Reproductive toxicity

There is some evidence to suggest that toluene exposure may have adverse effects on reproductive parameters. However, the data are conflicting and no definite conclusion can be reached.

Toxicology of Solvents Fertility

Male workers exposed to toluene have lower luteinising hormone (LH), follicle stimulating hormone (FSH) and testosterone levels (Svensson et al., 1992a,b). This may be due to toluene induced suppression of LH and FSH secretion by the pituitary and/or suppression of hypothalamic gonadotrophic releasing hormone (GnRH). This is supported by the findings in animals and a human postmortem, that toluene preferentially distributes to the brainstem, including the hypothalamus (Ameno et al., 1992). An experimental study in men and women found no changes in LH or FSH secretion after a 3 hour exposure to toluene (Luderer et al., 1999). A study of toluene exposed workers found that low level exposure was associated with reduced fertility in women but not in men (Plenge-Bonig and Karmaus, 1999).

Testicular atrophy with evidence of impaired or suppressed spermatogenesis was noted at postmortem examination of a 28 year old male who was found dead after toluene abuse (Suzuki et al., 1983).

Some studies suggest that women exposed to toluene have a higher incidence of menstrual disorders (reviewed in Barlow and Sullivan, 1982). However, these data are difficult to evaluate; there may have been other factors affecting gynaecological function and the workers were exposed to a mixture of solvents. A more recent study did not demonstrate a higher incidence of menstrual disorders in workers exposed to toluene (Ng et al., 1992a).

Pregnancy

Extrapolation from animal data, suggests that well controlled occupational exposure to toluene does not pose a significant risk to the fetus (Wilkins-Haug, 1997). Teratogenicity can occur, however, following exposure through intentional abuse (Toutman and Lippmann, 1979; Streicher et al., 1981; Hersh et al., 1985; Goodwin, 1988; Wilkins-Haug and Gabow, 1991; Arnold et al., 1994; Pearson et al., 1994; Wilkins-Haug, 1997) and chronic or excessive industrial accidents (Wilkins-Haug, 1997). The teratogenic effects of toluene in utero may be influenced by co-exposure to other substances, particularly ethanol, and intermittent toluene induced metabolic acidosis which may cause fetal hypoxia (Wilkins-Haug, 1997).

In a study of laboratory workers exposed to various chemicals, exposure to toluene was associated with an increased risk of spontaneous abortion (Taskinen et al., 1994). Similarly, there were higher rates of spontaneous abortion in workers exposed to high concentrations of toluene (mean 88 ppm, range 50-150 ppm; 12.4 per 100 pregnancies) compared to controls. There were two groups of controls, workers exposed to little or no toluene (0.25 ppm; 2.9 per 100 pregnancies) and women from a community antenatal and postnatal clinic (4.5 per 100 pregnancies). Among the exposed workers there were also differences in the rate of spontaneous abortion before (2.9 per 100 pregnancies) and after employment (12.6 per 100 pregnancies) in the factory (Ng et al., 1992b).

A study of men exposed to a mixture of solvents found that spontaneous abortion in their partners was significantly associated with paternal exposure to organic solvents in general, high/frequent exposure to toluene and miscellaneous organic solvents (Taskinen et al., 1989).

Abuse of toluene during pregnancy has caused fetal abnormalities (Streicher et al., 1981) which resemble those seen with fetal alcohol syndrome (Toutman and Lippmann, 1979; Wilkins-Haug and Gabow, 1991; Pearson et al., 1994). These include microcephaly, narrow bi-frontal diameter, short palpebral fissures, deep set eyes, flat mid-face, flat nasal bridge and small nose (Wilkins-Haug, 1997). Digital hypoplasia and minor urinary tract abnormalities have also been reported (Hersh et al., 1985; Goodwin, 1988; Pearson et al., 1994). There is also a risk of interuterine growth retardation and developmental and neurological effects including language impairment, developmental delays, hyperactivity and cerebellar dysfunction (Streicher et al., 1981; Hersh et al., 1985; Goodwin, 1988; Wilkins-Haug and Gabow, 1991; Arnold et al., 1994; Pearson et al., 1994; Wilkins-Haug, 1997). A study of 18 children born to mothers who abused toluene during pregnancy found that 83% had craniofacial features similar to those seen with fetal alcohol syndrome; in addition 89% of these children had other minor anomalies. Other findings were: 39% of children were born prematurely, 9% died during the perinatal period, 54% were small for their gestational age, 52% had continued postnatal growth deficiency, 33% had prenatal microcephaly, 67% had postnatal microcephaly and 80% had developmental delay (Pearson et al., 1994).

Hyperchloraemic acidosis was reported in 2 neonates born to mothers who presented with renal tubular acidosis after chronic toluene abuse (Goodwin, 1988). The hyperchloraemic acidosis resolved in the newborns within 72 hours. The urinary hippurate concentration was not elevated in these babies but toluene was found in the serum (1.2 mg/l) of one child. Hypocalcaemia has also been reported in neonates born to mothers admitted to hospital with toluene abuse (Wilkins-Haug and Gabow, 1991).

Toluene has also been implicated in cases of congenital abnormalities where the mother was occupationally exposed to organic solvent mixtures during pregnancy (Holmberg, 1979; McDonald et al., 1987). In a study of occupational chemical exposure in 301 women, there was an excess of congenital defects in those exposed to aromatic hydrocarbons compared to controls. Of this group most of the cases involved toluene, and the defects were predominantly renal or gastrointestinal (McDonald et al., 1987).

In animal studies toluene does not appear to be teratogenic but it is fetotoxic (Barlow and Sullivan, 1982; IPCS, 1985). However, this may be because the concentrations used may not reflect those which cause abnormalities in children borne to mothers who abuse toluene. A study in pregnant mice using high intermittent exposure, to mimic exposure in toluene abusers, found behavioural and neurological effects consistent with those findings in children born to mothers abusing toluene during pregnancy. These effects occurred in the absence of obvious maternal or fetal toxicity (Jones and Balster, 1997).

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