Chloroform Toxicity

Etiology

Chloroform is a colorless, sweet-smelling, nonflammable liquid with low water solubility. This compound was initially synthesized in the 1830s and has historically been used for various purposes, including anesthesia and water purification.[6][7] Chloroform was used as a general anesthetic in the late 1800s until its associated complications, resulting in fatalities, prompted its replacement by nitric oxide. Chloroform was also used to disinfect drinking water until 1979 when the US Environmental Protection Agency (EPA) commenced regulating disinfection byproducts in drinking water.[3] This raised concerns, particularly as rat studies had previously linked exposure to chloroform and other disinfection byproducts in drinking water with heightened cancer risk and other health issues. While some countries still use chloroform for water disinfection, this practice is not universal.[1] Recent research indicates a limited association with human cancers attributed to decreased chloroform usage in water purification processes.[2][3][4]

Currently, chloroform finds limited application in industrial manufacturing and scientific investigation. Chloroform is used as a solvent in the industry for the production of pharmaceuticals, automobiles, plastics, and other chemicals such as cleaners and refrigerants.[1][5] Moreover, chloroform is utilized in scientific research, particularly in chemistry, where it functions as a solvent and reagent in various reactions.[5] Due to its toxicity and potential health hazards, the use of chloroform is strictly regulated.[9][1] As a result, chloroform toxicity remains relatively uncommon in modern times, predominantly arising from unintentional inhalation during occupational exposures. Nonetheless, documented instances of chloroform-related toxicity include cases of suicide, homicide, and other criminal activities involving its ingestion or inhalation.[4][5][10]

Epidemiology

Exposure to chloroform can occur in various settings, including occupational environments, manufacturing industries, and laboratories, as well as through intentional ingestions or inhalations for recreational purposes or suicide attempts. In cases of acute ingestions, the minimal fatal dose is reported to be 30 mL, although fatalities have been documented for dosages as low as 10 mL.[5][6]

Pathophysiology

Due to its lipid solubility, chloroform can easily traverse lipid membranes and disperse through highly vascularized organs such as the brain, liver, heart, and kidneys. Acute exposure to chloroform results in acute central nervous system (CNS) depression, while chronic exposure causes hepatotoxicity and other CNS symptoms.[4] As a halogenated hydrocarbon, chloroform's vapor form undergoes rapid absorption into the bloodstream and accumulates in fatty tissue.[11] Chloroform activates GABA receptors and causes hyperpolarization of neurons via an influx of chloride ions, thereby causing sedation.[12] 

Hepatic and renal chloroform metabolism is mediated by cytochrome P450 2E1 or cytochrome P450 2A6, depending on oxygen availability and substance concentration, resulting in the formation of phosgene.[2][13][14] Subsequently, phosgene binds to glutathione in the liver and kidneys, depleting it and enabling free radicals to cause hepatotoxicity and nephrotoxicity. The injury is heightened by alcohol consumption, as CYP2E1 also metabolizes alcohol.[15]  

In addition, chloroform inhibits complex IV, the terminal enzyme complex in the electron transport chain responsible for transferring electrons from cytochrome c to molecular oxygen, ultimately forming water.[7][8] By inhibiting complex IV, chloroform disrupts the final step of electron transfer and hampers the efficient utilization of oxygen for ATP production. Consequently, the inhibition of these key enzymes by chloroform disrupts electron flow along the electron transport chain, leading to reduced ATP synthesis and energy depletion within the affected cells. Such mitochondrial dysfunction contributes to chloroform-induced toxicity, including hepatotoxicity and nephrotoxicity, given the liver and kidneys' reliance on this energy production pathway. Moreover, rhabdomyolysis has been reported, likely attributable to the toxic effects of phosgene, chloroform's degradation byproduct, and other metabolites on muscle tissue.[9]

Additionally, chloroform can cause cardiac arrhythmias and hypotension by depressing myocardial contractility and reducing cardiac output via vagal stimulation. Chloroform can affect the ion channels responsible for generating and propagating electrical signals in cardiac cells. Notably, chloroform has been observed to inhibit potassium channels, which are pivotal for repolarization and maintaining the isoelectric baseline in cardiac cells. This inhibition may result in delayed repolarization, heightening the risk of arrhythmias.[16][10][11]

Chloroform toxicity symptoms can mimic systemic inflammatory response syndrome (SIRS). Researchers have postulated that chloroform or its breakdown products could stimulate pattern recognition receptors, eliciting similar proinflammatory responses akin to those observed in bacterial sepsis and triggering SIRS. Chloroform may directly activate this immunological response. In addition, chloroform activates enzymes responsible for converting plasminogen into plasmin—a process that can lead to disseminated intravascular coagulation—a common complication of SIRS.[12]

Histopathology

In cases of fatality resulting from chloroform toxicity, histopathological examination can detect observable alterations in the liver and kidneys.[16] Findings from hepatic examination include hepatocellular steatosis and centrilobular necrosis (zone 3).[13] Renal findings include renal tubular necrosis and glomerular hyaline sclerosis.

Toxicokinetics

Absorption: Chloroform is absorbed through the skin, respiratory tract, and gastrointestinal tract.[2][13][14]

Distribution: Chloroform is distributed throughout the body via the bloodstream. Chloroform penetrates various tissues, including the liver, kidneys, lungs, and brain. Distribution is influenced by factors such as blood flow, tissue composition, and lipid solubility.

Metabolism: Chloroform primarily undergoes oxidative or reductive metabolism in the liver. The cytochrome P450 2E1 enzyme system facilitates this process, breaking chloroform down into phosgene, hydrochloric acid, dichloromethane, and carbon monoxide. Phosgene, a product of oxidative metabolism, can further react with water to generate carbon dioxide and hydrogen chloride or form covalent bonds with tissue macromolecules.[15] These metabolites, exhibiting higher solubility in water than chloroform, are more readily eliminated from the body. In cases where oxygen is unavailable, chloroform undergoes reductive metabolism.[14] The primary metabolite produced via reduction is the dichloromethyl free radical, which causes lipid peroxidation.

Elimination: Chloroform and its metabolites are eliminated from the body through various routes. Although the primary route of elimination is pulmonary exhalation, chloroform can also be eliminated in small amounts through feces and urine.[17] When circulating in the bloodstream, chloroform and its acidic metabolites undergo filtration by the kidneys and are subsequently excreted in the urine. The elimination rate is influenced by factors such as the pH of the urine and the drug's characteristics.

History and Physical

Specific tests for clinically diagnosing chloroform toxicity do not exist. Therefore, successful identification requires a comprehensive history-taking of the patient's medical history. Thorough questioning about the patient's occupation is crucial, especially for individuals employed in industries where chloroform is utilized. Additionally, a history of psychiatric illness is important to consider in cases of intentional toxicity. 

Oral chloroform toxicity presents similarly to that of inhaled chloroform.[9] However, differences can be observed depending on whether the exposure is acute or chronic. In acute cases, patients may exhibit symptoms such as seizures, headache, dizziness, altered mental status, delirium, sedation, chest pain, palpitations, abdominal pain, nausea, and vomiting.[18][16][2]

In acute exposures, vital signs can vary depending on the time elapsed between ingestion and presentation. Initially, vital signs may appear normal, but they can progress to tachycardia, tachypnea, apnea, and hypotension, with decreased oxygen saturation. While the reported minimal fatal dose of ingested chloroform is 30 mL, fatalities have been documented with doses as low as 10 mL. CNS depression leading to respiratory depression is the most common finding in chloroform ingestion cases.[18][7] During a physical examination, the patient may appear diaphoretic, apneic, and cyanotic, with dilated pupils that react sluggishly to light. In cases of ingestion, the provider may notice a "pleasant" odor emanating from the patient. Dermal exposure to chloroform can result in irritation, erythema, and blistering, or even chemical burns if the skin remains in contact with the substance for an extended period.[15]

Chronic toxicity from chloroform affects multiple organ systems. Chronic exposure to chloroform can affect the CNS, leading to symptoms such as headaches, dizziness, confusion, impaired concentration, memory problems, and irritability. Furthermore, inhaling chloroform vapors can irritate the respiratory mucosa, leading to multiple symptoms such as coughing, shortness of breath, wheezing, and chest discomfort. Additionally, chronic exposure to chloroform may induce gastrointestinal symptoms, including nausea, vomiting, and abdominal discomfort.

Chloroform undergoes primary metabolism in the liver, and prolonged exposure can lead to liver toxicity. Symptoms may manifest as abdominal pain, jaundice, liver enlargement, and abnormal liver function test (LFT) results. Metabolism via the cytochrome P450 2E1 system results in the formation of a trichloromethyl radical, which is responsible for zone 3 centrilobular necrosis of the liver.[13][16] Chronic exposure to chloroform can lead to alterations in urine output, which may manifest as either increased or decreased urine production. Additionally, chronic exposure may result in symptoms such as hematuria, proteinuria, and impaired kidney function.[19][4][13]

Evaluation

Initial chemistry findings may reveal no abnormalities in acute chloroform toxicity. Evidence of harm typically becomes apparent only between 12 and 48 hours after exposure to chloroform, with abnormal laboratory levels continuing to escalate over the subsequent days. LFTs may indicate elevated levels of aspartate transaminase, alanine transaminase, and glutamate dehydrogenase. Additionally, increasing levels of blood urea nitrogen (BUN) and creatinine may suggest acute kidney injury. Coagulation abnormalities may occur due to acute liver failure.[19][16] Elevations in lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) levels may also be observed. Furthermore, an abdominal x-ray may detect a radiopaque material, indicating the ingestion of a halogenated hydrocarbon, such as chloroform.[7]

Elevations in liver enzymes are notably higher compared to those observed in acute exposures in cases of chronic toxicity. Elevations in ammonia and LDH levels, as well as coagulation profiles, are also observable. Testing for hepatitis and rheumatological panels can aid in ruling out hepatitis as an underlying condition. Ultrasound examinations conducted in cases of chronic toxicity may reveal hepatomegaly, fatty liver, and signs of hepatitis.[16]

Treatment / Management

The initial assessment requires a comprehensive evaluation of the airway, breathing, and circulation, complemented by continuous cardiac monitoring and pulse oximetry. Intubation may be considered based on the patient's cognitive state and oxygen needs. Following intubation, activated charcoal and sorbitol should be administered via a nasogastric tube.[17][6] Incorporating N-acetylcysteine can be beneficial to restore glutathione levels and mitigate the circulation of free radicals.[18][13] In contrast, routine gastric lavage is not advised.[2][17][2] (B2)

The management of hypotension involves the administration of intravenous fluids and vasopressors.[5] Consultation with nephrology specialists is recommended to assess the need for urine alkalization.[9] The rationale behind urine alkalization in chloroform toxicity is grounded in the compound's nature as a weak acid. By increasing the alkalinity of urine, the elimination of chloroform is enhanced. Moreover, the alkalization of urine facilitates the transformation of acidic chloroform into a less toxic, alkaline form.[19] Patients with renal failure and metabolic acidosis should undergo dialysis to address their condition effectively.[5] Patients should be admitted for close monitoring in an intensive care unit setting. In cases involving voluntary ingestion or inhalation, referral to psychiatry is recommended once the patient has been medically stabilized and cleared for discharge.(B3)

In cases of chronic toxicity, a pragmatic approach involving hydration and conservative care is advised.[6] Seeking additional consultation with gastroenterology experts can help assess elevated liver enzyme levels. In addition, timely removal of the patient from chloroform exposure is essential for an effective management strategy.(B3)

Differential Diagnosis

Acute Toxicity

Acute chloroform toxicity presents similar to other conditions that cause acute mental status changes with respiratory distress, including:

• Carbon monoxide poisoning
• Alcohol intoxication
• Heroin intoxication
• Inhalant abuse
• Mushroom toxicity
• Opioid toxicity

Chronic Toxicity  

Differential diagnoses for chronic chloroform toxicity include:

• Viral hepatitis
• Wilson disease
• Autoimmune liver diseases

Prognosis

Patients generally experience a complete recovery from chloroform toxicity. In cases of acute toxicity, laboratory findings typically exhibit nearly complete resolution of abnormal liver enzymes, serum chemistry, coagulation profiles, LDH, and CPK within 2 weeks of initiating management. Outpatient follow-up confirms complete resolution of all laboratory values. Similarly, chronic toxicity resolves entirely within 1 month after discontinuing exposure to the causative agent, as indicated by laboratory results.[7]

Complications

Potential complications that may develop in patients with chloroform toxicity include:

• Acute liver failure
• Acute renal failure
• Disseminated intravascular coagulation
• Respiratory failure
• Cardiac arrhythmia