| Autor: |
Elespuru R; Division of Biology, Chemistry and Materials Science, US Food and Drug Administration, CDRH/OSEL, Silver Spring, Maryland 20993., Pfuhler S; The Procter & Gamble Company, Mason Business Centre, Mason, Ohio 45040., Aardema MJ; Marilyn Aardema Consulting LLC, Fairfield, Ohio 45014., Chen T; Division of Genetic and Molecular Toxicology, US Food and Drug Administration, NCTR, Jefferson, Arkansas 72079., Doak SH; Institute of Life Science, Swansea University Medical School, Swansea, Wales SA2 8PP, UK., Doherty A; Discovery Safety, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca Genetic Toxicology, AstraZeneca, Cambridge CB4 0WG, UK., Farabaugh CS; Charles River Laboratories Skokie, LLC, Skokie, Illinois 60077., Kenny J; Genetic Toxicology & Photosafety, David Jack Centre for Research & Development, GlaxoSmithKline, Ware, Hertfordshire SG12 0DP, UK., Manjanatha M; Division of Genetic and Molecular Toxicology, US Food and Drug Administration, NCTR, Jefferson, Arkansas 72079., Mahadevan B; Global Pre-clinical Development Innovation & Development, Established Pharmaceuticals, Abbott, Mumbai 400072, India., Moore MM; Ramboll Environ, Little Rock, Arkansas 72201., Ouédraogo G; L'Oreal, Research & Innovation, Aulnay sous Bois, France., Stankowski LF Jr; Charles River Laboratories Skokie, LLC, Skokie, Illinois 60077., Tanir JY; ILSI Health and Environmental Sciences Institute (HESI), Washington, District of Columbia 20005. |
| Abstrakt: |
Nanomaterials (NMs) present unique challenges in safety evaluation. An international working group, the Genetic Toxicology Technical Committee of the International Life Sciences Institute's Health and Environmental Sciences Institute, has addressed issues related to the genotoxicity assessment of NMs. A critical review of published data has been followed by recommendations on methods alterations and best practices for the standard genotoxicity assays: bacterial reverse mutation (Ames); in vitro mammalian assays for mutations, chromosomal aberrations, micronucleus induction, or DNA strand breaks (comet); and in vivo assays for genetic damage (micronucleus, comet and transgenic mutation assays). The analysis found a great diversity of tests and systems used for in vitro assays; many did not meet criteria for a valid test, and/or did not use validated cells and methods in the Organization for Economic Co-operation and Development Test Guidelines, and so these results could not be interpreted. In vivo assays were less common but better performed. It was not possible to develop conclusions on test system agreement, NM activity, or mechanism of action. However, the limited responses observed for most NMs were consistent with indirect genotoxic effects, rather than direct interaction of NMs with DNA. We propose a revised genotoxicity test battery for NMs that includes in vitro mammalian cell mutagenicity and clastogenicity assessments; in vivo assessments would be added only if warranted by information on specific organ exposure or sequestration of NMs. The bacterial assays are generally uninformative for NMs due to limited particle uptake and possible lack of mechanistic relevance, and are thus omitted in our recommended test battery for NM assessment. Recommendations include NM characterization in the test medium, verification of uptake into target cells, and limited assay-specific methods alterations to avoid interference with uptake or endpoint analysis. These recommendations are summarized in a Roadmap guideline for testing. |
