Potential of ToxCast Data in the Safety Assessment of Food Chemicals
Punt, Ans ; Firman, James ; Boobis, Alan ; Cronin, Mark ; Gosling, John Paul ; Wilks, Martin F. ; Hepburn, Paul A. ; Thiel, Anette ; Fussell, Karma C. - \ 2020
Toxicological sciences 174 (2020)2. - ISSN 1096-6080 - p. 326 - 340.
food chemicals - high-throughput in vitro screening - read-across - risk-benefit - ToxCast
Tox21 and ToxCast are high-throughput in vitro screening programs coordinated by the U.S. National Toxicology Program and the U.S. Environmental Protection Agency, respectively, with the goal of forecasting biological effects in vivo based on bioactivity profiling. The present study investigated whether mechanistic insights in the biological targets of food-relevant chemicals can be obtained from ToxCast results when the chemicals are grouped according to structural similarity. Starting from the 556 direct additives that have been identified in the ToxCast database by Karmaus et al. [Karmaus, A. L., Trautman, T. D., Krishan, M., Filer, D. L., and Fix, L. A. (2017). Curation of food-relevant chemicals in ToxCast. Food Chem. Toxicol. 103, 174-182.], the results showed that, despite the limited number of assays in which the chemical groups have been tested, sufficient results are available within so-called "DNA binding" and "nuclear receptor" target families to profile the biological activities of the defined chemical groups for these targets. The most obvious activity identified was the estrogen receptor-mediated actions of the chemical group containing parabens and structurally related gallates, as well the chemical group containing genistein and daidzein (the latter 2 being particularly active toward estrogen receptor β as a potential health benefit). These group effects, as well as the biological activities of other chemical groups, were evaluated in a series of case studies. Overall, the results of the present study suggest that high-throughput screening data could add to the evidence considered for regulatory risk assessment of food chemicals and to the evaluation of desirable effects of nutrients and phytonutrients. The data will be particularly useful for providing mechanistic information and to fill data gaps with read-across.
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.
Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution
Rotter, S. ; Beronius, A. ; Boobis, A.R. ; Hanberg, A. ; Klaveren, J. Van; Luijten, M. ; Machera, K. ; Nikolopoulou, D. ; Voet, H. Van Der; Zilliacus, J. ; Solecki, R. - \ 2018
Critical Reviews in Toxicology 48 (2018)9. - ISSN 1040-8444 - p. 796 - 814.
This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project “EuroMix” aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.
Towards microbial fermentation metabolites as markers for health benefits of prebiotics
Verbeke, Kristin A. ; Boobis, Alan R. ; Chiodini, Alessandro ; Edwards, Christine A. ; Franck, Anne ; Kleerebezem, Michiel ; Nauta, Arjen ; Raes, Jeroen ; Tol, Eric A.F. Van; Tuohy, Kieran M. - \ 2015
Nutrition Research Reviews 28 (2015)1. - ISSN 0954-4224 - p. 42 - 66.
Metagenome - Microbial metabolites - Nutrikinetics - Prebiotic health benefits
Available evidence on the bioactive, nutritional and putative detrimental properties of gut microbial metabolites has been evaluated to support a more integrated view of how prebiotics might affect host health throughout life. The present literature inventory targeted evidence for the physiological and nutritional effects of metabolites, for example, SCFA, the potential toxicity of other metabolites and attempted to determine normal concentration ranges. Furthermore, the biological relevance of more holistic approaches like faecal water toxicity assays and metabolomics and the limitations of faecal measurements were addressed. Existing literature indicates that protein fermentation metabolites (phenol, p-cresol, indole, ammonia), typically considered as potentially harmful, occur at concentration ranges in the colon such that no toxic effects are expected either locally or following systemic absorption. The endproducts of saccharolytic fermentation, SCFA, may have effects on colonic health, host physiology, immunity, lipid and protein metabolism and appetite control. However, measuring SCFA concentrations in faeces is insufficient to assess the dynamic processes of their nutrikinetics. Existing literature on the usefulness of faecal water toxicity measures as indicators of cancer risk seems limited. In conclusion, at present there is insufficient evidence to use changes in faecal bacterial metabolite concentrations as markers of prebiotic effectiveness. Integration of results from metabolomics and metagenomics holds promise for understanding the health implications of prebiotic microbiome modulation but adequate tools for data integration and interpretation are currently lacking. Similarly, studies measuring metabolite fluxes in different body compartments to provide a more accurate picture of their nutrikinetics are needed.
|Stereoselective metabolism of polycyclic aromatic hydrocarbons to carcinogenic metabolites
Jerina, D.M. ; Jager, J.M. ; Yagi, H. ; Bladeren, P.J. van; Thakker, D.R. ; Levin, W. ; Chang, R.L. ; Wood, A.W. ; Conney, A.H. - \ 1985
In: Microsomes and drugoxidations / Boobis, A.R., Coldwell, J., de Mattes, F., Elcombe, C.R., London : Taylor & Francis - p. 310 - 319.