Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action

Abstract

The Toxicology Forum sponsored a workshop in October 2016, on the human relevance of rodent liver tumors occurring via nongenotoxic modes of action (MOAs). The workshop focused on two nuclear receptor-mediated MOAs (Constitutive Androstane Receptor (CAR) and Peroxisome Proliferator Activated Receptor-alpha (PPARα), and on cytotoxicity. The goal of the meeting was to review the state of the science to (1) identify areas of consensus and differences, data gaps and research needs; (2) identify reasons for inconsistencies in current regulatory positions; and (3) consider what data are needed to demonstrate a specific MOA, and when additional research is needed to rule out alternative possibilities. Implications for quantitative risk assessment approaches were discussed, as were implications of not considering MOA and dose in hazard characterization and labeling schemes. Most, but not all, participants considered the CAR and PPARα MOAs as not relevant to humans based on quantitative and qualitative differences. In contrast, cytotoxicity is clearly relevant to humans, but a threshold applies. Questions remain for all three MOAs concerning what data are necessary to determine the MOA and to what extent it is necessary to exclude other MOAs.

Development of an oral reference dose for the perfluorinated compound GenX

“…Notably, many peroxisome proliferators (i.e., PPARα activators) induce a so‐called tumor triad of liver adenomas/carcinomas (mice and rats), testicular Leydig cell tumors (rats) and pancreatic acinar cell tumors (rats) (Corton, Peters, & Klaunig, ; Felter et al, ; Klaunig et al, ). Thus, the toxicity profile for GenX is consistent with other PPARα activators, inducing changes in the three tissues associated with the tumor triad (Table ).…”

Hazard identification, classification, and risk assessment of carcinogens: too much or too little? – Report of an ECETOC workshop

“…The 2-year bioassay has a high false-positive rate and can produce tumors that are irrelevant to humans. It is time-and resource-consuming and uses large numbers of animals (Cohen 2017;Felter et al 2018;Doe et al 2019;Sauve-Ciencewicki et al 2019).…”

“…the maximum tolerated dose (MTD)) that rarely, if ever, reflect human exposure scenarios. It does not provide mechanistic information nor does it consider toxicokinetics, both of which are often different at high versus lower doses (Cohen 2017;Felter et al 2018;Doe et al 2019;Sauve-Ciencewicki et al 2019). This is explicitly recognized by the US National Toxicology Program (NTP 2016), which states that its conclusions on rodent carcinogenicity are relevant only to the conditions of the bioassay under which the respective substance was tested.…”

Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

“…A combination of prolonged oxidative damage, due to peroxisome proliferation‐related hydroperoxide formation and hepatocellular proliferation, is postulated to be responsible for liver tumour development . However, liver tumours after PPARα ligand exposures are regarded specific to rodents and thus probably devoid of human relevance . Additionally, prolonged activation of PPARα has been shown to induce disturbance of the liver–thyroid axis due to UGT induction and consequent thyroid hypertrophy, hyperplasia and tumour development .…”