Adipokine genes and radiographic hand osteoarthritis in Finnish women: a cross-sectional study.

OBJECTIVES: Available evidence suggests that genetic factors and overweight play major roles in the aetiology of osteoarthritis (OA). We analysed the association of 18 single-nucleotide polymorphisms (SNPs) from nine adipokine and adipokine receptor genes (LEP, LEPR, ADIPOQ, RETN, NAMPT, SERPINA12, ITLN1, RARRES2, and APLN) with radiographic hand OA. METHOD: The study design was cross-sectional. Bilateral hand radiographs of 542 occupationally active Finnish female dentists and teachers aged 45-63 years were examined and classified for the presence of hand OA using reference images. Hand OA was defined as at least three finger joints with radiographic OA of grade 2-4. The genotypes were determined using polymerase chain reaction-based methods. Body mass index (BMI) was calculated based on self-reported height and measured weight. Associations of the individual SNPs and their haplotypes with hand OA were tested using logistic regression analysis. RESULTS: The minor allele of RETN rs10401670 was associated with a decreased [odds ratio (OR) = 0.73, 95% confidence interval (CI) 0.55-0.97, p = 0.03] and RARRES2 rs4721 with an increased (OR 1.41, 95% CI 1.07-1.87, p = 0.01) prevalence of hand OA. Also, LEPR AC (OR 1.54, 95% CI 1.01-2.35, p = 0.05) and RETN GGTT (OR 0.58, 95% CI 0.37-0.93, p = 0.02) haplotypes were associated with hand OA. These associations were modified by BMI when comparing normal and overweight women. However, the associations lost their statistical significance after adjusting for multiple testing. CONCLUSION: Our results suggest weak associations between the studied variations in LEPR, RARRES2, and RETN genes and hand OA in Finnish women, and that the associations are modified by BMI. However, these associations could not be verified in the current study.

Genetic susceptibility to asbestos-related fibrotic pleuropulmonary changes.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

Gender-related differences in response to mutagens and carcinogens.

The incidences of many cancers can be very different in men and women. Besides differences in exposures to putative causative agents, it is plausible that both genetic and epigenetic effects play roles in these differences. In addition, gender-specific lifestyle and behavioural factors may modulate the effects of exposure to genotoxins. This commentary focuses on several aspects of gender-related differences in responses to mutagens and carcinogens, including sensitivity to chromosome damage, the contribution of genotypic variation and the role of DNA methylation. It is concluded that the reasons for gender differences in cancer susceptibility remain largely unknown in many cases, and the subject deserves more attention and study.

COL2A1 gene polymorphisms and susceptibility to osteoarthritis of the hand in Finnish women.

OBJECTIVES: To study the role of two COL2A1 single nucleotide polymorphisms (rs3737548 and rs2276455) and their haplotypes in individual susceptibility to osteoarthritis (OA) of the hand in Finnish women. METHODS: Bilateral hand radiographs of 543 Finnish female dentists and teachers aged 45-63 years were examined and classified for the presence of OA by using reference images. The COL2A1 genotypes were determined by PCR-based methods. Data regarding other risk factors were collected by questionnaire. The haplotypes were statistically reconstructed from the genotype data by the PHASE program. Associations between the genotypes/diplotypes and hand OA were studied by logistic regression. RESULTS: Allowing for age and occupation, the carriage of at least one COL2A1 intron 33 minor allele was associated with an increased risk of hand OA (odds ratio (OR) 1.58, 95% CI 1.05 to 2.36) and the number of affected joints. When stratified by occupation, the increased risk associated with the intron 33 minor allele carriage appeared to be mainly attributable to the dentists (OR 2.18, 95% CI 1.18 to 4.06). The 2-1 haplotype (exon 5B minor allele-intron 33 major allele) posed a significantly higher risk of hand OA (OR 3.21, 95% CI 1.08 to 9.55) compared with non-carriers. Moreover, an interaction was observed between intron 33 minor allele carriage and low task variation history in dental work (OR 2.87, 95% CI 1.05 to 7.89 for their joint effect). CONCLUSIONS: The results suggest that the studied COL2A1 gene polymorphisms may play a role in the aetiology of hand OA and that this effect may be enhanced by repetitive loading work tasks.

Ozone-based advanced oxidation processes in nuclear laundry water treatment.

The efficiency of ozone treatment in the degradation of organic compounds of nuclear laundry water is presented. Ozonation experiments were performed in different combinations of pH, hydrogen peroxide and ultraviolet radiation. The degradation of non-ionic surfactant and other organic compounds was analysed by chemical oxygen demand, total organic carbon, biochemical oxygen demand and the molecular weight distribution measurements. The optimal degradation circumstances were found to be at pH 7 with ozone, UV radiation and hydrogen peroxide addition. The transfer of ozone increased substantially thus resulting in decreased treatment time compared to our previous experiments. The reductions of chemical oxygen demand, total organic carbon and biochemical oxygen demand were about 46%, 32% and 70%, respectively.

Comparison of biomarkers in workers exposed to 2,4,6-trinitrotoluene.

2,4,6-Trinitrotoluene (TNT) is an important occupational and environmental pollutant. In TNT-exposed humans, notable toxic manifestations have included aplastic anaemia, toxic hepatitis, cataracts, hepatomegaly, and liver cancer. Therefore, methods were developed to biomonitor workers exposed to TNT. The workers were employed in a typical ammunition factory in China. The external dose (air levels and skin exposure), the internal dose (urinary metabolites), the biologically effective dose (haemoglobin adducts, urinary mutagenicity), biological effects (chromosomal aberrations and health effects), and individual susceptibility (genotypes of xenobiotic-metabolizing enzymes) were determined. Haemoglobin-adducts of TNT, 4-amino-2,6-dinitrotoluene (4ADNT) and 2-amino-4,6-dinitrotoluene (2ADNT), and the urinary metabolites of TNT, 4ADNT and 2ADNT, were found in all workers and in some controls. The levels of the haemoglobin-adducts or the urinary metabolites correlated weakly with the skin or air levels of TNT. The urinary mutagenicity determined in a subset of workers correlated strongly with the levels of 4ADNT and 2ADNT in urine. The haemoglobin-adducts correlated moderately with the urinary metabolites and with the urinary mutagenicity. The genotypes of glutathione S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) were determined. In general, the genotypes did not significantly influence the haemoglobin-adduct levels and the urine metabolite levels. However, TNT-exposed workers who carried the NAT1 rapid acetylator genotype showed an increase in urinary mutagenicity and chromosomal aberrations as compared with slow acetylators. The haemoglobin adduct 4ADNT was significantly associated with a risk of hepatomegaly, splenomegaly and cataract; urine metabolites and genotypes were not associated with health effects. These results indicate that a set of well-selected biomarkers may be more informative regarding exposure and effect than routinely performed chemical measurements of pollutants in the air or on the skin.

Psychosocial stress attenuates general sound processing and duration change detection.

An EEG-compatible adaptation of the Trier Social Stress Test was developed to induce psychosocial stress in healthy subjects while investigating their auditory processing of unattended sounds and salivary levels of the stress hormone cortisol. The mismatch negativity (MMN) and N1/P2 were assessed using a multifeature paradigm, while subjects were attending to visual tasks with high or low attentional workload. Only the responses to duration change were affected by the stress manipulation. Cortisol levels during stress were inversely related to the MMN amplitudes of duration deviants. During anticipatory stress, responses to the standard tones (general sound processing) increased, but their amplitude was not correlated with cortisol levels. We found that psychosocial stressor anticipation attenuates both general and deviance-specific sound processing, suggesting that cortisol interferes with cortical memory-trace formation.

Meta- and pooled analysis of GSTT1 and lung cancer: a HuGE-GSEC review.

Lung cancer is the most common malignancy in the Western world, and the main risk factor is tobacco smoking. Polymorphisms in metabolic genes may modulate the risk associated with environmental factors. The glutathione S-transferase theta 1 gene (GSTT1) is a particularly attractive candidate for lung cancer susceptibility because of its involvement in the metabolism of polycyclic aromatic hydrocarbons found in tobacco smoke and of other chemicals, pesticides, and industrial solvents. The frequency of the GSTT1 null genotype is lower among Caucasians (10-20%) than among Asians (50-60%). The authors present a meta- and a pooled analysis of case-control, genotype-based studies that examined the association between GSTT1 and lung cancer (34 studies, 7,629 cases and 10,087 controls for the meta-analysis; 34 studies, 7,044 cases and 10,000 controls for the pooled analysis). No association was observed between GSTT1 deletion and lung cancer for Caucasians (odds ratio (OR) = 0.99, 95% confidence interval (CI): 0.87, 1.12); for Asians, a positive association was found (OR = 1.28, 95% CI: 1.10, 1.49). In the pooled analysis, the odds ratios were not significant for either Asians (OR = 0.97, 95% CI: 0.83, 1.13) or Caucasians (OR = 1.09, 95% CI: 0.99, 1.21). No significant interaction was observed between GSTT1 and smoking on lung cancer, whereas GSTT1 appeared to modulate occupational-related lung cancer.

Bromide affecting drinking water mutagenicity.

The effect of bromide on the mutagenicity of artificially recharged groundwater and purified artificially recharged groundwater after chlorine, ozone, hydrogen peroxide, permanganate, and UV treatments alone and in various combinations was studied. The highest mutagenicity was observed after chlorination, while hydrogen peroxide-ozone-chlorine treatment produced the lowest value for both waters. Chlorinated waters, which were spiked with bromide, had up to 3.7 times more mutagenic activity than waters without bromide after every preoxidation method. 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) was found to correspond as much as 76% of the overall mutagenicity in the waters not spiked with bromide. MX formation was found to be lower when the treated water contained bromide, implicating the formation of brominated MX analogues. Trihalomethane formation increased when the treated water contained bromide.

Polymorphisms in CYP1A1, GSTM1, GSTT1 and lung cancer below the age of 45 years.

BACKGROUND: A genetic component of early-onset lung cancer has been suggested. The role of metabolic gene polymorphisms has never been studied in young lung cancer cases. Phase 1 and Phase 2 gene polymorphisms are involved in tobacco carcinogens' metabolism and therefore in lung cancer risk. METHODS: The effect of metabolic gene polymorphisms on lung cancer at young ages was studied by pooling data from the Genetic Susceptibility to Environmental Carcinogens (GSEC) database. All primary lung cancer cases of both sexes who were Caucasian and

Genetic polymorphisms of cytochrome P450 19 and 1B1, alcohol use, and breast cancer risk in Korean women.

A case-control study was performed to assess the potential influence of CYP19 Arg(264)Cys and CYP1B1 Leu(432)Val polymorphisms on breast cancer risk in a series of Korean breast cancer patients and controls. The results suggest that the CYP19 Arg(264)Cys polymorphism modifies breast cancer risk (OR=1.5, 95% CI=1.1-2.2), especially in association with alcohol consumption (P for interaction=0.04), whereas the CYP1B1 Leu(432)Val polymorphism appears to play no role here.

Metabolic gene polymorphism frequencies in control populations.

Using the International Project on Genetic Susceptibility to Environmental Carcinogens (GSEC) database containing information on over 15,000 control (noncancer) subjects, the allele and genotype frequencies for many of the more commonly studied metabolic genes (CYP1A1, CYP2E1, CYP2D6, GSTM1, GSTT1, NAT2, GSTP, and EPHX) in the human population were determined. Major and significant differences in these frequencies were observed between Caucasians (n = 12,525), Asians (n = 2,136), and Africans and African Americans (n = 996), and some, but much less, heterogeneity was observed within Caucasian populations from different countries. No differences in allele frequencies were seen by age, sex, or type of controls (hospital patients versus population controls). No examples of linkage disequilibrium between the different loci were detected based on comparison of observed and expected frequencies for combinations of specific alleles.

Lack of interaction between asbestos exposure and glutathione S-transferase M1 and T1 genotypes in lung carcinogenesis.

An interaction between occupational carcinogens and genetic susceptibility factors in determining individual lung cancer risk is biologically plausible, but the interpretation of available studies are limited by the small number of exposed subjects. We selected from the international database on Genetic Susceptibility and Environmental Carcinogens the studies of lung cancer that included information on metabolic polymorphisms and occupational exposures. Adequate data were available for asbestos exposure and GSTM1 (five studies) and GSTT1 (three studies) polymorphisms. For GSTM1, the pooled analysis included 651 cases and 983 controls. The odds ratio (OR) of lung cancer was 2.0 [95% confidence interval (CI) 1.4-2.7] for asbestos exposure and 1.1 (95% CI 0.9-1.4) for GSTM1-null genotype. The OR of interaction between asbestos and GSTM1 polymorphism was 1.1 (95% CI 0.6-2.1) based on 54 cases and 53 controls who were asbestos exposed and GSTM1 null. The case-only approach, which was based on 869 lung cancer cases and had an 80% power to detect an OR of interaction of 1.56, also provided lack of evidence of interaction. The analysis of possible interaction between GSTT1 polymorphism and asbestos exposure in relation to lung cancer was based on 619 cases. The prevalence OR of GSTT1-null genotype and asbestos exposure was 1.1 (95% CI 0.6-2.0). Our results do not support the hypothesis that the risk of lung cancer after asbestos exposure differs according to GSTM1 genotype. The low statistical power of the pooled analysis for GSTT1 genotypes hampered any firm conclusion. No adequate data were available to assess other interactions between occupational exposures and metabolic polymorphisms.

CYP1A1 levels in lung tissue of tobacco smokers and polymorphisms of CYP1A1 and aromatic hydrocarbon receptor.

Induction of a polycyclic aromatic hydrocarbon-metabolizing cytochrome P450 isoform CYP1A1 is regulated by aromatic hydrocarbon receptor (AHR). High inducibility of CYP1A1, possibly due to genetic polymorphisms, has been considered to be a risk factor for lung cancer in tobacco smokers. The relationship between low or high pulmonary expression of CYP1A1 and polymorphic genotypes of CYP1A1 and AHR was investigated in 73 active smokers. CYP1A1 expression was determined in surgical lung samples by measuring ethoxyresorufin O-deethylase (EROD) activity and by immunostaining for CYP1A1 protein. The most common allelic variants of CYP1A1 and AHR in Finns, i.e. the MspI variant (CYP1A1*2A), I462V variant (CYP1A1*2B), and -459C to T variant of CYP1A1 and the R554K variant (AHR*2) of AHR were studied using polymerase chain reaction based methods. EROD activity correlated positively with the daily cigarette consumption (r = 0.45). There was additional variation in EROD activity independent of the amount of smoking e.g. among those who smoked one pack per day until the day of operation, EROD activity ranged from 4-142 (median 48) pmol/min/mg. The frequencies of the MspI, 462V, and -459T variant alleles of CYP1A1 and 554K variant allele of AHR were 0.158, 0.055, 0.055 and 0.075, respectively. No differences were observed in the frequencies of polymorphic genotypes between the smokers with low and those with high expression, when the relationship was studied using a regression analysis adjusted for cigarette consumption. Our results thus indicate that the interindividual variation of CYP1A1 levels in smokers' lung tissue is not attributable to genetic polymorphisms of CYP1A1 or AHR tested in this study.

Exposure to 2,4- and 2,6-toluene diisocyanate (TDI) during production of flexible foam: determination of airborne TDI and urinary 2,4- and 2,6-toluenediamine (TDA).

Occupational exposure to 2,4- and 2,6-toluene diisocyanate (2,4- and 2,6-TDI) was measured during the production of flexible foam. The usefulness of urinalysis of the TDI-derived amines, 2,4- and 2,6-toluenediamine (2,4- and 2,6-TDA), for exposure assessment was compared with air monitoring. Urine samples were collected from 17 employees at two plants. The workers' personal exposure was measured using 1-(2-methoxyphenyl)-piperazine (2MP)-impregnated glass fibre filters for sampling and high-performance liquid chromatography (HPLC) with ultraviolet (UV) and electrochemical (EC) detection for quantification. The limit of detection (LOD) of 2,4- and 2,6-TDI was 0.01 microtg ml(-1) for a 20 microl injection. The precision of sample preparation, expressed as the relative standard deviation (RSD), was 0.6% with UV detection and 0.8% with EC detection at a 2,4-TDI concentration of 0.2 microg ml(-1) (n = 6). For 2,6-TDI, the corresponding RSDs were 0.5% and 0.8%. The urinary 2,4- and 2,6-TDA metabolites were determined after acid hydrolysis as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry. The LOD in urine was 0.35 nmol l(-1) for 2,4-TDA and 0.04 nmol l(-1) for 2,6-TDA. The precision (RSD) of six analyses of human urine spiked to a concentration of 100 nmol l(-1) was 3.7% for 2,4-TDA and 3.6% for 2,6-TDA. There was a trend for linear correlation between urinary TDA concentration and the product of airborne TDI concentration and sampling time. Urinalysis of TDA is proposed as a practical method for assessing personal exposures in workers exposed intermittently to TDI.

Glutathione S-transferase genotypes and allergic responses to diisocyanate exposure.

Diisocyanates are the most common low molecular weight chemicals to cause occupational asthma. However, only some 5-10% of exposed workers develop asthma, which suggests an underlying genetic susceptibility. Diisocyanates and their metabolites may be conjugated with glutathione by glutathione S-transferases (GSTs). We examined whether polymorphisms in the GSTM1, GSTM3, GSTP1 and GSTT1 genes modify allergic responses to diisocyanate exposure. The study population consisted of 182 diisocyanate exposed workers, 109 diagnosed with diisocyanate-induced asthma and 73 without asthma. Lack of the GSTM1 gene (null genotype) was associated with a 1.89-fold risk of diisocyanate-induced asthma [95% confidence interval (CI) 1.01-3.52]. Moreover, among the asthma patients, the GSTM1 null genotype was associated with lack of diisocyanate-specific immunoglobulin (Ig)E antibodies [odds ratio (OR) 0.18, 95% CI 0.05-0.61] and with late reaction in the specific bronchial provocation test (OR 2.82, 95% CI 1.15-6.88). Similarly, GSTM3 AA genotype was related to late reaction in the specific bronchial provocation test (OR 3.75, 95% CI 1.26-11.2). The GSTP1 Val/Val genotype, on the other hand, was related to high total IgE levels (OR 5.46, 95% CI 1.15-26.0). The most remarkable effect was seen for the combination of GSTM1 null and the GSTM3 AA genotype which was strongly associated with lack of diisocyanate-specific IgE antibodies (OR 0.09, 95% CI 0.01-0.73) and with late reaction in the bronchial provocation test (OR 11.0, 95% CI 2.19-55.3). The results suggest, for the first time, that the polymorphic GSTs, especially the mu class GSTs, play an important role in inception of ill effects related to occupational exposure to diisocyanates.

Relationship between the Val158Met polymorphism of catechol O-methyl transferase and breast cancer.

A case-control study was performed to assess the potential influence of catechol O-methyl transferase (COMT) genotype on the risk of breast cancer in Korean women. One hundred and sixty-three histologically confirmed incident breast cancer cases and 163 age- and menopausal status-matched control individuals with no present or previous history of cancer were selected as study subjects. COMT genetic polymorphism was determined by gel electrophoresis after NlaIII enzyme digestion of amplified DNA. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression after adjustment for known or suspected risk factors of breast cancer. Women with at least one COMT lower enzyme activity associated allele (COMT-L) were at elevated risk for breast cancer (OR = 1.7, 95% CI = 1.04-2.78) compared with those homozygous for high enzyme activity associated COMT-H alleles. Among women with low (> or = 23.1) body mass index the COMT-L allele containing genotypes posed a marginally significant increased risk of breast cancer compared to the COMT-HH genotype (OR = 1.8, 95% CI = 0.95-3.48). Women with at least one COMT-L allele who had experienced a full-term pregnancy when aged over 30 years or were nulliparous had 2.7-fold increased risk; however, this increase did not reach statistical significance (OR = 2.7, 95% CI = 0.64-11.35). Furthermore, never-drinking and never-smoking women with at least one COMT-L allele were at increased risk of breast cancer compared to those with COMT-HH genotype with ORs of 2.0 (95% CI = 1.23-3.38) and 1.7 (95% CI = 1.04-2.62), respectively. These results are consistent with studies showing that COMT genotype of lower enzyme activity might be related to increase in risk of breast cancer, and extend this finding to Korean women.

Polymorphic catechol-O-methyltransferase gene and breast cancer risk.

We examined 483 Finnish breast cancer cases and 482 population controls to determine the potential effect of catechol-O-methyltransferase (COMT) genotype in individual susceptibility to breast cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression after adjustment for known or suspected risk factors for breast cancer. When studied separately by menopausal status, the COMT-L allele-containing genotypes were inversely associated with premenopausal breast cancer, especially with advanced stage of the disease (OR, 0.44; 95% CI, 0.22-0.87). Among postmenopausal women a similar decreased risk was seen for local carcinoma associated with the COMT-LL genotype (OR, 0.55; 95% CI, 0.31-0.98). The lowest breast cancer risk was seen in the postmenopausal women with the COMT-LL genotype and low body-mass index (30 months) use of estrogen (OR, 4.02; 95% CI, 1.13-14.3), or with the COMT-L allele-containing genotypes and early age (

Chromosomal aberrations in peripheral lymphocytes of train engine drivers.

Studies of Swedish railway employees have indicated that railroad engine drivers have an increased cancer morbidity and incidence of chronic lymphatic leukemia. The drivers are exposed to relatively high magnetic fields (MF), ranging from a few to over a hundred microT. Although the possible genotoxic potential of MF is unclear, some earlier studies have indicated that occupational exposure to MF may increase chromosome aberrations in blood lymphocytes. Since an increased level of chromosomal aberrations has been suggested to predict elevated cancer risk, we performed a cytogenetic analysis on cultured (48 h) peripheral lymphocytes of Swedish train engine drivers. A pilot study of 18 engine drivers indicated a significant difference in the frequency of cells with chromosomal aberrations (gaps included or excluded) in comparison with seven concurrent referents (train dispatchers) and a control group of 16 office workers. The engine drivers had about four times higher frequency of cells with chromosome-type aberrations (excluding gaps) than the office workers (P < 0.01) and the dispatchers (P < 0.05). Seventy-eight percent of the engine drivers showed at least one cell per 100 with chromosome-type aberrations compared with 29% among the dispatchers and 31% among the office workers. In a follow-up study, another 30 engine drivers showed an increase (P < 0.05) in the frequency of cells with chromosome-type aberrations (gaps excluded) as compared with 30 referent policemen. Sixty percent of the engine drivers had one or more cells (per 100 cells) with chromosome-type aberrations compared with 30% among the policemen. In conclusion, the results of the two studies support the hypothesis that exposure to MF at mean intensities of 2-15 microT can induce chromosomal damage.

Exposure to 4,4'-methylenediphenyl diisocyanate (MDI) during moulding of rigid polyurethane foam: determination of airborne MDI and urinary 4,4'-methylenedianiline (MDA).

Occupational exposure to 4,4'-methylenediphenyl diisocyanate (MDI) was measured during moulding of rigid polyurethane foam. The aim of the study was to find out whether an MDI-derived urinary amine metabolite could be detected in the urine of workers exposed to apparently low levels of MDI. Airborne MDI was sampled on 1-(2-methoxyphenyl)-piperazine (2MP)-impregnated glass fibre filters and determined by high-performance liquid chromatography (HPLC) using ultraviolet (UV) and electrochemical (EC) detection. The limit of detection of MDI was 3 ng ml-1 for a 20 microliters injection. The precision of sample preparation, expressed as relative standard deviation (RSD), was 1.3% with UV detection and 2.1% with EC detection at a concentration of 70 ng MDI ml-1 (n = 6). The 2MP-MDI derivative was stable at +4 degrees C up to eight weeks. The accuracy of the method was validated in an international quality control programme. Workers (n = 57) from three different factories participated in the study. Urinary 4,4'-methylenedianiline (MDA) metabolite was determined after acid hydrolysis as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry using chemical ionisation and monitoring negative ions. The limit of detection in urine was 0.2 nmol l-1. The precision of six analyses for a urine sample spiked to a concentration of 1 nmol l-1 was 29% (RSD). The MDI concentrations were below the limit of detection in most (64%) of the air samples collected in the worker's breathing zone. Still, detectable amounts of MDA were found in 97% of the urine samples. Monitoring of urinary MDA appears to be an appropriate method of assessing MDI exposure in work environments with low or undetectable MDI concentrations in the workplace air.