The safety assessment of chemicals is traditionally based on experimental animal tests. But society is increasingly resistant to this approach and the results are not always satisfactory. Regulatory toxicology has begun to embrace new hazard characterisation approaches which could be integrated into regulatory safety assessments. The vision is to fundamentally change the way we assess the safety of chemicals, by superseding traditional animal experiments with a predictive toxicology that is based on a comprehensive understanding of how chemicals can cause adverse effects in humans.
Beyond animal testing: the frontiers of predictive toxicology
Keynote speaker Thomas Hartung, of John Hopkins University, made no bones about the issue: “Animal testing is not good enough,” he said. Complementing and gradually replacing this mainstay of traditional toxicological testing will not be easy but Prof Hartung mapped out some of the challenges and novel approaches emerging for assessing chemical hazards.
Alternative and integrated testing strategies
Germany boasts one of the world’s first regulatory bodies for alternatives to animal testing (ZEBET) and Horst Spielmann, recently retired from Freie Universitat, Berlin, was its head until recently. An experienced scientific researcher and regulator, Prof. Spielmann detailed how integrated testing strategies that combine in vitro (testing of cells or tissues, not whole animals) with previously performed in vivo (tests on animals or humans) is already a reality for cosmetics regulation.
Managing toxicological knowledge, information and data
The adverse outcome pathway (AOP) concept provides a framework for managing our knowledge of the mode of action of compounds that helps to weed out causality from the mass of available information. Ellen Fritsche of Leibniz Research Institute for Environmental Medicine, Germany, presented and put forward the AOP for positioning toxicity data generated by alternative methods in a regulatory context.
Predictive toxicology: in vitro data and in silico models
The European Commission’s Joint Research Centre is leading Europe’s efforts to replace in vivo repeated dose systemic toxicity testing. Its SEURAT project, explained Elisabet Berggren, aims to devise a toxicological mode-of-action framework to describe how any substance may adversely affect human health, and to use this knowledge to develop complementary theoretical, computational and experimental (in vitro) models for safety assessments.
Simulating chemical effects
Computer simulations are being extensively used as support to human experts in evaluating chemical effects, explained Emilio Benfenati from Italy’s Istituto di Ricerche Farmacologiche Mario Negri. Computer processing power can perform quantitative structure-activity relationship analyses that integrated multiple approaches.
A toxicological compound library
Scientific agencies in the US are working together to develop innovative approaches to characterise pathways of toxicity in chemical testing. Raymond Tice, of the US National Institute of Environmental Health Sciences (NIEHS), shed considerable light on the Tox21 Program. A vast toxicological compound library is being used as a source of information for predicting the likely responses of organisms when exposed to an array of chemicals, mainly used in pesticides.
“Lung-on-chip” generating human relevant data
Remi Villenave, from Emulate in the US, is using organs-on-chips technology to better understand mechanisms of diseases, study host pathogen interaction and test new therapeutics. These 3D microfluidic cell chips reproduce living tissue and are already being used to simulate biological behaviour and generate data for testing medicines.
Promising developments but further work is needed
The speakers agreed that 3D cultures are evolving and promising, but the level of standardisation needs to be carefully considered to avoid additional uncertainty in their future uses. Large institutional databases will improve and increase the availability of data, and the transition to alternative testing methods needs to proceed faster. Enhanced dialogue and collaboration between regulators, academia and data providers (e.g. companies, laboratories) is crucial.