Exposure to glycol ethers among 6-year-old children in France.

Glycol ethers are an oxygenated solvent family widely present in consumer products. Some of them are recognized reproductive, developmental or hematological toxicants. Although several glycol ether biomonitoring studies have been performed on adults from working or general populations, no studies have hitherto been carried out on children. The aim of our study was to explore the detection of glycol ether metabolites in the urinary samples of 6-year-old children, and if any were found, to describe them. The PELAGIE mother-child cohort included 3421 pregnant women from the general population of Brittany, France, between 2002 and 2006. Our biomonitoring study included a random sample of 110 children from the PELAGIE cohort who had participated in a neurodevelopment evaluation at the age of six. First morning voids were collected from all of the children. Eight urinary glycol ether metabolites were measured using gas chromatography with mass spectrometry. The limit of detection was 0.003 mg/L for all metabolites. Glycol ether metabolites were detected at rates varying from 33.5% of samples for propoxyacetic acid to 100% of samples for phenoxyacetic acid and methoxyacetic acid. The highest median concentration observed was for phenoxyacetic acid (0.141 mg/l). Our study reported the ubiquitous presence of glycol ether metabolites in children's urinary samples. These results call for larger biomonitoring surveys of the general population and study of the potential sources and determinants of these exposures.

Prenatal exposure to glycol ethers and motor inhibition function evaluated by functional MRI at the age of 10 to 12 years in the PELAGIE mother-child cohort.

BACKGROUND: Pregnant women are ubiquitously exposed to organic solvents, such as glycol ethers. Several studies suggest potential developmental neurotoxicity following exposure to glycol ethers with a lack of clarity of possible brain mechanisms. OBJECTIVES: We investigated the association between urinary levels of glycol ethers of women during early pregnancy and motor inhibition function of their 10- to 12-year-old children by behavioral assessment and brain imaging. METHODS: Exposure to glycol ethers was assessed by measuring six metabolites in urine (<19 weeks of gestation) of 73 pregnant women of the PELAGIE mother-child cohort (France). Maternal urinary levels were classified as low, medium, or high. Children underwent functional magnetic resonance imaging (fMRI) examinations during which motor inhibition function was assessed with a Go/No-Go task. Analyses were performed using linear regression for task performance and generalized linear mixed-effect models for brain activation, FWER-corrected for multiple testing at the spatial cluster level. Confounders were considered by restriction and a priori adjustment. RESULTS: Higher maternal butoxyacetic acid (BAA) urinary concentrations were associated with poorer child performance (ß = -1.1; 95% CI: -1.9, -0.2 for high vs low). There was also a trend for ethoxyacetic acid (EAA) towards poorer performance (ß = -0.3; 95% CI: -0.7, 0.01). Considering inhibition demand, there were increased activity in occipital regions in association with moderate EAA (left cuneus) and moderate methoxyacetic acid (MAA) (right precuneus). When children succeeded to inhibit, high ethoxyethoxyacetic acid (EEAA) and moderate phenoxyacetic acid (PhAA) levels were associated with differential activity in frontal cortex, involved in inhibition network. DISCUSSION: Prenatal urinary levels of two glycol ether metabolites were associated with poorer Go/No-Go task performance. Differential activations were observed in the brain motor inhibition network in relation with successful inhibition, but not with cognitive demand. Nevertheless, there is no consistence between performance indicators and cerebral activity results. Other studies are highly necessary given the ubiquity of glycol ether exposure.

Prenatal Exposure to Glycol Ethers and Neurocognitive Abilities in 6-Year-Old Children: The PELAGIE Cohort Study.

BACKGROUND: Glycol ethers (GE) are widely used organic solvents. Despite the potential neurotoxicity of several families of organic solvents, little is known about the impact of GE on the neurodevelopment of infants and children. OBJECTIVES: We investigated the relation between urinary concentrations of GE metabolites in pregnant women and neurocognitive abilities in their 6-year-old children in the PELAGIE mother-child cohort. METHODS: Five GE metabolites were measured in first morning void urine samples of 204 French pregnant women in early pregnancy (< 19 weeks of gestation). Psychologists assessed the neurocognitive abilities of their 6-year-old children with the Wechsler Intelligence Scale for Children IV (WISC) and the Developmental Neuropsychological Assessment (NEPSY). We analyzed the results with linear (WISC) and Poisson regression models (NEPSY), adjusted for potential confounders, including child's stimulation at home. RESULTS: GE metabolites were detected in 90-100% of maternal urine samples. The WISC Verbal Comprehension score was significantly lower for children with the highest tertile of urinary phenoxyacetic acid (PhAA) [ß (third vs. first tertile) = -6.53; 95% CI: -11.44, -1.62]. Similarly, the NEPSY Design Copying subtest score was lower in those with the highest tertile of urinary ethoxyacetic acid (EAA) [ß (third vs. first tertile) = -0.11; 95% CI: -0.21, 0.00]. The other GE metabolites we studied were not significantly associated with WISC or NEPSY scores. CONCLUSIONS: Prenatal urine concentrations of two GE metabolites were associated with lower WISC Verbal Comprehension Index scores and NEPSY Design Copying subscale scores, respectively, at age 6 years. PhAA is the primary metabolite of 2-phenoxyethanol (EGPhE), which is commonly found in cosmetics, and precursors of EAA are frequently used in cleaning agents. Additional research is needed to confirm our findings and further explore potential effects of prenatal GE exposures on neurocognitive performance in children.

Deriving Biomonitoring Equivalents for selected E- and P-series glycol ethers for public health risk assessment.

Glycol ethers are a widely used class of solvents that may lead to both workplace and general population exposures. Biomonitoring studies are available that have quantified glycol ethers or their metabolites in blood and/or urine amongst exposed populations. These biomonitoring levels indicate exposures to the glycol ethers, but do not by themselves indicate a health hazard risk. Biomonitoring Equivalents (BEs) have been created to provide the ability to interpret human biomonitoring data in a public health risk context. The BE is defined as the concentration of a chemical or metabolite in a biological fluid (blood or urine) that is consistent with exposures at a regulatory derived safe exposure limit, such as a tolerable daily intake (TDI). In this exercise, we derived BEs for general population exposures for selected E- and P-series glycol ethers based on their respective derived no effect levels (DNELs). Selected DNELs have been derived as part of respective Registration, Evaluation, Authorisation and Regulation of Chemicals (REACh) regulation dossiers in the EU. The BEs derived here are unique in the sense that they are the first BEs derived for urinary excretion of compounds following inhalation exposures. The urinary mass excretion fractions (Fue) of the acetic acid metabolites for the E-series GEs range from approximately 0.2 to 0.7. The Fues for the excretion of the parent P-series GEs range from approximately 0.1 to 0.2, with the exception of propylene glycol methyl ether and its acetate (Fue = 0.004). Despite the narrow range of Fues, the BEs exhibit a larger range, resulting from the larger range in DNELs across GEs. The BEs derived here can be used to interpret human biomonitoring data for inhalation exposures to GEs amongst the general population.

Influence of sevoflurane on the metabolism and renal effects of compound A in rats.

BACKGROUND: The sevoflurane degradation product compound A is nephrotoxic in rats. In contrast, patient exposure to compound A during sevoflurane anesthesia has no clinically significant renal effects. The mechanism for this difference is incompletely understood. One possibility is that the metabolism and toxicity of compound A in humans is prevented by sevoflurane. However, the effect of sevoflurane on compound A metabolism and nephrotoxicity is unknown. Thus, the purpose of this investigation was to determine the effect of sevoflurane on the metabolism and renal toxicity of compound A in rats. METHODS: Male rats received 0.25 mmol/kg intraperitoneal compound A, alone and during sevoflurane anesthesia (3%, 1.3 minimum alveolar concentration, for 3 h). Compound A metabolites in urine were quantified, and renal function was evaluated by serum creatinine and urea nitrogen, urine volume, osmolality, protein excretion, and renal tubular histology. RESULTS: Sevoflurane coadministration with compound A inhibited compound A defluorination while increasing relative metabolism through pathways of sulfoxidation and beta-lyase-catalyzed metabolism, which mediate toxicity. Sevoflurane coadministration with compound A increased some (serum creatinine and urea nitrogen, and necrosis) but not other (urine volume, osmolality, and protein excretion) indices of renal toxicity. CONCLUSIONS: Sevoflurane does not suppress compound A nephrotoxicity in rats in vivo. These results do not suggest that lack of nephrotoxicity in surgical patients exposed to compound A during sevoflurane anesthesia results from an inhibitory effect of sevoflurane on compound A metabolism and toxicity. Rather, these results are consistent with differences between rats and humans in compound A exposure and inherent susceptibility to compound A nephrotoxicity.

Optimization of the headspace solid-phase microextraction for determination of glycol ethers by orthogonal array designs.

A headspace solid-phase microextraction (HS-SPME), in conjunction with gas chromatography-flame ionization detection for use in the determination of six frequently used glycol ethers at the microg/l level is described. A 75 microm Carboxenpolydimethylsiloxane fiber was used to extract the analytes from an aqueous solution. Experimental HS-SPME parameters such as extraction temperature, extraction time, salt concentration and sample volume, were investigated and optimized by orthogonal array experimental designs. The relative standard deviations for the reproducibility of the optimized HS-SPME method varied from 1.48 to 7.59%. The correlation coefficients of the calibration curves exceeded 0.998 in the microg/l range of concentration with at least two orders of magnitude. The method detection limits for glycol ethers in deionized water were in the range of 0.26 to 3.42 microg/l. The optimized method was also applied to the analysis of glycol ethers in urine and blood samples with the method detection limits ranged from 1.74 to 23.2 microg/l.

Haematological and spermatotoxic effects of ethylene glycol monomethyl ether in copper clad laminate factories.

OBJECTIVES: To investigate the effects of ethylene glycol monomethyl ether (EGME) on haematology and reproduction in exposed workers. METHODS: 53 Impregnation workers from two factories that make copper clad laminate with EGME as a solvent were recruited as the exposed group. Another group of 121 lamination workers with indirect exposure to EGME was recruited as the control group. Environmental monitoring of concentrations of EGME in air and biological monitoring of urinary methoxyacetic acid (MAA) concentrations were performed. Venous blood was collected for routine and biochemical analyses. Semen was collected from 14 workers exposed to EGME for sperm analysis and was compared with 13 control workers. RESULTS: Results of haematological examination showed that the haemoglobin, packed cell volume, and red blood cell count in the male workers exposed to EGME were significantly lower than in the controls. The frequency of anaemia in the exposed group (26.1%) was significantly higher than in the control group (3.2%). However, no differences were found between the female workers exposed and not exposed to EGME. After adjustment for sex, body mass index, and duration of employment, red blood cell count was significantly negatively associated with air concentrations of EGME, and haemoglobin, packed cell volume, and red blood cell count were significantly negatively associated with urinary concentrations of MAA. The pH of semen in the exposed workers was significantly lower than in the control workers, but there were no significant differences in the sperm count or sperm morphology between the exposed and control groups. CONCLUSION: It can be concluded that EGME is a haematological toxin, which leads to anaemia in the exposed workers. However, the data from this study did not support the theory of a spermatotoxic effect of EGME.

Compound A uptake and metabolism to mercapturic acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid during low-flow sevoflurane anesthesia: biomarkers for exposure, risk assessment, and interspecies comparison.

BACKGROUND: Sevoflurane is degraded during low-flow anesthesia to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether ("compound A"), which causes renal necrosis in rats but is not known to cause nephrotoxicity in surgical patients. Compound A is metabolized to glutathione S-conjugates and then to cysteine S-conjugates, which are N-acetylated to mercapturic acids (detoxication pathway), or metabolized by renal beta-lyase to reactive intermediates (toxification pathway) and excreted as 3,3,3-trifluoro-2-fluoromethoxypropanoic acid. This investigation quantified compound A metabolites in urine after low-flow sevoflurane administration, to assess relative flux via these two pathways. METHODS: Patients (n = 21) with normal renal function underwent low-flow (11 min) sevoflurane anesthesia designed to maximize compound A formation. Inspiratory, expiratory, and alveolar compound A concentrations were quantified. Urine mercapturic acids and 3,3,3-trifluoro-2-fluoromethoxypropanoic acid concentrations were measured by gas chromatography and mass spectrometry. RESULTS: Sevoflurane exposure was 3.7 +/- 2.0 MAC-h. Inspired compound A maximum was 29 +/- 14 ppm; area under the inspired concentration versus time curve (AUCinsp) was 78 +/- 58 ppm x h. Compound A dose, calculated from pulmonary uptake, was 0.39 +/- 0.35 mmol (4.8 +/- 4.0 micromol/kg) and correlated with AUCinsp (r2 = 0.84, P < 0.001). Mercapturic acids excretion was complete after 2 days, whereas 3,3,3-trifluoro-2-fluoromethoxypropanoic acid excretion continued for 3 days in some patients. Total (3-day) mercapturates and fluoromethoxypropanoic acid excretion was 95 +/- 49 and 294 +/- 416 micromol, respectively (1.2 +/- 0.6 and 3.6 +/- 5.0 micromol/kg). CONCLUSION: Compound A doses during 3.7 MAC-h, low-flow sevoflurane administration in humans are substantially less than the threshold for renal toxicity in rats (200 micromol/kg). Compound A metabolites quantification may provide a biomarker for compound A exposure and relative metabolism via toxification and detoxication pathways. Compared with previous investigations, relative metabolic flux (fluoromethoxypropanoic acid/mercapturates) through the toxification pathway was sixfold greater in rats than in humans. Species differences in dose and metabolism may influence compound A renal effects.

Cysteine conjugate beta-lyase-dependent metabolism of compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene) in human subjects anesthetized with sevoflurane and in rats given compound A.

BACKGROUND: Sevoflurane undergoes Baralyme- or soda lime-catalyzed degradation in the anesthesia circuit to yield compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluroro-1-propene), which is nephrotoxic in rats and undergoes metabolism via the cysteine conjugate beta-lyase pathway in those animals. The objective of these experiments was to test the hypothesis that compound A undergoes beta-lyase-dependent metabolism in humans. METHODS: Human volunteers were anesthetized with sevoflurane (1.25 minimum alveolar concentration, 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after anesthesia. Rats, which served as a positive control, were given compound A intraperitoneally, and urine was collected for 24 h afterward. Human and rat urine samples were analyzed by 19F nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry for the presence of compound A metabolites. RESULTS: Analysis of human and rat urine showed the presence of the compound A metabolites S-[2(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L- cysteine, (E)- and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl- L-cysteine, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride. The presence of 2-(fluoromethoxy)3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in human urine was confirmed by gas chromatography-mass spectrometry. CONCLUSIONS: The formation of compound A-derived mercapturates shows that compound A undergoes glutathione S-conjugate formation. The identification of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in the urine of humans anesthetized with sevoflurane shows that compound A undergoes beta-lyase-dependent metabolism. Metabolite formation was qualitatively similar in both human volunteers anesthetized with sevoflurane, and thereby exposed to compound A, and in rats given compound A, indicating that compound A is metabolized by the beta-lyase pathway in both species.

Relationship of inspired anesthetic concentration to plasma concentration and urinary excretion of sevoflurane metabolites in rats.

In patients, plasma concentrations of sevoflurane metabolites may be independent of inspired sevoflurane concentration over a defined dose range. In contrast, studies using rabbits have found that plasma concentrations and urinary excretion of fluoride ion are dose-dependent up to 3% inspired sevoflurane. We measured sevoflurane metabolite concentrations in adult male Sprague-Dawley rats and related them to inspired sevoflurane concentrations. When plasma concentrations and urinary excretion of metabolites were measured in vivo, they were dependent on inspired anesthetic concentration at concentrations less than 1.25%, but became less dose-dependent at higher anesthetic concentrations. Sevoflurane metabolism by precision-cut liver slices in vitro became dose-independent at more than 10-30 microM sevoflurane. No evidence of substrate inhibition was observed. These data provide evidence that sevoflurane metabolite concentrations are almost independent of inspired anesthetic concentration over at least part of the clinically used concentration range.

Measurement of methyl tert-butyl ether and tert-butyl alcohol in human blood by purge-and-trap gas chromatography-mass spectrometry using an isotope-dilution method.

We developed an isotope-dilution method for measuring methyl tert-butyl ether (MTBE) and tert-butyl alcohol (TBA) in whole human blood using a purge-and-trap gas chromatographic-mass spectrometric method. The labeled analogues for MTBE and TBA were [2H12]methyl tert-butyl ether and [2H9]-tert-butyl alcohol, respectively. Volatiles were removed from the blood by direct helium purging of the liquid; were trapped on a Tenax trap; and were desorbed, cryofocused, and chromatographed on a DB-624 capillary column that was connected directly to the ion source of a mass spectrometer. Detection was by mass analysis using a double-focusing magnetic-sector mass spectrometer operating in the full-scan mode at the medium mass resolution of 3000. For the isotope-dilution method, the minimum detection limits in blood (5-10 mL) are 0.01 microgram/L for MTBE and 0.06 microgram/L for TBA. The isotope-dilution method proved to be a big improvement in recovery, reproducibility, and sensitivity over our previous analytical method, which used the labeled ketone, [4-2H3]-2-butanone, as the internal standard for both MTBE and TBA. The isotope-dilution method has sufficient sensitivity for monitoring blood levels of MTBE and TBA in populations exposed to oxygenated fuels containing MTBE.

Tissue distribution metabolism and excretion of 2,2',4,4',5-pentachlorodiphenyl ether in the rat.

The tissue distribution, metabolism and excretion of 14C-2,2',4,4',5-pentachlorodiphenyl ether (PCDE) were studied in the rat. Radioactivity was distributed in all tissues examined, with the highest concentrations being found in the fat followed by the skin, liver, kidney and muscle. Most of the radioactivity found in the tissues was due to unchanged PCDE. Decay of PCDE in the blood was fitted to a four-compartment pharmacokinetic model, and the last compartment had a half-life of 5.8 days. A total of 55% and 1.3% of an orally administered dose was excreted in feces and urine, respectively, in 7 days. More than 64% of the fecal radioactivity was due to unchanged PCDE, while hydroxylated PCDE accounted for 23%.

Indican, ethereal and other forms of S eliminated in 24 hours urine by elderly Indian subjects.

Average daily excretion of Indican in urine of 42 healthy elderly men, av. age 69.9 +/- 5.0 years, (60 observations) was 60.7 +/- 17.4 mg/24 hrs. This is slightly higher than reported values for younger subjects. Average ethereal S elimination by Indian subjects has varied from 72-150 mg/day. Indican is the chief ethereal S eliminated in urine. Other forms of S excreted by elderly subjects were: Inorganic S 720 +/- 150 mg; Ethereal S 74 +/- 22 mg. Indican in them was 53.8 +/- 17.4 mg. This shows that the remaining 20 mg or about 1/4 of the ethereal S is eliminated in urine in other forms. Relationship with age, diet, common disorders along with findings in literature etc. are discussed.

n-Butoxyacetic acid, a urinary metabolite from inhaled n-butoxyethanol (Butylcellosolve).

Male albino rats were exposed to butylcellosolve (n-butoxyethanol). Collected urine was found to contain a characteristic metabolite, identified as n-butoxyacetic acid by mass spectrometry. The identity of the compound was confirmed by synthesis.

A comparison of t-butyldimethylsilyl and trimethylsilyl ether derivatives for the characterization of urinary metabolites of prostaglandin F2alpha by gas chromatography mass spectrometry.

t-Butyldimethylsilyl and trimethylsilyl ether derivatives of a series of methylated prostaglandin F2alpha metabolites have been compared with respect to their gas chromatographic and mass spectrometric properties. The t-butyldimethylsilyl derivatives had considerably higher retention indices (approximately 2.2 C units per silyl group) than their trimethylsilyl ether counterparts when analysed on the (non-polar) OV-1 stationary phase. Electron impact induced fragmentation patterns were strongly dependent upon the type of silyl ether employed and on the nature of the prostaglandin omega sidechain; the mass spectra of pairs of t-butyldimethylsilyl and trimethylsilyl ether derivatives were found to differ appreciably in several respects and to afford complementatary structural information.

Absorption, distribution and excretion of a dihydroxydibutyl ether labelled with 14C in animals.

Kinetic studies were performed in rats, dogs and monkeys after oral administration of 14C-labelled dihydroxy-dibutyl ether (DHBE; Discinil), a known choleretic agent. The data presented indicate that the compound was intirely and readily absorbed and that it was excreted mainly with the urine in all the three species. The complete distribution pattern was investigated in rats. In most tissues high levels of radioactivity were already present after 10 min and the peak concentration was reached within the first 30 min. The decay was rapid and at the fourth hour only traces of radioactivity could be still detected in the tissues. Liver and kidney were the target organs for the radioactive material (which is in accordance with the activity and the excretory route of DHBE). The blood levels paralleled the general tissue distribution. The excretion of radioactivity was completed within 24 h in the three animal species and it took place by the urinary route, mainly witin the first 7--8 h.

Tritiated glycerol triether as an oil phase marker in man.

3H-labeled glycerol triether has been suggested as a marker of the oil phase during digestion and absorption of a lipid test meal. This study examines the behavior of this isotope in the human alimentary tract. The results suggest that it is completely recovered from the gastrointestinal tract, and thus it remains solely with the oil phase of emulsions in vivo and with the oil phase of intestinal aspirates. (3)H-labeled glycerol triether may thus be an appropriate marker of the oil phase for use in human studies of lipid absorption.