Evaluation of a Proposed Approach to Refine Inhalation Risk Assessment for Point of Contact Toxicity: a Case Study Using a New Approach Methodology (NAM)
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Issue Paper Evaluation of a Proposed Approach to Refine Inhalation Risk Assessment for Point of Contact Toxicity: A Case Study Using a New Approach Methodology (NAM) EPA’s Office of Chemical Safety and Pollution Prevention August 30, 2018 Page 1 of 33 Table of Contents 1.0 Introduction .......................................................................................................................... 7 1.1 Background .......................................................................................................................... 7 1.2 Inhalation Risk Assessment: Typical Methods Using In Vivo Laboratory Animal Data.... 8 1.3 Comparison of Rat & Human Respiratory Tract ............................................................... 10 1.4 Using New Approach Methodologies (NAMs) to Refine Inhalation Risk Assessment .... 11 1.4.1 Overview: Alternative Test Methods ............................................................................. 11 1.4.2 In Vitro Test Systems for Inhalation Toxicity ............................................................... 12 2.0 Case Study Using a Respiratory Irritant: Chlorothalonil ................................................... 13 2.1 Inhalation Risk Assessment for Chlorothalonil ................................................................. 14 2.2 Source to Outcome Approach ............................................................................................ 16 2.2.1 Source ............................................................................................................................. 16 2.2.2 Exposure ......................................................................................................................... 16 2.2.3 Dosimetry ....................................................................................................................... 17 2.2.4 Outcome ......................................................................................................................... 18 2.2.5 Chlorothalonil Inhalation Risk Assessment Utilizing Refined Approach ..................... 21 2.2.5.1 Calculation of Human Equivalent Concentrations (HECs) ........................................... 21 2.2.5.2 Calculation of Spray Applicator Risk Estimates ............................................................ 23 3.0 Conclusions ........................................................................................................................ 25 4.0 References .......................................................................................................................... 26 Appendix A. Comparison of untransformed and log transformed BMD analysis results. ........... 29 Appendix B. Evaluation of Reliability and Relevance ................................................................ 30 Page 2 of 33 List of Acronyms ACGIH: American Conference of Governmental Industrial Hygienists AIC: Akaike Information Criterion BMD: Benchmark Dose BMDsd: BMD for One Standard Deviation Change BMDLsd: Lower Bound of the 95% Confidence Interval on the BMDsd BMR: Benchmark Response CEN: European Committee for Standardization CF: Composite Factor CFD: Computational Fluid Dynamic DDEF: Data-Derived Extrapolation Factor EFAD: Extrapolation Factor for Interspecies Toxicodynamics EFAK: Extrapolation Factor for Interspecies Toxicokinetics EFHD: Extrapolation Factor for Intraspecies Toxicodynamics EFHK: Extrapolation Factor for Intraspecies Toxicokinetics EPA: Environmental Protection Agency EURL ECVAM: European Union Reference Laboratory for Alternatives to Animal Testing FIFRA: Federal Insecticide, Fungicide, and Rodenticide Act GD: Guidance Document GSD: Geometric Standard Deviation HEC: Human Equivalent Concentrations ICATM: International Cooperation on Alternative Test Methods ICCVAM: Interagency Coordinating Committee on the Validation of Alternative Methods ISO: International Organization for Standardization LC50: Median Lethal Concentration LDH: Lactate Dehydrogenase LOAEC: Lowest Observed Adverse Effect Concentration Page 3 of 33 LOAEL: Lowest Observed Adverse Effect Level LOC: Level of Concern MMAD: Mass Median Aerodynamic Diameter MOE: Margin of Exposure MPPD: Multiple Path Particle Deposition MSDS: Material Safety Data Sheets NAM: New Approach Methodology NICEATM: National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods NOAEC: No Observed Adverse Effect Concentration NOAEL: No Observed Adverse Effect Level NRC: National Research Council OCSPP: Office of Chemical Safety and Pollution Prevention OECD: Organisation for Economic Co-operation and Development OPP: Office of Pesticide Programs OPPT: Office of Pollution Prevention and Toxics OSHA: Occupational Safety and Health Administration OVS: OSHA Versatile Samplers POD: Point of Departure PSD: Particle Size Distribution RfC: Reference Concentration SAP: Scientific Advisory Panel SC: Suspension Concentrates SDS: Sodium Dodecyl Sulphate SE: Suspo-Emulsions TD: Toxicodynamic TEER: Transepithelial Electrical Resistance TK: Toxicokinetic TSCA: Toxic Substances Control Act Page 4 of 33 UFA: Interspecies Factor for Animal-to-Human Extrapolation UFH: Intraspecies Factor for Differences in Sensitivity Among Humans WDG: Water Dispersible Granule WOE: Weight of Evidence Page 5 of 33 List of Figures Figure 1. Adverse outcome pathway for irritant induced laryngeal squamous metaplasia adapted from Renne et al. 2009. List of Tables Table 2.1.1. Study Design of Inhalation Studies Submitted to the Agency Following Registration Review DCI Table 2.2.2.1. Summary of Particle Size Distribution (PSD) for Proposed Approach Table 2.2.3.1. Human CFD simulation results for 1 mg/L aerosol, assuming 4.9% (w/w) chlorothalonil formulation for aerosol sizes ranging from 1 to 30 µm MMAD. 2 Table 2.2.4.1. Chlorothalonil BMDLsd values in mg/cm calculated from MucilAir™ data Table 2.2.5.1.1. Percent Contribution of Discrete Particles to the Relevant Particle Size Distributions (MMAD = 35 µm, GSD = 1.5) Table 2.2.5.1.2. Cumulative particle deposition for 1 mg/L aerosol in site-specific regions of the respiratory tract for each exposure scenario assuming 4.9% (w/w) chlorothalonil formulation. Table 2.2.5.1.3. Total deposition of chlorothalonil in site-specific regions of the respiratory tract for each exposure scenario assuming 4.9% (w/w) chlorothalonil formulation Table 2.2.5.1.4. HEC values assuming 4.9% (w/w) chlorothalonil formulation Page 6 of 33 1.0 Introduction 1.1 Background The mission of the Environmental Protection Agency’s (EPA) Office of Chemical Safety and Pollution Prevention (OCSPP) is to protect humans and the environment from potential risks associated from exposure to pesticides and toxic chemicals. In order to achieve this, two offices within OCSPP are responsible for evaluating these potential risks. The Office of Pesticide Programs (OPP) regulates the use of all pesticide chemicals, while the Office of Pollution Prevention and Toxics (OPPT) evaluates new and existing chemical substances (excluding, among others, pesticides, tobacco and tobacco products, food, food additives, drugs, and cosmetics). EPA regulates chemicals under authority granted by statutes, such as the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Toxic Substances Control Act (TSCA), which allow the Agency to require or request a suite of data and relevant information from pesticide registrants and chemical manufacturers to support scientifically-based risk assessment. To assess the potential hazard of a chemical for human health risk assessment, toxicological studies in laboratory animals are used to provide information on a wide range of adverse health outcomes, routes of exposure, exposure durations, species, and lifestages. EPA’s test guidelines for pesticides and toxic substances are harmonized with those established by the Organisation for Economic Co-operation and Development (OECD) and specify EPA-recommended methods to generate data that is submitted to EPA1; however, it should be noted that the statutory requirements differ between FIFRA and TSCA for data requirements (e.g., breadth and issues which trigger data requirements). Under 40 CFR Part 1582, the OPP requires toxicology data to support registration of food and non-food use pesticides. The regulations give EPA substantial discretion to make registration decisions based on what the Agency deems are the most relevant and important data for each action. The actual data and studies required may be modified on an individual basis to fully characterize the use and properties of specific pesticide products under review (40 CFR §158.30). Also, the data requirements may not always be considered appropriate. For instance, the properties of a chemical or an atypical use pattern could make it impossible to generate the required data or the data would not be considered useful in the Agency’s evaluation. Therefore, the Agency may waive data requirements, but must ensure that sufficient data are available to make the determinations required by the applicable statutory standards (40 CFR §158.45). The 40 CFR also provides EPA with broad flexibility under 158.75 to request additional data beyond the Part 158 data requirements that may be important to the risk management decision. Alternative methods and approaches can be considered and accepted for these additional data, when appropriate. 1 https://www.epa.gov/test-guidelines-pesticides-and-toxic-substances 2 https://www.ecfr.gov/cgi-bin/text-idx?tpl=/ecfrbrowse/Title40/40cfr158_main_02.tpl