Elsevier

Toxicology Letters

Volume 109, Issues 1–2, 20 September 1999, Pages 11-20
Toxicology Letters

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

https://doi.org/10.1016/S0378-4274(99)00063-6Get rights and content

Abstract

Occupational painters are exposed to ethylene glycol monoethyl ether (EGEE), a widely used emulsifying solvent known to cause testicular degeneration and bone marrow depression, together with toluene (TOL) and xylene (XYL) as a mixture. In the previous study (Chung et al., Tox. Lett. 104:143, 1999), testicular atrophy caused by EGEE (200 mg/kg) was shown to be antagonized by co-administration of TOL (250 mg/kg) and XYL (500 mg/kg). This study was conducted to provide histological support for the previously observed antagonistic protective effect of TOL+XYL on EGEE inducible testicular toxicity and to determine whether a similar antagonistic effect can be demonstrated against the EGEE derived hematopoietic toxicity. Compared to the extent of seminiferous tubule degeneration caused by EGEE (150 mg/kg, six times per week for 4 weeks), testes of rats given co-administration of TOL (250 mg/kg)+XYL (500 mg/kg) showed dramatically reduced tubular degeneration. Hyperplasia of Leydig cells in the interstitium was observed in both EGEE and EGEE+TOL+XYL-treated rats. Although a minimal dose of EGEE causing testicular atrophy was used, WBC and platelet counts were decreased significantly. In the TOL+XYL-treated control group, the WBC and platelet counts were not decreased. However, the bone marrow depression caused by EGEE was not reversed by the combined administration of TOL+XYL. In all experimental groups (EGEE alone, TOL+XYL, EGEE+TOL+XYL), plasma levels of creatinine and alkaline phosphatase were significantly decreased. In addition to the marked testicular atrophy, EGEE also decreased the weights of adrenal glands and epididymis. In conclusion, while the testicular degeneration caused by EGEE was antagonized by TOL+XYL, the EGEE derived hematopoietic suppression was not reversed.

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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