Several factors are classically associated with pulmonary toxicity after hydrocarbon ingestion. These include specific physical properties of the xenobiotics ingested, the volume ingested, and the occurrence of vomiting. Physical properties of viscosity, surface tension, and volatility are primary determinants of aspiration potential.
Dynamic (or absolute) viscosity is the measurement of the ability of a fluid to resist flow. This property is measured with a rheometer and is typically given in units of pascal-seconds. More frequently, engineers work with kinematic viscosity, measured in square millimeters per second, or centistokes. Dynamic viscosity is converted to kinematic viscosity by dividing the dynamic viscosity by the density of the fluid. An older system for measuring viscosity was initially popularized by the petroleum industry and expresses kinematic viscosity in units of Saybolt Universal seconds (SUS). Unfortunately, many policy statements were developed in an era when SUS units were popular, and many still describe viscosity in SUS units. Various look-up tables and calculators are available to convert kinematic viscosity to SUS units. Table 108–1 shows kinematic viscosity of common hydrocarbons, measured in SUS. A unit conversion approximation is given in the table’s footnote.
Hydrocarbons with low viscosities (<60 SUS; eg, turpentine, gasoline, naphtha) have a higher tendency for aspiration in animal models. The US Consumer Products Safety Commission issued a rule in 2001, requiring child-resistant packaging for products that contain 10% or more hydrocarbon by weight and have a viscosity less than 100 SUS.
Surface tension is a cohesive force generated by attraction due to the Van der Waals forces between molecules. This influences adherence of a liquid along a surface (“its ability to creep”). The lower the surface tension, the more effectively the liquid will creep, producing a higher aspiration risk.57
Volatility is the tendency for a liquid to become a gas. Hydrocarbons with high volatility tend to vaporize, displace oxygen, and potentially lead to transient hypoxia.
Early reports conflicted in their attempts to relate risk of pulmonary toxicity (1) to the amount of hydrocarbon ingested or (2) to the presence or absence of vomiting. One prospective study addressed both these variables. The cooperative kerosene poisoning (COKP) study was a multicenter study that enrolled 760 patients with hydrocarbon ingestion. Of these, 409 individuals could provide an estimate of the amount ingested. Patients who reportedly ingested more than 30 mL had a 52% chance of developing pulmonary complications, compared with 39% of those who ingested less than 10 mL. Risk of central nervous complications was 41%, compared with 24% using the same criterion. There was a 53% incidence of pulmonary toxicity when vomiting occurred, compared with 37% when there was no history of vomiting.121 While this knowledge may help modify the index of suspicion regarding possible pulmonary toxicity, none of these parameters is completely predictive. Severe hydrocarbon pneumonitis may occur after ingestion of “low-risk” hydrocarbons.131 Patients may develop severe lung injury after low-volume (<5 mL) ingestions, as well as after ingestions with no history of coughing, gagging, or vomiting.8
It is widely held that aspiration is the main route of injury from ingested simple hydrocarbons. The mechanism of pulmonary injury, however, is not fully understood. Intratracheal instillation of 0.2 mL/kg of kerosene causes physiologic abnormalities in lung mechanics (decreased compliance and total lung capacity) and pathologic changes such as interstitial inflammation, polymorphonuclear exudates, intraalveolar edema and hemorrhage, hyperemia, bronchial and bronchiolar necrosis, and vascular thrombosis.61 These changes most likely reflect both direct toxicity to pulmonary tissue and disruption of the lipid surfactant layer.171
Most patients who develop pulmonary toxicity following hydrocarbon ingestion will have an initial episode of coughing, gagging, or choking. This usually occurs within 30 minutes after ingestion and is presumptive evidence of aspiration. The majority of patients who have respiratory signs and symptoms in addition to the initial history of gagging, choking, and coughing develop radiographic pneumonitis. Pulmonary toxicity may manifest as crackles, rhonchi, bronchospasm, tachypnea, hypoxemia, hemoptysis, acute respiratory distress syndrome (hemorrhagic or nonhemorrhagic), or respiratory distress. Cyanosis develops in approximately 2% to 3% of patients. This may result from simple asphyxiant effects from volatilized hydrocarbons, from ventilation–perfusion mismatch, or, rarely, from methemoglobinemia (aniline, nitrobenzene, or nitrite-containing hydrocarbons). Clinical findings often worsen over the first several days but typically resolve within a week. Death is distinctly uncommon and typically occurs after a severe, progressive respiratory insult marked by hypoxia, ventilation–perfusion mismatch, and barotrauma.75,92,179
Intravenous (IV), subcutaneous, and even intrapleural injection of hydrocarbons are reported.45,129,163 Severe hydrocarbon pneumonitis may occur following IV exposure. Animal experiments show that intravascular hydrocarbons injure the first capillary bed encountered.127,173 The clinical course after IV hydrocarbon injection is comparable to that of aspiration injury.
Radiographic evidence of pneumonitis develops in 40% to 88% of patients admitted following aspiration.16,44,115 Findings can develop as early as 15 minutes or as late as 24 hours after exposure (Fig. 108–1).22,54,121,164 Chest radiographs performed immediately on initial presentation are not useful in predicting infiltrates in either symptomatic or asymptomatic patients.8 Ninety percent of patients who develop radiographic abnormalities do so by 4 hours postingestion.22 Clinical signs of pneumonia (eg, crackles, rhonchi) are evident in 40% to 50% of patients.44 A small percentage (<5%) are completely asymptomatic after a period of observation, yet to have radiographic findings.8
Initial: Patchy densities appear in the basilar areas of both lung fields with increased interstitial markings and peribronchial thickening.
Day 2: More extensive diffuse alveolar infiltrates are apparent.
Day 6: Dense consolidation and atelectasis are evident in the right lower lobe. (Used with permission of Nancy Genieser, MD, Professor of Radiology, New York University.)
Specific radiologic findings include perihilar densities, bronchovascular markings, bibasilar infiltrates, and pneumonic consolidation.58 Right-sided involvement occurs in 75% of cases and bilateral involvement in approximately 50%. Upper-lobe involvement is uncommon. Pleural effusions develop in 3% of cases, with one-third appearing within 24 hours.100 Pneumothorax, pneumomediastinum, and pneumatoceles occur uncommonly.10,20,78 Initial radiographs after ingestion may reveal two liquid densities in the stomach, known as the “double-bubble” sign. This represents an air–fluid (hydrocarbon or water) and a hydrocarbon–water interface, as the hydrocarbon is not miscible with gastric (aqueous) fluid and may have a specific gravity less than that of water.38
Radiographic resolution does not correlate with clinical improvement but rather lags behind by several days to weeks. There are few reports of long-term follow-up on patients with hydrocarbon pneumonitis.64,154 Frequent respiratory tract infections are described after hydrocarbon pneumonitis, but these studies are not well controlled.54,157 Delayed formation of pneumatoceles may occur.20,78 Bronchiectasis and pulmonary fibrosis are reported but appear to be uncommon.60,124 In one study, 82% of patients examined 8 to 14 years after hydrocarbon-induced pneumonitis had asymptomatic minor pulmonary function abnormalities. The abnormalities were consistent with small-airway obstruction and loss of elastic recoil. The authors hypothesized that this group may be predisposed to chronic obstructive pulmonary disease.64
The most concerning cardiac effect from hydrocarbon exposure is precipitation of dysrhythmias through myocardial sensitization.110 Malignant dysrhythmias may occur after exposure to high concentrations of volatile inhalants or inhaled anesthetics. Such events are described with all classes of hydrocarbons, but halogenated compounds are most frequently implicated, followed by aromatic compounds.13,126 Atrial fibrillation, ventricular tachycardias, junctional rhythms, ventricular fibrillation, and cardiac arrest are reported.29,105,111,126 This is termed the “sudden sniffing death syndrome.”14 Prolongation of the QT interval in some cases raises additional concern for the development of torsade de pointes.14,133
Cardiac sensitization is incompletely understood.43,110,134 Halothane and isoflurane inactivate sodium channels,142 whereas chloroform and others attenuate potassium efflux through voltage-gated channels.133 Sensitization may be mediated by slowed conduction velocity through membrane gap junctions. Dephosphorylation of connexin-43 results in a conformational change that increases gap junctional resistance. Halocarbons, in the presence of epinephrine, cause dephosphorylation of this gap junction protein, thereby increasing resistance and slowing conduction velocity in myocardial tissue.76
Any route of exposure to hydrocarbons may result in cardiotoxicity. Classically, sudden death follows an episode of sudden exertion, presumably associated with an endogenous catecholamine surge.14 Tachydysrhythmias, cardiomegaly, and myocardial infarction are rarely reported after ingestion of hydrocarbons.72,144 A retrospective follow-up cohort of exposed methylene chloride workers did not find evidence of excess long-term cardiac disease.116
Transient CNS excitation may occur after acute hydrocarbon inhalation or ingestion, but more commonly, CNS depression or general anesthesia occurs.44 In cases of aspiration, hypoxemia from pulmonary damage may contribute to CNS depression.95,174 Coma and seizures are reported in 1% to 3% of cases.115,124,178 Chronic occupational exposure or volatile substance use may lead to a chronic neurobehavioral syndrome, the painter’s syndrome, most notably described after toluene overexposure. Clinical features include ataxia, spasticity, dysarthria, and dementia, consistent with leukoencephalopathy.50,51,52, and 53 Autopsy studies of the brains of chronic toluene abusers show atrophy and mottling of the white matter, as though the lipid-based myelin were dissolved away. Microscopic examination shows a consistent pattern of myelin and oligodendrocyte loss with relative preservation of axons.84 Animal models of toluene poisoning reveal norepinephrine and dopamine depletion. The severity and reversibility of this syndrome depends on the intensity and duration of toluene exposure.132 Infrequent exposure may produce no clinical neurologic signs, whereas severe (daily) use can lead to significant neurologic impairment after as little as 1 year, but more commonly after 2 to 4 years of continuous exposure. The specific cognitive and neuropsychological findings in toluene-induced dementia have been termed a white matter dementia.50,51, and 52
Initial findings of white matter dementia include behavioral changes, impaired sense of smell, impaired capacity to concentrate, and mild unsteadiness of hand movements and gait. Further exposure leads to slurred speech, head tremor, poor vision, deafness, stiff-legged and staggering gait, and subsequent dementia. Physical findings may include nystagmus, ataxia, tremor, spasticity with hyperreflexia, plantar extension, deafness, impaired vision, and a broad-based, staggering gait. An abnormal brainstem auditory-evoked response appears to be a sensitive indicator of toluene-induced CNS damage. The electroencephalogram can show mild, diffuse slowing. Computed tomography in severe cases shows mild-to-moderate cerebellar and cortical atrophy. Magnetic resonance imaging (MRI) findings are consistent with white matter disease. Most cases show clinical improvement after 6 months of abstinence, although with moderate to severe abuse, improvement may be incomplete. While toluene abuse is addicting, withdrawal or abstinence syndrome is surprisingly uncommon and, when present, appears relatively benign.50,51, and 52
Exposures in the occupational setting are rarely as extreme as those that occur with intentional volatile substance misuse. Given the significantly lesser exposures, the findings among workers overexposed to solvent concentrations above permissible exposure limits are often subclinical and detected primarily through neurobehavioral testing. In rare cases, however, a worker may be acutely overexposed to solvent concentrations that can produce acute CNS depression. Repeated, symptomatic overexposures over a protracted period of time have the potential to lead to a chronic encephalopathy, as evident from the experience with solvent abusers.51
Peripheral Nervous System
Peripheral neuropathy is well described following occupational exposure to n-hexane or methyl-n-butyl ketone (MnBK).25 This axonopathy results from a common metabolic intermediate, 2,5-hexanedione. The mechanism by which this intermediate causes peripheral neuropathy probably relates to decreased phosphorylation of neurofilament proteins, with disruption of the axonal cytoskeleton. Methyl ethyl ketone may exacerbate this neurotoxicity, probably by interfering with metabolic pathways of n-hexane and MnBK.7,130 Other organic solvents, such as carbon disulfide, acrylamide, and ethylene oxide, may cause a similar peripheral axonopathy.59 Cranial and peripheral neuropathies are reported after acute and chronic exposure to trichloroethylene (TCE).77,90,151 Pathologically, TCE appears to induce a myelinopathy.48,59
TCE exposure is associated with trigeminal neuralgia.34,47,90 Symptoms can develop within 12 hours of a single intense exposure and persist for many years.48 Trigeminal nerve damage was documented by evoked potentials following 15 minutes of TCE inhalation.90 Some evidence suggests that decomposition products or impurities in TCE may be responsible for cranial neuropathy.34,47,85
Axonopathy from MnBK or n-hexane exposure typically begins in the distal extremities and progresses proximally (a classic, “dying-back” neuropathy) (Chap. 24). Exposure to one of these hydrocarbons should be considered in the differential diagnosis of the patient with Guillain-Barré syndrome (GBS), although sensory findings are present with MnBK and absent in GBS.140 The longest axons appear to be affected initially, so that the patient manifests a “length-dependent polyneuropathy.” With discontinuation of exposure many of the effects reverse over weeks to months.69,80,122,177 Alternatively, the phenomenon of “coasting” may occur, in which neuropathy progresses for a time (weeks to months) after discontinuation of the toxic insult.140 A reversible peripheral neuropathy occurred in 40% of chronic toluene abusers and was characterized by severe motor weakness without sensory deficits or areflexia.150 It is unclear whether the toluene in this series might have been contaminated by n-hexane or MnBK.7
Hydrocarbons irritate gastrointestinal mucous membranes. Nausea and vomiting are common after ingestion. As discussed earlier, vomiting may increase the risk of pulmonary toxicity.113,115 Hematemesis was reported in 5% of cases in one study,113 and gastrointestinal ulcerations are reported in animal studies81.
The chlorinated hydrocarbons (Table 108–1) and their metabolites are hepatotoxic. In most cases, activation occurs via a phase I reaction to form a reactive intermediate (Chap. 13). In the case of carbon tetrachloride, this intermediate is the trichloromethyl radical. This radical forms covalent bonds with hepatic macromolecules and may initiate lipid peroxidation.27 Carbon tetrachloride causes centrilobular necrosis after inhalational, oral, or dermal exposure.102 Hepatotoxicity in animals has been ranked for common hydrocarbons as follows: carbon tetrachloride is greater than benzene, and trichloroethylene is greater than pentane.172 Vinyl chloride is a liver carcinogen, and trichloroethylene, tetrachloroethylene, and 1,1,1-trichloroethane are considered less acutely hepatotoxic than vinyl chloride.102 Hepatotoxicity rarely follows ingestion of petroleum distillates.73 Hepatic injury, manifested as aminotransferase elevation and hepatomegaly, is usually reversible except in massive exposures.
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, ethylene dichloride, tetrachloroethane, 1,1,1-trichloroethane, and TCE are nephrotoxic. Acute kidney injury (AKI) and distal renal tubular acidosis occur in some painters and volatile-substance abusers.15 Toluene causes a renal tubular acidosislike syndrome (see Toluene later in the chapter).
Hemolysis has been sporadically reported to occur following hydrocarbon ingestion.2,6,148 One retrospective study of 12 patients showed hemolysis in three individuals and disseminated intravascular coagulation in another.6 Although one patient required transfusion, hemolysis is usually mild and typically does not require red blood cell transfusion (also see discussion of the effects of benzene on bone marrow, under Benzene later in the chapter).
Hydrocarbons disturb the integrity of membrane lipid bilayers, causing swelling and increased permeability to protons and other ions. This alters the structural and functional integrity of the membrane. Changes in the lipid composition of the membrane occur, and membrane lipopolysaccharides and proteins are disturbed.138 Resultant toxicity may directly destroy capillary endothelium.26 Additionally, there appears to be significant basement membrane dysfunction, and this is postulated to underlie both alveolar and glomerular toxicity of hydrocarbons.145 Immune mechanisms may account for basement membrane dysfunction in chronic exposures. Hydrocarbon exposure is suggested as one possible cause of the Goodpasture syndrome (immune dysfunction causing both pulmonary damage and glomerulonephritis),24 although the association is not widely accepted. Measurable changes in immune function occur after hydrocarbon exposure,12 but our knowledge of any clinical relevance is incomplete.
Most hydrocarbon solvents cause nonspecific irritation of skin and mucous membranes. Repeated, prolonged contact can dry and crack the skin. The mechanism of dermal injury appears to be defatting of the lipid layer of the stratum corneum. Up to 9% of workers may develop eczematous lesions from dermal contact.176 Limonene and turpentine contain sensitizers that can rarely result in contact allergy (Chap. 18).
Contact dermatitis and blistering may progress to partial- and even full-thickness burns.67 Severity is proportional to duration of exposure. Hydrocarbons are irritating to skin. Acute, prolonged exposure can cause dermatitis and even full-thickness dermal damage.67 Chronic dermal exposure to kerosene or diesel fuel can cause oil folliculitis.39,162 A specific cutaneous lesion called chloracne is associated with exposure to chlorinated aromatic hydrocarbons with highly specific stereochemistry such as dioxins and polychlorobiphenyls.
Soft tissue injection of hydrocarbon is locally toxic, leading to necrosis.45 Secondary cellulitis, abscess formation, and fasciitis can occur. Infectious complications are treated by meticulous wound care, with surgical débridement as necessary. A particularly destructive injury involves high-pressure injection gun injury. These injuries typically involve the extremities, with high-pressure injection of grease or paint into the fascial planes and tendon sheaths. Emergent surgical débridement is necessary in most of these cases.49,107