Veterans and Agent Orange Length of Presumptive Period for Association Between Exposure and Respiratory Cancer (2004) / Chapter Skim
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2 Evaluation of Latent and Presumptive Periods
2 Evaluation of Latent and Presumptive Periods
Pages 14-39
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From page 14... ...
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 chemicals 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)
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From page 15... ...
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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From page 16... ...
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 "presumptive 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)
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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.
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From page 18... ...
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 account, the presumptive period must be the maximal interval between cessation of exposure and detection of disease ascribable to that exposure.
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From page 19... ...
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)
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From page 20... ...
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)
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From page 21... ...
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 carcinogenic properties of a chemical by a mechanistic approach (Barrett, 1993; Pitot, 1986)
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From page 22... ...
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.
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From page 23... ...
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 respiratory cancer. Most of the experimental data on respiratory cancer are for TCDD, not the herbicides themselves.
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. Any of those studies that are relevant to the presumptive or latent periods and respiratory cancer are discussed in Chapter 3 of this report.
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From page 25... ...
. Given the tumor-promoting potential of TCDD and the persistent nature of this chemical, it is possible that, as indicated above, a cancer could be detected either a short or long time after the external exposure to TCDD because promoting effects might occur at any time while the body burden of TCDD is high.
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From page 26... ...
Because of the potential for high correlations among time-related factors, changes in the magnitude of exposure over time are especially important in attempts to identify latent periods or presumptive periods because those periods are likely to be dose-dependent (Enterline and Henderson, 1973; Peto, 1985; Thomas, 1987)
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From page 27... ...
Cumulative-Exposure Model This method, which assumes that risks at various times since exposure have equal weight, estimates a single relative risk for the sum of protracted exposures by assuming that the total cumulative dose is the effective dose. Given the published evidence on latency and lung cancer, which suggests that risk starts at null, rises to a peak, and can then decline to null (Langholz et al., 1999)
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From page 28... ...
Because the exposures in adjacent time-window intervals are likely to be correlated, the estimated heights of the time-window specific relative-effect estimates can be statistically unstable, particularly when the time windows are narrow. Here, the time-window-specific relative-effect estimates can be interpreted as excess relative risks per unit dose received during the corresponding time window.
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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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From page 30... ...
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.
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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.
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From page 32... ...
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.
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From page 33... ...
and about factors known to be confounders 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.
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From page 34... ...
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)
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From page 35... ...
That is, the other exposures could be modifiers of the latent period or presumptive period. Whether smoking or other factors that contribute to respiratory carcinogenesis could modify the distribution of latent periods over which TCDD or herbicides used in Vietnam could cause respiratory cancer is unclear from the empirical evidence; much of the literature reviewed in Chapter 3 of this report regarding the carcinogenicity of TCDD, however, comes from studies in occupational settings or of the population exposed environmentally to TCDD after an industrial accident in Seveso, Italy (Bertazzi et al., 1989a,b)
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From page 36... ...
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 associated with respiratory cancer indicate presumptive periods of at least 20 years.
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1987. Use of multistage models to infer stage affected by carcinogenic expo sures: example of lung cancer and cigarette smoking.
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1991. Use of "time windows" to investigate lung cancer latency intervals at an Ontario steel plant.
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From page 39... ...
1990. The relationship of smoking cessation to coronary heart disease and lung cancer in the Multiple Risk Factor Intervention Trial (MRFIT)
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