Propylene oxide: genotoxicity profile of a rodent nasal carcinogen

Propylene oxide (PO) is a DNA-reactive genotoxic agent; that is, it reacts with DNA to produce lesions in the genetic material. PO also induces tumors in rodents, although only at high concentrations and at portals of entry. This review of PO's genotoxicity profile is organized according to endpoints measured, that is, nonmutational or mutational endpoints, and as to whether the results were from in vitro or in vivo studies. In addition to results of experimental studies, PO's genotoxicity for humans is assessed by reviewing results of published biomarker studies. The weight of evidence indicates that although it is genotoxic, PO's potency as a DNA-reactive mutagen is weak. Other aspects of PO's overall tissue toxicities are also reviewed, with attention to glutathione (GSH) depletion and its consequences, that is, cell proliferation, death, and necrosis. These toxic tissue responses occur in the same anatomical regions in rodents as do the PO-induced tumors. Furthermore, some of these tissue toxicities can produce effects that may either augment PO's DNA-reactive mutagenicity or be genotoxic in themselves, not dependent on PO's DNA reactivity. Although its DNA reactivity may be a necessary component of PO's overall genotoxicity and rodent carcinogenicity, it is likely not sufficient, and the associated tissue toxicities, which are rate-limiting, also seem to be required. This complex mode of action has implications for estimations of PO's cancer potential in humans, especially at low exposure concentrations.