Health Risk Assessment of Air Pollutants: Air Pollutant Genotoxicity and Its Enhancement by Suppression of Phase II Drug-metabolizing Enzymes

Abstract

In Japan, to reduce the health risks associated with hazardous air pollutants, Environmental Quality Standards have been set for certain chemicals in ambient air, and national or local government and industry are required to ensure that the concentrations of those chemicals remain below the Environmental Quality Standards. Guideline Values have also been set to reduce health risks resulting from hazardous air pollutants in the atmosphere. Whether carcinogenicity has a threshold or not is an important factor for risk assessments and for setting Environmental Quality Standards and Guideline Values for carcinogens. In the “Guidelines on Health Risk Assessment Methods for Hazardous Air Pollutants”, carcinogenic air pollutants are proposed to be grouped according to judgment of whether carcinogenicity has a threshold. However, factors for determining the existence, and actual value of threshold of carcinogenicity have not yet been identified. Our research group believes that susceptibility to genotoxic carcinogens is a determinant of carcinogenic threshold, and that metabolic activation of mutagens, excision DNA repair, translesional DNA synthesis, and apoptosis are the main factors determining susceptibility. We have investigated metabolic activation (especially the level of phase II-drug metabolizing enzymes) as a factor in susceptibility to genotoxic carcinogens. Our studies of mice deficient in Nrf2 (a gene of a transcription factor for inducing phase II enzymes ) suggest that expression of phase II enzymes prevents the induction of certain mutations caused by genotoxic carcinogens such as benzo[a]pyrene.