- Email: [email protected]
Risk assessment of flavouring substances used in foods
S144
Abstracts / Toxicology Letters 164S (2006) S1–S324
based on common substructure, and has predicting tool based on analyzing the correlation between common substructures and biological activities. We evaluated two optimized prediction models in the ClassPharmer, and the concordance lead to around 70–75%. Adding this new prediction system to the above combination approach may be useful for increasing applicability. Additionally, in the course of optimizing the prediction models by using ClassPharmer, we found some possible toxicophores, which may be correlated to potency of chromosomal aberration. The information would be helpful for improvement of accuracy on the above three in silico systems. doi:10.1016/j.toxlet.2006.06.300 P8-11 A proposed framework for the interpretation of biomonitoring data P.J. Boogaard 1 , P.B. Farmer 2 , M. Holt 3 , L.E. Knudsen 4 , C.D. Money 5 , L. Onyon 6 , D.E. Owen 7 , S.H. Robison 8 , G. Schoeters 9 , G.D. Stropp 10 , M.F. Wilks 11 , W. Will 12 1 Shell
International, Netherlands; 2 University of Leicester, UK; 3 ECETOC, Belgium; 4 University of Copenhagen, Denmark; 5 ExxonMobil, Belgium; 6 World Health Organization, CH, Switzerland; 7 Shell Chemicals, UK; 8 Procter and Gamble, USA; 9 VITO, Belgium; 10Bayer HealthCare, Germany; 11Syngenta Crop Protection, CH, Switzerland; 12BASF, Germany Biomonitoring (BM) becomes more frequently used and has the potential to increase our knowledge on the extent of human exposure to chemicals. This creates a number of opportunities for improving human health risk assessment (HRA). Not only by giving further insights into exposure to chemicals, but also by triggering research investigating links between low-level exposures, adverse health effects and vulnerable subpopulations. However, it also creates a number of challenges, not least because the integrity of BM data is heterogeneous. Therefore, it should be ensured that BM data are interpreted within the boundary in which they can be reliably applied. Given the emerging trend for increased availability of BM data, ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals, a scientific non-profit organisation) formed a Task Force to develop a framework in which BM data can be consistently evaluated and which can be used to foster a consistent basis for the application of BM data in HRA.
A document (“Guidance for the Interpretation of Biomonitoring Data”, ECETOC, Brussels, 2005) was developed that sets out the considerations which enable the relevance of any BM result to be reliably interpreted. Specifically, four elements are identified that allow any set of BM data to be evaluated with respect to the extent to which it can be applied in different stages of the HRA process. The elements are: (1) analytical integrity, (2) ability to describe exposure (toxicokinetics), (3) ability to relate data to effects, and (4) overall evaluation and weight of evidence. The framework builds off the general guidance contained in an earlier publication (“Biomarkers and risk assessment: concepts and principles”, Environmental Health Criteria #155, WHO-IPCS, Geneva, 1993) and describes the required knowledge for each element to apply in HRA, notably to: (1) establish exposure trends, (2) characterise the nature of exposures, (3) investigate linkages between exposure and adverse health effects, and (4) facilitate risk management and standard setting. It was validated with a series of illustrative case studies identifying (1) where different types of BM data can be reliably used, (2) their relative importance, (3) where and how they can consistently interpreted whilst accounting for the current level of understanding of the supporting science. This approach intended both to offer a considered view of the available science and to serve as a catalyst for stimulating discussion on some of the broader issues presented by the application of BM technologies today. doi:10.1016/j.toxlet.2006.06.301 P8-12 Risk assessment of flavouring substances used in foods Karin Norby, Vibe Beltoft, Krestine Greve, Trine K. Reffstrup, Jørn Gry Danish Institute for Food and Veterinary Research, Soborg, Denmark The aim of the present project, the FLAVIS project, is to perform risk assessment of chemically defined flavouring substances. The evaluations are then presented to the European Food Safety Authority (EFSA) for final adoption in its Scientific Panel on food additives, flavourings, processing aids and materials in contact with food. The regulatory background for the work is found in the European Parliament and Council Regulation No. 2232/96 laying down a procedure for the establishment of a list of flavouring substances the use of which will be authorised to the exclusion of all others in the EU.
Abstracts / Toxicology Letters 164S (2006) S1–S324
In application of this Regulation, a Register of about 2800 flavouring substances used in or on foodstuffs in the EU Member States was adopted and are currently being evaluated according to the evaluation programme laid down by Commission Regulation. The EU Safety Evaluation Procedure is derived from the approach developed by the “Joint FAO/WHO Expert Committee on Food Additives” (JECFA) and referred to in Commission Regulation EC No. 1565/2000. First, the 2800 flavouring substances are divided into groups of structurally related substances. The Procedure is then a stepwise approach that integrates information on intake from current uses, structure–activity relationships, metabolism and toxicity. One of the key elements in the Procedure is the subdivision of flavourings into three structural classes (I, II, III) for which thresholds of concern (human exposure thresholds), that are considered not to present a safety concern, have been specified. In the project a very comprehensive database (the FLAVIS database) has been developed for the evaluation. It compiles information on the about 2800 flavouring substances used in Europe: specifications, structural class, food categories used in, intake data, natural occurrence as well as metabolism and toxicological data. The EFSA Panel has now adopted most of the safety evaluations of the Register compounds, but still another 435 flavouring substances need to be evaluated in the FLAVIS project and adopted by the Panel in due time before July 2007, where the EU Commission (DG SANCO) plans to issue the first European Positive list on flavouring substances. The project is financial supported by EFSA and the Danish Institute for Food and Veterinary Research. doi:10.1016/j.toxlet.2006.06.302 P8-13 Causality assessment of drug-related liver toxicity J. Schulze 1 , C.-P. Siegers 2 1 Office
of the Dean, Medical Faculty, Theodor SternKai 7, 60590 Frankfurt, Main, Germany; 2 Institute of Experimental and Clinical Pharmacology and Toxicology, Ratzeburger Allee 160, 23538 L¨ubeck, Germany On two recent occasions in Germany, drug regulatory decisions for herbal drugs (kava kava, chelidonium extracts) have been based on hepatotoxicity as suspected adverse effects. Causality was mainly based on reported time coincidence between drug intake and symptom development, as well as a “positive dechallenge” indicating improvement after hospitalization. However, incidentally elevated enzymes or decreased hepatic protein
S145
synthesis are common, with GOT or GPT increases observed in up to 1/3 of all outpatients. For drug hepatotoxicity, two principally different modes of actions can be separated with relevance to incidence and population risk. For liver damage exerted by toxic mechanisms (i.e. direct reaction of a drug or its metabolites) only an increase in liver damage (e.g. GPT, GOT increase, coagulation decrease) should be taken as proof for a causal correlation requiring stringent data collection criteria; detection of enzyme elevation at the time of hospitalization alone cannot be sufficient. Additionally, in the cohort of affected patients a dose response correlation should be observed. Idiosyncratic liver damage on the other hand is dependent upon antibodies or leukocytes specifically reacting with drugs or drugs bound to liver membranes. In both cases the presence of specific antibodies or immune cells can be proven by rather simple laboratory methods (antibody binding, lymphocyte proliferation), as has been shown in one of the kava cases under discussion. The presence of specific reaction in either of these tests strongly suggests immunologically mediated mechanisms whereas the absence does not necessary rule out immunologically mediated hepatotoxicity. Whereas toxic liver damage may be limited by intake limitation, restricting daily intake is no preventive strategy for idiosyncratic reactions. Whether or not regulatory actions should be taken ought to be based on proven (or likely) causal association indicated by the parameters given above; also the availability of safer therapeutic alternatives should be considered in a risk–benefit analysis. doi:10.1016/j.toxlet.2006.06.303 P8-14 Assessment of environmental health risks of chemicals associated with industry: The experience of EDF and Gaz de France Sylvaine Ronga-Pezeret, Ga¨elle Boize, Pierre-Andr´e Cabanes
Guillossou, Magali
Industry EDF-Gaz de France, Paris, France At the beginning of the 1990s, Electricit´e de France (EDF) and Gaz de France began conducting health risk assessments of the effects of chemicals released into the environment in the course of energy production. From 2000 onward, French regulations have required studies to detail the environmental impact and management of sites and polluted soils. Because of its tasks of surveillance, research, and management support, the Medical Studies Department of EDF-Gaz de France has a privileged viewpoint of this
Abstracts / Toxicology Letters 164S (2006) S1–S324
based on common substructure, and has predicting tool based on analyzing the correlation between common substructures and biological activities. We evaluated two optimized prediction models in the ClassPharmer, and the concordance lead to around 70–75%. Adding this new prediction system to the above combination approach may be useful for increasing applicability. Additionally, in the course of optimizing the prediction models by using ClassPharmer, we found some possible toxicophores, which may be correlated to potency of chromosomal aberration. The information would be helpful for improvement of accuracy on the above three in silico systems. doi:10.1016/j.toxlet.2006.06.300 P8-11 A proposed framework for the interpretation of biomonitoring data P.J. Boogaard 1 , P.B. Farmer 2 , M. Holt 3 , L.E. Knudsen 4 , C.D. Money 5 , L. Onyon 6 , D.E. Owen 7 , S.H. Robison 8 , G. Schoeters 9 , G.D. Stropp 10 , M.F. Wilks 11 , W. Will 12 1 Shell
International, Netherlands; 2 University of Leicester, UK; 3 ECETOC, Belgium; 4 University of Copenhagen, Denmark; 5 ExxonMobil, Belgium; 6 World Health Organization, CH, Switzerland; 7 Shell Chemicals, UK; 8 Procter and Gamble, USA; 9 VITO, Belgium; 10Bayer HealthCare, Germany; 11Syngenta Crop Protection, CH, Switzerland; 12BASF, Germany Biomonitoring (BM) becomes more frequently used and has the potential to increase our knowledge on the extent of human exposure to chemicals. This creates a number of opportunities for improving human health risk assessment (HRA). Not only by giving further insights into exposure to chemicals, but also by triggering research investigating links between low-level exposures, adverse health effects and vulnerable subpopulations. However, it also creates a number of challenges, not least because the integrity of BM data is heterogeneous. Therefore, it should be ensured that BM data are interpreted within the boundary in which they can be reliably applied. Given the emerging trend for increased availability of BM data, ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals, a scientific non-profit organisation) formed a Task Force to develop a framework in which BM data can be consistently evaluated and which can be used to foster a consistent basis for the application of BM data in HRA.
A document (“Guidance for the Interpretation of Biomonitoring Data”, ECETOC, Brussels, 2005) was developed that sets out the considerations which enable the relevance of any BM result to be reliably interpreted. Specifically, four elements are identified that allow any set of BM data to be evaluated with respect to the extent to which it can be applied in different stages of the HRA process. The elements are: (1) analytical integrity, (2) ability to describe exposure (toxicokinetics), (3) ability to relate data to effects, and (4) overall evaluation and weight of evidence. The framework builds off the general guidance contained in an earlier publication (“Biomarkers and risk assessment: concepts and principles”, Environmental Health Criteria #155, WHO-IPCS, Geneva, 1993) and describes the required knowledge for each element to apply in HRA, notably to: (1) establish exposure trends, (2) characterise the nature of exposures, (3) investigate linkages between exposure and adverse health effects, and (4) facilitate risk management and standard setting. It was validated with a series of illustrative case studies identifying (1) where different types of BM data can be reliably used, (2) their relative importance, (3) where and how they can consistently interpreted whilst accounting for the current level of understanding of the supporting science. This approach intended both to offer a considered view of the available science and to serve as a catalyst for stimulating discussion on some of the broader issues presented by the application of BM technologies today. doi:10.1016/j.toxlet.2006.06.301 P8-12 Risk assessment of flavouring substances used in foods Karin Norby, Vibe Beltoft, Krestine Greve, Trine K. Reffstrup, Jørn Gry Danish Institute for Food and Veterinary Research, Soborg, Denmark The aim of the present project, the FLAVIS project, is to perform risk assessment of chemically defined flavouring substances. The evaluations are then presented to the European Food Safety Authority (EFSA) for final adoption in its Scientific Panel on food additives, flavourings, processing aids and materials in contact with food. The regulatory background for the work is found in the European Parliament and Council Regulation No. 2232/96 laying down a procedure for the establishment of a list of flavouring substances the use of which will be authorised to the exclusion of all others in the EU.
Abstracts / Toxicology Letters 164S (2006) S1–S324
In application of this Regulation, a Register of about 2800 flavouring substances used in or on foodstuffs in the EU Member States was adopted and are currently being evaluated according to the evaluation programme laid down by Commission Regulation. The EU Safety Evaluation Procedure is derived from the approach developed by the “Joint FAO/WHO Expert Committee on Food Additives” (JECFA) and referred to in Commission Regulation EC No. 1565/2000. First, the 2800 flavouring substances are divided into groups of structurally related substances. The Procedure is then a stepwise approach that integrates information on intake from current uses, structure–activity relationships, metabolism and toxicity. One of the key elements in the Procedure is the subdivision of flavourings into three structural classes (I, II, III) for which thresholds of concern (human exposure thresholds), that are considered not to present a safety concern, have been specified. In the project a very comprehensive database (the FLAVIS database) has been developed for the evaluation. It compiles information on the about 2800 flavouring substances used in Europe: specifications, structural class, food categories used in, intake data, natural occurrence as well as metabolism and toxicological data. The EFSA Panel has now adopted most of the safety evaluations of the Register compounds, but still another 435 flavouring substances need to be evaluated in the FLAVIS project and adopted by the Panel in due time before July 2007, where the EU Commission (DG SANCO) plans to issue the first European Positive list on flavouring substances. The project is financial supported by EFSA and the Danish Institute for Food and Veterinary Research. doi:10.1016/j.toxlet.2006.06.302 P8-13 Causality assessment of drug-related liver toxicity J. Schulze 1 , C.-P. Siegers 2 1 Office
of the Dean, Medical Faculty, Theodor SternKai 7, 60590 Frankfurt, Main, Germany; 2 Institute of Experimental and Clinical Pharmacology and Toxicology, Ratzeburger Allee 160, 23538 L¨ubeck, Germany On two recent occasions in Germany, drug regulatory decisions for herbal drugs (kava kava, chelidonium extracts) have been based on hepatotoxicity as suspected adverse effects. Causality was mainly based on reported time coincidence between drug intake and symptom development, as well as a “positive dechallenge” indicating improvement after hospitalization. However, incidentally elevated enzymes or decreased hepatic protein
S145
synthesis are common, with GOT or GPT increases observed in up to 1/3 of all outpatients. For drug hepatotoxicity, two principally different modes of actions can be separated with relevance to incidence and population risk. For liver damage exerted by toxic mechanisms (i.e. direct reaction of a drug or its metabolites) only an increase in liver damage (e.g. GPT, GOT increase, coagulation decrease) should be taken as proof for a causal correlation requiring stringent data collection criteria; detection of enzyme elevation at the time of hospitalization alone cannot be sufficient. Additionally, in the cohort of affected patients a dose response correlation should be observed. Idiosyncratic liver damage on the other hand is dependent upon antibodies or leukocytes specifically reacting with drugs or drugs bound to liver membranes. In both cases the presence of specific antibodies or immune cells can be proven by rather simple laboratory methods (antibody binding, lymphocyte proliferation), as has been shown in one of the kava cases under discussion. The presence of specific reaction in either of these tests strongly suggests immunologically mediated mechanisms whereas the absence does not necessary rule out immunologically mediated hepatotoxicity. Whereas toxic liver damage may be limited by intake limitation, restricting daily intake is no preventive strategy for idiosyncratic reactions. Whether or not regulatory actions should be taken ought to be based on proven (or likely) causal association indicated by the parameters given above; also the availability of safer therapeutic alternatives should be considered in a risk–benefit analysis. doi:10.1016/j.toxlet.2006.06.303 P8-14 Assessment of environmental health risks of chemicals associated with industry: The experience of EDF and Gaz de France Sylvaine Ronga-Pezeret, Ga¨elle Boize, Pierre-Andr´e Cabanes
Guillossou, Magali
Industry EDF-Gaz de France, Paris, France At the beginning of the 1990s, Electricit´e de France (EDF) and Gaz de France began conducting health risk assessments of the effects of chemicals released into the environment in the course of energy production. From 2000 onward, French regulations have required studies to detail the environmental impact and management of sites and polluted soils. Because of its tasks of surveillance, research, and management support, the Medical Studies Department of EDF-Gaz de France has a privileged viewpoint of this