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Commentary on the paper by Hsieh et al (see page 510)
The simultaneously hydrophilic and lipophilic properties of glycol ethers account for their use as solvents in a wide range of industrial and domestic products, including paints, varnishes, cleaning agents, and cosmetics. These dozens of compounds are grouped into two main classes: ethylene glycol ethers (EGEs) and propylene glycol ethers (PGEs). Because animal experiments show several EGEs to have high potential for toxicity, especially for testicular function, there has been a shift since 1990 in European countries towards replacing short chain EGEs with PGEs. In various sectors, however, including the semiconductor industry, several short chain EGEs are still in use.1
Short chain EGEs, more specifically, ethylene glycol methyl ether (EGME), ethylene glycol ethyl ether (EGEE), and their acetates, were first shown to affect testicular function, and more precisely, spermatocytes in the pachytene stage, dose dependently in all species tested, resulting in reduced fertility.2 Several other EGEs have also shown testicular toxicity, although at higher doses. Epidemiological investigations have examined sperm quality and male fertility in groups of workers occupationally exposed to EGEs as shipyard painters, in metal casting processes, and in the semiconductor industry. Even though studies on sperm quality are generally limited by low participation rates, these findings indicate that glycol ether exposure appeared to affect sperm production. The wives of male production workers in the semiconductor industry, that is, those exposed to glycol ethers, show a slightly longer average time to pregnancy compared to non-production workers.3
The reproductive toxicity of these compounds among females has been the object of much less study. A few animal studies show ovarian cycle perturbations secondary to luteal cell alterations and diminished fertility potential. Methoxyacetic acid (MAA), EGME’s principal metabolite, increases progesterone production in cultured human luteal cells at the same concentration that increases progesterone in rat luteal cells in vivo. Evidence in humans is even more sparse. In this issue, Hsieh and colleagues4 report on altered prolonged menstrual cycles in female employees in the semiconductor industry in Taiwan. This investigation is a complement to and a possible explanation of a previous association with prolonged time to pregnancy found in the same population.5 Previously, two large US studies in the semiconductor industry (the Semi-Conductor Health Study (SHS)6 and the IBM study3,7) used prospective follow up of conceptions and clinically recognised pregnancies among women exposed to glycol ethers to study menstrual functions and fecundability. Their results do not lend themselves to clear-cut interpretation and were unfortunately not substantiated by the simultaneous biological assessment of exposure to glycol ethers, which should have been useful in disentangling the many co-exposures.
Male reproductive insults have been studied in a variety of occupational settings, but most studies of women have taken place in the semiconductor industry, which is also characterised by exposure to mixtures of other compounds (arsenic, isopropyl alcohol, hydrofluoric acid, phosphorous compounds, xylene, etc), several suspected of reproductive toxicity. Both co-exposures and extent of EGEs use differ between work areas, and in most studies in this industry, risk classification according to work area has been used as a proxy for assessment of EGEs exposure. Risks are suspected to be highest in the photolithography sector; this is one of the two areas where Hsieh and colleagues4 found the highest risk of long menstrual periods, together with the diffusion area, where EGEs are much less frequent. The authors suggest that exposure to isopropyl alcohol may also play a role in the increased risks they found. The US studies also found contradictory results for risks according to work area. Classification according to semiquantitative levels of glycol ether exposure shows an association with fecundability in the prospective study of conception in the SHS study but not the IBM study. Only rarely have urinary levels of EGEs metabolites been used to characterise exposure. In one small study, these metabolites showed no association with menstrual cycle duration.8
Studies of women’s reproductive health in relation to environmental or occupational exposures have rarely looked at menstrual cycle characteristics or ovarian function, probably because of the specific difficulties associated with this evaluation. Measurement tools range from simple questionnaire reports of menstrual cycle characteristics to daily collection of urine samples to determine hormone levels. Systematic study of factors affecting menstrual cycle characteristics is only now beginning.9 For these reasons, it is hard to decide whether the contradictory results observed in different populations exposed to similar compounds are inherent to the outcome under study and the uncertainties in its measurement, or to random fluctuation. For instance, both short (<24 days in the SHS study)6 and long (>35 days in Hsieh and colleagues’ report)4 menstrual cycles have been observed in association with glycol ether exposure. Recent evaluations of the impact of other chemicals, such as organochlorine compounds, on menstrual function have also yielded contradictory results.10,11 These discrepancies underline the need for additional information about validated tools to evaluate ovarian function properly, by measuring different endpoints including steroid hormone levels to determine follicular and luteal phases, and to analyse their validity and feasibility for use in epidemiological assessment.
Commentary on the paper by Hsieh et al (see page 510)
Competing interests: none declared