Applicability of Cancer Risk Assessment Techniques To Other Toxic Effects

Abstract

The purpose of this paper is to investigate the applicability of cancer risk assessment techniques to other endpoints. The discussion is limited to the problem of high to low dose extrapolation. Although developed to describe cancer data, the multistage model has a general sigmoidal shape which makes it amenable to describe the dose-response of many non-cancer endpoints. At low doses the multistage model is essentially a general polynomial model. Low-dose linear extrapolation provides an upper limit on convex (curving upward) dose-response curves. Low-dose linearity is expected if exposure to a toxic substance augments a disease process which is already operating in unexposed animals. Incorporation of pharma. cokinetic information may prove useful in simplifying dose-response relationships and may result in lower estimates of risk. A descriptive model can be used to estimate a lower confidence limit on a dose expected to produce a disease incidence, for example, of 1% of the animals (LED₀₁). Then, the LED₀₁/100 provides an estimate of the dose for which the risk is estimated to be less than 10^-4. It appears that some of the techniques used for cancer risk assessment can be used or modified for quantal non-cancer endpoints.

Keywords

dose-response relationship extrapolation multistage model risk assessment.

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References

Anderson, E.L. and the Carcinogen Assessment Group, U.S. Epa. (1983). Quantitative approaches in use to assess cancer risk. Risk Analysis 3:277-295.

Crump, K.S. , Hoel, D.G. , Langley, C.H. and Peto, R. (1976). Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Res. 36:2973-2979.

Food And Drug Administration (Fda). (1971). Advisory Committee on Protocols for Safety Evaluation. Panel on carcinogenesis report on cancer testing in the safety evaluation of food additives and pesticides . Toxicol. Appl. Pharmacol. 20:419-438.

Gaylor, D.W. (1986). Linear-rionparametric low dose disease risk estimation . Proc. Soc. Risk Analysis, in press.

Gaylor, D.W. (1988). Quantitative risk analysis for quantal reproductive and developmental effects. Environ. Health Perspect. (in press).

Gaylor, D.W. and Kodell, R.L. (1980). Linear interpolation algorithm for low dose risk assessment of toxic substances. J. Environ. Path. Toxicol . 4:305-312.

Hoel, D.G. (1980). Incorporation of background in dose-response models . Federation Proc. 39:73-75.

Howe, R.B. and Crump, K.S. (1982). GLOBAL82: A computer program to extrapolate quantal animal toxicity data to low doses. K.S. Crump and Co., Inc., Ruston, LA.

Kodell, R.L. , Shaw, G.W. and Johnson, A.M. (1982). Nonparametric joint estimators for disease resistance and survival functions in survival/sacrifice experiments. Biometrics 38:43-58.

10.

Kodell, R.L. , Gaylor, D.W. and Chen, J.J. (1986). Standardized tumor rates for chronic bioassays . Biometrics 42:867-873.

11.

Kuna, R.A. and Kapp, R.W., JR. (1981). The embryotoxic/teratogenic potential of benzene vapor in rats. Toxicol. Appl. Pharmacol. 57:1-7.

12.

Peto, R. (1978). Carcinogenic effects of chronic exposure to very low levels of toxic substances. Environ. Health Perspect. 22:155-159.