Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

Carlson Jeffrey M.; Janulewicz Patricia A.; Kleinstreuer Nicole C.Heiger-Bernays Wendy

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Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

机译：Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

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Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelop-mental outcomes in offspring. US federal risk assessments relyalmost exclusively on apical endpoints in animal models forderiving points of departure (PODs). New approach method-ologies (NAMs) such as high-throughput screening (HTS) andmechanistically informative in vitro human cell-based systems,combined with in vitro to in vivo extrapolation (IVIVE),supplement in vivo studies and provide an alternative approachto calculate/determine PODs. We examine how parameterizationof IVIVE models impacts the comparison between IVIVE-derivedequivalent administered doses (EADs) from thyroid-relevant invitro assays and the POD values that serve as the basis for riskassessments. Pesticide chemicals with thyroid-based in vitro bioactivity data from the US Tox21 HTS program were included (n=45). Depending on the model structure used for IVIVE analysis, up to 35 chemicals produced EAD values lower than the POD. Atotal of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVE-derived EAD values and the in vivo-derived POD values is highly dependent on model parameterization. Here, we derive a range of potentially thyroid-relevant doses that incorporate uncertainty in modeling choices and in vitro assay data.

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《Environmental Science & Technology: ES&T》 |2022年第9期|5620-5631|共12页
作者
Carlson Jeffrey M.; Janulewicz Patricia A.; Kleinstreuer Nicole C.Heiger-Bernays Wendy;
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作者单位

Boston Univ;

NIEHS;

NIEHS;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类环境科学、安全科学;
关键词
pesticides; point of departure; in vivo to in vitro extrapolation; thyroid; EDSP; NAMs; hazard assessment; PRENATAL EXPOSURE; IN-VITRO; ORGANOCHLORINE PESTICIDES; HORMONE LEVELS; SCREENING DATA; TOXICITY; RISK; PREGNANCY; NEWBORNS; PRIORITIZATION;

Impact of High-Throughput Model Parameterization and Data Uncertainty on Thyroid-Based Toxicological Estimates for Pesticide Chemicals

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