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

Abstract

Chemical-induced alteration of maternal thyroid hormone levels may increase the risk of adverse neurodevelopmental outcomes in offspring. US federal risk assessments rely almost exclusively on apical endpoints in animal models for deriving points of departure (PODs). New approach methodologies (NAMs) such as high-throughput screening (HTS) and mechanistically informative in vitro human cell-based systems, combined with in vitro to in vivo extrapolation (IVIVE), supplement in vivo studies and provide an alternative approach to calculate/determine PODs. We examine how parameterization of IVIVE models impacts the comparison between IVIVE-derived equivalent administered doses (EADs) from thyroid-relevant in vitro assays and the POD values that serve as the basis for risk assessments. 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. A total of 10 chemicals produced EAD values higher than the POD regardless of the model structure. The relationship between IVIVEderived 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. KEYWORDS: pesticides, point of departure, in vivo to in vitro extrapolation, thyroid, EDSP, NAMs, hazard assessment

Dissecting the Enantioselective Neurotoxicity of Isocarbophos: Chiral Insight from Cellular, Molecular, and Computational Investigations

“…In environmental toxicology research, animal testing is a frequently used experimental method, but it has some potential disadvantages such as time-consuming, laborious, high cost, and many uncontrollable factors. , Conversely, in vitro cell-based assays have the advantages of rapidity, simplicity, and low cost, and the use of cell-based assays to replace in vivo testing has gradually become an important development trend in the toxicological risk assessments of environmental pollutants. , Meanwhile, the validity of such technique has been proved by different studies related to environmental toxicities, for instance, endocrine disrupting toxicity, genotoxicity, immunotoxicity, neurotoxicity, and reproductive toxicity. , In order to inspect the neurotoxicity of chiral isocarbophos on human health, we first used the classical neuronal cell modelhuman neuroblastoma cell line SH-SY5Yto probe the hidden secret at the enantiomeric scale. Figure shows the relationships between exposure time and cell survival rate with different concentrations of isocarbophos enantiomers.…”

“…69,70 Meanwhile, the validity of such technique has been proved by different studies related to environmental toxicities, for instance, endocrine disrupting toxicity, genotoxicity, immunotoxicity, neurotoxicity, and reproductive toxicity. 71,72 In order to inspect the neurotoxicity of chiral isocarbophos on human health, we first used the classical neuronal cell model�human neuroblastoma cell line SH-SY5Y�to probe the hidden secret at the enantiomeric scale. Figure 2 shows the relationships between exposure time and cell survival rate with different concentrations of isocarbophos enantiomers.…”

Disruption of the thyroid hormone system and patterns of altered thyroid hormones after gestational chemical exposures in rodents – a systematic review

“…However, most of the studies considered here measured only a few endpoints useful for elucidating potential MOAs. Accordingly, we had to make inferences about MOAs from extraneous sources, which may compromise their validity due to complications with in vitro to in vivo extrapolations and differences in exposure time scales ( 32 – 35 ).…”

Advancing Toxicity Predictions: A Review on in Vitro to in Vivo Extrapolation in Next-Generation Risk Assessment

“…Endocrine-disrupting chemicals (EDCs) are an important category of new pollutants that can disrupt an organism’s endocrine system, causing adverse effects on the organism and even its offspring. IVIVE-related studies of EDC focus on compounds that affect estrogen, androgen, and the thyroid system …”