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New tools for evidence-based risk assessment of chemical mixtures
Abstracts / Toxicology Letters 229S (2014) S4–S21
extended beyond metabolic interactions, into the realm of cellular effects. http://dx.doi.org/10.1016/j.toxlet.2014.06.099 PS7.1-O3 New tools for evidence-based risk assessment of chemical mixtures Billy Amzal 1,∗ , Nadia Quignot 1 , Jean-Lou Dorne 2 , Frederic Bois 3,4 , Camille Bechaux 2 LASER Analytica, Paris, France, 2 EFSA, Parma, Italy, 3 UTC, Compiegne, France, 4 INERIS, Verneuil en Halatte, France
S19
PS7.1-O5 The relevance of combined action of chemicals through dissimilar modes of action. A science based approach for performing cumulative risk assessment of pesticides residues Andrea Terron 1,∗ , Karen Ildico Hirsch-Ernst 2 , Luc Mohimont 1 , Hans Steinkellner 1 European Food Safety Authority, Parma, Italy, 2 Bundesinstitut für Risikobewertung, Berlin, Italy
1
1
Risk assessment of chemical mixture has brought a number of scientific challenges, e.g. with respect to relevant data collection and robust quantitative methods to assess risks in humans. In this talk, the challenges will be presented in both regulatory and scientific viewpoints. Then, new tools for evidence-based risk assessment of chemical mixtures will be discussed in the context of the application of the systematic review methodology and metaanalysis to integrate metabolic interactions and toxicodynamic interactions for substances of priority in the food safety area. Examples of application and perspectives for embedding such techniques in routine risk assessment bodies will be presented. http://dx.doi.org/10.1016/j.toxlet.2014.06.100 PS7.1-O4 Harmonisation of ecological and human risk assessment of chemical mixtures
An approach that unifies the assessment of substances acting through similar and dissimilar modes of action can be based on pragmatic use of assessment approaches derived from the concept of dose addition (DA). However, this would be scientifically credible if: there is no examples where independent action (IA) provides a more conservative prediction than DA, a practicable assessment concept based on IA is not available, the distinctions in terms of MOA are hard to use in practice, the prediction differences between the two concepts are small and that dissimilarly acting mixtures are safe because ADIs are true no effect levels are difficult to prove. Our analysis showed that: - DA yielded the more conservative prediction, - no established method for cumulative risk assessment based on IA exist, - the assumption that mixture effects will not arise below their individual ADIs is difficult to verify, - the quantitative differences from mathematical simulations derived from DA or IA are likely to be small.
Ad Ragas 1,2 Radboud University, Nijmegen, The Netherlands, 2 Open Universiteit, Heerlen, The Netherlands 1
Risk assessment traditionally focuses on single chemicals, and is performed separately for humans and ecosystems. On the one hand, awareness is growing that exposure to single substances is the exception rather than the rule. In practice, humans and ecological receptors are often exposed to multiple chemicals which may or may not influence each other before or after reaching the molecular site of toxic action. On the other hand, awareness is growing that collaboration between human and environmental risk assessors, e.g. by exchanging experiences, data and methods, may improve assessment quality and efficiency. The present contribution compares human and ecological risk assessment practices for chemical mixtures in terms of legislation and regulations, institutionalization, endpoints, effect assessment concepts, exposure assessment concepts and the treatment of uncertainty. The comparison shows that similar approaches are present for both sub-disciplines, but some approaches are more common in one sub-discipline than the other. For example, toxicity tests for uncharacterized whole mixtures, such WET tests, are more common in ecological risk assessment. In contrast, refined mechanistic approaches are further developed in human risk assessment, like Biochemical Reaction Networks, PBPK-models, in silico-approaches, in vitro techniques and interaction-based models. It is concluded that there is a clear need for a comprehensive and conceptual framework that integrates the assessment of human and ecological risks of chemical mixtures. http://dx.doi.org/10.1016/j.toxlet.2014.06.101
As a consequence, pesticides that produce common adverse outcomes on the same target organ/system should be grouped together and the combined effects should be assessed by using the concept of dose DA. http://dx.doi.org/10.1016/j.toxlet.2014.06.102 Symposia 12: Target organ toxicity of recreational substances and anabolic drugs PS7.2-O1 Involvement of mitochondria in the neurotoxicity of ecstasy Felix Carvalho REQUIMTE, Toxicology Laboratory, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal 3,4-Methylenedioxymethamphetamine (ecstasy; MDMA) is a worldwide major drug of abuse with reported neurotoxic potential. Though the molecular and cellular mechanisms related to MDMA-induced neurotoxicity remain unclear, recent studies have attributed a possible key role to mitochondrial pathways. The pharmacodynamics of MDMA involves the release of monoamine neurotransmitters, part of which become metabolized by monoamine oxidase (MAO), leading to the formation of hydrogen peroxide (H2 O2 ), and consequently to H2 O2 -mediated oxidative stress. As MAO is localized in the outer membrane of mitochondria, oxidative stress will mostly affect mitochondria itself. MDMA, and its main metabolites, were also shown to impair axonal transport of mitochondria in hippocampal neurons, at non-
extended beyond metabolic interactions, into the realm of cellular effects. http://dx.doi.org/10.1016/j.toxlet.2014.06.099 PS7.1-O3 New tools for evidence-based risk assessment of chemical mixtures Billy Amzal 1,∗ , Nadia Quignot 1 , Jean-Lou Dorne 2 , Frederic Bois 3,4 , Camille Bechaux 2 LASER Analytica, Paris, France, 2 EFSA, Parma, Italy, 3 UTC, Compiegne, France, 4 INERIS, Verneuil en Halatte, France
S19
PS7.1-O5 The relevance of combined action of chemicals through dissimilar modes of action. A science based approach for performing cumulative risk assessment of pesticides residues Andrea Terron 1,∗ , Karen Ildico Hirsch-Ernst 2 , Luc Mohimont 1 , Hans Steinkellner 1 European Food Safety Authority, Parma, Italy, 2 Bundesinstitut für Risikobewertung, Berlin, Italy
1
1
Risk assessment of chemical mixture has brought a number of scientific challenges, e.g. with respect to relevant data collection and robust quantitative methods to assess risks in humans. In this talk, the challenges will be presented in both regulatory and scientific viewpoints. Then, new tools for evidence-based risk assessment of chemical mixtures will be discussed in the context of the application of the systematic review methodology and metaanalysis to integrate metabolic interactions and toxicodynamic interactions for substances of priority in the food safety area. Examples of application and perspectives for embedding such techniques in routine risk assessment bodies will be presented. http://dx.doi.org/10.1016/j.toxlet.2014.06.100 PS7.1-O4 Harmonisation of ecological and human risk assessment of chemical mixtures
An approach that unifies the assessment of substances acting through similar and dissimilar modes of action can be based on pragmatic use of assessment approaches derived from the concept of dose addition (DA). However, this would be scientifically credible if: there is no examples where independent action (IA) provides a more conservative prediction than DA, a practicable assessment concept based on IA is not available, the distinctions in terms of MOA are hard to use in practice, the prediction differences between the two concepts are small and that dissimilarly acting mixtures are safe because ADIs are true no effect levels are difficult to prove. Our analysis showed that: - DA yielded the more conservative prediction, - no established method for cumulative risk assessment based on IA exist, - the assumption that mixture effects will not arise below their individual ADIs is difficult to verify, - the quantitative differences from mathematical simulations derived from DA or IA are likely to be small.
Ad Ragas 1,2 Radboud University, Nijmegen, The Netherlands, 2 Open Universiteit, Heerlen, The Netherlands 1
Risk assessment traditionally focuses on single chemicals, and is performed separately for humans and ecosystems. On the one hand, awareness is growing that exposure to single substances is the exception rather than the rule. In practice, humans and ecological receptors are often exposed to multiple chemicals which may or may not influence each other before or after reaching the molecular site of toxic action. On the other hand, awareness is growing that collaboration between human and environmental risk assessors, e.g. by exchanging experiences, data and methods, may improve assessment quality and efficiency. The present contribution compares human and ecological risk assessment practices for chemical mixtures in terms of legislation and regulations, institutionalization, endpoints, effect assessment concepts, exposure assessment concepts and the treatment of uncertainty. The comparison shows that similar approaches are present for both sub-disciplines, but some approaches are more common in one sub-discipline than the other. For example, toxicity tests for uncharacterized whole mixtures, such WET tests, are more common in ecological risk assessment. In contrast, refined mechanistic approaches are further developed in human risk assessment, like Biochemical Reaction Networks, PBPK-models, in silico-approaches, in vitro techniques and interaction-based models. It is concluded that there is a clear need for a comprehensive and conceptual framework that integrates the assessment of human and ecological risks of chemical mixtures. http://dx.doi.org/10.1016/j.toxlet.2014.06.101
As a consequence, pesticides that produce common adverse outcomes on the same target organ/system should be grouped together and the combined effects should be assessed by using the concept of dose DA. http://dx.doi.org/10.1016/j.toxlet.2014.06.102 Symposia 12: Target organ toxicity of recreational substances and anabolic drugs PS7.2-O1 Involvement of mitochondria in the neurotoxicity of ecstasy Felix Carvalho REQUIMTE, Toxicology Laboratory, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal 3,4-Methylenedioxymethamphetamine (ecstasy; MDMA) is a worldwide major drug of abuse with reported neurotoxic potential. Though the molecular and cellular mechanisms related to MDMA-induced neurotoxicity remain unclear, recent studies have attributed a possible key role to mitochondrial pathways. The pharmacodynamics of MDMA involves the release of monoamine neurotransmitters, part of which become metabolized by monoamine oxidase (MAO), leading to the formation of hydrogen peroxide (H2 O2 ), and consequently to H2 O2 -mediated oxidative stress. As MAO is localized in the outer membrane of mitochondria, oxidative stress will mostly affect mitochondria itself. MDMA, and its main metabolites, were also shown to impair axonal transport of mitochondria in hippocampal neurons, at non-