In recent years, human and wildlife monitoring studies have identified perfluoroalkyl acids (PFAA) worldwide. This has led to efforts to better understand the hazards that may be inherent in these compounds, as well as the global distribution of the PFAAs. Much attention has focused on understanding the toxicology of the two most widely known PFAAs, perfluorooctanoic acid, and perfluorooctane sulfate. More recently, research was extended to other PFAAs. There has been substantial progress in understanding additional aspects of the toxicology of these compounds, particularly related to the developmental toxicity, immunotoxicity, hepatotoxicity, and the potential modes of action. This review provides an overview of the recent advances in the toxicology and mode of action for PFAAs, and of the monitoring data now available for the environment, wildlife, and humans. Several avenues of research are proposed that would further our understanding of this class of compounds.

A shuttle vector was constructed in which a single O4-methylthymine (O4MeThy) or O6-methylguanine (O6MeGua) was positioned within a unique NheI restriction site. These lesions are among the many produced when alkylating agents interact with DNA and are the two most widely believed to account for the mutagenicity that follows the alkylation event. The shuttle vectors were transfected in parallel into Chinese hamster ovary cells that were either proficient (mex+) or deficient (mex-) in an endogenous alkyltransferase protein. The vectors integrated into the genome of the host, and the lesions were replicated along with the host chromosome. A portion of the integrated vector encompassing the originally adducted site was subsequently amplified by the polymerase chain reaction from the host genome to mediate analysis of mutation frequency and type. O4MeThy induced a high mutation frequency in both mex- and mex+ cells (28-50% in mex- and 22-42% in mex+). O6MeGua induced a significant but lower level of mutagenesis in the repair-deficient (mex-) cells (7-8.5%) and was not detectably mutagenic in mex+ cells. Mutations induced by the methylated thymine in both cell types were T-->C transitions; the guanine adduct in mex- cells induced G-->A transitions. These results indicate that the O4MeThy lesion is more highly mutagenic than O6MeGua in the same genetic background, and that the former adduct, unlike the latter, does not appear to be repaired to a significant extent by the alkyltransferase or any other mammalian repair enzyme.