Evaluation of the Threshold of Toxicological Concern (TTC) – Challenges and approaches |
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| Authors: | I Dewhurst AG Renwick |
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| Institution: | 1. Mammalian Toxicology, Chemicals Regulation, Directorate Health and Safety Executive, Mallard House, York YO1 7PX, UK;2. Faculty of Medicine, Highfield, University of Southampton, Southampton SO17 1BJ, UK;1. Novartis Pharma AG, TechOps, HSE, CH-4057 Basel, Switzerland;2. Novartis Pharma AG, NIBR, PCS, CH-4057 Basel, Switzerland;1. Research Group of In VitroToxicology and Dermato-Cosmetology, Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Brussels, Belgium;2. Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy;3. Altertox, Brussels, Belgium;4. Department of Biochemistry and Molecular Biology, University of Valencia-Spain, and Experimental Hepatology Unit, IIS Hospital La Fe of Valencia, CIBERehd, Spain;5. Machine Learning Research, Bayer AG, Berlin, Germany;6. Department of Toxicogenomics, GROW School for Oncology and Developmental Biology, Maastricht University, the Netherlands;7. Department of Environmental Health, Norwegian Institute of Public Health, Oslo, Norway;8. IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany, and Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany;9. Biomechanics Research Unit, GIGA In Silico Medicine, University of Liège, Belgium;10. ProtoQSAR SL, European Center of Innovative Companies, Technological Park of Valencia, Spain;11. Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;12. Center for Alternatives to Animal Testing-Europe, University of Konstanz, Konstanz, Germany;13. Centre of Experimental Medicine SAS, Slovak Academy of Sciences, Bratislava, Slovakia;14. Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands;15. Innovative Testing in Life Sciences and Chemistry, Hogeschool Utrecht University of Applied Sciences Utrecht, the Netherlands;p. ToxTrack, Bethesda, MD, USA;q. Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands;r. 3Rs Management and Consulting ApS, Lyngby, Denmark;s. esqLABS GmbH, Saterland, Germany;t. Molecular Networks GmbH, Nürnberg, Germany;u. Centre for Health Protection (RIVM), Bilthoven, the Netherlands;1. Instem, 1393 Dublin Rd, Columbus, OH 43215, USA;2. Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA;3. Alpha-PreTox, via G.Pascoli 1, 00184 Roma, Italy;4. Merck Healthcare KGaA, Frankfurter Str. 250, U009/101, Germany;5. R3Fellows LLC, Durham, NC, USA;6. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK;7. Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, 4123 Allschwill, Switzerland;8. BASF SE, APD/ET, Li 444, Speyerer St 2, 67117 Limburgerhof, Germany;9. FStox Consulting LTD, 2 Brooks Road Raunds, Wellingborough NN9 6NS, UK;10. Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy;11. Chemical Food Safety Group, Nestlé Research, Lausanne, Switzerland;12. RTice Consulting, Hillsborough, NC 27278, USA;13. Transendix LLC, 1407 Moores Manor, Indianapolis, IN 46229, USA |
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| Abstract: | Thresholds of Toxicological Concern (TTCs) have been used in the risk assessment of chemicals to which humans are exposed at very low levels. TTC values were developed using data from rodent cancer bioassays and from oral chronic and sub-chronic toxicity studies for non-cancer effects. The workshop assessed the adequacy and fitness for purpose of the TTC approach and the potential for future modifications of critical aspects. The current TTC value for cancer was considered adequate and fit for purpose because it is derived by linear extrapolation from the lowest TD50 for each compound in the largest available rodent carcinogenicity database. The database on non-cancer endpoints was considered adequate and fit for purpose because the chemical domain, the distributions of NOAELs and the calculated TTC values are comparable across different databases. Application of the TTC approach gives conclusions compatible with the risk assessment approaches currently used by international advisory committees. The workshop recognised the desirability of developing better tools to assess the comparability of the chemical domain covered in different toxicological databases, and the need to develop an internationally acceptable framework and databases for updating the aspects critical to application of the TTC approach. |
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