A STRATEGY FOR ESTABLISHING MODE OF ACTION OF CHEMICAL CARCINOGENS ASA GUIDE FOR APPROACHES TO RISK ASSESSMENTS

The current standard approach for assessing carcinogenic potential is to conduct a near lifetime rodent pathology study with the high dose s et to the maximum tolerated dose (MTD) of the test chemical. The linea rized multistage model is then used as the default approach to estimat e the potential human cancer risk at environmental levels of the chemi cal. There is an increasing appreciation in the scientific and regulat ory communities that chemical carcinogens differ dramatically in poten cy, exhibit a high degree of tissue and species specificity, and act t hrough different modes of action. This paper advocates a decision tree strategy for classifying carcinogens that are acting primarily throug h genotoxic, cytotoxic, or mitogenic pathways. A primary concern is wh ether the chemical has direct genotoxic potential resulting from DNA r eactivity or clastogenicity of the compound or its metabolite(s). Know ledge of the exposure-response curve for cytotoxicity is important bec ause initiation and promotion events may occur secondary to a variety of associated activities such as regenerative cell proliferation. Mito gens induce direct stimulation of growth and may provide a selective g rowth advantage to spontaneously initiated precancerous cells. Of part icular concern is the situation where pathological changes induced dur ing the course of the treatment at high doses near the MTD are absent at lower, environmentally relevant, doses. If the tumor response is co incident with the preceding toxic response, it may not be justified to use the high-dose data in extrapolating to expected responses at low environmental exposures where no induced tissue abnormalities occur. S uggestions are presented for appropriate risk assessment approaches fo r different modes of action. Examples discussed are formaldehyde, a we akly genotoxic rodent nasal carcinogen; chloroform, a nongenotoxic-cyt otoxic rodent liver and kidney carcinogen; and phenobarbital, a nongen otoxic-mitogenic rodent liver carcinogen.