Abstract
The rapid characterization of risk to humans and ecosystems from exogenous chemicals requires information on both hazard and exposure. The U.S. Environmental Protection Agency’s ToxCast program and the interagency Tox21 initiative have screened thousands of chemicals in various high-throughput (HT) assay systems for in vitro bioactivity. EPA’s ExpoCast program is developing complementary HT methods for characterizing the human and ecological exposures necessary to interpret HT hazard data in a real-world risk context. These new approach methodologies (NAMs) for exposure include computational and analytical tools for characterizing multiple components of the complex pathways chemicals take from their source to human and ecological receptors. Here, we analyze the landscape of exposure NAMs developed in ExpoCast in the context of various chemical lists of scientific and regulatory interest, including the ToxCast and Tox21 libraries and the Toxic Substances Control Act (TSCA) inventory. We examine the landscape of traditional and exposure NAM data covering chemical use, emission, environmental fate, toxicokinetics, and ultimately external and internal exposure. We consider new chemical descriptors, machine learning models that draw inferences from existing data, high-throughput exposure models, statistical frameworks that integrate multiple model predictions, and non-targeted analytical screening methods that generate new HT monitoring information. We demonstrate that exposure NAMs drastically improve the coverage of the chemical landscape compared to traditional approaches and recommend a set of research activities to further expand the development of HT exposure data for application to risk characterization. Continuing to develop exposure NAMs to fill priority data gaps identified here will improve the availability and defensibility of risk-based metrics for use in chemical prioritization and screening.
Impact
This analysis describes the current state of exposure assessment-based new approach methodologies across varied chemical landscapes and provides recommendations for filling key data gaps.
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Data availability
All data analyzed in this paper are available at data.gov, indexed by first author and title.
References
Muir DCG, Howard PH. Are there other persistent organic pollutants? A challenge for environmental chemists. Environ Sci Tech. 2006;40:7157–66.
Egeghy PP, Judson R, Gangwal S, Mosher S, Smith D, Vail J, et al. The exposure data landscape for manufactured chemicals. Sci Total Environ. 2012;414:159–66.
Kavlock R, Chandler K, Houck K, Hunter S, Judson R, Kleinstreuer N, et al. Update on EPA’s ToxCast program: providing high throughput decision support tools for chemical risk management. Chem Res Toxicol. 2012;25:1287–302.
Thomas RS, Paules RS, Simeonov A, Fitzpatrick SC, Crofton KM, Casey WM, et al. The US Federal Tox21 Program: A strategic and operational plan for continued leadership. ALTEX. 2018;35:163–8.
National Research Council. Risk Assessment in the Federal Government: Managing the Process, 1983.
U.S. Congress. Frank R. Lautenberg Chemical Safety for the 21st Century Act. 2016.
Cohen Hubal EA, Richard A, Aylward L, Edwards S, Gallagher J, Goldsmith MR, et al. Advancing exposure characterization for chemical evaluation and risk assessment. J Toxicol Environ Health B Crit Rev. 2010;13:299–313.
Wambaugh JF, Bare JC, Carignan CC, Dionisio KL, Dodson RE, Jolliet O, et al. New approach methodologies for exposure science. Curr Opin Toxicol. 2019;15:76–92.
Kavlock RJ, Bahadori T, Barton-Maclaren TS, Gwinn MR, Rasenberg M, Thomas RS. Accelerating the Pace of Chemical Risk Assessment. Chem Res Toxicol. 2018;31:287–90.
U.S. Environmental Protection Agency. Accelerating the Pace of Chemical Risk Assessment (APCRA) 2020 Public Webinar Presentations. https://doi.org/10.23645/epacomptox.12009120.v1 2020.
Paul Friedman K, Gagne M, Loo LH, Karamertzanis P, Netzeva T, Sobanski T, et al. Utility of In Vitro Bioactivity as a lower bound estimate of in vivo adverse effect levels and in risk-based prioritization. Toxicol Sci. 2020;173:202–25.
Williams AJ, Grulke CM, Edwards J, McEachran AD, Mansouri K, Baker NC, et al. The CompTox Chemistry Dashboard: a community data resource for environmental chemistry. J Cheminformatics. 2017;9:61.
U.S. Environmental Protection Agency. TSCA Active Inventory non-confidential portion. 2020. https://www.epa.gov/tsca-inventory.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: TSCA Active Inventory non-confidential portion (updated March 20th 2020). https://comptox.epa.gov/dashboard/chemical-lists/TSCA_ACTIVE_NCTI_0320 2020.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: EPA|ENDOCRINE: EDSP Universe of Chemicals. https://comptox.epa.gov/dashboard/chemical-lists/EDSPUoC 2022.
U.S. Food and Drug Administration Substances Added to Food (formerly EAFUS). https://www.fda.gov/food/food-additives-petitions/substances-added-food-formerly-eafus 2022.
U.S. Food and Drug Administration Inventory of Effective Food Contact Substance (FCS) Notifications. https://www.fda.gov/food/packaging-food-contact-substances-fcs/inventory-effective-food-contact-substance-fcs-notifications 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: EPA ToxCast Screening Library. 2022. https://comptox.epa.gov/dashboard/chemical-lists/TOXCAST.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: TOX21SL: Tox21 Screening Library. 2022. https://comptox.epa.gov/dashboard/chemical-lists/TOX21SL.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: PESTICIDES|EPA: List of Active Ingredients UPDATED 10/25/2019. https://comptox.epa.gov/dashboard/chemical-lists/PESTACTIVES 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: PESTICIDES|EPA: List of Inert Ingredients Food and Nonfood Use UPDATED 10/25/2019. https://comptox.epa.gov/dashboard/chemical-lists/PESTINERTS 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: EPA: IRIS Chemicals. https://comptox.epa.gov/dashboard/chemical-lists/IRIS 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: WATER|EPA: Chemical Contaminants - CCL 4. https://comptox.epa.gov/dashboard/chemical-lists/CCL4 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: Canadian Domestic Substances List. https://comptox.epa.gov/dashboard/chemical-lists/CANADADSL 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: NIOSH: International Chemical Safety Cards. 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: OSHA Chemicals. https://comptox.epa.gov/dashboard/chemical-lists/NIOSHICSC 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: Clean Water Act (CWA) Section 311(b)(2)(A). https://comptox.epa.gov/dashboard/chemical-lists/CWA311HS 2022
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: Chemicals in biosolids (2021). https://comptox.epa.gov/dashboard/chemical-lists/BIOSOLIDS2021 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: NORMAN: List of PFAS from the OECD Curated by Nikiforos Alygizakis. https://comptox.epa.gov/dashboard/chemical-lists/PFASOECDNA 2022.
Yang C, Cronin MTD, Arvidson KB, Bienfait B, Enoch SJ, Heldreth B, et al. COSMOS next generation—A public knowledge base leveraging chemical and biological data to support the regulatory assessment of chemicals. Comput Toxicol. 2021;19:100175.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: CATEGORY|COSMETICS: COSMOS DB cosmetics database. https://comptox.epa.gov/dashboard/chemical-lists/COSMOSDB 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: EPA|ECOTOX: Ecotoxicology knowledgebase. https://comptox.epa.gov/dashboard/chemical-lists/ECOTOX_v2 2022.
U.S. Environmental Protection Agency. CompTox Dashboard Chemical List: Minnesota Department of Health Chemicals of High Concern and Priority Chemicals. https://comptox.epa.gov/dashboard/chemical-lists/MNDOHTOXFREE 2022.
Grulke CM, Williams AJ, Thillanadarajah I, Richard AM. EPA’s DSSTox database: History of development of a curated chemistry resource supporting computational toxicology research. Comput Toxicol. 2019;12:100096.
Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, et al. ClassyFire: automated chemical classification with a comprehensive, computable taxonomy. J cheminformatics. 2016;8:61.
Heller S, McNaught A, Stein S, Tchekhovskoi D, Pletnev I. InChI - the worldwide chemical structure identifier standard. J Cheminformatics. 2013;5:1–9.
Judson RS, Martin MT, Egeghy P, Gangwal S, Reif DM, Kothiya P, et al. Aggregating data for computational toxicology applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System. Int J Mol Sci. 2012;13:1805–31.
Dionisio KL, Frame AM, Goldsmith MR, Wambaugh JF, Liddell A, Cathey T, et al. Exploring consumer exposure pathways and patterns of use for chemicals in the environment. Toxicol Rep. 2015;2:228–37.
Dionisio KL, Phillips K, Price PS, Grulke C, Williams A, Biryol D, et al. The chemical and products database, a resource for exposure-relevant data on chemicals in consumer products. Scientific Data. 2018;5:1–9.
Wambaugh JF, Wang A, Dionisio KL, Frame A, Egeghy P, Judson R, et al. High throughput heuristics for prioritizing human exposure to environmental chemicals. Environ Sci Tech 2014;48:12760–7.
Mansouri K, Grulke CM, Judson RS, Williams AJ. OPERA models for predicting physicochemical properties and environmental fate endpoints. J Cheminform. 2018;10:10 https://doi.org/10.1186/s13321-018-0263-1
European Commission. QSAR model reporting format (QMRF). 2016. https://qmrf.sourceforge.net/. Accessed 4 Oct 2022.
U.S. Environmental Protection Agency. The Chemical and Products Database (CPDat) MySQL Data File. V3. https://doi.org/10.23645/epacomptox.5352997. Accessed 11 July 2022.
Phillips KA, Wambaugh JF, Grulke CM, Dionisio KL, Isaacs KK. High-throughput screening of chemicals as functional substitutes using structure-based classification models. Green Chem. 2017;19:1063–74.
Ring CL, Arnot J, Bennett DH, Egeghy P, Fantke P, Huang L et al. Consensus modeling of median chemical intake for the U.S. population based on predictions of exposure pathways. Environmental Sci Tech. 2018; https://doi.org/10.1021/acs.est.8b04056.
Wambaugh JF, Setzer RW, Reif DM, Gangwal S, Mitchell-Blackwood J, Arnot JA, et al. High-throughput models for exposure-based chemical prioritization in the expo cast project. Environ Sci Tech 2013;47:8479–88.
U.S. Environmental Protection Agency. 2016 CDR Data (updated May 2020). https://www.epa.gov/chemical-data-reporting/access-cdr-data#2016. Accessed 7 July 2022.
Organisation for Economic Co-operation and Development. Internationally Harmonised Functional Product and Article Use Categories ENV/JM/MONO (2017) 14, 2017.
U.S. Environmental Protection Agency. Multimedia Monitoring Database (MMDB). https://doi.org/10.23645/epacomptox.17065024.v1 Accessed 7 July 2022.
Isaacs KK, Wall JT, Williams AR, Hobbie KA, Sobus JR, Ulrich E, et al. A harmonized chemical monitoring database for support of exposure assessments. Sci Data. 2022;9:1–11.
Phillips KA, Yau A, Fayela KA, Isaacs KK, McEachran A, Grulke C, et al. Suspect screening analysis of chemicals in consumer products. Environ Sci Tech. 2018;52:3125–35.
Lowe CN, Phillips KA, Favela KA, Yau AY, Wambaugh JF, Sobus JR, et al. Chemical characterization of recycled consumer products using suspect screening analysis. Environ Sci Tech. 2021;55:11375–87.
Rager JE, Strynar MJ, Liang S, McMahen RL, Richard AM, Grulke CM, et al. Linking high resolution mass spectrometry data with exposure and toxicity forecasts to advance high-throughput environmental monitoring. Environ Int. 2016;88:269–80.
Newton SR, McMahen RL, Sobus JR, Mansouri K, Williams AJ, McEachran AD, et al. Suspect screening and non-targeted analysis of drinking water using point-of-use filters. Environ Pollut. 2018;234:297–306.
Schymanski EL, Jeon J, Gulde R, Fenner K, Ruff M, Singer HP, et al. Identifying small molecules via high resolution mass spectrometry: communicating confidence. Environ Sci Tech. 2014;48:2097–8.
Wetmore BA, Wambaugh JF, Allen B, Ferguson SS, Sochaski MA, Setzer RW, et al. Incorporating high-throughput exposure predictions with dosimetry-adjusted in vitro bioactivity to inform chemical toxicity testing. Toxicol Sci. 2015;148:121–36.
Government of Canada. List of substances in the third phase of CMP (2016-2021): July 2019 update. 2019. https://www.canada.ca/en/environment-climate-change/services/evaluating-existing-substances/cmp-third-phase-update.html.
Sayre RR, Wambaugh JF, Grulke CM. Database of pharmacokinetic time-series data and parameters for 144 environmental chemicals. Sci Data 2020;7:1–10.
Wambaugh JF, Hughes MF, Ring CL, MacMillan DK, Ford J, Fennell TR, et al. Evaluating in vitro-in vivo extrapolation of toxicokinetics. Toxicol Sci. 2018;163:152–69.
Pearce RG, Setzer RW, Strope CL, Sipes NS, Wambaugh JF. httk: R package for high-throughput toxicokinetics. J Stat Softw 2017;79:1–26.
Obach RS, Lombardo F, Waters NJ. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab Dispos 2008;36:1385–405.
Obach RS. Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos. 1999;27:1350–9.
Wetmore BA, Wambaugh JF, Ferguson SS, Sochaski MA, Rotroff DM, Freeman K, et al. Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment. Toxicol Sci. 2012;125:157–74.
Wambaugh JF, Wetmore BA, Ring CL, Nicolas CI, Pearce RG, Honda GS, et al. Assessing toxicokinetic uncertainty and variability in risk prioritization. Toxicol Sci 2019;172:235–51.
Sipes NS, Wambaugh JF, Pearce R, Auerbach SS, Wetmore BA, Hsieh JH, et al. An intuitive approach for predicting potential human health risk with the Tox21 10k Library. Environ Sci Tech 2017;51:10786–96.
Dawson DE, Ingle BL, Phillips KA, Nichols JW, Wambaugh JF, Tornero-Velez R. Designing QSARs for Parameters of High-Throughput Toxicokinetic Models Using Open-Source Descriptors. Environ Sci Tech 2021;55:6505–17.
Pradeep P, Patlewicz G, Pearce R, Wambaugh J, Wetmore B, Judson R. Using chemical structure information to develop predictive models for in vitro toxicokinetic parameters to inform high-throughput risk-assessment. Comput Toxicol. 2020;16:1–9.
Arnot JA, Brown TN, Wania F, Breivik K, McLachlan MS. Prioritizing chemicals and data requirements for screening-level exposure and risk assessment. Environ Health Perspect. 2012;120:1565–70.
Judson R, Richard A, Dix DJ, Houck K, Martin M, Kavlock R, et al. The toxicity data landscape for environmental chemicals. Environ Health Perspect. 2009;117:685–95.
Richard AM, Judson RS, Houck KA, Grulke CM, Volarath P, Thillainadarajah I, et al. ToxCast chemical landscape: paving the road to 21st century toxicology. Chem Res Toxicol. 2016;29:1225–51.
Nicolas CI, Mansouri K, Phillips KA, Grulke CM, Richard AM, Williams AJ, et al. Rapid experimental measurements of physicochemical properties to inform models and testing. Sci Total Environ. 2018;636:901–9.
Addington CK, Phillips KA, Isaacs KK. Estimation of the emission characteristics of SVOCs from household articles using group contribution methods. Environ Sci Tech. 2020;54:110–9.
Huang L, Fantke P, Ritscher A, Jolliet O. Chemicals of concern in building materials: A high-throughput screening. J Hazard Mater. 2022;424:127574.
Tao M, Li D, Song R, Suh S, Keller AA. OrganoRelease - A framework for modeling the release of organic chemicals from the use and post-use of consumer products. Environ Pollut. 2018;234:751–61.
Li L, Sangion A, Wania F, Armitage JM, Toose L, Hughes L, et al. Development and Evaluation of a Holistic and Mechanistic Modeling Framework for Chemical Emissions, Fate, Exposure, and Risk. Environmental. Health Perspect. 2021;129:127006.
Young B, Ingwersen WW, Bergmann M, Hernandez-Betancur JD, Ghosh T, Bell E, et al. A System for Standardizing and Combining U.S. Environmental Protection Agency Emissions and Waste Inventory Data. Appl Sci. 2022;12:3447.
National Water Quality Monitoring Council. The Water Quality Portal. https://www.waterqualitydata.us. 2022.
Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. In. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2019.
European Commission. Information Platform for Chemical Monitoring. https://ipchem.jrc.ec.europa.eu/. 2022.
Mattingly CJ, Colby GT, Forrest JN, Boyer JL. The comparative toxicogenomics database (CTD). Environ Health Perspect. 2003;111:793–5.
Peter KT, Phillips AL, Knolhoff AM, Gardinali PR, Manzano CA, Miller KE, et al. Nontargeted analysis study reporting tool: a framework to improve research transparency and reproducibility. Anal Chem. 2021;93:13870–9.
Dulio V, van Bavel B, Brorstrom-Lunden E, Harmsen J, Hollender J, Schlabach M, et al. Emerging pollutants in the EU: 10 years of NORMAN in support of environmental policies and regulations. Environ Sci Eur. 2018;30:5.
Pourchet M, Debrauwer L, Klanova J, Price EJ, Covaci A, Caballero-Casero N, et al. Suspect and non-targeted screening of chemicals of emerging concern for human biomonitoring, environmental health studies and support to risk assessment: From promises to challenges and harmonisation issues. Environ Int. 2020;139:105545.
McCord JP, Groff LC, Sobus JR. Quantitative non-targeted analysis: Bridging the gap between contaminant discovery and risk characterization. Environ Int. 2022;158:107011.
Guo J, Sinclair CJ, Selby K, Boxall AB. Toxicological and ecotoxicological risk-based prioritization of pharmaceuticals in the natural environment. Environ Tox Chem. 2016;35:1550–9.
Occupational Safety and Health Administration. Chemical Exposure Health Data. https://www.osha.gov/opengov/health-samples. 2022.
Tolonen A, Pelkonen O. Analytical challenges for conducting rapid metabolism characterization for QIVIVE. Toxicology. 2015;332:20–29.
Zavala J, Freedman AN, Szilagyi JT, Jaspers I, Wambaugh JF, Higuchi M, et al. New approach methods to evaluate health risks of air pollutants: critical design considerations for in vitro exposure testing. Int J Environ Res Public Health. 2020;17:1–28.
Clark AM, McEwen LR, Gedeck P, Bunin BA. Capturing mixture composition: an open machine-readable format for representing mixed substances. J Cheminformatics. 2019;11:33.
Dimitrov SD, Georgieva DG, Pavlov TS, Karakolev YH, Karamertzanis PG, Rasenberg M, et al. UVCB substances: methodology for structural description and application to fate and hazard assessment. Environ Toxicol Chem. 2015;34:2450–62.
Acknowledgements
We would like to thank Drs. Zachary Stanfield and Daniel Vallero of EPA Office of Research and Development and Tariq Francis and Andy Nong of Health Canada for their technical review of this manuscript. The information in this document has been funded wholly or in part by the US Environmental Protection Agency. It does not signify that the contents necessarily reflect the views of the U.S. EPA or U.S. CPSC, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The paper has been subjected to the U.S. EPA review process and approved for publication. No funding sources are associated with this study.
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KKI performed data analyses and drafted figures, tables, and text. PE, KD, KP, AZ, CR, JRS, BAW, EMU, AJW, and JW developed/provided exposure NAM or cheminformatic datasets and contributed to text.
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Isaacs, K.K., Egeghy, P., Dionisio, K.L. et al. The chemical landscape of high-throughput new approach methodologies for exposure. J Expo Sci Environ Epidemiol 32, 820–832 (2022). https://doi.org/10.1038/s41370-022-00496-9
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DOI: https://doi.org/10.1038/s41370-022-00496-9
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