The use of Bayesian methodology in the development and validation of a tiered assessment approach towards prediction of rat acute oral toxicity

Abstract

There exists consensus that the traditional means by which safety of chemicals is assessed—namely through reliance upon apical outcomes obtained following in vivo testing—is increasingly unfit for purpose. Whilst efforts in development of suitable alternatives continue, few have achieved levels of robustness required for regulatory acceptance. An array of “new approach methodologies” (NAM) for determining toxic effect, spanning in vitro and in silico spheres, have by now emerged. It has been suggested, intuitively, that combining data obtained from across these sources might serve to enhance overall confidence in derived judgment. This concept may be formalised in the “tiered assessment” approach, whereby evidence gathered through a sequential NAM testing strategy is exploited so to infer the properties of a compound of interest. Our intention has been to provide an illustration of how such a scheme might be developed and applied within a practical setting—adopting for this purpose the endpoint of rat acute oral lethality. Bayesian statistical inference is drawn upon to enable quantification of degree of confidence that a substance might ultimately belong to one of five LD50-associated toxicity categories. Informing this is evidence acquired both from existing in silico and in vitro resources, alongside a purposely-constructed random forest model and structural alert set. Results indicate that the combination of in silico methodologies provides moderately conservative estimations of hazard, conducive for application in safety assessment, and for which levels of certainty are defined. Accordingly, scope for potential extension of approach to further toxicological endpoints is demonstrated.

A framework for chemical safety assessment incorporating new approach methodologies within REACH

“…This type of process has been developed in the concept of the Integrated Approach to Testing and Assessment (IATA) (OECD 2016 , 2021a ), where information from in silico, in vitro, and in vivo sources is considered within a structured framework. In some cases, the IATA uses cross-referencing to other compounds in a read-across procedure (van der Stel et al 2021 ), in others, a Bayesian statistical approach to integrate the information coming from the various sources, for instance in assessing dermal sensitisation (Jaworska et al 2013 ) or acute lethality (Firman et al 2022 ). This approach could be extended to other hazards.…”

“…There are established schemes for using NAMs in skin and eye irritancy/corrosion (Alepee et al 2019 ; OECD 2017 ), dermal sensitization (Jaworska et al 2013 ; Natsch et al 2021 ), and mutagenicity (Petkov et al 2015 ; Corvi and Madia 2017 ) which can be used now with reasonable confidence. There are in silico, in vitro, and focussed in vivo methods for acute toxicity which can also be used now with confidence (Erhirhie et al 2018 ; Firman et al 2022 ). NAMs for repeat dose toxicity are being actively developed and as discussed earlier should be judged on a case by case basis.…”