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Valifenalate-induced non-adverse thyroid changes via adaptive induction of uridine 5'-diphospho-glucuronosyltransferase (UGT) in the liver of dogs and rats but not humans

  • 0Regulatory Science Associates, Largs, UK; Certis Belchim BV, Utrecht, the Netherlands.
Toxicology and Applied Pharmacology +

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November 5, 2024

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November 5, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Valifenalate fungicide causes thyroid changes in rats and dogs through liver enzyme induction. This mode of action is not relevant to humans, making valifenalate unlikely to affect human thyroid hormone levels.

Area Of Science

  • Toxicology
  • Endocrinology
  • Pharmacology

Background

  • Valifenalate fungicide exposure in toxicology studies induced minimal thyroid changes in rats and dogs.
  • These changes occurred at high doses and were associated with liver effects, necessitating investigation into the mode of action (MOA).

Purpose Of The Study

  • To elucidate the MOA of valifenalate-induced thyroid changes using in vivo and new approach methodologies (NAMs).
  • To assess the human relevance of the identified MOA for thyroid and developmental neurotoxicity risk assessment.

Main Methods

  • Weight of evidence approach combining in vivo and in vitro studies.
  • Investigated liver enzyme induction via nuclear receptors (CAR/PXR) and subsequent effects on thyroxine (T4) metabolism and thyroid stimulating hormone (TSH).
  • Cross-species in vitro assays using rat, dog, and human hepatocytes to evaluate cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) activity.

Main Results

  • Valifenalate induces liver enzyme expression and activity, increasing T4 metabolism and TSH levels, leading to thyroid follicular cell hypertrophy in rats and dogs.
  • In vitro studies confirmed increased T4 clearance and/or glucuronidation in rat and dog hepatocytes, but not in human hepatocytes.
  • Valifenalate did not affect T4-UGT activity or T4 clearance in human hepatocytes, and alternative human-relevant thyroid MOAs were excluded.

Conclusions

  • A causal relationship between liver enzyme induction and thyroid effects in rats and dogs was established.
  • The identified MOA is not relevant to humans, as human hepatocytes showed no significant response.
  • Valifenalate exposure is unlikely to cause adverse thyroid or developmental neurotoxicity effects in humans.

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