Advancing systemic toxicity risk assessment: Evaluation of a NAM-based toolbox approach

For many years, a method that allowed systemic toxicity safety assessments
to be conducted without generating new animal test data, seemed out of
reach. However, several different research groups and regulatory
authorities are beginning to use a variety of in silico, in chemico, and
in vitro techniques to inform safety decisions. To manage this transition
to animal-free safety assessments responsibly, it is important to ensure
that the level of protection offered by a safety assessment based on new
approach methodologies (NAMs), is at least as high as that provided by a
safety assessment based on traditional animal studies. To this end, we
have developed an evaluation strategy to assess both the level of
protection and the utility offered by a NAM-based systemic safety
“toolbox.” The toolbox comprises physiologically based kinetic models to
predict internal exposures, and bioactivity NAMs designed to give broad
coverage across many different toxicity modes of action. The output of the
toolbox is the calculation of a bioactivity:exposure ratio (analogous to a
margin of internal exposure), which can be used to inform decision-making.
In this work, we have expanded upon an initial pilot study of 10 chemicals
with an additional 38 chemicals and 70 consumer exposure scenarios. We
found that, for the majority of these (>90%), the NAM-based
workflow is protective of human health, enabling us to make animal-free
safety decisions for systemic toxicity and preventing unnecessary animal
use. We have also identified critical areas for improvement to further
increase our confidence in the robustness of the approach.