Strategic Vision for Adopting New Approach Methodologies - Replacement Strategies
One of EPA’s goals is to replace complex laboratory animal studies with new approach methodologies (NAMs) while maintaining the scientific defensibility of pesticide assessments. NAMs include alternative test methods and strategies, and refer to any non-animal technology, methodology, approach or combination thereof that can be used to provide information on chemical hazard and risk assessment.
EPA has already taken steps to replace in vivo animal studies through engagement with the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to draft documents and strategies moving towards eye irritation and skin sensitization testing based on in silico A general term used to mean "performed on computer or via computer simulation.", in chemico and in vitro Experiments or tests done under controlled experimental conditions outside of the body, such as in a test tube or laboratory dish. These tests tend to focus on organs, tissues, cells, cellular components, proteins, and/or biomolecules. approaches.
Approach to Refine Inhalation Risk Assessment for Point of Contact Toxicity
Draft risk assessment for Chlorothalonil
EPA continues to work with the National Toxicology Program’s Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) (headquartered at the National Institute of Environmental Health Sciences), other Federal agencies, the European Union Joint Research Centre, and Health Canada to develop a defined approach for skin sensitization as presented and discussed in international settings such as the Organisation for Economic Co-operation and Development (OECD).
EPA released a new draft interim science policy, Use of Alternative Approaches for Skin Sensitization as a Replacement for Laboratory Animal Testing, in April 2018. This draft policy document describes the science behind the non-animal alternatives that can be used (in vitro, in silico, in chemico) to identify skin sensitization.
Given the substantial scientific evidence and international activities supporting the NAMs for skin sensitization testing, EPA began accepting these approaches under the conditions described in the draft policy document immediately upon its release.
EPA established the mixtures equations pilot program to evaluate the utility and acceptability of a mathematical tool (GHS Mixtures Equation) as an alternative to animal oral and inhalation toxicity studies for pesticide formulations. The Mixtures Equation is used in the Globally Harmonized System of Classification and Labeling of Chemicals (GHS).
Under this pilot, registrants had the option of submitting calculations (GHS Mixtures Equation data), paired with the required acute oral and inhalation acute toxicity data, to support the evaluation of pesticide toxicity. In FY 2019, OPP closed the submission period for new data and began working with NICEATM to perform the analysis.
The retrospective analysis of the concordance of the in vivo acute oral toxicity results and the calculated LD50 values using the equation was determined from 671 formulations (620 agrochemical formulations and 51 antimicrobial cleaning products) and was completed in 2021. The overall concordance with EPA classification was 55%. When less toxic mixtures were combined together (LD50>500 mg/kg), overall concordance improved to 82%. The comprehensive results of this retrospective analysis are available in the following manuscript: Hamm Jon, et al. “Performance of the GHS Mixtures Equation for Predicting Acute Oral Toxicity.” Regulatory Toxicology and Pharmacology, 125 (2021):105007.
Alternative Testing Framework for Classification of Eye Irritation Potential of EPA-Regulated Pesticide Products
In May 2015, EPA released updated guidance for testing antimicrobial cleaning products for their potential to cause eye irritation. The updated guidance describes a testing framework for assessing eye irritation potential using three in vitro/ex vivo assays: Bovine Corneal Opacity and Permeability assay, EpiOcular assay, and the Cytosensor Microphysiometer assay. The same testing approach is considered on a case-by-case basis for other classes of pesticides and pesticide products.
In December 2018, EPA presented the document Evaluation of a Proposed Approach to Refine the Inhalation Risk Assessment for Point of Contact Toxicity: A Case Study Using a New Approach Methodology (NAM) to the FIFRA Scientific Advisory Panel (SAP). The proposed approach calculates human equivalent concentrations (HECs) for inhalation risk assessment using an in vitro point of departure in conjunction with computational fluid dynamic (CFD) modeling that incorporates human relevant particle size distributions. The approach was originally developed by Syngenta for the fungicide chlorothalonil, which was presented to the SAP as proof of concept for this NAM. The SAP’s report was released in April 2019.
Throughout FY 2019, OPP continued to work with Syngenta Crop Protection on science activities to address the SAP’s recommendations, such as evaluation of in vitro repeat dosing, determination of appropriate particle size distributions for dosimetry modeling, and updates to human equivalent concentration calculations.
In May 2021, OPP published its draft risk assessments for chlorothalonil and additional supporting documents in the Federal Register docket number EPA-HQ-OPP-2011-0840 at www.regulations.gov. This was the first DRA that applied this NAM to calculate HEC's for conventional and antimicrobial uses of chlorothalonil. More information on the application of the NAM for inhalation risk assessment can be found in the document titled "Chlorothalonil: Revised Human Health Draft Risk Assessment for Registration Review".
EPA’s Office of Research and Development (ORD) has been developing in vitro assays to evaluate key neurodevelopmental processes for inclusion in a NAM battery for evaluating developmental neurotoxicity (DNT). In September 2020, a FIFRA SAP Peer Review meeting was held on “The Use of NAMs to Derive Extrapolation Factors and Evaluate Developmental Neurotoxicity (DNT) for Human Health Risk Assessments”. At this meeting, technical presentations were given by members of OPP and ORD on the assay development and regulatory use of the available DNT-NAM battery along with a case study demonstrating its potential application. In December 2020, the SAP’s report was released. All meeting material is available in the Federal Register docket number EPA-HQ-OPP-2020-0263 at www.regulations.gov.
As part of this work, EPA is also releasing data evaluation records (DERs) for DNT studies along with support memos that provide additional information on the results of those reviews that have been generated by OPP. These DERs will also contribute to EPA's ongoing collaboration with European Food Safety Authority (EFSA) and other international partnerships to further evaluate the DNT-NAM batter. The DERs and support memos are publicly available in docket EPA-HQ-OPP-2016-0093 at www.regulations.gov.
EPA continues to collaborate with NICEATM and the Humane Society on the use of the CATMos computational model for acute mammal toxicity endpoints in mammalian wildlife ecological risk assessment for pesticides. This effort involves a retrospective analysis of the effect on wild mammal risk assessment conclusions when replacing the routinely required acute oral rat toxicity study-derived effects endpoint with one generated by CATMos.
EPA will determine if direct replacement provides a consistent and protective acute wild mammal risk assessment conclusion, the most quantitative use of the acute mammal toxicity data in OPP.
EPA’s Office of Research and Development (ORD)’s CompTox Chemicals Dashboard is a tool that provides risk assessors access to in vivo toxicity and in vitro bioassay data for thousands of substances searchable by chemical structures.