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

ABSTRACT

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.

KEYWORDS:

• Bioassays
• mutagenicity
• packaging
• NIAS
• TTC
• safety

Acknowledgments

This manuscript has been shared and debated during a workshop organised on 8-9 November 2018 in Brussels by the European branch of the International Life Sciences Institute, ILSI Europe, through the financial support from ILSI Europe’s Packaging Materials Task Force. We wish to thank all workshop participants for their valuable comments. The authors carried out the work that is, writing the scientific paper; separate to other activities of the task force.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes

1. OECD Test No. 471: Bacterial Reverse Mutation Test.

2. OECD Test Guideline No. 487: In Vitro Mammalian Cell Micronucleus Test (MNvit).

3. European Commission, Council Directive 93/42/EEC of 14 June 1993 concerning medical devices.

4. ISO 10993–1:2009. Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.

5. ISO 10993–3:2014. Biological evaluation of medical devices – Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity.

6. OECD Test No. 473: In vitro Mammalian Chromosome Aberration Test.

7. OECD Test No. 490: In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene.

8. EMEA/HMPC/107079/2007: Committee on herbal medicinal products – Guideline on the assessment of genotoxicity of herbal substances/preparations.

9. OECD Test No. 476: In vitro Mammalian Cell Gene Mutation Test.

10. TA 1535, TA1537 1.5-fold; TA 1538, TA 98, TA100 2-fold; TA102 3-fold increases, respectively.

11. OECD Guidance Document No. 34 on The Validation and International Acceptance of New or Updated Test Methods for Hazard Assessment.

Additional information

Funding

This work was conducted by an expert group of the European branch of the International Life Sciences Institute, ILSI Europe. This publication was coordinated by the Packaging Materials Task Force. Industry members of this task force are listed on the ILSI Europe website at http://www.ilsi.eu. Experts were not paid for the time spent on this work; however, the non-industry members within the expert group were offered support for travel and accommodation costs from the Packaging Materials Task Force to attend meetings to discuss the manuscript and a small compensatory sum (honoraria) with the option to decline. The expert group carried out the work, i.e. collecting/analysing data/information and writing the scientific paper. The research reported is the result of a scientific evaluation in line with ILSI Europe’s framework to provide a precompetitive setting for public–private partnership. ILSI Europe facilitated scientific meetings and coordinated the overall project management and administrative tasks relating to the completion of this work. The opinions expressed herein and the conclusions of this publication are those of the authors and do not necessarily represent the views of ILSI Europe or those of its member companies. For further information about ILSI Europe, please email [email protected] or call [phone].