Evaluation of research activities and research needs to increase the impact and applicability of alternative testing strategies in risk assessment practice |
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Authors: | Punt Ans Schiffelers Marie-Jeanne W A Jean Horbach G van de Sandt Johannes J M Groothuis Geny M M Rietjens Ivonne M C M Blaauboer Bas J |
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Affiliation: | a Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80176, 3508 TD Utrecht, The Netherlands b Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands c Utrecht School of Governance (USG), Utrecht University, Bijlhouwerstraat 6, 3511 ZC Utrecht, The Netherlands d MSD, Toxicology and Drug Disposition, P.O. Box 20, 5340 BH Oss, The Netherlands e TNO Quality of Life, P.O. Box 360, 3700 AJ Zeist, The Netherlands f Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, University of Groningen, The Netherlands |
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Abstract: | The present paper aims at identifying strategies to increase the impact and applicability of alternative testing strategies in risk assessment. To this end, a quantitative and qualitative literature evaluation was performed on (a) current research efforts in the development of in vitro methods aiming for alternatives to animal testing, (b) the possibilities and limitations of in vitro methods for regulatory purposes and (c) the potential of physiologically-based kinetic (PBK) modeling to improve the impact and applicability of in vitro methods in risk assessment practice. Overall, the evaluation showed that the focus of state-of-the-art research activities does not seem to be optimally directed at developing in vitro alternatives for those endpoints that are most animal-demanding, such as reproductive and developmental toxicity, and carcinogenicity. A key limitation in the application of in vitro alternatives to such systemic endpoints is that in vitro methods do not provide so-called points of departure, necessary for regulators to set safe exposure limits. PBK-modeling could contribute to overcoming this limitation by providing a method that allows extrapolation of in vitro concentration-response curves to in vivo dose-response curves. However, more proofs of principle are required. |
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Keywords: | ADI, acceptable daily intake ADME, absorption, distribution, metabolism, and excretion BMC, benchmark concentration BMD, benchmark dose BMDL, lower confidence interval of the benchmark dose EC, effective concentration ECVAM, European center for the validation of alternative methods EPA, US environmental protection agency EST, embryonic stem cell test EU, European Union HBROEL, health based recommended occupational exposure limit ITS, integrated testing strategy LOAEL, lowest observed adverse effect level MM, micromass embryotoxicity assay NOAEL, no observed adverse effect level NAS, US national research council OECD, organization for economic co-operation and development PBBK, physiologically based biokinetic PBK, physiologically based kinetic PBPK, physiologically based pharmacokinetic PBTK, physiologically based toxicokinetic QSAR, quantitative structure activity relationship QSPR, quantitative structure property relationship REACH, registration evaluation authorization and restriction of chemical substances RIVM, Dutch national institute for public health and the environment TER, transcutaneous electrical resistance TDI, tolerable daily intake WEC, whole embryo culture |
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