POINT ESTIMATES OF CANCER RISK AT LOW-DOSES

There has been considerable discussion regarding the conservativeness of low-dose cancer risk estimates based upon linear extrapolation from upper confidence limits. Various groups have expressed a need for bes t (point) estimates of cancer risk in order to improve risk/benefit de cisions. Point estimates of carcinogenic potency obtained from maximum likelihood estimates of low-dose slope may be highly unstable, being sensitive both to the choice of the dose-response model and possibly t o minimal perturbations of the data. For carcinogens that augment back ground carcinogenic processes and/or for mutagenic carcinogens, at low doses the tumor incidence versus target tissue dose is expected to be linear. Pharmacokinetic data may be needed to identify and adjust for exposure-dose nonlinearities. Based on the assumption that the dose r esponse is linear over low doses, a stable point estimate for low-dose cancer risk is proposed. Since various models give similar estimates of risk down to levels of 1%, a stable estimate of the low-dose cancer slope is provided by s = 0.01/ED01, where ED01 is the dose correspond ing to an excess cancer risk of 1%. Thus, low-dose estimates of cancer risk are obtained by, risk = s X dose. The proposed procedure is simi lar to one which has been utilized in the past by the Center for Food Safety and Applied Nutrition, Food and Drug Administration. The upper confidence limit, s, corresponding to this point estimate of low-dose slope is similar to the upper limit, q1, obtained from the generaliz ed multistage model. The advantage of the proposed procedure is that s provides stable estimates of low-dose carcinogenic potency, which are not unduly influenced by small perturbations of the tumor incidence r ates, unlike q1.