Mode of action: neurotoxicity induced by thyroid hormone disruption during development--hearing loss resulting from...

Area of Science:

• Environmental Toxicology
• Developmental Neurotoxicity
• Risk Assessment

Background:

• Mode of action (MOA) information is increasingly used in risk assessments to evaluate animal data relevance to humans.
• The MOA/Human Relevance Framework (Meek et al., 2003) is utilized to assess animal MOAs for human applicability.
• Polychlorinated biphenyls (PCBs) are environmental contaminants with potential developmental neurotoxic effects.

Purpose of the Study:

• To examine the MOA of ototoxicity induced by PCBs in rats.
• To evaluate the human relevance of the identified animal MOA using the MOA/Human Relevance Framework.
• To identify data gaps and uncertainties in the interspecies extrapolation of the PCB ototoxicity MOA.

Main Methods:

• Review of existing literature on PCB exposure, ototoxicity, and developmental neurotoxicity in animal models.
• Application of the MOA/Human Relevance Framework to assess the confidence in the animal MOA and its relevance to humans.
• Identification of key events in the MOA and evaluation of interspecies concordance.

Main Results:

• High confidence in the postulated MOA of PCB-induced ototoxicity in rats.
• Medium confidence in the interspecies concordance of key MOA events, with toxicodynamic differences moderating certainty.
• Uncertainty regarding whether typical human exposures are sufficient to cause the hypothyroxinemia observed in rats, potentially impacting human fetal development and hearing.

Conclusions:

• The MOA for PCB-induced ototoxicity in rats is well-established.
• Confidence in human relevance is moderate due to potential interspecies differences in toxicodynamics and exposure levels.
• Further research is needed on human fetal uridine diphosphoglucuronyltransferases (UGTs) inducibility and comparative sensitivity to xenobiotics to increase confidence in human risk assessment.