Quaternary Ammonium Compound Toxicity

Etiology

The toxic effects of QACs are dictated by the chemical structure of the compound and the route, dose, and duration of the exposure. Despite a long history of human use, there is limited data or research regarding QAC toxicity in the human body.[4]

Generally, ready-to-use QAC disinfectants are considered a low risk to humans because these products contain low concentrations of QACs. There is a higher risk of toxicity with highly concentrated QACs and inhaled or ingested exposure routes.[7] QACs induce oxidative stress by generating reactive oxygen species (ROS), which can disrupt normal cellular function. The cationic structure of QACs allows interaction with negatively charged cell membranes, leading to membrane disruption and cell death.

Epidemiology

There is limited epidemiological data on the toxicity of QACs in humans.[6] A recent study suggests that QACs can be detected at mean concentrations ranging from 0.01 to 1.58 ng/mL in 80% of human blood samples collected from the general United States population.[6] Several case reports have documented adverse, even fatal, effects of exposure to QACs in humans and animals.[8][9][10] However, toxic and lethal doses have yet to be established in humans.

Numerous studies estimate that about 75% of the QACs utilized annually are released into the water supply through wastewater treatment systems; the other 25% are released directly into the environment.[11] Additionally, due to the SARS-Cov-2 pandemic, the use of QAC-containing products has increased, resulting in burgeoning environmental effects and potential health hazards such as the detectable presence of QACs in breast milk and blood samples.[3][12][13]

Pathophysiology

The general chemical structure of QACs comprises a central nitrogen atom with four organic substituents or R groups. The substituents may be alkyl or aryl groups that vary in size and complexity. The classification of QACs is dictated by the number and type of R groups attached to the central nitrogen atom.

The toxicity of QACs is secondary to a combination of cell membrane disruption, nervous system overstimulation, and mucosal irritation leading to oropharyngeal, respiratory, and gastrointestinal distress. The intended antimicrobial effects of QACs occur via similar mechanisms.[11] 

Lending to the positively charged nitrogenous center, QACs interact with negatively charged cell membranes, leading to physical damage and membrane function disruption.[14] The subsequent inflammatory response is characterized by the recruitment of neutrophils and macrophages to the affected tissues and the release of proinflammatory cytokines, resulting in increased membrane permeability, loss of ion homeostasis, leakage of proteins and nucleic acids, and cell death.[15][16]

QACs have also been shown to disrupt mitochondrial function resulting in decreased ATP production and cell death.[1][6][17][4] Direct contact of QACs with the lipid bilayer can lead to significant irritation of the respiratory and gastrointestinal tracts resulting in inflammation, swelling, and pain. This can manifest as nausea, vomiting, and diarrhea due to the irritation of the intestinal lining and disruption of normal gut microbiota.[18][19]

Toxicokinetics

QACs can be absorbed through skin and mucous membranes, inhaled through the respiratory tract, or absorbed through the gastrointestinal tract. The amount of QAC absorption depends on the concentration of the QAC; the route, duration, and frequency of QAC exposure; and the presence of other chemicals that might affect exposure.

Once absorbed, QACs can be distributed throughout the body. QACs are primarily metabolized by the hepatic cytochrome p450 enzyme system and phase II hepatic metabolism via glucuronosyltransferases. QACs can accumulate in organs, including the liver, lungs, and kidneys.[6]

There are no established toxic or lethal doses for QACs in humans. QACs generally have low acute toxicity and only cause severe toxicity after significant exposures. However, chronic exposure to QACs has been associated with respiratory and dermal irritation, and some studies suggest that long-term exposure may be linked to the development of asthma.[6]

History and Physical

Clinicians should consider QAC toxicity if the medical history includes exposure to various industrial or household products, such as disinfectants, fabric softeners, and personal care products.[11] QACs are generally considered safe when products that contain them are used as directed. However, they can cause significant toxicity when ingested, inhaled, or absorbed in large amounts.

Symptoms of QAC toxicity are nonspecific and depend on the route, dose, and duration of exposure, and metabolic factors. Ingestion of QACs can cause gastrointestinal symptoms such as nausea, vomiting, diarrhea, bloody stools, and abdominal pain. Dermal exposure may lead to irritation, dermatitis, and chemical burns. Oropharyngeal exposure can lead to oral soft tissue swelling or posterior pharyngeal irritation; these may lead to airway compromise. Inhalation causes respiratory irritation and bronchospasm.[19] Ocular exposure can result in conjunctivitis, corneal abrasions or ulcers, and keratitis.[20]

Severe QAC toxicity can induce acute hepatic, respiratory, or renal failure, cardiovascular collapse, seizures, coma, and death.

Evaluation

The diagnosis and management of QAC toxicity are based on the clinical presentation, history of QAC exposure, and clinician gestalt. While laboratory tests, such as blood tests and urinalysis, may help assess the severity of toxicity and organ damage, there is currently no standardized biomarker or analyte testing for QAC exposure.

In patients with respiratory manifestations of QAC toxicity, pulmonary function tests or chest imaging may assist with evaluating lung function. Skin testing can be performed to identify the culprit allergen in cases of contact dermatitis.[21][22] Slit-lamp examination with fluorescein staining and tonometry should be performed in cases of ocular involvement. The upper eyelids should be everted and examined to evaluate potential abrasions from scratching or rubbing due to irritation.

In cases of QAC ingestion, liver and renal function tests should be performed to assess for organ damage. Abdominal radiography can be obtained to look for signs of perforation. Upper endoscopy may be considered in patients with stridor, dysphagia, or odynophagia.

Treatment / Management

No antidote or reversal agents exist for QAC toxicity. All toxicologic exposures should be evaluated as any emergency, focusing on airway establishment and maintenance, respiratory support, and circulation management. Decontamination should be prioritized to decrease exposure to the patient and healthcare workers; contaminated clothing should be removed. An on-staff medical toxicologist or local Poison Control Center should be consulted promptly to provide the best management.

The mainstay of treatment for QAC toxicity is supportive care. This may include administration of supplemental oxygen or intravenous fluids, electrolyte supplementation, and seizure management. However, only observation and supportive care may be required in cases of mild toxicity. In severe cases, more aggressive interventions may be necessary, such as mechanical ventilation or elimination via hemodialysis.In cases of QAC ingestion, gastric lavage or activated charcoal may be considered if the patient presents early and with significant exposure. However, these measures are generally not recommended in inhalation or dermal exposure cases.It is imperative to identify and manage any comorbidities that may exacerbate QAC toxicity, including conditions such as asthma and hepatic or renal disease, which can impair toxin elimination.[23](B3)

It is essential to provide appropriate follow-up care and monitoring to ensure full recovery from QAC toxicity; this may include ongoing monitoring of liver and kidney function. Most patients will recover fully without long-term consequences with appropriate care and monitoring.

Differential Diagnosis

The signs and symptoms of QAC toxicity may be subtle or overt but mimic those of several other disease processes. Many symptoms and signs of QAC toxicity occur secondary to the route of exposure.

Skin irritation or dermatitis from QAC exposure may mimic other causes of contact or allergic dermatitis, including that due to metals, fabric softeners, or personal care products such as lotion, shampoo, or fragrances.

Exacerbations of asthma or other chronic respiratory diseases should be considered and excluded when diagnosing QAC toxicity from inhalation exposure.

Gastrointestinal distress caused by infectious etiologies, food intolerances or allergies, adverse drug effects, or other acute gastrointestinal disorders may mimic QAC toxicity from ingestion.

Exposure to eye irritants such as smoke, dust, or other chemicals should be excluded.

Allergic reactions of any kind may mirror the symptoms of QAC toxicity.

Prognosis

The prognosis of QAC toxicity depends on the severity, duration, and quantity of QAC exposure and early supportive intervention. Overall, QAC toxicity is rare; most QAC exposures do not result in significant toxicity.[7] Most reported cases of QAC toxicity are mild and self-limiting.[24] In severe cases of QAC toxicity, life-threatening complications, including respiratory failure, seizures, and end-organ damage, may occur.[25]

Complications

The most significant complications of QAC exposure result from localized tissue irritation.[7] QACs are known irritants and corrosive agents at high concentrations; repeated exposures can result in severe burns, persistent dermatitis, and ocular damage.[19][21] Gastrointestinal distress caused by QAC toxicity can lead to severe dehydration from vomiting and diarrhea.

Downstream complications can arise in higher-risk patients with specific comorbidities. QAC exposure can exacerbate and worsen certain underlying conditions. For example, patients with known hepatic dysfunction could develop acute liver injury or cirrhosis. Similarly, patients with renal insufficiency can develop acute kidney injury leading to end-stage renal disease. Chronic respiratory exposures could lead to acute asthma exacerbations.[6]

The Environmental Influences on Child Health Outcomes (ECHO) program categorizes QACs as a high priority for biomonitoring in children due to the lack of toxicity data on human populations and no known biomarker testing.[26]