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Areas of uncertainty in toxicity values generally include extrapolation from controlled high-dose animal studies to the human general population (including potentially sensitive subgroups) and generally lower exposure levels, determining if rodent endpoints are relevant to humans (e.g., tumors in the Zymbals gland of rodents), route-to-route extrapolation if toxicity values are lacking for certain exposure pathways, extrapolation from shorter-duration exposure studies to chronic or lifetime risk, and data gaps in the underlying toxicity database

& Barrett, J

These data demonstrate that H 2 O 2 induces TM3 Leydig cell senescence in vitro and that, in these senescent Leydig cells, FOXO4 is translocated to the nucleus and activates a senescence-associated pathway

Additionally, the mTOR, IL-17, NOD-like receptor and HIF-1 signaling pathways were involved (Supplementary Fig