Making in silico predictive models for toxicology FAIR.

In silico predictive models for toxicology include quantitative structure-activity relationship (QSAR) and physiologically based kinetic (PBK) approaches to predict physico-chemical and ADME properties, toxicological effects and internal exposure. Such models are used to fill data gaps as part of chemical risk assessment. There is a growing need to ensure in silico predictive models for toxicology are available for use and that they are reproducible. This paper describes how the FAIR (Findable, Accessible, Interoperable, Reusable) principles, developed for data sharing, have been applied to in silico predictive models. In particular, this investigation has focussed on how the FAIR principles could be applied to improved regulatory acceptance of predictions from such models. Eighteen principles have been developed that cover all aspects of FAIR. It is intended that FAIRification of in silico predictive models for toxicology will increase their use and acceptance.

Probabilistic modelling of developmental neurotoxicity based on a simplified adverse outcome pathway network.

In a century where toxicology and chemical risk assessment are embracing alternative methods to animal testing, there is an opportunity to understand the causal factors of neurodevelopmental disorders such as learning and memory disabilities in children, as a foundation to predict adverse effects. New testing paradigms, along with the advances in probabilistic modelling, can help with the formulation of mechanistically-driven hypotheses on how exposure to environmental chemicals could potentially lead to developmental neurotoxicity (DNT). This investigation aimed to develop a Bayesian hierarchical model of a simplified AOP network for DNT. The model predicted the probability that a compound induces each of three selected common key events (CKEs) of the simplified AOP network and the adverse outcome (AO) of DNT, taking into account correlations and causal relations informed by the key event relationships (KERs). A dataset of 88 compounds representing pharmaceuticals, industrial chemicals and pesticides was compiled including physicochemical properties as well as in silico and in vitro information. The Bayesian model was able to predict DNT potential with an accuracy of 76%, classifying the compounds into low, medium or high probability classes. The modelling workflow achieved three further goals: it dealt with missing values; accommodated unbalanced and correlated data; and followed the structure of a directed acyclic graph (DAG) to simulate the simplified AOP network. Overall, the model demonstrated the utility of Bayesian hierarchical modelling for the development of quantitative AOP (qAOP) models and for informing the use of new approach methodologies (NAMs) in chemical risk assessment.

Pharmacokinetic Tools and Applications.

Drug toxicity, as well as therapeutic activity, is contingent upon the parent drug, or a derivative thereof, reaching the relevant site of action in the body, at sufficient concentration, over a given period of time. Thus, the potential to truly elicit an effect is governed by both the intrinsic activity/toxicity of the drug (or its transformation products) and its pharmacokinetic profile. As the pharmaceutical industry has become increasingly aware of the role of pharmacokinetics in determining drug activity and toxicity, the range of software, both freely available and commercial, to predict relevant properties has proliferated. Such tools can be considered on three different levels, applicable at different stages within the drug development process and providing increasing detail and relevance of information. Level (i) is the prediction of fundamental physicochemical properties that can be used to screen vast virtual libraries of potential candidates. Level (ii), predicting the individual absorption, distribution, metabolism, and excretion (ADME) characteristics of potential drugs, can also be applied to many compounds simultaneously. Level (iii), predicting the concentration-time profile of a drug in blood or specific tissues/organs for individuals or a population, is the most sophisticated level of prediction, applied to fewer candidates. In this chapter, in silico tools for predicting ADME-relevant properties, across these three levels, and the applications of this information, are described using exemplar, freely available resources. Further resources are signposted but not all are considered in detail as the purpose here is more to provide an introduction to the capabilities and practicalities of the tools, rather than to provide an exhaustive review of all the tools available.

A matter of trust: Learning lessons about causality will make qAOPs credible.

Toxicology in the 21st Century has seen a shift from chemical risk assessment based on traditional animal tests, identifying apical endpoints and doses that are "safe", to the prospect of Next Generation Risk Assessment based on non-animal methods. Increasingly, large and high throughput in vitro datasets are being generated and exploited to develop computational models. This is accompanied by an increased use of machine learning approaches in the model building process. A potential problem, however, is that such models, while robust and predictive, may still lack credibility from the perspective of the end-user. In this commentary, we argue that the science of causal inference and reasoning, as proposed by Judea Pearl, will facilitate the development, use and acceptance of quantitative AOP models. Our hope is that by importing established concepts of causality from outside the field of toxicology, we can be "constructively disruptive" to the current toxicological paradigm, using the "Causal Revolution" to bring about a "Toxicological Revolution" more rapidly.

A Systematic Review of Published Physiologically-based Kinetic Models and an Assessment of their Chemical Space Coverage.

Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration-time profile at the target site. Physiologically-based kinetic (PBK) models can predict organ-level concentration-time profiles, however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.

Determination of "fitness-for-purpose" of quantitative structure-activity relationship (QSAR) models to predict (eco-)toxicological endpoints for regulatory use.

In silico models are used to predict toxicity and molecular properties in chemical safety assessment, gaining widespread regulatory use under a number of legislations globally. This study has rationalised previously published criteria to evaluate quantitative structure-activity relationships (QSARs) in terms of their uncertainty, variability and potential areas of bias, into ten assessment components, or higher level groupings. The components have been mapped onto specific regulatory uses (i.e. data gap filling for risk assessment, classification and labelling, and screening and prioritisation) identifying different levels of uncertainty that may be acceptable for each. Twelve published QSARs were evaluated using the components, such that their potential use could be identified. High uncertainty was commonly observed with the presentation of data, mechanistic interpretability, incorporation of toxicokinetics and the relevance of the data for regulatory purposes. The assessment components help to guide strategies that can be implemented to improve acceptability of QSARs through the reduction of uncertainties. It is anticipated that model developers could apply the assessment components from the model design phase (e.g. through problem formulation) through to their documentation and use. The application of the components provides the possibility to assess QSARs in a meaningful manner and demonstrate their fitness-for-purpose against pre-defined criteria.