Possibilities for a New Approach to Chemicals Risk Assessment — The Report of a FRAME Workshop a

This is the report of a workshop organised by FRAME and held at The Blakeney Hotel, Blakeney, Norfolk, UK, in December 2005. The workshop was co-chaired by Michael Balls and Paul Illing, and there were 12 participants with a wide range of expertise, in risk assessment (RA), in vitro and in vivo toxicology, biokinetic modelling, genomics and proteomics, and regulatory affairs. The discussions focused on ways to improve the process of assessing the risks from exposure to chemicals. In particular, the workshop was conceived in order to consider and make recommendations to allow the maximum use of advanced, non-animal approaches, in order to enhance the RA process in terms of both science and efficiency. The aim was to identify how the existing RA process for chemicals could be improved, by considering: a) the principles of risk analysis and how they are applied to toxicological endpoints; b) the principles for using non-animal methods in hazard identification and characterisation; c) current and future opportunities for using advanced, non-animal methods for RA; and d) the factors that may influence the regulatory acceptance of such alternative methods. It was recognised that the demands of both European Union (EU) and global legislation would have to be accommodated. Based on discussions of the above issues, a series of recommendations were developed, addressing the adaptation of the RA process to deal with non-animal endpoints, and how non-animal endpoints could be more actively included in the regulatory process. Risk Assessment in the Context of Safety Testing and Hazard Identification

[1]  D. M. Conning,et al.  Risk assessment of chemicals , 1993 .

[2]  F W Schildberg,et al.  Protein binding capacity in vitro changes metabolism of substrates and influences the predictability of metabolic pathways in vivo. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[3]  John M Frazier.  A theoretical model for simulating the outcome of mechanism based in vitro toxicity testing strategies. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[4]  T R Sutter,et al.  Molecular and cellular approaches to extrapolation for risk assessment. , 1995, Environmental health perspectives.

[5]  R. Bloch,et al.  Monocarboxylic acid transporters, MCT1 and MCT2, in cortical astrocytes in vitro and in vivo. , 2000, American journal of physiology. Cell physiology.

[6]  Robert Combes,et al.  An Assessment of Progress in the Use of Alternatives in Toxicity Testing since the Publication of the Report of the Second FRAME Toxicity Committee (1991) , 2002, Alternatives to laboratory animals : ATLA.

[7]  Robert D. Combes,et al.  14 – In Vitro Genotoxicity and Cell Transformation Assessment , 1996 .

[8]  P. Schmezer,et al.  Cells of different tissues for in vitro and in vivo studies in toxicology: Compilation of isolation methods. , 1994, Toxicology in vitro : an international journal published in association with BIBRA.

[9]  H. Illing,et al.  Toxicity and Risk: Context, Principles and Practice , 2001 .

[10]  Hanneke van Helvoort,et al.  THE USE OF SANDWICH-CULTURED RAT HEPATOCYTES TO DETERMINE THE INTRINSIC CLEARANCE OF COMPOUNDS WITH DIFFERENT EXTRACTION RATIOS: 7-ETHOXYCOUMARIN AND WARFARIN , 2005, Drug Metabolism and Disposition.

[11]  Raffaella Corvi,et al.  The Assessment of Repeated Dose Toxicity In Vitro: A Proposed Approach , 2006, Alternatives to laboratory animals : ATLA.

[12]  Hasso Seibert,et al.  Impact of bioavailability on the correlation between in vitro cytotoxic and in vivo acute fish toxic concentrations of chemicals. , 2005, Aquatic toxicology.

[13]  Aldert Piersma,et al.  The ECVAM International Validation Study on In Vitro Embryotoxicity Tests: Results of the Definitive Phase and Evaluation of Prediction Models , 2002, Alternatives to laboratory animals : ATLA.

[14]  Horst Spielmann,et al.  Validation Successes: Chemicals , 2002, Alternatives to laboratory animals : ATLA.

[15]  Bas J Blaauboer,et al.  Modeling the in vitro intrinsic clearance of the slowly metabolized compound tolbutamide determined in sandwich-cultured rat hepatocytes. , 2004, Drug metabolism and disposition: the biological fate of chemicals.

[16]  L. Lorenz,et al.  Accelerated cure of phenol–formaldehyde resins: Studies with model compounds , 2002 .

[17]  B J Blaauboer,et al.  An alternative approach for the safety evaluation of new and existing chemicals, an exercise in integrated testing. , 2005, Regulatory toxicology and pharmacology : RTP.

[18]  Helmut Greim,et al.  Toxicological comments to the discussion about REACH , 2006, Archives of Toxicology.

[19]  R. W. Setzer,et al.  Use of NOAEL, benchmark dose, and other models for human risk assessment of hormonally active substances , 2003 .

[20]  Hasso Seibert,et al.  Serum albumin binding at cytotoxic concentrations of chemicals as determined with a cell proliferation assay. , 2003, Toxicology letters.

[21]  F. Johannsen,et al.  Risk assessment of carcinogenic and noncarcinogenic chemicals. , 1990, Critical reviews in toxicology.

[22]  B. van Ravenzwaay,et al.  The significance of in vitro rat skin absorption studies to human risk assessment. , 2004, Toxicology in vitro : an international journal published in association with BIBRA.

[23]  C. Eskes,et al.  Alternative (non-Animal) Methods for Cosmetics Testing : Current Status and Future Prospects. A Report Prepared in the Context of the 7th Amendment to the Cosmetics Directive for Establishing the Timetable for Phasing Out Animal Testing , 2005 .

[24]  Andrew Worth,et al.  Metabolism: A Bottleneck in In Vitro Toxicological Test Development , 2006, Alternatives to laboratory animals : ATLA.

[25]  Minne B Heringa,et al.  Toward more useful in vitro toxicity data with measured free concentrations. , 2004, Environmental science & technology.

[26]  Johannes J M van de Sandt,et al.  Prediction of in vivo embryotoxic effect levels with a combination of in vitro studies and PBPK modelling. , 2006, Toxicology letters.

[27]  Robert Combes,et al.  Introduction to the EU REACH Legislation , 2008, Alternatives to laboratory animals : ATLA.

[28]  Hasso Seibert,et al.  Impact of protein binding on the availability and cytotoxic potency of organochlorine pesticides and chlorophenols in vitro. , 2002, Toxicology.

[29]  Hasso Seibert,et al.  Validation of a prediction model for estimating serum concentrations of chemicals which are equivalent to toxic concentrations in vitro. , 2006, Toxicology in vitro : an international journal published in association with BIBRA.

[30]  Elaine M Faustman,et al.  Investigations of methylmercury-induced alterations in neurogenesis. , 2002, Environmental health perspectives.

[31]  I. Wilson,et al.  The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in man. , 1987, Xenobiotica; the fate of foreign compounds in biological systems.

[32]  Robert D Combes,et al.  Assessing risk to humans from chemical exposure by using non-animal test data. , 2005, Toxicology in vitro : an international journal published in association with BIBRA.

[33]  H B Koëter,et al.  Work in OECD on chemical safety: approaches for human risk assessment. , 2000, Industrial health.

[34]  Thomas Hartung,et al.  Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use , 2005, Environmental health perspectives.

[35]  Otto Geßner.  Tödliche Vergiftung durch Früchte des Ligusterstrauches (Ligustrum vulgare L.) bei einem 5-jährigen Kinde , 2006, Fühner-Wieland's Sammlung von Vergiftungsfällen.

[36]  Silvia Casati,et al.  In Vitro Tests for Haematotoxicity: Prediction of Drug-induced Myelosuppression by the CFU-GM Assay , 2002, Alternatives to laboratory animals : ATLA.

[37]  H Seibert,et al.  Factors influencing nominal effective concentrations of chemical compounds in vitro: cell concentration. , 2001, Toxicology in vitro : an international journal published in association with BIBRA.

[38]  E J Calabrese,et al.  Improved method for selection of the NOAEL. , 1994, Regulatory toxicology and pharmacology : RTP.

[39]  A. Renwick.  Data-derived safety factors for the evaluation of food additives and environmental contaminants. , 1993, Food additives and contaminants.

[40]  Hasso Seibert,et al.  In Vitro-In Vivo Extrapolation of Toxic Potencies for Hazard and Risk Assessment - Problems and New Developments , 2006 .

[41]  S. P. Asprey,et al.  Modelling of Mammalian Cells and Cell Culture Processes , 2004, Cytotechnology.

[42]  C. K. Atterwill,et al.  APPROACHES TO HIGH THROUGHPUT TOXICITY SCREENING. , 1999 .

[43]  Robert Combes,et al.  Toxicity testing: creating a revolution based on new technologies. , 2005, Trends in biotechnology.

[44]  Shiyin Vee,et al.  Applications of Caco-2 Cells in Drug Discovery and Development , 1999 .

[45]  A. Stammati,et al.  The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics , 2005, Cell Biology and Toxicology.

[46]  F. H. Sobels,et al.  Evaluating the mutagenic potential of chemicals the minimal battery and extrapolation problems , 1980, Archives of Toxicology.

[47]  Robert Combes,et al.  A Scientific and Animal Welfare Assessment of the OECD Health Effects Test Guidelines for the Safety Testing of Chemicals under the European Union REACH System , 2004, Alternatives to laboratory animals : ATLA.

[48]  H Seibert,et al.  Factors influencing nominal effective concentrations of chemical compounds in vitro: medium protein concentration. , 2002, Toxicology in vitro : an international journal published in association with BIBRA.

[49]  Ronald E. Hester,et al.  General overview of the safety evaluation of chemicals , 2006 .

[50]  Hasso Seibert,et al.  In vitro-in vivo extrapolation: estimation of human serum concentrations of chemicals equivalent to cytotoxic concentrations in vitro. , 2003, Toxicology.

[51]  J B Houston,et al.  An Integrated Approach to the Prediction of Systemic Toxicity using Computer-based Biokinetic Models and Biological In vitro Test Methods: Overview of a Prevalidation Study Based on the ECITTS Project. , 1999, Toxicology in vitro : an international journal published in association with BIBRA.

[52]  C K Atterwill,et al.  BTS working party report on in vitro toxicology , 1997, Human & experimental toxicology.

[53]  K Walton,et al.  An analysis of the need for an additional uncertainty factor for infants and children. , 2000, Regulatory toxicology and pharmacology : RTP.

[54]  John K Leighton,et al.  Application of Emerging Technologies in Toxicology and Safety Assessment: Regulatory Perspectives , 2005, International journal of toxicology.

[55]  Bas J Blaauboer,et al.  The applicability of in vitro-derived data in hazard identification and characterisation of chemicals. , 2002, Environmental toxicology and pharmacology.

[56]  Derek J Knight,et al.  Alternatives to Animal Testing in the Safety Evaluation of Products , 2002, Alternatives to laboratory animals : ATLA.

[57]  I. Wilson,et al.  The metabolism of [14C]N-ethoxycarbonyl-3-morpholinosydnonimine (molsidomine) in laboratory animals. , 1986, Xenobiotica; the fate of foreign compounds in biological systems.

[58]  J R Fry,et al.  Evaluation of a Short-term Rat Proximal Tubule Incubation System for the Detection of Nephrotoxicants , 1999, Alternatives to laboratory animals : ATLA.

[59]  Robert Combes,et al.  The establishment of a network of European human research tissue banks , 2004, Cell and Tissue Banking.

[60]  Hasso Seibert,et al.  Inclusion of Physicochemical Data in Quantitative Comparisons of In Vitro and In Vivo Toxic Potencies , 1994 .

[61]  Julia Fentem,et al.  The Feasibility of Replacing Animal Testing for Assessing Consumer Safety: A Suggested Future Direction , 2004, Alternatives to laboratory animals : ATLA.

[62]  Marilyn J. Aardema,et al.  Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies. , 2002 .

[63]  Robert D Combes,et al.  The Use of Human Cells in Biomedical Research and Testing , 2004, Alternatives to laboratory animals : ATLA.

[64]  C. Kahn,et al.  Human corneal epithelial primary cultures and cell lines with extended life span: in vitro model for ocular studies. , 1993, Investigative ophthalmology & visual science.

[65]  H P Illing,et al.  Absorption and disposition of [14C]-molsidomine in laboratory animals. , 1981, Arzneimittel-Forschung.

[66]  A G Renwick.  The use of an additional safety or uncertainty factor for nature of toxicity in the estimation of acceptable daily intake and tolerable daily intake values. , 1995, Regulatory toxicology and pharmacology : RTP.

[67]  M Chamberlain,et al.  Hazard and risk based on in vitro test data. , 1990, Toxicology in vitro : an international journal published in association with BIBRA.

[68]  R D Combes,et al.  The use of in vivo-like concentrations of chemicals for validation of in vitro short-term genotoxicity assays--an in vivo equivalent dose concept. , 1987, Mutagenesis.

[69]  H Seibert,et al.  Influence of protein binding and lipophilicity on the distribution of chemical compounds in in vitro systems. , 1997, Toxicology in vitro : an international journal published in association with BIBRA.

[70]  I. Hertz-Picciotto,et al.  Risk characterisation of chemicals in food and diet. , 2003, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[71]  Worth Andrew,et al.  Alternative (Non-Animal) Methods for Chemicals Testing: Current Status and Future Prospects (A Report Prepared by ECVAM and the ECVAM WG on Chemicals) , 2002 .