Bisphenol A concentration in human saliva related to dental polymer-based fillings.

OBJECTIVES: The aims of this study were to quantify salivary concentrations of bisphenol A (BPA) and to assess if presence of dental composite fillings is associated with higher BPA levels in saliva. MATERIALS AND METHODS: Twenty individuals with six or more tooth surfaces filled with polymer-based dental materials (composite group) and 20 individuals without any polymer-based materials (control group) were included in the study. Saliva was collected in polypropylene tubes and stored at -80 °C before analysis. Concentration of free (unconjugated) and total bisphenol A was determined by liquid chromatography/mass spectrometry (LC/MS). Values below limit of detection (0.1 ng/mL) were set to one-half of the limit of detection. Mann-Whitney U test (one sided; the Exact Tests Option in IBM-SPSS version 21) was used for the statistical analyses. RESULTS: The concentration of BPA in saliva was very low. In the composite group, 8 of 20 samples had detectable concentrations of BPA. In the control group, 3 of 20 samples had detectable concentrations of BPA. Statistical analysis indicated that the concentration of unconjugated BPA was slightly higher in the composite group (p = 0.044) than in the control group. CONCLUSIONS: Presence of dental composites may be associated with slightly higher concentration of unconjugated BPA in saliva. However, additional studies using sensitive analytical methods are needed before firm conclusions can be drawn. Influence from other factors, like food intake and time of the day for saliva sampling, must be considered. CLINICAL RELEVANCE: The relative contribution of existing polymer-based dental fillings to total BPA exposure seems to be low.

Prenatal exposure to environmental chemical contaminants and asthma and eczema in school-age children.

BACKGROUND: Emerging evidence suggests that prenatal or early-life exposures to environmental contaminants may contribute to an increased risk of asthma and allergies in children. We aimed to the explore associations of prenatal exposures to a large set of environmental chemical contaminants with asthma and eczema in school-age children. METHODS: We studied 1024 mother-child pairs from Greenland and Ukraine from the INUENDO birth cohort. Data were collected by means of an interview-based questionnaire when the children were 5-9 years of age. Questions from the ISAAC study were used to define asthma, eczema, and wheeze. We applied principal components analysis (PCA) to sixteen contaminants in maternal serum sampled during pregnancy, including perfluoroalkyl substances (PFASs), metabolites of diethylhexyl (DEHP) and diisononyl (DiNP) phthalates, PCB-153, and p,p'-DDE. Scores of five principal components (PCs) explaining 70% of the variance were included in multiple logistic regression models. RESULTS: In a meta-analysis that included both populations, the PC2 score, reflecting exposure to DiNP, was negatively associated with current eczema (OR 0.71, 95% CI 0.52-0.96). Other associations were not consistent between the two populations. In Ukrainian children, the PC3 score (DEHP) was positively associated with current wheeze (adjusted OR 1.56, 95% CI 1.03-2.37), whereas the PC5 score, dominated by perfluorooctanoic acid (PFOA), was inversely associated with current wheeze (OR 0.64, 0.41-0.99). In Greenlandic children, a negative association of PC4 (organochlorines) with ever eczema (OR 0.78, 0.61-0.99) was found. CONCLUSIONS: We found limited evidence to support a link between prenatal exposure to environmental chemical contaminants and childhood asthma and eczema.

Body mass index in young school-age children in relation to organochlorine compounds in early life: a prospective study.

OBJECTIVE: To investigate the association between maternal pregnancy and estimated postnatal serum concentrations of the organochlorines 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and body mass index (BMI) z-scores in 5- to 9-year-old children. METHODS: Maternal sera from the INUENDO birth cohort (2002-2004) comprising mother-child pairs (N=1109) from Greenland, Warsaw (Poland), and Kharkiv (Ukraine) were analysed for CB-153 and p,p'-DDE, using gas chromatography-mass-spectrometry, and were grouped into tertiles for statistical analyses. A toxicokinetic model was used to estimate the first 12 months cumulative exposure to the compounds. Associations between these compounds and child age- and sex-specific BMI z-scores were calculated at follow-up (2010-2012), using multiple linear regression analysis. RESULTS: No clear associations between pregnancy CB-153 and p,p'-DDE and child BMI were observed (the pooled differences in BMI z-score (95% confidence interval) comparing 3rd tertile to 1st tertile were -0.07 (-0.32 to 0.18) and -0.10 (-0.30 to 0.10) kg m(-2), respectively). For postnatal CB-153 and p,p'-DDE and BMI, the overall differences in BMI z-score comparing 3rd tertile to 1st tertile were 0.12 (-0.15 to 0.39) and -0.03 (-0.20 to 0.27) kg m(-2), respectively. CONCLUSIONS: This follow-up study of Greenlandic, Polish and Ukrainian populations showed no clear association between pregnancy and postnatal exposure to p,p'-DDE and CB-153 and BMI at the age of 5-9 years.

Menstrual cycle characteristics in fertile women from Greenland, Poland and Ukraine exposed to perfluorinated chemicals: a cross-sectional study.

STUDY QUESTION: Does perfluorooctane sulfonate (PFOS) and perfluorooctanate (PFOA) exposure disrupt the menstrual cyclicity? SUMMARY ANSWER: The female reproductive system may be sensitive to PFOA exposure, with longer menstrual cycle length at higher exposure. WHAT IS KNOWN ALREADY: PFOS and PFOA are persistent man-made chemicals. Experimental animal studies suggest they are reproductive toxicants but epidemiological findings are inconsistent. STUDY DESIGN, SIZE, DURATION: A cross-sectional study including 1623 pregnant women from the INUENDO cohort enrolled during antenatal care visits between June 2002 and May 2004 in Greenland, Poland and Ukraine. PARTICIPANTS/MATERIALS, SETTING, METHODS: Information on menstrual cycle characteristics was obtained by questionnaires together with a blood sample from each pregnant woman. Serum concentrations of PFOS and PFOA were measured by liquid chromatography tandem mass spectrometry. Multiple imputations were performed to account for missing data. The association between PFOS/PFOA and menstrual cycle length (short cycle: ≤24 days, long cycle: ≥32 days) and irregularities (≥7 days in difference between cycles) was analyzed using logistic regression with tertiles of exposure. Estimates are given as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). MAIN RESULTS AND THE ROLE OF CHANCE: Higher exposure levels of PFOA were associated with longer menstrual cycles in pooled estimates of all three countries. Compared with women in the lowest exposure tertile, the adjusted OR of long cycles was 1.8 (95% CI: 1.0; 3.3) among women in the highest tertile of PFOA exposure. No significant associations were observed between PFOS exposure and menstrual cycle characteristics. However, we observed a tendency toward more irregular cycles with higher exposure to PFOS [OR 1.7 (95% CI: 0.8; 3.5)]. The overall response rate was 45.3% with considerable variation between countries (91.3% in Greenland, 69.1% in Poland and 26.3% in Ukraine). LIMITATIONS, REASONS FOR CAUTION: Possible limitations in our study include varying participation rates across countries; a selected study group overrepresenting the most fertile part of the population; retrospective information on menstrual cycle characteristics; the determination of cut-points for all three outcome variables; and lacking information on some determinants of menstrual cycle characteristics, such as stress, physical activity, chronic diseases and gynecological disorders, thus confounding cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: The generalizability of the study results is restricted to fertile women who manage to conceive and women who do not use oral contraceptives when getting pregnant or within 2 months before getting pregnant. To our knowledge only one previous epidemiological study has addressed the possible association between perfluorinated chemical exposure and menstrual disturbances. Though pointing toward different disturbances in cyclicity, both studies suggest that exposure to PFOA may affect the female reproductive function. This study contributes to the limited knowledge on effects of exposure to PFOA and PFOS on female reproductive function and suggests that the female reproductive system may be affected by environmental exposure to PFOA. STUDY FUNDING/COMPETING INTEREST(S): Supported by a scholarship from Aarhus University Research Foundation. The collection of questionnaire data and blood samples was part of the INUENDO project supported by The European Commission (Contract no. QLK4-CT-2001-00 202), www.inuendo.dk. The Ukrainian part of the study was possible by a grant from INTAS (project 012 2205). Determination of PFOA and PFOS in serum was part of the CLEAR study (www.inuendo.dk/clear) supported by the European Commission's 7th Framework Program (FP7-ENV-2008-1-226217). No conflict of interest declared.

Indices of methylation in sperm DNA from fertile men differ between distinct geographical regions.

STUDY QUESTION: Which are the main determinants, if any, of sperm DNA methylation levels? SUMMARY ANSWER: Geographical region resulted associated with the sperm methylation status assessed on genome-wide repetitive sequences. WHAT IS KNOWN ALREADY: DNA methylation level, assessed on repetitive sequences from peripheral blood lymphocyte, can vary with age, gender, alcohol consumption and white blood cell counts. STUDY DESIGN, SIZE, DURATION: A cross-sectional study. Individual data were collected from 269 young healthy men of proven fertility living in three geographical regions: Inuits from Greenland, Caucasians from Warsaw (Poland) and Kharkiv (Ukraine). Semen samples were collected between May 2002 and February 2004 and aliquots were immediately frozen. PARTICIPANTS/MATERIALS, SETTING, METHODS: We estimated sperm DNA global methylation level (DGML) in two ways. First DNA methylation in repetitive DNA sequences (LINE-1, Satα and Alu) was quantified by PCR pyrosequencing after bisulfite conversion and second by flow cytometry (FCM) using fluorescently labeled monoclonal antibodies anti-5-methylcytosine. We analyzed whether personal characteristics and habits, body mass index, semen quality parameters, sperm chromatin integrity, biomarkers of accessory gland function and the plasma concentration of reproductive hormones were associated with sperm DNA methylation levels in men. Associations were evaluated by analysis of variance and linear regression analyses. MAIN RESULTS AND THE ROLE OF CHANCE: The geographical location emerged as the main determinant when using the methylation level in repetitive sequences. FCM DGML results were not associated with those from repetitive sequence analysis. No other consistent associations between methylation markers and the assessed variables were identified across countries. LIMITATIONS, REASONS FOR CAUTION: The methods used are only surrogates of the actual sperm methylome and the methylation levels at individual specific loci were not explored. WIDER IMPLICATIONS OF THE FINDINGS: Sperm DGML is relatively independent from semen quality parameters and is a new candidate biomarker for epidemiological studies of the impact of environmental contaminants on male fertility. STUDY FUNDING/COMPETING INTERESTS: The study is part of the project CLEAR (Climate change, Environmental contaminants and Reproductive health) supported by the European Commission 7th framework program, contract no: FP7-ENV-2008-1-226217. No competing interest is declared.

Work-related airway symptoms, nasal reactivity and health-related quality of life in female hairdressers: a follow-up study during exposure.

OBJECTIVES: Hairdressers often complain of work-related rhinitis (WR). They are infrequently sensitized to persulphates. The cause and mechanism of the symptoms and the effects on their health-related quality of life (HRQoL) remains unclear. The objectives were to follow female hairdressers with WR mainly from bleaching powder regarding nasal reactivity to persulphate and to evaluate symptoms, HRQoL and inflammatory markers in nasal lavage during a working period after vacation and compared with hairdressers without symptoms and pollen allergic women. METHODS: Skin prick tests to persulphate were performed in the hairdressers. Participants kept a diary of symptoms and of work tasks (hairdressers only). They completed HRQoL questionnaires. Eosinophil cationic protein (ECP) in nasal lavage fluid was examined. The symptomatic hairdressers performed nasal challenges with persulphate before and after the exposure. RESULTS: Skin prick tests were negative. Although the nasal reactivity to persulphate did not change a steady increase in nasal symptoms, especially blockage, and in ECP was noticed in the symptomatic hairdressers. The HRQoL deteriorated in the symptomatic hairdressers indicating an effect on their working situation and daily life. The atopics had more, but varying symptoms (itching, sneezing and secretion). CONCLUSIONS: The difference in the clinical picture between the symptomatic hairdressers and the pollen allergic women, the increase in symptoms and ECP in the nasal lavage support the view that a sensitization to hairdresser chemicals by a mechanism not yet understood is operating. The deterioration of the HRQoL in the symptomatic hairdressers indicates a considerable effect on their life.

PVC flooring is related to human uptake of phthalates in infants.

UNLABELLED: Polyvinyl chloride (PVC) flooring material contains phthalates, and it has been shown that such materials are important sources for phthalates in indoor dust. Phthalates are suspected endocrine-disrupting chemicals (EDCs). Consecutive infants between 2 and 6 months old and their mothers were invited. A questionnaire about indoor environmental factors and family lifestyle was used. Urinary metabolites of the phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP), butylbenzyl phthalate (BBzP), and dietylhexyl phthalate (DEHP) were measured in the urine of the children. Of 209 invited children, 110 (52%) participated. Urine samples were obtained from 83 of these. Urine levels of the BBzP metabolite monobenzyl phthalate (MBzP) was significantly higher in infants with PVC flooring in their bedrooms (P < 0.007) and related to the body area of the infant. Levels of the DEHP metabolites MEHHP (P < 0.01) and MEOHP (P < 0.04) were higher in the 2-month-old infants who were not exclusively breast-fed when compared with breast-fed children. The findings indicate that the use of soft PVC as flooring material may increase the human uptake of phthalates in infants. Urinary levels of phthalate metabolites during early life are associated with the use of PVC flooring in the bedroom, body area, and the use of infant formula. PRACTICAL IMPLICATIONS: This study shows that the uptake of phthalates is not only related to oral uptake from, for example, food but also to environmental factors such as building materials. This new information should be considered when designing indoor environment, especially for children.

Exposure to perfluorinated compounds and human semen quality in Arctic and European populations.

BACKGROUND: Perfluorinated compounds (PFCs) have been suspected to adversely affect human reproductive health. The aim of this study was to investigate the associations between PFC exposure and male semen quality. METHODS: PFCs were measured in serum from 588 partners of pregnant women from Greenland, Poland and Ukraine who provided a semen sample, using liquid chromatography tandem mass spectrometry. Perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) could be detected in >97% of the samples. The associations between levels of these compounds and semen volume, sperm concentration, total sperm count, motility and morphology were assessed. RESULTS: Across countries, sperm concentration, total sperm count and semen volume were not consistently associated with PFOS, PFOA, PFHxS or PFNA levels. The proportion of morphologically normal cells was 35% lower [95% confidence interval (CI): 4-66%) for the third tertile of PFOS exposure as compared with the first. A similar reduction was found in relation to increasing PFHxS levels. At the third PFOA exposure tertile, the percentage of motile spermatozoa was 19% (95% CI: 1 to 39%) higher than in the first. CONCLUSIONS: The most robust finding in the present study was the negative associations between PFOS exposure and sperm morphology suggesting adverse effects of PFOS on semen quality, possibly due to interference with the endocrine activity or sperm membrane function. It cannot be excluded that this association and the positive association between PFOA and semen motility, which was not consistent across countries, might represent a chance finding due to the multiple statistical tests being performed.

Aniline in hydrolyzed urine and plasma--possible biomarkers for phenylisocyanate exposure.

There are few studies on phenylisocyanate (PhI) exposure, although there are studies indicating that PhI is a very potent chemical sensitizer. The aim of this study was to evaluate aniline in urine and plasma as possible biomarkers of exposure to PhI. Occupational airborne exposure to PhI was measured during one day for 11 workers exposed to thermal degradation products from polyurethane with filters impregnated with 2-methoxyphenyl piperazine. A urine sample was collected from each worker on measurement day, and plasma samples were collected within the following 2 weeks. Urine and plasma samples also were collected from four unexposed subjects. The biological samples were hydrolyzed and analyzed with gas chromatography mass spectrometry. The time-weighted averages (TWA) for the workers were between 0.1 and 1.6 microg/m3. Aniline levels in urine were in the same range for the exposed and unexposed workers, but there was a significant correlation between air and urinary levels (Pearson's correlation coefficient r = 0.518; p = 0.05). All exposed workers had higher levels in the plasma samples than the highest control, and there was a significant correlation between the plasma levels and measured air levels (r = 0.675; p = 0.008). The conclusion is that aniline in hydrolyzed urine and plasma are possible biomarkers of exposure to PhI, and that the plasma biomarker is more sensitive, at least at this rather low exposure.

Environmental cadmium and lead exposure and anti-Müllerian hormone in pregnant women.

BACKGROUND: Anti-Müllerian Hormone (AMH) has been suggested as a marker for ovarian function. Cadmium and lead have been suggested to reduce female fecundity. In this study we aimed to investigate whether environmental exposure to cadmium and lead was associated with alterations in serum-AMH. MATERIALS AND METHOD: The associations between serum-AMH and whole blood cadmium or lead were investigated by general linear models in a population-based sample of 117 pregnant women. RESULTS: The mean concentrations of blood cadmium and lead were 0.71µg/L and 17.4µg/L, respectively. The mean serum-AMH was 17.3pmol/L. No association between lead and AMH was detected. In the cadmium analysis the adjusted mean AMH level (95% CI) in the highest exposure tertile was 12.4 (6.4;23.8) compared to 5.6 (2.7;11.4) in the lowest exposure tertile (p=0.06). CONCLUSION: The study provides suggestive evidence that environmental exposure to cadmium, but not lead, may alter the level of AMH.

Exposure to PCBs and p,p'-DDE and human sperm chromatin integrity.

Persistent organochlorine pollutants (POPs) such as polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (p,p'-DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), are stable lipophilic compounds widely found in the environment and in the general population. They can enter the food chain, and their negative impact on male reproduction is currently under active scrutiny. To explore the hypothesis that environmental exposure to these compounds is associated with altered sperm chromatin structure integrity in human sperm, we conducted a study of 176 Swedish fishermen (with low and high consumption of fatty fish, a very important exposure source of POPs). We determined serum levels of 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and p,p'-DDE, and we used the sperm chromatin structure assay (SCSA) to assess sperm DNA/chromatin integrity. When CB-153 serum levels (individual dose range, 39-1,460 ng/g lipid) were categorized into equally sized quintiles, we found an association with the DNA fragmentation index (%DFI). A significantly lower %DFI was found in the lowest CB-153 quintile (< 113 ng/g lipid) compared with the other quintiles; there was a similar tendency, although not statistically significant, between %DFI and p,p'-DDE. These results suggest that POP exposure may have a slight negative impact on human sperm chromatin integrity.

Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality.

Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (AHRR P185A) and serum levels of markers of POP exposure 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (p,p'-DDE) and 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) are associated with 21 parameters of male reproductive function in 581 proven-fertile European and Greenlandic men. In Greenlandic men, AHR variants significantly modified the association between serum levels of both p,p'-DDE and CB-153 and inhibin B levels, sperm chromatin integrity, and seminal zinc levels. In the total cohort, interactions between AHRR variants and serum levels of CB-153 were associated with sperm chromatin integrity and the expression of the pro-apoptotic marker protein Fas. The data indicate that susceptibility to adverse effects of POP exposure on male reproductive function is dependent on polymorphisms in genes involved in AHR signalling.

Environmental and biological monitoring of antineoplastic drugs in four workplaces in a Swedish hospital.

OBJECTIVES: Exposure to antineoplastic drugs should be avoided due to the risk of getting adverse health effects. Antineoplastic drugs such as cyclophosphamide (CP) and ifosfamide (IF) are commonly used in medical attendance. In this study the variability of surface contamination of CP and IF was investigated by repeated wipe sampling over time in four workplaces in a university hospital. The surface contamination levels were also evaluated and health care workers were biologically monitored. METHODS: A hospital pharmacy, two oncology wards and one oncology outpatient department were selected. Between 10 and 13 different surface areas such as work areas, floors and handles were selected in each workplace and wiped between 7 and 8 times during 9 months. Pre- and post-shift urine samples were collected from the workers in the investigated workplaces. Analysis was performed by liquid chromatography combined with tandem mass spectrometry. RESULTS: Measurable amounts of CP and IF were detected on the majority of the sampled surfaces. The highest concentrations were found on the floors in the patient lavatories and utility rooms (up to 95 ng cm(-2)). In general, the surface contamination of CP and IF on floors did not vary much over time. Work areas and handles had larger variability. Neither CP nor IF were detected in any of the collected urine samples. CONCLUSIONS: The variability in surface contamination of CP and IF was rather low especially on floors. Higher concentrations of CP and IF were found on the floors compared with the work areas. The highest surface loads were found on floors (in patient lavatories and utility rooms) that were related to patient activities such as handling of patients' urine. Although high contaminations were found, the biological monitoring showed no uptake. Wipe sampling is a good method to improve the work practices.

Physiological restitution after night-call duty in anaesthesiologists: impact on metabolic factors.

BACKGROUND: Several studies have shown impaired mental well-being and performance in physicians work on call, but knowledge of the physiological effects is scarce. The aims of the present study were to investigate if there was a metabolic stress response in the restitutional phase after night-call duty, indicating potential negative health effects, and determine whether there were differences between physician specialities. METHODS: Anaesthesiologists (n = 19) were compared with paediatricians/ear, nose and throat (ENT) surgeons (n = 18). On an ordinary workday, 1 and 3 days after work on night call, blood samples were taken for analysis of glucose, thyroid-stimulating hormone (TSH), free thyroxine, testosterone, insulin growth factor-1 (IGF-1), high- and low-density lipoprotein cholesterol (HDL and LDL), triglycerids (TG) and insulin. Saliva cortisol was sampled on an ordinary working day, a day including 16-h night call, the third day following, and for anaesthesiologists also on a day off work. RESULTS: TSH differed significantly between days in both groups, with a 26% lower level 1 day after on-call duty (P < 0.001). A 48% cortisol rise in the morning preceding night duty was found for paediatricians/ENT surgeons (P < 0.01). CONCLUSION: The significant dip in TSH level 24 h after night-call duty indicates a metabolic effect of working on night call and should be studied further. However, the levels were within the normal range and the overall results do not imply any serious metabolic changes and only minor differences were seen between specialist groups.

Modifying effect of the AR gene trinucleotide repeats and SNPs in the AHR and AHRR genes on the association between persistent organohalogen pollutant exposure and human sperm Y:X ratio.

Persistent organohalogen pollutants (POPs) have been suggested to be involved in changing the proportion of ejaculated Y-bearing sperm. The androgen receptor (AR), aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor repressor (AHRR) may modulate the effect of POPs with regard to previously observed sperm Y:X ratio changes. The objective of this study was to investigate whether sperm Y:X ratio changes in subjects exposed to 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and dichlorodiphenyl dichloroethene (p,p'-DDE) were modified by polymorphisms in the AR, AHR and AHRR genes. Semen for analysis of Y- and X-bearing sperm by two-colour fluorescence in situ hybridization and blood for leukocyte DNA genotyping and analysis of CB-153 and p,p'-DDE concentrations were obtained from 195 Swedish fishermen. The polymorphic CAG and GGN repeats in the AR and the R554K and P185A single-nucleotide polymorphisms in the AHR and AHRR genes, respectively, were determined by direct sequencing and allele-specific PCR. The effect of p,p'-DDE was modified by CAG or GGN repeat category in relation to the proportion of Y-bearing sperm (P = 0.005 and 0.02 for CAG and GGN, respectively). Moreover, p,p'-DDE, but not CB-153, levels were associated with Y-sperm proportion in men with CAG < 22 (P < 0.001), but not in those carrying CAG > or = 22 (P = 0.73). This association was even more pronounced in subjects carrying a short CAG repeat in combination with an AHRR G-allele. The association in regard to p,p'-DDE was found for GGN = 23 but not for the GGN < 23 or GGN > 23 subgroups (P = 0.01, 0.44 and 0.99, respectively). In conclusion The endocrine-disrupting action of POPs, in relation to the observed changes in sperm Y:X ratio, may be modulated by the genes involved in sex steroid and dioxin-mediated pathways.

Biological monitoring of exposure to 1,5-naphthalene diisocyanate and 4,4'-methylenediphenyl diisocyanate.

OBJECTIVES: Biological monitoring of occupational sensitizers, such as 1,5-naphthalene diisocyanate (NDI) and 4,4'-methylenediphenyl diisocyanate (MDI) is of high importance. In this study, 1,5-naphthalenediamine (NDA) and 4,4'-methylenedianiline (MDA) in hydrolysed urine and plasma were evaluated as biomarkers of exposure to NDI and MDI, respectively. METHODS: The air exposure to NDI and MDI was monitored for 30 exposed workers at four different plants. In parallel, urinary as well as blood plasma samples were collected. Biomarker levels were determined in hydrolysed urine and plasma by means of gas chromatography-mass spectrometry. RESULTS: Air exposure to both MDI and NDI was correlated to their corresponding urinary and plasma biomarkers. The correlation coefficients for the associations between air and biomarker levels were in the range of 0.51-0.65 and 0.53-0.96 for MDI and NDI, respectively. For NDI, but not for MDI, the significance and correlation coefficients were increased by adjusting the urinary biomarker levels for creatinine content or density. CONCLUSIONS: Biomarker and air levels of MDI and NDI were correlated, but there was a large individual variation.

Time to pregnancy as a function of male and female serum concentrations of 2,2'4,4'5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE).

BACKGROUND: Persistent organochlorine pollutants (POP) may affect both the female and male reproductive system in animals as well as in humans. METHODS: Blood samples were collected from pregnant women and their partners from Greenland, Warsaw and Kharkiv, and from a cohort of Swedish fishermen's wives. Blood samples were analysed for 2,2',4,4',5,5'-hexachlorobiphenyl (CB-153) and 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE). Information on the participants' fertility, measured as time to pregnancy (TTP), was collected. In total, 778 men and 1505 women were included in the analyses. RESULTS: The data from Warsaw, Kharkiv and the Swedish fishermen's wives indicated no effect of either male or female exposure to POP on TTP. However, among men and women from Greenland, there seemed to be an association between serum concentrations of CB-153 and p,p'-DDE and prolonged TTP. Due to the strong intra-individual correlation between CB-153 and p,p'-DDE in the Greenlandic population, it was not possible to determine whether the risk was associated with CB-153 or p, p'-DDE or was an interaction between the two compounds. CONCLUSIONS: The overall results of the present study create a somewhat ambiguous pattern, but give some support to the idea that dietary POP exposure might be harmful for couple fertility.

Relationships between sperm DNA fragmentation, sperm apoptotic markers and serum levels of CB-153 and p,p'-DDE in European and Inuit populations.

Persistent organochlorine pollutants (POPs) are suspected to interfere with hormone activity and the normal homeostasis of spermatogenesis. We investigated the relationships between sperm DNA fragmentation, apoptotic markers identified on ejaculated spermatozoa and POP levels in the blood of 652 adult males (200 Inuits from Greenland, 166 Swedish, 134 Polish and 152 Ukrainian). Serum levels of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (CB-153), as a proxy of the total POP burden, and of 1,1-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE), as a proxy of the total DDT exposure were determined. Sperm DNA fragmentation was measured by using the TUNEL assay, whereas immunofluorescence methods were utilized for detecting pro-apoptotic (Fas) and anti-apoptotic (Bcl-xL) markers. Both TUNEL assay and apoptotic markers were statistically differed across the four populations. No correlation between neither sperm DNA fragmentation nor apoptotic sperm parameters and the large variations in POPs exposure was observed for the separate study groups. However, considering the European populations taken together, we showed that both %TUNEL positivity and Bcl-xL were related to CB-153 serum levels, whereas our study failed to demonstrate any relations between DDE and %TUNEL positivity and apoptotic sperm biomarkers (Fas and Bcl-xL) in any region or overall regions. These results suggest that CB-153 and related chemicals might alter sperm DNA integrity and Bcl-xL levels in European adult males, but not in the highly exposed Inuit men. Additional issues (genetic background, lifestyle habits and characterization of total xeno-hormonal activities) need to be investigated in order to fully assess the population variations observed.

Adducts between nucleophilic amino acids and hexahydrophthalic anhydride, a structure inducing both types I and IV allergy.

Haptens causing type I allergy have been shown to predominantly form lysine adducts in the carrier protein, while many haptens giving rise to type IV allergy preferentially form adducts with cysteine residues. Hexahydrophthalic anhydride derivatives are strong sensitizers capable of inducing allergic rhinitis, asthma and urticaria (type I allergy) and allergic contact dermatitis (type IV allergy). The ability of hexahydrophthalic anhydride (HHPA) to form adducts with nucleophilic amino acids and a model peptide in vitro is presented. Adduct formation was monitored by high-performance liquid chromatography with ultraviolet light/vis detection (LC-UV/vis) and high-performance liquid chromatography with mass spectrometric detection (LC/MS). The characterization was obtained by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS and MS/MS). It was found that HHPA formed adducts with N(alpha)-acetylated lysine and cysteine and the non-acetylated alpha-amino group of proline and, to some extent, also with other nucleophilic amino acids. The adducts with lysine and proline were chemically stable. Addition of one HHPA to a model carrier peptide with all important nucleophilic amino acid residues showed N-terminal proline to be the major site of reaction. The addition of a second hapten gave a lysine adduct, but a minor cysteine adduct was also found. The cysteine-HHPA adducts were shown to be chemically unstable and participated in further reactions with lysine forming lysine-HHPA adducts. The results will be useful for understanding the formation of HHPA-protein adducts with the capability of being markers of exposure, and also to a deeper understanding of the chemical structures causing types I and IV allergy.

Surface contamination of cyclophosphamide packaging and surface contamination with antineoplastic drugs in a hospital pharmacy in Sweden.

Workplaces, e.g. hospital pharmacies and hospital departments, where antineoplastic drugs are handled might be contaminated with these drugs, and pharmacy personnel and health care workers may be exposed. In this study potential sources for exposure of antineoplastic drugs were investigated. Unbroken drug vials and tablet blister packages, both containing cyclophosphamide (CP) and their outer packaging were wipe sampled. Analysis was performed by liquid chromatography combined with tandem mass spectrometry (LC-MS/MS). The result showed that almost every part of the primary packaging was contaminated with CP and ifosfamide (IF). However, the amounts of CP and IF were low, and most likely not harmful for the personnel handling these packaging in association with drug preparation. The contamination must originate from the pharmaceutical manufacturer. Different surfaces in the preparation unit of a Swedish hospital pharmacy were also investigated at two different occasions by wipe sampling. In the preparation unit CP and IF were found as contaminants on the majority of the investigated surfaces. After the first measurement the hospital pharmacy improved its routines. Lower amounts of CP and IF were detected at the second measurement. A low degree of contamination with CP and IF was also detected on the floor outside the preparation unit and this indicated a small distribution of antineoplastic drugs to the surroundings.