Carbon Disulfide Toxicity

Etiology

CS₂ primarily affects individuals through inhalation. Factory workers and others in industrial settings face a higher risk of exposure. Acceptable exposure limits typically range from 10 to 20 ppm.[2][3] Various animal studies have demonstrated that symptoms can occur at levels ranging from 1 to 10 ppm following acute exposure. Respiratory symptoms may develop at concentrations as low as 1 ppm, while lethal levels have been reported around 500 ppm.[1][2] The effects of chronic exposure to CS₂ have been extensively studied. Maintaining exposure levels below 10 ppm is recommended, as prolonged exposure above this threshold can lead to significant health effects. In particular, multiple studies have demonstrated an increased risk of cardiovascular disease with chronic exposure at levels around 20 ppm.[1][2]

Symptoms have also been reported at exposure levels within the 10- to 20-ppm range.[2] In cases of acute exposure, symptoms can develop rapidly, starting with nonspecific or constitutional complaints such as headache, shortness of breath, and irritation of the eyes and mucous membranes. These effects have been observed at concentrations ranging from 17 to 51 ppm.[4] Although lower-dose exposures may produce mild and transient symptoms that resolve upon removal from the source, prolonged exposure can lead to symptoms that are slower to resolve and may become persistent and long-lasting over time.

At concentrations between 20 and 400 ppm, individuals may develop significant CNS disturbances.[1][4][5] Respiratory symptoms may worsen, and cutaneous manifestations can also occur. Exposure levels exceeding 2000 ppm can lead to severe CNS depression and respiratory compromise. Such high-volume exposures typically result from industrial accidents or ingestion of liquid CS₂. Although acute exposures are uncommon and often involve small quantities, chronic exposure remains a concern due to its potential to cause adverse health effects.[3]

Chronic exposure to CS₂ is most commonly seen in factory workers who are exposed to low-dose CS₂ over many years. Although acute symptoms may not develop, cumulative exposure can lead to a range of chronic health issues. Chronic lung disease is one of the most frequent outcomes, with CS₂ recognized as a significant contributor to progressive lung damage. Additionally, workers exposed to CS₂ may develop coronary artery disease, renal disease, and neurological symptoms.[2] These neurological symptoms can include neuropathy, vertigo, pseudobulbar signs, and paralysis. Given the severe long-term risks, minimizing exposure through proper protective measures is essential. 

CS₂ toxicity is primarily associated with occupational exposure, although environmental and accidental exposures have also been reported. The highest-risk populations include workers in industries where CS₂ is commonly used, such as rayon manufacturing (historically the most significant source of exposure), pesticide production, rubber manufacturing, chemical production, and solvent use.[1] Several studies have identified that workers in these industries are often exposed to CS₂ levels well above established safety limits, placing them at a high risk of toxicity. Although occupational exposure remains the primary source of CS₂ toxicity, occasional environmental exposures have also been reported, particularly near industrial facilities or after accidental spills. Additionally, CS₂ can occur naturally in the environment, primarily in areas surrounding marshes, lakes, and volcanic regions.[2] 

CS₂ is volatile and has low environmental longevity. However, it can still pose risks in poorly ventilated areas or where safety protocols are not adequately followed. Regulatory standards and improved safety protocols have helped reduce occupational exposure and the incidence of acute toxicity, though long-term health risks persist. Countries with active rayon and chemical industries, such as China, India, and regions of Southeast Asia, continue to report occupational health concerns related to CS₂. Moreover, underdeveloped countries with manufacturing facilities face even greater exposure risks due to inadequate regulations and safety standards.

Epidemiology

Numerous studies have reported CNS toxicity associated with CS₂ exposure.[6][7][8] In addition, a study found that female workers exposed to CS₂ had a higher incidence of adverse pregnancy outcomes, including preterm birth, congenital malformations, emesis gravidarum, and preeclampsia.[9] Another study involving rayon factory workers demonstrated significantly slower sensory and motor nerve conduction velocities, alongside increased self-reported rates of depression.[10] Although the carcinogenic potential of CS₂ has not been extensively studied, prior research linked occupational exposure in rubber industry workers to higher mortality from lymphatic leukemia.[11] These risks may be compounded by smoking, which has a synergistic effect.[12] 

CS₂ exposure is also strongly associated with an increased risk of cardiovascular disease. An interventional study that followed a cohort of rayon mill workers in Finland over 5 years reported a 4.7-fold increase in heart disease–related mortality among those exposed to CS₂. An intervention aimed to reduce CS₂ exposure successfully normalized this risk.[13][14]

Pathophysiology

The exact mechanism of CS₂ toxicity is not fully understood, but it likely involves multiple direct effects on various organ systems.[15][16] Following absorption, CS₂ is metabolized into acid-labile dithiocarbamate compounds. These metabolites are believed to contribute to its toxic effects, including the inhibition of dopamine beta-hydroxylase (DBH)—an enzyme responsible for converting dopamine to norepinephrine in the brain.[17][18] This partly accounts for some of the neurological symptoms reported in CS₂ exposures.

Additionally, CS₂ exposure is linked to pyridoxine (vitamin B6) deficiency, resulting in reduced production of gamma-aminobutyric acid (GABA), which may lead to benzodiazepine-resistant seizures.[1] CS₂ also alters the metabolism of vitamin B6, further exacerbating deficiency. These effects are compounded by oxidative damage and inflammation, which can impact multiple organ systems exposed to CS₂.[1]

CS₂ also affects hepatic function by altering the liver’s ability to metabolize lipids, which can lead to elevated serum cholesterol levels. This disruption may contribute to the increased rates of atherosclerosis observed in individuals with chronic exposures to CS₂. Additionally, several studies suggest that CS₂ may inhibit aldehyde dehydrogenase (ALDH), resulting in higher acetaldehyde concentrations and a potential increased risk of disulfiram-like reactions.[1][16][19]

CS₂ may also inhibit nitric oxide synthase, leading to reduced nitric oxide levels. This decrease can significantly impact the reproductive system, resulting in lowered levels of gonadotropin-releasing hormone, luteinizing hormone, sperm motility, sperm count, and testosterone.[20] Conversely, CS₂ exposure may increase follicle-stimulating hormone concentrations, collectively contributing to decreased libido, infertility, and overall reproductive dysfunction.[1][21][22]

Common metabolites of CS₂ include thiourea and 2-thiothiazolidine-4-carboxylic acid (TTCA). TTCA, in particular, has been associated with impaired lung function, including reduced pulmonary capacity. Studies indicate that higher exposure levels correspond with a reduced FEV₁/FVC ratio compared to lower exposure levels.[23] TTCA can also serve as a biomarker to monitor clearance after exposure, as its levels are detectable in urine.[1][22]

Toxicokinetics

CS₂ is a volatile molecule with double covalent bonds that exists as a liquid at room temperature but readily evaporates upon exposure to air. CS₂ can be absorbed through inhalation, ingestion, or dermal contact. Inhalation results in significant systemic uptake, with approximately 80% to 90% of the inhaled dose being absorbed into the bloodstream. Dermal absorption can also be substantial, depending on the dose and duration of exposure. Although ingestion is rare, it leads to rapid absorption and high bioavailability. Once absorbed, CS₂ demonstrates a large volume of distribution and high lipophilicity.

Animal studies indicate that CS₂ is primarily metabolized and eliminated through hepatic metabolism and renal excretion. CS₂ is metabolized by cytochrome P450 (CYP450) enzymes within the liver. The primary metabolites of CS₂ include carbonyl sulfide, thiocarbamates, and thiol derivatives. The elimination rate varies depending on the dose, duration of exposure, and the individual’s underlying health conditions. CS₂ has a half-life of approximately 1 to 4 hours, a volume of distribution ranging from 0.7 to 1.0 L/kg, and a lipophilicity index of 2.6 to 2.8. (Please refer to PubChem, Carbon Disulfide.) 

History and Physical

Acute CS₂ toxicity commonly presents with respiratory symptoms such as shortness of breath, bronchospasm, wheezing, and hypoxia. Constitutional symptoms, including nausea, vomiting, headache, lightheadedness, and dizziness, are also frequently reported following acute exposure to the substance. As exposure levels increase, both the number and severity of symptoms intensify, with high-dose exposures potentially resulting in CNS depression, paralysis, and coma.[1][4][24]

Chronic exposure to CS₂ can lead to a range of long-term health conditions, most notably chronic lung disease and cardiovascular disease. Additional complications may include microangiopathy, peripheral neuropathy, kidney disease, and reproductive dysfunction.[25] CS₂ affects multiple organ systems with varying degrees of severity, as mentioned below.

• Central nervous system: Headaches, nausea, dizziness, hallucinations, mania, psychosis, seizures, coma, neuropathy, vertigo, vomiting, central paralysis, and narcosis.[5][17][18][24]
• Respiratory: Wheezing, coughing, upper airway irritation, and dyspnea.
• Ocular: Corneal burns, conjunctivitis, retinopathy, blurred vision, and eye irritation.
• Cardiac: Coronary artery disease, chest pain, and palpitations.[26][27]
• Dermal: Pain, redness, blisters, and chemical burns (second- and third-degree).
• Gastrointestinal: Nausea, vomiting, and abdominal pain.
• Renal: Acute kidney injury, increased 24-hour glucose clearance, and elevated urinary protein concentration.[6][25]
• Genitourinary: Reduced sperm count, altered sperm morphology and hormone levels, decreased libido and potency, and spontaneous abortions.[20][21]

Evaluation

CS₂ has limited diagnostic testing options. Research has been conducted on various endpoints to determine the exposure and clearance of CS₂; however, its clinical utility is limited. For instance, TTCA can correlate with exposure amount in cases of known CS₂ exposure. Low levels can also be detected in individuals without known exposure to CS₂, which is believed to be related to dietary sources.[2][23] Furthermore, treatment is primarily based on symptom management and reduction of adverse outcomes rather than acutely trying to address CS₂ toxicity.

Initial evaluation and workup of individuals exposed to CS₂ should prioritize stabilization, followed by assessment for signs of organ injury. In critically ill patients, addressing the critical needs is first and foremost. Decontamination must be performed promptly as the initial step to prevent further exposure and protect both the patient and healthcare staff, as well as those caring for the individual. Individuals who were exposed to high levels of CS₂ may require intubation for respiratory compromise and vasopressor support for circulatory instability.

Following stabilization, laboratory and diagnostic evaluations should focus on assessing potential damage to the cardiovascular system, kidneys, and lungs. Considering the possibility of additional toxic exposures or alternative diagnoses is also important. Diagnostic testing may include an electrocardiogram (ECG), chest x-ray, and computed tomography (CT) scan. Laboratory assessments such as a complete blood count, comprehensive metabolic panel, lipase, liver function tests, arterial or venous blood gas, troponin, coagulation profile, salicylate and acetaminophen levels, ethanol level, urinalysis, urine drug screen, and pregnancy test (if applicable) can help identify evidence of end-organ damage and guide further management.

Treatment / Management

Antidotes for the treatment of CS₂ toxicity do not exist; therefore, treatment is primarily supportive and focused on treating symptoms related to exposure. Early recognition and intervention are crucial, with a particular focus on respiratory and neurological complications.[1] The risk of secondary exposure to healthcare providers is low, especially once the patient has been removed from the source. This is primarily due to the high volatility and rapid dissipation of CS₂ gas at standard temperature and pressure. Although the risk of secondary contamination in CS₂ toxicity is generally low, significant exposures—particularly to the liquid form—may necessitate decontamination. All patients with environmental exposure should undergo decontamination.[2][3][22]

Differential Diagnosis

As CS₂ toxicity often presents with many nonspecific symptoms, clinicians should consider and rule out multiple alternative diagnoses when evaluating a patient with suspected CS₂ exposure.

Common conditions with similar presentations include:

• Viral infection
• Pneumonia
• Gastroenteritis
• Tension headache
• Migraines
• Vertigo
• Asthma
• Chronic obstructive pulmonary disease exacerbation
• Meningitis
• Medication overdose
• Pulmonary embolism,
• Other toxic exposures, such as carbon monoxide and toxic alcohols
• Metal fume fever
• Pneumoconioses

Prognosis

The prognosis of CS₂ toxicity depends on the intensity and duration of exposure, as well as the timeliness of medical intervention. Although the severity of the toxic effects of CS₂ can vary considerably among individuals, it generally leads to progressive symptoms with increasing exposure levels. However, evidence suggests that significant exposures are associated with significant impacts on health and an increased risk of mortality. However, the effects of moderate exposure remain less well understood, and the timeline for recovery and return to baseline functioning is unclear.[1][4] 

Low-level exposure to CS₂, typically at concentrations below 20 ppm, may cause symptoms such as headache, dizziness, fatigue, nausea, and irritation of the eyes and skin. Individuals with low exposure generally recover well without severe long-term effects. Moderate or intermediate exposures, ranging from 20 to 100 ppm, can result in more pronounced symptoms, including muscle weakness, mood changes, memory impairment, peripheral neuropathy, and shortness of breath. Recovery in these cases is variable and largely depends on both the duration and intensity of exposure.

With intermediate exposure to CS₂, recovery outcomes can vary. Some individuals may achieve full recovery, while others may experience only partial improvement. Persistent symptoms, including fatigue, neurological complaints, or respiratory issues, can persist for weeks to months, and some individuals may not fully recover to their baseline. Prolonged exposure at intermediate concentrations may also increase the long-term risk of cardiovascular disease and neurological complications, including memory impairment and peripheral neuropathy.

High levels of CS₂ exposure, typically concentrations above 100 ppm, can lead to severe complications. Affected individuals may present with acute respiratory distress, significant neurological impairment, or coma. In addition to the immediate risks, high-level exposures are associated with long-term complications, including cardiovascular, reproductive, and thyroid dysfunction.[28] The prognosis for individuals exposed to high concentrations or prolonged exposure is generally poor. Without prompt removal from the source and appropriate treatment, outcomes may include respiratory failure, cardiovascular collapse, or death.[2]

Complications

Complications from acute CS₂ toxicity primarily result from CNS depression and respiratory system compromise. As discussed, management is focused on supportive care.

Chronic exposure to CS₂ can affect multiple organ systems, and has been associated with renal disease, including chronic kidney disease; cardiovascular diseases such as coronary artery disease and hyperlipidemia; and CNS effects, including microvascular changes, which may lead to memory and cognition decline.[2][3][17][27][28]