Co-administration of toluene and xylene antagonized the testicular toxicity but not the hematopoietic toxicity caused by ethylene glycol monoethyl ether in Sprague–Dawley rats
Introduction
Ethylene glycol ethers like monoethyl ether (EGEE), monomethyl ether and their acetates are used widely as industrial solvents in resins, lacquers, dyes, paints, and inks. Ethylene glycol monoethyl ether (EGEE) is a water miscible organic solvent used extensively as an emulsifier in the chemical industry (Vincent et al., 1994). EGEE is absorbed rapidly through the skin and some studies suggest that percutaneous absorption is more important than respiratory absorption (Guest et al., 1984). EGEE has commanded public attention because it has been demonstrated to cause marked testicular atrophy in a number of animal species including man (Morris et al., 1942, Nagano et al., 1979, Foster et al., 1983). After exposure to 9.9 mg/m3 of EGEE (range: 0–80.5 mg/m3), painters had an increased prevalence of oligospermia and azoospermia (Welch et al., 1988). Animal experiment and exposed human case reports demonstrated that EGEE is toxic not only to the reproductive system but also to the hematopoietic system (Nagano et al., 1979). Ethoxyacetic acid (EAA) has been identified as the major and final metabolite of EGEE excreted in urine and is considered to be the active agent producing the testicular toxicity (Jonsson et al., 1982, Cheever et al., 1984, Gray et al., 1985).
In the actual occupational settings, EGEE is used generally as a mixture with other organic solvents like toluene (TOL) and xylene (XYL), typically in lacquers, thinners, adhesives, inks, and paint preparations (Seedorff and Olsen, 1990). Thus, a recent report on air monitoring at a shipyard demonstrated that painters are exposed to EGEE, EGE acetate, TOL, and XYL, at concentrations over the occupational exposure limits. While reproductive toxicity (testicular atrophy) was not studied, the report showed that the shipyard painters had high rates of hematologic abnormalities and bone marrow smears of three painters revealed that they had mild to moderate hypocellularity (Kim et al., 1999). In a previous study conducted with male rats comparing the testicular toxicity caused by EGEE alone and in combination with TOL and XYL, the extent of atrophy caused by EGEE was reduced by combined administration with TOL and XYL (Chung et al., 1999). The combined administration delayed the Tmax, decreased the Cmax and reduced the plasma AUC of EAA, the toxic metabolite and explained the diminished testicular atrophy observed when EGEE was given as a solvent mixture containing TOL and XYL. However, this study was not accompanied by the supportive histological data.
Thus, in this report, we provide the supportive histological data for the protective effect of TOL and XYL against the EGEE caused testicular toxicity. Further, we examined whether the hematopoietic toxicity caused by EGEE is also antagonized by the combined administration of TOL and XYL. This was done to determine whether the hematological abnormality observed in shipyard painters is already at a reduced state by the combined exposure to EGEE, TOL and XYL, the three most widely used organic solvents in painting.
Section snippets
Chemicals
Ethylene glycol monoethyl ether (EGEE) was purchased from Wako Chemicals (Japan) and toluene (TOL) and xylene (XYL) were purchased from Junsei (Japan).
Animals and treatments
Eight week old male, specific pathogen-free (SPF) Sprague–Dawley rats were purchased from Daehan Animal Center (Korea) and were acclimated for 1 week before the start of experiments. During the acclimation and experimental periods, rats in polycarbonate cages (five rats per cage) were housed in a room with controlled temperature (23±2°C) and
Effects on body weights and reproductive organ weights
The ranges of organic solvent concentrations to be given to rats in the initial dose finding studies were based on the results of air monitoring at a Korean shipbuilding site (Kim et al., 1999). Our rationale for establishing the experimental doses of EGEE, TOL and XYL was to find the minimal doses of these organic solvents causing measurable testicular atrophy with minimal effects on growth rate (body weight), blood biochemistry and hematology. Once the individual doses of EGEE (150 mg/kg) and
Discussion
EGEE is known to cause atrophy of testes, degeneration of seminiferous tubules and loss of spermatocytes in a number of animal species including male rats (Morris et al., 1942, Nagano et al., 1979, Foster et al., 1983, Welch et al., 1988). Ethoxyacetate (EAA), the final and major metabolite generated from EGEE, is considered to be the active agent producing the testicular toxicity (Jonsson et al., 1982, Cheever et al., 1984, Gray et al., 1985). In the paint industry, EGEE is used extensively,
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