D Groeseneken

Exposure to ethylene glycol ethers and spermatogenic disorders in man: a case-control study.

A case-control study was conducted among first time patients at a clinic for reproductive disorders. The study group consisted of 1019 cases, defined as patients diagnosed infertile or subfertile on the basis of a spermiogram and 475 controls who were diagnosed as normally fertile by the same procedure. Possible exposure to ethylene glycol ethers was assessed by the presence of the urinary metabolites methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) respectively for 2-methoxyethanol and 2-ethoxyethanol or their acetates. In total, EAA was detected in 39 cases and six controls, with a highly significant odds ratio of 3.11 (p = 0.004). On the other hand, MAA was only found in one case and two controls. The presence of EAA in urine proved to be strongly associated with exposure to preparations containing solvents, especially paint products, and with some groups of occupations, the most important of which were also directly or possibly connected with paint products. The absence of a significant correlation between the concentration of urinary EAA and the various measures of sperm quality could be explained by the expected latent period between exposure and observed effects. Other temporal aspects of the relation between exposure as judged from the presence of urinary EAA and diagnosis are also discussed.

Experimental human exposure to ethylene glycol monomethyl ether

SummaryThe uptake of EGME and the urinary excretion of its major metabolite (MAA) was studied in seven male volunteers during experimental exposure to EGME at rest. The exposure concentration was set at 16 mg/m3, the present Threshold Limit Value. A high retention (0.76) remained unchanged during the 4-h exposure period. In combination with a constant pulmonary ventilation and a fixed exposure concentration this resulted in an uptake rate that showed no significant variation in time. The total amount of EGME inhaled corresponded to a dose of only 0.25 mg/kg. During and up to 120h after the start of the exposure, MAA was detected in the urine. The elimination half-life was on average 77.1 h. The total amount of MAA excreted was calculated by extrapolation and averaged 85.5% of the inhaled EGME. The pharmacokinetic data are compared with those obtained from other human exposure studies to ethylene glycol ethers (EGEE and EGBE).

Respiratory uptake and elimination of ethylene glycol monoethyl ether after experimental human exposure.

Ten male volunteers were exposed to ethylene glycol monoethyl ether (EGEE) under various conditions of exposure concentration and physical workload. Steady state levels of retention, atmospheric clearance, and rate of uptake were reached immediately after the start of the exposure period for all experimental conditions. Retention was high (64% in resting condition) and increased as physical exercise was performed during exposure. Atmospheric clearance increased as the pulmonary ventilation rate increased. The rate of uptake was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Individual uptake appeared to be governed mainly by transport mechanisms (pulmonary ventilation or cardiac output or both) and not by anthropometric factors. Respiratory elimination of unchanged EGEE accounted for less than or equal to 0.4% of the total body uptake. Postexposure breath concentrations declined rapidly during the first minutes after cessation of exposure, after which a much slower decrease was observed. This slow decrease could be described by a regression equation containing two exponential terms indicating that at least two pharmacological compartments are concerned.

Gas chromatographic determination of methoxyacetic and ethoxyacetic acid in urine.

Methoxyacetic acid (MAA) and ethoxyacetic acid (EAA), the major metabolites of, respectively, ethylene glycol monomethyl ether and ethylene glycol monoethyl ether and their acetates, are determined by gas chromatography after extraction from urine and methylation using 2-furoic acid (2-FA) as an internal standard. The mean recoveries (n = 30) from urine of MAA, EAA, and 2-FA are 31.4 +/- 7.0%, 62.5 +/- 13.4%, and 58.4 +/- 8.7%, respectively. The recoveries decreased (p less than 0.001), however, as the total amount of acids increased. Standard curves for MAA and EAA in urine are presented. The detection limits of MAA and EAA are 0.15 and 0.07 mg/l. Intra-assay variation for MAA and EAA was 6.0 +/- 2.5% and 6.4 +/- 2.8% and inter-assay variation was 6.2 +/- 2.2% and 8.9 +/- 2.4%. When volunteers were exposed to air containing ethylene glycol monoethyl ether (20 mg/m3), urinary concentration of EAA rose significantly one hour after the exposure period (2.39 +/- 1.03 v less than or equal to 0.07 mg/l, t = 5.2, p less than 0.005).

Survey of Ethylene Glycol Ether Exposures in Belgian Industries and Workshops

From 1983 onward, 2654 air samples from 336 different plants from the northern part of Belgium were analyzed for the presence of ethylene glycol ethers. One or more ethylene glycol ethers were detected in 262 air samples (9.9%) covering 78 plants or small establishments (23.2%) from a wide variety of industries. Ethylene glycol ethers were mainly present in establishments or operations where printing pastes, inks, paints and varnishes were used. About one third of the air samples covered various other industries. Car repair shops took a major part of this group. It was not always clear, however, in what precise operation the glycol ethers were involved. The ethylene glycol ethers most frequently identified were ethylene glycol monoethyl ether (EGEE) and its acetate (EGEE-Ac). Furthermore, ethylene glycol monomethyl ether (EGME), its acetate (EGME-Ac), and ethylene glycol monobutyl ether (EGBE) also were present in a large number of air samples. The glycol ethers were not distributed equally among the various groups of operations. Most exposure levels were far below the respective Threshold Limit Value (TLVs) (approximately less than 0.5 x TLV). About 25% of ethylene glycol concentrations, however, were higher than the current TLV. Most of the excursions were slight to moderate, although in selected cases extremely high concentrations were recorded. The majority of air samples revealed complex mixtures of ethylene glycol ethers with other solvents, the glycol ethers often being minor components. The possible implication of these other solvents on glycol ether toxicity and metabolism is discussed.

An improved method for the determination in urine of alkoxyacetic acids

SummaryA sensitive and specific method for the determination in urine of alkoxyacetic acids, the metabolites of ethylene glycol monoalkyl ethers, was developed by combining the advantages of two previously described methods. The acids were determined gas chromatographically as their pentafluorobenzylesters. The alkylation with pentafluorobenzylbromide was performed after dissolving the dry residue of lyophilized urine in methanol. Quantitative derivatization was obtained when the urinary pH was adjusted to pH 7.0, when the reagent concentration was 5% v/v, and when the reaction mixture was heated at 90°C for 3 h. Sample clean-up was performed by adding bidistilled water and the esters were extracted with methylene chloride with high yields (95%). Alkoxyacetic acid concentrations in the range of 0.1 to 200 mg/l could be determined with an average imprecision of ± 3.5%.

Ethoxyacetic acid: a metabolite of ethylene glycol monoethyl ether acetate in man

Urinary excretion of ethoxyacetic acid during and after exposure to ethylene glycol monoethyl ether acetate (EGEE-Ac) was followed up in ten healthy male volunteers. During exposure to EGEE-Ac, ethoxyacetic acid levels appeared with a half life of 2.3 +/- 0.1 h. Ethoxyacetic acid excretion continued to increase after exposure was discontinued reaching maximal levels three to four hours later. The decline afterwards could generally be described assuming a half life of 23.6 +/- 1.8 h. A second maximum excretion of ethoxyacetic acid, however, was noticed about three hours after the first. Redistribution of EGEE-Ac or ethoxyacetic acid, or both, from a peripheral compartment to the central compartment could explain this observation. Ethoxyacetic acid excretion increased with an increase in the uptake of EGEE-Ac due to higher exposure concentrations or pulmonary ventilation rate during physical exercise. On average 22.2 +/- 0.9% of the absorbed EGEE-Ac was recovered within 42 hours. Recovery did not change with a higher intake of EGEE-Ac. At any time after the exposure, quantitative relations between ethoxyacetic acid excretion rate and absorbed dose of EGEE-Ac were found. Monitoring ethoxyacetic acid excretion may therefore be used as a measure of a single exposure to EGEE-Ac.

Pulmonary absorption and elimination of ethylene glycol monoethyl ether acetate in man.

Ten male volunteers were exposed to ethylene glycol monoethyl ether acetate (EGEE-Ac) under various conditions of exposure and physical workload. As exposure proceeded, retention, atmospheric clearance, and uptake rate declined slowly to reach steady state levels after three to four hours. Retention increased as a consequence of higher exposure concentrations and of physical workload performed during exposure. Uptake rate was higher as exposure concentration or pulmonary ventilation rate, or both, increased. Subject related factors such as pulmonary ventilation, cardiac output, height, and body fat content also determined individual uptake. During exposure, partial respiratory elimination of EGEE was observed. This finding confirms the hypothesis that EGEE-Ac is first converted to EGEE by (plasma) esterases. The amount of EGEE eliminated at steady state levels correlated more with uptake rate of EGEE-Ac than with exposure concentration. Respiratory elimination of unmetabolised EGEE-Ac accounted for less than or equal to 0.5% of total body uptake. The elimination curves were biexponential indicating that at least two pharmacological compartments are involved. Postexposure breath concentrations were higher as total body uptake increased. Several observations may indicate that the hydrolysis of the ester moiety of EGEE-Ac is hindered by the presence of the natural esterase substrates. With increasing plasma concentrations, however, EGEE-Ac competed more favourably for the available esterase.