Opportunities for Regulatory Toxicology

The past quarter-century has seen a shift in how chemicals are tested. Non-animal tests are gradually replacing tests on animals as a result of our better understanding of biological processes and the emergence of new technology, which have supported the development of testing methods that can look directly at cellular mechanisms, rather than depending on results from tests on animals that may be unreliable and difficult to interpret. This change is also the result of public pressure and, as explained below, dissatisfaction among scientists with the results of tests on animals. Cellular and genetic information about the potential toxicity of a chemical, such as the potential for receptor binding or gene or pathway activation, can be obtained more readily with non-animal tests (such as in vitro and in silico (computer) approaches) than with tests on animals.¹

Regulators and the regulated community are increasingly recognizing that tests on animals do not adequately protect either human health or the environment and that “the current approach is time-consuming and costly, resulting in an overburdened system that leaves many chemicals untested, despite potential human exposure to them.”²

In 2007, the U.S. National Academies of Science, Engineering, and Medicine (NASEM) published a landmark report titled “Toxicity Testing in the 21^st Century: A Vision and a Strategy.”³ It states that advances in toxicogenomics, bioinformatics, systems biology, epigenetics, and computational toxicology could transform toxicity testing from a system based on whole-animal testing to one founded primarily on in vitro methods that evaluate changes in biologic processes using cells, cell lines, or cellular components, preferably of human origin. The proposed changes would generate better data on the potential risks that humans face from environmental agents, such as pesticides, building a stronger scientific foundation that could improve regulatory decisions to mitigate those risks, while reducing the time, money, and number of animals needed for testing.

The report recommends an approach that would take advantage of rapidly evolving scientific understanding of the way genes, proteins, and small molecules interact to maintain normal cell function and how some of these interactions can be perturbed in ways that could lead to adverse health outcomes. Specifically, testing could focus on relevant toxicity pathways—also known as “adverse outcome pathways” (AOPs). These are cellular pathways that, when sufficiently perturbed, are expected to lead to adverse health effects. Robust in vitro toxicity tests can be designed to evaluate the effects of chemicals on specific events in these toxicity pathways and, therefore, help researchers understand how and at what exposure level an adverse outcome may occur.⁴

The current processes by which new in vitro approaches are validated must be adapted to account for their capacity to assess mechanisms of toxicity or specific events within an AOP.⁵ The traditional approach to assessing the accuracy of a new method typically requires a one-to-one comparison of the new data with data from tests on animals. This is problematic not only because of the lack of reproducibility of many in vivo tests but also because in vivo tests often produce species-specific apical results that do not necessarily correlate with human biology, mechanisms of toxicity, or specific AOP events.

To keep up with the rapidly evolving field of non-animal toxicology testing, research funds must be dedicated to training opportunities for regulators and researchers. Furthermore, it’s critical to maintain databases of the number of animals used in each type of experiment so that efforts to replace tests on animals can be prioritized and progress monitored.

By eliminating the use of tests on animals for regulatory purposes when replacements exist and by promoting further optimization of methods currently in development, the U.S. has the opportunity to better protect human health and the environment.

Regulators have since adopted this approach. The U.S. Environmental Protection Agency (EPA), for example, published its “New Approach Methods Work Plan,” which outlines concrete steps the agency will take in the coming years to reduce tests on vertebrates for pesticides and chemicals.⁶ Going even further, the European Commission has committed to developing a roadmap to end all mandated tests on animals for industrial chemicals, pesticides, biocides, and human and veterinary medicines in the European Union.⁷ The latter was a direct result of a European Citizens’ Initiative signed by more than 1.2 million people across the EU asking the commission for a future in Europe without animal testing.

Opportunities to end the use of animals for regulatory testing immediately or within the coming years are elaborated on in the appendices. These include tests for eye and skin irritation, skin sensitization, and the safety and efficacy of vaccines and biologics.