Strategies in genotoxicology: Acceptance of innovative scientific methods in a regulatory context and from an industrial perspective

Abstract

The tests used and the general principles behind test strategies are now often over 30 years old. It may be time by now, given that our knowledge of genetic toxicology has improved and that we also technically are better able to investigate DNA damage making use of modern molecular biological techniques, to start thinking on a new test strategy. In the present paper, it is demonstrated that the time is there to consider a new approach for genotoxicity assessment of substances. A fit for all test strategy was discussed making use of the most recent technological methods and techniques. It was also indicated that in silico tools should be more accepted by regulatory institutes/bodies as supporting information to better conclude which tests should be required for each separate substance to demonstrate its genotoxic potency. Next to that there should be a good rationale for performing in vivo studies. Finally, the need for germ cell genotoxicity testing, essential when classification and labeling of substances is mandatory, was discussed. It was suggested to change the GHS for genotoxicity classification and labelling from in vivo tests in germ cells into in vivo tests in somatic cells. Quantitative genotoxicology was also discussed. It appeared that we are currently at a transition, where the science developing to justify carrying out human health risk assessments based on genetic toxicology data sets supported by mechanistic data and exposure data. However, implementation will take time, and acceptance will be supported through the development of numerous case studies. Major remaining questions are: is genetic damage a relevant endpoint in itself, or should the risk assessment be carried out on the apical endpoint of cancer and which genotoxic endpoint should be used to derive the point of departure (PoD) for the human exposure limit?

Gene expression response of the non-target gastropod Physella acuta to Fenoxycarb, a juvenile hormone analog pesticide

“…Advances in toxicological studies demand the extension of toxicity tests to additional levels beyond traditional endpoints such as survival, reproduction, or development. Nowadays, a molecular approach to toxicity evaluation is frequently taken, and it requires additional putative biomarkers that assess the modulation of different cellular processes and physiological mechanisms [23][24][25] . In this sense, adding new genes to the battery of biomarkers extends the number of processes studied and the levels of response, depending on the pathway analyzed.…”

The State of the Art and Challenges of In Vitro Methods for Human Hazard Assessment of Nanomaterials in the Context of Safe-by-Design

“…Due to the important consequences to human health, mutagenicity is a hazard endpoint required in all product regulations (chemicals, biocides, pharmaceuticals, medical devices, food additives, cosmetics, etc.) [ 224 ]. The assessment of genotoxicity is based on validated in vitro assays, which can be followed up by validated in vivo assays, depending on the in vitro outcome and the regulation involved [ 225 ].…”

Genotoxicity of Graphene-Based Materials

“…Due to the important consequences to human health, together with the fact that genotoxic carcinogens are regarded as having no threshold that would allow establishing a non-observed adverse effect level, mutagenicity is a hazard endpoint required in all product regulations, e.g., Registration, Evaluation, Authorization and Restriction of Chemicals (REACH), biocides, medical devices, food additives, cosmetics, etc. [ 22 ]. Genotoxicity is also a key point in most of the testing strategies suggested for nanomaterials [ 16 , 23 , 24 , 25 ], and its assessment has been highly recommended at early stages of the innovation process [ 4 ].…”