Tetrahydrofuran-induced tumors in rodents are not relevant to humans: Quantitative weight of evidence analysis of mode of action information does not support classification of tetrahydrofuran as a possible human carcinogen

Abstract

Inhalation of tetrahydrofuran (THF) causes a marginal increase in the incidence of renal tumors in male rats and an increase in the incidence of liver tumors in female mice. Quantitative weight of evidence (QWoE) was applied to assess experimental support for biologically plausible modes of action (MoA) of tumor formation by THF and their human relevance. QWoE did not obtain support for a MoA to induce kidney tumors in male rats from THF exposure via α2u -globulin nephropathy, exacerbation of chronic progressive nephropathy (CPN), DNA-damage, or recurrent cytotoxicity but obtained moderate to good support for a constitutive androgen receptor (CAR)-mediated MoA for the induction of liver tumors in female mice. Tumors as a consequence of CAR-activation are not considered relevant to humans. Considering the previous conclusion that the increases in kidney tumors in male rats are unlikely related to THF-exposure and the support for a CAR-mediated MoA in mice obtained here, these tumors should not be used as a basis for THF cancer classification.