Citation:

LaLone, C., N. Basu, P. Browne, S. Edwards, M. Embry, F. Sewell, AND G. Hodges. International Consortium to Advance Cross-Species Extrapolation of the Effects of Chemicals in Regulatory Toxicology. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 40(12):3226-3233, (2021). https://doi.org/10.1002/etc.5214

Impact/Purpose:

The global regulatory landscape surrounding chemical safety is shifting away from animal testing and moving toward greater reliance on New Approach Methodologies (NAMs) including a rapid growth in molecular data and computational methods to achieve human and environmental protection goals. This change presents both new challenges and opportunities for advancing NAMs focused on a non-animal testing agenda and accelerating them into mainstream regulatory decision-making. One of the challenges in this regard is understanding how existing data on effects observed in few species, typically model test species, translate to the diversity of life and so can be used as surrogate information across a broader biological domain, reducing the need for additional data generation. To capitalize on advances in OMICs technologies and take advantage of existing toxicity data that can be generated without the use of whole animal models (e.g., high throughput screening and transcriptomics data, in vitro, and fish embryo testing), approaches in bioinformatics are starting to demonstrate  application for cross species extrapolations. Bioinformatics applies computational techniques to understand and organize information associated with molecules, including sequence and structural alignments, phylogeny evaluations, prediction of protein structures and function, gene annotation, and gene expression analyses, as examples, to understand biology and biological pathways. Advances in bioinformatics have begun to inform chemical safety evaluations, specifically informing species extrapolation. Tools and methods for species extrapolation that are built with bioinformatic approaches have been peer reviewed, published, and publicly accessible to enable their use in research and regulatory decision-making. To advance cross species extrapolation with an objective to inform a 21st century regulatory non-animal testing agenda for assessing human and ecological health, a global, cross-sector consortium has been created with the researchers, regulators, and advocates working toward integration of approaches in bioinformatics. knowledge for a larger diversity of species it is timely to bring together a global consortium to focus efforts. If successful, this will allow risk assessors to make better use of existing toxicological information and more easily consider the impact of chemicals on a variety of species.

Description:

Regulatory decisions surrounding chemical safety are based on human and environmental (ecological) protection goals. Historically, such decisions have relied on data from animal toxicity testing to inform hazard and risk assessment and determine whether chemicals pose a threat to human or environmental health. Traditionally, mammalian toxicity test data have driven human health considerations, and studies from select species representing different taxa have driven ecological considerations. Crosstalk and collaboration between human and ecological health knowledge¿streams have been limited. This represents a barrier for realizing the ultimate protection goal, which is the health of the planet and all its inhabitants, as exemplified by the One Health approach (https://www.cdc.gov/onehealth/). However, there are global efforts within governments, non-governmental organizations, academic research organizations, and industry sectors to bridge this gap and focus on achieving optimal health outcomes without the need for animal testing through recognition of the interconnectedness between people and all species that share the environment. With this in mind, it is recognized that focused and concerted efforts to advance methods for cross¿species extrapolation that leverage existing toxicity data from both mammals and other model organisms can be used to protect all species. To expedite the development and regulatory acceptance of computational methods, particularly bioinformatics, for informing cross¿species extrapolation for the evaluation of chemical safety, there is a need to bring together tool/database/method developers and regulators in a global cross¿sector collaborative consortium. These collaborations will help define regulatory needs, spark the creation of a bioinformatics toolbox, demonstrate the utility of various tools through coordinated application, and enhance communications with various stakeholders. The International Consortium to Advance Cross¿Species Extrapolation in Regulation (ICACSER; https://www. setac.org/page/scixspecies) is being developed to align with both the One Health approach and the shifting paradigm in regulatory toxicology articulated by the National Research Council in 2007. Specifically, a strategy was described to include more efficient and cost¿effective toxicity testing that takes advantage of cell¿based and computational approaches for evaluating chemical safety in the 21st century (National Research Council, 2007). Such methods move away from the whole animal testing that historically focused on apical endpoints, such as reproduction, growth, development, and mortality, toward testing molecular¿, cellular¿, and organ¿level changes that can be predictive of upstream apical changes in biology and used for regulatory decision¿making (National Research Council, 2007). It was envisioned that such a shift in toxicology would simultaneously reduce animal use. The objective of the present Focus article was to describe the challenges surrounding cross-species extrapolation in regulation and introduce new approach methods (NAMs) in bioinformatics that can enhance and broaden the ability to extrapolate toxicity knowledge beyond model organisms to the diversity of species through efforts lead by the developing ICACSER (Textbox 1).

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