Computational Toxicology as Implemented by the U.S. EPA: Providing High Throughput Decision Support Tools for Screening and Assessing Chemical Exposure, Hazard and Risk

Computational toxicology is the application of mathematical and computer models to help assess chemical hazards and risks to human health and the environment. Supported by advances in informatics, high-throughput screening (HTS) technologies, and systems biology, the U.S. Environmental Protection Agency EPA is developing robust and flexible computational tools that can be applied to the thousands of chemicals in commerce, and contaminant mixtures found in air, water, and hazardous-waste sites. The Office of Research and Development (ORD) Computational Toxicology Research Program (CTRP) is composed of three main elements. The largest component is the National Center for Computational Toxicology (NCCT), which was established in 2005 to coordinate research on chemical screening and prioritization, informatics, and systems modeling. The second element consists of related activities in the National Health and Environmental Effects Research Laboratory (NHEERL) and the National Exposure Research Laboratory (NERL). The third and final component consists of academic centers working on various aspects of computational toxicology and funded by the U.S. EPA Science to Achieve Results (STAR) program. Together these elements form the key components in the implementation of both the initial strategy, A Framework for a Computational Toxicology Research Program (U.S. EPA, 2003), and the newly released The U.S. Environmental Protection Agency's Strategic Plan for Evaluating the Toxicity of Chemicals (U.S. EPA, 2009a). Key intramural projects of the CTRP include digitizing legacy toxicity testing information toxicity reference database (ToxRefDB), predicting toxicity (ToxCast) and exposure (ExpoCast), and creating virtual liver (v-Liver) and virtual embryo (v-Embryo) systems models. U.S. EPA-funded STAR centers are also providing bioinformatics, computational toxicology data and models, and developmental toxicity data and models. The models and underlying data are being made publicly available through the Aggregated Computational Toxicology Resource (ACToR), the Distributed Structure-Searchable Toxicity (DSSTox) Database Network, and other U.S. EPA websites. While initially focused on improving the hazard identification process, the CTRP is placing increasing emphasis on using high-throughput bioactivity profiling data in systems modeling to support quantitative risk assessments, and in developing complementary higher throughput exposure models. This integrated approach will enable analysis of life-stage susceptibility, and understanding of the exposures, pathways, and key events by which chemicals exert their toxicity in developing systems (e.g., endocrine-related pathways). The CTRP will be a critical component in next-generation risk assessments utilizing quantitative high-throughput data and providing a much higher capacity for assessing chemical toxicity than is currently available.

[1]  Daniel L Villeneuve,et al.  Transcription of key genes regulating gonadal steroidogenesis in control and ketoconazole- or vinclozolin-exposed fathead minnows. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[2]  J. Wendt,et al.  Relationships between composition and pulmonary toxicity of prototype particles from coal combustion and pyrolysis , 2008 .

[3]  Shayn M Peirce,et al.  Agent-based modeling of multicell morphogenic processes during development. , 2007, Birth defects research. Part C, Embryo today : reviews.

[4]  Takahiro Kobayashi,et al.  Bioassay-directed fractionation and salmonella mutagenicity of automobile and forklift diesel exhaust particles. , 2003, Environmental health perspectives.

[5]  Daniel B. Oerther,et al.  Assessment of fecal pollution sources in a small northern-plains watershed using PCR and phylogenetic analyses of Bacteroidetes 16S rRNA gene. , 2007, FEMS microbiology ecology.

[6]  Julian Lewis,et al.  From Signals to Patterns: Space, Time, and Mathematics in Developmental Biology , 2008, Science.

[7]  Daniel L Villeneuve,et al.  Relationship of plasma sex steroid concentrations in female fathead minnows to reproductive success and population status. , 2008, Aquatic toxicology.

[8]  Melvin E Andersen,et al.  Molecular circuits, biological switches, and nonlinear dose-response relationships. , 2002, Environmental health perspectives.

[9]  Robert J Kavlock,et al.  Computational toxicology--a state of the science mini review. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[10]  David Basanta,et al.  The Evolution of Robust Development and Homeostasis in Artificial Organisms , 2008, PLoS Comput. Biol..

[11]  L. Gray,et al.  Effects of two fungicides with multiple modes of action on reproductive endocrine function in the fathead minnow (Pimephales promelas). , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  Michael W Hornung,et al.  Inhibition of thyroid hormone release from cultured amphibian thyroid glands by methimazole, 6-propylthiouracil, and perchlorate. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[13]  Daniel L Villeneuve,et al.  Gene expression responses in male fathead minnows exposed to binary mixtures of an estrogen and antiestrogen , 2009, BMC Genomics.

[14]  Mary Daniels,et al.  Modulation of pulmonary inflammatory responses and antimicrobial defenses in mice exposed to diesel exhaust. , 2008, Toxicology and applied pharmacology.

[15]  Robert Kavlock,et al.  The U.S. Environmental Protection Agency Strategic Plan for Evaluating the Toxicity of Chemicals , 2010, Journal of toxicology and environmental health. Part B, Critical reviews.

[16]  Frank E. Huggins,et al.  Ultrafine ash aerosols from coal combustion: Characterization and health effects ☆ , 2007 .

[17]  Michael W Hornung,et al.  Early temporal effects of three thyroid hormone synthesis inhibitors in Xenopus laevis. , 2010, Aquatic toxicology.

[18]  L. Neas,et al.  Increased Plasma Reactive Oxidant Levels and Their Relationship to Blood Cells, Total IgE, and Allergen-specific IgE Levels in Asthmatic Children , 2009, The Journal of asthma : official journal of the Association for the Care of Asthma.

[19]  Indoor and outdoor concentrations of nitrogen dioxide, volatile organic compounds, and polycyclic aromatic hydrocarbons among MICA-Air households in Detroit, Michigan , 2010 .

[20]  Wei Wang,et al.  The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics , 2007, Mammalian Genome.

[21]  Richard S. Judson,et al.  Profiling Bioactivity of the ToxCast Chemical Library Using BioMAP Primary Human Cell Systems , 2009, Journal of biomolecular screening.

[22]  Daniel L Villeneuve,et al.  A graphical systems model to facilitate hypothesis-driven ecotoxicogenomics research on the teleost brain-pituitary-gonadal axis. , 2007, Environmental science & technology.

[23]  Rajiv K. Saxena,et al.  Suppression of Basal and Cytokine Induced Expression of MHC, ICAM 1 and B7 Markers on Mouse Lung Epithelial Cells Exposed to Diesel Exhaust Particles , 2007 .

[24]  Rong-Lin Wang,et al.  DNA microarray application in ecotoxicology: Experimental design, microarray scanning, and factors affecting transcriptional profiles in a small fish species , 2008, Environmental toxicology and chemistry.

[25]  Ann Richard,et al.  ACToR--Aggregated Computational Toxicology Resource. , 2008, Toxicology and applied pharmacology.

[26]  Daniel B. Oerther,et al.  Bifidobacteria in Feces and Environmental Waters , 2007, Applied and Environmental Microbiology.

[27]  Ilona Jaspers,et al.  Diesel Exhaust Enhanced Susceptibility to Influenza Infection is Associated with Decreased Surfactant Protein Expression , 2007, Inhalation toxicology.

[28]  F. Collins,et al.  Transforming Environmental Health Protection , 2008, Science.

[29]  J. Domingo,et al.  Turkey fecal microbial community structure and functional gene diversity revealed by 16S rRNA gene and metagenomic sequences , 2008, The Journal of Microbiology.

[30]  Ann M. Richard,et al.  Toward a public toxicogenomics capability for supporting predictive toxicology: survey of current resources and chemical indexing of experiments in GEO and ArrayExpress. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[31]  Gerald T Ankley,et al.  What is normal? A characterization of the values and variability in reproductive endpoints of the fathead minnow, Pimephales promelas. , 2007, Comparative biochemistry and physiology. Toxicology & pharmacology : CBP.

[32]  Abraham Nyska,et al.  One-Month Diesel Exhaust Inhalation Produces Hypertensive Gene Expression Pattern in Healthy Rats , 2008, Environmental health perspectives.

[33]  Gerald T. Ankley,et al.  Profiling lipid metabolites yields unique information on sex- and time-dependent responses of fathead minnows (Pimephales promelas) exposed to 17α-ethynylestradiol , 2009, Metabolomics.

[34]  Stephen W. Edwards,et al.  Endocrine disrupting chemicals in fish: developing exposure indicators and predictive models of effects based on mechanism of action. , 2009, Aquatic toxicology.

[35]  Ann M Richard,et al.  Future of toxicology--predictive toxicology: An expanded view of "chemical toxicity". , 2006, Chemical research in toxicology.

[36]  Gerald T. Ankley,et al.  Characterization of Reproductive Toxicity of Vinclozolin in the Fathead Minnow and Co-Treatment with an Androgen to Confirm an Anti-Androgenic Mode of Action , 2007 .

[37]  Richard Newman,et al.  Shape Homeostasis in Virtual Embryos , 2009, Artificial Life.

[38]  Gerald T. Ankley,et al.  Mechanistic Computational Model of Ovarian Steroidogenesis to Predict Biochemical Responses to Endocrine Active Compounds , 2007, Annals of Biomedical Engineering.

[39]  Alexander Golbraikh,et al.  A Novel Two-Step Hierarchical Quantitative Structure–Activity Relationship Modeling Work Flow for Predicting Acute Toxicity of Chemicals in Rodents , 2009, Environmental health perspectives.

[40]  Ann M Richard,et al.  Chemical structure indexing of toxicity data on the internet: moving toward a flat world. , 2006, Current opinion in drug discovery & development.

[41]  Nicholas S. Flann,et al.  Discovering novel cancer therapies: A computational modeling and search approach , 2008, 2008 IEEE Symposium on Computational Intelligence in Bioinformatics and Computational Biology.

[42]  Joseph E Tietge,et al.  Progress towards development of an amphibian-based thyroid screening assay using Xenopus laevis. Organismal and thyroidal responses to the model compounds 6-propylthiouracil, methimazole, and thyroxine. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  Seung-Hyun Cho,et al.  Differential potentiation of allergic lung disease in mice exposed to chemically distinct diesel samples. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[44]  Orin C. Shanks,et al.  Identification of chicken-specific fecal microbial sequences using a metagenomic approach. , 2007, Water research.

[45]  Ivan Rusyn,et al.  The Use of Cell Viability Assay Data Improves the Prediction Accuracy of Conventional Quantitative Structure Activity Relationship Models of Animal Carcinogenicity , 2007 .

[46]  Robert Kavlock,et al.  The Future of Toxicity Testing for Environmental Contaminants , 2009, Environmental health perspectives.

[47]  Christopher S Mazur,et al.  Cross-species comparison of conazole fungicide metabolites using rat and rainbow trout (Onchorhynchus mykiss) hepatic microsomes and purified human CYP 3A4. , 2008, Environmental science & technology.

[48]  Gerald T Ankley,et al.  Characterization of ontogenetic changes in gene expression in the fathead minnow (Pimephales promelas) , 2009, Environmental toxicology and chemistry.

[49]  Richard S. Judson,et al.  Profiling the activity of environmental chemicals in prenatal developmental toxicity studies using the U.S. EPA's ToxRefDB. , 2009, Reproductive toxicology.

[50]  G. Ankley,et al.  NMR analysis of male fathead minnow urinary metabolites: a potential approach for studying impacts of chemical exposures. , 2007, Aquatic toxicology.

[51]  T. B. Knudsen,et al.  Virtual Tissues and Developmental Systems Biology , 2010 .

[52]  Robert J Kavlock,et al.  Understanding mechanisms of toxicity: insights from drug discovery research. , 2008, Toxicology and applied pharmacology.

[53]  Melvin E Andersen,et al.  Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment , 2009, Risk analysis : an official publication of the Society for Risk Analysis.

[54]  Stefan Wuertz,et al.  Quo vadis source tracking? Towards a strategic framework for environmental monitoring of fecal pollution. , 2007, Water research.

[55]  Michael B. Yaffe,et al.  Cytokine-Induced Signaling Networks Prioritize Dynamic Range over Signal Strength , 2008, Cell.

[56]  S. Hester,et al.  Differential Transcriptional Changes in Mice Exposed to Chemically Distinct Diesel Samples , 2010, Biomedical informatics insights.

[57]  John C. Lipscomb,et al.  In Vitro Metabolism of the Fungicide and Environmental Contaminant trans-bromuconazole and Implications for Risk Assessment , 2007, Journal of toxicology and environmental health. Part A.

[58]  James A Glazier,et al.  Analysis of tissue flow patterns during primitive streak formation in the chick embryo. , 2005, Developmental biology.

[59]  R. Judson,et al.  The Toxicity Data Landscape for Environmental Chemicals , 2008, Environmental health perspectives.

[60]  David M. Reif,et al.  Profiling Chemicals Based on Chronic Toxicity Results from the U.S. EPA ToxRef Database , 2008, Environmental health perspectives.

[61]  Rong-Lin Wang,et al.  Altered gene expression in the brain and ovaries of zebrafish (Danio Rerio) exposed to the aromatase inhibitor fadrozole: Microarray analysis and hypothesis generation , 2009, Environmental toxicology and chemistry.

[62]  Daniel L Villeneuve,et al.  Effects of a 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane, on the fathead minnow reproductive axis. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[63]  S A Newman,et al.  On multiscale approaches to three-dimensional modelling of morphogenesis , 2005, Journal of The Royal Society Interface.

[64]  David M. Reif,et al.  In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project , 2009, Environmental health perspectives.

[65]  Daniel L Villeneuve,et al.  Quantitative proteomic profiles of androgen receptor signaling in the liver of fathead minnows (Pimephales promelas). , 2009, Journal of proteome research.

[66]  Karen Lowrie,et al.  Toxicity testing in the 21st century. , 2009, Risk analysis : an official publication of the Society for Risk Analysis.

[67]  Robert J Kavlock,et al.  Profiling the reproductive toxicity of chemicals from multigeneration studies in the toxicity reference database. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[68]  Elaine A. Cohen Hubal,et al.  Exposure as Part of a Systems Approach for Assessing Risk , 2009, Environmental health perspectives.

[69]  Elaine A Cohen Hubal,et al.  Biologically relevant exposure science for 21st century toxicity testing. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[70]  Dongsun Cao,et al.  Diesel exhaust particulate-induced activation of Stat3 requires activities of EGFR and Src in airway epithelial cells. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[71]  Ann M. Richard,et al.  DSSTox chemical-index files for exposure-related experiments in ArrayExpress and Gene Expression Omnibus: enabling toxico-chemogenomics data linkages , 2009, Bioinform..

[72]  Philipp J. Keller,et al.  Reconstruction of Zebrafish Early Embryonic Development by Scanned Light Sheet Microscopy , 2008, Science.

[73]  Daniel L Villeneuve,et al.  Linkage of biochemical responses to population‐level effects: A case study with vitellogenin in the fathead minnow (Pimephales promelas) , 2007, Environmental toxicology and chemistry.

[74]  Halûk Özkaynak,et al.  A participant-based approach to indoor/outdoor air monitoring in community health studies , 2009, Journal of Exposure Science and Environmental Epidemiology.

[75]  G. Ankley,et al.  Investigating compensation and recovery of fathead minnow (Pimephales promelas) exposed to 17alpha-ethynylestradiol with metabolite profiling. , 2008, Environmental science & technology.

[76]  S. Hester,et al.  Increased transcription of immune and metabolic pathways in naive and allergic mice exposed to diesel exhaust. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[77]  Daniel L Villeneuve,et al.  Ketoconazole in the fathead minnow (Pimephales promelas): Reproductive toxicity and biological compensation , 2007, Environmental toxicology and chemistry.

[78]  Orin C. Shanks,et al.  Competitive Metagenomic DNA Hybridization Identifies Host-Specific Microbial Genetic Markers in Cow Fecal Samples , 2006, Applied and Environmental Microbiology.

[79]  Gerald T. Ankley,et al.  Direct Effects, Compensation, and Recovery in Female Fathead Minnows Exposed to a Model Aromatase Inhibitor , 2008, Environmental health perspectives.

[80]  D. Dix,et al.  The ToxCast program for prioritizing toxicity testing of environmental chemicals. , 2007, Toxicological sciences : an official journal of the Society of Toxicology.

[81]  David M. Reif,et al.  Comparative microarray analysis and pulmonary changes in Brown Norway rats exposed to ovalbumin and concentrated air particulates. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[82]  Alexander Golbraikh,et al.  Predictive QSAR modeling workflow, model applicability domains, and virtual screening. , 2007, Current pharmaceutical design.

[83]  Gerald T Ankley,et al.  Computational toxicology: framework, partnerships, and program development. September 29-30, 2003, Research Triangle Park, North Carolina. , 2005, Reproductive toxicology.

[84]  Ann M Richard,et al.  Exposure science and the U.S. EPA National Center for Computational Toxicology , 2010, Journal of Exposure Science and Environmental Epidemiology.

[85]  I. Rusyn,et al.  Genomic Profiling in Nuclear Receptor-Mediated Toxicity , 2007, Toxicologic pathology.

[86]  Daniel B. Oerther,et al.  Identifying fecal sources in a selected catchment reach using multiple source-tracking tools. , 2007, Journal of environmental quality.

[87]  Daniel L Villeneuve,et al.  Perturbation of gene expression and steroidogenesis with in vitro exposure of fathead minnow ovaries to ketoconazole. , 2008, Marine environmental research.