Mode of action: neurotoxicity induced by thyroid hormone disruption during development--hearing loss resulting from exposure to PHAHs.
An increasing incorporation of mode of action (MOA) information into risk assessments has led to examination of animal MOAs to determine relevance to humans. We examined a specific MOA for developmental neurotoxicity using the MOA/Human Relevance Framework (Meek et al., 2003). The postulated MOA of ototoxicity in rats involves early postnatal exposure to polychlorinated biphenyls (PCBs) via lactation, an upregulation of hepatic uridine diphosphoglucuronyltransferases (UGTs), and subsequent hypothyroxinemia during a critical period of cochlear development, with the ultimate neurotoxic consequence of hearing loss. This review concludes with high confidence in the animal MOA and medium confidence for the interspecies concordance for the key events in the MOA. Possible interspecies differences in toxicodynamic factors moderate confidence in some key events. In addition, there is a question of whether ambient human exposures are large enough to cause human fetal hypothyroxinemia to the degree needed to cause hearing loss. Data gaps identified by this analysis include a need to characterize the induciblity of human fetal UGTs and the comparative sensitivity of UGT induction by xenobiotics in rats and humans. Research on these areas of uncertainty will increase confidence that this MOA for PCBs is not likely to not occur in humans, assuming normal conditions of limited ambient exposure.
Crofton
Kevin M
KM
US Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. crofton.kevin@epa.gov
Zoeller
R Thomas
RT
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D034381:Hearing Loss / Q000139:chemically induced* / Q000151:congenital*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity*; D011247:Pregnancy; D013045:Species Specificity; D013959:Thyroid Diseases / Q000139:chemically induced* / Q000473:pathology; D013963:Thyroid Hormones / Q000378:metabolism / Q000502:physiology*
D006846:Hydrocarbons, Halogenated; D011084:Polycyclic Aromatic Hydrocarbons; D013963:Thyroid Hormones