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Application of adverse outcome pathways in chemical risk assessment, Dan Villeneuve from the US Environmental Protection Agency

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On 30 April 2019, the OECD organised a webinar on the Adverse Outcome Pathway (AOP) framework. The AOP framework is a collaborative tool that applies an innovative approach for collecting mechanistic knowledge from various sources that can eventually support chemical safety assessment.

The following questions were addressed:

What is the AOP framework and why should you care?
Why are we developing AOPs?
Why collaborations are encouraged and why should scientific societies be brought in?
What are the opportunities for collaboration in AOP development?

Published in: Environment
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Application of adverse outcome pathways in chemical risk assessment, Dan Villeneuve from the US Environmental Protection Agency

  1. 1. APPLICATION OF AOPS IN CHEMICAL RISK ASSESSMENT Daniel L. Villeneuve, US EPA Mid-Continent Ecology Division, Duluth, MN, USA
  2. 2. Recap • AOPs are a conceptual framework • 5 principles of AOP development • Modular structure and AOP-Wiki were designed to support collaborative / crowd-sourced development Content Developer AOP Knowledge Base • Document • Store • Curate and Review • Disseminate Content Consumer How are AOPs and the AOP framework being used?
  3. 3. Applications • Development of alternative testing approaches • Supporting tiered testing strategies / IATA • Framework for organizing and evaluating evidence for causality • Bioactivity-based environmental monitoring • Quantitative BMD Estimation (hazard id versus risk estimation)
  4. 4. Amphibian metamorphosis (frog) – thyroid hormone dependent Thyroxin (T4) in serum, decreased Metamorphosis, impaired OECD 231: Amphibian Metamorphosis Assay – Tier 1 • Median estimated cost: $75,000 [OECD 2012; ENV/JM/MONO(2012)22] • Animal use: ≈ 320 tadpoles per test • Time: 21 d test; histology; husbandry and staging Alternative Testing Approaches
  5. 5.  Thyroid AOP Network identification of MIE space to cover in a HTS battery TPO inhibition TH synthesis, decreased Thyroxine (T4) in serum, decreased Thyroxine (T4) in tissues, decreased Metamorphic development, altered NIS inhibition DIO1 inhibition Nuclear receptor activation (Liver) IYD inhibition Thyroidal iodide, decreased DIO3 inhibition DUOX inhibition Pendrin inhibition DIO2 inhibition TH transport into liver, increased Upregulation of glucuronyltransferase activity, induction Biliary excretion TH glucuronide, increased Triiodothyronine (T3) in tissues, Increased Triiodothyronine (T3) in tissues, Decreased TH in neuronal tissues, decreased Hippocampal gene expression, altered Hippocampal anatomy, altered Hippocampal function, decreased Cognitive function, decreased Swim bladder inflation, reduced Swimming performance, reduced Hearing, reduced Young of year survival, reduced Population trajectory, decreased Triiodothyronine (T3) in serum, Decreased MIE KE AO Slide courtesy of Jon Haselman, US EPA
  6. 6. TPO inhibition IYD inhibition NIS inhibition DIO1 inhibition DIO2 inhibition HT assay under development HT assay under development HT assay developed >1000 chemicals screened HT assay developed >100 chemicals screened HT assay developed >100 chemicals screened Alternative Testing Approaches
  7. 7. • IATA is about effective use of available data and strategic/efficient generation of new data. • AOPs help to INTEGRATE existing information and put it into the context of existing knowledge. • Because all KEs in an AOP are observable, they can be employed to FORMULATE testable hypotheses. • The supporting information in an AOP regarding life stage, taxa, sex, applicability and ability to probe and visualize AOP networks allows users to TARGET their data collection based on the body of existing knowledge. Supporting tiered testing strategies / IATA
  8. 8. Metabolism Penetration Electrophilic substance Direct Peptide Reactivity Assay (DPRA) QSARs • human Cell Line Activation Test (h-CLAT) • Mobilisation of DCs • Activation of inflammatory cytokines • KeratinoSens • Histocompatibility complexes presentation by DCs • Activation of T cells • Proliferation of activated T-cells • Inflammation upon challenge with allergen Dendritic Cells (DCs) Keratinocyte responses Key Event 1 (KE1) Key Event 2 Key Event 3 Key Event 4 Adverse OutcomeT-cell proliferation Chemical Structure & Properties Molecular Initiating Event Cellular Response Organ Response Organism Response AOP for Skin Sensitization (AOP #40; https://aopwiki.org ) Supporting tiered testing strategies / IATA Roberts and Patlewicz. 2018. J Appl. Toxicol. 38: 41-50. • Consensus that no single non-animal method can replace animal testing for skin sensitization. • A combination of assays placed in an AOP context can be used. Patlewicz et al. 2014. Regulat. Toxicol. Pharmacol. 69: 529-524.
  9. 9. Supporting tiered testing strategies / IATA Cyclooxygenase inhibition Ca2+ and HCO3 transport to shell-gland lumen impaired Eggshell thickness reduced Crushed eggs, breeding failure Prostaglandin concentrations in eggshell gland mucosa, reduced High Throughput Screening In vivo – 96 h Avian reproduction study (OPPTS 850.2300; OECD 206) $>250,000 >30 weeks to perform https://aopwiki.org/aops/28
  10. 10. • Role of particulate matter (PM) in the induction of metabolic syndrome (e.g., diabetes) • Linkage of neonicotinoids to adverse effects on pollinators • High visibility topics of concern to regulatory community and general public • Establishing WoE-based plausibility of linkage(s) between stressor and effects critical to guiding research and mitigation • Both issues feature extensive, complex and quite varied data streams relevant to assessing/establishing linkages Organizing and evaluating evidence for causality Examples
  11. 11. • Integrated Science Assessments (ISAs) • ISAs form the scientific foundation for the review of National Ambient Air Quality Standards NAAQS standards. • General Process: • Literature searches • Study selection • Evaluation of individual study quality • Evaluation, synthesis, and integration of the evidence • Development of scientific conclusions and causal determinations U.S. EPA. Preamble to the Integrated Science Assessments (ISA). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R- 15/067, 2015. Organizing and evaluating evidence for causality
  12. 12. Knowledge Streams Contributing to Assessment of Possible PM-Metabolic Syndrome Linkage(s) • Animal Toxicology • Controlled Human Exposure Provide coherence to the diverse evidence streams by describing possible pathways anchoring exposure to outcome US EPA Integrated Science Assessment for PM 2.5 Organizing and evaluating evidence
  13. 13. AOP:88 AOP:89 AOP:77 AOP:87 AOP:79 AOP:178 AOP:81 AOP:179 AOP:181 AOP:185 Contributed to EFED FIFRA assessment and White House - Initiated Pollinator RAP LaLone, C.A., D.L. Villeneuve, J. Wu-Smart, R.Y. Milsk, K. Sappington, K.V. Garber, J. Housenger and G.T. Ankley. 2017. Weight of evidence evaluation of a network of adverse outcome pathways linking activation of the nicotinic acetylcholine receptor in honey bees to colony death. Sci. Total Environ. 584-585, 751-775. Organizing and evaluating evidence
  14. 14. Bioactivity-based Environmental Monitoring Biological Characterization Hazard Identification
  15. 15. Ambient water sample extract Complex mixture Attagene battery of Toxcast Assays “Unknown” Chemical Mixture A. 6 MIEs identified as hits by Attagene assay are KEs in global AOP network. B. Network filtered to subset of AOPs directly linked to the 6 MIEs C. Further filtered by taxonomic applicability. Embryolethality Reproductive hazard Knapen et al. 2018, Environ. Toxicol. Chem. 37: 1723-1733 2015 S. Platte R.
  16. 16. Quantitative Understanding What’s the tipping point? Hazard: Standing at the edge of a cliff Exposure: How hard the wind is blowing? How hard are you being pushed? Vulnerability: Is there a guard rail? Are you anchored? What is your strength and balance as an individual? Benchmark Dose Estimation Arriving at an effect concentration to compare with anticipated exposure concentrations.
  17. 17. Population size, reduced A B C D A Aromatase inhibition Plasma E2 In vitro, HTS In vivo https://aopwiki.org/aops/25 y= -8e-7x2 – 7e-5x + 0.016 Conolly RB, Ankley GT, Cheng W, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology. Environ Sci Technol. 2017 Apr 18;51(8):4661-4672. doi: 10.1021/acs.est.6b06230. Benchmark Dose Estimation
  18. 18. Population size, reduced A B C D C Plasma Vtg Avg Fecundity In vivo In vivo https://aopwiki.org/aops/25 y = 24.7714 1+𝑒𝑥𝑝( 64.4184−𝑥 24.7923 ) Conolly RB, Ankley GT, Cheng W, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology. Environ Sci Technol. 2017 Apr 18;51(8):4661-4672. doi: 10.1021/acs.est.6b06230. Benchmark Dose Estimation
  19. 19. Population size, reduced A C D E Equipotent concentration of reference chemical Conolly RB, Ankley GT, Cheng W, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH. Quantitative Adverse Outcome Pathways and Their Application to Predictive Toxicology. Environ Sci Technol. 2017 Apr 18;51(8):4661-4672. doi: 10.1021/acs.est.6b06230. Benchmark Dose Estimation
  20. 20. • AOPs are a multi-purpose tool • They have already been applied in many different contexts to support chemical risk assessment • The greatest current limitation to their application is the limited number of high quality AOPs currently available in the AOP-Wiki • Our collective goal is to remedy that • We welcome your participation!
  21. 21. Acheson, Carolyn Adams, Linda Ankley, Gerald Bencic, David Batt, Angela Biales, Adam Blackwell, Brett Borsay, Doranne Buckalew, Angela Bruon, Maribel Cardon, Mary Carswell, Gleta Chorley, Brian Collette, Tim Conolly, Rory Corton, Chris Davis, John Degitz, Sigmund Edwards, Stephen Ekman, Drew El-Masri, Hisham Evans, Nicola Flick, Robert Furr, Johnathan Gilbert, Mary E. Gordon, Denise Gray, Leon Hallinger, Daniel Hartig, Phil Haselman, Jon Hazari, Medhi Herr, David Hester, Susan Hotchkiss, Michelle Hornung, Michael Hughes, Michael Jayaraman, Saro Jensen, Karl Jensen, Kathleen Judson, Richard Kahl, Michael Kenyon, Elaina Klinefelter, Gary Kodavanti, Prasada Rao Korte, Joe Kosian, Pat Kostich, Mitch LaLone, Carlie Lake, April Lambright, Christy Lasat, Mitch Lattier, David Laws, Susan Lyke, Danielle McQueen, Charlene Miller, David H. Mills, Lesley Mills, Marc Moore, Tanya Mortensen, Holly Moser, Ginger Murr, Ashley Nelson, Gail Pleil, Joachim Rosen, Mitch Ross, Jeff See, MJ Sey, Yusupha Skelton, David Stoker, Tammy Strader, Lilly Suarez, Juan Tan, Cecilia Teng, Quincy Tennant, Alan VanDuyn, Natalia VanEmon, Jeanette Villeneuve, Dan Wang, Rong-Lin Ward, William Welch, Jeff Wilson, Vickie Wood, Charles Contact: Villeneuve.dan@epa.gov 218-529-5217 National Program Director: Jeff Frithsen Deputy NPD: Joseph Tietge Research Area Coordinator: Jill Franzosa CSS 12.01 AOPDD Project TeamIntroductionAcknowledgements CSS AOPDD Project Team

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