality (Merrill and Brawley, 1997). Therefore, a study of prostate cancer mortal- ity would be less likely to detect the effect of a carcinogenic agent than would a study of prostate cancer incidence, unless the agent increased the severity of disease. But because prostate cancer is so common and occurs with increasing frequency as men age, any study of prostate cancer incidence should examine whether those exposed to the agent of interest develop the cancer at an earlier age than those not exposed. That type of analysis could be accomplished by using age-specific rates. Caution would have to be exercised in interpreting inci- dence studies because of the recent introduction of prostate-specific-antigen (PSA), a marker for prostate tumors that are not clinically detectable, as a screen- ing tool. Differences among populations in the extent to which PSA is used could confound results (Gann, 1997). In the investigation of cancer latency, changes in relative risk with time since exposure will occur later in mortality studies than in incidence studies by an amount approximately equal to the average time from cancer occurrence to death. Given the short survival of lung cancer patients, it is likely that the pattern with time since exposure will be similar in a mortality study, but the latent period will be longer than an incidence study. The same would be true of the presumptive period. As a result, at any given point in the follow-up period, a mortality study will record fewer events than a study of incidence and so will have lower statistical power even if the exposed and nonexposed cases have the same prognosis. Similarly, if there is a substantial group in the population that is genetically susceptible to the effects of a carcinogen or has an acquired state of susceptibil- ity, there may be a phenomenon similar to "exhaustion of susceptibles", which is more commonly observed in infectious disease. In an infectious-disease out- break, people lacking immunity or natural resistance develop the disease; when this pool of susceptible people is exhausted, the incidence in the population declines, perpetuated only by outbreaks among new entrants. In a chronic dis- ease, such as cancer, there may be a pool of susceptible people who, when challenged by exposure to a carcinogen, get cancer at an earlier age than they would otherwise, and that can cause an apparent decline in incidence in the older age groups. However, one would expect conspicuous excess mortality in the younger groups for this effect to explain a later dip in incidence. A further consideration is competing mortality. When people who are at risk

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 33 for a cancer die earlier than they otherwise might, they are not available for causes of death later. If the diseases are linked by an exposure, one disease may "hide" the other. For example, a person who smokes heavily may develop lung cancer or chronic obstructive lung disease. The two are related, and there is evidence that a common trait of individual susceptibly plays a role in both. A person who develops lung cancer, which is usually fatal, is not available later in life to develop chronic obstructive pulmonary disease, which is less often fatal in younger people. The sparseness of empirical data available on Vietnam veterans makes it difficult to ascertain whether those complicated effects are occurring. Most of the relevant epidemiologic data for TCDD and herbicides reviewed to date have used the simplest models based on time since exposure. LATENCY AND RESPIRATORY CANCER As discussed in Update 1998 (IOM, 1999), a substantial body of literature explores issues of timing of exposure and respiratory cancer, especially for some agents whose carcinogenic properties in the respiratory system are well studied. This section discusses briefly what is known about the latent period and pre- sumptive period of well-studied respiratory carcinogens (gamma rays, radon daughters, smoking, arsenic, and asbestos) and about factors known to be con- founders and effect modifiers for respiratory cancer. Time Course for Respiratory Carcinogens Other Than TCDD In an investigation of latency issues in radiation exposure of atomic-bomb survivors, it was found that the relative risk of lung cancer began to rise 510 years after exposure and reached a plateau about 15 years after exposure to gamma rays. Thirty years after exposure, there was no evidence of a decrease in relative risk (Land, 1987). In addition, the effects of age at exposure are quite pronounced for some sites, such as leukemia, digestive cancers, and breast can- cer (NAS, 1990). In miners exposed to radon daughters (radon decay products), the relative risk of lung cancer was seen to peak 510 years after first exposure and then to decline slowly, although the risk appears to be increased even 30 years after exposure (Lubin et al., 1994; Thomas et al., 1994). In addition, the effect of exposure varies with age at exposure: a given exposure results in a lower relative risk in older workers than in younger workers. Langholz et al. (1999) analyzed data on Colorado Plateau miners exposed to radon and concluded that the risk returns to the background value after 34 years. Hazelton et al. (2001) analyzed data from a historical cohort of Chinese tin miners, investigating the contribu- tions of arsenic, radon, cigarette smoke, and pipe smoke to lung cancer risk. With respect to radon, their analyses indicate that the hazard posed by radon

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34 VETERANS AND AGENT ORANGE increases sharply 45 years after first exposure and does not appear to decrease with increasing time since last exposure. Analyses of lung cancer indicate that the relative risk posed by smoking begins to rise substantially about 20 years after the initiation of cigarette- smoking. Among ex-smokers, the relative risk declines to about half that of smokers by 12 years after cessation but then remains fairly constant--and higher than in those who never smoked (IOM, 2001). Analyses by Ockene et al. (1990) indicate that it takes as long as 20 years for the benefit of cessation of smoking (a decrease in risk of lung cancer) to be seen. Burns (2000) found that the risk of lung cancer remains increased up to 20 years after cessation of smoking, and Ebbert et al. (2003) found no decrease in risk 30 years after cessation. The analyses for smoking by Hazelton et al. (2001) of the Chinese tin miners show risk remaining increased for at least 30 years. In a cohort of workers exposed to arsenic from a copper smelter in Montana, relative risk of lung cancer was observed to increase with time after exposure, reaching a maximum 1520 years after first exposure, after which it slowly declined (Breslow and Day, 1987). There was little change in relative risk with age at first exposure. Brown and Chu (1983, 1987) observed a stronger effect of time since last exposure than of time since first exposure, although a model with both gave an excellent fit. The statistical models of arsenic exposure in Chinese tin miners were very similar to those of radon exposure, with a sharp rise in hazard 45 years after first exposure and no apparent drop in risk more than 50 years after last exposure (Hazelton et al., 2001). In a cohort of workers exposed briefly to high concentrations of asbestos during World War II, the relative risk of lung cancer rose sharply 510 years after exposure, after which it remained constant up to 40 years after exposure (US EPA, 1986). Relative risk was independent of age at exposure. More recent data on asbestos confirm that the risk of lung cancer after asbestos exposure remains increased for many years, although the risk decreased to less than one- half of the peak 20 years after cessation of exposure (Hauptmann et al., 2002). Thus, after some exposures, relative risks reached a plateau or peaked within 510 years; but after most exposures, it took at least 20 years after exposure began for relative risks to peak. In addition, most of the data on those exposures indicate that risks remain increased for many decades after cessation. Data on some of the better-studied lung carcinogens indicate that lung cancer might be attributable to exposure to them for 20, 30, 40, or even more than 50 years after exposure has ended. Potential for Confounding and Effect Modification In any person, multiple factors can contribute to or cause respiratory can- cer. Those factors can include genes that confer a predisposition to cancer, age, and various exogenous factors, such as diet, smoking, and other environmental

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EVALUATION OF LATENT AND PRESUMPTIVE PERIODS 35 chemical or physical agents. Substances known to be associated with lung can- cer are nickel, chromium, arsenic, cadmium, polycyclic aromatic hydrocarbons, radon, gamma rays, and asbestos. There is great concern with smoking in con- nection with lung cancer, but it is important to remember that although it is estimated that about 90% of lung cancers in males are the result of smoking tobacco (ACS, 2003), only 10% of smokers will ever develop this cancer. Thus, smoking is not deterministic, and other factors clearly play a role in increasing the risk of cancer. In estimating the risk of respiratory cancer associated with exposure to a given agent, ideally the extent of exposure to those other agents associated with respiratory cancer would be known. If any other such agents are associated with exposure to the herbicides used in Vietnam, they could confound the relationship with respiratory cancer unless adjusted for in statistical analysis. If such con- founding exists, the risk of respiratory cancer associated with exposure to the herbicides or TCDD might be over- or under-estimated. The most pertinent question for this report, however, is whether other respi- ratory carcinogens might affect the duration of latent periods and presumptive periods and, if so, how. Specifically, what is the effect of coexposures on the longest latency to be expected from TCDD? A cofactor, such as smoking, could have a different distribution of latencies; as a result, the apparent distribution of latencies associated with the exposure of interest would be distorted (it could be shorter or longer on the average, and it could show more or less variability). In addition, if the exposure to the cofactor was shorter or longer than the exposure to the main agent of interest, further distortion in the observed latent periods could take place. To evaluate the length of time that a respiratory cancer might be presumed to be associated with exposure, it is necessary to address how coexposures might alter the presumptive period. If other factors alter the rate of cellular processes that affect carcinogenesis (apoptosis, cellular transformation, etc.) or alter the internal doses of herbicides or their contaminants (lengthening or shortening half-lives, blocking absorption), then latent periods or presumptive periods could be shortened or lengthened according to the extent of exposure to the co-factor and the strength of its association with either carcinogenesis or dose modifica- tion. That is, the other exposures could be modifiers of the latent period or presumptive period. Whether smoking or other factors that contribute to respiratory carcinogen- esis could modify the distribution of latent periods over which TCDD or herbi- cides used in Vietnam could cause respiratory cancer is unclear from the empiri- cal evidence; much of the literature reviewed in Chapter 3 of this report regarding the carcinogenicity of TCDD, however, comes from studies in occupational set- tings or of the population exposed environmentally to TCDD after an industrial accident in Seveso, Italy (Bertazzi et al., 1989a,b). It should also be recognized that the observed latent or presumptive periods

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36 VETERANS AND AGENT ORANGE could be confounded. For instance, if people exposed to TCDD at the highest levels or for the longest time were also more highly exposed to cigarette smoke or other environmental agents, some of the earliest or latest effects could be mostly or wholly attributable to the other exposures. Since the specific causes of individual cases of disease are not easily identified, confounding of this type would be exceedingly difficult to assess. To address the question of how coexposures alter the latent period and presumptive period, smoking data would be needed, in addition to detailed exposure histories. However, many studies of TCDD that are the most useful for examining the time between exposure and respiratory cancer appear not to include individual-level smoking data in their analyses. Therefore, the possibil- ity that smoking could alter the presumptive period must be considered. Studies that conduct analyses of presumptive periods stratified by smoking status are needed to address that issue. SUMMARY AND CONCLUSIONS Of the chemicals sprayed in Vietnam, TCDD is of greatest concern for the development of respiratory cancer. In evaluating the time course between expo- sure to TCDD and respiratory cancer, it is important to differentiate between the true latent period (time from the induction of disease 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). The presumptive period can be affected by the duration of exposure and the mechanism of carcinogenicity. The effects of chemicals that act early in the carcinogenic process (initiators) generally end earlier than the effects of chemi- cals that act later in the carcinogenic process (promoters or tumor-progression factors). Evidence indicates that TCDD is not an initiator but has tumor- promoting activity. Target organ exposure due to release of chemicals from stores in the body must be taken into account in considering the duration of exposure to chemicals, such as TCDD, that are not rapidly eliminated from the body. A number of statistical methods are available to assist in the analysis of the temporal relation between exposure and disease. If mechanistic data are available, models that incorporate them can be informative. In general, data on chemicals other than TCDD that are known to be associ- ated with respiratory cancer indicate presumptive periods of at least 20 years. In some studies, the risk of respiratory cancer had not dropped to background val- ues even 50 years after cessation of exposure. It is possible that exposure to chemicals other than TCDD, such as by smoking, could modify the length of the presumptive period for TCDD and respiratory cancer, but there are no data on what any such modification might be.

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