Use of computational toxicology tools to predict in vivo endpoints associated with Mode of Action and the endocannabinoid system: A case study with chlorpyrifos, chlorpyrifos-oxon and Δ9Tetrahydrocannabinol

Silva, Marilyn H.; Kwok, Ryan Kin-Hin

doi:10.1016/j.crtox.2022.100064

Cited by 4 publications

(3 citation statements)

References 162 publications

(305 reference statements)

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“…In addition, when the results were not clear, as was the case when a single endpoint was explored with 2 different assays with conflicting results, we added an “?” in our extraction files. The cytotoxicity limit for each chemical affected the number of active hit calls ( 18 ), however, we did not exclude chemicals that may be active only at high concentrations.…”

Section: Methodsmentioning

confidence: 99%

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

Forner-Piquer,

Baig,

Kortenkamp

2024

Front. Endocrinol.

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We present a comprehensive overview of changes in thyroxine (T4) and thyroid stimulating hormone (TSH) serum concentrations after pre-gestational, gestational and/or lactation exposures of rodents to various chemicals that affect the thyroid hormone system. We show that T4 and TSH changes consistent with the idealized view of the hypothalamic-pituitary-thyroid (HPT) feedback loop (T4 decrements accompanied by TSH increases) are observed with only a relatively small set of chemicals. Most substances affect concentrations of various thyroid hormones without increasing TSH. Studies of altered T4 concentrations after gestational exposures are limited to a relatively small set of chemicals in which pesticides, pharmaceuticals and industrial chemicals are under-represented. Our risk-of-bias analysis exposed deficits in T4/TSH analytics as a problem area. By relating patterns of T4 – TSH changes to mode-of-action (MOA) information, we found that chemicals capable of disrupting the HPT feedback frequently affected thyroid hormone synthesis, while substances that produced T4 serum decrements without accompanying TSH increases lacked this ability, but often induced liver enzyme systems responsible for the elimination of TH by glucuronidation. Importantly, a multitude of MOA leads to decrements of serum T4. The current EU approaches for identifying thyroid hormone system-disrupting chemicals, with their reliance on altered TH serum levels as indicators of a hormonal mode of action and thyroid histopathological changes as indicators of adversity, will miss chemicals that produce T4/T3 serum decreases without accompanying TSH increases. This is of concern as it may lead to a disregard for chemicals that produce developmental neurotoxicity by disrupting adequate T4/T3 supply to the brain, but without increasing TSH.

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Section: Methodsmentioning

confidence: 99%

“…in our extraction files. The cytotoxicity limit for each chemical affected the number of active hit calls (18), however, we did not exclude chemicals that may be active only at high concentrations.…”

Section: Data Extraction and Synthesismentioning

confidence: 99%

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

Forner-Piquer,

Baig,

Kortenkamp

2024

Front. Endocrinol.

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“…As a clarification, "HTTK," is a methodology using in vitro TK assays and generic TK to make predictions by IVIVE, provided in the "httk" R package (Wambaugh et al, 2019 (Breen et al, 2021;Ring et al, 2017;Tan et al, 2007;Wambaugh et al, 2019). The initial R codes for HTTK-Pop were provided by Dr. John Wambaugh, PhD, US EPA and then modified to compute age-specific values for each of the selected ToxCast/ Tox21 assays used as data inputs (Silva & Kwok, 2022). Predictions in young children are higher than adults because of (based on per kilogram body weight) their larger livers, greater blood flow and higher clearance at ages 2-10 ( Ginsberg et al, 2002;Ginsberg, Slikker Jr, Bruckner, & Sonawane, 2004).…”

Section: Age-refined Population-based High Throughput Toxicokinetics ...mentioning

confidence: 99%

Use of computational toxicology models to predict toxicological points of departure: A case study with triazine herbicides

Silva

Kwok

2022

Birth Defects Research

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Background: Atrazine simazine and propazine, widely used triazine herbicides on food crops and in residential areas, disrupt the neuroendocrine system raising human health concerns. USEPA developed a PBPK model based on triazine common Mode of Action (MOA)-suppression of luteinizing hormone surge in female rats-to generate human regulatory points of departure (POD: mg/kg/day). We compared triazine Human Administered Equivalent Dose (AED Human mg/kg/day) predictions from open access computational tools to the PBPK PODs to assess concordance.Methods: Computational tools were the following: ToxCast/Tox21 in vitro assays; Toxicogenomic databases to assess concordance with ToxCast/Tox21 targets; integrated chemical environment (ICE) models with ToxCast/Tox21 inputs to predict AED Human PODs and population-based age-refined high throughput toxicokinetics (HTTK-Pop) to compare to age-related PBPK PODs.Results: ToxCast/Tox21 assays identified critical targets in the triazine common MOA and gene databases; ICE AED Human predictions were mainly concordant with the USEPA PBPK PODs quantitatively. Low fold-differences between PBPK POD and ICE AED Human predictions indicated that the ICE models are health-protective. HTTK-Pop age-refinements were within 10-fold of the USEPA PBPK PODs. Conclusions: CompTox tools were used to identify assay targets in the MOA and identify potential molecular initiating targets in the adverse outcome pathway for potential use in risk assessment.

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CompTox Chemicals Dashboard

2024

Encyclopedia of Toxicology

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Use of computational toxicology tools to predict in vivo endpoints associated with Mode of Action and the endocannabinoid system: A case study with chlorpyrifos, chlorpyrifos-oxon and Δ9Tetrahydrocannabinol

Cited by 4 publications

References 162 publications

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

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

Use of computational toxicology models to predict toxicological points of departure: A case study with triazine herbicides

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