The use of adverse outcome pathways in the safety evaluation of food additives.

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.

Value and limitation of in vitro bioassays to support the application of the threshold of toxicological concern to prioritise unidentified chemicals in food contact materials.

Some of the chemicals in materials used for packaging food may leak into the food, resulting in human exposure. These include so-called Non-intentionally Added Substances (NIAS), many of them being unidentified and toxicologically uncharacterized. This raises the question of how to address their safety. An approach consisting of identification and toxicologically testing all of them appears neither feasible nor necessary. Instead, it has been proposed to use the threshold of toxicological concern (TTC) Cramer class III to prioritise unknown NIAS on which further safety investigations should focus. Use of the Cramer class III TTC for this purpose would be appropriate if amongst others sufficient evidence were available that the unknown chemicals were not acetylcholinesterase inhibitors or direct DNA-reactive mutagens. While knowledge of the material and analytical chemistry may efficiently address the first concern, the second could not be addressed in this way. An alternative would be use of a bioassay capable of detecting DNA-reactive mutagens at very low levels. No fully satisfactory bioassay was identified. The Ames test appeared the most suitable since it specifically detects DNA-reactive mutagens and the limit of biological detection of highly potent genotoxic carcinogens is low. It is proposed that for a specific migrate, the evidence for absence of mutagenicity based on the Ames test, together with analytical chemistry and information on packaging manufacture could allow application of the Cramer class III TTC to prioritise unknown NIAS. Recommendations, as well as research proposals, have been developed on sample preparation and bioassay improvement with the ultimate aim of improving limits of biological detection of mutagens. Although research is still necessary, the proposed approach should bring significant benefits over the current practices used for safety evaluation of food contact materials.

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

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.