title: Evaluation of in vivo mutagenesis for assessing the health risk of air pollutants.
abstract: Various kind of chemical substances, including man-made chemical products and unintended products, are emitted to ambient air. Some of these substances have been shown to be mutagenic and therefore to act as a carcinogen in humans. National pollutant inventories (e.g., Pollutant Release and Transfer Registration in Japan) have estimated release amounts of man-made chemical products, but a major concern is the release of suspended particulate matter containing potent mutagens, for example, polycyclic aromatic hydrocarbons and related compounds generated by the combustion of fossil fuel, which are not estimated by PRTR system. In situ exposure studies have revealed that DNA adducts in the lung, and possibly mutations in germline cells are induced in rodents by inhalation of ambient air, indicating that evaluating in vivo mutations is important for assessing environmental health risks. Transgenic rodent systems (Muta, Big Blue, andgptdelta) are good tools for analyzing in vivo mutations induced by a mixture of chemical substances present in the environment. Following inhalation of diesel exhaust (used as a model mixture), mutation frequency was increased in the lung ofgptdelta mice and base substitutions were induced at specific guanine residues (mutation hotspots) on the target transgenes. Mutation hotspots induced by diesel exhaust were different from those induced by benzo[a]pyrene, a typical mutagen in ambient air, but nearly identical to those induced by 1,6-dinitropyrene contained in diesel exhaust. Comparison between mutation hotspots in theTP53(p53) gene in human lung cancer (data extracted from the IARC TP53 database) and mutations we identified ingptdelta mice showed that G to A transitions centered in CGT and CGG trinucleotides were mutation hotspots on bothTP53genes in human lung cancers andgptgenes in transgenic mice that inhaled diesel exhaust. The carcinogenic potency (TD50value) of genotoxic carcinogen was shown to be correlated with the in vivo mutagenicity (total dose per increased mutant frequency). These results suggest that the mutations identified in transgenic rodents can help identify environmental mutagens that cause cancer.
authors.affiliation: National Institute for Environmental Studies, Center for Health and Environmental Risk Research, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506 Japan.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Aoki
keywords: Air pollutant; Environmental mutagen; Genotoxic carcinogen; In situ exposure; Lung; Mutation hotspot; Polycyclic aromatic hydrocarbon; Risk assessment; Transgenic rodent gene mutation assay