a) ACUTE OCULAR EXPOSURE: Toluene is a strong eye irritant, causing reversible superficial injury after splash contact, healing within 48 hours. Findings include immediate, severe burning pain, blepharospasm, moderate conjunctival hyperemia, and corneal edema (Grant & Schuman, 1993; Lewis, 2000).
b) CHRONIC INHALATION ABUSE: Decreased color discrimination, optic atrophy with blindness, and pendular nystagmus (in patients with atrophy or visual dysfunction) have been reported with chronic inhalation abuse (Ehyai & Freemon, 1983; Maas et al, 1991; Williams, 1988).

a) Eye exposure results in ocular irritation, lacrimation, pain and possible corneal burns if the liquid is directly splashed in the eye. Slight transient conjunctival irritation and involuntary blepharospasm have also been reported; this resolves within 48 hours (Grant & Schuman, 1993).
b) At 300 to 400 parts per million (ppm), irritation is noticeable. At 800 ppm, this irritation is still slight, with pupil dilation and impaired pupil reaction and fatigue (Grant & Schuman, 1993).
c) 'Polisher's keratitis' (fine vacuolar corneal lesions) is associated with chronic toluene exposure (ITI, 1995).

a) Optic neuropathy resulting from exposure has been documented to produce bilateral vision loss (Baxter et al, 2000).
b) Two case reports of optic atrophy with blindness and sensorineural hearing loss were described in glue sniffers. Four chronic toluene abusers with nystagmus had evidence of visual dysfunction or optic atrophy (Ehyai & Freemon, 1983; Maas et al, 1991; Williams, 1988).
c) CASE REPORT: A 27-year-old man developed bilateral optic atrophy with blindness and sensorineural hearing loss after 5 years of extensive glue sniffing (Ehyai & Freemon, 1983).
d) CASE REPORT: A 27-year-old woman developed optic atrophy, sensorineural hearing loss, and global brain damage after chronic glue sniffing (Williams, 1988).

1) pharmacokinetic differences in the uptake of the solvents
2) differences in metabolism
3) a difference in glutathione concentrations within the sensory epithelium
4) morphological differences of the lateral membranes of the outer hair cells

a) Sudden death after acute inhalation (usually in chronic abusers) is most often due to hypoxia during toluene narcosis, but occasionally is due to fatal dysrhythmia possibly secondary to sensitization to endogenous catecholamines (Bingham et al, 2001; Carlsson, 1982). Sinus bradycardia, ventricular fibrillation and myocardial infarction have been reported.
b) CONTRIBUTING FACTORS: Hypoxia, hypokalemia and concurrent alcohol abuse may increase risk of dysrhythmias (Boon, 1987). Arrhythmogenesis may be related to sudden surges in sympathetic outflow associated with a fight or flight response as well as hypoxia. Electrolyte abnormalities including severe hypokalemia and metabolic acidosis may also contribute to arrhythmogenesis.
c) CASE REPORT: A 16-year-old toluene sniffer developed myocardial infarction and ventricular fibrillation (Cunningham et al, 1987).
d) CASE REPORT: Acute massive inhalation exposure resulted in sinus bradycardia, resolving within 5 hours, in an adult male (Meulenbelt et al, 1990).
e) CASE SERIES: Two men, 34 and 20 years old, developed severe sinus bradycardia (45 and 42 bpm, respectively) after acute exposure to toluene-containing compounds. One patient required intubation and supportive care; the other remained hemodynamically stable. Normal cardiac rhythm returned several hours later in both patients (Einav et al, 1997).
f) Bradycardia, muscle weakness and rhabdomyolysis were reported after toluene inhalation (Zee-Cheng et al, 1985).
g) CASE SERIES: In a study of 25 adult hospitalized paint sniffers, 5 developed cardiac dysrhythmias, including multifocal premature ventricular contractions associated with electrolyte imbalance, but one occurred after correction of hypokalemia (Streicher et al, 1981).

a) CASE REPORT: A 46-year-old man presented to the emergency department with a heart rate of 96 bpm, 30 minutes after ingesting approximately 1 quart of a paint thinner that contained toluene (Caravati & Bjerk, 1997).

a) Isolated cases of dilated cardiomyopathy have been reported in chronic toluene abusers; one case of chronic workplace exposure and recent acute spill exposure was described. Either acute or chronic myocarditis may be found on biopsy.
b) CASE REPORT: A 15-year-old boy developed dilated cardiomyopathy after 2 years of intermittent glue sniffing, 2 weeks after a "heavy" session. Biopsy showed chronic myocarditis (Wiseman & Banim, 1987).
c) CASE REPORT: Dilated cardiomyopathy with evidence of acute myocarditis was reported in an adult chronic solvent abuser who died of cardiac failure (Mee & Wright, 1980).
d) CASE REPORT: A 20-year-old man with documented recent influenza B infection and 3-year occupational toluene exposure developed severe myocarditis 1 week after exposure to a 15-L glue spill. Findings included T-wave inversion, heart block, and an increased MB fraction; biopsy confirmed myocarditis, which resolved within 2 weeks (Knight et al, 1991).

a) CASE REPORT: A 55-year-old man with hypertension, congestive heart failure, cardiomyopathy, and chronic toluene abuse sustained 11 non-Q-wave myocardial infarctions in an 18-month period. He had normal coronary arteries on angiography (Hussain et al, 1996).
b) CASE REPORT: A 22-year-old asthmatic man experienced a subacute lateral myocardial infarction after spending the day stripping varnish from the inside of a boat with pure toluene. Lab studies revealed a CPK of 2760 units/L and a CPK-MB fraction of 40 units/L. ST elevation and T-wave inversion were evident on ECG. A two-dimensional echocardiography showed anterolateral hypokinesis with ejection fraction of 40%. The patient recovered with supportive care (Carder & Fuerst, 1997).

a) CASE REPORT: A 46-year-old man presented to the emergency department with a blood pressure of 147/92 mmHg 30 minutes after ingestion of approximately 1 quart of a paint thinner that contained toluene (Caravati & Bjerk, 1997).

a) A 34-year-old man presented to the hospital with a systolic blood pressure of 60 mmHg and a pulse of 45 bpm after an acute inhalation of paint thinner containing 50% toluene (Einav et al, 1997).

a) AV CONDUCTION ABNORMALITY
b) AV DISSOCIATION

a) Animal experiments suggest that most cases of sudden death after toluene sniffing are due to severe hypoxia during narcosis, but occasionally are due to fatal dysrhythmias from a direct effect of toluene on the myocardial conduction system (Ikeda & Tsukagoshi, 1990).

a) Acute inhalation may result in respiratory failure from bronchospasm or pulmonary edema. Chronic abusers have presented with respiratory failure after acute episodes of abuse.
b) CASE REPORT: A 24-year-old man presented with respiratory failure, acidosis, and muscle weakness after sniffing paint fumes; mechanical ventilation was required for 3 days (Chowdhury, 1977).
c) CASE REPORT: A 21-year-old with a history of massive abuse presented with respiratory arrest after a 6-hour sniffing session; no dysrhythmias or muscle weakness were present (Cronk et al, 1985).

a) Chemical pneumonitis has been reported after aspiration (Snyder, 1987).
b) CASE REPORT: A 49-year-old paint factory worker was found unconscious after being exposed to toluene from a burst hose. It was estimated that he had been lying in toluene for 18 hours. Findings included chemical pneumonitis, renal failure, myoglobinemia, superficial burns, and dehydration; he recovered within 6 months (Reisin et al, 1975).

a) Toluene abusers may asphyxiate while inhaling from a plastic bag. Sudden death after acute inhalation is most often due to hypoxia during toluene narcosis.
b) CASE REPORT: A boy was discovered 12 hours after death from apparent asphyxiation after narcotization by toluene in a plastic bag. Postmortem examination of lungs showed congestion; tracheal and laryngeal petechial hemorrhages were present (CESARS , 1990).

a) An obstructive ventilatory pattern was present in 9 of 10 subjects who had abused spray paint for an average of 34.9 months. In 7 subjects there was a significant increase of airway resistance before exercise and 5 of the 10 subjects exercise provocation produced an increase in residual volume. Five of six subjects who received a trial of bronchodilator had significant improvement (Reyes de la Roche et al, 1987).
b) CASE REPORT: Increasing dyspnea and cough were reported in an 18-year-old man, with a history of asthma, following unintentional inhalation of a toluene-containing solvent. On physical examination, the patient exhibited shallow breathing and nasal flaring. Breath sounds were diminished and O2 saturation was 82%. Chest x-ray revealed pulmonary hyperinflation. Suspecting mucus plugging, high-frequency chest wall oscillation (HFCWO) was initiated. Because of increased agitation and severe fatigue, noninvasive positive-pressure ventilation (NPPV) via nasal mask was added, in order to reduce the work of breathing and to avoid endotracheal intubation. Within minutes of initiating HFCWO-NPPV, the patient began to expectorate bronchial casts and his O2 saturation increased to 93% (Koga et al, 2004).

a) CASE REPORT: A 34-year-old man, chronically addicted to paint thinner, presented to the hospital with a respiratory rate of 6 breaths/minute, hypotension, and a pulse of 45 beats/minute after an acute inhalation of paint thinner containing 50% toluene (Einav et al, 1997).

a) Transient CNS excitation (euphoria, giddiness, tremors, nervousness, insomnia) followed by CNS depression is common after exposure to 400 to 800 parts/million (Snyder, 1987). Chronic exposure has led to hyperreflexia and tremors (CESARS , 1990; HSDB , 2002; von Oettingen et al, 1942).
b) CASE REPORT: A 25-year-old man who sniffed toluene for 10 years had symmetrically hyperactive muscle stretch reflexes and unsustained ankle clonus; bilateral Babinski signs were present (CESARS , 1990).
c) CASE REPORT: Exaggerated deep tendon reflexes and upper extremity tremors were seen in a habitual toluene sniffer (HSDB , 2002).
d) Moderate insomnia and restless sleep have been reported after exposure to 200 parts per million (ppm) for 7 hours; moderate to severe insomnia lasting several days occurred after exposure to 800 ppm. Nervousness was reported after exposure to 600 ppm (von Oettingen et al, 1942).

a) Toluene is a central nervous system depressant in animals and humans (ACGIH, 1991).
b) Exposure to 100 to 200 parts per million results in headache and mild, transient upper respiratory tract irritation. Levels of 200 ppm or more may produce encephalopathy, headache, depression, lassitude, impaired concentration, transient memory loss, and impaired reaction time (ACGIH, 1991).
c) CNS depression follows excitation after exposure to 400 to 800 parts per million (ppm), with signs/symptoms of headache, dizziness, fatigue, drowsiness, lassitude, confusion, hilarity, vertigo, increased reaction time, and perceptual speed; ataxia, severe fatigue are reported above 800 ppm. Rapid general anesthesia occurs at 10,000 ppm or greater (ACGIH, 1991; Budavari, 1996; Snyder, 1987).
d) Intentional inhalational abuse, with very high concentrations, can result in cerebellar ataxia and cognitive dysfunction (ACGIH, 1991). The effects can be severe and are likely to be permanent in individuals with a history of chronic misuse (ie, glue sniffing) (Karmakar & Roxburgh, 2008).
e) Changes in cortical and subcortical EEGs have been noted to appear in the early stages of exposure to high concentrations of toluene vapor (Takeichi et al, 1986).
f) CASE REPORT: A 46-year-old man developed ataxia, disorientation, and belligerence followed by progressive CNS depression after ingesting approximately one quart of a paint thinner containing toluene (Caravati & Bjerk, 1997).

a) Reversible acute behavioral effects after a single toluene inhalation exposure to over 100 parts per million may be a sign of CNS impairment leading to irreversible performance loss with repeated exposure (Escheverria et al, 1989).
b) In a worker acutely exposed to toluene, formal neuropsychological assessments over 2.5 years revealed cognitive, motor, and behavioral changes (Welch et al, 1991).
c) Decrease in both reaction time and perceptual speed after exposures to toluene at 300 parts per million (ppm) and 700 ppm, respectively, have been reported (Snyder, 1987).

a) Moderate insomnia and restless sleep have been reported after exposure to 200 parts per million (ppm) for 8 hours. Moderate to severe insomnia lasting several days has been reported after exposure to 800 ppm (von Oettingen et al, 1942).

a) Nervousness and confusion have been reported after exposure to 600 parts per million (von Oettingen et al, 1942).

a) Progressive, irreversible mixed encephalopathy with cognitive difficulty and cerebellar ataxia, and organic affective syndromes have occurred after chronic workplace or abuse exposures. MRI showed abnormal gray-white matter differentiation with cerebral/cerebellar atrophy, correlating with neuropsychological impairment (HSDB , 2002; Larsen & Leira, 1988).
b) INCIDENCE: The prevalence of mild chronic encephalopathy and organic affective syndrome was greater in workers with chronic toluene exposure (Larsen & Leira, 1988). Organic brain syndrome (cognitive impairment, memory impairment) was found in 21% of printers and 40 of their assistants exposed to toluene; prevalence was related to exposure levels (300 parts per million (ppm) in printers; 430 ppm in assistants) (Snyder, 1987).
c) CASE REPORT: Progressive memory loss, fatigue, impaired concentration, irritability, persistent headaches, and cerebellar dysfunction were reported in one case 8 months after initial, acute exposure to toluene in spray paint (Carlton et al, 1989).
d) CASE REPORT: Permanent encephalopathy was reported in a man who inhaled toluene regularly for over 14 years (HSDB , 2002).
e) CASE REPORT: A 14-year-old boy developed extensive hypothalamic dysfunction (diabetes insipidus, adipsia, hyperprolactinemia, poikilothermia) and central sleep apnea after exposure to toluene-containing glue for hours at a time, several times a week for 2 years in a poorly ventilated room (Teelucksingh et al, 1991).
f) RADIOGRAPHIC CHANGES

a) INCIDENCE: Two of twenty-five hospitalized paint sniffers developed peripheral neuropathy (Streicher et al, 1981).
b) ONSET has been reported after months to years of chronic abuse (King et al, 1985; Shannon, 1987).
c) FINDINGS can be sensorimotor or predominantly motor. It often has a glove-stocking distribution, with or without muscle atrophy. It is associated with loss of deep tendon reflexes, slowed sensory nerve conduction velocity, and gait disturbance (Shannon, 1987).
d) PROGNOSIS: This may resolve rapidly or persist for several years; it can deteriorate for several weeks after discontinuation of exposure (King et al, 1985).
e) CONFOUNDING FACTORS: Some cases of peripheral neuropathy in toluene glue sniffers have been attributed to other ingredients in the glue (hexane, methyl ethyl ketone) or concurrent drug abuse (Snyder, 1987).
f) Some sources claim peripheral neuropathy is NOT a feature of chronic exposure to toluene (ACGIH, 1991; Neundorfer & Reinhardt, 1998).

a) Isolated cases of grand mal epilepsy, status epilepticus, choreoathetosis, temporal lobe epilepsy, and opisthotonus have been reported in chronic abusers of toluene (Allister et al, 1981; Arthur & Curnock, 1982; Bartolucci & Pellettier, 1984; Byrne & Zibin, 1991; Helliwell & Murphy, 1979; Lamont & Adams, 1982).

a) CASE REPORT: A 44-year-old man developed Bell's palsy after an acute exposure superimposed on chronic exposure 1 to 3 times/week for 3 years to a toluene-containing lacquer thinner; the thinner was always used in a poorly ventilated, enclosed area without a respirator (Aleguas et al, 1991).

a) CASE REPORT: A 48-year-old man who had been exposed to toluene in thinner for more than 30 years developed postural tremor of his fingers as well as stimulus-sensitive spinal myoclonus, with rhythmic myoclonic jerks of the right upper limb produced by tendon tap of the right brachioradialis (Sugiyama-Oishi et al, 2000).
b) CASE REPORT: A 25-year-old man who had been sniffing toluene for 10 years reportedly had symmetrically hyperactive muscle stretch reflexes and unsustained clonus at the ankles; bilateral Babinski signs were present (CESARS , 1990).
c) Exaggerated deep tendon reflexes were noted in a habitual toluene sniffer (HSDB , 2002).

a) Dizziness has been reported in toluene-exposed workers (Ukai et al, 1993).

a) EEG changes and electrophysiological alterations in brain function have been reported in experimental animals (Dyer et al, 1984; Takeuchi & Hisanaga, 1977).

a) In experimental animals exposed to toluene vapor, decreased brain weight and decreased weight of the cerebral cortex were noted when compared with controls (HSDB , 2002).

a) One of the main presenting syndromes in chronic toluene abusers is gastrointestinal, with abdominal pain, nausea, vomiting, and/or hematemesis (HSDB , 2002; Streicher et al, 1981).
b) CASE REPORT: An adult with a 10-year history of glue sniffing presented with abdominal cramps, vomiting, and loose bowel movements 2 weeks after abruptly stopping this behavior due to difficulty in obtaining further glue because of an inability to walk (Karmakar & Roxburgh, 2008).
c) CASE SERIES: Six of twenty-five paint sniffers hospitalized presented with mainly gastrointestinal effects; 3 had a history of concurrent alcohol use. Serum bicarbonate in the 5 with vomiting did not reflect gastric alkalosis, but was low and consistent with toluene-induced metabolic acidosis (Streicher et al, 1981).
d) CASE REPORT: A 46-year-old man complained of diffuse abdominal pain and began vomiting a solvent-smelling clear fluid upon presentation to the emergency department approximately 30 minutes after ingesting approximately 1 quart of a paint thinner that contained toluene. The patient also had 4 episodes of diarrhea. Bloody gastric contents were obtained by a nasogastric tube. The hemorrhagic gastritis resolved within 36 hours (Caravati & Bjerk, 1997).

a) CASE REPORT (ABUSE): Hepatorenal failure was attributed to abuse of a toluene-based cleaning fluid in a 19-year-old man (O'Brien et al, 1971).
b) CASE REPORT (ABUSE): A 19-year-old developed acute renal and hepatic failure after inhalation of an industrial glue containing 29% toluene (Taverner et al, 1988).
c) CASE REPORT (OCCUPATIONAL): A 20-year-old man with documented recent influenza B infection and 3-year occupational toluene exposure developed perivenular hepatic necrosis and acute renal failure one week after exposure to a 15 L glue spill (Knight et al, 1991).

a) Hepatomegaly has been documented in cases of toluene exposure; an enlarged liver is likely to be found on physical exam (Baxter et al, 2000; Zenz, 1994).
b) Impaired liver function with hepatomegaly were reported in a case of chronic toluene exposure (CESARS , 1990).

a) Fatty liver and increased ALT/AST ratio has been associated with chronic workplace exposure, but concurrent alcohol use has been a confounding variable and a cause-effect relationship is unproven; alcoholism increased the risk of severe steatosis in animal studies (Guzelian et al, 1988; Howell et al, 1986; Shiomi et al, 1993).
b) PROSPECTIVE SURVEY: Of 289 workers exposed to toluene vapors in a printing factory, 8 had persistent abnormalities in liver function studies (3 or more consecutive ALT, AST or alkaline phosphate values). All had ALT/AST ratios greater than 1.0 (range: 1.09 to 2.46). Liver biopsy in 7 cases showed mild to marked centrilobular and midzonal fatty change (Guzelian et al, 1988).

a) Animal studies have suggested that toluene abuse may increase the severity of alcoholic fatty liver and may increase the risk of alcoholics for developing serious liver disease (Howell et al, 1986).

a) DISTAL RENAL TUBULAR ACIDOSIS
b) PROXIMAL RENAL TUBULAR ACIDOSIS

a) Isolated cases of acute renal failure secondary to interstitial nephritis, myoglobinuria, or acute toxic tubular necrosis have been reported after workplace exposure, accidental ingestion, and glue sniffing. One case of irreversible renal injury has been reported (Voights & Kaufman, 1983; Gupta et al, 1991).
b) CASE REPORT: A 19-year-old developed acute interstitial nephritis and hepatic failure after inhaling an industrial glue containing 29% toluene (Taverner et al, 1988).
c) CASE REPORT: A 49-year-old paint factory worker, found unconscious after lying in toluene from a burst hose for about 18 hours, developed acute renal failure, dehydration, and heavy myoglobinuria. Recovery was complete after 6 months (Reisin et al, 1975).
d) CASE REPORT: A 26-year-old chronic solvent sniffer developed myoglobinemia, rhabdomyolysis, and acute renal failure after accidentally ingesting 100 mL of a solvent containing 79% toluene during a sniffing session. As a potential confounding factor, he was tied to a pole with wrists and ankles tied behind his back for 9 hours in the hot sun as punishment (Mizutani et al, 1989).

a) CASE REPORT (OCCUPATIONAL): A 60-year-old man with a 40-year history of workplace exposure to toluene presented with focal segmental glomerulosclerosis, characterized by hematuria, proteinuria, and immune complex deposition in glomerular lesions (Bosch et al, 1988).
b) CASE REPORT (GLUE SNIFFING): Glomerulonephritis was reported in a 16-year-old girl with a history of heavy smoking and glue sniffing. The glue contained n-hexane, toluene, ethyl acetate, and petrol fraction (Bonzel et al, 1987).

a) Menstrual abnormalities and uterine or vaginal prolapse have been reported in female workers exposed to toluene (Snyder, 1987a; CESARS , 1990; Ng et al, 1992).

a) Thirty-eight female shoe workers exposed to 60 to 100 parts per million of toluene reported dysmenorrhea significantly more often than the 16 unexposed women (Snyder, 1987).
b) In another study of 231 female production workers with high exposure to toluene, it was uncertain whether dysmenorrhea was associated specifically with exposure to toluene, as other behavioral and work-related factors may also have resulted in dysmenorrhea (Ng et al, 1992).
c) Hypermenorrhea and polymenorrhea were reported in female workers in a rubber factory (CESARS , 1990).

a) An increased incidence of uterine and vaginal wall prolapse occurred in female workers exposed to toluene compared with a control group (CESARS , 1990).

a) SUMMARY
b) CASE REPORTS

a) Two cases of bone marrow dysplasia have been reported after exposure to toluene proven to have no benzene contamination; most older studies linking toluene to blood dyscrasias involved benzene contamination (Hathaugy et al, 1991). Such high-level benzene contamination rarely occurs with modern distillation techniques.
b) CASE REPORT: A 13-year-old boy developed fatal aplastic anemia after exposure to toluene-containing glue during assembly of model airplanes. No benzene was detected on analysis of the glue (Snyder, 1987).
c) CASE REPORT: A 60-year-old man with workplace exposure to a solvent containing 90% toluene (confirmed not to contain benzene) for 40 years presented with anemia and glomerulosclerosis; with a hematocrit of 24%, hemoglobin 8 g/dL, anisocytosis and poikilocytosis. Biopsy confirmed myelofibrosis, osteosclerosis, megakaryocytic hyperplasia and decreased erythroid and myeloid elements (Bosch et al, 1988).
d) CASE REPORT: In workers exposed to concentrations greater than 500 parts per million, bone marrow biopsy showed partial destruction of the blood-forming elements and aplastic anemia was diagnosed (CESARS , 1990).

a) Increased coagulation time and hypoprothrombinemia were reported in workers in a pharmaceutical plant (Clayton & Clayton, 1981).

a) OCCUPATIONAL EXPOSURE: A study conducted in 34 male-factory workers in Taiwan to assess continuous low-level toluene exposure found that workers continuously exposed to toluene had a lower platelet count (216 +/- 41 x 10(6)/mcgL) than workers intermittently exposed (252 +/- 40 x 10(6)/mcgL). Other hematologic studies (ie, RBC and WBC) were similar between the 2 groups. The alteration in platelet count following low-level toluene exposure may be due to increasing platelet damage, transient hyperagglutination, or disturbance of platelet synthesis (Shih et al, 2011).

a) Rats injected subcutaneously with toluene developed transient granulocytopenia (Clayton & Clayton, 1981).

a) After prolonged contact with skin, toluene may cause drying and defatting, which results in fissured dermatitis (Bingham et al, 2001; HSDB , 2002).

a) CASE REPORT: Superficial burns over 10% of the body occurred in a worker rendered unconscious while laying in a pool of toluene for 18 hours (Reisin et al, 1975).
b) CASE REPORT: A 22-year-old man developed 71% body surface area burns after dermal contact with a sealer containing 65% toluene, 20% acetone, and 12% acrylic resin. The patient sustained cardiac arrest immediately after arrival in the emergency department. The burns became necrotic over several days and resulted in massive fluid loss, rhabdomyolysis, renal failure, and disseminated intravascular coagulation, and the patient died 6 days after admission of uncal herniation secondary to anoxic cerebral injury (Shibata et al, 1994).

a) Rhabdomyolysis is present in as many as 40% of chronic toluene abusers, secondary to hypokalemia, hypophosphatemia, compression ischemia in comatose patients, or direct muscle toxicity (Karmakar & Roxburgh, 2008; Shannon, 1987; Streicher et al, 1981).

a) A common presenting syndrome in chronic abusers is severe muscle weakness, sometimes misdiagnosed as Guillain-Barre syndrome. Respiratory and central muscles are usually spared with no change in reflexes or sensory deficits. The weakness resolves within 72 hours after fluid/electrolyte repletion.
b) CASE SERIES: Of 25 adults admitted with symptoms from paint sniffing, 9 had predominant complaints of muscle weakness and 4 had quadriparesis. Electrolyte abnormalities, especially hypokalemia and hypophosphatemia, were more severe in this group; 75% had rhabdomyolysis (Streicher et al, 1981).
c) HYPOTONIC MUSCLE TONE was noted in a habitual toluene sniffer. Muscle atrophy and weakness were not seen (HSDB , 2002).

a) CASE REPORT: A 19-year-old woman was found at autopsy to have adrenal insufficiency secondary to fatal adrenal hemorrhage from prolonged inhalation of lacquer thinner (67% toluene). Severe degeneration and necrosis of the adrenal cortex was visible at autopsy. She had been sniffing this product intermittently for 5 years (Kamijo et al, 1998).

a) Studies in toluene exposed workers have demonstrated lower levels of follicle stimulating hormone, luteinizing hormone, and testosterone (Svensson et al, 1992; Svensson et al, 1992a).

a) However, although there are reports of reproductive effects of toluene abuse or heavy occupational exposure in humans, because of confounding concomitant exposure to other solvents or alcohol, no causal link has been established (ACGIH, 1991). Still, toluene has been linked, along with many other solvents, to the occurrence of birth defects in the national registry in Finland (Holmberg, 1979; Kurppa, 1983).
b) Some sources report that toluene produces more developmental effects than teratogenic effects (Bingham et al, 2001).

a) Two infants born to mothers who had abused organic solvents during pregnancy had severe motor and intellectual disabilities, microcephaly, cerebral palsy, seizures, mental retardation, growth deficiency, and minor craniofacial abnormalities (Arai et al, 1997).
b) Three of five children born to women who had sniffed paint were growth-retarded, and 2 had dysmorphic features, anomalies, craniofacial abnormalities, and hyperchloremic acidosis (Goodwin, 1988).
c) Two infants born to mothers who abused pure toluene during pregnancy, without excessive alcohol consumption, were reported to have developmental delay, attention deficits, growth retardation, and phenotypic abnormalities (microcephaly, narrow bifrontal diameter, short palpebral fissures, deep-set eyes, low-set ears, flat nasal bridge, micrognathia, and blunt fingertips) (Hersh, 1989).
d) One study reported a child with multiple physical deformities and symptoms similar to fetal alcohol syndrome born to a mother who consumed significant amounts of alcohol in addition to chronically inhaling toluene throughout pregnancy. The author suggested that toluene may have diminished the mother's ability to detoxify alcohol (Toutant, 1979).
e) In another study, no excess blood loss was reported after delivery in women exposed to toluene (and benzene) (Michon & Tadeusz, 1968). Intrauterine growth retardation has been linked to toluene exposure (Schardein, 2000).
f) Isolated cases of birth defects have been reported in the children of women heavily exposed to toluene in shoe making (also exposed to trichloroethylene) (Euler, 1967), in an alcoholic (Toutant & Lippmann, 1979), and in persons abusing toluene (Hersh et al, 1985). In these latter cases, exposures were probably mixed with alcohol, which is known to cause fetal alcohol syndrome in humans.
g) Women exposed to toluene in laboratory work had a 4.7-fold increased risk of spontaneous abortions, but no increase in birth defects was found (Taskinen et al, 1994). Women exposed to toluene in the printing industry had reduced fecundity; there was no male-mediated effect on fecundity (Plenge-Bonig & Karmaus, 1999).
h) Toluene is a major solvent of abuse. Glue sniffers may be exposed to concentrations in excess of 10,000 parts per million (ACGIH, 1991). Case reports have identified a syndrome of defects resulting from toluene abuse similar to that seen in fetal alcohol syndrome (Schardein, 2000).
i) In one study, children of women who abused toluene during pregnancy were at significant risk for preterm delivery, perinatal death, and growth retardation (Wilkins-Haug & Gabow, 1991). Birth defects in children of women who abused toluene include CNS deficiencies, hydronephrosis, and craniofacial abnormalities (including microcephaly), as well as intrauterine growth retardation and postnatal growth retardation (Hersh et al, 1985; Schardein, 2000).
j) Two infants born to mothers who had abused organic solvents during pregnancy had severe motor and intellectual disabilities, microcephaly, cerebral palsy, seizures, mental retardation, growth deficiency, and minor craniofacial abnormalities (Arai et al, 1997).
k) The spectrum of defects in children of women who have abused toluene and other solvents has been called fetal solvents syndrome or toluene embryopathy (Schardein, 2000). This syndrome is becoming more well-defined, as demonstrated by 2 studies of groups of infants born to mothers abusing toluene.

a) In 2 studies involving rats and mice, no teratogenic effects were found. In another study, exposed rats showed a statistically significantly higher incidence of skeletal malformations than controls. Although it was not teratogenic in mice at 500 mg/m(3), it reduced fetal weight (Hudak & Ungvary, 1978).
b) It was not teratogenic in rats, but produced decreased fetal weight and delayed ossification at the high dose of 1500 mg/m(3), which was toxic to the mothers (Hudak, 1977).

a) Listed as: Toluene
b) Carcinogen Rating: 3

a) LOW-LEVEL OCCUPATIONAL EXPOSURE: A study conducted in 34 male-factory workers in Taiwan to assess continuous low-level toluene exposure found that workers continuously exposed to toluene had a lower platelet count (216 +/- 41 x 10(6)/mcgL) than workers intermittently exposed (252 +/- 40 x 10(6)/mcgL). Other hematologic studies (ie, RBC and WBC) were similar between the 2 groups. The alteration in platelet count following low-level toluene exposure may be due to increasing platelet damage, transient hyperagglutination, or disturbance of platelet synthesis (Shih et al, 2011).

a) Hippuric acid (a metabolite of toluene) in urine is used as a biological marker of toluene exposure; however, it is not specific. It is only reliable for exposures to high levels and levels may not correlate with exposure (Bingham et al, 2001; Harbison, 1998; Lof et al, 1993).
b) Diets high in certain fruits (prunes, cranberries, plums) and vegetables that contain benzoic acid or precursors (such as quinic acid) can affect the validity of these measurements by increasing hippuric acid excretion (Ng et al, 1990). Cigarette smoking and ethanol consumption may decrease urinary excretion of hippuric acid (Kawamoto et al, 1995).

a) According to some sources, however, end-of-shift urine hippuric acid measurement is the established biological exposure index for workplace exposure and correlates linearly with TWA; nonexposed people have levels of 0.4 to 1.4 g/L.
b) There was a significant linear correlation between TWA toluene concentrations and shift-end urine hippuric acid levels in Chinese workers. Urine hippuric acid increased by 9 mg/L per ppm of breathing zone toluene; ethnic differences and/or smoking history were confounding variables (Liu et al, 1992).
c) LOW-LEVEL TOLUENE EXPOSURE: A study conducted in 34 male-factory workers in Taiwan to assess continuous low-level toluene exposure found that workers continuously exposed to toluene had a difference in the mean value of urinary hippuric acid between the two periods (ie, testing on Monday morning and Friday afternoon) (p less than 0.01) and the odds ratio of impairment of sympathetic ()R = 4.13, p = 0.11) and peripheral nerves (OR = 6.94, p = 0.074) were higher in worker continuously exposed to toluene (Shih et al, 2011).

a) Toluene abusers may produce excessive amounts of hippuric acid and this may be used to aid identification of suspected, recent toluene abuse(Raikhlin-Eisenkraft et al, 2001).

a) URINE O-CRESOL: Urine o-cresol levels have been proposed to become the established biological exposure index for workplace exposure; they are suggested to be more specific and correlate better with daily environmental concentrations (ACGIH, 1991; De Rosa et al, 1987; Ng et al, 1990).
b) URINE D-GLUCARIC ACID: Urine D-glucaric acid has been proposed as a noninvasive indicator of toluene-induced liver enzyme induction. End-of-shift levels were higher in exposed workers compared to controls (Moretto & Lotti, 1990).

a) Changes in cortical and subcortical EEGs have been noted to appear in the early stages of exposure to high concentrations of toluene vapor (Takeichi et al, 1986).

a) BIOLOGICAL MONITORING LEVELS: The concentration of toluene in expired air that corresponds to airborne toluene exposure at 377 mg/m(3) is 40 mg/m(3) (Periago et al, 1994).

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
b) ADVERSE EFFECTS/CONTRAINDICATIONS

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

a) Administer beta2 adrenergic agonists. Consider use of inhaled ipratropium and systemic corticosteroids. Monitor peak expiratory flow rate, monitor for hypoxia and respiratory failure, and administer oxygen as necessary.

a) 2.5 to 5 milligrams diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response, administer 2.5 to 10 milligrams every 1 to 4 hours as needed OR administer 10 to 15 milligrams every hour by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.5 milligram by nebulizer every 30 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

a) 0.15 milligram/kilogram (minimum 2.5 milligrams) diluted with 4 milliliters of 0.9% saline by nebulizer every 20 minutes for three doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulizer as needed. Consider adding ipratropium to the nebulized albuterol; DOSE: 0.25 to 0.5 milligram by nebulizer every 20 minutes for three doses then every 2 to 4 hours as needed, NOT administered as a single agent (National Heart,Lung,and Blood Institute, 2007).

a) The incidence of adverse effects of beta2-agonists may be increased in older patients, particularly those with pre-existing ischemic heart disease (National Asthma Education and Prevention Program, 2007). Monitor for tachycardia, tremors.

a) Consider systemic corticosteroids in patients with significant bronchospasm. PREDNISONE: ADULT: 40 to 80 milligrams/day in 1 or 2 divided doses. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 or 2 divided doses (National Heart,Lung,and Blood Institute, 2007).

a) High frequency chest wall oscillation (HFCWO) was used in an 18-year-old man, with a history of asthma, who developed severe respiratory distress (dyspnea, diminished breath sounds) following aspiration of a toluene-containing solvent, and in whom symptomatic treatment, including bronchodilators, were ineffective. A chest x-ray had revealed pulmonary hyperinflation and an initial pulse oximetry showed an O2sat of 82%. After a few seconds of beginning HFCWO treatment, the patient developed increased agitation and severe fatigue, therefore NPPV was added via nasal mask in order to reduce the work of breathing and to avoid endotracheal intubation. After a few minutes of this combined treatment, the patient was able to expectorate bronchial casts and his O2 saturation increased to 93%. Initially, he was given 3 10-minute HFCWO treatments the first day with NPPV continued until the next morning. Then, 10-minute HFCWO treatments were administered twice daily for 7 days. At the end of the HFCWO treatments (8 days after initial presentation), the patient's symptoms had resolved and a repeat chest x-ray indicated that his pulmonary hyperinflation had improved significantly (Koga et al, 2004).

a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)

1) The first patient was exposed for 3 hours before being found with eye irritation, slurred speech, stupor, and inability to walk or sit. The anion gap was 16.5 and blood toluene level was 4.1 mg/L. Sinus bradycardia was found on the ECG. He was amnesic for the last 2 hours of the exposure and for the hour after his rescue. He was discharged 5 hours after being found.
2) The second patient was exposed for 2 hours before being found with eye irritation, drowsiness, and headache. He was just able to walk. The anion gap was 14.3 and the blood toluene level was 2.2 mg/L. His ECG showed sinus tachycardia. Amnesia was present for the duration of exposure until shortly after rescue. He recovered within 2 hours.

a) Abusers with mild signs of intoxication had blood levels of 1 to 2.5 mg/L; 50% of those with levels of 2.5 to 10 mg/L had marked intoxication (hospitalized, hallucinations). Coma or death was associated with levels greater than 10 mg/L (Baselt, 2000).
b) CASE SERIES: In 51 patients hospitalized for toluene abuse, the threshold level associated with neuropsychiatric events (0.8 mcg/g in blood) was lower than that associated with physical signs (30 mcg/g in blood) (Miyazaki et al, 1990).
c) Toluene, the main ingredient in some glues, was shown in one study to account for no more than 40% of the vapor "cocktail" in inhalation of the glue. After several minutes, the concentration of toluene vapor dropped, and the concentrations of less toxic n-heptane and methyl ethyl ketone vapors increased. The toxic effects of long-term exposure to toluene via glue sniffing may not be demonstrated well due to the slower evaporation of toluene in the glues (Midford et al, 1993).

a) There was no simple relationship between blood toluene levels and degree of impairment in 114 drivers arrested with blood toluene concentrations greater than 10 micromolar (Gjerde et al, 1990).

a) Post-shift blood levels correlate with the daily TWA (Baselt, 2000; Nise et al, 1989):
b) 100 parts per million for 30 minutes to 2 hours: 0.4 to 1.2 mg/L
c) 191 to 309 parts per million for 8 hours: mean 5.9 to 6.7 mg/L (up to 20.3 mg/L)
d) STUDY: A close correlation between time weighted toluene exposure and subcutaneous adipose tissue levels was found in printers. The elimination of toluene was followed in 11 subjects, and the median half time of 79 hours (range 44 to 178 hours) reflected the decline in adipose tissue. Exposure continued from endogenous adipose tissue redistribution after the end of exogenous exposure (Nise et al, 1989).

a) Toluene blood concentrations have ranged from 10 to 119 mcg/L in fatal cases of acute toluene poisoning (Ameno et al, 1989; Baselt, 2000; Kashima et al, 1969; Takeichi et al, 1986).

1) Toluene

a) TWA: 100 ppm (375 mg/m(3))
b) STEL: 150 ppm (560 mg/m(3))
c) Ceiling:
d) Carcinogen Listing: (Not Listed) Not Listed
e) Skin Designation: Not Listed
f) Note(s):

a) IDLH: 500 ppm
b) Note(s): Not Listed

a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

a) 8-hour TWA:

a) 8-hour TWA:200 ppm
b) Acceptable Ceiling Concentration: 300 ppm
c) Acceptable Maximum Peak above the Ceiling Concentration for an 8-hour Shift:
d) Notation(s): Not Listed

a) 59 mg/kg
b) 640 mg/kg (Lewis, 2000)

a) 2250 mg/kg

a) 800 mg/kg (OHM/TADS, 2002)
b) 1332 mg/kg
c) 1640 mg/kg (OHM/TADS, 2002)

a) 636 mg/kg
b) 5000 mg/kg (Lewis, 2000)
c) 5850 mg/kg (OHM/TADS, 2002)
d) 7530 mg/kg for 14D (OHM/TADS, 2002)
e) 7.0 g/kg (Bingham et al, 2001; OHM/TADS, 2002)
f) 7.4 g/kg (Bingham et al, 2001)
g) 7.53 g/kg (Bingham et al, 2001)
h) 14D-old, 3.0 mL/kg (Bingham et al, 2001)

a) 5000 mg/kg (OHM/TADS, 2002)

a) 100 ppm -- hallucinations and distorted perceptions; changes in motor activity and psychophysiological test results
b) 200 ppm -- changes in CNS recordings; antipsychotic effects; bone marrow changes
c) 500 ppm (OHM/TADS, 2002)

a) 1000 ppm for 6H/20D - intermittent -- somnolence (general depressed activity); changes in erythrocyte and leukocyte count
b) 1250 ppm for 6H/14W - intermittent -- changes in liver weight; death
c) 12,000 ppm for 10M/8W - intermittent -- changes in liver and bladder weights; weight loss or decreased weight gain
d) Female, 500 mg/m(3) for 24H at 6-13D of pregnancy -- fetotoxicity
e) Female, 200 ppm for 7H at 7-16D of pregnancy -- developmental abnormalities of the urogenital system
f) Female, 400 ppm for 7H at 7-16D of pregnancy -- musculoskeletal developmental abnormalities; biochemical and metabolic effects in newborn
g) Female, 1000 ppm for 6H at 2-17D of pregnancy --musculoskeletal system developmental abnormalities

a) 300 mg/m(3) for 5H/21D - intermittent -- changes in sense organs and special senses
b) 300 ppm for 6H/2Y - intermittent -- changes in blood, including pigmented or nucleated red blood cells; weight loss or decreased weight gain
c) 320 ppm for 24H/30D - continuous -- changes in brain weight; weight loss or decreased weight gain; effects on lipids, including transport
d) 1500 ppm for 6H/26W - intermittent -- degenerative changes in the brain and its coverings; kidney, ureter and bladder changes; dopamine in striatum
e) 1600 ppm for 20H/7D - intermittent -- kidney, ureter and bladder changes; weight loss or decreased weight gain; death
f) 2200 ppm for 8H/23W - intermittent -- ataxia; musculoskeletal changes; weight loss or decreased weight gain
g) 2500 ppm for 6.5H/15W - intermittent -- changes in heart, liver and bladder weights
h) 12,000 ppm for 10M/8W - intermittent -- changes in bladder weight; weight loss or decreased weight gain; effects on transaminases
i) Female, 800 mg/m(3) for 6H at 14-20D of pregnancy -- fetotoxicity; behavioral effects in newborn
j) Female, 1000 mg/m(3) for 24H at 7-14D of pregnancy -- developmental abnormalities of the musculoskeletal system
k) Female, 1500 mg/m(3) for 24H at 1-8D of pregnancy --fetotoxicity; musculoskeletal system developmental abnormalities
l) Female, 1200 ppm for 6H at 9-12D of pregnancy -- delayed effects in newborn
m) Female, 2000 ppm for 6H at 7-17D of pregnancy -- maternal effects; physical effects in newborn
n) Female, 6000 ppm for 2H/5W - intermittent

a) 1200 ppm for 6.5H/D for 5D/W for 2Y (Bingham et al, 2001)

a) 1200 ppm for 6.5H/D for 5D/W for 2Y (Bingham et al, 2001)

a) Female, 118 mg/kg/day for 193D (Bingham et al, 2001)
b) Female, 353 mg/kg/day for 193D (Bingham et al, 2001)
c) Female, 590 mg/kg/day for 193D (Bingham et al, 2001)

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

a) Emesis is probably not indicated due to the possibility of aspiration of gastric contents.
b) Activated charcoal in some cases may cause vomiting, which may be hazardous to a patient who has ingested a volatile hydrocarbon. Limited data exist on the adsorption of petroleum distillates by activated charcoal.
c) Consider gastric lavage following a large overdose (more than 4 times the therapeutic dose) within 2 hours of ingestion. Place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 mL/kg water or lavage solution, then aspirate. Repeat 10 times.

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) Remove the patient and other animals from the source of contamination.
5) Treatment should always be done on the advice and with the consultation of a veterinarian. Additional information regarding treatment of poisoned animals may be obtained from a Board Certified (ABVT) Veterinary Toxicologist (check with nearest veterinary school or veterinary diagnostic laboratory) or the National Animal Poison Control Center.
6) ANIMAL POISON CONTROL CENTERS
7) Due to the lack of reports of large animal intoxication with this substance, the animal poisoning sections of this management address small animals (dogs and cats) only. In case of a poisoning involving large animals, consult a veterinary poison control center.

1) DOGS/CATS