Strategic Vision for Adopting 21st Century Science Methodologies
To better protect human health and the environment, EPA’s Office of Pesticide Programs (OPP) is developing and evaluating new technologies in molecular, cellular, computational sciences to supplement or replace more traditional methods of toxicity testing and risk assessment and enhancing our ability to use integrated approaches to testing and assessment (IATA), which promotes a hypothesis based, systematic, integrative use of exposure and hazard information.
Adopting IATA and new technologies will improve hazard and exposure assessments that form the basis for understanding pesticide risks. With these improvements EPA can better achieve its goal of ensuring reliable protection of human health and the environment from adverse effects resulting from pesticide use.
This Web page illustrates the approach EPA’s Pesticide Program is using to pursue IATA and new technologies that predict and characterize potential human health and environmental hazards and exposures to pesticides.
Letter from OPP Director Jack E. Housenger to Stakeholders
Anticipated Results and Benefits of 21st Century Science Methodologies
The approach will result in:
- A broader suite of computer-aided methods to better predict potential hazards and exposures, and to focus testing on likely risks of concern.
- Improved approaches to more traditional toxicity tests to minimize the number of animals used while expanding the amount of information obtained
- Improved understanding of toxicity pathways to allow development of non-animal tests that better predict how exposures relate to adverse effects.
- Improved diagnostic biomonitoring and surveillance methods to detect chemical exposures and identify causes of toxic effects.
- A suite of spatial databases and geographic information tools, which will aid in developing more spatially explicit risk assessments that identify geographic areas of concern for both human health and ecological exposure.
Benefits of the approach:
- Can evaluate more chemicals across a broader range of potential effects in a shorter time frame.
- Potential to increase the feasibility of assessing the risks posed by mixtures.
- Enhanced predictive ability to determine whether animal testing is needed to refine a risk assessment and to inform management decisions.
- Refining and reducing animal testing by maximizing information obtained from animal studies, and focusing on effects of concern.
- Opportunities for improved diagnostic biomonitoring and surveillance methods to detect chemical exposures and identify causes of toxic effects.
- Enhancing the quality and efficiency of risk assessment and risk management decisions.
The Critical Path to an Integrated Approach
Our critical path focuses on fully utilizing an integrated approach to testing and assessment that promotes a hypothesis based, systematic, integrative use of exposure and hazard information. The goal is to move toward a new paradigm where in vivo
in vivoTests or evaluations performed within an intact, living organism such as a laboratory animal or humans. (animal) testing is targeted to the most likely hazards of concern. This progressive, tiered-testing approach starts with hazard-based hypotheses about the plausible toxicological potential of a pesticide or group of pesticides based on their physical-chemical properties. Existing exposure and toxicity information is then combined with computer modeling and ‘new’ diagnostic in vitroin vitroExperiments 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. (non-animal) assays to target toxicity testing to the specific data needed for human health and ecological risk assessments.
The path forward will require an improved ability to predict chemical toxicity and exposure through application of efficient and effective screeningscreeningAn activity using less expensive tests typically of shorter duration to provide preliminary information about chemical toxicity potential. Results from screening assays are typically used to set priorities for those chemicals (or groups of chemicals) that need further evaluation. These tests may consist of in vivo or in vitro assays. Screening can also be done by the use of QSAR modeling. tools including new in vitro assays that rapidly provide biological profiles of the toxicological potential of chemicals. New technological advances to support more effective means of screening chemicals for potential effects will include new computer modeling approaches to predict chemical toxicity and exposure as well as the development of new sensitive biomarkers that will enable tracking of pesticide exposures and their early effects in human and wildlife populations. Exposure and biomonitoring surveys of populations will be critical to interpreting toxicity data and for evaluating the effectiveness of the new testing and assessment paradigm.
Our approach also includes the development of increasingly effective laboratory animal tests that are designed to maximize the information generated about the nature of the effects being studied. These advances will be incorporated within a risk assessment framework of problem formulation, hazard, dose response, exposure assessment, and risk characterization to support pesticide registration decisions.
Achieving our objectives will require close collaboration with the scientific community, international organizations, and our government partners to build the foundation for understanding chemically-induced toxicity pathways. This understanding will allow our program to enhance the direct relevance of our risk assessments to people and wildlife by moving toward a paradigm that is based on a chemical’s mode of actionmode of actionUnderstanding how chemicals perturb normal biological function; the key steps in the toxic response after chemical interaction at the target site that is responsible for the physiological outcome or pathology of the chemical. and a better understanding of real world exposures to pesticides. Consistent with the 2007 National Research Council (NRC) of the National Academy of Sciences report on Toxicology Testing in the 21st Century (PDF)(4pp, 418 K, About PDF), this scientific foundation will enable a shift to an integrated testing and assessment approach. The goal of IATA is to refine, reduce or even replace data requirements for complex laboratory animal studies while maintaining the scientific defensibility of pesticide assessments.
Pesticide Program Objectives
No single tool is intended to be used alone in a regulatory decision, but, rather, in combination with other methods. For chemicals that typically lack extensive existing test data, the new toxicity and exposure approaches will enhance priority settingpriority settingAn activity that ranks chemicals on their hazard and/or exposure potential based on specified criteria in a defined regulatory context. Priority setting takes full advantage of existing knowledge about potential chemical exposure and toxicity and computer-aided predictions such as QSAR to determine which chemicals (or group of chemicals), and for which end points, are of greater concern in gathering additional data (typically in vivo) to better evaluate potential adverse effects on humans and wildlife. and screeningscreeningAn activity using less expensive tests typically of shorter duration to provide preliminary information about chemical toxicity potential. Results from screening assays are typically used to set priorities for those chemicals (or groups of chemicals) that need further evaluation. These tests may consist of in vivo or in vitro assays. Screening can also be done by the use of QSAR modeling. approaches that will focus Agency and societal resources on those chemicals with the greatest risk potential. Directing subsequent test data generation on the most probable adverse effects with more effective and focused assays will reduce the time required for testing and also result in the use of fewer laboratory animals in toxicity testing. The agency’s goals for alternative testing approaches include: assessing a broader range and potentially more human-relevant adverse effects, faster and less expensive data generation and review, and reducing use of laboratory animals in regulatory testing.
Recent and Short-term Activities
OPP’s strategic vision for implementing the 2007 NRC report on Toxicity Testing in the 21st Century has multiple components involving a combination of computational and predictive modeling approaches, in vitro techniques, and limited, targeted in vivo testing, to supplement or replace the existing toxicity tests required in 40 CFR part 158 (40CFR158) in support of pesticide registration.
In May 2011, the agency sought expert advice and input from its the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) on OPP's vision and scientific issues associated with adopting integrated approaches to testing and assessment (IATA) and strategies for using new computational and molecular tools. The Panel concurred that OPP’s strategic vision clearly articulated a sound scientific basis for utilizing the NRC’s recommendations regarding “21st Century Toxicity Testing” in a manner that makes the risk assessment process more efficient and informative. And, the Panel commented that utilizing data from rapidly and inexpensively performed in silico and in vitro technologies appears to be the most logical way to address the need to improve efficiency.
OPP provided staff the Guiding Principles for Data Requirements to enhance consistency in the identification of data needs, promote and optimize full use of existing knowledge, and focus on the critical data needed for risk assessment. OPP also developed policies that will reduce animal testing such as the "Part 158 Toxicology Data Requirements: Guidance for Neurotoxicity Battery, Subchronic Inhalation, Subchronic Dermal and Immunotoxicity Studies" to provide guidance on using a weight of evidence evaluation to determine data needs and the policy Advances in Genetic Toxicology and Integration of in vivo Testing into Standard Repeat Dose Studies and the Alternate testing framework for classifying eye irritation potential for labeling antimicrobial pesticide products with cleaning claims under the U.S. EPA classification and labeling system.
In 2012, we published "Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides and Pesticide Products," which provides a foundation for reducing redundant or unnecessary testing and thus reducing animal use. In 2016, we completed a related document: "Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations and Supporting Retrospective Analysis." View these two bridging and data waiver documents.
In addition, OPP is actively engaged with a consortium of pyrethroid registrants known as the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA) who are undertaking a substantial research effort to assess the potential for pyrethroid juvenile sensitivity using a strategy consistent with the new vision for toxicology described in the 2007 NRC report. The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) has undergone significant changes in leadership and strategic direction.
These changes include the drafting of a document entitled, “A New Vision and Direction for ICCVAM.” OPP played a major role in drafting this document. Two IATA related ICCVAM projects pertinent to OPP have been recently initiated---analysis of the need for acute lethality dermal toxicity testing for purposes of pesticide labeling and development of a strategy to move towards skin sensitization testing based on in silico, in chemico, and in vitro approaches, without the use of whole animals. Stakeholders inform and guide OPP’s application of IATA through the Pesticide Program Dialogue Committee (PPDC) 21st Century Toxicology/ New Integrated Testing Strategies Workgroup, which recently held a stakeholder workshop on application of 21st century methods to pesticide assessment.
The Pesticide Program will continue to enhance its integrated approach to testing and assessment to better determine what toxicity data are needed to further refine risk assessments for chemicals that do not have extensive toxicity information (e.g., inert ingredientsinert pesticide ingredientSubstances that are not an active ingredient (http://www.alanwood.net/pesticides/glossary.html#active) and are included in a pesticide formulation (http://www.alanwood.net/pesticides/glossary.html#formulation) for reasons other than pesticidal activity. Read more about inerts (http://www.epa.gov/opprd001/inerts/)., certain antimicrobialantimicrobial pesticideSubstance or mixture of substances used to kill or suppress the growth of harmful microorganisms such as bacteria, viruses, or fungi on inanimate objects and surfaces. Read more about antimicrobial pesticides (http://www.epa.gov/pesticides/factsheets/antimic.htm). and biochemical pesticides, and metabolitesmetabolitesBreakdown products, intermediates, and other biochemical substances produced by biological processes. and degradates of pesticide active ingredientsactive ingredientChemical or substance component of a pesticide product that can kill, repel, attract, mitigate or control a pest or that acts as a plant growth regulator, desiccant, or nitrogen stabilizer. The remainder of a formulated pesticide product consists of one or more "inert ingredients" (such as water, solvents, emulsifiers, surfactants, clay and propellants), which are there for reasons other than pesticidal activity. By law, the active ingredient must be identified by name on the label together with its percentage by weight.).
OPP plans to maximize use of existing data from similar compounds, computer hazard and exposure modeling, and in vitroin vitroExperiments 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. data to prioritize specific animal toxicity testing that is needed to assess and manage risks appropriately for these chemicals. As science is rapidly advancing and new technologies are emerging, including some alternatives assays with Organization for Economic Co-operation and Development (OECD) guidelines, there is increasing potential for the use of alternative methods in regulatory risk assessment. OPP plans to continue to expand its acceptance of alternative methods for acute toxicity testing. Additionally, the current status of monitoring or biomarker methods for population surveillance, which can easily measure exposure, susceptibility and biological outcomes, will be assessed and the need for additional research will be identified.
Long-term Objectives to Realize a Risk Assessment Paradigm Shift
As experience is gained and as our understanding of toxicity pathways increases, an enhanced integrated testing and assessment approach will be implemented for all pesticides including conventional agricultural pesticides. The approach will fully integrate hazard and exposure data along with advanced computer modeling based on new in vitroin vitroExperiments 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. data and an understanding of toxicity pathways to better predict risks and to determine what additional data are necessary to provide a sound basis to characterize risks of concern. Data from improved biomarkers of exposure and biological outcomes from population-based studies will be used to evaluate the effectiveness of this new risk assessment paradigm, to readily identify early effects in exposed populations, and to improve the approach.
OPP has partnered across EPA and with other federal agencies and international organizations to work collaboratively in an open and transparent manner. As we move forward, we will employ external scientific peer review and public participation as new integrated tools are developed and evaluated for inclusion in risk assessment methods. Enhancing the ability to use integrated approaches to testing and assessment holds the potential to usher in a new era of certainty, predictability and timeliness in the assessment of products that the Pesticide Program regulates.
Understanding Integrated Approaches to Testing and Assessment
The challenge of evaluating the potential effects of thousands of chemicals in the environment cannot be met by the current testing and assessment approach alone. The current approach relies on data from many costly animal tests that can require years to complete.
Integrated approaches to testing and assessment will increase the information available to EPA for risk management decisions and accomplish this in less time with less animal testing. Implementing this approach requires scientists to make initial predictions of toxicity to create a tailored toxicity testing strategy for each chemical, including carefully targeted animal tests when needed for decision-making. This will be achieved by:
- combining different types of existing information on a similar chemical or group of similar compounds;
- using predictive computer modeling (e.g., quantitative structure activity relationshipsQuantitative Structure-Activity RelationshipA mathematical relationship between a quantifiable aspect of chemical structure and a chemical property or reactivity or a well defined biological activity, such as toxicity. Using a sample set of chemicals, a relationship is established between one or many physical-chemical properties a chemical possesses due to its structure and a chemical property or biological activity of concern. This mathematical expression is then used to predict the chemical property or biological response expected from other chemicals with similar structures. It is based on the presumption that similar molecules or chemical structures have similar properties or biological activities or toxicity potential. Read about the principles that OECD has developed to facilitate the appropriate use of QSAR modeling for regulatory purposes (http://www.oecd.org/dataoecd/33/37/37849783.pdf).); and
- non-animal toxicology testing such as in vitroin vitroExperiments 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. and high-throughput screeninghigh-throughput systemsIn vitro biochemical or cellular assays that can be run efficiently on a large number of compounds to determine their activity on different biological targets such as ion channels, receptors, enzymes, proteins, and signaling pathways. assays.
The key goals of integrated approaches to testing and assessment are to:
- improve our ability to set priorities for what data to require;
- ensure that the data requirements are focused on the right issues; and
- efficiently reach the end result of effective risk assessment.
This approach will help us focus testing on pesticide chemicals and the effects that could most likely result in harm. As a result, testing would:
- use fewer animals;
- take less time;
- be less expensive for data generation and review; and
- explore a broader range of potential adverse effects.
For the Pesticide Program, these new approaches will allow better use of government and societal resources for evaluation of pesticide active and inert ingredients to consider a broader range of potential toxic effects that may not have been considered previously, and to provide a better understanding of the mechanisms underlying potential areas of concern.
The ultimate outcome of this new approach will be enhancement of the quality of risk assessments and risk management decisions.
We are developing a tiered framework for extrapolation modeling, to take advantages of recent scientific advances. View our paper: Proposed Approach to Efficiently Develop Physiologically Based Pharmacokinetic and Physiologically Based Pharmacokinetic-Pharmacodynamic Models for Pesticides.
Partnerships
To advance integrated testing and assessment and enhance the capacity for priority-settingPriority SettingAn activity that ranks chemicals on their hazard and/or exposure potential based on specified criteria in a defined regulatory context. Priority setting takes full advantage of existing knowledge about potential chemical exposure and toxicity and computer-aided predictions such as QSAR to determine which chemicals (or group of chemicals), and for which end points, are of greater concern in gathering additional data (typically in vivo) to better evaluate potential adverse effects on humans and wildlife. , screeningscreeningAn activity using less expensive tests typically of shorter duration to provide preliminary information about chemical toxicity potential. Results from screening assays are typically used to set priorities for those chemicals (or groups of chemicals) that need further evaluation. These tests may consist of in vivo or in vitro assays. Screening can also be done by the use of QSAR modeling., and evaluation of pesticide hazards, there are a wide variety of activities that involve various partners. These activities are part of an evolving process.
Partnerships within EPA
OPP is working closely with partners across EPA to define the research and to evaluate new tools to improve the efficiency and reliability of testing and assessment. These partners include:
- other programs in the Office of Chemical Safety and Pollution Prevention, and
- the Office of Research and Development.
For example, the U.S. Environmental Protection Agency’s Strategic Plan for Evaluating the Toxicity of Chemicals will serve as a blue print for implementing the 2007 NAS recommendations on Toxicity Testing in the 21st Century.
Partnerships With Other Federal Agencies
- EPA and two National Institutes of Health Institutes (National Institute of Environmental Health Science’s National Toxicology Program and National Human Genome Research Institute) signed a five-year Memorandum of Understanding (MOU). This MOU leverages the strengths of each organization to advance high-speed, automated screening tools to test chemicals in vitroin vitroExperiments 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. instead of in laboratory animals.
- EPA is also partnering with the U.S. Food and Drug Administration to exchange toxicity data to build better predictive models.
International Projects
- EPA is partnering with the Pest Management Regulatory Agency of Health Canada to test the predictive performance of selected (Q)SAR models for pesticides and develop guidance for the application of (Q)SARQSARA mathematical relationship between a quantifiable aspect of chemical structure and a chemical property or reactivity or a well defined biological activity, such as toxicity. Using a sample set of chemicals, a relationship is established between one or many physical-chemical properties a chemical possesses due to its structure and a chemical property or biological activity of concern. This mathematical expression is then used to predict the chemical property or biological response expected from other chemicals with similar structures. It is based on the presumption that similar molecules or chemical structures have similar properties or biological activities or toxicity potential. Read about the principles that OECD has developed to facilitate the appropriate use of QSAR modeling for regulatory purposes (http://www.oecd.org/dataoecd/33/37/37849783.pdf). models to pesticide risk assessments.
- The Agency is working with the Organization for Economic Cooperation and Development (OECD) on a number of activities including the application of toxicogenomic methods, development of non-animal testing methods (e.g., in vitroin vitroExperiments 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. and (Q)SAR approaches for endocrine disrupting chemicals), and on reducing and refining animal testing approaches.
- In December 2007, EPA hosted an OECD workshop in Washington, DC to discuss integrated testing and assessment approaches.
- EPA has also contributed to several of OECD’s reports and guidance documents on practical applications of (Q)SARs in specific regulatory contexts by governments and industry and to the development of the OECD (Q)SAR Application Toolbox.
The ways in which computer-aided approaches are used to predict effects on human health and the environment depends on the requirements of the specific legislation and needs of the regulatory authority. There is global interest in facilitating and expanding the role of predictive computer approaches in regulatory settings (for example see Joint Meeting of the Chemicals Committee and the Working Party on Chemicals, Pesticides and Biotechnology (PDF)(79 pp, 558 K, About PDF) Exit.
Opportunities for Collaborating on Data Collection Efforts
Instructions for submitting these data to OPP will be available soon on this website.
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Acute Skin Sensitization Test Data
EPA is seeking paired in vitro/in vivo skin sensitization data to assist in our efforts to move to alternative approaches for acute skin sensitization studies. The data will be used to evaluate Integrated Assessment and Testing Approached (IATA) case studies as part of an International Cooperation on Alternative Test Methods (ICATM) workshop in October 2016.
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GHS Dose Additive Mixtures Equation Pilot
EPA is requesting submission of acute oral and acute inhalation toxicity study data paired with GHS calculations to support the evaluation of pesticide product formulations. The GHS dose additive mixtures equation, used to classify the toxicity of mixtures based on the available data on the individual ingredients in them, could be an alternative to animal testing of pesticide formulations. OPP will use submissions under this pilot to evaluate the utility and acceptability of the GHS dose additive mixtures equation as an alternative to oral and inhalation toxicity studies for pesticide formulations. For information on how to submit data for the pilot and an example submission template, visit our Mixtures Equation Pilot Program page.
Related Guidance Documents
- Process for Evaluating & Implementing Alternative Approaches to Traditional in Vivo Acute Toxicity Studies for FIFRA Regulatory Use
- Use of an Alternate Testing Framework for Classification of Eye Irritation Potential of EPA Pesticide Products
- Retrospective Analysis & Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations
- Guiding Principles for Data Requirements
- Test Guidelines/Acute Toxicity - Acute Oral Toxicity Up-And-Down-Procedure
- Bridging or Waiving Data Requirements:
- Guidance for Waiving or Bridging of Mammalian Acute Toxicity Tests for Pesticides and Pesticide Products
- Guidance for Waiving Acute Dermal Toxicity Tests for Pesticide Formulations and Supporting Retrospective Analysis
- Guidance for Neurotoxicity Battery, Subchronic Inhalation, Subchronic Dermal and Immunotoxicity Studies
- Genetic Toxicology: Integration of in vivo Testing into Standard Repeat Dose Studies
- Update on the Use of the Local Lymph Node Assay for End Use Pesticide Products and Adoption of the Reduced Dose Protocol for LLNA (rLLNA)
- Guidance for Identifying, Selecting and Evaluating Open Literature Studies