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A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm
Citation:
Johnson, K., S. Auerbach, T. Stevens, T. Barton-Maclaren, E. Costa, R. Currie, D. Dalmas Wilk, S. Haq, J. Rager, A. Reardon, L. Wehmas, A. Williams, J. O'Brien, C. Yauk, J. LaRocca, AND S. Pettit. A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 190(2):127-132, (2022). https://doi.org/10.1093/toxsci/kfac097
Impact/Purpose:
With advances in technology, increases in throughput, and reductions in cost, the use of molecular data ,like gene expression, to assess the risk of environmental chemicals has been expected but rarely used. This paper proposes a framework to explore the practical, future development of gene expression methods to refine and replace traditional, regulatory toxicity testing based on long term whole animal, tissue, and organ level effects. Four basic principles are described that would need to be accepted by stakeholders for this effort to be realized. 1) Messenger RNAs, which are copies of genes used to make proteins necessary for normal cell function and growth, are a reliable tool for measuring changes in gene expression that will lead to physical effects on an animal. 2) Changes in gene expression can signal harm or return-to-normal in an animal after exposure to chemicals or other stressors, like heat or diet. 3) Gene expression changes consistently with chemical exposure in a way that can be modeled to set a dose level where molecular (and physical) effects are not expected. This can be done in short-term animal tests. 4) This dose level will help protect human health resulting from chemical exposures. If all four principles are supported and accepted, this framework could transform chemical risk assessment by more quickly setting health protective chemical thresholds while reducing long term animal studies. This effort should be of interest to multiple EPA program and regional offices.
Description:
Use of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic framework is proposed to explore the feasibility and future development of transcriptomic methods to refine and replace the current apical endpoint-based regulatory toxicity testing paradigm. Four foundational principles are outlined and discussed that would need to be accepted by stakeholders prior to this transformative vision being realized. Well-supported by current knowledge, the first principle is that transcriptomics is a reliable tool for detecting alterations in gene expression that result from endogenous or exogenous influences on the test organism. The second principle states that alterations in gene expression are indicators of adverse or adaptive biological responses to stressors in an organism. Principle 3 is that transcriptomics can be employed to establish a benchmark dose-based point of departure (POD) from short-term, in vivo studies at a dose level below which a concerted molecular change (CMC) is not expected. Finally, Principle 4 states that the use of a transcriptomic POD (set at the CMC dose level) will support a human health-protective risk assessment. If all four principles are substantiated, this vision is expected to transform aspects of the industrial chemical and agrochemical risk assessment process that are focused on establishing safe exposure levels for mammals across numerous toxicological contexts resulting in a significant reduction in animal use while providing equal or greater protection of human health. Importantly, these principles and approaches are also generally applicable for ecological safety assessment.
URLs/Downloads:
DOI: A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm
https://pubmed.ncbi.nlm.nih.gov/36165699