Mechanistic Influences for Mutation Induction Curves after Exposure to DNA-Reactive Carcinogens

A mechanistic understanding of carcinogenic genotoxicity is necessary to determine consequences of chemical exposure on human populations and improve health risk assessments. Currently, linear dose-responses are assumed for DNA reactive compounds, ignoring cytoprotectiveprocesses that may limit permanent damage. To investigate the biological significance of low-dose exposures, human lymphoblastoid cells were treated with alkylating agents that have different mechanisms of action and DNA targets: methylmethane sulfonate (MMS), methylnitrosourea (MNU), ethylmethane sulfonate (EMS), and ethylnitrosourea(ENU). Chromosomal damage and point mutationswere quantified with the micronucleusand hypoxanthine phosphoribosyltransferaseforward mutation assays. MNU and ENU showed linear dose-responses, whereas MMS and EMS had nonlinear curves containing a range of nonmutagenic low doses. The lowest observed effect level for induction of chromosomal aberrations was 0.85 μg/mL MMS and 1.40 μg/mL EMS; point mutationsrequired 1.25 μg/mL MMS and 1.40 μg/mL EMS before a mutagenic effect was detected. This nonlinearity could be due to homeostatic maintenance by DNA repair, which is efficient at low doses of compounds that primarily alkylate N 7 -G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins. [Cancer Res 2007;67(8):3904–11]