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TOWARDS A COMPREHENSIVE CATALOG

Considering the scale of the current problem, and realistic future projections, a shift to next-generation assays is both timely and necessary. The proposed solution is to apply ultra-high-throughput toxicity testing with data-rich transcriptomic (RNA profiling), epigenomic (DNA methylation and histone modification) and metabolomic assays applied to genetic resources of non-mammalian, ecological plus biomedical, model species (e.g. Daphnia plus Drosophila, Hyallela plus C. elegans, killifish plus zebrafish embryos), made reliable, inexpensive and efficient by laboratory automation.

Only by obtaining millions of standardized and quantitative genetic measurements will shared mechanisms of toxicity be tied to “susceptibility” or “adverse outcome” pathways and subsequently extrapolated to humans and used in understanding and managing risks. By contrast to alternative proposed cell-based assays, a molecular database from toxicity testing on genetic panels of these selected whole-animal species that include well understood sentinels within natural ecosystems will facilitate across-evolution extrapolations that address both environment and human health issues.

In practice, three steps are proposed:

Step 1 is already underway by establishing a global collaborations around a new class of model species with genetic resources, explicitly chosen for this purpose, which are amendable to high-throughput assays and extrapolation to natural populations.

Step-2 builds the fit-for-purpose facilities necessary to generate the unprecedentedly large and comprehensive datasets that are otherwise not accessible to single or small groups of investigators. This ultra-high-throughput (robotics) infrastructure will give scientific support to the growing international Consortium for Environmental Omics and Toxicology (CEOT) and to environmental protection agencies and industries.

Step-3 improves the assays and technologies to further increase throughput and reduce costs to levels that deliver a comprehensive catalog of the molecular signatures and fitness related effects of all high-priority compounds and their mixtures.

This catalog can form the basis for a shared understanding of “tolerable risk” between regulators and industry. Commercialization of this knowledge and technology should allow unexpected developments that reduce the burden of screening for toxicity onto companies at the earliest stages of developing new consumer products (called responsible innovation). However, institutional support is needed to ensure that this enterprise can deliver solutions in time to be of practical value to REACH and WFD.

Environmental Genomics using high-throughput technologies (robots and DNA sequencers) can deliver a catalog of the effects of chemicals (e.g., metals) on gene responses in selected “sentinel organisms” such as the ecological genomic model species called Daphnia (commonly known as waterflea), used to monitor the presence of known chemicals, to detect the activities of unknown toxicants and, with additional research, used to predict the nature of the chemical effects on animals (including humans), their populations, and on ecosystem functions.

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