title: Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.
abstract: The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Ji
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: LeBaron
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Schisler
authors.forename: Fagen
authors.initials: F
authors.lastname: Zhang
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bartels
authors.affiliation: Present address: Exponent, Midland, MI 48640, USA. mjlebaron@dow.com.
authors.forename: B Bhaskar
authors.initials: BB
authors.lastname: Gollapudi
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
mesh_terms: D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D015415:Biomarkers; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D006454:Hemoglobins / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D008770:Methylnitrosourea / Q000633:toxicity*; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity; D009928:Organ Specificity; D051381:Rats; D011916:Rats, Inbred F344; D012156:Reticulocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D015415:Biomarkers; D018736:DNA Adducts; D006454:Hemoglobins; D009153:Mutagens; D008770:Methylnitrosourea; D004247:DNA; D008741:Methyl Methanesulfonate