Abstract:
The aromatic solvent toluene is widely used and has been associated with reproductive and developmental toxicity in epidemiological and animal studies. Decreased fertility and instrumental menstrual cycle disturbances have been reported in women who worked with toluene and other solvents. Both suppression of and enhancement of serum gonadotropin (luteinizing hormone, LH and follicle-stimulating hormone, FSH) concentrations have been reported in men chronically exposed to toluene occupationally. Some of the contradictory results obtained in previous studies may be due to the single determinations of gonadotropin levels which were made in these studies. Since gonadotropins are released in a pulsatile fashion, single measurements, especially from a small group of subjects, are likely to miss subtle differences in gonadotropin secretion among groups or to suggest differences when none are in fact present. Together, the previous findings suggested the hypothesis that toluene, due to its ability to easily cross the blood-brain-barrier and ability to alter neuronal function, can acutely suppress pulsatile gonadotropin secretion via suppressive effects on the hypothalamic gonadotropin-releasing hormone (GnRH) neurons or on inputs to these neurons. Furthermore, due to differential pharmacokinetics of toluene, as well as the hormonal differences, between men and women, there may be gender differences in the response of gonadotropins to acute exposures to toluene.
Ten healthy males and healthy females in the follicular (n=10) and luteal phases (n=11) of the menstrual cycle were randomized to inhale filtered air containing 50 ppm toluene or 38% of the American Conference of Government Industrial Hygienists Threshold Limit Value Time-Weighted Average (ACGIH TLV-TWA) or no solvent by mouthpiece for 3 hours. Blood sampling by intravenous catheter was done at 20 min intervals for 3 h before, 3 h during and 3 h after the exposure. Plasma LH and FSH were measured by fluoroimmunoassay. LH and FSH pulse amplitude, pulse frequency, and mean concentrations were calculated using the ULTRA pulse detection program and compared by ANOVA and ANCOVA with repeated measures for the periods before, during and after toluene versus sham exposure.
There was no significant effect of treatment on LH or FSH mean levels, pulse amplitude or pulse frequency in men or women. However, in men there was a significant interaction (p<0,05) between treatment and exposure interval on LH mean levels by ANOVA, with the toluene exposed individuals' mean levels declining during and after exposure, while those of the sham exposed subjects increased. When body mass index or adipose tissue fraction was included as a covariate in the analysis, this significant difference disappeared.
Three hour exposure to 50ppm toluene had no significant effect on pulsatile LH or FSH secretion, and therefore no apparent effects on GnRH secretion, in either men or women in the follicular or luteal phase. Therefore, intermittent, acute exposures to toluene at currently recommended levels, separated by sufficient time for toluene to be cleared completely, do not appear to pose a risk to fertility by hypothalamic or pituitary mechanisms.