Methodology for health risk assessment of combined exposures to multiple chemicals
Beronius, Anna ; Zilliacus, Johanna ; Hanberg, Annika ; Luijten, Mirjam ; Voet, Hilko van der; Klaveren, Jacob van - \ 2020
Food and Chemical Toxicology 143 (2020). - ISSN 0278-6915
Adverse outcome pathway - Combined exposure - Mixture - Risk assessment
Focus on risks to human health and the environment from combined exposure to multiple chemicals (“mixture risk assessment”) has increased in the last couple of decades. There has been a rise in awareness and concern in the community, especially concerning unintentional environmental exposure to unknown chemical mixtures. The Horizon 2020 project EuroMix has developed methodologies and tools for mixture risk assessment with a focus on component-based approach where substances are grouped based on toxicological considerations. Dose addition is used as the model for calculating the combined toxicity of mixture components. The methodology is anchored in the Adverse Outcome Pathway (AOP) concept, which provides a structured basis for e.g. grouping substances into assessment groups and identifying and collecting relevant toxicity data. The aim of this paper is to describes development of the methodology for mixture risk assessment and to provide detailed methodology for problem formulation, use of AOP networks for development of tiered testing strategies and grouping of substances, as well as considerations for use of dose addition methodology.
The use of adverse outcome pathways in the safety evaluation of food additives
Vinken, Mathieu ; Kramer, Nynke ; Allen, Timothy E.H. ; Hoffmans, Yvette ; Thatcher, Natalie ; Levorato, Sara ; Traussnig, Heinz ; Schulte, Stefan ; Boobis, Alan ; Thiel, Anette ; Rietjens, Ivonne M.C.M. - \ 2020
Archives of Toxicology 94 (2020). - ISSN 0340-5761
Adverse outcome pathway - Food additive - Safety evaluation
In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.
Characterizing the coverage of critical effects relevant in the safety evaluation of food additives by AOPs
Kramer, Nynke I. ; Hoffmans, Yvette ; Wu, Siyao ; Thiel, Anette ; Thatcher, Natalie ; Allen, Timothy E.H. ; Levorato, Sara ; Traussnig, Heinz ; Schulte, Stefan ; Boobis, Alan ; Rietjens, Ivonne M.C.M. ; Vinken, Mathieu - \ 2019
Archives of Toxicology 93 (2019)8. - ISSN 0340-5761 - p. 2115 - 2125.
3Rs - Acceptable daily intake - Adverse outcome pathway - Critical adverse effect - Food additives
There is considerable interest in adverse outcome pathways (AOPs) as a means of organizing biological and toxicological information to assist in data interpretation and method development. While several chemical sectors have shown considerable progress in applying this approach, this has not been the case in the food sector. In the present study, safety evaluation reports of food additives listed in Annex II of Regulation (EC) No 1333/2008 of the European Union were screened to qualitatively and quantitatively characterize toxicity induced in laboratory animals. The resulting database was used to identify the critical adverse effects used for risk assessment and to investigate whether food additives share common AOPs. Analysis of the database revealed that often such scrutiny of AOPs was not possible or necessary. For 69% of the food additives, the report did not document any adverse effects in studies based on which the safety evaluation was performed. For the remaining 31% of the 326 investigated food additives, critical adverse effects and related points of departure for establishing health-based guidance values could be identified. These mainly involved effects on the liver, kidney, cardiovascular system, lymphatic system, central nervous system and reproductive system. AOPs are available for many of these apical endpoints, albeit to different degrees of maturity. For other adverse outcomes pertinent to food additives, including gastrointestinal irritation and corrosion, AOPs are lacking. Efforts should focus on developing AOPs for these particular endpoints.
Applying the adverse outcome pathway (AOP) for food sensitization to support in vitro testing strategies
Lozano-Ojalvo, Daniel ; Benedé, Sara ; Antunes, Celia M. ; Bavaro, Simona L. ; Bouchaud, Grégory ; Costa, Ana ; Denery-Papini, Sandra ; Díaz-Perales, Araceli ; Garrido-Arandia, María ; Gavrovic-Jankulovic, Marija ; Hayen, Simone ; Martínez-Blanco, Mónica ; Molina, Elena ; Monaci, Linda ; Pieters, Raymond H.H. ; Villemin, Clelia ; Wichers, Harry J. ; Wróblewska, Barbara ; Willemsen, Linette E.M. ; Roggen, Erwin L. ; Bilsen, Jolanda H.M. van - \ 2019
Trends in Food Science and Technology 85 (2019). - ISSN 0924-2244 - p. 307 - 319.
Adverse outcome pathway - Dendritic cells - Epithelial cells - IgE-mediated food allergy - In vitro models - T and B cells
Background: Before introducing proteins from new or alternative dietary sources into the market, a compressive risk assessment including food allergic sensitization should be carried out in order to ensure their safety. We have recently proposed the adverse outcome pathway (AOP) concept to structure the current mechanistic understanding of the molecular and cellular pathways evidenced to drive IgE-mediated food allergies. This AOP framework offers the biological context to collect and structure existing in vitro methods and to identify missing assays to evaluate sensitizing potential of food proteins. Scope and approach: In this review, we provide a state-of-the-art overview of available in vitro approaches for assessing the sensitizing potential of food proteins, including their strengths and limitations. These approaches are structured by their potential to evaluate the molecular initiating and key events driving food sensitization. Key findings and conclusions: The application of the AOP framework offers the opportunity to anchor existing testing methods to specific building blocks of the AOP for food sensitization. In general, in vitro methods evaluating mechanisms involved in the innate immune response are easier to address than assays addressing the adaptive immune response due to the low precursor frequency of allergen-specific T and B cells. Novel ex vivo culture strategies may have the potential to become useful tools for investigating the sensitizing potential of food proteins. When applied in the context of an integrated testing strategy, the described approaches may reduce, if not replace, current animal testing approaches.
Application of the adverse outcome pathway (AOP) concept to structure the available in vivo and in vitro mechanistic data for allergic sensitization to food proteins
Bilsen, Jolanda H.M. Van; Sienkiewicz-Szłapka, Edyta ; Lozano-Ojalvo, Daniel ; Willemsen, Linette E.M. ; Antunes, Celia M. ; Molina, Elena ; Smit, Joost J. ; Wróblewska, Barbara ; Wichers, Harry J. ; Knol, Edward F. ; Ladics, Gregory S. ; Pieters, Raymond H.H. ; Denery-Papini, Sandra ; Vissers, Yvonne M. ; Bavaro, Simona L. ; Larré, Colette ; Verhoeckx, Kitty C.M. ; Roggen, Erwin L. - \ 2017
Clinical and Translational Allergy 7 (2017)1. - ISSN 2045-7022
Adverse outcome pathway - Food allergy - Food proteins - Key event relations - Key events - Mechanistic understanding - Molecular initiating event - Sensitization
Background: The introduction of whole new foods in a population may lead to sensitization and food allergy. This constitutes a potential public health problem and a challenge to risk assessors and managers as the existing understanding of the pathophysiological processes and the currently available biological tools for prediction of the risk for food allergy development and the severity of the reaction are not sufficient. There is a substantial body of in vivo and in vitro data describing molecular and cellular events potentially involved in food sensitization. However, these events have not been organized in a sequence of related events that is plausible to result in sensitization, and useful to challenge current hypotheses. The aim of this manuscript was to collect and structure the current mechanistic understanding of sensitization induction to food proteins by applying the concept of adverse outcome pathway (AOP). Main body: The proposed AOP for food sensitization is based on information on molecular and cellular mechanisms and pathways evidenced to be involved in sensitization by food and food proteins and uses the AOPs for chemical skin sensitization and respiratory sensitization induction as templates. Available mechanistic data on protein respiratory sensitization were included to fill out gaps in the understanding of how proteins may affect cells, cell-cell interactions and tissue homeostasis. Analysis revealed several key events (KE) and biomarkers that may have potential use in testing and assessment of proteins for their sensitizing potential. Conclusion: The application of the AOP concept to structure mechanistic in vivo and in vitro knowledge has made it possible to identify a number of methods, each addressing a specific KE, that provide information about the food allergenic potential of new proteins. When applied in the context of an integrated strategy these methods may reduce, if not replace, current animal testing approaches. The proposed AOP will be shared at the www.aopwiki.org platform to expand the mechanistic data, improve the confidence in each of the proposed KE and key event relations (KERs), and allow for the identification of new, or refinement of established KE and KERs.