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Many individual polycyclic aromatic hydrocarbons (PAH) are genotoxic carcinogens. One of the parent PAH, pyrene, undergoes simple metabolism to 1-hydroxypyrene. 1-Hydroxypyrene and its glucuronide are excreted in urine. Biological monitoring of exposure to PAH has rapidly been expanded since urinary 1-hydroxypyrene was suggested as a biological index of dose of pyrene. Since pyrene is always present in PAH mixtures, the biological indicator is not only an indicator of uptake of pyrene, but also an indirect indicator of all PAH. At present, several hundreds of papers reporting on urinary concentrations of 1-hydroxypyrene in workers' urine are available. It appeared that urinary 1-hydroxypyrene is a sound biomarker and that the analytical method is robust and non-laborious. Since epidemiological studies of cancer mortality related to long-term average urinary 1-hydroxypyrene concentration are lacking, a sound health-based limit value of 1-hydroxypyrene in urine cannot be set as yet. Since PAH exposure is widespread and the dermal uptake is substantial among exposed workers, an attempt was made to propose a three-level benchmark guideline for urinary 1-hydroxypyrene. The reference value as a 95th percentile in non-occupational exposed controls is 0.24 micromol mol(-1) creatinine and 0.76 micromol mol(-1) creatinine for non-smokers and smokers, respectively. This is the first level of the benchmark guideline. A no-biological-effect-level of 1-hydroxypyrene in urine of exposed workers was found at 1.4 micromol mol(-1) creatinine. It is the lowest reported level at which no genotoxic effects were found and therefore the estimate for the second level of the benchmark guideline. In two types of industry, coke ovens and primary aluminium production, the regression of airborne PAH concentrations and urinary 1-hydroxypyrene concentrations in exposed workers has been studied. The correlation of airborne concentrations and urinary 1-hydroxypyrene in urine of workers from coke ovens and in the primary aluminium industry was used to estimate the level of urinary 1-hydroxypyrene equal to the present occupational exposure limit (OEL) of PAH. The concentration of 1-hydroxypyrene in urine equal to the OEL is 2.3 micromol mol(-1) creatinine and 4.9 micromol mol(-1) creatinine, respectively, in these two industries. These latter values present the third level of the benchmark guideline.

We examined a group of 105 workers from a primary aluminum plant for the presence of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in their WBC and 1-hydroxypyrene in their urine. Workers were recruited from five job categories with different PAH exposure: the anode factory; the bake oven; and the electrolysis and the pot-relining departments. Unexposed workers from the foundry department served as the control group. The exposure to PAH was measured by personal monitoring, and the average PAH concentrations in the work atmosphere ranged from 0.4 micrograms/m3 in the foundry to 150 micrograms/m3 in the pot-relining department. The average exposure to benzo(a)pyrene was under the Swedish exposure limit of 5 micrograms/m3. The internal dose of pyrene was measured utilizing the 1-hydroxypyrene concentration in pre- and postshift urine samples. Higher exposure to PAH in the work atmosphere was associated with increased concentrations of 1-hydroxypyrene in the urine. The average increase in concentration of 1-hydroxypyrene ranged from 0.2 mumol/mol creatinine in the control group to 5.9 mumol/mol creatinine in the pot-relining department; an accumulation of 1-hydroxypyrene over a 5-day working period was observed. A good correlation was found between PAH exposure and the concentration of 1-hydroxypyrene in the urine on a group level (rs = 0.90; P = 0.02). PAH-DNA adducts were determined by 32P-postlabeling analysis (nuclease P1 enrichment procedure).(ABSTRACT TRUNCATED AT 250 WORDS)

Primary hepatocyte cultures derived from rat, rabbit, guinea pig and monkey have been treated in vitro with metabolites of di(2-ethylhexyl)phthalate, i.e. mono(2-ethylhexyl)phthalate (MEHP), mono(5-carboxy-2-ethylpentyl)phthalate (metabolite V) and mono(2-ethyl-5-oxohexyl)phthalate (metabolite VI). In rat hepatocyte cultures MEHP and metabolite VI were equally potent in inducing peroxisome proliferation, while metabolite V was much less potent. In rat hepatocytes a 50% increase in both peroxisomal palmitoyl-CoA oxidase activity and microsomal lauric acid omega-hydroxylation activity was found after treatment with 5-15 microM MEHP. In guinea pig, rabbit and monkey hepatocyte cultures, a 50% increase in peroxisomal palmitoyl-CoA oxidase activity was found after treatment with 408-485 microM MEHP. No induction of lauric acid omega-hydroxylation activity was found. These results indicate that peroxisome proliferation can be induced by MEHP in rabbit, guinea pig and monkey hepatocytes, but that these species are at least 30-fold less sensitive to peroxisome proliferation induction than rats. The proposed mechanistic inter-relationship between induction of lauric acid omega-hydroxylation activity and peroxisome proliferation is found in rat hepatocytes, but not in hepatocytes of the other three species. Treatment of guinea pig hepatocyte cultures with MEHP resulted in an increase in triglyceride concentrations in the hepatocytes. In rat and rabbit hepatocyte cultures, triglyceride concentrations were much less altered by MEHP. In monkey hepatocytes a decrease in hepatic triglyceride concentration was found after treatment with MEHP. These effects are in agreement with in vivo effects observed before. After treatment of primary hepatocyte cultures with MEHP, high concentrations of omega- and (omega-1)-hydroxylated metabolites of MEHP were found in media from rat, rabbit and guinea pig cultures. The formation of these metabolites did not decline in time. During treatment the metabolite profile in media from rat hepatocyte cultures moved towards omega-hydroxy metabolites of MEHP. In media from monkey hepatocyte cultures the lowest concentrations of hydroxylated metabolites were determined. No major species differences were found in the potency to form oxidized MEHP metabolites, and thus no unique metabolite differences were found, which could explain the species differences in sensitivity for peroxisome proliferation.

Large amounts of PAH's are released in the electrode production departments of pre-bake cell aluminium reduction plants. Emission sources are mixing, shaping and baking of the anode (paste plant and bake oven) and pot relining operations. A study was performed to quantify the importance of dermal uptake of PAH's among exposed workers. Twenty workers in the anode production departments (paste plant (N = 8) and bake oven (N = 5)) and the pot relining department (N = 7) volunteered for the study. Monitoring was performed over a period of 5 consecutive days using personal air sampling, dermal contamination sampling and biological monitoring. Pyrene concentrations measured in the respirable air samples, ranged up to 320 micrograms/m3. Dermal contamination of pyrene was monitored at three skin sites (wrist, jaw/neck and groin) using exposure pads as pseudo-skin. The skin contamination with pyrene ranged up to 375 ng/cm2. Contamination of the groin skin site, although covered by work clothes ranged up to 106 ng/cm2. The concentration of 1-hydroxypyrene in pre and post-shift urine ranged up to 27 mumol/mol creatinine and showed an increase during the day and a decrease during the night. Pyrene in air and pyrene on the skin were tested for significance of correlation with urinary 1-hydroxypyrene in samples taken at several moments: end-of-shift, pre-shift next morning and weekly increase. The correlation coefficients between dermal contamination and urinary 1-hydroxypyrene were equal or higher than the correlation coefficient between pyrene air concentration and urinary 1-hydroxypyrene. The total skin contamination in exposed workers is estimated to be more than three times higher than the intake via the respiratory tract. The contribution of dermal exposure to the total PAH body burden of exposed workers therefore appears to be significant.

Biological monitoring of exposure to bitumen fumes during road-paving operations was carried out. In order to evaluate the biological uptake of the workers, the nonselective urinary thioether assay and a selective method for the determination of urinary 1-hydroxypyrene were used. Urinary thioether data of exposed workers were higher than those of nonexposed subjects. The effect of smoking, however, was stronger than the effect of occupational exposure. Levels of 1-hydroxypyrene in road-paving workers were significantly higher than those in control subjects. The 1-hydroxypyrene level was also influenced by smoking habits, but the effect of occupational exposure was stronger. Our present data suggest that enhanced urine levels of both thioethers and 1-hydroxypyrene in bitumen workers may indicate an increased genotoxic risk. Furthermore, our results demonstrate the applicability of the 1-hydroxypyrene assay after occupational exposure to petroleum-based products.

Biological monitoring of exposure to coal-tar products has been carried out using the nonselective urinary mutagenicity and thioether assays and a selective method for the detection of 1-hydroxypyrene in urine. The sensitivities of the three methods have been compared. In several work environments, no increase that could be related to exposure to coal-tar products was found with the nonselective methods, whereas the levels of 1-hydroxypyrene in urine were enhanced. The applicability of the method for the detection of 1-hydroxypyrene in urine is further demonstrated.

Creosote P1 is mutagenic in the Salmonella microsome assay towards strains TA1537, TA1538, TA98 and TA100 in the presence of S9 mix. The mutagenic polycyclic aromatic hydrocarbons benzo[a]pyrene and benz[a]anthracene in this mixture are detected in concentrations of 0.18 and 1.1%, respectively. Spot samples taken from contaminated surfaces in several areas of a wood-preserving industry were tested for mutagenicity. The positive results suggest that a wipe test can give a first indication of occupational exposure to mutagenic substances, particularly when greater exposure occurs via skin contact than via inhalation. In urine of rats, mutagens appeared after treatment with creosote. However, no increase in mutagenicity could be detected in urine of creosote workers in relation to their work.

An increased lung cancer risk has been described among foundry workers. Polycyclic aromatic hydrocarbons (PAHs) and silica are possible aetiological factors. This study describes a urinary PAH metabolite, 1-hydroxypyrene (hpU), as well as the degree of cytochrome P450IA2 activity/induction as reflected by the urinary caffeine ratio (IA2) in 45 foundry workers and 52 controls; IA2 was defined as the ratio of paraxanthine 7-demethylation products to a paraxanthine 8-hydroxylation product (1,7-dimethyluric acid). Mean exposure concentrations for foundry workers were defined by breathing zone hygienic samples (respirable dust 1.2 to 3.52 mg/m3 (93 samples)) and as total PAH (0.46 micrograms/m3) and pyrene concentrations (0.28 micrograms/m3) (six samples). Non-smoking controls and foundry workers had similar IA2 ratios (5.63, 95% confidence interval (95% CI) 4.56-6.70 and 4.40, 95% CI 3.56-5.24). The same was true for smoking controls and foundry workers (9.10, 95% CI 8.00-10.20 and 8.69, 95% CI 7.37-10.01). Both smoking groups had raised IA2 ratios compared with non-smokers (p less than 0.01). Non-smoking controls and foundry workers had similar hpU concentrations (0.16, 95% CI 0.10-0.22 and 0.11, 95% CI 0.09-0.13 mumol/mol creatinine). Smoking foundry workers had raised hpU concentrations (0.42, 95% CI 0.25-0.59) compared with smoking controls (0.26, 95% CI 0.18-0.34) (p less than 0.01). A small subgroup of smoking foundry workers with the highest exposures to both silica and PAH also had the highest hpU concentrations (0.70, 95% CI - 0.07-1.47 mumol/mol creatinine) (p less than 0.04). Increased hpU concentrations in smoking foundry workers suggest a more than additive effect from smoking and foundry exposures resulting in increased PAH uptake. Increased P450IA2 enzyme activity was only found in smokers and no additional effect of foundry exposures was seen. These data suggest that smoking as well as work related PAH exposure may be casually related to increased risk of lung cancer in foundry workers.