title: Defining EMS and ENU dose-response relationships using the Pig-a mutation assay in rats.
abstract: In recent years, experimental evidence has accumulated that supports the existence of sublinear dose-response relationships at low doses of DNA reactive mutagens. However, creating the in vivo data necessary to allow for a more detailed dose-response modeling with the currently available tools might not always be practical. The purpose of the current work was to evaluate the utility of the Pig-a gene mutation assay to rapidly identify dose-response relationships for direct acting genotoxicants. The induction of mutations in the peripheral blood of rats was evaluated following 28 days of exposure down to low doses of the direct acting alkylating agents ethyl methane sulfonate (EMS) and ethylnitrosourea (ENU). Using statistical modeling based on the 28-day studies, a threshold for mutation induction for EMS was estimated to be 21.9mg/kg, whereas for the more potent ENU, the threshold was estimated to be 0.88mg/kg. Comparing mutation frequencies from acute and sub-chronic dosing indicated less than additive dose-response relationships, further confirming the possibility of a threshold dose-response relationship for both compounds. In conclusion, the work presented provides evidence that the Pig-a assay might be a practical alternative to other in vivo mutation assays when assessing dose-response relationships for direct acting mutagens and that an experimental approach using fractionated dosing could be used to substantiate a biological mechanism responsible for the observation of a sublinear dose-response relationship.
authors: Pfizer Global Research and Development, Genetic Toxicology Center of Emphasis, Eastern Point Road, Groton, CT 06340, United States. krista.l.dobo@pfizer.com
authors: Krista L
authors: KL
authors: Dobo
authors: Ronald D
authors: RD
authors: Fiedler
authors: William C
authors: WC
authors: Gunther
authors: Catherine J
authors: CJ
authors: Thiffeault
authors: Zoryana
authors: Z
authors: Cammerer
authors: Stephanie L
authors: SL
authors: Coffing
authors: Thomas
authors: T
authors: Shutsky
authors: Maik
authors: M
authors: Schuler
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D005038:Ethylnitrosourea / Q000633:toxicity*; D008565:Membrane Proteins / Q000235:genetics*; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats
chemical_list: D008565:Membrane Proteins; D009153:Mutagens; C080086:phosphatidylinositol glycan-class A protein; D005020:Ethyl Methanesulfonate; D005038:Ethylnitrosourea