Dose response from chemical carcinogens

The U.S. EPA applies an alternative dose-response evaluation of carcinogens using a low-dose, linear model (EPA 2005). The linear extrapolation is applied under two circumstances (1) when there are data to indicate that the dose-response curve has a linear component below the point of departure or (2) as a default for a tumor site where the mode of action is not established. For a linear extrapolation, a straight line is drawn from the point of departure to the origin. The slope of the line, known as the slope factor, is an upper-bound estimate of risk per increment of dose that can be used to estimate risk probabilities for different exposure levels. The slope factor is equal to 0.01/LEDoi, for example, if the LEDqi is used as the point of departure. The lower hmit on effective doscoi (LEDoi) is the 95% lower confidence hmit of the dose of a chemical needed to produce an adverse effect in 1% of those exposed to the chemical, relahve to control. If, however, there are sufficient data to ascertain that a chemicaTs mode of action supports modeling at low doses, a reference dose or concentrahon may be developed in lieu of a cancer slope factor. 

In contrast, nominal probability coefficients for chemical carcinogens are derived from upper 95 percent confidence limits of observed responses at high doses, mainly in studies in animals. In some studies, the difference between the upper 95 percent confidence limit and MLE of the observed responses at high doses is an order of magnitude or more. Furthermore, several models have been used to extrapolate the observed responses to the low doses of concern in health protection of the public, with the result that estimated probability coefficients at low doses can differ by several orders of magnitude depending on the extrapolation model chosen. 

For any hazardous substance, estimates of the relationship of dose to response in humans are based on either animal or human data. For example, only about 20 of the approximately 300 chemical carcinogens regulated by EPA have dose-response relationships based on human data from epidemiologic studies the remainder are based on animal bioassays. In contrast, the dose-response relationships for radiation are based primarily on the results of human epidemiologic studies. 

In the evaluation of carcinogenicity of chemicals, data obtained from human and animal studies are analyzed for hazard identification and dose-response relationships. The results are used in combination with exposure assessment and risk characterization for the assessment of cancer risks of the chemicals to humans. 

Overall, cancer risk assessment involves the four steps of hazard identification, dose-response, exposure assessment, and risk characterization. The dose-response curve established for cancer potency derivation for a chemical is based on evaluation of data on the carcinogenicity and dose-response characteristics of the chemical. The pharmacokinetics and mechanistic data evaluation (e.g., genotoxic or nongenotoxic) and a dose-response review of all adequate bioassays are conducted to determine, if target dose estimates or a dose-response model different from the default may be suggested. 

Figure 5. Hypothetical dose-response curves for chemically-induced carcinogenicity, showing measured dose-response curves from three studies (top right-hand quadrant) and some possible ways those curves might behave in the low dose-low risk region (lower left-hand quadrant, in The Range of Extrapolation). Note The graph is not drawn to scale. The lower left-hand quadrant has been greatly expanded to show the possibilities for extrapolation. See text, pages 174 to 179 for a full discussion of this graph.

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