Evaluation of an anti-thyroid mode of action for thyroid follicular cell adenomas in female mice exposed to tertiary butyl alcohol

Chronic exposure to tertiary butyl alcohol (TBA) in drinking water (DW) is associated with low but increased incidence (15 % vs 3 % in controls) of thyroid follicular cell adenomas in female mice. The U.S. Environmental Protection Agency evaluated this data in the context of an anti-thyroid mode of action (MOA) and identified data gaps while noting evidence for thyroid adenomas as “suggestive”. A study was designed to address data gaps in the MOA for TBA thyroid tumors. Female mice were exposed for 5 days to TBA by oral gavage (500 or 1000 mg/kg) or via DW (5–40 mg/mL) for up to 28 days. TBA activated upstream key events (KEs) within the anti-thyroid MOA framework including CAR/PXR signaling and upregulation of UGT and SULT transcripts. However, increased UGT and SULT activity was not observed. Downstream events (decreased serum TSH and thyroid histopathology prior to 2-years) were not demonstrated. The inability to demonstrate downstream KEs is likely a consequence of a weak tumor response with chronic exposure to TBA. With previously published data, an anti-thyroid MOA is a plausible explanation for a weak TBA tumor response, with analysis highlighting important consequences of conducting risk assessments on weak, suggestive tumor data.