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Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

ABSTRACT: The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chromosomal damage in various tissues were considered the most relevant for assessing risk from EO, since these effects are likely to contribute to adverse health consequences in exposed individuals. The PoD estimates were screened for precision and the values were divided by data-derived adjustment factors. For gene mutations, the lowest PDE was 285 parts per trillion (ppt) based on the induction of lacI mutations in the testes of mice following 48?weeks of exposure to EO. The corresponding lowest PDE value for chromosomal mutations was 1,175?ppt for heritable translocations in mice following 8.5?weeks of EO exposure. The lowest PDE for chromosomal aberrations was 238?ppt in the mouse peripheral blood lymphocytes following 48?weeks of inhalation exposure. The diverse dose-response data for EO-induced genotoxicity enabled the derivation of PoDs for various endpoints, tissues, and species and identified 238?ppt as the lowest PDE in this retrospective analysis.

SUBMITTER: Gollapudi BB

PROVIDER: S-EPMC7756744 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

Gollapudi Bala Bhaskar BB Su Steave S Li Abby A AA Johnson George E GE Reiss Richard R Albertini Richard J RJ

Environmental and molecular mutagenesis 20200928 9

The purpose of the present investigation is to analyze the in vivo genotoxicity dose-response data of ethylene oxide (EO) and the applicability of the derived point-of-departure (PoD) values when estimating permitted daily exposure (PDE) values. A total of 40 data sets were identified from the literature, and benchmark dose analyses were conducted using PROAST software to identify a PoD value. Studies employing the inhalation route of exposure and assessing gene or chromosomal mutations and chro ...[more]

PMID: 32926486

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Project description:BackgroundThe regulatory definition(s) of nanomaterials (NMs) frequently uses the term 'agglomerates and aggregates' (AA) despite the paucity of evidence that AA are significantly relevant from a nanotoxicological perspective. This knowledge gap greatly affects the safety assessment and regulation of NMs, such as synthetic amorphous silica (SAS). SAS is used in a large panel of industrial applications. They are primarily produced as nano-sized particles (1-100?nm in diameter) and considered safe as they form large aggregates (>?100?nm) during the production process. So far, it is indeed believed that large aggregates represent a weaker hazard compared to their nano counterpart. Thus, we assessed the impact of SAS aggregation on in vitro cytotoxicity/biological activity to address the toxicological relevance of aggregates of different sizes.ResultsWe used a precipitated SAS dispersed by different methods, generating 4 ad-hoc suspensions with different aggregate size distributions. Their effect on cell metabolic activity, cell viability, epithelial barrier integrity, total glutathione content and, IL-8 and IL-6 secretion were investigated after 24?h exposure in human bronchial epithelial (HBE), colon epithelial (Caco2) and monocytic cells (THP-1). We observed that the de-aggregated suspension (DE-AGGR), predominantly composed of nano-sized aggregates, induced stronger effects in all the cell lines than the aggregated suspension (AGGR). We then compared DE-AGGR with 2 suspensions fractionated from AGGR: the precipitated fraction (PREC) and the supernatant fraction (SuperN). Very large aggregates in PREC were found to be the least cytotoxic/biologically active compared to other suspensions. SuperN, which contains aggregates larger in size (>?100?nm) than in DE-AGGR but smaller than PREC, exhibited similar activity as DE-AGGR.ConclusionOverall, aggregation resulted in reduced toxicological activity of SAS. However, when comparing aggregates of different sizes, it appeared that aggregates >?100?nm were not necessarily less cytotoxic than their nano-sized counterparts. This study suggests that aggregates of SAS are toxicologically relevant for the definition of NMs.

Dataset Information

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

Publications

Genotoxicity as a toxicologically relevant endpoint to inform risk assessment: A case study with ethylene oxide.

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