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.
Risk assessment paradigm for glutamate
Roberts, Ashley ; Lynch, Barry ; Rietjens, Ivonne M.C.M. - \ 2018
Annals of Nutrition & Metabolism 73 (2018)Suppl 5. - ISSN 0250-6807 - p. 53 - 64.
Acceptable daily intake - Glutamate - Macronutrient - Risk assessment
Background: Re-evaluation of the use of glutamic acid and glutamate salts (referred to as glutamate hereafter) by the European Food Safety Authority (EFSA) proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight (bw)/day. Summary: This ADI is below the normal dietary intake, while even intake of free glutamate by breast-fed babies can be above this ADI. In addition, the pre-natal developmental toxicity study selected by EFSA, has never been used by regulatory authorities worldwide for the safety assessment of glutamate despite it being available for nearly 40 years. Also, the EFSA ignored that toxicokinetic data provide support for eliminating the use of an uncertainty factor for interspecies differences in kinetics. Key Messages: A 3-generation reproductive toxicity study in mice that includes extensive brain histopathology, provides a better point of departure showing no effects up to the highest dose tested of 6,000 mg/kg bw/day. Furthermore, kinetic data support use of a compound-specific uncertainty factor of 25 instead of 100. Thus, an ADI of at least 240 mg/kg bw/day would be indicated. In fact, there is no compelling evidence to indicate that the previous ADI of "not specified" warrants any change.