Mode-of-Action and Human Relevance Assessment for Diisononyl Phthalate-Induced Liver Tumors in Rodents

Diisononyl phthalate (DINP) is a high molecular weight phthalate and high production volume chemical. DINP's carcinogenic potential has been investigated in four rodent bioassays, with liver tumors observed in three of the studies. Authoritative assessments have hypothesized that DINP acts through the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced mode of action (MOA) for rodent hepatocarcinogenesis. However, these assessments reported disparate conclusions regarding the human relevance of this rodent-specific MOA, and alternative MOAs for DINP-induced rodent liver tumors have been proposed, albeit with limited evidence. Herein, the MOA for DINP-induced rodent liver tumors is assessed according to the MOA framework for PPARα activator-induced rodent hepatocarcinogenicity, which includes four key events (KEs). Findings demonstrate strong evidence that DINP induces KE 1 (PPARα activation) and KE 3 (perturbation of cell growth and survival) in vitro and in vivo in wild-type and PPARα-null rodent models. KE 2 and KE 4 are reasonably inferred, given the strong data for KE 1, KE 3, and the adverse outcome (liver tumors). Alternative MOAs, including genotoxicity, endocrine disruption, other nuclear receptor activation, and cytotoxicity, are not supported by the evidence. The human and nonhuman primate evidence for DINP supports the lack of human relevance of this MOA, as well as the divergent PPARα-mediated pathways between species, with evidence in humans limited to PPARα activation (KE 1). Overall, the weight of evidence strongly supports that DINP acts through the nonhuman-relevant PPARα MOA for rodent hepatocarcinogenesis; therefore, rodent liver tumors and upstream KEs 2-4 should not serve as the basis for human health risk conclusions.