Abstract
The continual introduction of new chemicals into the market necessitates fast, efficient testing strategies for evaluating their toxicity. Ideally, these high-throughput screening (HTS) methods should capture the entirety of biological complexity while minimizing reliance on expensive resources that are required to assess diverse phenotypic endpoints. In recent years, the zebrafish (Danio rerio) has become a preferred vertebrate model to conduct rapid in vivo toxicity tests. Previously, using HTS data on 1060 chemicals tested as part of the ToxCast program, we showed that early, 24 h post-fertilization (hpf), behavioral responses of zebrafish embryos are predictive of later, 120 h post-fertilization, adverse developmental endpoints—indicating that embryonic behavior is a useful endpoint related to observable morphological effects. Here, our goal was to assess the contributions (i.e., information gain) from multiple phenotypic data streams and propose a framework for efficient identification of chemical hazards. We systematically swept through analysis parameters for data on 24 hpf behavior, 120 hpf behavior, and 120 hpf morphology to optimize settings for each of these assays. We evaluated the concordance of data from behavioral assays with that from morphology. We found that combining information from behavioral and mortality assessments captures early signals of potential chemical hazards, obviating the need to evaluate a comprehensive suite of morphological endpoints in initial screens for toxicity. We have demonstrated that such a screening strategy is useful for detecting compounds that elicit adverse morphological responses, in addition to identifying hazardous compounds that do not disrupt the underlying morphology. The application of this design for rapid preliminary toxicity screening will accelerate chemical testing and aid in prioritizing chemicals for risk assessment.
Highlights
New chemicals are continually introduced into commerce and the environment
Using approaches detailed in sections Value of Information of Morphological Endpoints and Sensitivity Analysis of Behavioral Responses under Methods, we compared the sensitivities of behavior in detecting chemicals that elicited adverse effects in each Super Endpoint (SE) separately
When mortality (SE1) was treated as the truth set, we found that both 24 hpf and 120 hpf behavioral assays have sensitivities of 0.65 and 0.7 respectively
Summary
New chemicals are continually introduced into commerce and the environment. Numerous efforts have been made by the U.S Environmental Protection Agency (EPA) and other regulatory agencies to assess hazards and exposures of these emerging chemicals and the huge backlog of untested chemicals (Pool and Rusch, 2014). ToxCastTM and Tox21TM use a wide variety of in-vitro (biochemical and cell-based) assays, and in-silico methods for testing large compound libraries for their potential toxicity (US EPA, 2015) Such in-vitro high-throughput screening (HTS) methods are useful because they are quick, relatively cheap and reduce the need for traditional animal-based toxicity testing. They have the potential to consider multiple cell types, assess the effects of mixtures, and test effects at several different doses. Toxicity testing using zebrafish can inform adverse outcome pathways by capturing relevant biology from a broad spectrum of observable phenotypes across developmental stages Data collected from such whole animal studies carry information that helps us in understanding the full implications of these chemicals in an organism. Given the large number of chemicals that need to be evaluated, the time and costs associated with generating such hazard data are significant and can be difficult to systematically implement
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