Mechanistic Models Fit to Ed001 Data on >40,000 Trout Exposed to Dibenzo[A,L]Pyrene Indicate Mutations Do Not Drive Increased Tumor Risk

摘要: ED001-study data on increased liver and stomach tumor risks in >40,000 trout fed dibenzo[a,l]pyrene (DBP), one of the most potently mutagenic chemical carcinogens known, provide greatest low-dose dose-response resolution any experimentally induced set to date. Although multistage somatic mutation/clonal-expansion cancer theory predicts that genotoxic increase risk linear no-threshold proportion dose at low doses, ED001 curiously exhibit substantial nonlinearity. To explore role nongenotoxic mechanisms may have played yield such nonlinearity, sets were each fit by two models assume a pathway risk: stochastic 2-stage (MVK) model, model implementing more recent dysregulated adaptive hyperplasia (DAH) tumorigenesis. MVK DAH fits excellent, but unexpectedly implies DBP acts entirely non-mutagenic mechanisms. Given is potent mutagen, MVK-model obtained appear be biologically implausible, whereas DAH-model reflect model’s assumption chemical-induced tumorigenesis typically driven elevated repair-cell populations rather than mutations per se.