Isocyanates are increasingly being used for manufacturing polyurethane foam, elastomers, adhesives, paints, coatings, insecticides, and many other products. At present, they are regarded as one of the main causes of occupational asthma. The large number of workers who are exposed to these chemicals have a concentration-dependent risk of developing chronic airway disorders, especially bronchial asthma. Different pathophysiologic mechanisms are involved. Immunoglobulin E (IgE)-mediated sensitization and irritative effects have been clearly demonstrated in both exposed subjects and animals. Presumably, neural inflammation due to neuropeptide release of capsaicin-sensitive afferent nerves is crucial. We collected data on 1780 isocyanate workers who had been examined by our groups. Of them 1095 (including subjects from outpatient departments) had work-related symptoms, predominantly of the respiratory tract. Specific IgE antibodies were found in 14% of the 1095 subjects. The methacholine challenge test was shown to be an inadequate predictor of the results of inhalative isocyanate provocation tests in workers and in asthmatic controls. Isocyanate (toluene diisocyanate TDI) air concentrations of 10 ppb (0.07 mg/m3) and 20 ppb (0.14 mg/m3), respectively, did not cause significant bronchial obstruction in the majority of previously unexposed asthmatics with bronchial hyperreactivity. IgG-mediated allergic alveolitis, a rare disease among isocyanate workers, was found in approximately 1% of the symptomatic subjects. Experimental studies exhibit dose-dependent toxic effects and give evidence for tachykinin-mediated bronchial hyperreactivity after exposure to isocyanates. The clinical role of genotoxic effects of isocyanates and their by-products demonstrated here in vitro and in vivo has yet to be clarified.

The relationship between biomarkers of effect (8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo, HPLC system) and tail extent moment (comet assay)), markers of external and internal exposure, and biomarkers of susceptibility was evaluated for coke-oven and graphite-electrode-producing plant workers exposed to polycyclic aromatic hydrocarbons (PAHs). Mean 8-oxodGuo levels in white blood cells (WBC) of exposed workers were between 1.38 times (coke-oven, n = 20; P < 0.01) and 2.15 times (graphite-electrode-producing plant, n = 30; P < 0.01) higher than levels found in control samples (mean +/- SD 0.52 +/- 0.16 8-oxodGuo/10(5) dGuo, n = 47). The mean tail extent moment in lymphocytes was 1.38 times higher for coke-oven workers (n = 19; P = 0.09) and 3.13 times higher for graphite-electrode-producing plant workers (n = 29; P < 0.01) when compared with controls (mean plus minus SD 2.54 +/- 0.68, n = 32). Elevated tail extent moments (>3.73) were found in the majority (84%) of PAH-exposed workers showing increased DNA adduct levels (>0.78 8-oxodGuo/10(5) dGuo). However, no association (P > 0.05) was found between DNA damage (8-oxodGuo/10(5) dGuo or tail extent moment) in WBC of all PAH-exposed workers and either benzo[a]pyrene levels or the sum of 16 PAH levels in the air at work place. Furthermore, no relation (P > 0.05) could be established between DNA damage in WBC and biomarkers of internal exposure (1-hydroxypyrene (1-OHP) and sum of five hydroxyphenanthrenes (OHPHs)). Higher exposure to airborne pyrene and phenanthrene led to increasing concentrations of the metabolites 1-OHP (P < 0.01) and the sum of five OHPHs (P < 0.01) in the urine of PAH-exposed workers. The polymorphisms of genes CYP1A1, GSTM1, GSTT1 and GSTP1 (biomarkers of susceptibility) showed no association with biomarkers of effect. In conclusion, both biomarkers of effect may be appropriate for further surveillance studies of workers under PAH exposure.

Diisocyanates are highly reactive compounds widely used, for example, in the production of polyurethane foams, elastomers, paints, and adhesives. The high chemical reactivity of these compounds is also reflected in their toxicity: diisocyanates are one of the most important causes of occupational asthma but also other adverse effects, such as irritation and toxic reactions, have been described in exposed subjects. One of the open questions is whether occupational isocyanate exposure is a carcinogenic hazard. The few epidemiological studies available have been based on young cohorts and short follow-up and are not conclusive. Toluene diisocyanate (TDI) has been classified as carcinogenic in animals on the basis of gavage administration studies, but no conclusions are available on inhalation exposure. For 4,4'-methylene diphenyldiisocyanate (MDI) there is suggestive evidence for carcinogenicity in rats. The possible carcinogenic mechanism of TDI and MDI is not clear. Both chemicals have been positive in a number of short-term tests inducing gene mutations and chromosomal damage. The reactive form could be either the diisocyanate itself or may derive from the metabolic activation of the aromatic diamine derivatives formed by hydrolysis. TDI and MDI react with DNA in vivo and in vitro. However, the structure of the adducts has not been identified. Especially from the in vivo experiment it is not known if the adducts are a product from the reaction with the isocyanate or the corresponding amine. In conclusion, both TDI and MDI are highly reactive chemicals that bind to DNA and are probably genotoxic. The alleged animal carcinogenicity of TDI and MDI would suggest that occupational exposure to these compounds is a carcinogenic risk. The few epidemiological studies available have not, however, been able to clarify if TDI and MDI are occupational carcinogens.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in our environment and can cause cancer. Exposure to PAHs can be assessed by protein adduct dosimetry using benzo[a]pyrene (B[a]P) as a model compound. We present an overview of analytical methods to detect B[a]P- derived protein adducts in humans, their uses in exposure assessment, and recommendations for future research. Two major methodologies, enzyme-linked immunosorbent assay (ELISA) and chemical-specific assays, could be traced in the literature but there remains limitations with both assays. ELISA is nonspecific due to cross-reactivity of the antibody with other PAHs and results are better interpreted in terms of PAH exposure. ELISA is unable to distinguish between exposed and nonexposed persons in the majority of studies. Adduct concentrations are higher by several orders of magnitude compared to those determined by chemical-specific methods. The latter methods mostly analyzed protein adducts derived by (+)-anti-B[a]P-diol epoxide. For this purpose, gas or liquid chromatography in combination with mass spectrometry or fluorescence detection were used. However, the prevalence of positive samples remained low when chemical- specific assays were used mainly due to the lack of sensitivity. Overall, data on B[a]P-derived protein adducts in humans remain inconclusive. Future research should focus on the development and standardization of a sensitive and specific method for B[a]P-derived protein adducts prior to its use in field studies. Finally, exposures of B[a]P at the workplace and via diet, a major route of exposure of the general population, can be studied. The results will contribute to the understanding of B[a]P-induced cancer and will allow for health preventive measures.

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Exposure to polycyclic aromatic hydrocarbons (PAH) and DNA damage were analyzed in coke oven (n = 37), refractory (n = 96), graphite electrode (n = 26), and converter workers (n = 12), whereas construction workers (n = 48) served as referents. PAH exposure was assessed by personal air sampling during shift and biological monitoring in urine post shift (1-hydroxypyrene, 1-OHP and 1-, 2 + 9-, 3-, 4-hydroxyphenanthrenes, SigmaOHPHE). DNA damage was measured by 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and DNA strand breaks in blood post shift. Median 1-OHP and SigmaOHPHE were highest in converter workers (13.5 and 37.2 microg/g crea). The industrial setting contributed to the metabolite concentrations rather than the air-borne concentration alone. Other routes of uptake, probably dermal, influenced associations between air-borne concentrations and levels of PAH metabolites in urine making biomonitoring results preferred parameters to assess exposure to PAH. DNA damage in terms of 8-oxo-dGuo and DNA strand breaks was higher in exposed workers compared to referents ranking highest for graphite-electrode production. The type of industry contributed to genotoxic DNA damage and DNA damage was not unequivocally associated to PAH on the individual level most likely due to potential contributions of co-exposures.

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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.