An Adjustment Factor for Mode‐of‐Action Uncertainty with Dual‐Mode Carcinogens: The Case of Naphthalene‐Induced Nasal Tumors in Rats

The U.S. Environmental Protection Agency (USEPA) guidelines for cancer risk assessment recognize that some chemical carcinogens may have a site‐specific mode of action (MOA) involving mutation and cell‐killing‐induced hyperplasia. The guidelines recommend that for such dual MOA (DMOA) carcinogens, judgment should be used to compare and assess results using separate “linear” (genotoxic) versus “nonlinear” (nongenotoxic) approaches to low‐level risk extrapolation. Because the guidelines allow this only when evidence supports reliable risk extrapolation using a validated mechanistic model, they effectively prevent addressing MOA uncertainty when data do not fully validate such a model but otherwise clearly support a DMOA. An adjustment‐factor approach is proposed to address this gap, analogous to reference‐dose procedures used for classic toxicity endpoints. By this method, even when a “nonlinear” toxicokinetic model cannot be fully validated, the effect of DMOA uncertainty on low‐dose risk can be addressed. Application of the proposed approach was illustrated for the case of risk extrapolation from bioassay data on rat nasal tumors induced by chronic lifetime exposure to naphthalene. Bioassay data, toxicokinetic data, and pharmacokinetic analyses were determined to indicate that naphthalene is almost certainly a DMOA carcinogen. Plausibility bounds on rat‐tumor‐type‐specific DMOA‐related uncertainty were obtained using a mechanistic two‐stage cancer risk model adapted to reflect the empirical link between genotoxic and cytotoxic effects of the most potent identified genotoxic naphthalene metabolites, 1,2‐ and 1,4‐naphthoquinone. Bound‐specific adjustment factors were then used to reduce naphthalene risk estimated by linear extrapolation (under the default genotoxic MOA assumption), to account for the DMOA exhibited by this compound.