Characterizing the coverage of critical effects relevant in the safety evaluation of food additives by AOPs

Nynke I Kramer,Mathieu Vinken,Siyao Wu,Stefan Schulte,Timothy E H Allen,Ivonne M C M Rietjens,Anette Thiel,Heinz Traussnig,Natalie Thatcher,Alan Boobis,Sara Levorato,Yvette Hoffmans

doi:10.1007/s00204-019-02501-x

Abstract

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.

Highlights

The safety of food additives has been assessed according to the risk assessment paradigm described by the World Health Organization (WHO) (WHO 2009)
In the last 2 decades, a clear tendency has emerged to move to the use of mechanistic and 3R-based strategies for the safety evaluation of chemicals
The application of adverse outcome pathways (AOPs) in chemical risk assessment involves the possibility to predict apical toxic outcomes using molecular effects, which runs in parallel with the development and implementation of mechanistic approaches in toxicity testing (Willet et al 2018)

Summary

Introduction

The safety of food additives has been assessed according to the risk assessment paradigm described by the World Health Organization (WHO) (WHO 2009). Safety evaluation of food additives consists of four steps: (1) hazard identification, i.e., the assessment of the intrinsic toxic properties of the compound; (2) hazard characterization, which includes dose–response assessment, identification of critical toxic endpoints and derivation of health-based guidance values; (3) exposure assessment, i.e., the estimation of exposure/intake; (4) risk characterization, which integrates the information from the previous steps to evaluate the risk associated with the exposure to the food additive. To conclude on safe use, the estimated daily intake (EDI) of the consumer resulting from the use of a food additive should not exceed the ADI (i.e., risk characterization). The evaluation of systemic endpoints generally relies on toxicity studies in laboratory animals. This safety assessment paradigm is used worldwide by (inter)national regulatory authorities, for food additives, and for industrial chemicals, plant protection products, biocides and (veterinary) pharmaceuticals (Embry et al 2014)

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