Current status and future directions for a neurotoxicity hazard assessment framework that integrates in silico approaches

Kevin M Crofton; Arianna Bassan; Mamta Behl; Yaroslav G Chushak; Ellen Fritsche; Jeffery M Gearhart; Mary Sue Marty; Moiz Mumtaz; Manuela Pavan; Patricia Ruiz; Magdalini Sachana; Rajamani Selvam; Timothy J Shafer; Lidiya Stavitskaya; David T Szabo; Steven T Szabo; Raymond R Tice; Dan Wilson; David Woolley; Glenn J Myatt

doi:10.1016/j.comtox.2022.100223

Current status and future directions for a neurotoxicity hazard assessment framework that integrates in silico approaches

Comput Toxicol. 2022 May:22:100223. doi: 10.1016/j.comtox.2022.100223. Epub 2022 Mar 17.

Authors

Kevin M Crofton¹, Arianna Bassan², Mamta Behl³, Yaroslav G Chushak⁴, Ellen Fritsche⁵, Jeffery M Gearhart⁴, Mary Sue Marty⁶, Moiz Mumtaz⁷, Manuela Pavan², Patricia Ruiz⁷, Magdalini Sachana⁸, Rajamani Selvam⁹, Timothy J Shafer¹⁰, Lidiya Stavitskaya⁹, David T Szabo¹¹, Steven T Szabo¹², Raymond R Tice¹³, Dan Wilson⁶, David Woolley¹⁴, Glenn J Myatt¹⁵

Affiliations

¹ R3Fellows LLC, Durham, NC, 27705, USA.
² Innovatune srl, Via Giulio Zanon 130/D, 35129 Padova, Italy.
³ Division of the National Toxicology Program, National Institutes of Environmental Health Sciences, Durham, NC 27709, USA.
⁴ Henry M Jackson Foundation for the Advancement of Military Medicine, Wright-Patterson AFB, OH 45433, USA.
⁵ IUF - Leibniz Research Institute for Environmental Medicine & Medical Faculty Heinrich-Heine-University, Düsseldorf, Germany.
⁶ The Dow Chemical Company, Midland, MI 48667, USA.
⁷ Agency for Toxic Substances and Disease Registry, US Department of Health and Human Services, Atlanta, GA, USA.
⁸ Environment Health and Safety Division, Environment Directorate, Organisation for Economic Co-Operation and Development (OECD), 75775 Paris Cedex 16, France.
⁹ Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Silver Spring, MD 20993, USA.
¹⁰ Biomolecular and Computational Toxicology Division, Center for Computational Toxicology and Exposure, US EPA, Research Triangle Park, NC, USA.
¹¹ PPG Industries, Pittsburgh, PA 15146, USA.
¹² Szabo Consulting LLC, Durham, NC 27703, USA.
¹³ RTice Consulting, Hillsborough, NC 27278, USA.
¹⁴ ForthTox Limited, Linlithgow, UK.
¹⁵ Instem, Columbus, OH 43215, USA.

Abstract

Neurotoxicology is the study of adverse effects on the structure or function of the developing or mature adult nervous system following exposure to chemical, biological, or physical agents. The development of more informative alternative methods to assess developmental (DNT) and adult (NT) neurotoxicity induced by xenobiotics is critically needed. The use of such alternative methods including in silico approaches that predict DNT or NT from chemical structure (e.g., statistical-based and expert rule-based systems) is ideally based on a comprehensive understanding of the relevant biological mechanisms. This paper discusses known mechanisms alongside the current state of the art in DNT/NT testing. In silico approaches available today that support the assessment of neurotoxicity based on knowledge of chemical structure are reviewed, and a conceptual framework for the integration of in silico methods with experimental information is presented. Establishing this framework is essential for the development of protocols, namely standardized approaches, to ensure that assessments of NT and DNT based on chemical structures are generated in a transparent, consistent, and defendable manner.

Keywords: Computational toxicology; Developmental neurotoxicity; Expert system; Hazard identification; In silico; In silico toxicology protocols; Neurotoxicity; Profilers; QSAR; Read-across; Risk assessment.

Grants and funding

R44 ES026909/ES/NIEHS NIH HHS/United States