Mercaptan Toxicity

Etiology

The sources of mercaptan exposure include occupational, environmental, and accidental exposures. Mercaptans are sulfur-containing compounds primarily used as odorants in natural gas, propane, and other fuel gases to provide a detectable odor for safety purposes.[4] Examples of these odorants are methyl mercaptan and ethyl mercaptan, sometimes referred to as ethanethiol. While these mercaptans are generally considered safe at low concentrations, accidental releases, occupational exposures, or intentional misuse can lead to toxicity.

Deliberate mercaptan poisoning is uncommon. The Acute Exposure Guideline Level (AEGL) for humans, derived from rat studies, recommends not exceeding exposure to concentrations greater than 120 ppm for 10 minutes.[5] Acute inhalation of mercaptans can lead to hypoventilation and apnea and, in severe exposures, may cause seizures, paralysis, myocardial infarction, coma, and death. Additionally, the United States Department of Homeland Security (DHS) has classified methyl mercaptan as a potential chemical weapon of mass effect.

Epidemiology

The prevalence and incidence of mercaptan toxicity are challenging to determine accurately due to the limited available data and underreporting of cases. Mercaptan toxicity is relatively rare, and specific statistics regarding its prevalence and incidence are not extensively documented in scientific literature. However, some general observations can be made. Occupational exposures to mercaptans, particularly among workers in the natural gas and fuel gas industry, are more commonly reported than other exposure types. Instances of intentional misuse or abuse of mercaptan-containing products are sporadic and not systematically documented. 

Pathophysiology

The metabolic transformations of mercaptans within the body generate reactive intermediates. Oxidative stress is a key mechanism underlying mercaptan-induced cellular damage.[4] Mercaptans induce oxidative stress via various mechanisms, generating intracellular reactive oxygen species (ROS) and inducing antioxidant defense dysregulation. For example, mercaptans can undergo oxidation reactions mediated by enzymes such as cytochrome P450 or peroxidases, producing superoxide anion (O₂^-) and hydrogen peroxide (H₂O₂).[6]

Mercaptan-induced oxidative stress can overwhelm intracellular antioxidant defense systems. ROS can react directly with antioxidants, such as glutathione, depleting their levels. Mercaptans may also inhibit antioxidant enzymes like catalase, superoxide dismutase, and glutathione peroxidase, impairing their ability to neutralize ROS.[7]

ROS generated during toxic mercaptan exposures may initiate lipid peroxidation, damaging cell membranes. ROS reacts with polyunsaturated fatty acids in cell membranes to form lipid peroxides. These lipid peroxides can propagate oxidative damage, disrupting the integrity and function of cellular membranes. Lipid peroxidation may damage and destroy erythrocytes leading to low oxygen-carrying capacity.[8]

Mercaptan-induced oxidative stress may also result in DNA damage. ROS can react directly with DNA, causing base modifications, single- and double-stranded DNA breaks, and DNA cross-linking. DNA damage can lead to genetic mutations, impaired DNA repair mechanisms, and potentially contribute to the development of various diseases.[5] Mercaptans can also interfere with Na⁺/K⁺-ATPases, impairing the bioelectrical activities of neuronal signaling and increasing the risk of muscle weakness, seizures, and paralysis.[2]

Toxicokinetics

Pharmacological data for all specific mercaptan compounds is not available. However, the general pharmacological aspects of mercaptan toxicity are known.[1]

Absorption

Mercaptans can be absorbed via inhalation, ingestion, and dermal contact. Inhalation of airborne mercaptans is a frequent route of exposure in occupational settings. Mercaptans can also be absorbed through the gastrointestinal tract following ingestion or through the skin upon direct contact.

Distribution

Once absorbed, mercaptans distribute throughout the body. Their distribution is influenced by lipophilicity, molecular size, and protein binding. Mercaptans can cross cell membranes and spread to various organs and tissues, including the liver, kidneys, lungs, brain, and adipose tissue.

Metabolism

Mercaptans undergo metabolism primarily via enzymatic processes. The specific enzymes involved in mercaptan metabolism will vary with the particular compound. Some mercaptans are metabolized by cytochrome P450 or peroxidases. These metabolic processes can lead to the formation of reactive intermediates and metabolites, which can contribute to the toxic effects of mercaptans.

Elimination

Mercaptans and their metabolites are eliminated from the body through various routes. The primary route of elimination is via urine, as mercaptan metabolites are often excreted as conjugated compounds. Some mercaptans may also undergo biliary excretion or biotransformation to less toxic metabolites before elimination.

History and Physical

The clinical manifestations and severity of mercaptan toxicity will vary with the specific mercaptan compound, route of exposure, concentration, duration of exposure, and individual susceptibility. Prompt recognition of symptoms and appropriate medical intervention are essential for managing and treating mercaptan toxicity.

Mercaptans can have systemic effects on multiple organ systems, including the respiratory, cardiovascular, nervous, gastrointestinal, renal, and hepatobiliary systems. Mercaptans may also have dermatological or hematological adverse effects.[4][9]

Respiratory System 

Inhalation of high concentrations of mercaptans may irritate the mucous membranes lining the nasal passages, throat, and respiratory tree, leading to airway compromise, dyspnea, coughing, chest tightness, and wheezing. Prolonged exposure to mercaptans can cause bronchial constriction, bronchitis, and pulmonary edema.

Cardiovascular System

Mercaptans alter vascular tone, leading to vasodilation or vasoconstriction, depending on the specific compound and concentration. Changes in vascular tone may lead to blood pressure lability and decreased peripheral perfusion. Additionally, mercaptans may disrupt endothelial function and impair cardiac contractility, potentially leading to cardiovascular collapse.

Nervous System

Neurological symptoms of mercaptan toxicity include headache, dizziness, confusion, and impaired cognitive function. Mercaptans can also affect neurotransmitter systems and neuronal function, leading to neurobehavioral abnormalities and potential long-term neurological consequences.

Gastrointestinal System

Mercaptan-induced gastrointestinal symptoms can be attributed to the irritant effects on the gastrointestinal mucosa and disturbances in digestive processes. Symptoms may include nausea, vomiting, abdominal pain, and diarrhea. 

Renal and Hepatic System

Mercaptan toxicity can impact renal and hepatic function. Exposure to mercaptans may lead to renal tubular dysfunction, impairing the excretion of toxins and waste products and contributing to electrolyte disturbances. Hepatic effects of mercaptans may include hepatotoxicity, interference with hepatic metabolic processes, and disruption of detoxification pathways.

Dermatological Effects

Direct contact with mercaptans can result in skin irritation and chemical burns. These effects can occur when mercaptans contact the skin or through exposure to contaminated clothing or equipment.

Hematological Effects

High levels of mercaptan exposure can lead to oxidative damage to erythrocytes and hemolysis.[10] If severe, anemia and its related symptoms of fatigue, weakness, and shortness of breath may result.

Evaluation

Diagnosing mercaptan toxicity requires a comprehensive evaluation of the clinical presentation, exposure history, and laboratory investigations. There are no specific diagnostic tests for mercaptan toxicity. Laboratory investigations are predominately performed to evaluate for end-organ dysfunction.

Clinical Assessment

A comprehensive medical history should include questioning about recent unintentional exposures and occupation history. The signs and symptoms of mercaptan toxicity vary and are nonspecific, presenting a challenge to timely diagnosis.

The route of exposure dictates the clinical manifestations of mercaptan toxicity and may include coughing, wheezing, shortness of breath, nausea, vomiting, abdominal pain, headache, confusion, skin irritation, and chemical burns. 

Laboratory Tests

Laboratory tests help support the diagnosis and assess the extent of mercaptan toxicity. A complete blood count (CBC) and comprehensive metabolic panel are recommended to evaluate for anemia, acute liver injury, or acute kidney injury with or without electrolyte disturbances. An arterial blood gas (ABG) is helpful in instances of hypoxia or respiratory symptoms to assess gas exchange and identify any acid-base disturbances cause by mercaptan exposure. A urinalysis may be employed to test for mercaptan metabolites where such tests are available.

Imaging Studies

Imaging modalities serve a limited role in the diagnosis of mercaptan toxicity. However, imaging can be important in evaluating the undifferentiated and differentiated poisoned patient by assessing signs of toxicity pertinent to a specific organ system. Imaging can assist the clinician in excluding nontoxic causes of presenting symptomatology.

Treatment / Management

Currently, there is no specific antidote or pharmacological treatment for mercaptan toxicity. Therefore, the management of mercaptan toxicity focuses on supportive care and symptomatic treatment. If a patient presents with a known or suspected exposure to mercaptans or any toxicity is being considered, prompt consultation with a medical toxicologist or local poison control center (PCC) is recommended. In cases of uncommon exposures or those with nonspecific symptoms, consultation aids the evaluation of an otherwise broad differential. The symptomatic treatment and management of mercaptan toxicity follow general guidelines.[4][11](B3)

Removal from Exposure

The first step in managing mercaptan toxicity is to follow facility self-containment protocols to decrease the transmission of toxins to the patient and medical personnel. If emergency services evaluate the patient before hospital arrival, the patient should be safely and promptly removed from the source of exposure. The patient should be appropriately placed in the correct isolation or containment setting. All articles of clothing should be removed employing meticulous strategies to contain contaminated clothing in sealed bags as per facility protocols. If the mercaptan exposure occurred via ingestion, the individual should be instructed to rinse their mouth.

Familiarity with prehospital and facility protocols for any known or suspected toxin exposure is imperative. Personal protective equipment (PPE) is important in safely managing the differentiated or undifferentiated poisoned patient suspected of exposure to a toxin(s). 

Decontamination

In dermal exposure to mercaptans, decontaminating the affected area is essential. Contaminated clothing should be removed, and the skin should be thoroughly washed with soap and water to remove residual mercaptan. If eye exposure occurs, rinsing the eyes with clean water for at least 15 minutes is necessary. Eyes wash stations in medical facilities serve as a quick and readily available resource. Morgan lenses may be employed when decontaminating eye exposures for patients that cannot use an eye wash station or require a longer duration of eye washing. Assessing ocular pH via bedside pH paper should be considered before, during, and after ocular decontamination to help further guide the duration of eye washing.  

Supportive Measures

Regular monitoring of blood pressure, heart rate, respiratory rate, and oxygen saturation is an essential assessment that guides interventions. An electrocardiogram (ECG) should be considered for signs or symptoms suggestive of cardiac dysrhythmias, such as witnessed ectopy on the monitor, and for symptoms suggestive of arrhythmias or ischemia, including lightheadedness, presyncope, syncope, palpitations, or chest pain.

Intravenous fluids may be administered to maintain hydration and correct any electrolyte imbalances.

In respiratory symptoms, beta-agonist bronchodilators may relieve bronchospasm and improve breathing. Supplemental oxygen, non-invasive ventilation, and definitive airway management may be indicated; airway management should be prioritized after the patient has been safely triaged and contained.

Symptomatic Relief

Antiemetic medications, such as ondansetron, may be given to alleviate nausea and vomiting. Nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids may be used for pain relief, depending on the severity of the symptoms. Antihistamines can be administered to reduce itching and inflammation if an allergic reaction or skin irritation occurs. 

Specific Complications

Severe skin burns or irritations may require topical treatments and wound care to promote healing and prevent infection. In the event of renal or hepatic dysfunction, standard medical protocols for managing these conditions should be followed. 

In preclinical studies involving 3 mammalian models, cobinamide, a vitamin B12 analog administered via intramuscular injection, has demonstrated promising efficacy against hydrogen cyanide, hydrogen sulfide, and methyl mercaptan toxicity. Furthermore, in swine exposed to methyl mercaptan, cobinamide effectively reversed all the methanethiol-induced alterations, possibly by directly binding with methyl mercaptan and reducing oxidative stress.[12][13][14][15][16][17](B3)

Differential Diagnosis

Given that the signs and symptoms of mercaptan toxicity can overlap with other conditions, a thorough differential diagnosis is essential. Conditions that may present with similar symptoms include respiratory tract infections, chemical pneumonitis, gastrointestinal disorders, and other toxic exposures such as other gaseous toxins.

Carbon monoxide poisoning should be considered when toxicity is undifferentiated, particularly when gaseous toxicity is known or suspected. The clinician should have a low threshold to order a blood gas and carbon monoxide level which would help to rule out this potentially deadly toxin that is more commonly encountered than other gaseous toxins. 

Prognosis

The prognosis of mercaptan toxicity will vary with the specific mercaptan compound involved, the route and duration of exposure, underlying comorbidities, decontamination success, timely consultation with a medical toxicologist or PCC, and the promptness of medical intervention.[18][19] 

In general, the prognosis for mercaptan toxicity is favorable if appropriate supportive care is provided promptly. Most individuals exposed to mercaptan experience mild to moderate symptoms that resolve spontaneously or with symptomatic treatment. However, the prognosis may be more guarded in severe mercaptan toxicity or prolonged exposure, especially if there are significant systemic effects. Severe respiratory distress, cardiovascular instability, or neurologic complications may indicate a more serious condition requiring intensive medical management.

Prolonged hospital management of mercaptan toxicity poses risks similar to any condition warranting admission, such as deep vein thrombosis, pneumonia and other hospital-acquired infections, and ventilator-related complications. Patients presenting with mild toxicity may be safely observed in a setting such as an emergency department and thus avoid unnecessary hospital-related complications. Consultation with medical toxicologists can guide the appropriate disposition of the patient, potentially decreasing hospital-related complications and healthcare costs.

Complications

The most severe respiratory complication of mercaptan toxicity is acute respiratory distress syndrome (ARDS), a potentially life-threatening condition characterized by rapid onset of respiratory distress and hypoxemia.[20] Cardiovascular effects may lead to dysrhythmias, myocardial ischemia, acute decompensated heart failure in patients without cardiac comorbidities, or acute on chronic heart failure in patients with preexisting heart disease. Cardiac arrest can occur in severe cases secondary to arrhythmogenic causes, heart failure, and ischemic events.

Gastrointestinal complications of mercaptan exposure most commonly are secondary to significant gastrointestinal fluid losses from vomiting or diarrhea.

Neurological complications of mercaptan toxicity include altered mental status, seizures, and coma in the acutely toxic patient. Future neurological sequelae and neurobehavioral disturbances can result from more chronic exposures.

Skin irritation secondary to dermal contact with mercaptans may range from mild rashes to serious chemical burns.[18] Consultation with wound care and a burn center may help guide management.