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BackgroundThe liver has a crucial role in metabolic homeostasis as well as being the principal detoxification centre of the body, removing xenobiotics and waste products which could potentially include some nanomaterials (NM). With the ever increasing public and occupational exposure associated with accumulative production of nanomaterials, there is an urgent need to consider the possibility of detrimental health consequences of engineered NM exposure. It has been shown that exposure via inhalation, intratracheal instillation or ingestion can result in NM translocation to the liver. Traditional in vitro or ex vivo hepatic nanotoxicology models are often limiting and/or troublesome (i.e. reduced metabolism enzymes, lacking important cell populations, unstable with very high variability, etc.).MethodsIn order to rectify these issues and for the very first time we have utilised a 3D human liver microtissue model to investigate the toxicological effects associated with a single or multiple exposure of a panel of engineered NMs (Ag, ZnO, MWCNT and a positively charged TiO2).ResultsHere we demonstrate that the repeated exposure of the NMs is more damaging to the liver tissue as in comparison to a single exposure with the adverse effects more significant following treatment with the Ag and ZnO as compared with the TiO2 and MWCNT NMs (in terms of cytotoxicity, cytokine secretion, lipid peroxidation and genotoxicity).ConclusionsOverall, this study demonstrates that the human microtissue model utilised herein is an excellent candidate for replacement of traditional in vitro single cell hepatic models and further progression of liver nanotoxicology.

This study investigated a number of biomarkers, associated with systemic inflammation as well as genotoxicity, in 53 young and healthy subjects participating in a course to become firefighters, while wearing personal protective equipment (PPE). The exposure period consisted of a 3-day training course where the subjects participated in various live-fire training exercises. The subjects were instructed to extinguish fires of either wood or wood with electrical cords and mattresses. The personal exposure was measured as dermal polycyclic aromatic hydrocarbon (PAH) concentrations and urinary excretion of 1-hydroxypyrene (1-OHP). The subjects were primarily exposed to particulate matter (PM) in by-stander positions, since the self-contained breathing apparatus effectively prevented pulmonary exposure. There was increased dermal exposure to pyrene (68.1%, 95% CI: 52.5%, 83.8%) and sum of 16 polycyclic aromatic hydrocarbons (ƩPAH; 79.5%, 95% CI: 52.5%, 106.6%), and increased urinary excretion of 1-OHP (70.4%, 95% CI: 52.5%; 106.6%) after the firefighting exercise compared with the mean of two control measurements performed 2 weeks before and 2 weeks after the firefighting course, respectively. The level of Fpg-sensitive sites in peripheral blood mononuclear cells (PBMCs) was increased by 8.0% (95% CI: 0.02%, 15.9%) compared with control measurements. The level of DNA strand breaks was positively associated with dermal exposure to pyrene and ƩPAHs, and urinary excretion of 1-OHP. Fpg-sensitive sites were only associated positively with PAHs. Biomarkers of inflammation and lung function showed no consistent response. In summary, the study demonstrated that PAH exposure during firefighting activity was associated with genotoxicity in PBMCs.

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The formamidopyrimidine DNA glycosylase (Fpg) and human 8-oxoguanine DNA glycosylase (hOGG1)-modified comet assays have been widely used in human biomonitoring studies. The purpose of this article is to assess differences in reported levels of Fpg- and hOGG1-sensitive sites in leukocytes and suggest suitable assay controls for the measurement of oxidatively damaged DNA. An assessment of the literature showed a large variation in the reported levels of Fpg-sensitive sites (range 0.05-1.31 lesions/106 bp). The levels of Fpg-sensitive sites are lower in studies where Fpg has been obtained from commercial suppliers or unknown sources as compared to Fpg from one particular non-commercial source (χ2 = 7.14, P = 0.028). The levels of hOGG1-sensitive sites are lower (range: 0.04-0.18 lesions/106 bp in leukocytes) compared to the Fpg-sensitive sites. Surprisingly, few publications have reported the use of oxidising agents as assay controls, with the exception of hydrogen peroxide. This may be due to a lack of consensus about suitable controls for the Fpg- and hOGG1-modified comet assay. A major challenge is to find an oxidising agent that only oxidises nucleobases and does not generate DNA strand breaks because this reduces the dynamic range of Fpg- and hOGG1-sensitive sites in the comet assay. Based on a literature search we selected the photosensitiser Ro19-8022 plus light, KBrO3, 4-nitroquinoline-1-oxide, Na2Cr2O7 and ferric nitrilotriacetate as possible assay controls. A subsequent assessment of these compounds for generating cryopreserved assay controls in mononuclear blood cells showed that Ro19-8022 plus light, KBrO3 and 4-nitroquinoline-1-oxide provided suitable assay controls. We recommend these compounds as comet assay controls for oxidatively damaged DNA.

Firefighting is regarded as possibly carcinogenic, although there are few mechanistic studies on genotoxicity in humans. We investigated exposure to polycyclic aromatic hydrocarbons (PAH), lung function, systemic inflammation and genotoxicity in peripheral blood mononuclear cells (PBMC) of 22 professional firefighters before and after a 24-h work shift. Exposure was assessed by measurements of particulate matter (PM), PAH levels on skin, urinary 1-hydroxypyrene (1-OHP) and self-reported participation in fire extinguishing activities. PM measurements indicated that use of personal protective equipment (PPE) effectively prevented inhalation exposure, but exposure to PM occurred when the environment was perceived as safe and the self-contained breathing apparatuses were removed. The level of PAH on skin and urinary 1-OHP concentration were similar before and after the work shift, irrespective of self-reported participation in fire extinction activities. Post-shift, the subjects had reduced levels of oxidatively damaged DNA in PBMC, and increased plasma concentration of vascular cell adhesion molecule 1 (VCAM-1). The subjects reporting participation in fire extinction activities during the work shift had a slightly decreased lung function, increased plasma concentration of VCAM-1, and reduced levels of oxidatively damaged DNA in PBMC. Our results suggest that the firefighters were not exposed to PM while using PPE, but exposure occurred when PPE was not used. The work shift was not associated with increased levels of genotoxicity. Increased levels of VCAM-1 in plasma were observed. Environ. Mol. Mutagen. 59:539-548, 2018. © 2018 Wiley Periodicals, Inc.