Regulatory Research Agencies


Last updated: October 22, 2015

The US Environmental Protection Agency (EPA) is charged with administering all or part of 23 laws enacted by Congress and 3 executive orders issued by Presidents to protect human health and the environment. Based on its expertise, and public input, EPA develops and enforces regulations and employs other means to implement the laws delegated to it by Congress, following the guidance in the Presidential executive orders to prevent pollution and to protect human health and the environment from hazardous chemicals and other stressors.

EPA has 13 headquarter offices and 10 regional offices. Four of the headquarter offices (often referred to as Program Offices) are responsible for writing the regulations, and are basically organized around the major environmental recipients of pollutants (i.e., air, water, and land) as well as by the major source of pollution (i.e., commercial chemicals, including pesticides). There is also an office to enforce compliance with these regulations, although enforcement and compliance are largely handled by the regional offices. The other headquarter offices handle the administrative, legal, research, and development activities needed to support the Program Offices and Regions.

EPA has 24 laboratories: 7 under the Office of Research and Development (ORD) (3 under the Office of Air and Radiation and 4 under the Office of Chemical Safety and Pollution Prevention) and 10 regional laboratories. The regional laboratories tend to be analytical support laboratories to assist monitoring compliance with regulations. The ORD laboratories develop methods and models needed to improve the agency’s capacity to evaluate risk through research on better ways to assess exposure, to improve its ability to measure effects of chemicals and other stressors to humans and the environment, and to develop prevention and control technologies.

EPA supported the two National Academy of Sciences/National Research Council projects tasked with taking advantage of new advances in biology and computing to develop more informative, efficient, and inexpensive means to inform safety decisions. These resulted in two reports, Toxicity Testing in the 21st Century: A Vision and a Strategy and Exposure Science in the 21st Century: A Vision and a Strategy.

EPA has developed a strategy for using NAS’ guidance to develop a more informative and efficient approach to testing that will rely less heavily on animals over time. EPA’s National Center for Computational Toxicology (NCCT) has been a leader in moving towards predictive toxicology and away from the use of conventional tests to inform regulatory decisions. Other EPA laboratories, such as the National Health and Environmental Effects Laboratory (NHEERL), have collaborated with the Office of Pesticide Programs (OPP) and other program offices to develop adverse outcome pathways for toxic endpoints of regulatory concern. AOPs are designed to help provide the basis to link conventional toxicity tests to the rapidly evolving computational toxicology (Tox21) tests to provide the means to identify where the Tox21 tests predict well, and where improvements are needed. The strategy is to move in an orderly and informed fashion to replace less informative and less efficient methods and models with more informative, predictive, and efficient ones that use few or no animals.

To help accomplish this EPA signed a memorandum of understanding in February 2008, with the National Toxicology Program and National Institutes of Health Chemical Genomics Center and the Food and Drug Administration outlining a strategy for interagency cooperation in “the research, development, validation, and translation of new and innovative test methods that characterize key steps in toxicity pathways.”

EPA’s Office of Chemical Safety and Pollution Prevention

Animal Use
While ORD does use animals in its research, the major use of animals for regulatory testing to inform EPA decisions is conducted by industry to comply with Program Office requirements. In the context of regulatory toxicology, the majority of EPA’s animal use and/or testing requirements result from compliance with regulations issued by the Office of Chemical Safety and Pollution Prevention (OCSPP), primarily under the Office of Pesticide Programs (OPP), and to a certain extent under the Office of Pollution Prevention and Toxics (OPPT).

All products that are intended to manage, destroy, attract, or repel “pests” and that are used, sold, or imported into the US are regulated by the EPA’s Office of Pesticide Programs (OPP), a subdivision of OCSPP. These products include synthetic and bio-chemicals (including chemicals with antimicrobial activity), genetically engineered toxins, and even other organisms that are collectively referred to as “pesticides.” EPA’s statutory authority for regulating pesticides is primarily derived from the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) and the Food Quality Protection Act (FQPA); however, provisions in the Federal Food, Drug and Cosmetic Act (FFDCA) and the Endangered Species Act (ESA) also strongly impact EPA’s activities in the pesticides sector.

The goal of the EPA registration data requirements for pesticide chemicals is to mimic all the likely types of exposures that humans and species in the environment are expected to encounter during the manufacture, use, and consumption of pesticides. By their nature pesticides are designed to kill, harm, or hinder organisms, and so the assessment of pesticides is not about whether or not they are poisonous, but rather about characterizing the routes of exposures, as well as the doses and combinations of pesticides that can be used safely. Thus, an extensive range of testing is required to characterize the chemical nature of pesticide products, their uses, their potential to cause a wide variety of adverse effects to humans, plants, and other animals, as well as their ability to cause effects from aggregate and, in the case of pesticides in the same chemical class that share the same mode of action, the cumulative exposure effects. These testing requirements are codified under Title 40, Part 158 of the Code of Federal Regulations (40 CFR § 158) and are summarized in EPA’s Data Requirements for Pesticide Registration webpage.

The test requirements vary depending on the type of pesticide product being evaluated. EPA generally accepts reduced data sets for naturally occurring biochemical and microbial pesticides (e.g., pheromones) and for germ-killing antibacterial cleaning products, but not for conventional pesticides. The active ingredients in the latter undergo more extensive testing, including:

  • Acute systemic toxicity in rodents and/or rabbits via oral, inhalation, and dermal routes
  • Eye and skin irritation in rabbits
  • Skin sensitization in mice or guinea pigs
  • Subacute and/or subchronic studies via the dermal route
  • Subchronic (3 month) feeding studies in rodents and dogs
  • Chronic (12-24 month) feeding studies in rodents
  • Lifetime (18-24 month) carcinogenicity studies in rats and mice
  • Mutagenicity and genotoxicity studies of at least 2 varieties
  • Reproductive toxicity in at least 2 generations of rodents
  • Prenatal developmental toxicity in rodents and rabbits
  • Metabolism and toxicokinetic studies in rodents
  • Acute aquatic toxicity to fish of two or more species
  • Partial or full life-cycle toxicity to fish of two or more species
  • Acute and/or dietary toxicity to birds of two or more species
  • Reproductive toxicity to birds
  • And more…

In addition to mandatory testing of each active ingredient in a pesticide formulation, each finished product is also required to undergo separate acute toxicity testing via the oral, dermal, and inhalation routes, skin and eye irritation, and skin sensitization (known as the acute toxicity “six-pack”) for labeling purposes. Recognized testing methods to generate data to inform OPP’s decisions include the OCSPP Harmonized Test Guidelines, as well as the internationally harmonized OECD Guidelines for the Testing of Chemicals. However, FIFRA grants the agency broad discretion to request testing data for any effect(s) of interest under the pesticide program, including by means of “special” non-guideline studies.

The 2011 updates, Estimating the Data Generation Costs for Registration of a New Conventional Pesticide Active Ingredient and Estimated Data Costs, estimate that upwards of 12,000 animals and $10 M may be consumed during the extensive toxicological evaluation of each conventional chemical pesticide on the US market.

To take advantage of the recent advances in high speed computing and molecular biology, EPA’s Pesticides Program has adopted the NRC’s Toxicity Testing in the 21st Century vision, and it has developed a strategic plan about how to apply this approach in conjunction with the OECD concepts of Adverse Outcome Pathways (AOPs) and Integrated Approach to Testing and Assessment (IATA) in its pesticide testing activities to make the safety evaluation process more informative and efficient. In 2007, EPA adopted the integrated testing strategy recommendations of a multi-stakeholder technical committee under the auspices of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) to abolish the one-year general toxicity studies in dogs. A non-animal testing approach to EPA labeling for eye irritation for antimicrobial cleaning products (AMCPs) was launched in 2009, and determined in 2013 as acceptable for eye hazard classification and labeling for AMCPs and for satisfying the in vivo data requirement for eye irritation in 40CFR Part 158W for AMCPs. Most recently, in June 2015 the EPA announced it would use the results from ToxCast and other Tox21 approaches in Tier 1 of the Endocrine Disruption Screening Program to select which chemicals merit follow up testing in Tier 2 (see below).

The agency solicits independent scientific input through the FIFRA Scientific Advisory Panel and advice from pesticide stakeholders through its Pesticide Program Dialogue Committee to ensure the soundness of its science and the acceptance, relevance, and utility of its regulatory approach. In May 2011, OPP, working in concert with its partners from ORD and members of the Pesticide Program Dialog Committee, presented plans to move from the current animal testing approach to a more hypothesis-based and predictive approach to evaluating pesticide safety at a SAP meeting entitled “Integrated Approaches to Testing and Assessment Strategies: Use of New Computational and Molecular Tools.” The objective was to receive guidance about plans to improve the pesticide safety evaluation program which is based on traditional, largely animal-based toxicity tests, and make it more informative and efficient by developing an alternative, non-animal-based, Tox21 testing program. OPP used several case studies to illustrate how the new approach might proceed and its vision and plans for the future. The SAP concluded that the approach offers promise as a more informative, efficient, and economical approach to regulatory testing to inform decisions, and that it should be pursued. OPP has stated that it is committed to pursue this course of action into the future and those interested in keeping up to date are encouraged to periodically check OPP’s web page.

Acute Toxicity Data
In 2015, OPP proposed draft guidance, Process for establishing & implementing alternative approaches to traditional in vivo acute toxicity studies, to reduce the use of lab animals and increase the relevance of acute toxicity data on pesticides. The guidance describes a process for evaluating and implementing alternative methods for so-called “six pack studies” examining acute oral, dermal, and inhalation toxicity, as well as skin irritation, eye irritation, and skin sensitization on commercial chemical products. These tests, which currently rely heavily on the use of animals, examine the adverse effects that take place following a single or short-term exposure to a substance. EPA’s goal for moving to alternatives to animal tests is to assess a broader range and potentially more human-relevant adverse effects, to generate and review data more quickly and less expensively, and to reduce use of laboratory animals in regulatory testing. The guidance is one of the steps that OPP is taking to help implement the NRC Tox21 vision demonstrating its commitment to moving to more informative and efficient testing strategies for safety evaluation than is provided by current animal based toxicity testing.

Alternate Testing Framework for Classification of Eye Irritation Potential of EPA Pesticide Products
In May 2009, OPP issued a non-animal testing approach that could be used voluntarily to submit antimicrobial cleaning products for EPA labeling for eye irritation purposes. Previously, only the Draize rabbit eye test was used to determine ocular hazards, and the required hazard labeling for pesticide products. The voluntary pilot project was designed to evaluate the effectiveness of a specific alternative testing approach as a potential replacement for the Draize rabbit eye test for labeling antimicrobial products with cleaning claims. The testing strategy used the Bovine Corneal Opacity and Permeability test (BCOP), the EpiOcularTM model (EO), and the Cytosensor Microphysiometer assay (CM) to allow OPP to differentiate among the four eye irritation hazard categories used by the Agency. OPP also asked participating registrants to submit available consumer incident data and any existing Draize test results on similar or structurally-related chemicals or products as further support for the testing approach.

Based on this experience and an evaluation of submitted data by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), it was determined that the in vitro BCOP and EO alternative tests did not under-predict the results of the traditional Draize rabbit eye test. This supported the use of these assays in the decision tree approach for classification of eye irritation potential of antimicrobial pesticides with cleaning claims. Although no assays using the CM test were submitted under the pilot program, an analysis of the predictions of the CM assay published in the 2009 OPP pilot document as well as a background review document by the European Union Reference Laboratory for Alternatives to Animal Testing also supported the use of the CM assay for classification of mild and minimal irritants (EPA Category III and IV).

On this basis, in May 2015 OPP issued updated guidance for testing antimicrobial cleaning products for their potential to cause eye irritation using a non-animal testing approach for labeling for eye irritation. The update includes additional analysis that expands the applicability of the BCOP assay for identifying toxicity category III eye irritants for antimicrobial cleaning products (AMCPs). Previously, the BCOP was applicable only to identification of AMCP category I and II eye irritants. EPA/OPP has concluded that the additional analysis supports the use of the BCOP for identification of toxicity category III eye irritants for AMCPs.

For other classes of pesticides and pesticide products, including conventional, biochemical, and other antimicrobial pesticides not in the scope of those with cleaning claims, the agency will consider alternative tests conducted and submitted on a case-by-case basis. The acceptability of test results for these other classes will be determined using a weight-of-evidence approach that considers, for example, any in vivo testing, structure-activity relationships, and bridging arguments from results on similar test materials to support a classification under this testing scheme.

Endocrine Disruptors
The Food Quality Protection Act of 1996 required EPA to develop and implement “a screening program, using appropriate validated test systems and other scientifically relevant information, to determine whether certain substances may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect as [EPA] may designate.” Responsibility for developing a “toolbox” of validated screens and tests for this Endocrine Disruptor Screening Program (EDSP) was delegated to EPA’s Office of Science Coordination and Policy (OSCP) within OCSPP, although decisions about how to use the results of testing were left with the regulatory units of the program offices. Using the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) recommendations and working with ORD, OECD, and others, both in the United States and abroad, OSCP developed a two-tiered testing approach to evaluate the potential of chemicals of interest to EPA to cause endocrine disruption.

The Tier 1 tests are screening assays designed to determine if a chemical substance has endocrine disrupting properties, and the tests being developed for Tier 2 are intended to characterize those substances identified by the Tier 1 tests as chemicals that might be endocrine disruptors with respect to whether they are actually endocrine disruptors. To date the EDSP has employed animal models in both the Tier 1 and proposed Tier 2 batteries. This is because when EDSTAC developed its recommendations animal test approaches were the “gold standard” for safety evaluation. Further, even now there are no generally accepted alternatives to animal tests for certain organism-wide functions that require interaction between organs, cognitive processing, hormonal action, and immunological effects or interactions between organisms such as neurobehavioral effects. However, this situation is changing.

In 2009, EPA published an initial list of chemicals to be screened in Tier 1 tests for potential endocrine disrupting effects and the first test orders were issued late that year. The initial focus was on pesticides and drinking water contaminants to which a large population may be exposed. As part of this process, EPA described how it is working to integrate high throughput screening data with structure-activity relationships (SAR), estrogen receptor (ER) binding, and other approaches to develop AOPs for endocrine disruptors and incrementally move towards more predictive approaches through the use of IATA during a January 29-31, 2013 SAP meeting on “Prioritizing the universe of Endocrine Disruptor Screening Program (EDSP) chemicals using computational toxicology tools.”

On June 18, 2015, EPA announced a plan for incorporating validated high throughput assays and a computational model into the EDSP to screen chemicals for their ability to interact with the endocrine system. The proposed new method serves as an alternative for three of the eleven current assays in the EDSP Tier 1 screening battery (estrogen receptor binding, estrogen receptor transactivation, and uterotrophic).

EPA has partial screening results for over 1,800 chemicals that have been evaluated using high throughput assays and a computational model for the estrogen receptor pathway. In the future, EPA plans to develop alternative screening methods for the remaining eight Tier 1 assays using further advancements in high throughput assays and computational models. Use of these alternative methods is designed to accelerate the pace of screening, decrease costs, and reduce animal testing. In addition, the approach advances the goal of providing sensitive, specific, quantitative, and efficient screening using alternative test methods to some assays in the Tier 1 battery to protect human health and the environment.

Commercial Chemicals
OPPT administers the Toxic Substances Control Act (TSCA) and the Pollution Prevention Act, as well as parts of all of other statutes. Before a new chemical is marketed in the US, TSCA requires that a premanufacture notice be filed with EPA providing information on the chemical’s identity, intended uses, production volume, anticipated exposure and emission levels, as well as any toxicity data in the company’s possession. EPA uses the information in premanufacture notices, together with structure-activity relationship modeling, to determine whether there is a need to impose restrictions on the release and/or marketing of a chemical in order to ensure there is “no unreasonable risk of injury to health or the environment.” No testing beyond this is required under TSCA for new chemical substances as defined under the act.

With respect to existing chemicals, TSCA provides EPA with the authority to require companies to submit “all existing data concerning the environmental and health effects of [a chemical] or mixture.” Under TSCA section 4, EPA is further empowered to compel companies to generate test data when the agency finds that a chemical (1) may present an unreasonable risk of injury to health or the environment, or (2) is or will be produced in substantial quantities and (a) there is or may be significant or substantial human exposure to the chemical or (b) it enters or may reasonably be anticipated to enter the environment in substantial quantities. Many of the chemicals on the TSCA inventory, a list of chemical substances manufactured or imported into the US, are polymers with chemical properties that make it unlikely that they will be absorbed into the body or cause adverse effects. Many others are made in quantities below 10,000 pounds per year with such low exposure potential that risks are considered to be minimal. Thus, of the over 70,000 chemicals on the TSCA inventory only about 15,000 have the chemical characteristics and are made in such quantities that they may pose an environmental risk. Of these, about 540 chemicals have been issued test requirements, and EPA has made the decision not to test about 250 other chemical substances.

Most of 540 chemicals undergoing testing under Section 4 are high production volume (HPV) chemicals made or imported into the US in quantities of at least one million pounds per year. There are about 2,200 HPV chemicals on the TSCA inventory. While many HPV test rules are the result of EPA regulation, other testing has been done as a result Section 4 Enforceable Consent Agreements, and Voluntary Testing Agreements such as the HPV Challenge. Rather than “one size fits all” testing which might have resulted in wasted resources, both in terms of dollars and animals, efforts have been made to evaluate what is known about the chemicals of interest as a basis to identify data gaps and to focus the testing on filling those gaps. The HPV Information System database provides access to information, test plans, and data on HPV chemicals obtained through the HPV Challenge. Making this kind of information available to the public is part of the EPA’s duty to disseminate public health and environmental testing data under the Chemical Right to Know Initiative of 1998.

Testing to inform TSCA decisions is conducted using the tests identified in the OCSPP Test Guidelines, and the internationally harmonized OECD Test Guidelines. These require a set of methods to estimate risk based on the physical and chemical properties of a chemical substance, its exposure characteristics including absorption, distribution, metabolism, and excretion in the body, as well as its fate and transport in the environment and potential effects on humans and ecological species of interest. Depending on the type of tests required, such testing can use a substantial number of animals.

EPA is also working to ameliorate the need for testing through its Design for the Environment (DfE) Program. Under DfE, EPA works with chemical manufacturers to develop safer products by replacing toxic ingredients with less toxic substances, and to inform substitution to safer alternatives and reduce the likelihood of unintended consequences that might result if poorly understood alternatives were chosen. The DfE program alternatives assessment criteria for hazard evaluation document contains guidelines for testing the alternatives and references to the OSCPP test guidelines.

As is the case in the pesticides program, OPPT staff are developing a focused, hypothesis-based approach to testing. What is known about a chemical substance, including its physical and chemical properties, is used to identify data gaps, and then structure activity relationship predictions coupled with high throughput testing are used to determine testing needs and priorities.

Without compelling reasons to do so, the current requirements of TSCA do not allow EPA to require industry to conduct testing of chemical substances on the TSCA inventory for the wide range of human and environmental health endpoints that are evaluated for pesticides. As a result, there are many chemicals on the inventory for which there is little or no exposure, hazard, or dose-response information that can be used to assess risk. To obtain an approximation of what potential hazards might exist from exposure to chemical substances on the inventory, OPPT is partnering with EPA’s National Center for Computational Toxicology (NCCT). NCCT has developed a variety of tools, including the ToxCastTM battery of high throughput assays covering the range of human health outcomes of concern, ToxRefDB, a database that has systematically captured 30 years and over $2 billion worth of animal test data, ExpoCastDB,a database of exposure data, as well as bioinformatics machine learning. These and other tools are being applied to screen previously untested chemicals in the TSCA inventory as a means to evaluate and prioritize them with respect to testing needs. From the 3Rs perspective, the use of conventional testing approaches to do so would require an extensive use of animal studies.

Nanoscale Materials
Chemical substances that have structures with dimensions at the nanoscale — approximately 1-100 nanometers (nm) — are commonly referred to as nanoscale materials or nanoscale substances. Many nanoscale materials are regarded as “chemical substances” under TSCA. They may have properties different than the same chemical substances with structures at a larger scale, such as greater strength, lighter weight, and greater chemical reactivity. These properties may be beneficial, but also may cause some of these chemical substances to behave differently than conventional chemicals under specific conditions. To ensure that nanoscale materials are manufactured and used in a manner that protects against unreasonable risks to human health and the environment, EPA is pursuing a comprehensive regulatory approach under TSCA through premanufacture notifications for new nanomaterials and an information gathering rule on new and existing nanomaterials.

Voluntary Children’s Chemical Evaluation Program
The Voluntary Children’s Chemical Evaluation Program (VCCEP) was called for by the 1998 Chemical Right to Know Initiative which requires EPA to give citizens information on the effects of chemicals to enable them to make wise choices in the home and marketplace. VCCEP is the portion of that initiative that deals with risks to children. It was launched in 2000, and companies that manufactured or imported one or more of 23 chemicals to which children have a high likelihood of exposure were asked by EPA to voluntarily provide information on health effects, exposure, risk, and data needs. Thirty-five companies and 10 consortia responded, volunteering to sponsor 20 of the 23 chemicals. The goal is to learn from this trial before a final VCCEP process is determined and before additional chemicals are selected.

Other EPA Regulatory Programs

Regulatory testing requirements imposed by other EPA program offices are generally more limited than those of OCSPP. However, a certain amount of acute and chronic testing of aquatic organisms is prescribed, for example, under water quality standards and whole effluent toxicity methods promulgated by EPA’s Office of Water. For more, see the Ecotoxicity testing page.

Office of the Science Advisor

EPA’s Office of the Science Advisor resides in the Office of Research and Development (ORD) and provides leadership on science and technology issues and policy to facilitate the integration of the highest quality science into the Agency’s policies and decisions. It supports all Agency offices and provides a variety of products and publications relating to the conduct of risk assessment.

Adoption of Alternatives

EPA is engaged in several activities to develop new and revised testing methods and guidelines that take full advantage of scientific and technical advances and that have the promise to move to alternatives to animal tests in an expeditious manner. EPA’s ORD is actively working, in concert with NCCT and others, to develop the methods, models, and data needed to provide the tools and capabilities that can be reliably used to move from the traditional animal-based toxicity testing approaches to the more informative and efficient, largely non-animal, testing approaches of the future. EPA’s program offices implement the regulatory programs, and use tools and capabilities to inform their decisions. These offices apply the tools, methods, and models that are most informative and best suited to meet their regulatory requirements so their plans and operations are not based on moving to alternatives to animal tests per se, but rather on moving to more informative, efficient, and cost-effective ways to evaluate toxicity to inform the decisions required by their legislative mandates.

In the first few years of this century senior EPA managers, primarily in OCSPP, realized that new, more efficient and informative alternatives were needed to traditional toxicity testing if the universe of substances in commerce were to be tested in a sustainable way. At that time, advances in high speed computing and molecular biology had reached the point where they were recognized as providing at least a theoretical basis for a new hypothesis-based and predictive toxicity testing approach. Thus, working in concert, ORD, OCSPP, and primarily OPP designed and began to implement EPA’s initial computational toxicology activities in 2003. They formally established the computational toxicology research program in 2005, and charged the NRC to provide advice about how best to do this – resulting in the 2007 report, Toxicity Testing in the 21st Century: A Vision and a Strategy.

Many exciting advances have occurred since then, and the agency is moving in a strategic way to implement alternative testing approaches. This involves carefully defining the purpose(s) for which the data will be used, evaluating the science supporting use of the alternative approaches being considered for that purpose, and selecting the subset of alternative tests that are fit for that purpose. EPA then conducts “pilot” applications to evaluate how well they really do work. Recognizing that moving to alternatives represents a big change in how “business is done,” the Agency started with low risk, high payoff applications having minimum health and economic impacts (e.g., through ToxCast to screen inventories of previously untested chemicals to identify those with biological activity and then use this information to select which chemicals to test next, in what order and for what endpoints). A second initial pilot was application of alternative testing approaches to evaluate products with ingredients in a defined chemical structure space that experience has shown to be safe (i.e., antimicrobial cleaning products). These initial efforts were successful, and the agency built on the experience to progressively move to applications that may have more health and economic impacts (e.g., use in Tier 1 of the endocrine disruptor screening program).

In addition, EPA is considering a variety of incremental steps to further the use of alternative testing approaches for acute toxicity testing, such as the guidance for waiving or bridging mammalian acute toxicity tests for pesticides. At this time, such efforts are linked to OPP’s web page on test guidelines for data requirements.

The goal is to build a basis to apply more informative and efficient Tox21 and other alternative to animal testing approaches to inform major regulatory decisions through incremental steps, but this will likely take a very long time. Before alternative approaches are used for such purposes, each one must be shown to have a strong scientific basis and be as good as, if not better than, the traditional testing approach(es) in evaluating toxicity. This will take a great deal of time and effort. Perhaps even more time will be needed to address the political, legal, economic, and societal aspects of reaching a new “social contract,” where these alternative approaches are tacitly accepted by society as being fit for the purpose of informing regulatory decisions.

The Office of Pesticide Programs has described its strategic direction for new pesticide testing and assessment approaches, and the Office of Science Coordination and Policy, also within OCSPP, has described its plan to use “cutting edge” technology for endocrine disruptor screening. These lay out key aspects of the “glide path” to the future. ORD also has a variety of activities underway to provide the capability to move to a future where alternative approaches are used to inform regulatory decisions, including the development of virtual organs, such as the virtual liver and virtual embryo.

Exposure Evaluation

Because risk is a function of exposure as well as hazard, extensive efforts are also underway to reliably predict exposures through the development of models and tools such as ExpoCast and a variety of other methods. EPA’s EXPOsure toolBOX (EPA-Expo-Box) is a compendium of exposure assessment tools that links to guidance documents, databases, models, reference materials, and other related resources for use by EPA’s risk assessors and others. EPA’s Exposure Factors Handbook: 2011 Edition is a key document used by exposure assessors to calculate exposure to stressors from drinking water consumption, soil ingestion, inhalation rates, dermal factors, and food intake. It also contains information about human activity factors, consumer product use, and building characteristics. The document contains recommended exposure values to calculate risk for the general population as well as different subpopulations.


The agency also funds efforts to leverage research underway in academia and the broader scientific community to advance alternatives to animal testing through its Science to Achieve Results (STAR) program, and with the business community by funding small business innovation grants (SBIR) through the National Center for Environmental Research (NCER). The agency’s web page lists EPA’s grants and other funding opportunities.

Validation of New or Revised Test Methods

With the exception of EDSP, whose enabling legislation requires the use of validated methods, the use of non-animal alternatives for evaluation of adverse effects to human health or the environment do not have to be formally validated by the OECD or other validation authority in order to be accepted for regulatory purposes. The EPA has the authority to review data on a new or revised test method (including animal alternative methods) and decide whether that method/approach is acceptable for its context of use, and is thus valid for that purpose.

Nonetheless, EPA prefers to use information from “validated” methods and models to inform decisions, not only because they help ensure scientific rigor and accuracy, but also because they are generally more acceptable to the Congress, the courts, various stakeholders, and the public. Thus, EPA has suggested ICCVAM validation projects (e.g., Acute Systemic Toxicity and Use of Acute Oral Systemic Toxicity Data to Predict EPA Acute Dermal Hazard Classification), supports EPA members on ICCVAM, and currently co-Chairs the committee. Extensive efforts have been conducted by ICCVAM to “validate” alternatives to animal tests, and a number of others are currently underway and planned for the future.

Further information about EPA programs on AltTox:

Older EPA documents that are no longer on the current EPA website can often be located by searching the EPA Web Archive.


John R. (Jack) Fowle III, PhD

This section was adapted from Fowle III, J.R., Jacobs, A., & Fitzpatrick, S. (2014). Regulatory testing to inform decisions: National and international requirements. In D.G. Allen & M.D. Waters (Eds.). Reducing, refining and replacing the use of animals in toxicity testing (pp. 44-98). Cambridge, UK: Royal Society of Chemistry. Used with permission from the Royal Chemical Society.