Computational chemistry, systems biology and toxicology. Harnessing the chemistry of life: revolutionizing toxicology. A commentary

Abstract

There is a continuing interest in, and increasing imperatives for, the development of alternative methods for toxicological evaluations that do not require the use of animals. Although a significant investment has resulted in some achievements, progress has been patchy and there remain many challenges. Among the most significant hurdles is developing non-animal methods that would permit assessment of the potential for a chemical or drug to cause adverse health effects following repeated systemic exposure. Developing approaches to address this challenge has been one of the objectives of the European Partnership for Alternative Approaches to Animal Testing (EPAA). The EPAA is a unique partnership between the European Commission and industry that has interests in all aspects of reducing, refining and replacing the use of animals (the '3Rs'). One possible strategy that emerged from a broad scientific debate sponsored by the EPAA was the opportunity for developing entirely new paradigms for toxicity testing based upon harnessing the increasing power of computational chemistry in combination with advanced systems biology. This brief commentary summarizes a workshop organized by the EPAA in 2010, that had the ambitious title of 'Harnessing the Chemistry of Life: Revolutionizing Toxicology'. At that workshop international experts in chemistry, systems biology and toxicology sought to map out how best developments in these sciences could be exploited to design new strategies for toxicity testing using adverse effects in the liver as an initial focus of attention. Here we describe the workshop design and outputs, the primary purpose being to stimulate debate about the need to align different areas of science with toxicology if new and truly innovative approaches to toxicity testing are to be developed.

Human-based Systems in Drug and Chemical Safety Testing — toward Replacement, the ‘Single R’

“…As for toxicities that only appear after chronic treatment, again, these will result from discrete disturbances in certain biological pathways, and there is no reason to suppose that high-content type assays conducted to mimic acute exposure would not uncover indications of such disturbances, particularly if they were directed toward Adverse Outcome Pathways (AOPs). It also ignores the significant developments being made in extending the viability of certain in vitro assays, which are making chronic treatment increasingly feasible (49).…”

Novel in vitro and mathematical models for the prediction of chemical toxicity

“…The two main principles underlying this approach are (1) that similar chemicals should elicit similar downstream toxicological profiles and (2) both unbiased and case-study approaches are required to address this issue. [26][27][28][29] Therefore, chemicals that have well characterised pharmacokinetic, metabolic and toxicological profiles can be placed into specific categories, either based upon similarity profiles across both chemistry and nature of the downstream biological perturbation elicited. Subsequently, chemicals with less data available (e.g.…”

Chip-based liver equivalents for toxicity testing – organotypicalness versus cost-efficient high throughput

“…These are aimed at the transition to an AOP-based paradigm for chemical safety assessment, with a main focus on the integration of existing in vivo data with in vitro and in silico approaches. [10][11][12][13] It has been thoroughly recognised that physiological fluid flow through the liver tissue is one essential prerequisite on the biological side of the coin. Miniaturisation for high throughput at a minimal liver tissue requirement is the other prerequisite on the economical side of the coin.…”