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Utility of Developmental Neurotoxicity In Vitro Battery to Address Regulatory Challenges
Citation:
Jackson, B., L. Minnema, Y. Wu, C. Schlosser, A. Hofstra, K. Carstens, AND T. Shafer. Utility of Developmental Neurotoxicity In Vitro Battery to Address Regulatory Challenges. 12th World Congress on Alternatives and Animal Use in the Life Sciences, Niagara Falls, CANADA, August 27 - 31, 2023. https://doi.org/10.23645/epacomptox.24058698
Impact/Purpose:
Poster presented to the 12th World Congress on Alternatives and Animal Use in the Life Sciences meeting August 2023. Assessment of Developmental Neurotoxicity (DNT) using animal-based Guideline studies is expensive, time consuming, and does not always yield actionable data. Further, DNT assessment is not required under TSCA and the Guideline DNT study is a triggered study under FIFRA. Consequently, few of the tens of thousands of chemicals to which humans may be exposed have been evaluated for DNT hazard. To address this issue, New Approach Methodologies (NAMs) are being developed that can help provide data for risk decisions under FIFRA and TSCA. As these methods become more widely utilized, they can also provide information for other types of environmental decision-making as well.
Description:
Limitations to the in vivo developmental neurotoxicity (DNT) test are well known, including high variability, low reproducibility, and limited historical control data. Neuropathological and neurobehavioral assessments in the DNT guideline are challenging due to methodology, lack of mechanistic understanding, and the high level of expertise required to conduct these assessments. The DNT in vitro battery (IVB) is an alternative testing strategy that is mechanistically informed and can be useful for screening and weight of evidence evaluations. This case study investigates the utility of the DNT IVB to inform uncertainties in an existing in vivo DNT study to refine toxicity endpoint selection for regulatory risk assessment. Acibenzolar-S-methyl was tested in the DNT IVB, and data were analyzed using the US EPA ToxCast Pipeline. Outcomes were examined in terms of consistency of evidence between assays assessing the same neurodevelopmental endpoint and with known biological relationships. Results of the battery were compared to in vivo results using an Integrated Approaches to Testing and Assessment (IATA) framework. Examination of outcomes across the DNT IVB revealed that acibenzolar-S-methyl does not interact with key neurodevelopmental processes in vitro, such as proliferation, migration, apoptosis, differentiation, neurite maturation, synaptogenesis, and neural network connectivity. These results indicate that acibenzolar-S-methyl does not disrupt key neurodevelopmental processes in vitro. This case study highlights the ability of the DNT IVB provide evidence to inform onpotential DNT hazard without the need to conduct further vertebrate testing. (This abstract does not reflect the policy of the US Environmental Protection Agency)
URLs/Downloads:
DOI: Utility of Developmental Neurotoxicity In Vitro Battery to Address Regulatory Challenges
ASM DNT IVB (WC12 CANADA) POSTER_FINAL.PDF (PDF, NA pp, 877.682 KB, about PDF)