EPA Testing Changes
Safety Assessment
Clive Roper

The EPA’s Bold Decision

The agency is actively phasing out animal testing. Is the industry ready for it?

Last fall, the US Environmental Protection Agency announced that it wanted to see a reduction in animal testing by 30% by 2025 and would stop conducting or funding studies or requiring data from animal tests by 2035. The EPA identified key stakeholders to attend an inaugural meeting in December 2019. This is now an annual meeting with the second being held virtually in October 2020.

The key stakeholders are from a diverse set of backgrounds and interests such as industry (chemical, agrochemical, cosmetic and consumer product companies), NGOs and CROs. All key stakeholders have been actively involved in developing new technologies or new ways of determining chemical risk or hazard. Charles River is actively involved in some of these programs; (a) replacing in vivo acute tests, such as ocular irritation and severe damage, skin irritation and skin corrosion (b) replacing the dermal absorption triple pack with human in vitro only and (c) creating new methods for respiratory toxicology testing.

The EPA has published a list of replacement tests, also known as New Approach Methodologies (NAMs), that are acceptable to the EPA for identifying chemical risk and hazard. This list includes tests that have been used for many years in Europe as well as innovations that fulfill the agency's data requirements.

Advances in in vitro tissue and cell-based models, in chemico models, in silico (computational) models and read-across from data from similar chemicals now offer very different approaches for conducting safety studies that are as good as and in many cases better than the animal version. Most of the in vitro tissue and cell-based models utilize human tissue or human derived tissue, so are arguably more relevant than the animal test.

We at Charles River, for instance, now use 3D human-derived reconstructed airway tissue models that measure toxicity or assess efficacy of inhalable chemicals. Using these 3D tissue models, we identify, test and routinely use specific markers of toxicity associated with epithelial damage. These human tissue models have been used in support of our 3Rs program by helping us to design better animal inhalation toxicology tests or as replacement of the animal tests in clinical, occupational and consumer toxicology risk and hazard assessments as well as in pharmaceutical drug development for safety and efficacy.

Some of this data was evaluated by the EPA and then by an independent scientific advisory panel, with recommendations to perform these tests in advance of running in vivo tests. These and other approaches have been discussed by an internationally renowned group of scientists in more detail (Virtual Exhibitor-Hosted Sessions).

Safety assessments for topically exposed chemicals, agrochemicals, cosmetics and pharmaceuticals are now tested using in vitro human skin models as the gold standard. The EPA is working with stakeholder groups to replace the in vivo rat skin penetration test (Organisation for Economic Cooperation and Development (OECD) Test Guideline No. 427) with the in vitro human skin penetration test (OECD Test Guideline No. 428). Phototoxicity testing uses cells (OECD Test Guideline No. 432) as a first screening test. Skin irritation and corrosion is being evaluated to replace animals with the in vitro 3D human-derived skin model tests (OECD Test Guidelines 431 and 439). Charles River, with our industry partners, is developing skin irritation and corrosion tests for formulations, which the current tests have not been designed to do.

The EPA expects skin sensitization to be performed in vitro models to be used (OECD Test Guideline 442 group). For ocular irritation and severe damage testing, US agencies are now accepting the in vitro models (OECD Test Guidelines 437, 438 and 492) often as standalone or as a battery of tests at least on a case by case basis.

And since 2012, the EPA’s Endocrine Disruptor Screening Program has been in the process of validating and using computational models and high-throughput approaches to screen for potential endocrine disruptor effects.
At the same time, there are still tests for which there is no alternative to animals in the offing. What do we do about those?

Moreover, many scientists believe to correctly assess the toxic effects of a chemical you need to demonstrate it in whole living organisms. And in the absence of mammalian testing, will it still be possible to determine the adverse health effects of environmental contaminants?

Clearly the EPA thinks the industry is ready to act, and by throwing down the gauntlet it is setting the stage for other public agencies to do the same. Are we ready?

One way to think about all of this is to look beyond what the 3Rs has meant historically. In 1959, when Russell and Burch published their Principles of Humane Experimental Technique, and introduced the concept of the 3Rs, (replacement, reduction and refinement,) their concerns were largely around ethical ones. In fact, these 3Rs principles have served for decades as an important guide for researchers who use animals in their laboratory studies. (Some follow them better than others.) To that I think we need to also add two more Rs – responsibility and redundancy. In situations where you can gather your data using alternative methods, is it really necessary to follow with animal test that tells you essentially the same thing?

We are well past the stage where this argument for alternative testing centers around ethics and we can now effectively argue for certain alternative strategies on the merits of the science. Those data speaks for themselves. It is in everyone’s best interest to determine what works and what doesn’t and plan accordingly.