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

School of Medicine, University of Wales Swansea, Swansea, Wales, United Kingdom

Requests for reprints: Shareen H. Doak, School of Medicine, University of Wales Swansea, Singleton Park, Swansea SA2 8PP, Wales, United Kingdom. Phone: 44-1792-295388; Fax: 44-1792-295447; E-mail: s.h.doak{at}swansea.ac.uk.

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 cytoprotective processes 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 mutations were quantified with the micronucleus and hypoxanthine phosphoribosyltransferase forward 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 mutations required 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 N⁷-G and rarely attack O atoms. A pragmatic threshold for carcinogenicity may therefore exist for such genotoxins. [Cancer Res 2007;67(8):3904–11]

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