Comparison of cancer risk estimates based on a variety of risk assessment methodologies

Abstract

The EPA guidelines recommend a benchmark dose as a point of departure (PoD) for low-dose cancer risk assessment. Generally the PoD is the lower 95% confidence limit on the dose estimated to produce an extra lifetime cancer risk of 10% (LTD(10)). Due to the relatively narrow range of doses in two-year bioassays and the limited range of statistically significant tumor incidence rates, the estimate of the LTD(10) is constrained to a relatively narrow range of values. Because of this constraint, simple, quick estimates of the LTD(10) can be readily obtained for hundreds of rodent carcinogens from the Carcinogenic Potency Database (CPDB) of Gold et al. Three estimation procedures for LTD(10) are described, using increasing information from the CPDB: (A) based on only the maximum tolerated dose (the highest dose tested); (B) based on the TD(50); and (C) based on the TD(50) and its lower 99% confidence limit. As expected, results indicate overall similarity of the LTD(10) estimates and the value of using additional information. For Method (C) the estimator based on the [[(TD(50))(0.36) x (LoConf)(0.64)]/6.6] is generally similar to the estimator based on the one-hit model or multistage model LTD(10). This simple estimate of the LTD(10) is applicable for both linear and curved dose responses with high or low background tumor rates, and whether the confidence limits on the TD(50) are wide or tight. The EPA guidelines provide for a margin of exposure approach if data are sufficient to support a nonlinear dose-response. The reference dose for cancer for a nonlinear dose-response curve based on a 10,000-fold uncertainty (safety) factor from the LTD(10), i.e., the LTD(10)/10,000, is mathematically equivalent to the value for a linear extrapolation from the LTD(10) to the dose corresponding to a cancer risk of <10(-5) (LTD(10)/10,000). The cancer risk at <10(-5) obtained by using the q(1)(*) from the multistage model, is similar to LTD(10)/10,000. For a nonlinear case, an uncertainty factor of less than 10,000 is likely to be used, which would result in a higher (less stringent) acceptable exposure level.