Abstract
Sources of time-variant exposure to toxic substances are identified and examined for their effects on the estimation of response. It is shown that only time-averaged target tissue concentrations are required to obtain rigorous risk estimates from the one-hit and multihit models. In contrast, detailed concentration histories need to be retained throughout analyses involving two-event models with intermediate-stage clonal growth advantage (clonal two-stage) and multistage models. Cumulative incidence ratios, based on the exact to time-averaged treatment of concentration time dependencies, are evaluated for substances whose toxic responses exhibit moderate (arsenic) and strong (ethylene dibromide) dependence on time of actual exposure. These ratios reveal that time-averaged dose approximations may lead to several orders of magnitude error in both the multistage and clonal two-stage models if exposure periods are short, and that 3.4-fold (arsenic) and 8-fold (ethylene dibromide) errors still exist even when an actual two-thirds lifetime exposure is averaged over a full lifetime. Finally, the effects of time-variant exposure on risk estimation due to migration and birth-death in an epidemiological setting are examined. A residence time distribution calculation shows that, if these effects are ignored for a population orally exposed to arsenic and characterized by an out-migration rate in excess of 5%/yr, response errors will exceed an order of magnitude.
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- ARMITAGE P., DOLL R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer. 1957 Jun;11(2):161–169. doi: 10.1038/bjc.1957.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- ARMITAGE P., DOLL R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br J Cancer. 1954 Mar;8(1):1–12. doi: 10.1038/bjc.1954.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Day N. E., Brown C. C. Multistage models and primary prevention of cancer. J Natl Cancer Inst. 1980 Apr;64(4):977–989. [PubMed] [Google Scholar]
- FISHER J. C. Multiple-mutation theory of carcinogenesis. Nature. 1958 Mar 1;181(4609):651–652. doi: 10.1038/181651b0. [DOI] [PubMed] [Google Scholar]
- Hartley H. O., Sielken R. L., Jr Estimation of "safe doses" in carcinogenic experiments. Biometrics. 1977 Mar;33(1):1–30. [PubMed] [Google Scholar]
- Lutz R. J., Dedrick R. L., Tuey D., Sipes I. G., Anderson M. W., Matthews H. B. Comparison of the pharmacokinetics of several polychlorinated biphenyls in mouse, rat, dog, and monkey by means of a physiological pharmacokinetic model. Drug Metab Dispos. 1984 Sep-Oct;12(5):527–535. [PubMed] [Google Scholar]
- Moolgavkar S. H., Day N. E., Stevens R. G. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst. 1980 Sep;65(3):559–569. [PubMed] [Google Scholar]
- Tseng W. P. Effects and dose--response relationships of skin cancer and blackfoot disease with arsenic. Environ Health Perspect. 1977 Aug;19:109–119. doi: 10.1289/ehp.7719109. [DOI] [PMC free article] [PubMed] [Google Scholar]