Integrated Testing Strategies for Toxicity Employing New and Existing Technologies

• Published in: Alternatives to laboratory animals Vol. 39; no. 3; pp. 213 - 225
• Main Authors: Combes, Robert D, Balls, Michael
• Format: Journal Article
• Language: English
• Published: Nottingham FRAME 01-07-2011; Fund for the Replacement of Animals in Medical Experiments
• Subjects: Administration, Inhalation; Animal Testing Alternatives; Animals; Biological and medical sciences; Cell Culture Techniques; cosmetics; Cosmetics - toxicity; decision support systems; Domestic and cosmetic products toxicology; Drug-Related Side Effects and Adverse Reactions; drugs; hazard identification; Humans; laboratory animals; Medical sciences; nanoparticles; Nervous System Diseases - chemically induced; neurotoxicity; Pharmaceutical Preparations; pharmacokinetics; prediction; tissue culture; Tissue Culture Techniques; Toxicity Tests - methods; Toxicology; Validation Studies as Topic; volunteers; weight-of-evidence; Cosmetic; Nanoparticle; Toxicity; nanoparticle testing; Ultrafine particle; REACH system; animal testing; Neurotoxicity; weight-of-evidence; Technology; integrated testing; cosmetics testing; neurotoxicity testing; alternative tests; Nervous system diseases; drug testing; Evidence-based practice; Prediction; Toxicity test; Medical screening; In vitro; Inhalation; Animal; Registration, Evaluation and Authorization of CHemicals regulation; In silico; Alternative method; inhaled particle testing
• ISSN: 0261-1929; 2632-3559
• DOI: 10.1177/026119291103900303

We have developed individual, integrated testing strategies (ITS) for predicting the toxicity of general chemicals, cosmetics, pharmaceuticals, inhaled chemicals, and nanoparticles. These ITS are based on published schemes developed previously for the risk assessment of chemicals to fulfil the requirements of REACH, which have been updated to take account of the latest developments in advanced in chemico modelling and in vitro technologies. In addition, we propose an ITS for neurotoxicity, based on the same principles, for incorporation in the other ITS. The technologies are deployed in a step-wise manner, as a basis for decision-tree approaches, incorporating weight-of-evidence stages. This means that testing can be stopped at the point where a risk assessment and/or classification can be performed, with labelling in accordance with the requirements of the regulatory authority concerned, rather than following a checklist approach to hazard identification. In addition, the strategies are intelligent, in that they are based on the fundamental premise that there is no hazard in the absence of exposure - which is why pharmacokinetic modelling plays a key role in each ITS. The new technologies include the use of complex, three-dimensional human cell tissue culture systems with in vivo-like structural, physiological and biochemical features, as well as dosing conditions. In this way, problems of inter-species extrapolation and in vitro/in vivo extrapolation are minimised. This is reflected in the ITS placing more emphasis on the use of volunteers at the whole organism testing stage, rather than on existing animal testing, which is the current situation.