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The International Agency for Research on Cancer considers the carcinogenicity of welding fume of priority for re-evaluation. Genotoxic effects in experimental animals are still inconclusive. Here, we investigated the association of personal exposure to metals in respirable welding fumes during a working shift with oxidatively damaged guanosine in DNA of white blood cells (WBC) and in postshift urine samples from 238 welders. Medians of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) were 2.35/106 dGuo in DNA of WBC and 4.33 µg/g creatinine in urine. The median of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) was 7.03 µg/g creatinine in urine. The extent of both urinary parameters was higher in welders applying techniques with high particle emission rates to stainless steel than in tungsten inert gas welders (8-oxodGuo: 9.96 vs. 4.49 µg/L, 8-oxoGuo: 15.7 vs. 7.7 µg/L), but this apparent difference diminished after creatinine adjustment. We applied random intercept models to estimate the influence of airborne and systemic exposure to metals on oxidatively damaged guanosine in WBC and urine together with covariates. We observed a highly significant nonlinear association of urinary 8-oxoGuo with serum ferritin (P 1,000 µg/m3 compared to ≤57 µg/m3. Similar effects were found for manganese. Airborne chromium but not nickel was associated with all oxidatively modified guanosine measures, whereas urinary chromium as well as nickel showed associations with urinary modified guanosines. In summary, oxidatively damaged urinary guanosine was associated with airborne and systemic exposure to metals in welders and showed a strong relation to body iron stores. Electronic supplementary material The online version of this article (doi:10.1007/s00204-014-1319-2) contains supplementary material, which is available to authorized users.

N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2-550 mg/kg b.w.) and 2NA (0.075-75 mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC-MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100-200-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated.

Circadian variations in immune defense and tissue repair may interfere with shift effects of occupational exposure when investigating biomarkers in cross-shift studies. This investigation compared biomarkers of inflammation and DNA damage in 59 nonsmoking and 59 smoking male construction workers pre- (6-10 a.m.) versus postshift (4-7 p.m.). Cellular compositions were analyzed in blood, induced sputum (IS), and nasal lavage fluid (NALF) and soluble inflammatory biomarkers were analyzed in IS and NALF. DNA damage was measured as 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) adducts and DNA strand breaks (alkaline Comet assay) in white blood cells (WBC). Apoptosis was quantified as percent apoptotic cells by annexin V and 7-amino-actinomycin staining in blood lymphocytes using flow cytometry. In nonsmokers higher preshift than postshift levels of interleukin-8 (IL-8) in IS and more DNA strand breaks were detected. However, more DNA adducts were found postshift. Among smokers, the cellular composition of IS and NALF differed between pre- and postshift samples, in particular more neutrophils pre- than postshift. In contrast, more cells in early apoptosis were observed post shift in both smokers and nonsmokers. These results indicate a potential influence of circadian rhythms on several biomarkers used in epidemiological studies. Data suggest interference with shift-work effects of occupational exposure in cross-shift studies and also the need to consider smoking as a modifying variable.

To study the associations between exposure to vapours and aerosols of bitumen and genotoxic effects, a cross-sectional and cross-shift study was conducted in 320 exposed workers and 118 non-exposed construction workers. Ambient air measurements were carried out to assess external exposure to vapours and aerosols of bitumen. Hydroxylated metabolites of naphthalene, phenanthrene and pyrene were measured in urine, whereas (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide ((+)-anti-BPDE), 8-oxo-7,8-dihydro-2'-deoxyguanosine (8oxodGuo) and DNA strand breaks were determined in blood. Significantly higher levels of 8-oxodGuo adducts and DNA strand breaks were found in both pre- and post-shift blood samples of exposed workers compared to those of the referents. No differences between exposed workers and referents were observed for (+)-anti-BPDE. Moreover, no positive associations between DNA damage and magnitude of airborne exposure to vapours and aerosols of bitumen could be observed in our study. Additionally, no relevant association between the urinary metabolites of PAH and the DNA damage in blood was observed. Overall, our results indicate increased oxidative DNA damage in workers exposed to vapours and aerosols of bitumen compared to non-exposed referents at the group level. However, increased DNA strand breaks in bitumen workers were still within the range of those found in non-exposed and healthy persons as reported earlier. Due to the lack of an association between oxidative DNA damage and exposure levels at the workplaces under study, the observed increase in genotoxic effects in bitumen workers cannot be attributed to vapours and aerosols of bitumen.

The chemical complexity of emissions from bitumen applications is a challenge in the assessment of exposure. Personal sampling of vapours and aerosols of bitumen was organized in 320 bitumen-exposed workers and 69 non-exposed construction workers during 2001-2008. Area sampling was conducted at 44 construction sites. Area and personal sampling of vapours and aerosols of bitumen showed similar concentrations between 5 and 10 mg/m(3), while area sampling yielded higher concentrations above the former occupational exposure limit (OEL) of 10 mg/m(3). The median concentration of personal bitumen exposure was 3.46 mg/m(3) (inter-quartile range 1.80-5.90 mg/m(3)). Only few workers were exposed above the former OEL. The specificity of the method measuring C-H stretch vibration is limited. This accounts for a median background level of 0.20 mg/m³ in non-exposed workers which is likely due to ubiquitous aliphatic hydrocarbons. Further, area measurements of polycyclic aromatic hydrocarbons (PAHs) were taken at 25 construction sites. U.S. EPA PAHs were determined with GC/MS, with the result of a median concentration of 2.47 μg/m(3) at 15 mastic asphalt worksites associated with vapours and aerosols of bitumen, with a Spearman correlation coefficient of 0.45 (95% CI -0.13 to 0.78). PAH exposure at mastic-asphalt works was higher than at reference worksites (median 0.21 μg/m(3)), but about one order of magnitude lower compared to coke-oven works. For a comparison of concentrations of vapours and aerosols of bitumen and PAHs in asphalt works, differences in sampling and analytical methods must to be taken into account.

Bitumen (referred to as asphalt in the United States) is a widely used construction material, and emissions from hot bitumen applications have been a long-standing health concern. One objective of the Human Bitumen Study was to identify potential determinants of the exposure to bitumen. The study population analysed comprised 259 male mastic asphalt workers recruited between 2003 and 2008. Personal air sampling in the workers' breathing zone was carried out during the shift to measure exposure to vapours and aerosols of bitumen. The majority of workers were engaged in building construction, where exposure levels were lower than in tunnels but higher than at road construction sites. At building construction sites, exposure levels were influenced by the room size, the processing temperature of the mastic asphalt and the job task. The results show that protective measures should include a reduction in the processing temperature.

Potential effects of xenobiotics on humans are largely derived from studies with animal models. However, due to species-specific processing of xenobiotics, susceptibilities to xenobiotic-dependent adverse effects are known to differ between species. We analysed the basal expression of cytochrome P450 (CYP) enzymes in several organs of minipigs and rats, and their inducibility upon oral intake of soils containing polycyclic aromatic hydrocarbons (PAH). CYP-specific enzymatic activities were determined in duodenum, liver and kidney microsomes. Upon ingestion of PAH-contaminated soils, CYP1A1 is differentially induced in a tissue-specific and dose-dependent manner in duodenum, liver and kidney of minipigs and rats. In the duodenum, the induction response is low in rats (about 4-fold) but it is high in minipigs (8-230-fold). By contrast, induced hepatic CYP1A1-dependent EROD-activity is higher in rats than in minipigs. The dose-response profile for renal CYP1A1 parallels that in the liver of either species but EROD-activities are 10-20 times lower than in the liver. Liver microsomal CYP2E1 is only slightly modulated in its expression by ingestion of PAH-contaminated soils in both species, whereas CYP3A-dependent testosterone 2beta- and 6beta-hydroxylation is increased in liver of rats but not in minipigs. The hepatic capacity for catechol oestrogen formation, i.e., the 2-hydroxylation of 17beta-oestradiol, is markedly increased in rats but not in minipigs by ingested PAH. It is concluded that different metabolic and transport pathways are used by minipigs and rats to process ingested PAH. Whereas in minipigs the duodenum appears as the first efficient barrier, rats respond by efficient metabolism in the liver. What is not known is which response profile is operative in man.

We have used the minipig as a prospective animal model for human risk characterization to study primary biochemical alterations upon oral contaminant intake. The effects of three orally administered soils containing polycyclic aromatic hydrocarbons (PAH) on the expression pattern of the cytochrome P450 enzyme CYP1A1 in various organs have been analyzed. Dependent on the soil sample, subchronic daily oral PAH doses ranged from 0.38 to 1.90 mg PAH(EPA)/kg body weight. In all cases, soil administration lead to significant CYP1A1 induction in several organs of minipigs to a different extent, following the order liver approximately = duodenumlungkidney approximately = spleen. Hepatic ethoxyresorufin- O-deethylase activities were elevated to 310, 1250 and 1780 compared with a background level of 200 pmol resorufin/mg protein per min. Induced duodenal activities appear to be even higher than in the liver, namely 405, 1280 and 2500 compared with a basal activity of 11 pmol resorufin/mg protein per min. CYP1A1 induction in several organs is clear evidence for successful contaminant mobilization and absorption in the duodenum and subsequent distribution of contaminant into diverse body compartments. As is shown in one case, impairment of CYP1A1 induction in the liver and thus breakdown of its PAH-metabolizing activity appears to have no effect on induced CYP1A1 levels in other organs. It appears important with respect to risk assessment that induction of CYP1A1 is particularly sensitive in the duodenum of minipigs and is achieved with soil doses which are in the range of amounts ingested by playing children due to hand-to-mouth activities. Induced duodenal CYP1A1 activities obtained in minipigs by oral exposure to PAH largely exceed maximal duodenal activities so far observed in rats. This is equally relevant for risk assessment and for selection of a suitable animal model that reflects effects of PAH exposure in humans.

Iron is the major metal found in welding fumes, and although it is an essential trace element, its overload causes toxicity due to Fenton reactions. To avoid oxidative damage, excess iron is bound to ferritin, and as a result, serum ferritin (SF) is a recognized biomarker for iron stores, with high concentrations linked to inflammation and potentially also cancer. However, little is known about iron overload in welders. Within this study, we assessed the iron status and quantitative associations between airborne iron, body iron stores, and iron homeostasis in 192 welders not wearing dust masks. Welders were equipped with personal samplers in order to determine the levels of respirable iron in the breathing zone during a working shift. SF, prohepcidin and other markers of iron status were determined in blood samples collected after shift. The impact of iron exposure and other factors on SF and prohepcidin were estimated using multiple regression models. Our results indicate that respirable iron is a significant predictor of SF and prohepcidin. Concentrations of SF varied according to the welding technique and respiratory protection used, with a median of 103 μg l(-1) in tungsten inert gas welders, 125 μg l(-1) in those wearing air-purifying respirators, and 161 μg l(-1) in other welders. Compared to welders with low iron stores (SF < 25 μg l(-1)), those with excess body iron (SF ≥ 400 μg l(-1)) worked under a higher median concentration of airborne iron (60 μg m(-3) versus 148 μg m(-3)). Even though air concentrations of respirable iron and manganese were highly correlated, and low iron stores have been reported to increase manganese uptake in the gastrointestinal tract, no correlation was seen between SF and manganese in blood. In conclusion, monitoring SF may be a reasonable method for health surveillance of welders. Respiratory protection with air-purifying respirators can decrease iron exposure and avoid chronically higher SF in welders working with high-emission technologies.

We investigated the micronucleus frequencies in peripheral blood lymphocytes of 225 mastic asphalt workers (age 17–62 years) and 69 non-bitumen-exposed road construction workers (age 18–64 years) in Germany before and after the working shift. Median shift exposure to vapours and aerosols of bitumen of exposed workers was 3.0 mg/m³. Micronuclei (MN) were determined with a standard method using cytochalasin B. Median MN frequency was 6.0 (interquartile range (IQR) 4.0–8.5) MN/1,000 binucleated lymphocytes (MN/1,000 BNC) in exposed workers and 6.0 (IQR 4.0–8.3) MN/1,000 BNC in non-exposed workers before shift. After shift, we observed 6.5 (IQR 4.4–9.3) MN/1,000 BNC in exposed workers and 6.5 (IQR 4.0–9.0) MN/1,000 BNC in non-exposed workers. Regression models were applied with the log-transformed MN frequency as the dependent variable in order to estimate the effects of exposure to vapours and aerosols of bitumen and of potential confounders. Age was the strongest predictor of MN formation in both exposed workers and referents. Our data suggest that MN formation was not associated with concentration of vapours and aerosols of bitumen during shift at the individual level. Although similar MN frequencies were observed in both groups, the modelling of factors potentially influencing MN frequency revealed a weak group difference in the post-shift model. We conclude that this small difference cannot be judged to be a relevant mutagenic effect of exposure to vapours and aerosols of bitumen, also with regard to the lack of adjustment for multiple testing and the lack of a group effect in the original data.

Urinary hydroxylated metabolites of polycyclic aromatic hydrocarbons (PAH) were investigated as potential biomarkers of bitumen exposure in a cross-shift study in 317 exposed and 117 non-exposed workers. Personal measurements of the airborne concentration of vapours and aerosols of bitumen during a working shift were weakly associated with post-shift concentrations of 1-hydroxypyrene (1-OHP) and 1-, 2+9-, 3- and 4-hydroxyphenanthrenes (further referred to their sum as OHPHE), but not 1- and 2-hydroxynaphthalene (OHNA). Smoking showed a strong influence on the metabolite concentrations, in particular on OHNA. Pre-shift concentrations of 1-OHP and OHPHE did not differ between the study groups (P = 0.16 and P = 0.89, respectively). During shift, PAH metabolite concentrations increased in exposed workers and non-exposed smokers. Statistical modelling of post-shift concentrations revealed a small increase in 1-OHP by a factor of 1.02 per 1 mg/m3 bitumen (P = 0.02) and 1.04 for OHPHE (P < 0.001). A group difference was observed that was diminished in non-smokers. Exposed non-smokers had a median post-shift 1-OHP concentration of 0.42 μg/l, and non-smoking referents 0.13 μg/l. Although post-shift concentrations of 1-OHP and OHPHE were slightly higher than those in the general population, they were much lower than in coke-oven workers. The small content of PAHs in vapours and aerosols of bitumen, the increasing use of additives to asphalt mixtures, the strong impact of smoking and their weak association with airborne bitumen limit the use of PAH metabolites as specific biomarkers of bitumen exposure.

Emission levels of vapours and aerosols of bitumen are different when processing rolled asphalt compared to mastic asphalt, with working temperatures up to 180 and 250°C, respectively. During the Human Bitumen Study, we examined six workers handling rolled asphalt and mastic asphalt in two consecutive weeks at the same construction site in a tunnel. In addition to the determination of exposure to bitumen and polycyclic aromatic hydrocarbons (PAH) during shift, we examined urinary PAH metabolites, irritative and genotoxic effects before and after shift. Median personal shift concentration of vapours and aerosols of bitumen was 1.8 (range 0.9-2.4) mg/m(3) during the application of rolled asphalt and 7.9 (range 4.9-11.9) mg/m(3) when mastic asphalt was applied. Area measurement of vapours and aerosols of bitumen revealed higher concentrations than the personal measurements for mastic asphalt (mastic asphalt: 34.9 mg/m(3); rolled asphalt: 1.8 mg/m(3)). Processing mastic asphalt was associated also with higher PAH concentrations. Urinary 1-hydroxypyrene and the sum of 1-, 2+ 9-, 3- and 4-hydroxyphenanthrene increased slightly during shift without clear difference between mastic and rolled asphalt application. However, the post-shift urinary PAH-metabolite concentrations did not reflect the different PAH exposure during mastic and rolled asphalt application. Individual workers could be identified by their spirometry results indicating that these data reflect more chronic than acute effects. In most cases, an increase of 8-oxodGuo adducts was observed during shift that was independent of the asphalt application. 8-oxodGuo and (+)-anti-BPDE-DNA adducts were higher than in exposed workers of the Human Bitumen Study independent of the asphalt application. The DNA-strand breaks were considerably higher pre-shift and decreased during shift. In this study, mastic asphalt application led to significantly higher exposure to vapours and aerosols of bitumen, as well as to airborne PAH, compared to rolled asphalt application. Nevertheless, no differences in the excretion of urinary PAH metabolites, lung function impairment and genotoxic markers were detected. However, higher levels of genotoxicity markers on both examination days compared with the results of the Human Bitumen Study may indicate a possible influence of the specific tunnel setting.

In this study, 15 soils ranging in Pb content from 32 to 6330 mg kg(-1) were subjected to in vitro gastrointestinal extractions with and without added powdered milk. Before and after treatment, Pb in the soils was fractionated according to a 7-step sequential extraction procedure. A subset of five soils and Pb acetate was used for a minipig dosing study. The amount of bioaccessible Pb determined with the in vitro system ranged from 3 to 20% without powdered milk and from 11 to 56% with powdered milk. The higher bioaccessibility of Pb in the in vitro model with addition of powdered milk was related to a depletion of Pb in the organic Pb pool and indicates that soluble milk constituents compete with soil organic ligands for Pb. The absolute and relative bioavailabilities of Pb in the minipig dosing experiment were not related to bioaccessible Pb determined in any of the two in vitro systems. However, relative bioavailabilities in liver, kidney, and total uptake were highly correlated to Pb in the third fraction of the sequential extraction that is attributed to easily reducible Mn oxides. These results indicate that reductive processes in the intestine may be more relevant for Pb absorption than the initial solubilization in the acidic stomach.

Male Long-Evans rats were exposed to 0 (controls) or 500 ppm trichloroethylene (TRI) for 6 months, 6 h daily, and 5 days a week. The TRI metabolites trichloroethanol (TCE) in blood and trichloroacetic acid (TCA) in urine were measured. Specific parameters related to the renal damage were determined in urine [biomarker for glomerular damage: high molecular weight proteins (HMW), albumin (ALB); for proximal tubular damage: N-acetyl-beta-D-glucosaminidase (NAG), low-molecular-weight-proteins (LMW)]. Significantly increased concentrations of NAG and LMW in urine of exposed rats were detected. No DNA-strand breaks in kidney cells could be detected using the comet assay, and histological examinations were performed. Histological alterations were observed in glomeruli and tubuli of exposed rats. The release of biomarkers for nephrotoxicity suggested alterations preferably in the proximal tubules of the exposed rats.