title: Dose-response analysis of bromate-induced DNA damage and mutagenicity is consistent with low-dose linear, nonthreshold processes.
abstract: Mutagenic agents have long been inferred to act through low-dose linear, nonthreshold processes. However, there is debate about this assumption, with various studies interpreting datasets as showing thresholds for DNA damage and mutation. We have applied rigorous statistical analyses to investigate the shape of dose-response relationships for a series of in vitro and in vivo genotoxicity studies using potassium bromate (KBrO(3) ), a water ozonation byproduct that is bioactivated to a reactive species causing oxidative damage to DNA. We analyzed studies of KBrO(3) genotoxicity where no-effect/threshold levels were reported as well as other representative datasets. In all cases, the data were consistent with low-dose linear models. In the majority of cases, the data were fit either by a linear (straight line) model or a model which was linear at low doses and showed a saturation-like downward curvature at high doses. Other datasets with apparent upward curvature were still adequately represented by models that were linear at low dose. Sensitivity analysis of datasets showing upward curvature revealed that both low-dose linear and nonlinear models provide adequate fits. Additionally, a simple biochemical model of selected key processes in bromate-induced DNA damage was developed and illustrated a situation where response for early primary events suggested an apparent threshold while downstream events were linear. Overall, the statistical analyses of DNA damage and mutations induced by KBrO(3) are consistent with a low-dose linear response and do not provide convincing evidence for the presence of a threshold.
authors.affiliation: National Center for Environmental Assessment (NCEA), Office of Research and Development (ORD), U.S. Environmental Protection Agency (U.S.EPA), Washington, DC, USA. Spassova.maria@epa.gov
authors.forename: Maria A
authors.initials: MA
authors.lastname: Spassova
authors.forename: David J
authors.initials: DJ
authors.lastname: Miller
authors.forename: David A
authors.initials: DA
authors.lastname: Eastmond
authors.forename: Nadejda S
authors.initials: NS
authors.lastname: Nikolova
authors.forename: Suryanarayana V
authors.initials: SV
authors.lastname: Vulimiri
authors.forename: Jane
authors.initials: J
authors.lastname: Caldwell
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.forename: Paul D
authors.initials: PD
authors.lastname: White
mesh_terms: D000818:Animals; D001959:Bromates / Q000633:toxicity*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016014:Linear Models; D051379:Mice; D008957:Models, Genetic; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity
chemical_list: D001959:Bromates; D009153:Mutagens; C019536:potassium bromate