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Katie Paul Friedman, Bayer CropScience, RTP, NC USA <firstname.lastname@example.org>
Mary E. Gilbert, National Health and Environmental Effects Research Laboratory, US EPA, RTP, NC USA <email@example.com>
Kevin M. Crofton, National Center for Computational Toxicology, US EPA, RTP, NC USA <firstname.lastname@example.org>
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OECD Project 1.9: Upregulation of Thyroid Hormone Catabolism via Activation of Hepatic Nuclear Receptors, and Subsequent Adverse Neurodevelopmental Outcomes in Mammals.
This AOP was last modified on 12/5/2016.
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Data from rodent studies demonstrate that thyroid hormone disruption during cochlear development culminates in ototoxicity. Developmental exposure of rats to polychlorinated biphenyls (PCBs) results in a low-frequency hearing loss in adult offspring (Goldey et al., 1995a; Herr et al., 1996; 2001; Crofton and Rice, 1999; Laskey et al., 2002). A body of work now supports the hypothesis that this ototoxicity results from PCB-induced hypothyroxinemia during a critical period of auditory development. Evidence for this hypothesis includes: a correlation between the severity of functional auditory impairment and the degree of thyroid hormone depletion (Goldey et al., 1995a; 1995b; Goldey and Crofton, 1998; Crofton, 2004), a cross-fostering study demonstrating that the critical exposure period is postnatal (Crofton et al., 2000a), and amelioration of the hearing loss following postnatal thyroxine replacement (Goldey and Crofton, 1998). Below an adverse outcome pathway is described for chemicals that activate xenobiotic nuclear receptors, including AhR, CAR, and PXR, leading to thyroid hormone disruption during cochlear development and resulting in permanent auditory loss.
This AOP is a revision and update of the original started on the Chemical Mode of Action wiki sponsored by WHO/IPCS. This MOA was described and published by Crofton and Zoeller 2005).
Summary of the AOP
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Molecular Initiating Event
|Molecular Initiating Event||Support for Essentiality|
|Pregnane-X receptor, NR1l2, Activation||Moderate|
|Cochlear function, Loss|
Relationships Among Key Events and the Adverse Outcome
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Life Stage Applicability
|Fetal to Parturition||Moderate|
Overall Assessment of the AOP
Weight of Evidence Summary
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Concordance of dose-response relationships
Multiple studies provide limited (2-3 doses) dose-response data for many of the key events. These studies demonstrate similar magnitudes of effect on circulating hormones for doses of PCBs that are within an order of magnitude (3-25 mg/kg/day for Aroclor 1254) (e.g.,Morse et al., 1996; Goldey et al., 1998). Very limited data are available correlating any of the key events. One exception is the relationship between circulating serum T4 concentrations during development and the magnitude of hearing loss (Crofton, 2004). There is a very good correlation between total serum T4 concentrations on postnatal day (PND) 14 and hearing loss assessed in adult offspring of PCB exposed dams (Figure 2). All of these events occur within a 2-3 fold dose range.
Temporal concordance among the key events and the adverse outcome Strength, consistency, and specificity of association of adverse effect and initiating event Biological plausibility, coherence, and consistency of the experimental evidence Alternative mechanism(s) or MIE(s) that logically present themselves and the extent to which they may detract from the AOP Uncertainties, inconsistencies, and data gaps
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
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Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
Applicability of the AOP
Life Stage Applicability,
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