Development of a Dose-Response Model For Risk Assessment of Receptor-Mediated Effects

Abstract

Two dose response models have traditionally been used in risk assessment. Most regulatory agencies assume that there is no safe level of exposure to carcinogens but that a threshold, or “safe” exposure level exists for non-carcinogens. However, recent discoveries have cast serious doubt on the validity of this concept. Dose – response relationships of several neurotoxic non-carcinogens were recently shown to be identical to that of an alkylating carcinogen, and were theoretically explained by irreversible receptor binding with an associated irreversible effect. It is also clear by now that the threshold model for non-carcinogens may seriously underestimate actual risk. Risk assessments can no longer assume thresholds for non-carcinogens as a matter of principle when there is mechanistic evidence of receptor-mediated toxicity. A dose response model for receptor-mediated toxicity needs to be developed, and if the shape of the dose-response curve conveys a linear relationship between receptor occupancy and biological response at lower concentrations, a threshold may not exist. For chemicals with a linear dose-response relationship in low dose regions, risk management should be based on the ALARA principle (“as low as reasonably achievable”).