Mode-of-Action Uncertainty for Dual-Mode Carcinogens: A Bounding Approach for Naphthalene-Induced Nasal Tumors in Rats Based on PBPK and 2-Stage Stochastic Cancer Risk Models

摘要: A relatively simple, quantitative approach is proposed to address a specific, important gap in the appr recommended by USEPA Guidelines for Cancer Risk Assessment oach uncertainty carcinogenic mode of action certain chemicals when risk extrapolated from bioassay data. These recognize that some chemical carcinogens may have site-specific (MOA) dual, involving mutation addition cell-killing induced hyperplasia. Although genotoxicity contribute increased at all doses, imply dual MOA (DMOA) carcinogens, judgment be used compare and assess results obtained using separate 'linear' (genotoxic) vs. 'nonlinear' (nongenotoxic) approaches low low-level extrapolation. However, allow latter only evidence sufficient t parameterize biologically based model reliably o extrapolates levels concern. The thus effectively prevent being characterized addressed data are insufficient such model, but otherwise clearly support DMOA. bounding factor - similar reference dose procedures classic toxicity endpoints can way avoids explicit modelingmore » low-dose as function administere administered or internal dose. Even toxicokinetic cannot fully validated, implications DMOA on bounded with reasonable confidence target tumor types happen extremely rare. This concept was i illustrated llustrated likely rodent carcinogen naphthalene, specifically issue extrapolation naphthalene naphthalene-induced nasal tumors rats. Bioassay data, supplemental related physiologically p pharmacokinetic 2 harmacokinetic 2-stage stochastic carcinogenesis modeling indicate carcinogen. Plausibility bounds rat rat-tumor tumor-type specific DMOA-related were adapted reflec reflect empirical link between genotoxic cytotoxic effects most potent identified metabolites, 1,2 1,2- 1,4 1,4-naphthoquinone. Bound Bound-specific 'adjustment' factors then reduce estimated linear ex (under default assumption), account trapolation exhibited this compound.« less