IMPLICATIONS OF HORMESIS ON THE BIOASSAY AND HAZARD ASSESSMENT OF CHEMICAL CARCINOGENS

Hormesis has been defined as a dose-response relationship which depict s improvement in some endpoint (increased metabolic rates, reduction i n tumor incidence, etc.) at low doses of a toxic compound followed by a decline in the endpoint at higher doses. The existence of hermetic r esponses to carcinogenic agents has several implications for the bioas say and hazard assessment of carcinogens. To be capable of detecting a nd statistically testing for hermetic or other nonlinear dose-response functions, current study designs must be modified to include lower do ses and sufficiently large numbers of animals. In addition, improved s tatistical methods for testing nonlinear dose-response relationships w ill have to be developed. Research integrating physiologically-based p harmacokinetic model descriptions of target dose with mechanistic data holds the greatest promise for improving the description of the dose- response curve at low doses. The 1996 Proposed Carcinogen Risk Assessm ent Guidelines encourage the use of mechanistic data to improve the de scriptions of the dose-response curve at low doses, hut do not disting uish between the types of nonlinear dose-response curves. Should this refined approach lead to substantial support for hormesis in carcinoge nic processes, future guidelines will need to preside guidance on esta blishing safe doses and communicating the results to the public.