Abstract It is proposed that metabolism of several structurally-related chemicals by CYP2F isoforms of the cytochromes P450 family results in a cytotoxicity-driven mode of action in organs high in CYP2F; namely, CYP2F2 in nasal and lung tissue in mice and CYP2F4 in nasal tissues in rats. Importantly, the CYP2F1 isozyme expressed in humans appears to have a low capacity to metabolize these compounds. In mice, the resultant cytotoxicity and subsequent regenerative hyperplasia is hypothesized drive an increase in lung tumors that are mostly benign and are not life shortening. Although a complete picture of the mode of action has not been developed in any one model compound, data from the individual compounds can be combined to synthesize and reinforce confidence in the CYP2F toxicity hypothesis. For coumarin, naphthalene, and styrene, inhibition of toxicity with inhibition of CYP2F2 has been demonstrated. Rat CYP2F4 appears to be equally active in metabolizing these chemicals; however, CYP2F4 occurs to a much lower extent in rat Clara cells and levels of metabolites produced are not sufficient to cause lung cytotoxicity. Human lungs contain far fewer of Clara cells than rats or mice, and human lung microsomes failed to, or only marginally, metabolize these compounds. In addition, the human lung differs markedly from the mouse lung in the morphology of its Clara cells, which make humans much less sensitive than mice to toxicity due to reactive metabolites. The absence of a role for CYP2E1-generated metabolites (primarily alkyl oxidation vs. ring-oxidation) in mouse pulmonary effects was demonstrated by the lack of protection from styrene toxicity by CYP2E1 inhibitor, or reduction of toxicity in CYP2E1-knockout mice, and lack of lung toxicity of the primary metabolite of ethylbenzene. The chemicals used as examples of this mode of action generally are negative in standard genotoxicity assays. Apart from increased SCE, no consistent pattern in genotoxicity results was found among these chemicals. Thus, while lung tumors from bronchiolar cell cytotoxicity are theoretically possible in humans, it is unlikely that metabolism by CYP2F1 would produce levels of cytotoxic metabolites in human lungs sufficient to result in lung cytotoxic responses and thus tumors. Therefore, it is unlikely several chemicals that cause mouse lung tumors via CYP2F2 metabolism will cause lung tumors in humans.