Chronic exposure

Inhalation Neurological effects

• Occupational exposure

Schizophreniform psychosis has been reported following occupational exposure to toluene (Goldbloom and Chouinard, 1985) and intentional inhalation of toluene at work (Tarsh, 1979).

Neurobehavioural tests for manual dexterity, visual scanning and verbal memory were statistically different in toluene exposed workers (88 ppm, range 49-130 ppm) compared to controls (13 ppm). The exposed workers had no clinical signs or symptoms of toxicity (Foo et al., 1990). A psychiatric study of workers exposed to toluene (50-80 ppm) found a significantly greater prevalence of mild chronic encephalopathy and organic affective syndrome compared to controls (Larsen and Leira, 1988). In another study there was no significant difference in neurophysical measures, motor conduction velocity, sensory conduction, amplitude and distal latency in ulnar and median nerves in toluene exposed workers compared to controls (Cherry et al., 1985).

Toluene exposure is known to result in auditory and vestibular function alterations with hearing loss, motor inco-ordination and cerebellar dysfunction; in experimental animals there is strong evidence of toluene ototoxicity (Morata et al., 1995).

• Abuse of toluene

Blurred vision, nystagmus, tremor, anorexia, weight loss, inappropriate speech and behaviour, hallucinations, sensory function impairment including anosmia (loss of sense of smell) and hearing loss, memory loss, convulsions and cerebellar ataxia have been reported from toluene abuse (Streicher et al., 1981; Lazar et al., 1983; Hormes et al., 1986; Maas et al., 1991). Nausea, vomiting and haematemesis may also occur (Streicher et al., 1981).

Pancerebellar dysfunction, pyramidal tract abnormality, personality changes, emotional instability, paranoid psychosis (Byrne and Zibin, 1991), cognitive impairment and dementia (Hormes et al., 1986), central pontine myelinolysis (Hong et al., 1996) and Bell's palsy (Aleguas et al., 1991) have been reported from toluene abuse.

Hypothalamic syndrome with diabetes insipidus, adipsia, hypoprolactinaemia and poikilothermia with central sleep apnoea has been reported following use of a toluene-containing glue in a poorly ventilated over a period of 2 years (Teelucksingh et al., 1991).

EEG changes include slow wave abnormality (Lewis et al., 1981). Brain imaging of patients with chronic toluene abuse has shown diffuse atrophy including cerebral hemispheres, brain stem and cerebellum (Lewis et al., 1981; Hormes et al., 1986; Maas et al., 1991), cerebral perfusion impairment (Ryu et al., 1998), diffuse cortical atrophy (Hormes et al., 1986) and poor differentiation of grey and white matter (Rosenberg et al., 1988). Persistent neurological abnormality may occur in spite of some spontaneous recovery (Hormes et al., 1986).

Severe muscle weakness with paralysis (Taher et al., 1974; Bennett and Forman, 1980; Kroeger et al., 1980; Streicher et al., 1981) due to marked hypokalaemia and hypophosphataemia (Streicher et al., 1981) has been reported. This clinical picture may be mistaken for Guillain-Barre syndrome (Streicher et al., 1981).

Renal, electrolyte and hepatic effects

Although there are isolated cases of hepatorenal failure following abuse of toluene (O'Brien et al., 1971; Taverner et al., 1988) and accidental over-exposure at work (Knight et al., 1991), chronic exposure to toluene in the work environment is generally not associated with severe renal or hepatic effects (Low et al., 1988; Ukai et al., 1993). However, chronic abuse of toluene can cause renal toxicity.

• Occupational exposure

A study of 452 exposed workers found no significant differences in hepatic and renal function tests compared to controls (Ukai et al., 1993). A study of 181 male workers in a rotogravure printing plant found that 54 had evidence of liver damage (elevated AST, ALT, GGT or hepatomegaly). However, liver damage was related to alcohol use and obesity in most cases. The workers with the greatest exposure to toluene had lower liver enzyme concentrations than the controls.

In a survey of 289 workers exposed primarily to toluene, 8 were found to have consistently abnormal liver enzyme values (i.e., on 3 or more occasions). All had mild elevations of ALT and AST (less than 2-3 times normal) with a marked increase in the ratio of ALT/AST (this is opposite to that observed in individuals with alcoholic liver disease). Liver biopsy showed mild, pericentral fatty changes. Other causes of these liver changes (obesity, diabetes and alcoholism) were excluded. The toluene concentration was less than 200 ppm and the duration of exposure varied from 2-8 hours a day. Exposure to other solvents was minimal but included ethanol, methanol, trichloroethylene and diethyl ether. No measurements of solvent concentrations were made (Guzelian et al., 1988).

Workers exposed to toluene (<100 ppm) had a significantly higher and increased prevalence of elevated retinol-binding protein in the urine. The concentration was found to correlate with o-cresol, but not with hippuric acid. No difference in the urinary albumin was found compared to the controls. Increased urinary concentrations of retinol-binding protein suggests impaired proximal tubular function (Ng et al., 1990).

• Abuse of toluene

Jaundice and raised bilirubin and liver enzymes (O'Brien et al., 1971; Taverner et al., 1988) and heptaomegaly (Taverner et al., 1988) have been reported from toluene abuse.

Elevated creatine phosphokinase concentrations and rhabdomyolysis (due to marked hypokalaemia and hypophosphataemia), haematuria, pyuria, albuminuria (Streicher et al., 1981), myoglobinuria, glucosuria (Kamijima et al., 1994), aminoaciduria (Moss et al., 1980; Batlle et al., 1988), oliguric renal failure (Gupta et al., 1991) and anuria (O'Brien et al., 1971) have been reported. Ammonia excretion may be high but this is probably due to chronic potassium depletion (Batlle et al., 1988).

There are many cases of renal tubular acidosis reported from toluene abuse (Taher et al., 1974; Bennett and Forman, 1980; Kroeger et al., 1980; Kirk et al., 1984; Weinstein et al., 1985; Patel and Benjamin, 1986; Lavoie et al., 1987; Batlle et al., 1988; Goodwin, 1988; Kamijima et al., 1994; Carlisle et al., 1991; Hong et al., 1996; Gerkin and LoVecchio, 1998; Kamijo et al., 1998). Distal renal tubular acidosis is more common, but proximal renal tubular acidosis and Fanconi's syndrome (Moss et al., 1980) have been reported. There is usually hypokalaemia with hyperchloraemic acidosis (Taher et al., 1974) and respiratory compensation (Streicher et al., 1981). The anion gap is usually normal but may be elevated in patients with advanced renal failure (Hong et al., 1996). Hypomagnesaemia may produce severe hypocalcaemia secondary to parathyroid hormone suppression (Wilkins-Haug and Gabow, 1991). Rhabdomyolysis induced renal failure has also been reported (Kao et al., 2000).

Fatal bilateral adrenal haemorrhage (Kamijo et al., 1998) and nephrolithiasis (Kroeger et al., 1980; Lazar et al., 1983; Weinstein et al., 1985) have been reported from chronic toluene abuse.

Haematological effects

Haematological effects are not a common feature of toluene toxicity. Haematological effects reported in the older literature may have been due to the presence of benzene, which was a common contaminant of toluene before the 1950s (Hayden et al., 1977; Cohr and Stokholm, 1979; King, 1982).

A study of 452 toluene exposed workers found no significant differences in haematological parameters compared to controls (Ukai et al., 1993). Mild anaemia, moderate thrombocytopenia and leucopenia were reported in 7 of 24 workers exposed to toluene for 3-15 years (mean 9.75 years) (Forni et al., 1971).

Anaemia with low haemoglobin and haematocrit, anisocytosis and poikilocytosis on blood smear was reported in a worker exposed to toluene for 40 years. Biopsy confirmed myelofibrosis and osteosclerosis, megakaryocytic hyperplasia and decreased erthyroid and myeloid elements. No benzene was found in the solvent used (Bosch et al., 1988).

Immunotoxicity

A study of 35 painters exposed to benzene, toluene and xylene found that they had significantly lower immunoglobulin A (IgA) and IgG concentrations, but increased IgM. This was thought to be due to a suppressive action of benzene on immunoglobulin producing cells, resulting in inhibition of DNA synthesis (Lange et al., 1973). Serum complement concentrations were decreased in 62 of 79 workers exposed to benzene, toluene and xylene for 0.25 to 18 years (Smolik et al., 1973).

Workers exposed to n-hexane (mean breathing air zone concentration 58 ppm; range 4.3-300 ppm), toluene (mean 27 ppm; range 5.37-115.2 ppm) and methyl ethyl ketone (mean 11 ppm; range 2.43-47 ppm) had no impairment of natural killer cell activity or changes in interleukin-2 or gamma-interferon concentrations (Yücesoy et al., 1999).

Toxicology of Solvents Other effects

ECG changes including multifocal premature ventricular contractions and supraventricular tachycardia have been reported in toluene abusers (Streicher et al., 1981). These changes are probably due to electrolyte imbalance, particularly hypokalaemia and hypomagnesaemia. Myocardial infarction (Cunningham et al.,

1987), including recurrent non-Q-wave myocardial infarction (Hussain et al., 1996), has been reported after chronic abuse of toluene.

Myelofibrosis and focal segmental glomerulosclerosis have been reported in a worker exposed to toluene for 40 years (Bosch et al., 1988). Transient hypothyroidism has been reported from toluene abuse (Hong et al., 1996).

Behavioural studies in animals exposed to toluene have shown hyperactivity, ataxia, addiction, insomnia and memory disturbance (Saito and Wada, 1993).

Dermal

Contact dermatitis may occur following chronic dermal exposure to toluene (Gerarde, 1960; Low et al.,

1988). Repeated application of toluene to rabbit skin caused erythema, oedema, exfoliation, blistering and slight necrosis (Wolf et al., 1956).

Chronic exposure to toluene can cause neuro-ophthalmological changes and affect colour vision.

• Occupational exposure

Workers exposed long-term to low concentrations of toluene (as confirmed by measurement of hippuric acid and ortho-cresol in the urine) had changes in evoked visual potentials compared to controls (Vrca et al., 1995). Another survey found abnormal visual evoked potentials in 24% of exposed workers. The visual evoked potential measurements were repeated two years later in 78% of the group and no significant differences were found. Exposure was confirmed by urine hippuric acid and blood toluene measurements (Urban and Lukas, 1990). Such results are interpreted as a subclinical sign of dysfunction of the CNS.

Erythopsia (red vision) has occasionally been reported following occupational exposure and abuse of toluene (Grant and Schuman, 1993). Loss of colour vision has been reported with some organic solvents including toluene (Muttray et al., 1999), however some studies have demonstrated no colour vision loss with toluene exposure (Nakatsuka et al., 1992).

• Abuse of toluene

Neuro-ophthalmological changes have been reported after chronic abuse of toluene. These include pendular nystagmus, ocular flutter, opsoclonus, oscillopsia, ocular dysmetria and bilateral internuclear ophthalmoplegia (Lazar et al., 1983; Hormes et al., 1986; Maas et al., 1991; Hunnewell and Miller, 1998) and optic neuropathy (Keane, 1978).

Ingestion

No information available.

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