Acute toxicity prediction across multiple species
Bhhatarai, et al. (2015), in an upcoming article in the journal Toxicological Sciences, describe their study as a milestone for non-animal approaches for acute toxicity testing as it lays “the framework for broader approaches to read-across that includes interspecies and mechanistic HTS [high-throughput screening] data and also highlights the importance of addressing systemic bioavailability.”
The authors explain that acute toxicity testing as required by some regulatory authorities necessitates testing on multiple species and routes of exposure per test compound, resulting in substantial animal use “with almost no opportunity for alternative approaches.”
They propose that “mechanisms of acute toxicity are likely conserved across…species” so that mechanistic data such as adverse outcome pathways (AOPs), in vitro models, standardized read-across approaches, and reliable quantitative structure-activity relationship (QSAR) models “could predict responses in multiple species under conditions of similar bioavailability.” A quantitative model for acute toxicity for multiple species is proposed that could be based on assessing the limited number of pathways/mechanisms involved in high acute toxicity.
As a test case, their current study focuses on one of the mechanisms of acute toxicity, inhibition of mitochondria membrane potential (MMP), “because of its precedence in acute toxicity and because it was represented in ToxCast by many active compounds.” Concordance was examined for acute toxicity data (oral and intravenous) for rat, daphnia, and fish, obtained from various database sources, and the in vitro mechanistic endpoint MMP, obtained from the EPA’s ToxCast Phase II HTS database. “Logarithmic scatter plots of acute toxicity data showed a clear relationship between fish, daphnia, and intravenous rat, but not oral rat data. Similar plots versus MMP showed a well-delineated upper boundary for fish, daphnia, and intravenous data, but were scattered without an upper boundary for rat oral data.” Additional manipulations of the rat oral toxicity values are explained, but rat toxicity “was often attenuated.”
The authors conclude that “This use of a single HTS assay to predict acute toxicity in multiple species represents a milestone and highlights the promise of such approaches but also the need for refined tools to address systemic bioavailability and the impact of limited absorption and first pass metabolism.”
We were excited to see this application of the Toxcast HTS data in an approach with the potential to reduce animal use in acute toxicity testing, and look forward to seeing more studies that further develop this model/non-animal approach for predicting acute toxicity.
Bhhatarai, B., Wilson, D.M., Bartels, M.J., Chaudhuri, S., Price, P.S., Carney, E.W. (2015). Acute toxicity prediction in multiple species by leveraging mechanistic ToxCast mitochondrial inhibition data and simulation of oral bioavailability. Toxicol. Sci. Jul 2. pii: kfv135. [Epub ahead of print]. Available at: http://toxsci.oxfordjournals.org/content/early/2015/07/01/toxsci.kfv135.abstract
Posted: August 11, 2015