Forskning

May 12, 2020

Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next Generation Risk Assessment

S Hatherell et al, 2020. Identifying and Characterizing Stress Pathways of Concern for Consumer Safety in Next Generation Risk Assessment, Toxicol Sci published online.

ABSTRACT:

Many substances for which consumer safety risk assessments need to be conducted are not associated with specific toxicity modes of action, but rather exhibit non-specific toxicity leading to cell stress. In this work, a cellular stress panel is described, consisting of 36 biomarkers representing mitochondrial toxicity, cell stress and cell health, measured predominantly using high content imaging. To evaluate the panel, data were generated for thirteen substances at exposures consistent with typical use-case scenarios. These included some that have been shown to cause adverse effects in a proportion of exposed humans and have a toxicological mode-of-action associated with cellular stress (e.g. doxorubicin, troglitazone, diclofenac), and some that are not associated with adverse effects due to cellular stress at human-relevant exposures (e.g. caffeine, niacinamide and phenoxyethanol). For each substance, concentration response data were generated for each biomarker at three timepoints. A Bayesian model was then developed to quantify the evidence for a biological response, and if present, a credibility range for the estimated point of departure (PoD) was determined. PoDs were compared with the plasma Cmax associated with the typical substance exposures, and indicated a clear differentiation between ‘low’ risk and ‘high’ risk chemical exposure scenarios. Developing robust methods to characterize the in vitro bioactivity of xenobiotics is an important part of non-animal safety assessment. The results presented in this work show that the cellular stress panel can be used, together with other new approach methodologies, to identify chemical exposures that are protective of consumer health.