Millions of people in the world perform welding as their primary occupation resulting in exposure to metal-containing nanoparticles in the fumes generated. Even though health effects including airway diseases are well-known, there is currently a lack of studies investigating how different welding setups and conditions affect the toxicity of generated nanoparticles of the welding fume. The aim of this study was to investigate the toxicity of nine types of welding fume particles generated via active gas shielded metal arc welding (GMAW) of chromiumcontaining stainless steel under different conditions and, furthermore, to correlate the toxicity to the particle characteristics. Toxicological endpoints investigated were generation of reactive oxygen species (ROS), cytotoxicity, genotoxicity and activation of ToxTracker reporter cell lines. The results clearly underline that the choice of filler material has a large influence on the toxic potential. Fume particles generated by welding with the tested flux-cored wire (FCW) were found to be more cytotoxic compared to particles generated by welding with solid wire or metal-cored wire (MCW). FCW fume particles were also the most potent in causing ROS and DNA damage and they furthermore activated reporters related to DNA double-strand breaks and p53 signaling. Interestingly, the FCW fume particles were the most soluble in PBS, releasing more chromium in the hexavalent form and manganese compared to the other fumes. These results emphasize the importance of solubility of different metal constituents of the fume particles, rather than the total metal content, for their acute toxic potential.

This study aimed to investigate the influence of a single dose of either beetroot juice (BR) or sodium nitrate (NIT) on performance in a 10 km handcycling time trial (TT) in able-bodied individuals and paracyclists. In total, 14 able-bodied individuals [mean ± SD; age: 28 ± 7 years, height: 183 ± 5 cm, body mass (BM): 82 ± 9 kg, peak oxygen consumption (VO2peak): 33.9 ± 4.2 mL/min/kg] and eight paracyclists (age: 40 ± 11 years, height: 176 ± 9cm, BM: 65 ± 9 kg, VO2peak: 38.6 ± 10.5 mL/min/kg) participated in the study. All participants had to perform three TT on different days, receiving either 6 mmol nitrate as BR or NIT or water as a placebo. Time-to-complete the TT, power output (PO), as well as oxygen uptake (VO2) were measured. No significant differences in time-to-complete the TT were found between the three interventions in able-bodied individuals (p = 0.80) or in paracyclists (p = 0.61). Furthermore, VO2 was not significantly changed after the ingestion of BR or NIT in either group (p < 0.05). The PO to VO2 ratio was significantly higher in some kilometers of the TT in able-bodied individuals (p < 0.05). The ingestion of BR or NIT did not increase handcycling performance in able-bodied individuals or in paracyclists.

The increased use of nanoparticles (NPs) requires efficient testing of their potential toxic effects. A promising approach is to use reporter cell lines to quickly assess the activation of cellular stress response pathways. This study aimed to use the ToxTracker reporter cell lines to investigate (geno)toxicity of various metal- or metal oxide NPs and draw general conclusions on NP-induced effects, in combination with our previous findings. The NPs tested in this study (n = 18) also included quantum dots (QDs) in different sizes. The results showed a large variation in cytotoxicity of the NPs tested. Furthermore, whereas many induced oxidative stress only few activated reporters related to DNA damage. NPs of manganese (Mn and Mn3O4) induced the most remarkable ToxTracker response with activation of reporters for oxidative stress, DNA damage, protein unfolding and p53-related stress. The QDs (CdTe) were highly toxic showing clearly size-dependent effects and calculations suggest surface area as the most relevant dose metric. Of all NPs investigated in this and previous studies the following induce the DNA damage reporter; CuO, Co, CoO, CdTe QDs, Mn, Mn3O4, V2O5, and welding NPs. We suggest that these NPs are of particular concern when considering genotoxicity induced by metal- and metal oxide NPs.

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Abstract Understanding the mode-of-action (MOA) of genotoxic compounds and differentiating between direct DNA interaction and indirect genotoxicity is crucial for their reliable safety assessment. ToxTracker is a stem cell-based reporter assay that detects activation of various cellular responses that are associated with genotoxicity and cancer. ToxTracker consists of six different GFP reporter cell lines that can detect the induction of DNA damage, oxidative stress and protein damage in a single test. The assay can thereby provide insight into the MOA of compounds. Genotoxicity is detected in ToxTracker by activation of two independent GFP reporters. Activation of the Bscl2-GFP reporter is associated with induction of DNA adducts and subsequent inhibition of DNA replication and the Rtkn-GFP reporter is activated following the formation of DNA double-strand breaks. Here we show that the differential activation of these two genotoxicity reporters could be used to further differentiate between a DNA reactive and clastogenic or a non-DNA-reactive aneugenic mode-of-action of genotoxic compounds. For further classification of aneugenic and clastogenic compounds, the ToxTracker assay was extended with cell cycle analysis and aneuploidy assessment. The extension was validated using a selection of 16 (genotoxic) compounds with a well-established mode-of-action. Furthermore, indirect genotoxicity related to the production of reactive oxygen species (ROS) was investigated using the DNA damage and oxidative stress ToxTracker reporters in combination with different ROS scavengers. With these new extensions, ToxTracker was able to accurately classify compounds as genotoxic or non-genotoxic, and could discriminate between DNA reactive compounds, aneugens and indirect genotoxicity caused by oxidative stress.

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In vitro (geno)toxicity assessment of electronic vapour products (EVPs), relative to conventional cigarette, currently uses assays, including the micronucleus and Ames tests. Whilst informative on induction of a finite endpoint and relative risk posed by test articles, such assays could benefit from mechanistic supplementation. The ToxTracker and Aneugen Clastogen Evaluation analysis can indicate the activation of reporters associated with (geno)toxicity, including DNA damage, oxidative stress, the p53-related stress response and protein damage. Here, we tested for the different effects of a selection of neat e-liquids, EVP aerosols and Kentucky reference 1R6F cigarette smoke samples in the ToxTracker assay. The assay was initially validated to assess whether a mixture of e-liquid base components, propylene glycol (PG) and vegetable glycerine (VG) had interfering effects within the system. This was achieved by spiking three positive controls into the system with neat PG/VG or phosphate-buffered saline bubbled (bPBS) PG/VG aerosol (nicotine and flavour free). PG/VG did not greatly affect responses induced by the compounds. Next, when compared to cigarette smoke samples, neat e-liquids and bPBS aerosols (tobacco flavour; 1.6% freebase nicotine, 1.6% nicotine salt or 0% nicotine) exhibited reduced and less complex responses. Tested up to a 10% concentration, EVP aerosol bPBS did not induce any ToxTracker reporters. Neat e-liquids, tested up to 1%, induced oxidative stress reporters, thought to be due to their effects on osmolarity in vitro. E-liquid nicotine content did not affect responses induced. Additionally, spiking nicotine alone only induced an oxidative stress response at a supraphysiological level. In conclusion, the ToxTracker assay is a quick, informative screen for genotoxic potential and mechanisms of a variety of (compositionally complex) samples, derived from cigarettes and EVPs. This assay has the potential for future application in the assessment battery for next-generation (smoking alternative) products, including EVPs.