Dr Carol Treasure, Founder and CEO, XCellR8
New Approach Methodologies (NAMs) for product safety and claim support
What are NAMs and what are the regulators saying about them?
There’s no doubt that advances in animal-free science are outpacing regulatory change, so how can these New Approach Methodologies (NAMs) be employed to support product safety claims?
NAMs include in vitro methods (such as cell-based tests and reconstructed human tissues) and in silico approaches (computer-based modelling). Many regulators, including the European Chemicals Agency (ECHA) and the US Environmental Protection Agency (EPA), have been vocal in their support for the use of NAMs, but in practice, companies sometimes report push-back when submitting non-animal data in regulatory dossiers. The situation varies between industry sectors, with cosmetic ingredient suppliers most heavily impacted, given the rapidly increasing number of animal testing bans around the world.
Which NAMs are already the default expectation?
Various in vitro OECD Test Guidelines are now the default expectation for compliance with regulations such as EU REACH and CLP, with animal testing only acceptable as a last resort. Examples include longstanding methods for skin irritation (TG439) and corrosion (TG431), and eye irritation (TG492), with more recent additions for skin sensitisation (TG442 series). An updated protocol for eye irritation (TG492B) provides the long-awaited more comprehensive replacement for the Draize test in rabbits, with the capability to classify Category 1 (serious eye damage) and Category 2 (eye irritation) as well as No Category (non-irritants). However, the method does not differentiate between Category 2A and 2B, so some limitations persist where this is needed.
Unlike traditional animal tests, extensive international validation trials have proven the accuracy of the in vitro methods, so they have truly earned a high level of confidence in predicting product safety for humans. There are few regulatory circumstances in which these tests would not now be considered at least first tier and are usually sufficient as stand-alone.
What happens when there’s no validated NAM?
The situation becomes more complex when we move beyond local endpoints, which are relatively simple to model in vitro (such as those mentioned above), to those that occur systemically, often involving multiple organ systems. Technological challenges persist in areas such as DART (developmental and reproductive toxicology) and in chronic and repeat-dose scenarios, where more funding is needed to expedite progress. Solutions are becoming available for use as a weight of evidence for regulatory settings, in some cases enabling companies to build a robust scientific argument against unnecessary animal tests, and in other cases, reducing the numbers of animals that are used. Acute oral toxicity is a perfect example.
LD50 tests for acute toxicity are still widely used. How can they be replaced?
LD50 tests (Lethal Dose to 50% of animals) are almost 100 years old, and the tests are now widely discredited on both scientific and ethical grounds, bearing no resemblance to real-life human exposure to chemicals. In vitro and in silico methods are now available. XCellR8 has developed a fully human in vitro screen, incorporating liver metabolism and validated using a reference set of 68 substances with diverse chemistries. The test, known as AcutoX, has a prediction model capable of binary classification (toxic / non-toxic) as well as assigning an acute oral toxicity class under both GHS and EPA systems. Recently published in the ALTEX journal, the test is already being in use by companies, often in combination with in silico prediction using the CATMoS / OPERA system. Work continues to further develop the reference data set and prediction model.
Contact XCellR8 at info@x-cellr8.com;
+44 (0)1925 607 134; www.x-cellr8.com.