Ten years after: findings from the medical surveillance program on Health Effects in High-Level Exposure to PCB (HELPcB).

After the detection of high environmental and occupational exposure to polychlorinated biphenyls (PCBs) in a German recycling company for transformers and capacitors in 2010, the multidisciplinary medical surveillance program "HELPcB" (Health Effects in High-Level Exposure to PCB) was established for former PCB-exposed workers of the company, their family members, employees of surrounding companies, and area residents to investigate potential adverse health effects by PCB exposure in a longitudinal study approach with up to seven examination time points between 2010 and 2019. More than 300 individuals were enrolled into the program. Assessments particularly included plasma and urine concentrations of PCB congeners and their metabolites, clinical laboratory parameters, Comet assay, analysis of telomere length, neuropsychological examinations, psychological screening, abdominal and thyroid ultrasound examination. This review summarizes the main results of the studies conducted in the HELPcB program yielding relevant new data on potential adverse effects of PCB exposure in humans and potential mechanisms that underlie these effects. Even larger studies in PCB-exposed individuals are warranted to confirm the results of this program and to further establish causality between PCB exposure and clinical effects in humans.

Decomposition Products of the Initiator Bis(2,4-dichlorobenzoyl)peroxide in the Silicone Industry: Human Biomonitoring in Plasma and Urine of Workers.

Bis(2,4-dichlorobenzoyl)peroxide (2,4-DCBP) is used as an initiator for silicone rubber production. During hot curing, 2,4-DCBP decomposes into 2,4-dichlorobenzoic acid, 1,3-dichlorobenzene, and the polychlorinated biphenyl (PCB) congeners PCB-47, PCB-51, and PCB-68. The extent of occupational exposure to these decomposition products has not been investigated yet. We determined for the first time the corresponding internal exposure of employees (n = 104) of a German silicone rubber facility by human biomonitoring in plasma and urine. Collected samples were investigated by gas chromatography/mass spectrometry for levels of PCBs in plasma and by liquid chromatography/tandem mass spectrometry for urinary post-shift levels of 2,4-dichlorobenzoic acid (2,4-DCBA) and the metabolites 3,5-dichlorocatechol (3,5-DCK), 2,4-dichlorophenol (2,4-DCP), and 3,5-dichlorophenol (3,5-DCP). PCB-47 and PCB-68 levels correlated significantly and were found in >97% of all samples with maximum values of 4.43 and 0.77 µg/L, respectively. 2,4-DCBA, 3,5-DCK, 2,4-DCP, and 3,5-DCP were quantified in >80% of all urine samples with maximum levels of 1.46; 26.92; 7.68; and 0.39 mg/L, respectively. There is a considerable uptake of decomposition products of 2,4-DCBP in workers of a silicone rubber facility, affecting employees in all work areas. Individual levels depended on the work task. Considering the carcinogenic potential of PCBs, the workers' additional exposure to PCB-47 and PCB-68 might be of concern.

Maternal Perfluoroalkyl Substances, Thyroid Hormones, and DIO Genes: A Spanish Cross-sectional Study.

Results of studies on perfluoroalkyl substances (PFASs) and thyroid hormones (THs) are heterogeneous, and the mechanisms underlying the action of PFASs to target THs have not been fully characterized. We examined the relation between first-trimester maternal PFAS and TH levels and the role played by polymorphisms in the iodothyronine deiodinase 1 (DIO1) and 2 (DIO2) genes in this association. Our sample comprised 919 pregnant Spanish women (recruitment = 2003-2008) with measurements of perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), thyroid-stimulating hormone (TSH), total triiodothyronine (TT3), and free thyroxine (FT4), and we genotyped for single-nucleotide polymorphisms in the DIO1 (rs2235544) and DIO2 (rs12885300) genes. We performed multivariate regression analyses between PFASs and THs and included the interaction term PFAS-genotypes in the models. PFHxS was associated with an increase in TSH (% change in outcome [95% CI] per 2-fold PFAS increase = 6.09 [-0.71, 13.4]), and PFOA and PFNA were associated with a decrease in TT3 (-7.17 [-13.5, -0.39] and -6.28 [-12.3, 0.12], respectively). We found stronger associations between PFOA, PFNA, and TT3 for DIO1-CC and DIO2-CT genotypes, although interaction p-values were not significant. In conclusion, this study found evidence of an inverse association between PFOA and TT3 levels. No clear effect modification by DIO enzyme genes was observed.

New data on the metabolism of chloromethylisothiazolinone and methylisothiazolinone in human volunteers after oral dosage: excretion kinetics of a urinary mercapturic acid metabolite ("M-12").

Methylisothiazolinone (MI) as well as the mixture of chloromethylisothiazolinone/methylisothiazolinone [MCI/MI (3:1)] are biocides that are used in a variety of products of every-day life. Due to the skin sensitizing properties of these biocides, their use has come under scrutiny. We have previously examined the human metabolism of MI and MCI after oral dosage of isotope-labelled analogues in human volunteers and confirmed N-methylmalonamic acid to be a major, but presumably unspecific human urinary metabolite. In the present study, we have investigated the urinary kinetics of a mercapturic acid metabolite of MI and MCI using the same set of samples. Four human volunteers received 2 mg of isotopically labelled MI and MCI separately and at least 2 weeks apart. Consecutive urine samples were collected over 48 h and were examined for the content of the (labelled) 3-mercapturic acid conjugate of 3-thiomethyl-N-methyl-propionamide ("M-12"), a known metabolite in rats. On a molar basis, M-12 represented 7.1% (3.0-10.1%) of the dose excreted in urine after dosage of MI. Excretion of this mercapturate was fast with a mean half-life of 3.6 h. Surprisingly, for MCI the mercapturate M-12 represented only 0.13% of the dose excreted in urine. Thus, this biomarker is highly specific for exposures to MI and might be used to distinguish between different exposure patterns of these biocides [use of MI or MCI/MI (3:1)] in the general population.

Longitudinal changes in telomere length in PCB-exposed individuals: interaction with CMV infection.

We recently demonstrated a significant shortening of age-adapted telomere length (TL) in lymphocytes of polychlorinated biphenyls (PCB)-exposed individuals. Here, we analyzed TL in individuals of the same PCB-exposed cohort during a 6-year follow-up period, investigating the change in TL between the first and second measurement as a function of time, concentration of PCBs and cytomegalovirus (CMV) infection. The age-adjusted TL of lymphocytes within the cohort of PCB-exposed individuals recovered from a first assessment in 2011 to a second assessment in 2017. Remarkably, if the concentration of lower chlorinated PCBs (LC PCBs) in 2011 was high (≥ 0.055 µg/L), the TL of CMV seropositive individuals remained significantly shortened both compared to age-adjusted controls as well as intra individually. This was confirmed by analysis of covariance as well as by multivariate linear mixed effects models. Since telomeres are responsive to various stress response pathways, including viral infection, we conclude that PCBs could contribute to immune senescence-like phenotypes associated with CMV infections and exacerbate negative aspects associated with the aging of the immune system.

Which factors influence the frequency of participation in longitudinal cohort studies? - An analysis of demographics, social factors, and medical preconditions in participants of the health effects in high level exposure to polychlorinated biphenyls (HELPcB) cohort.

The continuous drop out of participants in longitudinal studies is a trend that may be observed in nearly all fields of medical research. A reduced participation rate might compromise the power of statistical analysis as well as lead to an attrition bias of the study. The aim of this analysis was to identify influencing factors on participation frequency in the monitoring program Health Effects in High Level Exposure to polychlorinated biphenyls (HELPcB) study, a cohort investigation of occupationally polychlorinated biphenyls (PCB) exposed individuals. The HELPcB study was initiated in 2010 and consisted of 7 study visits. At the last cross-section in 2019, less than one third of the included patients still actively participated. As possible influencing factors on study participation frequency, demographic, social, and medical characteristics of the participants were examined. In addition, a logistic regression model to predict study participation behavior was calculated. An overall higher frequency of participation was observed, if participants joined the program together with relatives or friends and had a higher age. For PCB plasma levels, an exceedance of the biological reference value (BAR) and further factors, such as (1) professional qualification, (2) later inclusion, (3) type of participant and (4) occupational-related disease notification, significant differences in the participation frequency were observed in the univariate analysis. Only age and joined study participation remained significant in the multivariate logistic regression. In conclusion, it was possible to identify several social and occupational-related factors that influence the frequency of participation of study attendees.

PCB plasma level in different occupational groups in Iran.

Despite the ban of polychlorinated biphenyls (PCBs) some decades ago, concerns regarding their adverse health effects are continuing, because the workers employed for installation and repair of electrical equipment may be still exposed to PCBs. This study aimed to assess serum PCBs levels in workers in different industries. To do this, we determined the serum concentrations of 9 non-dioxin-like PCBs and 12 dioxin-like PCBs in 147 workers from seven occupational groups and 35 housewives. An electrical distribution company, paint manufacturer, and pesticide manufacturer were categorized as high probability exposure jobs, whereas turning and casting operations, polymer plastic manufacturing, professional driving, and office work were categorized as low probability exposure jobs. In addition, the average of PCB 138, 153, and 180 and PCB sums were observed to be significantly higher in paint manufacture workers compared to the another groups. In addition, the average PCB 118 level was higher in electrical distribution workers and housewives. Following the adjustment for age, blood lipid, residency place, and seafood in the regression model, the association of PCB 118 in electrical distribution workers and PCB 153 in paint manufacture workers remained significant. The results of this study served as further support for the hypothesis for an occupational basis for bioaccumulation of some PCB types. However, the plasma levels of almost all PCB congeners in Iran were found to be lower than many other countries.

Assessment of a potential PCB exposure among (former) underground miners by hydraulic fluids.

Polychlorinated biphenyls (PCBs) were used in technical mixtures of different PCB congeners as hydraulic fluids in underground mining in Germany in North Rhine-Westphalia, Ibbenbueren, and Saarland from the mid-1960s to 1986. Mine workers who were involved in maintenance and repair or operation of hydraulically driven machines in underground mines were potentially exposed to liquids containing PCBs. The aim of the present study was to investigate whether this potential exposure which occurred more than 30 years ago was still detectable. Biomonitoring and a structured work anamnesis were conducted on a representative sample of 210 miners. PCBs in plasma were measured by gas chromatography coupled to mass spectrometry with an LOQ of 0.01 µg/L plasma for all congeners. The primary aim was comparison of the number of exceedances of the underlying comparative values for PCB congeners with those of the general population. Secondary endpoint was the question whether there were regional differences in potential PCB exposure. The biomonitoring showed a significant difference for PCB 74 with N= 94 (45%); for PCB 114 with N = 64 (31%) and for PCB 99 and PCB 105 with N = 23 (11%) and N = 19 (9%) of 210 measurements above the reference value compared to the general population (5%). The all over detection frequencies (µg/L plasma median | SD | min |max) of these congeners were as follows:PCB 74: 0.128 | 0.481 | < LOD | 3.098; PCB 99:0.035 | 0.078 | < LOD | 0.582PCB 105: 0.005 | 0.031 | < LOD | 0.307; PCB 114:0.005 | 0.024 | < LOD | 0.140Regional differences were not detectable.

Prediction of maternal and foetal exposures to perfluoroalkyl compounds in a Spanish birth cohort using toxicokinetic modelling.

Prenatal exposures to perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) have been associated with child health outcomes, but many of these associations remain poorly characterized. The aim of this work was to provide new indicators of foetal exposure for the Spanish INMA birth cohort. First, a pregnancy and lactation physiologically based pharmacokinetic (PBPK) model was calibrated in a population framework to provide quantitative estimates for the PFOA and PFOS placental transfers in humans. The estimated distributions indicated that PFOA crosses the placental barrier at a rate three times higher than PFOS and shows a higher variability between mothers. The PBPK model was then used to back-calculate the time-varying daily intakes of the INMA mothers corrected for their individual history from a spot maternal concentration. We showed the importance of accounting for the mothers' history as different dietary intakes can result in similar measured concentrations at one time point. Finally, the foetal exposure was simulated in target organs over pregnancy using the PBPK model and the estimated maternal intakes. We showed that the pattern of PFOA and PFOS exposures varies greatly among the foetuses. About a third has levels of either one compound always higher than the levels of the other compound. The other two thirds showed different ranking of PFOA and PFOS in terms of concentrations in the target organs. Our simulated foetal exposures bring additional information to the measured maternal spot concentrations and can help to better characterize the prenatal exposure in target organs during windows of susceptibility.

Exposure to Environmental Pollutants and Their Association with Biomarkers of Aging: A Multipollutant Approach.

Mitochondrial DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated ( p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.

Functional and structural liver abnormalities in former PCB exposed workers - analyses from the HELPcB cohort.

The effects of polychlorinated biphenyls (PCB) on liver function and structure are still under debate. Although higher transaminase activity and tumor promoting potential of PCB reported for animal and human studies was suggested, these studies were not able to provide definitive evidence on the ability of these chemicals to affect liver function and contribution to tumor development. The aim of this study was to determine the influence of PCB on liver function and morphology in a cohort of former PCB exposed workers. Over 5 years, a longitudinal analysis of the association between PCB concentration and hepatic transaminases such as alanine transaminase (ALT) aspartate amino transaminase (AST) and gamma glutamyltransferase (γGT), as well as liver size and structure was undertaken. Data demonstrated a significant inverse association between PCB concentration and γGT activity levels but there was no marked relationship with AST and ALT activities. Regarding sonographic examination, a significant association was found between liver size and PCB concentration. This association remained, even after adjusting for alcohol consumption, liver affecting drugs, timespan of internal exposure, or age. No marked correlation was noted between PCB concentration and liver structure changes. In summary, an association was observed between PCB concentration and γGT activity levels as well as liver size in humans. The long-term health consequences attributed to PCB on liver and in particular in tumorigenesis are not foreseeable in our cohort thus far, but remain a focus in further ongoing surveillance.

Hyperpigmentation and higher incidence of cutaneous malignancies in moderate-high PCB- and dioxin exposed individuals.

Polychlorinated biphenyls (PCB) are well known persistent and toxic environmental pollutants. Our aim was to identify effects of moderate-high exposure to dioxin-like (dl) and non-dioxin-like (ndl)-PCBs on the skin in order to provide more insight in the pathophysiological effects of these compounds. We performed a dermatological examination on 92 former workers from a transformer recycling company with known elevated serum PCB and/or dioxin (polychlorinated dibenzo-p-dioxin/polychlorinated dibenzo-p-furan (PCDD/F)) levels. In addition, we performed a skin cancer screening over a period of seven years (2010-2016) on resp. 268, 271, 210, 149, 92, 129 and 79 participants. We found a higher incidence of acne and malignancies of the skin (malignant melanoma, basal cell carcinoma and mycosis fungoides) in the workers compared to normal population. The probability of having hyperpigmentation on the skin was statistically significantly higher in workers with higher sumPCBs- (OR:1.09(1.12-2.17)), dioxin-like (dl)-PCBs- (OR:1.56(1.12-2.17)) and dioxin (PCDD/Fs) (OR:1.09(1.02-1.16)) levels. Age was a confounding factor in this model. Formation of hyperpigmentation could be an indicator for (moderate-high) exposure to toxic compounds like PCBs. The higher incidence of cutaneous malignancies found in the workers might be associated with PCB- and dioxin exposure, warranting further investigation on larger cohorts.

Environmental exposure to human carcinogens in teenagers and the association with DNA damage.

BACKGROUND: We investigated whether human environmental exposure to chemicals that are labeled as (potential) carcinogens leads to increased (oxidative) damage to DNA in adolescents. MATERIAL AND METHODS: Six hundred 14-15-year-old youngsters were recruited all over Flanders (Belgium) and in two areas with important industrial activities. DNA damage was assessed by alkaline and formamidopyrimidine DNA glycosylase (Fpg) modified comet assays in peripheral blood cells and analysis of urinary 8-hydroxydeoxyguanosine (8-OHdG) levels. Personal exposure to potentially carcinogenic compounds was measured in urine, namely: chromium, cadmium, nickel, 1-hydroxypyrene as a proxy for exposure to other carcinogenic polycyclic aromatic hydrocarbons (PAHs), t,t-muconic acid as a metabolite of benzene, 2,5-dichlorophenol (2,5-DCP), organophosphate pesticide metabolites, and di(2-ethylhexyl) phthalate (DEHP) metabolites. In blood, arsenic, polychlorinated biphenyl (PCB) congeners 118 and 156, hexachlorobenzene (HCB), dichlorodiphenyltrichloroethane (DDT) and perfluorooctanoic acid (PFOA) were analyzed. Levels of methylmercury (MeHg) were measured in hair. Multiple linear regression models were used to establish exposure-response relationships. RESULTS: Biomarkers of exposure to PAHs and urinary chromium were associated with higher levels of both 8-OHdG in urine and DNA damage detected by the alkaline comet assay. Concentrations of 8-OHdG in urine increased in relation with increasing concentrations of urinary t,t-muconic acid, cadmium, nickel, 2,5-DCP, and DEHP metabolites. Increased concentrations of PFOA in blood were associated with higher levels of DNA damage measured by the alkaline comet assay, whereas DDT was associated in the same direction with the Fpg-modified comet assay. Inverse associations were observed between blood arsenic, hair MeHg, PCB 156 and HCB, and urinary 8-OHdG. The latter exposure biomarkers were also associated with higher fish intake. Urinary nickel and t,t-muconic acid were inversely associated with the alkaline comet assay. CONCLUSION: This cross-sectional study found associations between current environmental exposure to (potential) human carcinogens in 14-15-year-old Flemish adolescents and short-term (oxidative) damage to DNA. Prospective follow-up will be required to investigate whether long-term effects may occur due to complex environmental exposures.

Polychlorinated biphenyls and depression: cross-sectional and longitudinal investigation of a dopamine-related Neurochemical path in the German HELPcB surveillance program.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) is associated with depressive symptomatology. A cause of depressive symptoms is a disturbance in the neurotransmitter system of dopamine (DA). Animal as well as human studies report that PCBs can influence the DA system. This study examined whether PCB-related depressive symptoms are affected by DA metabolites in humans with high PCB body burden. METHODS: This study is part of the German HELPcB surveillance program (Health Effects in high Level exposure to PCB) for occupationally exposed workers and their relatives. Data was collected from 178 participants on two measurement time points (t1 and t2) with a one-year time lag in between the two time points. PCBs were analyzed in plasma via human biomonitoring and a validated questionnaire was used to identify existence and severity of depressive symptoms. As a surrogate for DA, we measured its metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine. Mediation analyses were performed to test whether the association between PCB exposure and severity of depressive symptoms is mediated by urinary concentration of DA metabolites HVA and VMA. The mediation was tested with the SPSS macro MEDIATE. RESULTS: We found a significant mediation over time for lower-chlorinated, higher-chlorinated and dioxin-like PCBs. The positive association between PCB exposure with severity of depressive symptoms was mediated by the main DA metabolite HVA. At t1 a higher exposure with PCBs was associated with lower concentration in urinary HVA. A reduced HVA concentration at t1 was correlated with increased depressive symptoms severity at t2. No meditations were found for VMA. CONCLUSIONS: This work indicates that the association of PCB exposure and an increase of depressive symptoms after one year is mediated by the DA metabolite HVA as a surrogate for DA. These are first steps towards finding an explanation for an underlying neurochemical pathomechanism of PCB-related depressive symptomatology.

Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure.

Polychlorinated biphenyls (PCBs) are organochlorine pollutants with a worldwide dissemination. We examined telomere length (TL) in peripheral blood cells of 207 individuals with a high body burden of PCBs due to occupational exposure in a transformer recycling company. Whereas TL in granulocytes was not affected, the age-adjusted TL in lymphocytes (∆TLLymph) of exposed individuals was significantly shorter than expected [-0.77 kb; 95 % confidence interval (CI) -0.9316; -0.6052; p = 0.0001]. PCB exposure did not affect lymphocyte numbers or T cell receptor excision circle (TREC) levels in T cells, suggesting that PCBs cause loss of telomeric DNA in T cells due to their metabolic activation and antigen-stimulated proliferation. In support of this hypothesis, blood plasma levels of PCB-exposed individuals inhibited expression of telomerase, the telomere elongating enzyme in vitro in antigen-specific T cell proliferation assays. 3-OH-CB28, a downstream metabolite of the lower chlorinated PCB-28 in PCB-exposed individuals (mean blood plasma concentration: 0.185 ± 0.68 ng/mL), inhibited telomerase gene expression within 48 h of incubation in lymphoproliferative assays starting at a concentration of 0.27-6.75 µg/mL and accelerated telomere shortening in long-term cell culture experiments. Accelerated telomere shortening due to PCB exposure may lead to limitations of cell renewal and clonal expansion of lymphocyte populations. As PCB-related immune dysfunctions have been linked to increased susceptibility to infectious diseases and increased risk of cancer, our data provide a possible explanation, for how PCBs could promote infections and cancer through limiting immune surveillance.

[Electronic Shiazo waterpipes: a new source of indoor air pollutants]. / Elektrische Shiazo-Wasserpfeifen: eine neue Quelle für Innenraumluftschadstoffe.

BACKGROUND: For some time, a new form of waterpipe smoking has been advertised, where steam stones moistened with aroma fluids (Shiazo) are heated electronically. Since there is no combustion of tobacco, it is often assumed that the produced vapor is not harmful to health. To clarify this issue, we performed a comprehensive inner and outer exposure assessment during the use of an electronic Shiazo waterpipe. METHODS: Three volunteers smoked an electronic waterpipe operated with nicotine-free Shiazo stones in a thoroughly ventilated room for 2 h. In three smoking sessions, three fluids with different flavorings were vaporized. In parallel, emissions of particles, volatile organic compounds, polycyclic aromatic hydrocarbons (PAH), and metals were measured in indoor air. Within a biomonitoring study, urinary metabolite profiles of air pollutants were checked. For comparison, the components of the Shiazo fluids were also analyzed. RESULTS: During the smoking sessions, concentrations of formaldehyde, acetaldehyde, glycerine, and propylene glycol rose significantly in the indoor environment. The content of putative carcinogenic PAH in indoor air increased by 42% to 174 ng/m3. Particle number concentrations ranged from 39,968 to 65,610 particles/cm3 (median), with peaks at diameters from 25 to 31 nm. 3­HPMA, the mercapturic acid metabolite of the pyrolysis product acrolein, was strongly elevated in urine samples of the smokers. All fluids contained high amounts of contact allergens. CONCLUSIONS: Electronic Shiazo waterpipes release various harmful substances that considerably impact indoor air quality. Compared to conventional waterpipes, the release of pollutants is lower. Nevertheless, smoking with Shiazo waterpipes is a source of health risks for both users and bystanders.

A method for the simultaneous quantification of eight metabolites of synthetic pyrethroids in urine of the general population using gas chromatography-tandem mass spectrometry.

Synthetic pyrethroids are highly effective, widespread insecticides applied worldwide for different purposes. Among the possible sources of exposure for the general population, pyrethroid residues in food and their prominent use for the conservation of wool carpets or in indoor pest control might play a major role. On the basis of previous works, we have developed and validated a highly sensitive and specific GC/MS/MS-method to simultaneously quantify the metabolites of the most common synthetic pyrethroids in urine, namely cis- and trans-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DCCA), cis-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (DBCA), 4-fluoro-3-phenoxybenzoic acid (F-PBA), 3-phenoxybenzoic acid (3-PBA) as well as the metabolites cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-cyclopropanecarboxylic acid (ClF3CA, λ-cyhalothrin/bifenthrin), 4-chloro-α-isopropylbenzene acetic acid (CPBA, esfenvalerate), and 2-methyl-3-phenylbenzoic acid (MPB, bifenthrin). After acidic hydrolysis to cleave conjugates in urine, the analytes are subjected to a pH-controlled extraction into n-hexane. After concentration, the analytes are derivatised using MTBSTFA and finally quantified by GC/MS/MS in EI-mode using d6-trans-DCCA and (13)C6-3-PBA as internal standards. The limit of quantification for these metabolites was 0.01 µg/L urine. Precision within and between series was determined to range between 1.6 and 10.7 % using a native quality control sample as well as a urine sample spiked with 0.3 µg/L of the analytes. To investigate possible background excretions, we analysed spot urine samples of 38 persons of the general population in a pilot study. cis- and trans-DCCA as well as 3-PBA could be quantified in every urine sample investigated, while MPB and F-PBA could only be detected in two samples. The median levels for excretion of cis-DCCA, trans-DCCA, 3-PBA, ClF3CA, DBCA, CPBA, F-PBA and MPA were 0.08, 0.17, 0.22, 0.04, 0.04, <0.01, <0.01 and < 0.01 µg/L urine, respectively. The excretion of metabolites revealed excellent correlations between cyclopropane carboxylic acids and 3-PBA. Our method is highly suitable for human biomonitoring of exposures to synthetic pyrethroids in environmental medicine. Remarkable are the high detection rates for the metabolites ClF3CA (90 %) and CPBA (40 %), proving that their parent pyrethroids have entered the market in Germany.

Exposure to polychlorinated biphenyls and the thyroid gland - examining and discussing possible longitudinal health effects in humans.

BACKGROUND: Many previous studies have dealt with the effect of polychlorinated biphenyls (PCBs) on the thyroid gland, but their findings are inconsistent. One problem of these studies has been their use of cross-sectional designs. OBJECTIVES: The aim of the current study is to investigate longitudinal effects of PCBs on the thyroid gland, focusing on: morphological changes in thyroid tissue (i.e. thyroid volume), changes in thyroid hormones and in thyroid antibodies. METHODS: A total of 122 individuals (Mage=44.7) were examined over a period of four years (t(1) until t(4)). Medical history was collected via interviews, an ultrasound examination was performed and blood samples were taken to determine plasma PCB levels, thyroid stimulating hormone (TSH), free triiodthyronine (fT3), free thyroxine (fT4), thyroid peroxidase antibodies (TPOab), thyreoglobulin antibodies (TGab) and thyroid-stimulating hormone receptor antibodies (TSHRab). Rank correlation coefficients and mixed effect models were performed controlling for age and total lipids. RESULTS: There were negative correlations between higher chlorinated biphenyls and fT3, cross-sectionally as well as longitudinally. We also found an interaction effect of higher-chlorinated PCBs over time for fT4 as well as TSHRab. In case of high exposure, a decrease in fT4 and an increase in TSHRab level were found over time. In regards to the other variables, our findings yielded no clear results in the examined time period. CONCLUSION: This is the first study to shows a PCB-related effect on fT3, fT4 and TSHRab over a four year period. The data also suggest that morphological and antibody findings remain inconsistent and do not allow for unambiguous interpretation.