A systematic quality evaluation and review of nanomaterial genotoxicity studies: a regulatory perspective

Abstract

The number of publications in the field of nanogenotoxicology and the amount of genotoxicity data on nanomaterials (NMs) in several databases generated by European Union (EU) funded projects have increased during the last decade. In parallel, large research efforts have contributed to both our understanding of key physico-chemical (PC) parameters regarding NM characterization as well as the limitations of toxicological assays originally designed for soluble chemicals. Hence, it is becoming increasingly clear that not all of these data are reliable or relevant from the regulatory perspective. The aim of this systematic review is to investigate the extent of studies on genotoxicity of NMs that can be considered reliable and relevant by current standards and bring focus to what is needed for a study to be useful from the regulatory point of view. Due to the vast number of studies available, we chose to limit our search to two large groups, which have raised substantial interest in recent years: nanofibers (including nanotubes) and metal-containing nanoparticles. Focusing on peer-reviewed publications, we evaluated the completeness of PC characterization of the tested NMs, documentation of the model system, study design, and results according to the quality assessment approach developed in the EU FP-7 GUIDEnano project. Further, building on recently published recommendations for best practices in nanogenotoxicology research, we created a set of criteria that address assay-specific reliability and relevance for risk assessment purposes. Articles were then reviewed, the qualifying publications discussed, and the most common shortcomings in NM genotoxicity studies highlighted. Moreover, several EU projects under the FP7 and H2020 framework set the aim to collectively feed the information they produced into the eNanoMapper database. As a result, and over the years, the eNanoMapper database has been extended with data of various quality depending on the existing knowledge at the time of entry. These activities are highly relevant since negative results are often not published. Here, we have reviewed the NanoInformaTIX instance under the eNanoMapper database, which hosts data from nine EU initiatives. We evaluated the data quality and the feasibility of use of the data from a regulatory perspective for each experimental entry.

Enzymatic Hydrolysis of Rutin: Evaluation of Kinetic Parameters and Anti-Proliferative, Mutagenic and Anti-Mutagenic Effects

“…To assure this, the OECD 487 guidelines propose two parameters, named cytokinesis-block proliferation (CBPI) and replication (RI) indexes, to indicate cell proliferation and the number of cell cycles, respectively, during the time exposure to cytochalasin B [ 14 ]. It was established that CBPI values higher than 1.5 and RPI values higher than 55% were indicative of a low cytostatic effect of the sample under evaluation [ 14 , 20 , 21 ]. Considering the results described in Table 3 and Table 4 , the CBPI and RI values observed for MMS (lower in the first experiment in comparison to the second) may explain why MMS, at the same concentration, induced different rates of increase in CBMN.…”

Current status and future challenges of genotoxicity OECD Test Guidelines for nanomaterials: a workshop report

“…Furthermore, how these TGs can be/are implemented in practice is problematic because of omissions in nano-specific data requirements. For example, often adequate nanomaterial physicochemical characterization data are not provided; in which case a regulatory evaluator is not able to correlate what exactly the test material was with the nanomaterial under assessment [ 45 ]. This in turn makes it difficult to determine if the same nanomaterial was tested across a battery of assays where datasets are provided on different genotoxicity endpoints.…”

“…However, none of the studies considered in this review were conducted through the respiratory exposure route, which is one of the most relevant regarding nanomaterial exposure [ 38 ]. When focussing on the respiratory route, a more recent review found that positive outcomes were reported with TiO 2 nanoparticles, whereas nanofibres (mainly carbon nanotubes) recorded negative results [ 45 ]. On the other hand, Horibata et al focussed on genotoxicity studies performed with Mitsui-7, the only multiwalled carbon nanotube that has been classified as a possible carcinogen to humans (Group 2B) [ 46 , 47 ].…”

Correction: a systematic quality evaluation and review of nanomaterial genotoxicity studies: a regulatory perspective

“…org/ 10. 1186/ s12989-022-00499-2 Following publication of the original article [1], the authors reported an error in the name of the first author, it should change from "Kirsi K. Siivola" to "Kirsi M. Siivola".…”