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EFSA'S risk assessment of bisphenol A in food
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Abstracts / Toxicology Letters 205S (2011) S36–S59
OS8-8 EFSA’S risk assessment of bisphenol A in food A.F. Castoldi 1,∗ , W. Bursch 2 , T. Husoy 3 , W. Mennes 4 , I. Pratt 5 , U. Reuter 6 , E. Testai 7 , D. Woelfle 8 1
Cef Unit, European Food Safety Authority (EFSA), 43121 Parma, Italy, 2 Universität Wien, Wien, Austria, 3 Norwegian Institute of Public Health, Oslo, Norway, 4 RIVM/SIR, Bilthoven, The Netherlands, 5 Food Safety Authority of Ireland, Dublin, Ireland, 6 Technische Universität Muenchen, Muenchen, Germany, 7 Istituto Superiore di Sanità, Roma, Italy, 8 Bundesinstitut für Risikobewertung (BfR), Berlin, Germany Bisphenol A (BPA) is an endocrine active substance used in the manufacture of reusable plastic bottles, baby bottles, can coatings, etc. In 2006, EFSA set a Tolerable Daily Intake (TDI) of 0.05 mg BPA/kg bw/day based on the NOAEL of 5 mg/kg bw/day from a rat multi-generation reproductive toxicity study and using an uncertainty factor of 100 (UF; for inter- and intra-species differences). EFSA recently updated its previous risk assessment of BPA in light of newly available toxicity studies including an OECD TG 426-compliant developmental neurotoxicity study in rats (Stump, 2009). Based on toxicokinetic data in rodents and primates, the EFSA CEF Panel concluded that oral exposure results in lower internal BPA levels than parenteral exposure. Newborn primates eliminate ingested BPA faster than neonatal rodents. Human premature infants can efficiently metabolise and excrete BPA. Altogether, this information supports the conservative UF of 100 for deriving the TDI. The Panel did not identify any new valid toxicity studies necessitating a revision of the current TDI. The Panel expressed no concern for reproductive, developmental and neurobehavioural toxicity at BPA doses below 5 mg/kg bw/day. Some BPA-related effects deserving further consideration, i.e. biochemical changes in brain, immunomodulatory effects and enhanced susceptibility to breast tumours, were identified in studies in developing animals. However, the Panel considered that these investigations had several shortcomings that limited their relevance for human health. EFSA’s conclusions are discussed in light of the outcome of the recent Joint FAO/WHO Expert Meeting on bisphenol A and other risk assessments.
remodelling by inducing sustained inflammation and mucus secretion. Methods: Particles were sampled in Paris in order to collect coarse (10–1 m), fine (1–0.1 m) and ultrafine (<0.1 m) particles. Their effect was observed on primary cultures of normal human bronchial epithelial cells (NHBE) grown at an air–liquid interface. After four 48-h spaced treatments of 6 h, the evolution of the pro-inflammatory response, the epithelium differentiation and the fate of particles were studied during the 5 following weeks. Results of the study: Ultrastructural observations revealed that nanoparticles are still present in the bronchial epithelium 5 weeks after treatments. The expression of cytochrome P450 1A1, a xenobiotic metabolizing enzyme involved in their metabolism, is highly dose-dependently overexpressed during NP treatment. GM-CSF and IL-6, two biomarkers of a pro-inflammatory response, are slightly released after each treatment but increased and maintained up to 6 weeks. Amphiregulin (an EGFR ligand involved in the pro-inflammatory response) is released after each treatment but decrease after the end of the treatments. MUC5AC (mucin) and DNALI1 (cilia dynein) (differentiation markers) were measured. After 6 weeks, MUC5AC gene is strongly induced in cells exposed to NP. A weaker induction was observed for DNALI1. Our results suggest that bronchial epithelial cells repeatedly exposed to ambient urban nanoparticles exhibit a sustained pro-inflammatory response and evolve towards a mucous phenotype. doi:10.1016/j.toxlet.2011.05.203
OS9-2 Diversely-sized particulate matter air pollution (PM2,5 , PM10-2.5 ) is associated with different acute manifestations of diseases in Emergency Department D. Cigolini 1,∗ , N. Martinelli 2 , M. Zannoni 1 , G. Ricci 1 , P. Perfetti 3 , R. Codogni 1 , G. Rocca 3 , O. Olivieri 2 1
Clinical Toxicology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 2 Department of Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 3 Emergency Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
doi:10.1016/j.toxlet.2011.05.201
OS9 Environmental Toxicology
OS9-1 Use of bronchial epithelial cells in vitro to study the long-term effects of repeated exposure to Paris ambient particles L. Boublil 1,∗ , E. Assémat 1 , M.C. Borot 1 , L. Martinon 2 , F. Marano 1 , A. Baeza-Squiban 1 1
Unit of Functional and Adaptive Biology (bfa) Cnrs Eac 4413 Laboratory of Molecular and Cellular Responses to Xenobiotics, Université Paris Diderot - Paris 7, Paris, France, 2 Laboratoire des particules inhalées (LEPI), Paris, France Purpose: As the long term effects of atmospheric particles (PM) are misunderstood, we develop an experimental strategy using primary culture of human bronchial epithelial repeatedly exposed to PM to investigate whether particles could contribute to airway
Purpose: Particulate matter (PM) air pollution has been associated with cardiovascular and respiratory disease. Recent studies have proposed also a link with venous thromboembolism risk. This study suggests that diversely-sized PM air pollution may be associated with different acute manifestations of human diseases (COPD, heart failure and venous thromboembolism). In particular, PM10-2.5 may be related with thrombophilia and venous thromboembolism risk. Methods: We have collected data about Emergency Department (ED) accesses for cardiovascular or respiratory disease, as well as environmental data about daily levels of PM10 , PM2,5 , temperature, humidity and atmospheric pressure in the period between May 1st 2007 and June 30th 2009. Coarse PM (PM10-2.5 ) was calculated by subtracting PM2,5 from PM10 . Results of the study: During the considered period a total number of 7076 diagnosis of respiratory and cardiovascular acute diseases were observed. In a multiple regression model adjusted for other atmospheric parameter daily levels of PM2,5 presented a positive correlation with COPD exacerbation (beta-coefficient = 0.217; P = 0.003), while those of PM10-2.5 were correlated with heart failure (beta-coefficient = 0.151; P = 0.002) and venous thromboembolism (beta-coefficient = 0.237; P = 0.020). During the days with levels of PM10-2.5 higher that the 75th percentile, there was an increased
Abstracts / Toxicology Letters 205S (2011) S36–S59
OS8-8 EFSA’S risk assessment of bisphenol A in food A.F. Castoldi 1,∗ , W. Bursch 2 , T. Husoy 3 , W. Mennes 4 , I. Pratt 5 , U. Reuter 6 , E. Testai 7 , D. Woelfle 8 1
Cef Unit, European Food Safety Authority (EFSA), 43121 Parma, Italy, 2 Universität Wien, Wien, Austria, 3 Norwegian Institute of Public Health, Oslo, Norway, 4 RIVM/SIR, Bilthoven, The Netherlands, 5 Food Safety Authority of Ireland, Dublin, Ireland, 6 Technische Universität Muenchen, Muenchen, Germany, 7 Istituto Superiore di Sanità, Roma, Italy, 8 Bundesinstitut für Risikobewertung (BfR), Berlin, Germany Bisphenol A (BPA) is an endocrine active substance used in the manufacture of reusable plastic bottles, baby bottles, can coatings, etc. In 2006, EFSA set a Tolerable Daily Intake (TDI) of 0.05 mg BPA/kg bw/day based on the NOAEL of 5 mg/kg bw/day from a rat multi-generation reproductive toxicity study and using an uncertainty factor of 100 (UF; for inter- and intra-species differences). EFSA recently updated its previous risk assessment of BPA in light of newly available toxicity studies including an OECD TG 426-compliant developmental neurotoxicity study in rats (Stump, 2009). Based on toxicokinetic data in rodents and primates, the EFSA CEF Panel concluded that oral exposure results in lower internal BPA levels than parenteral exposure. Newborn primates eliminate ingested BPA faster than neonatal rodents. Human premature infants can efficiently metabolise and excrete BPA. Altogether, this information supports the conservative UF of 100 for deriving the TDI. The Panel did not identify any new valid toxicity studies necessitating a revision of the current TDI. The Panel expressed no concern for reproductive, developmental and neurobehavioural toxicity at BPA doses below 5 mg/kg bw/day. Some BPA-related effects deserving further consideration, i.e. biochemical changes in brain, immunomodulatory effects and enhanced susceptibility to breast tumours, were identified in studies in developing animals. However, the Panel considered that these investigations had several shortcomings that limited their relevance for human health. EFSA’s conclusions are discussed in light of the outcome of the recent Joint FAO/WHO Expert Meeting on bisphenol A and other risk assessments.
remodelling by inducing sustained inflammation and mucus secretion. Methods: Particles were sampled in Paris in order to collect coarse (10–1 m), fine (1–0.1 m) and ultrafine (<0.1 m) particles. Their effect was observed on primary cultures of normal human bronchial epithelial cells (NHBE) grown at an air–liquid interface. After four 48-h spaced treatments of 6 h, the evolution of the pro-inflammatory response, the epithelium differentiation and the fate of particles were studied during the 5 following weeks. Results of the study: Ultrastructural observations revealed that nanoparticles are still present in the bronchial epithelium 5 weeks after treatments. The expression of cytochrome P450 1A1, a xenobiotic metabolizing enzyme involved in their metabolism, is highly dose-dependently overexpressed during NP treatment. GM-CSF and IL-6, two biomarkers of a pro-inflammatory response, are slightly released after each treatment but increased and maintained up to 6 weeks. Amphiregulin (an EGFR ligand involved in the pro-inflammatory response) is released after each treatment but decrease after the end of the treatments. MUC5AC (mucin) and DNALI1 (cilia dynein) (differentiation markers) were measured. After 6 weeks, MUC5AC gene is strongly induced in cells exposed to NP. A weaker induction was observed for DNALI1. Our results suggest that bronchial epithelial cells repeatedly exposed to ambient urban nanoparticles exhibit a sustained pro-inflammatory response and evolve towards a mucous phenotype. doi:10.1016/j.toxlet.2011.05.203
OS9-2 Diversely-sized particulate matter air pollution (PM2,5 , PM10-2.5 ) is associated with different acute manifestations of diseases in Emergency Department D. Cigolini 1,∗ , N. Martinelli 2 , M. Zannoni 1 , G. Ricci 1 , P. Perfetti 3 , R. Codogni 1 , G. Rocca 3 , O. Olivieri 2 1
Clinical Toxicology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 2 Department of Medicine, Azienda Ospedaliera Universitaria Integrata, Verona, Italy, 3 Emergency Department, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
doi:10.1016/j.toxlet.2011.05.201
OS9 Environmental Toxicology
OS9-1 Use of bronchial epithelial cells in vitro to study the long-term effects of repeated exposure to Paris ambient particles L. Boublil 1,∗ , E. Assémat 1 , M.C. Borot 1 , L. Martinon 2 , F. Marano 1 , A. Baeza-Squiban 1 1
Unit of Functional and Adaptive Biology (bfa) Cnrs Eac 4413 Laboratory of Molecular and Cellular Responses to Xenobiotics, Université Paris Diderot - Paris 7, Paris, France, 2 Laboratoire des particules inhalées (LEPI), Paris, France Purpose: As the long term effects of atmospheric particles (PM) are misunderstood, we develop an experimental strategy using primary culture of human bronchial epithelial repeatedly exposed to PM to investigate whether particles could contribute to airway
Purpose: Particulate matter (PM) air pollution has been associated with cardiovascular and respiratory disease. Recent studies have proposed also a link with venous thromboembolism risk. This study suggests that diversely-sized PM air pollution may be associated with different acute manifestations of human diseases (COPD, heart failure and venous thromboembolism). In particular, PM10-2.5 may be related with thrombophilia and venous thromboembolism risk. Methods: We have collected data about Emergency Department (ED) accesses for cardiovascular or respiratory disease, as well as environmental data about daily levels of PM10 , PM2,5 , temperature, humidity and atmospheric pressure in the period between May 1st 2007 and June 30th 2009. Coarse PM (PM10-2.5 ) was calculated by subtracting PM2,5 from PM10 . Results of the study: During the considered period a total number of 7076 diagnosis of respiratory and cardiovascular acute diseases were observed. In a multiple regression model adjusted for other atmospheric parameter daily levels of PM2,5 presented a positive correlation with COPD exacerbation (beta-coefficient = 0.217; P = 0.003), while those of PM10-2.5 were correlated with heart failure (beta-coefficient = 0.151; P = 0.002) and venous thromboembolism (beta-coefficient = 0.237; P = 0.020). During the days with levels of PM10-2.5 higher that the 75th percentile, there was an increased