Bloomberg Law
Free Newsletter Sign Up
Bloomberg Law
Welcome
Go
Free Newsletter Sign Up

INSIGHT: Animal Protection and the Changing Landscape of Regulatory Testing

Dec. 10, 2018, 11:30 AM

In the fall of 1998, People for the Ethical Treatment of Animals (PETA) received a call from a high-level official with a multinational corporation. The caller notified the organization that the Environmental Protection Agency was on the verge of launching a massive animal testing program known as the “High Production Volume (HPV) Chemical Challenge Program.”

The news came as a surprise to the largest animal rights organization in the world. The plan had been largely conceived behind the scenes among the Environmental Defense Fund (EDF), the EPA, and then-Vice President Al Gore. There had been no public notice and comment on the program, no information published in the Federal Register, and no peer review of the claims that prompted it. The EPA had apparently not considered the U.S. animal protection community to be a stakeholder in a process that was expected to consume millions of animals in a checklist series of animal tests taken from an international “Screening Information Data Set.”

Because the program was due to launch in short order, PETA quickly mobilized a dozen animal-protection organizations and led the coalition in meetings with EPA and White House officials in an effort to mitigate the immense impact this testing program would have on animals. A large grassroots campaign, combined with an exhaustive scientific case, resulted in Congressional hearings on the program and a high-level agreement that recognized the suffering of animals in chemical tests and directed HPV participants to reduce the numbers of animals killed. This involved eliminating some animal tests, replacing others with in vitro tests, using “read-across” techniques to leverage known data about categories of similar chemicals, and applying a weight-of-evidence approach.

PETA and the Physicians Committee for Responsible Medicine (PCRM) subsequently addressed every HPV test plan that proposed to use animals and succeeded in eliminating a number of animal tests. For example, animals were spared from being used to test gases whose lower explosive limits (the concentration at which a gas will explode when ignited) were lower than the no-observed effect levels, or to test a nerve gas used in World War I. We obtained long-term changes in EPA testing policies and worked directly with chemical manufacturers to reduce and replace animal tests. As a result, an estimated 800,000 animals were saved from being used in HPV testing and, along with a series of citizens petitions, lawsuits, and scientific journal articles related to chemical and endocrine testing, we succeeded in dramatically raising agency awareness of these concerns.

Following the HPV controversy, EPA turned to the National Academy of Sciences for advice and in 2007 the National Research Council released its landmark report, Toxicity Testing in the 21st Century: A Vision and a Strategy. The report concluded: “Recent advances in systems biology, testing in cells and tissues, and related scientific fields offer the potential to fundamentally change the way chemicals are tested for risks they may pose to humans. …The new approach would generate more-relevant data to evaluate risks people face, expand the number of chemicals that could be scrutinized, and reduce the time, money, and animals involved in testing.” Almost overnight, developing and implementing a more accurate and effective chemical testing system became a priority.

Focus on the OECD

While working to gain a toehold at the EPA, we also focused on the Organization for Economic Cooperation and Development—an international entity that issues harmonized testing guidelines, guidance documents, and chemical assessment tools. Historically, decisions concerning new chemical testing guidelines have been made by individual national governments, with little or no international harmonization. However, these decisions are increasingly being made at the international level, through consensus among participating countries. This, combined with the fact that these testing guidelines have traditionally relied heavily on animal-based methods, made it critical for the animal protection community to be represented at the OECD.

Animal protection organizations representing more than 30 million members throughout Asia, Europe, and North America formed the International Council on Animal Protection in OECD Programs (ICAPO). In 2002, ICAPO gained official status as invited experts, joining other NGOs representing business, labor, and the environment.

With PCRM as Secretariat, ICAPO representatives work in such specific areas as adverse outcome pathways, endocrine disruptor testing, existing chemical testing, and validation of non-animal testing methods through working groups, providing outside experts, submitting input to draft test guidelines, and partnering with member countries to enforce Mutual Acceptance of Data provisions and ensure that the OECD leads efforts to reduce and replace animal use.

Focus on ICCVAM

Also in the late 1990s, it was clear to animal protection organizations and interested members of Congress that much more needed to be done to incorporate non-animal testing methods throughout regulatory agencies. In 2000, thanks in large part to the efforts of the Doris Day Animal League, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was created as a permanent committee of the National Institute of Environmental Health Sciences. ICCVAM is comprised of representatives from the 16 U.S. federal regulatory and research agencies that conduct, use, or require data from toxicity testing.

Within a few years of its founding, however, PETA and others became concerned with the direction of ICCVAM and its failure to address its Congressional mandate to “reduce, refine, or replace the use of animals in testing where feasible” and to “ensure that new and revised test methods are validated to meet the needs of U.S. federal agencies.” In 2007 PETA published a report detailing the problems; in 2008 the organization supplied evidence to the Washington Post, which investigated and published a front page expose on the failures of ICCVAM. Finally, in 2011, we launched a public campaign which resulted shortly thereafter in new leadership.

Under the guidance of the new National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) director and new ICCVAM co-chairs, there has been a sea change in the committee’s direction, purpose, vision, and accomplishments. ICCVAM has prioritized agency needs and short-term projects that are of particular interest to one or more agencies. As a result of a collaboration between NICEATM and the EPA, for example, the agency released a policy in April 2018 allowing the use of non-animal approaches for skin sensitization testing. There has also been increased transparency and improved communication with stakeholders and the public, including the launch of an annual public forum.

Evolution at the EPA

The change in some quarters of EPA has been profound. In the decade since EPA launched the ToxCast program—which develops high-throughput screening methods and computational toxicology approaches to predict chemical hazards—much has been done to advance in vitro tests for systemic endpoints and in vitro to in vivo extrapolation. Much of EPA’s Endocrine Disruptor Screening Program, which originally threatened to use tens of millions of animals, evolved into a Tox21 approach that was largely consistent with a plan laid out by PETA scientists in a Toxicological Sciences article several years prior. The EPA’s Office of Research and Development joined forces with the European Commission’s Joint Research Center and the U.S. Army Corps of Engineers to establish the AOP-Wiki, a global platform for the development of adverse outcome pathways—a powerful tool that can be used to organize existing data and design non-animal testing strategies.

Pesticide testing is one area where much effort has been invested in reducing the vast numbers of animals (7,500 to 10,000 rats, mice, rabbits, birds, fish, and dogs) who are used to test every pesticide active ingredient. The tests required include eye and skin irritation, skin sensitization, and acute oral, inhalation, and dermal toxicities—the so-called “six-pack” of acute toxicity tests—as well as tests related to reproduction and development, neurotoxicity, immunotoxicity, carcinogenicity, mutagenicity, and ecological effects.

In 2016, EPA’s Office of Pesticide Programs (OPP) announced its commitment to protecting human health and the environment while reducing the number of animals who suffer in acute toxicity testing along with the specific steps it would take to accomplish that goal. It formed a stakeholder group to focus its efforts and this opportunity for open dialogue is a model of a successful, proactive effort to engage outside groups.

Collaborative projects include the validation of in vitro assays to assess eye irritation from agrochemical formulations instead of using rabbits and a retrospective review to investigate reducing the number of mallard ducks and bobwhite quails used routinely in dietary tests. There have also been extensive multi-stakeholder discussions about alternative approaches for assessing acute inhalation toxicity, including a workshop on the topic co-organized by the PETA International Science Consortium and NICEATM in 2016. (The PETA International Science Consortium Ltd. was incorporated in 2012 to coordinate the regulatory and scientific expertise of PETA U.S. and its worldwide affiliates, as well as their funding of the development and validation of non-animal testing strategies.) OPP has shown a willingness to review new approaches that replace animal use, such as a proposed in silico and in vitro approach for assessing the inhalation risk of a fungicide.

In another recent collaborative effort, NICEATM, EPA’s National Center for Computational Toxicology, and the ICCVAM acute toxicity working group launched an effort to develop predictive models for acute oral toxicity. In total, 35 groups from the U.S., Europe, and Asia submitted 139 models for five different endpoints that meet various regulatory needs with a plan to optimize a consensus model that will be freely available and open to all on the NICEATM and EPA websites.

EPA’s Office of Pollution Prevention and Toxics (OPPT) is now under Congressional directive to reduce and replace animal tests. The Frank R. Lautenberg Chemical Safety for the 21st Century Act became law in 2016 and, following an extensive lobbying effort by the animal protection community, includes the first American legislative requirement to reduce and replace animal use in chemical testing. OPPT published a strategic plan outlining the steps it will take to “eventually eliminate” their use and is organizing a webinar series on the use of “new approach methodologies” in risk assessment with PCRM and the PETA International Science Consortium.

Other U.S. Agencies’ Challenges

The picture at other U.S. regulatory agencies is less clear, though progress is being made in some centers within the Food and Drug Administration and Agriculture Department. For example, in 2017, the PETA Science Consortium worked with a company to gain acceptance—for the first time—of the human repeat insult patch test in place of the rabbit vaginal irritation test and the guinea pig maximization test, both of which are routinely required by Center for Devices and Radiological Health (CDRH) reviewers before personal lubricant products can be marketed.

Also in 2017, CDRH introduced the Medical Device Development Tools (MDDT) program to streamline the process through which test method developers and companies can gain agency approval to use new methods in place of animal tests. A proposal from several major personal lubricant manufacturers, the PETA Science Consortium, and the Institute for In Vitro Sciences to demonstrate the efficacy of replacing two animal-based tests was accepted into the MDDT program. In September 2018, the PETA Science Consortium and NICEATM co-organized a workshop to plan an additional project aimed at replacing the rabbit pyrogen test—a required test for many types of medical devices—with the human cell-based monocyte activation test.

In 2017, following a multi-year tissue-chip collaboration among FDA, the Defense Advanced Research Projects Agency, and NIH, the FDA’s Center for Food Safety and Applied Nutrition announced a collaborative agreement with Emulate to evaluate the company’s organ-on-a-chip technology.

The U.S. Department of Agriculture’s Center for Veterinary Biologics (CVB) has spent years developing non-animal methods that can replace required vaccine potency tests. In 2018, both the CVB and the FDA participated in a workshop co-hosted by NICEATM and the International Alliance for Biological Standardization, which focused on improving industry implementation of a non-animal rabies vaccine potency test in lieu of an excruciating test on animals. The non-animal test has been available for almost two decades but technical barriers have kept it from being widely adopted.

Focus on the Future

Despite this progress, many millions of animals are still suffering in chemical, pesticide, drug, biologics, and medical device testing and sustained efforts are needed to delete requirements for tests whose results are not used by agencies as well as to develop and validate additional non-animal approaches. Tobacco-related testing, under the auspices of the FDA’s Center for Tobacco Products, is a prime example of animal tests that should be ruled out, and indeed, tobacco-related testing on animals is already prohibited in a number of countries.

Along with the will, agencies need resources to support alternatives efforts. Staffing and funding are needed to make advances within each agency and to allow for alternatives experts within one agency to present their work at other agencies—both within the U.S. and globally.

It is important that agencies clarify the specific ways in which they use the results of animal tests and the information that is needed from their replacements. They must interact with relevant stakeholders from industry, non-governmental organizations, and academia. As demonstrated by the successful collaborative efforts and forums for open dialog mentioned above, transparency allows for the formation of public-private partnerships that leverage the knowledge and experience of relevant experts and for the most efficient progress to be made.

Agency reviewers need to be well-trained in interpreting results from new approach methodologies—a process with which non-governmental organizations have and will continue to assist. Companies with expertise in various methodologies must be proactive in discussing alternatives with the agencies overseeing their products.

The journey of a thousand miles to replacing animal use in regulatory testing that began in part with the single step of that phone call two decades ago is far from complete. But the landscape of toxicity testing and the outlook for replacing animal use has changed considerably since those days. With sustained effort and collaborations across government agencies, NGOs, industry, and academia, the end of the days of poisoning animals in chemical tests is within our grasp.

Jessica Sandler, MHS, is PETA’s vice president for regulatory testing and the director of the PETA International Science Consortium. She heads an international team of scientists that has changed U.S. and European chemical testing policies and led multinational corporations, researchers, and government agencies to adopt modern, humane testing methods.

The opinions expressed here do not represent those of Bloomberg Environment, which welcomes other points of view.