Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption

Toxicol Sci. 2023 Aug 29;195(1):1-27. doi: 10.1093/toxsci/kfad063.


Thyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health. This review aimed to advance the description of the taxonomic domain of applicability (tDOA) in the network to improve its utility for cross-species extrapolation. We focused on the molecular initiating events (MIEs) and adverse outcomes (AOs) and evaluated both their plausible domain of applicability (taxa they are likely applicable to) and empirical domain of applicability (where evidence for applicability to various taxa exists) in a THSD context. The evaluation showed that all MIEs in the AOP network are applicable to mammals. With some exceptions, there was evidence of structural conservation across vertebrate taxa and especially for fish and amphibians, and to a lesser extent for birds, empirical evidence was found. Current evidence supports the applicability of impaired neurodevelopment, neurosensory development (eg, vision) and reproduction across vertebrate taxa. The results of this tDOA evaluation are summarized in a conceptual AOP network that helps prioritize (parts of) AOPs for a more detailed evaluation. In conclusion, this review advances the tDOA description of an existing THSD AOP network and serves as a catalog summarizing plausible and empirical evidence on which future cross-species AOP development and tDOA assessment could build.

Keywords: AOP network; taxonomic domain of applicability; thyroid hormone system disruption.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adverse Outcome Pathways*
  • Animals
  • Fishes
  • Humans
  • Mammals
  • Reproduction
  • Risk Assessment / methods
  • Thyroid Hormones


  • Thyroid Hormones