J: Household Products

INTRODUCTION

Joseph Lister, often considered the father of modern surgery, revolutionized surgical treatment and dramatically reduced surgical mortality by introducing the concept of antisepsis to the surgical theatre.⁴⁸ It was Lister’s understanding that microorganisms contributed to infection and sepsis from even the most trivial wounds that led to his search for chemicals that would prevent such infection. Lister demonstrated that phenol (carbolic acid), a chemical that was used to treat foul-smelling sewage, could be used to clean out dirty wounds of patients with compound fractures and dramatically increase survival rates. Soon thereafter, the use of phenol was expanded to surgical instrument cleaning and as a surgical hand scrub wash, ushering in the modern surgical era.

Antiseptics, disinfectants, and sterilants are a diverse group of germicides used to prevent the transmission of microorganisms to patients (Table 104–1). Although these terms are sometimes used interchangeably and some of these xenobiotics are used for both antisepsis and disinfection, the distinguishing characteristics between the groups are important to emphasize. An antiseptic is a chemical that is applied to living tissue to kill or inhibit microorganisms. Iodophors, chlorhexidine, and the alcohols (ethanol and isopropanol) are commonly used antiseptics. A disinfectant is a chemical that is applied to inanimate objects to kill microorganisms. Bleach (sodium hypochlorite), phenolic compounds, formaldehyde, hydrogen peroxide liquid, ortho-phthalaldehyde, and quaternary ammonium compounds are examples of currently used disinfectants. Neither antiseptics nor disinfectants have complete sporicidal activity. A sterilant is a chemical that is applied to inanimate objects to kill all microorganisms as well as spores. Ethylene oxide, glutaraldehyde, hydrogen peroxide gas, and peracetic acid are examples of sterilants. Not unexpectedly many of the xenobiotics used to kill microorganisms also demonstrate considerable human toxicity.^5,18,68

The choice of disinfectant or sterilant depends on the degree of risk for infection involved in use of medical and surgical instruments and patient care items. Surgical instruments and cardiac and urinary catheters that enter the vascular system or other sterile tissues (so called critical items) must be cleaned with a sterilant while instruments that contact mucous membranes or nonintact skin such as GI endoscopes and laryngoscope blades (semicritical items) can be cleaned with a high level disinfectant (ortho-phthalaldehyde, 7.5% hydrogen peroxide). Noncritical items such as bedpans, blood pressure cuffs, crutches, and computers are those that come in contact with intact skin but not mucous membranes and can be cleaned with intermediate level and low level disinfectants (bleach or phenol). Whether a chemical is classified as a sterilant or disinfectant may depend on how it is used. Device sterilization with glutaraldehyde 3% requires a 10-hour cleaning cycle while high-level disinfection using the same chemical requires a 25 minute cleaning cycle.

The use of these xenobiotics evolved during the 20th century as their toxicity and the principles of microbiology became better understood. Two of the more toxic antiseptics—iodine and phenol—were gradually replaced by the less toxic iodophors and substituted phenols. The use of mercuric chloride was superseded by the organic mercurials (eg, merbromin, thimerosal), which also proved toxic. In recent years, newer xenobiotics, such as quaternary ammonium compounds, ethylene oxide, glutaraldehyde, and a peractetic acid-hydrogen peroxide mixture, are more extensively used.

ANTISEPTICS

Chlorhexidine

This cationic biguanide has been in use as an antiseptic since the early 1950s. It is found in a variety of skin cleansers, usually as a 4% emulsion (Hibiclens), and may also be found in mouthwash. Chlorhexidine is reported to have low toxicity.

Clinical Effects.

Few cases of deliberate ingestion of chlorhexidine are reported. Symptoms are usually mild, and gastrointestinal irritation is the most likely effect after ingestion.²⁶ Chlorhexidine has poor enteral absorption. In one case, ingestion of 150 mL of a 20% chlorhexidine gluconate solution resulted in oral cavity edema and significant irritant injury of the esophagus.¹²³ In the same case, liver enzymes concentrations rose to30 times normal on the fifth day after ingestion. Liver biopsy showed lobular necrosis and fatty degeneration. In another case, the ingestion of 30 mL of a 4% solution by an 89 year-old woman did not result in any GI injury.⁵⁰ An 80 year-old woman with dementia ingested 200 mL of a 5% chlorhexidine solution and subsequently aspirated.⁷⁸ She rapidly developed hypotension, respiratory distress, coma, and died 12 hours following ingestion.

Intravenous administration of chlorhexidine is associated with acute respiratory distress syndrome (ARDS),⁸⁷ and hemolysis, although the latter may be caused by the hypotonicity of the injected solution.²⁷ Inhalation of vaporized chlorhexidine causes methemoglobinemia, likely as a consequence of the conversion of chlorhexidine to p-chloraniline.¹⁹⁹ In one patient, the rectal administration of 4% chlorhexidine resulted in acute colitis with ulcerations.⁶⁷

Topical absorption of chlorhexidine is negligible. Contact dermatitis is reported in up to 8% of patients who received repetitive topical applications of chlorhexidine.⁶⁸ More ominously, anaphylactic reactions, including shock, are associated with dermal application.^7,141 Some of these cases of chlorhexidine-related anaphylaxis occurred during surgery, appearing 15 to 45 minutes after application of the antiseptic.¹³ Eye exposure may result in corneal damage.¹⁹³

Management.

Treatment guidelines for chlorhexidine exposure are similar to those for other potential caustics (Chap. 106). Patients with significant symptoms may require endoscopy, but the need for such extensive evaluation is quite uncommon.

Hydrogen Peroxide

Hydrogen peroxide, an oxidizer with weak antiseptic properties, has been used for many years as an antiseptic and a disinfectant.²⁰² This oxidizer is generally available in two strengths: dilute, with a concentration of 3% to 9% by weight (usually 3%), sold for home use, and concentrated, with a concentration greater than 10%, used primarily for industrial purposes. Commercial strength hydrogen peroxide is commonly found in solutions varying from 27.5% to 70%. Home uses for dilute hydrogen peroxide include cerumen removal, mouth gargle, vaginal douche, enema, and hair bleaching. Dilute hydrogen peroxide is also sometimes used as a veterinary emetic. Commercial uses of the more concentrated solutions include bleaching and cleansing textiles and wool, and producing foam rubber and rocket fuel. A 35% hydrogen peroxide solution is also available to the general public in health food stores and is sold as “hyperoxygenation therapy” and as a health food additive to aerate health food drinks.⁸⁴ This potentially dangerous therapy is touted as a treatment for a variety of conditions, including AIDS and cancer.

Toxicity from hydrogen peroxide may occur after ingestion, inhalation, injection, wound irrigation, rectal administration, dermal exposure and ocular exposure.²⁰² Hydrogen peroxide has two main mechanisms of toxicity: local tissue injury and gas formation. The extent of local tissue injury and amount of gas formation are determined by the concentration of the hydrogen peroxide. Dilute hydrogen peroxide is an irritant, and concentrated hydrogen peroxide is a caustic. Gas formation results when hydrogen peroxide interacts with tissue catalase, liberating molecular oxygen, and water. At standard temperature and pressure, 1 mL of 3% hydrogen peroxide liberates 10 mL of oxygen, whereas 1 mL of the more concentrated 35% hydrogen peroxide liberates more than 100 mL of oxygen. Gas formation can result in life-threatening embolization. The ingestion of two sips of 33% hydrogen peroxide resulted in cerebral gas embolization and hemiplegia.¹⁶⁴ Gas embolization may be a result of dissection of gas under pressure into the tissues or of liberation of gas in the tissue or blood following absorption. The use of hydrogen peroxide in partially closed spaces, such as operative wounds, or its use under pressure during wound irrigation increases the likelihood of embolization.

Clinical Effects.

Airway compromise manifested by stridor, drooling, apnea, and radiographic evidence of subepiglottic narrowing may occur.⁴³ The combination of local tissue injury and gas formation from the ingestion of concentrated hydrogen peroxide may cause abdominal bloating, abdominal pain, vomiting, and hematemesis.^53,116 Endoscopy may show esophageal edema and erythema and significant gastric mucosal erosions.^154,171

Symptoms consistent with sudden oxygen embolization include rapid deterioration in mental status, cyanosis, respiratory failure, seizures, ischemic ECG changes, and acute paraplegia.^55,112 A 2 year-old boy died after ingesting 120 to 180 mL of 35% hydrogen peroxide.²⁹ Antemortem chest radiography showed gas in the right ventricle, mediastinum, and portal venous system. Portal vein gas is also a prominent feature in other cases.^53,84,147 Arterialization of oxygen gas embolization may result in cerebral infarction.¹⁷⁷ Encephalopathy with cortical visual impairment²³ and bilateral hemispheric infarctions detected by MRI imaging may occur after ingestion of concentrated hydrogen peroxide.⁸⁶ In a case of acute paraplegia after the ingestion of 50% hydrogen peroxide, MRI revealed discrete segmental embolic infarctions of the cervical and thoracic spinal cord as well as both cerebral hemispheres and left cerebellar hemisphere.¹¹²

Death from intravenous injection of 35% hydrogen peroxide is also reported.¹⁰⁵ The use of a concentrated hydrogen peroxide solution as part of a hair highlighting procedure resulted in a severe scalp injury including necrosis of the galea aponeurotica.¹⁷²

Clinical sequelae from the ingestion of dilute hydrogen peroxide are usually much more benign.^43,75 Nausea and vomiting are the most common symptoms.⁴³ A whitish discoloration may be noted in the oral cavity. Gastrointestinal injury is usually limited to superficial mucosal irritation, but multiple gastric and duodenal ulcers, accompanied by hematemesis, and diffuse hemorrhagic gastritis are reported.^75,129 Portal venous gas embolization may occur as a result of the ingestion of 3% hydrogen peroxide.^30,129,158

The use of 3% hydrogen peroxide for wound irrigation may result in significant complications. Extensive subcutaneous emphysema occurred after a dog bite to a human’s face was irrigated under pressure with 60 mL of 3% hydrogen peroxide.¹⁶² Systemic oxygen embolism, causing hypotension, cardiac ischemia, and coma, resulted from the intraoperative irrigation of an infected herniorrhaphy wound.¹² Gas embolism, resulting in intestinal gangrene, was reported to occur following colonic lavage with 1% hydrogen peroxide during surgical treatment of meconium ileus.¹⁷⁵ Multiple cases of acute colitis are reported as a complication of administering 3% hydrogen peroxide enemas.¹²⁵ The use of 3% hydrogen peroxide as a mouth rinse is associated with the development of oral ulcerations.¹⁶¹ Ophthalmic exposures may result in conjunctival injection, burning pain, and blurry vision.^43,124 Optic neuropathy including transient blindness (ability to visualize shadows only) and subsequent optic atrophy from possible inhalational of hydrogen peroxide is described.⁴⁴ Cough, wheezing, and shortness of breath is associated with occupational exposure to peracetic acid-hydrogen peroxide mixtures used to clean endoscopic equipment.³⁵

Diagnosis.

A careful examination should be performed to detect any evidence of gas formation. A chest radiograph might reveal gas in the cardiac chambers, mediastinum, or pleural space. An abdominal radiograph might show gas in the GI tract or portal system and define the extent of bowel distension. MRI and CT scan might be useful for detecting brain and spinal cord lesions secondary to gas embolism.^6,86,112 Endoscopic evaluation can help determine the extent of mucosal injury.¹⁵⁴

Management.

The treatment of patients with hydrogen peroxide ingestions depends, to a large degree, on whether the patient has ingested a diluted or concentrated solution. Those with ingestions of concentrated solutions require expeditious evaluation. Dilution with milk or water, although unstudied, is unlikely to be helpful. Nasogastric aspiration of hydrogen peroxide might be helpful if the patient presents immediately after ingestion. Induced emesis is contraindicated and activated charcoal offers no antidotal benefit. Patients with abdominal distension from gas formation should be treated with nasogastric suctioning. Those with clinical or radiographic evidence of gas in the heart should be placed in the Trendelenburg position to prevent gas from blocking the right ventricular outflow tract. Careful aspiration of intracardiac air through a central venous line may be attempted in patients in extremis.²⁹ Case reports suggest that hyperbaric therapy may be useful in cases of life-threatening gas embolization after hydrogen peroxide ingestion.^{53,84,112,131,147,199} Asymptomatic patients who unintentionally ingest small amounts of 3% hydrogen peroxide can be safely observed at home.

Iodine and Iodophors

Iodine is one of the oldest topical antiseptics.¹⁷³ Iodine usually refers to molecular iodine, also known as I₂, free iodine, and elemental iodine, which is the active ingredient of iodine-based antiseptics. The use of ethanol as the solvent, such as tincture of iodine, allows substantially more concentrated forms of I₂ to be available. I₂ and tincture of iodine ingestions are much less common than in the past as a result of the change in antiseptic use from iodine to iodophor antiseptics.⁴⁵

Iodophors have molecular iodine compounded to a high-molecular-weight carrier or to a solubilizing agent. Povidone-iodine (Betadine), a commonly used iodophor, consists of iodine linked to polyvinylpyrrolidone (povidone). Iodophors, which limit the release of molecular iodine and are generally less toxic, are the current standard iodine-based antiseptic preparations. Iodophor preparations are formulated as solutions, ointments, foams, surgical scrubs, wound-packing gauze, and vaginal preparations. The most common preparation is a 10% povidone-iodine solution that contains 1% “available” iodine (referring to all oxidizing iodine species), but only 0.001% free iodine (referring only to molecular iodine).^18,68

Iodine is used to disinfect medical equipment and drinking water. Iodine is effective against bacteria, viruses, protozoa, and fungi, and is used both prophylactically and therapeutically.³⁶ Iodine is cytotoxic and an oxidant. It is thought to work by binding amino and heterocyclic nitrogen groups, oxidizing sulfhydryl groups, and saturating double bonds. Iodine also iodinates tyrosine groups.⁶⁸

There may be significant systemic absorption of iodine from topical iodine or iodophor preparations.¹⁴⁹ Markedly elevated iodine concentrations occur in patients who receive topical iodophor treatments to areas of dermal breakdown, such as burn injuries.¹⁰² Significant absorption occurs when iodophors are applied to the vagina, perianal fistulas, umbilical cords, and the skin of low-birth-weight neonates.¹⁸⁴ The mucosal application of povidone-iodine during a hysteroscopy procedure resulted in acute kidney injury (AKI) that transiently required hemodialysis.¹⁷ A fatality following intraoperative irrigation of a hip wound with povidone-iodine is also reported.³⁷ In this latter case, the postmortem serum iodine concentration was 7000 μg/dL (normal: 5–8 μg/dL).

Clinical Effects.

Problems associated with the use of iodine include unpleasant odor, skin irritation, allergic reactions, and clothes staining. Ingestion of iodine may cause abdominal pain, vomiting, diarrhea, GI bleeding, delirium, hypovolemia, anuria, and circulatory collapse. Severe caustic injury of the GI tract may occur. The ingestion of approximately45 mL of a 10% iodine solution resulted in death from multisystem failure 67 hours after ingestion.⁴⁶ In another case, the ingestion of 200 mL of tincture of iodine containing 60 mg/mL iodine and 40 mg/mL potassium iodide in 70% v/v ethanol resulted in AKI and severe hemolysis.¹¹⁹

Reports of adverse consequences from iodophor ingestions are rare.In one case report, a 9 week-old infant died within 3 hours of receiving ­povidone-iodine by mouth.¹⁰⁰ In this unusual case, the child was administered 15 mL of povidone-iodine mixed with 135 mL of polyethylene glycol by nasogastric tube over a 3-hour period for the treatment of infantile colic. Postmortem examination showed an ulcerated and necrotic intestinal tract. A blood iodine concentration of 14,600 μg/dL was recorded. Significant toxicity from intentional ingestions of iodophors in adults is not documented.

Acid–base disturbances are among the most significant abnormalities associated with iodine and iodophors. Metabolic acidosis occurred in several burn patients after receiving multiple applications of povidone-iodine ointment.^102,150 These patients had elevated serum iodine concentrations and normal lactate concentrations. The exact etiology of the acidosis remains unclear. Postulated mechanisms for the acidosis include the povidone-iodine itself (pH 2.43), bicarbonate consumption from the conversions of I₂ to NaI, and decreased renal elimination of H⁺ as a consequence of iodine toxicity.¹⁵⁰ Metabolic acidosis associated with a high lactate concentration after iodine ingestion likely reflects tissue destruction.³⁶

Electrolyte abnormalities also may occur following the absorption of iodine. A patient with decubitus ulcers who received prolonged wound care with povidone-iodine–soaked gauze developed hypernatremia, hyperchloremia, metabolic acidosis, and AKI.³⁷ The hyperchloremia was thought to be caused by a spurious elevation of measured chloride ions as a consequence of iodine’s interference with the chloride assay. This interference occurs on the Technicon STAT/ION autoanalyzer, but does not occur when the silver halide precipitation assay is used.³⁶ Spurious hyperchloremia from iodine (or iodide) may result in the calculation of a low or negative anion gap (Chap. 19).^24,52

Other problems associated with topical absorption of iodine-containing preparations are hypothyroidism (particularly in neonates),^24,180 hyperthyroidism,^160,165 elevated liver enzyme concentrations, neutropenia anaphylaxis,¹ and hypoxemia.³⁶ Because of the lack of consistency between iodine concentrations and symptomatology, and because many of these patients had significant secondary medical problems that may have accounted for their symptoms, the exact relationship between iodine absorp­tion and the development of a specific clinical syndrome remains speculative. However, a clinical controlled trial that compared preterm infants exposed to either topical iodinated antiseptics or to chlorhexidine-containing antiseptics showed that the infants exposed to topical iodine-containing antiseptics were more likely to have higher TSH concentrations and elevated urine iodine concentrations than was the chlorhexidine group.¹⁰⁹

Contact dermatitis can result from repetitive applications of iodophors.¹²⁰ A dermal burn may result from the trapping of an iodophor solution under the body of a patient in a pooled dependent position or under a tourniquet.^111,135

Management.

The patient who ingests iodine (I₂) requires expeditious evaluation, stabilization, and decontamination. Careful nasogastric aspiration and lavage may be performed to limit the caustic effect of the iodine if signs of perforation are absent. Irrigation with a starch solution will convert iodine to the much less toxic iodide and, in the process, turn the gastric effluent dark blue-purple. This change in color may serve as a useful guide in determining when lavage can be terminated. If starch is not available, milk may be a useful alternative. Instillation of 100 mL of a solution of 1% to 3% sodium thiosulfate can also be used to convert any remaining iodine to iodide. Early endoscopy may help assess the extent of the gastrointestinal injury.

Most patients with iodophor ingestion require only supportive management. The use of starch or sodium thiosulfate may be considered in symptomatic patients. Hemodialysis and continuous venovenous hemodiafiltration were used successfully to enhance elimination of iodine in a patient with CKD who had become iodine toxic and developed renal deterioration after undergoing continuous mediastinal irrigation with povidone-iodine.⁹⁵ The benefit of hemodialysis or continuous venovenous hemodiafiltration is unknown in patients with normal renal function and therefore not recommended.

Potassium Permanganate

Potassium permanganate (KMnO₄) is a violet water-soluble xenobiotic that is usually sold as crystals or tablets or as a 0.01% dilute solution.⁹² Historically, it was used as an abortifacient, urethral irrigant, lavage fluid for alkaloid poisoning, and snakebite remedy. Currently, potassium permanganate is most often used in baths and wet bandages as a dermal antiseptic, particularly for patients with eczema.

Potassium permanganate is a strong oxidizer, and poisoning may result in local and systemic toxicity.¹⁸² Upon contact with mucous membranes, potassium permanganate reacts with water to form manganese dioxide, potassium hydroxide, and molecular oxygen. Local tissue injury is the result of contact with the nascent oxygen, as well as the caustic effect of potassium hydroxide. A brown-black staining of the tissues occurs from the manganese dioxide. Systemic toxicity may occur from free radicals generated by absorbed permanganate ions.²⁰⁸

Clinical Effects.

Following ingestion, initial symptoms include nausea and vomiting. Laryngeal edema and ulceration of the mouth, esophagus, and, to a lesser extent, the stomach, may result from the caustic effects. Airway obstruction and fatal gastrointestinal perforation and hemorrhage may occur.^42,126,143 Esophageal strictures and pyloric stenosis are potential late complications.⁹⁸

Although potassium permanganate is not well absorbed from theGI tract, systemic absorption may occur, resulting in life-threatening toxicity. Systemic effects include hepatotoxicity, AKI, methemoglobinemia, hemolysis, hemorrhagic pancreatitis, airway obstruction, ARDS, disseminated intravascular coagulation, and cardiovascular collapse.^{107,118,126,143} Elevation in blood or serum manganese concentration may also occur, confirming systemic absorption (normal concentrations blood manganese 3.9–15.0 μg/L; serum manganese 0.9–2.9 μg/L).

Chronic ingestion of potassium permanganate may result in classic manganese poisoning (manganism) characterized by behavioral changes, hallucinations, and delayed onset of parkinsonianlike symptoms. A 66 year-old man who mistakenly ingested 10 g of potassium permanganate instead of potassium iodate over a 4-week period (because of medication mislabeling) developed impaired concentration and autonomic and visual symptoms. He also developed abdominal pain, gastric ulceration, and alopecia. Serum manganese concentration was elevated. Nine months later, the patient’s neurologic examination displayed extrapyramidal signs consistent with parkinsonism (Chap. 97).⁸²

Management.

Because the consequential effects of potassium permanganate ingestion are a result of its liberation of strong alkalis, the initial treatment of such a patient should include assessment for evidence of airway compromise. Dilution with milk or water may be useful. Patients with symptoms consistent with caustic injury should undergo early upper GI endoscopy.⁹² Corticosteroids along with antibiotics may be warranted if laryngeal edema is present. Analysis of liver enzymes, BUN, creatinine, lipase, serum manganese, and methemoglobin concentrations should be performed when systemic toxicity is suspected. Methemoglobinemia, if clinically significant, should be treated with methylene blue (Antidotes in Depth: A42). Dermal irrigation with dilute oxalic acid may be successful in removing cutaneous staining.¹⁸² The administration of N-acetylcysteine (Antidotes in Depth: A3) to increase reduced glutathione production, thereby limiting free radical–mediated oxidative injury in cases of systemic potassium permanganate poisoning, has been suggested, but clinical trials have not been performed.²⁰⁸

OTHER ANTISEPTICS

Alcohols

Isopropanol and ethanol (Chaps. 80 and 109) are commonly used as skin antiseptics. When sold as rubbing alcohol, the standard concentration for these solutions is usually 70%. In recent years, alcohol-based hand sanitizers containing 60% to 95% ethyl or isopropyl alcohol have become ubiquitous throughout patient care units, jails, and some public buildings as a primary infection control measure. Their antiseptic action is thought to be a result of their ability to coagulate proteins. Isopropanol is slightly more germicidal than ethanol.⁶⁸ The alcohols have limited efficacy against viruses or spores. Isopropanol tends to be more irritating than ethanol and may cause more pronounced central nervous system depression.²⁰⁰ Unfortunately readily available alcohol-based sanitizer may be a tempting source for patients admitted with alcohol abuse disorders.^49,204 In a recent report a patient was admitted to the hospital with chest pain. While in the hospital the patient became hypotensive and delirious. He was later found in the bathroom drinking an alcohol-based hand wash that contained 63% isopropanol.⁴⁹ The clinical effects and treatment for alcohol poisoning are discussed in Chaps. 80 and 109.

Chlorine and Chlorophors

Chlorine, one of the first antiseptics, is still used in the treatment of the community water supply and in swimming pools. Chlorine is a potent pulmonary irritant that can cause severe bronchospasm and acute lung injury. Chapter 124 contains a further discussion of chlorine.

Sodium hypochlorite (NaClO), found in household bleaches and in Dakin solution, remains a commonly used disinfectant. First used in the late 1700s to bleach clothes, its usefulness arises from its oxidizing capability, measured as “available chlorine,” and its ability to release hypochlorous acid (HClO) slowly. It is used to clean blood spills and to sterilize certain medical instruments. A 0.5% hypochlorite solution is sometimes recommended for dermal and soft-tissue wound decontamination after exposure to biologic and chemical warfare agents (Chaps. 132 and 133).⁸⁵ Toxicity from hypochlorite is mainly a result of its irritant effects. The ingestion of large amounts of household liquid bleach (5% sodium hypochlorite) on rare occasions can result in esophageal burns with subsequent stricture formation.⁵⁴ In a cat model of bleach ingestion, a high incidence of mucosal injury and stricture formation was noted.²⁰³ However, the vast majority of household bleach ingestions in humans do not cause significant GI injuries.¹⁵¹ Accordingly, endoscopic evaluation is usually not warranted when assessing most patients with household liquid bleach ingestions. The ingestion of a more concentrated “industrial strength” bleach preparation (eg, 35% sodium hypochlorite) increases the likelihood of local tissue injury and should be managed accordingly (Chap. 106).

Mercurials

Both inorganic mercurials, such as mercuric bichloride (HgCl₂), and organic mercurials, such as merbromin (C₂₀H₈Br₂HgNa₂O₆) (mercurochrome) and thimerosal (C₉H₉HgNaO₂S) (merthiolate), which both contain 49% mercury, were used in the past as topical antiseptic agents. The usefulness of mercurials is significantly limited because of their relatively weak bacteriostatic properties and the many problems associated with mercury toxicity (Chap. 98). Repeated application of topical mercurials may result in significant absorption and systemic toxicity.^132,166 The use of high-dose hepatitis B immunoglobulin (HBIg) may cause mercury toxicity because of the use of thimerosal as a preservative in the HBIg preparation.¹¹⁴ In one case, a 44 year-old man received 250 mL of HBIg (containing about 30 mg of ­thimerosal) over 9 days following liver transplantation.¹¹⁴ He developed speech difficulties, tremor, and chorea. His whole blood mercury concentration was 104 μg/L (normal <10 μg/L). Increased mercury concentrations in both preterm and term infants, following immunizations with thimerosal-containing hepatitis B vaccine, have also generated much concern and led to the call to reduce or eliminate the mercury content of vaccines.^64,184

DISINFECTANTS

Formaldehyde

Formaldehyde is a water-soluble, highly reactive gas at room temperature. Formalin consists of an aqueous solution of formaldehyde, usually containing approximately 37% formaldehyde and 12% to 15% methanol. Formaldehyde is irritating to the upper airways, and its odor is readily detectable at low concentrations. Lethality in adults may follow ingestion of as little as 30 to 60 mL of formalin.⁴⁷

Formerly used as a disinfectant and fumigant, its role as a disinfectant is now largely confined to the disinfection of hemodialysis machines. Nonetheless, formaldehyde has many other applications. Formaldehyde is widely used in construction including the wood processing and the manufacturing of furniture, textiles, and carpeting.⁹⁶ Health care workers are probably most familiar with the use of formaldehyde as a tissue fixative and embalming agent. Medical students are routinely exposed to formalin in the anatomy laboratory.¹⁵⁹

Exposure to formaldehyde, a potent caustic, may result in both local and systemic symptoms, causing coagulation necrosis, protein precipitation, and tissue fixation. Ingestions of formalin may result in significant gastric injury, including hemorrhage, diffuse necrosis, perforation, and stricture.^3,11 The most extensive damage appears in the stomach, with only occasional involvement of the small intestine and colon.²⁰⁷ Chemical fixation of the stomach may occur. Esophageal involvement is not very prominent, and, if present, is usually limited to its distal segment.

The most striking and rapid systemic manifestation of formaldehyde poisoning is metabolic acidosis, resulting both from tissue injury and from the conversion of formaldehyde to formic acid. The patient may present with profound acidemia, accompanied by a large anion gap. Although the methanol component of the formalin solution is readily absorbed and has resulted in methanol concentrations as high as 40 mg/dL,^22,47 the rapid metabolism of formaldehyde to formic acid appears to be responsible for much of the acidosis (Chap. 109).

Clinical Effects.

Patients presenting after formalin ingestions complain of the rapid onset of severe abdominal pain, which may be accompanied by vomiting and diarrhea. Altered mental status and coma usually follow rapidly. Physical examination may demonstrate epigastric tenderness, hematemesis, cyanosis, hypotension, and tachypnea. Hypotension may be profound with decreased myocardial contractility, as well as hypovolemic shock, contributing to the cardiovascular instability.^77,191 Early endoscopic findings include ulceration, necrosis, perforation, and hemorrhage of the stomach, with infrequent esophageal involvement. Chemical pneumonitis occurs after significant inhalational exposure.¹⁵³ Intravascular hemolysis is described in hemodialysis patients whose dialysis equipment contained residual formaldehyde after undergoing routine cleaning.^145,157

Occupational and environmental exposure to formaldehyde receives considerable attention. In particular, there is concern over the potential off-gassing of formaldehyde from the widely used urea formaldehyde building insulation and particle boards.¹⁴² Headache, nausea, skin rash, sore throat, nasal congestion, and eye irritation are associated with the use of these polymers.³⁹ Formaldehyde, at concentrations as low as 1 ppm, may cause significant irritation to mucous membranes of the upper respiratory tract and conjunctivae.^81,113 Formaldehyde is also a potential sensitizer for immune-mediated reversible bronchospasm.⁷⁴ The exact immunologic mechanism is not yet elucidated, although it is likely that formaldehyde acts as a hapten. In addition, formaldehyde is thought to be a dermal sensitizer.¹⁸¹

Concerns about the health effects from the off-gassing of formaldehyde in trailers used by the Federal Emergency Management Agency (FEMA) after Hurricane Katrina illustrates the potential public health issues related to low-level formaldehyde exposure.¹¹⁷ A Center for Disease Control (CDC) investigation revealed that air formaldehyde concentrations in closed, unventilated trailers are, in fact, high enough to cause acute symptoms in some people.⁴ Long term effects after these exposures remain undefined.

Both animal and human data suggest that formaldehyde exposure is associated with an increased incidence of nasopharyngeal carcinoma.^2,70,148,167 Although its role in the pathogenesis of cancer in humans has been the subject of much debate,^32,121 the International Agency for Research on Cancer (IARC) classifies formaldehyde as a Group 1, known, carcinogen.

Management.

The immediate management of a patient who has ingested formalin includes dilution with water. Although such an approach may be useful in reducing the caustic effect, strong evidence for a beneficial result is lacking. Gastric aspiration with a small-bore nasogastric tube may limit systemic absorption. The role of activated charcoal is not studied, and it probably should not be used if endoscopy is considered likely. Significant acidemia should be treated with sodium bicarbonate and folinic acid (Chap. 109). Immediate hemodialysis may remove the accumulating formic acid as well as the parent molecules, formaldehyde, and methanol.⁴⁷ Independent treatment for methanol toxicity may be indicated (Antidotes in Depth: A30 and A31). Early endoscopy is recommended for all patients with significant GI symptoms to assess the degree of burn injury. Surgical intervention may be required for those with suspected severe burns and/or perforation.²⁰⁷ Emergent gastrectomy, as well as late surgical intervention to relieve formaldehyde induced gastric outlet obstruction, is infrequently required.^71,99

Phenol

Phenol, also known as carbolic acid, is one of the oldest antiseptics. It is rarely used as an antiseptic today, secondary to its toxicity, and has been replaced by the many phenolic derivatives. Currently, phenol is used as a disinfectant, chemical intermediary, and nail cauterizer. The last application uses a highly concentrated 89% solution. Phenol is also a component (0.1%–4.5%) of various lotions, ointments, gels, gargles, lozenges, and throat sprays.⁶⁸ Campho-Phenique and Chloraseptic contain 4.7% and 1.4% phenol, respectively. Although many cases of phenol poisoning were reported in the past, acute oral overdoses of phenol containing solutions are uncommon today.⁶⁰

Phenol acts as a caustic causing cell wall disruption, protein denaturation, and coagulation necrosis. It also acts as a central nervous system (CNS) stimulant. Intentional ingestion of concentrated phenol, ingestion of phenol-containing water, occupational exposure to aerosolized phenol, dermal contact, and parenteral administration may all result in symptomatic phenol poisoning. Phenol demonstrates excellent skin penetrance.¹⁵ Severe dermal burns from phenol have resulted in systemic toxicity, even death within minutes to hours.^15,106 Parenteral administration of phenol has also resulted in death. The lethal oral dose may be as little as 1 g.⁸³

Clinical Effects.

Clinical manifestations can be divided into local and systemic symptoms. Systemic symptoms from gastrointestinal (GI) or dermal absorption of phenol are usually more dangerous than the local effects. Manifestations of systemic toxicity include CNS and cardiac symptoms. CNS effects include central stimulation, seizures, lethargy, and coma.⁶³ In a study of patients who had ingested Creolin (26% phenol), CNS symptoms predominated.¹⁸³ Of the 52 patients who were evaluated at the hospital, 9 developed lethargy and 2 developed coma. Seizures were not reported. Cardiac symptoms from phenol include tachycardia, bradycardia, and hypotension.⁶³ Parenteral absorption of 10 mL concentrated 89% phenol resulted in hypoxemia, ARDS, pulmonary nodular opacities, and AKI requiring intubation and hemodialysis.⁶² This last case was associated with a phenol concentration of 87 mg/dL (normal <2 mg/dL).

Other systemic symptoms that may develop include hypothermia, metabolic acidosis, methemoglobinemia, and rabbit syndrome.^83,93 Rabbit syndrome is most commonly observed as a distinctive extrapyramidal effect from antipsychotic drugs and is characterized by fine rapid repetitive movements of the perioral musculature resembling a rabbit’s chewing movements. Increased acetylcholine release and a relative dopaminergic hypofunction may explain the development of rabbit syndrome after phenol exposure.⁹³

Local toxicity to the GI tract from the ingestion of phenol may result in nausea, painful oral lesions, vomiting, bloody diarrhea, dark urine, and severe abdominal pain.^8,91 Serious GI burns are uncommon, and strictures are rare. White patches in the oral cavity may be detected. In the Creolin study cited above, only 1 of 17 patients who underwent endoscopy had a significant esophageal burn.¹⁸³ Dermal exposures to phenol usually result in a light-brown staining of the skin. Excessive dermal absorption of phenol during chemical peeling procedures is associated with dysrhythmias and many of the other symptoms.^196,201

Markedly elevated blood and urine concentrations of phenol may be detected after ingestion, or dermal absorption, of phenol and phenol-containing compounds (eg, Campho-Phenique).^15,83

Management.

When phenol is mixed with water, a bilayer with unique properties is created that makes it difficult to remove from tissues. A variety of treatments have been suggested for dermal and gastric decontamination of phenol. A study using a rat model showed that cutaneous decontamination with a low-molecular-weight polyethylene glycol solution decreased mortality, systemic effects, and dermal burns.²¹ Although this study suggested that polyethylene glycol (PEG) was superior to water as a decontamination agent, a subsequent study using a swine model could not demonstrate a difference between these two therapies.¹⁵⁶ In another swine model, PEG 400 and 70% isopropanol were both superior to water washes and equally effective in decreasing dermal burn.¹²⁸ Given the lack of definitive efficacy data, either low-molecular-weight PEG, for example, PEG 300 or 400 (not to be confused with high-molecular-weight PEG that is used for whole-bowel irrigation), or high flow water is currently recommended for dermal irrigation and careful gastric decontamination. Isopropanol could also be considered as another treatment for dermal decontamination. Endoscopic evaluation, as needed to determine the extent of GI injury, and good supportive care are also recommended.

Substituted Phenols and Other Related Compounds

Hexachlorophene (pHisoHex), a trichlorinated bis-phenol, is considered generally less tissue-toxic than phenol. During the 1970s, an association was observed between repetitive whole-body washing of premature infants with 3% hexachlorophene and the development of vacuolar encephalopathy and cerebral edema.¹²² There were also multiple reports of significant neurologic toxicity and death in children who became toxic after ingesting hexachlorophene.⁷⁶ In addition, fatalities also occurred after patients absorbed substantial amounts of hexachlorophene during the treatment of burn injuries.²⁸ The use of hexachlorophene has declined significantly.

Clinical Effects.

pHisoDerm contains sodium octylphenoxyethoxyethyl ether sulfonate and lanolin, and is a safe antiseptic. Irritative effects (nausea, vomiting, diarrhea) would be the main adverse effects with ingestions.

In a study of poisoning admissions to Hong Kong hospitals, the ingestion of Dettol liquid, a household disinfectant that contains4.8% chloroxylenol, 9% pine oil, and 12% isopropanol, accounted for 10% of admissions.²⁵ Aspiration (perhaps, in part, because of the pine oil) occurred in 8% of these patients, resulting in upper airway obstruction, pneumonia, and acute respiratory distress syndrome. More common symptoms included nausea, vomiting, sore mouth, sore throat, drowsiness, abdominal pain, and fever. Dermal contact with Dettol may result in full-thickness chemical burns.⁴⁰

Cresol, a mixture of three isomers of methylphenol, has better germicidal activity than phenol and is a commonly used disinfectant. Exposure to concentrated cresol may result in significant local tissue injury, hemolysis, AKI, hepatic injury, and CNS and respiratory depression.^40,69,94,206 Phenol concentrations, as well as cresol concentrations, serve as markers of exposure.²⁰⁶

Management.

Treatment is mainly supportive.

Quaternary Ammonium Compounds

Quaternary ammonium compounds, positively charged compounds where four organic groups are linked to a nitrogen atom (NR₄⁺), are a type of cationic surfactant (surface-active agent) that are used as disinfectants, detergents, and sanitizers. Chemically, the quaternary ammonium compounds are synthetic derivatives of ammonium chloride, and structurally similar to other quaternary ammonium derivatives, such as carbamate cholinesterase inhibitors and neuromuscular blockers. Other cationic surfactants include the pyridinium compounds and the quinolinium compounds. Benzalkonium chloride (Zephiran) was one of the most commonly employed quaternary ammonium compounds in the past. Many newer quaternary ammonium compounds have supplanted its use. However, nebulized solutions used for the treatment of asthma, including albuterol and ipratropium bromide, may contain small amounts of benzalkonium chloride.

Clinical.

Quaternary ammonium compounds are usually less toxic than phenol or formaldehyde. Most of the infrequent complications that are described result from ingestions of benzalkonium chloride. Complications of these ingestions include burns to the mouth and esophagus, CNS depression, elevated liver enzyme concentrations metabolic acidosis, and hypotension.^79,140,198 Paralysis is also occasionally described as a complication of these ingestions and is presumably a result of cholinesterase inhibition at the neuromuscular junction.⁶⁰ Chronic inhalational exposure is associated with occupational asthma.¹⁶ Topical use of the quaternary ammonium compounds can cause contact dermatitis.¹⁷⁸ Ingestion of a 2.25% ammonium chloride solution marketed as a bacteriostatic algae and odor humidifier treatment resulted in serious gastrointestinal and pulmonary injury.⁶⁶

Ingestions of other cationic surfactants, such as the pyridinium agent cetrimonium bromide (Cetrimide), are associated with caustic burns to the mouth, lips, and tongue.¹³⁰ Peritoneal irrigation with cetrimonium bromide can produce metabolic abnormalities, hypotension, and methemoglobine­mia.^9,127 Intravenous administration of cetrimide produced cardiac arrest, hemolysis, and muscle paralysis.⁵⁶

Management.

Treatment recommendations following the ingestion of the quaternary ammonium compounds and other cationic surface-active agents are similar to those for other potentially caustic ingestions. Emergency department evaluation should be considered for all patients who ingest more than a taste of a dilute (less than 1%) solution. Therapy is mainly supportive. Endoscopy may be warranted if symptoms suggest the possibility of a burn injury.

STERILANTS

Ethylene Oxide

Ethylene oxide (C₂H₄O) is a gas that is commonly used to sterilize heat-sensitive material in health care facilities. Unlike antiseptics and disinfectants, which generally do not exhibit full sporicidal activity, sterilants, such as ethylene oxide, inactivate all organisms. Ethylene oxide is also used in the synthesis of many chemicals, including ethylene glycol, surfactants, rocket propellants, and petroleum demulsifiers, and has been used as a fumigant. Ethylene oxide has a cyclic ester structure that acts as an alkylating agent, reacting with most cellular components, including DNA and RNA.

Medical attention regarding ethylene oxide toxicity has centered on its mutagenic and possible carcinogenic effects.¹⁰¹ Approximately 270,000 workers (including 96,000 hospital workers) in the United States are at risk for occupational exposure to ethylene oxide.¹⁸⁷ Retrospective studies suggest a possible excess incidence of leukemia and gastric cancer in ethylene oxide exposed workers.^80,187 These studies are inconclusive, and the carcinogenicity of ethylene oxide remains subject to debate. It is also suggested that an increased incidence of spontaneous abortions may be associated with occupational exposure to ethylene oxide.⁷³

Clinical Effects.

The acute toxicity of ethylene oxide is mainly the result of its irritant effects. Conjunctival, upper respiratory tract, GI, and dermal irritation may occur. Dermal burns from acute exposure to ethylene oxide are reported. Acute exposure to a broken ethylene oxide ampule by a 43 year-old recovery room nurse resulted in nausea, lightheadedness, malaise, syncope, and recurrent seizures.¹⁷⁰ There were no long-term complications. In another case of acute exposure, coma was followed by an irreversible parkinsonism.¹⁰

Chronic exposure to high concentrations of ethylene oxide may cause mild cognitive impairment and motor and sensory neuropathies.^20,61,139 The risk of cancer with occupational exposure is low.^31,186,192

Management.

Treatment for patients with ethylene oxide exposure is supportive.

Glutaraldehyde

Glutaraldehyde is a liquid solution used in the cold sterilization of nonautoclavable endoscopic, surgical, and dental equipment. It is also employed as a tissue fixative, embalming fluid, preservative, and tanning agent, in radiographic solutions, and in the treatment of warts.⁵⁸ Glutaraldehyde (C₅H₈O₂) is a dialdehyde with two active carbonyl groups that is less volatile than formaldehyde. It kills all microorganisms, including viruses and spores. The germicidal ability of glutaraldehyde results from the alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups, within microbes interfering with RNA, DNA, and protein synthesis.¹⁶⁹ It is prepared as a 2% alkaline solution in 70% isopropanol (Cidex). Health care workers may be exposed to glutaraldehyde vapors when equipment is processed in poorly ventilated areas, or in open immersion baths or after spills. Under these circumstances, the evaporation of glutaraldehyde may result in the increase in ambient air concentrations that may easily exceed recommended limits. Approximately 35,000 workers are occupationally exposed to glutaraldehyde.¹⁵² Patients may be exposed when diagnostic instruments are inadequately rinsed following cold sterilization with glutaraldehyde.

Clinical.

Clinical signs and symptoms are thought to be comparable to those of formaldehyde exposure, although human toxicity data are limited. Animal studies show that the inhalational and dermal toxicity of glutaraldehyde are comparable to those of formaldehyde at equivalent doses.¹⁹⁰

Glutaraldehyde is a mucosal irritant. Coryza, epistaxis, headache, asthma, chest tightness, palpitations, tachycardia, and nausea are all associated with glutaraldehyde vapor exposure.^{14,33,136,146} Occupational asthma, contact dermatitis, and ocular inflammation may also occur.^38,144,174 Colitis is reported following the use of endoscopes contaminated with residual glutaraldehyde solution.¹⁷⁶ Patients with glutaraldehyde induced colitis typically present with fever, chills, severe abdominal pain, bloody diarrhea, and an elevated white blood cell count blood within 48 hours after colonoscopy or sigmoidoscopy.

The IARC has not ranked the carcinogenic potential of glutaraldehyde.

Management.

Treatment recommendations are similar to those for patients with formaldehyde exposure. Prompt removal from the exposure is essential. Copious irrigation with water provides adequate dermal decontamination. Severe inhalational exposures may require hospital admission for observation, supportive care, and treatment of bronchospasm.

In recent years, some hospitals have started using ortho-phthalaldehyde (OPA) or a mixture of hydrogen peroxide and peracetic acid as alterna­tives to glutaraldehyde for high-level disinfection.¹⁶³ These alternative disinfectants do not appear to have the pulmonary or dermal sensitizing properties associated with glutaraldehyde, although they may still cause some irritation to skin and mucus membranes.¹⁶³

OTHER PRODUCTS

Boric Acid

Boric acid is an odorless, transparent crystal, although it is most commonly available as a finely ground white powder. It is also available as a 2.5% to 5% aqueous solution. Boric acid (H₃BO₃), prepared from borax (sodium borate; Na₂B₄O₇·10 H₂O), was first used as an antiseptic by Lister in the late 19th century. Although used extensively over the years for antisepsis and irrigation, boric acid is only weakly bacteriostatic. As a result of its germicidal limitations and its inherent toxicity, boric acid is nearly obsolete in modern antiseptic therapy. Nonetheless, it continues to be used as an antimicrobial to treat such conditions as vulvovaginal candidiasis.¹⁵⁵ Boric acid is also employed in the treatment of cockroach infestation and as a soap, contact lens solution, toothpaste, and food preservative.⁶⁵

Boric acid is readily absorbed through the GI tract, wounds, abraded skin, and serous cavities. Absorption does not occur through intact skin. Boric acid is predominantly eliminated unchanged by the kidney. Small amounts are also excreted into sweat, saliva, and feces.⁵⁷ Boric acid is concentrated in the brain and liver.

The exact mechanism of action of toxicity remains unclear. Although it is an inorganic acid, it does not behave as a caustic. Local effects are limited to tissue irritation.

Over the years, boric acid has developed a reputation as an exceptionally potent toxin. This reputation was derived in great part from a series of reports involving neonatal exposures to boric acid resulting in high morbidity and mortality. Life threatening toxicity resulted from the repetitive topical application of boric acid for the treatment of diaper rash or the use of infant formulas unintentionally contaminated with boric acid.^57,205 Fatality rates greater than 50% were reported in some series.²⁰⁵ Although infants appear to be the most sensitive to the toxic effects of boric acid, many cases of significant toxicity are also reported in adults. These cases date predominantly from the time when boric acid was widely used as an irrigant. Routes of exposure to boric acid, resulting in fatalities, include wound irrigation, pleural irrigation, rectal washing, bladder irrigation, and vaginal packing.¹⁹⁷

Clinical Effects.

Classic boric acid poisoning usually involves multiple exposures over a period of days. Gastrointestinal, dermal, CNS, and renal manifestations predominate. The initial symptoms—nausea, vomiting, diarrhea, and occasionally crampy abdominal pain—may be confused with an acute gastroenteritis. At times, the emesis and diarrhea are greenish blue.²⁰⁵ Following the onset of GI symptoms, the majority of patients develop a characteristic intense generalized erythroderma.²⁰⁵ This rash, described as producing a “boiled lobster” appearance, may appear indistinguishable from toxic epidermal necrolysis or staphylococcal scalded skin syndrome in the neonate.^115,168 The rash may be especially noticeable on the palms, soles, and buttocks.⁵⁷ Typically, extensive desquamation takes place within 1 to 2 days. On occasion, prominent mucous membrane involvement of the oral cavity and conjunctivae is also apparent.²⁰⁵ At about the time of the development of the erythroderma, patients, particularly young infants, may develop prominent signs of CNS irritability, resembling meningeal irritation. Seizures, delirium, and coma can occur.⁵⁷ AKI is common, both a result of the renal elimination of this compound and prerenal azotemia from GI losses.⁵⁷ Other complications of boric acid poisoning include hepatic injury, hyperthermia, and cardiovascular collapse. The abandonment of boric acid as an irrigant and particularly its removal from the nursery setting have led to a marked decrease in the incidence of significant boric acid poisoning.

Two retrospective studies on boric acid ingestions suggest that a single acute ingestion of boric acid is generally quite benign.^108,110 In these studies, 79% to 88% of patients remained asymptomatic. Symptoms, when present, primarily consist of GI irritative symptoms, such as nausea and vomiting. None of the 1184 patients in these two studies manifested the generalized erythroderma so commonly described in previous reports. Central nervous system manifestations of acute overdose were infrequent and limited to occasional lethargy and headache. Renal toxicity did not occur following single acute ingestions.

Fatalities from massive acute ingestion of boric acid have been reported in both unintentional ingestions in children and intentional ingestions in adults.^65,162 Fatality resulted from a single ingestion of 2 cups (280 g) of boric acid crystals by a 45 year-old man.Signs and symptoms on presentation (2 days after ingestion) included nausea, vomiting, green diarrhea, lethargy, hypotension, AKI, and a prominent “boiled lobster” rash on his trunk and extremities. In another case, the ingestion of 30 g of boric acid by a 77 year-old man resulted in similar symptoms and death 63 hours postingestion, despite hemodialysis.⁸⁸ The diagnosis of boric acid poisoning can be confirmed with the measurement of blood or serum boric acid concentrations (normal = 1.4 nmol/mL), but this test is not routinely available.

Long-term chronic exposure to boric acid results in alopecia in adults and seizures in children.¹³⁸ A 32 year-old woman who chronically ingested mouthwash containing boric acid over a 7-month period developed progressive hair loss.¹⁸⁹ The chronic application of a borax and honey mixture to pacifiers resulted in the development of recurrent seizures in nine infants, which resolved after the mixture was withheld.^59,138

Management.

Treatment of boric acid toxicity is mainly supportive. Activated charcoal is not recommended because of its relatively poor adsorptive capacity for boric acid.⁴¹ Since boric acid has a low molecular weight and relatively small volume of distribution, in cases of massive oral overdose or AKI, hemodialysis, or perhaps exchange transfusion in infants, may be helpful in shortening the half-life of boric acid.^{34,110,134,194} Although forced diuresis is suggested to enhance renal elimination, this is highly unlikely to be successful and the risks outweigh the benefits.¹⁹⁵

Chlorates

Sodium chlorate is a strong oxidizer. At one time, the chlorate salts, sodium chlorate and potassium chlorate, were used as medicinals to treat inflammatory and ulcerative lesions of the oral cavity and could be found in various mouthwash, toothpaste, and gargle preparations.¹⁸⁵ Although their use as local antiseptics is obsolete, chlorates are used as herbicides and in the manufacture of matches, explosives, and dyestuffs.⁸⁹ More recent cases of chlorate poisoning resulted from the ingestion of sodium chlorate containing weed killers, or dispensing errors that confused sodium chlorate with sodium sulfate or sodium chloride.⁸⁹ Sodium chlorate in the form of white crystals has also been mistaken for table sugar.⁷² A case of significant toxicity from the inhalation of atomized chlorates is also reported.⁸⁹

Sodium chlorate is rapidly absorbed from the GI tract and eliminated predominantly unchanged from the kidneys.⁹⁰ Its systemic effects are chiefly hematologic and renal. The major mechanism of toxicity of chlorate is its ability to oxidize hemoglobin and increase red blood cell membrane rigidity.¹⁷⁹ Consequently, significant methemoglobinemia and hemolysis may result. Chlorates may also be directly toxic to the proximal renal tubule.¹⁰³ The hemolysis and the resultant hemoglobinuria may secondarily cause disseminated intravascular coagulation and potentiate renal toxicity. The worsening renal function is especially problematic because of its adverse effect on chlorate elimination. The methemoglobinemia may be severe and cause significant hypoxic stress. Methemoglobinemia may occur prior to or after the development of hemolysis.^137,188 Chlorates may also act locally as a GI irritant and cause mild CNS depression after absorption.⁶⁰

Clinical.

Clinical signs and symptoms of chlorate poisoning usually begin 1 to 4 hours after ingestion.⁹⁷ The earliest symptoms are GI, including nausea, vomiting, diarrhea, and crampy abdominal pain. Subsequently, the patient may exhibit cyanosis from the methemoglobinemia and black-brown urine from the hemoglobinuria. Obtundation and anuria may ensue. Laboratory studies may show methemoglobinemia, anemia, Heinz bodies, ghost cells, fragmented spherocytes, metabolic acidosis, decreased platelet count, and abnormal coagulation.⁵¹ Hyperkalemia may be particularly problematic if the patient ingests potassium chlorate preparations.¹³³ In a case of chlorate poisoning from the ingestion of 120 potassium chlorate–containing matchsticks, an MRI revealed symmetric abnormal signal intensity within the deep gray matter and medial temporal lobes.¹³³ This finding can be explained by the increased vulnerability to oxygen deprivation of the basal ganglia. Follow-up MRI two months later was normal.

Management.

Treatment of a patient with a significant chlorate inges­tion should include orogastric lavage and the use of activated charcoal.⁷² It has been suggested that administration of sodium thiosulfate may inactivate the chlorate ion by reducing it to the chloride ion,⁷² but an in vitro study did not confirm this hypothesis.¹⁸⁸ The utility of methylene blue in the treatment of symptomatic chlorate induced methemoglobinemia has been questioned as a consequence of the inactivation by chlorates of glucose-6-phosphate dehydrogenase, an enzyme that is required for methylene blue to effectively reduce methemoglobin.^179,188 More recent experience suggests that early use of methylene blue prior to the onset of hemolysis may be useful in the treatment of chlorate induced methemoglobinemia.^19,104 Exchange transfusion, peritoneal dialysis, and hemodialysis have also been advocated in the treatment of patients with severe chlorate poisoning.^137,188 Because the chlorate ion is easily dialyzable, hemodialysis is capable of removing this xenobiotic as well as treating any concomitant AKI that may have developed.^89,97,103

SUMMARY

• A chemically diverse group of antiseptics, disinfectants, and sterilants exist.

• Many of the more toxic xenobiotics, such as iodine, phenol, and chlorates, are no longer commonly used as cleansers but may still be available in some settings.

• Formaldehyde exposures, although also uncommon, can also cause significant toxicity.

• Frequently employed antiseptics, such as chlorhexidine, pHisoDerm, and many of the currently used quaternary ammonium compounds, have a relatively limited toxicity.

• Ingestions of the iodophors do not usually cause significant toxicity, but absorption through other routes may produce significant adverse effects. Ingestion of hydrogen peroxide, particularly the more concentrated formulations, may result in life threatening injuries.

References

INTRODUCTION

Many different products have been used as moth repellents. In the United States, paradichlorobenzene has largely replaced both camphor and naphthalene as the most common active component of moth repellent and moth flakes because of its lower toxicity. However, life threatening camphor and naphthalene toxicity still occurs, especially in immigrant communities, from exposures to imported camphor or naphthalene-containing pro­ducts.^3,49,64,80 Therefore, toxicity of camphor, naphthalene, and paradichlorobenzene should be considered when evaluating possible exposure to moth repellents.

CAMPHOR

History and Epidemiology

Camphor (2-bormanone, 2-camphonone), a cyclic ketone of the terpene group, is an essential oil originally distilled from the bark of the camphor tree, Cinnamomum camphora. Today, camphor is synthesized from the hydrocarbon pinene, a derivative of turpentine oil. Camphor has been used for centuries as an aphrodisiac, contraceptive, abortifacient, suppressor of lactation, analeptic, cardiac stimulant and antiseptic.^{43,55,57,61,72,96,109} Camphor is a commonly used ingredient found in many nonprescription remedies for cold symptoms, cold sores, and in muscle liniments.^{2,75,77,93,97} Camphor is also rarely abused as a stimulant.⁶⁹

Camphorated oil and camphorated spirits contain varying concentrations of camphor. Historically, most camphorated oil was prepared as a 20% weight (of solute) per weight (of solvent) (w/w) solution of camphor with cottonseed oil, and most camphorated spirits contained 10% w/w camphor with isopropyl alcohol. Toxicity and death following ingestion of camphorated oil, which was frequently confused with castor oil and cod liver oil, prompted the FDA to ban the nonprescription sale of camphorated oil in the United States in 1980.^{11,61,76,120,125} The FDA ban of camphorated oil was followed by a restriction on camphor content in 1983, limiting the camphor concentration to less than 11% in nonprescription camphor containing products in the United States.¹²⁶ However, camphorated oil is still used as an herbal remedy and muscle liniment, and products containing greater than 11% camphor can still be purchased in local stores of various ethnic communities in the United States and in other countries.^35,49,64,117

Common camphor-containing products include ointments often used for herpes simplex on the lips (usually <1% camphor), muscle liniments, rubefacients (usually 4%–7% camphor), and camphor spirits (usually 10% camphor). Paregoric, camphorated tincture of opium, contains a combination of anhydrous morphine (0.4 mg/mL), ethanol (46%), and benzoic acid (4 mg/mL) but only a small amount of camphor.⁶⁸ For industrial uses, camphor can be purchased legally in the United States and contains up to 100% camphor. Occupational exposures to camphor occur during the manufacture of plastic, celluloid, lacquer, varnish, explosives, embalming fluids, and numerous pharmaceuticals and cosmetics.⁶⁸

Although products containing lower concentrations of camphor are implicitly safer, life threatening toxicity and death may still result from misuse or intentional overdose. Most reported cases of acute camphor poisoning are unintentional ingestions of camphor containing products mistaken for other medications or therapeutic misadventures from nonprescription products, including home remedies.^{3,11,35,49,61,64,100,118,121} According to data obtained by the American Association of Poison Control Centers (AAPCC), there are approximately 13,000 exposures to camphor containing products each year with a majority of the exposure, approximately 80%, occurring in children under the age of 5 years (Chap. 136).

Prior to FDA ban of camphorated oil and restriction on camphor content in nonprescription products, high incidence of systemic symptoms and seizures, 46% and 20% respectively, were reported in children under5 years of age.¹²⁹ A group of 530 camphor exposure cases showed that among all reported cases, 15% presented with systemic symptoms, and 4% had seizures.^42,93 Unfortunately, limited data is available with regard to the true incidence of systemic toxicity and seizure since the FDA ruling in 1983. According to AAPCC data, seven reported deaths were attributable to camphor over the past 20 years, all in adults, and at least two of which occurred in the setting of an intentional suicidal ingestions. Although a majority of the patients with unintentional exposures remain asymptomatic and do not present to the health care facility, significant morbidity from unintentional camphor exposures still occurs in children.^{3,35,49,64,80,93,97,117} The public health implication of camphor exposure in children is of great concern because of its lack of therapeutic value and its potential life threatening toxicity.

Pharmacology

Camphor is a colorless glassy solid. Its pharmacologic activity is not well studied, and its mechanism of action remains unclear. It is unlikely that camphor has therapeutic benefit as an expectorant or an antiinfective. No therapeutic benefit of camphor has been proven in any well-controlled clinical trials. Camphor may provide some local analgesic and antipruritic effects, but much safer alternatives are available for these indications.

Pharmacokinetics and Toxicokinetics

There are limited data on the pharmacokinetics and toxicokinetics of camphor. Ingestion is the most common route of exposure, resulting in significant camphor toxicity.^{3,64,69,80,93,132} However, toxicity can be observed following inhalation, intranasal instillation, intraperitoneal administration, and from transplacental transfer, resulting in fetal death.^{29,102,107,111,115,132} Dermal exposures are also reported to cause systemic toxicity.^{35,49,64,98,121} Camphor is a highly lipophilic compound that is rapidly absorbed from the gastrointestinal tract and can be detected in the blood within 15 to 20 minutes following ingestion.^93,102 The presence of food in the stomach may delay the absorption of camphor.¹ Due to lack of experimental data, the bioavailability from each route of exposure is unknown. In an animal experiment, a peak blood camphor concentration was achieved in 90 minutes when rats were administered an oral dose of 1 g/kg.³⁴ A significant amount of camphor can be absorbed through normal skin. Dermal absorption of camphor is slow but can produce systemic toxicity up to 72 hours following exposure.^49,64 The volume of distribution is estimated at 2 to 4 L/kg with protein binding of approximately 61%.^68,69

Camphor is predominantly metabolized in the liver and eliminated by the kidneys. Up to 59% of the camphor is eliminated in urine asglucuronides but unchanged camphor (<1%) and other oxidative meta­bolites are eliminated without glucuronidation.^69,104,109 Five inactive meta-bolites are produced by hydroxylation of a methylene group (the predominant pathway) and reduction of the oxo group.¹⁰⁴ Inactive metabolites, 3-hydroxycamphor, 5-hydroxycamphor (major metabolite), 8-hydroxycampor, 9-hydroxycamphor, and borneol, are either conjugated with glucuronic acid or further oxidized and eliminated by the kidneys.^69,104 The exact site of camphor metabolism is unknown, but CYP 2A6 and NADPH-P450 reductase are known to be involved in two in vitro experiments.^50,84 Nine other CYP enzymes (1A1, 1A2, 2B6, 2C8, 2C9, 2C19, 2C6, 2E1, and 3A4) all failed to produce detectable metabolites of camphor.⁵⁰ CYP2A6 metabolized camphor to 5-hydroxycamphor, a major camphor metabolite.⁵⁰ In humans, a plasma elimination half-life of93 minutes and 167 minutes was reported after 200 mg of camphor was ingested by a volunteer, with Tween 80 as a solvent (10 mL) or without the solvent, respectively.⁶⁸ A comparable elimination half-life of 144 minutes was found in an animal study after an oral ingestion.³⁴ Small amounts of camphor may be eliminated by exhalation, as noted by characteristic odor in breath, but no studies have assessed the significance of this route of elimination.^69,75

The reported toxic dose of camphor is highly variable.^51,61,113 A potential lethal dose of 50 to 500 mg/kg of camphor is often cited for humans.^35,42,80,93 Yet, as little as 1 g of camphor has reportedly resulted in death in a 19 month-old infant, while up to 42 g of camphor was ingested by an adult who recovered.^2,113 There is insufficient data to suggest a clear toxic dose range of camphor. However, there is evidence to suggest that camphor can cause life threatening toxicity at low doses (estimated exposure of 700 to 1500 mg) based on a series of case reports in both adults and children.^{29,42,75,93,113,117} Currently, the AAPCC recommends that any patient who is exposed to 30 mg/kg or more of camphor should receive emergent medical attention.⁷⁷

Workplace standards determined by the Occupational Safety and Health Administration (OSHA) has set the permissible exposure limit (PEL) at 2 mg/m³.¹²³ The American Conference of Governmental Industrial Hygienists’ (ACGIH) threshold limit value (TLV) is 12 mg/m³ (2 ppm), while the short-term exposure limit (STEL) is 19 mg/m³ (3 ppm). The National Institute for Occupational Safety and Health (NIOSH) Immediately Dangerous To Life or Health Concentration (IDLH) is 200 mg/m³.¹²²

Pathophysiology

The mechanism of toxicity of camphor is unknown. Camphor is an irritant. Pathologic changes following ingestion include cerebral edema, neuronal degeneration, fatty changes, centrilobular congestion of the liver, and hemorrhagic lesions in the skin, gastrointestinal tract, and kidneys.^{35,62,113,132}

Clinical Manifestations

Exposure to camphor can often be detected by its characteristic aromatic odor (Chap. 26). Ingestion of camphor typically produces oropharyngeal irritation, nausea, vomiting, and abdominal pain. Generalized tonic–clonic seizures may be the first sign of camphor toxicity, usually occurring within 1 to 2 hours of ingestion.^13,18 The onset of systemic toxicity, particularly CNS toxicity, can occur as early as 5 minutes after ingestion.^29,32,75,113 Most seizures are brief and self-limited, although some patients may have a more protracted course, including status epilepticus.^{13,45,49,67,111} Delayed seizures, occurring up to 9 hours following ingestion and up to 72 hours following dermal exposure, are reported.^49,105 Central nervous system (CNS) depression is common, but camphor rarely compromises respiratory function.^29,68 Other neurologic manifestations include headache, lightheadedness, transient visual changes, confusion, myoclonus, and hyperreflexia.^65,102,107 Psychiatric manifestations include agitation, anxiety, and hallucinations.^51,65,68 Dermal effects include flushing and petechial hemorrhages.^29,55,115 Camphor does not typically cause life-threatening cardiovascular effects, although a case of myocarditis is reported.¹⁹ Deaths are reported secondary to status epilepticus.^16,29,77,113 Case reports suggest that acute ingestion of camphor can cause transient elevations of the hepatic aminotransferases.^{11,62,102,107,111} Chronic administration of camphor to a child caused altered mental status and elevated hepatic aminotransferases concentrations suggestive of Reye syndrome.⁶² When hepatotoxicity occurs, however, camphor does not typically produce morphologic changes in the liver characteristic of Reye syndrome. Albuminuria can also occur.¹¹³

Camphor crosses the placenta. Both fetal demise and delivery of healthy neonates are reported in mothers who experienced acute camphor toxicity from both intentional and unintentional ingestion and delivered during the following 24 hours.^20,102,132 Specific dose-related toxicity cannot be determined from these case reports.

Inhalational and dermal exposure from camphor usually produces only mucous membrane and dermal irritation, respectively.⁴⁸

Diagnostic Testing

No specific diagnostic test is available or indicated when managing patients with camphor toxicity. Camphor and its metabolites can be identified in blood and urine.^69,104 But these tests are not clinically useful in most cases of acute toxicity as they are not readily available and have not been shown to correlate with clinical toxicity.^55,69,104

Management

Patients who should be evaluated in a health care facility after an acute ingestion include those who have signs or symptoms consistent with camphor toxicity, those who have ingested more than 30 mg/kg of camphor, suicidal patients, and any patient with a significant occupational exposure.⁷⁷

Gastric decontamination is not well studied in patients with acute camphor ingestion. Camphor is rapidly absorbed in the gastrointestinal tract due to its high lipophilic property. Thus, the benefit of gastrointestinal (GI) decontamination rapidly diminishes with time following acute ingestion. Gastric decontamination may be difficult to perform at times, as GI symptoms (eg, active vomiting) are frequently encountered. Gastric lavage has been performed in patients with acute camphor ingestions, but clinical benefit of such procedure in setting of camphor toxicity is unknown.^42,93 If lavage is deemed necessary following recent ingestion of a camphor-containing solution, nasogastric suctioning and lavage are preferable to orogastric lavage. The utility of activated charcoal in acute camphor ingestion is unknown. One animal study showed that administration of activated charcoal (2 g/kg; 2:1 activated charcoal to toxin ratio) immediately following camphor ingestion did not alter the gastrointestinal absorption of camphor.³⁴ There are no human data in support for or against the use of activated charcoal in camphor ingestions. Given the lack of data, an AAPCC consensus panel has recommended against the use of activated charcoal in patients with isolated camphor ingestions.⁷⁷

There is no antidote for camphor. Most patients survive with supportive care. Although the management of camphor induced seizures is not well studied, the first line therapy for camphor induced seizures is a benzodiazepine. Repeat doses of benzodiazepines may be needed to control seizures. If benzodiazepines fail to control seizures, other sedative-hypnotics, including pentobarbital or propofol, should be administered. Case reports suggest that most patients who develop life-threatening camphor toxicity develop symptoms within a few hours postexposure. Based on this, an observation period of at least 4 hours following a potentially toxic ingestion of camphor is reasonable. In case reports, hemodialysis with a lipid dialysate and either hemoperfusion using an Amberlite resin or charcoal hemoperfusion successfully removed camphor.^{11,44,67,68,78} However, neither isolated lipid hemodialysis nor lipid dialysis in combination with hemoperfusion is routinely recommended or widely available.

NAPHTHALENE

History and Epidemiology

Naphthalene (C₁₀H₈), an aromatic bicyclic hydrocarbon, is commonly found in products such as moth repellents, toilet-bowl and diaper-pail deodorizers, and soil fumigants.¹¹⁴ It is the single most abundant component of coal tar, approximately 11% by weight, and is used in the manufacture of numerous commercial and industrial products.^24,114 Both crude oil and refined products such as gasoline and diesel fuels contain naphthalene.

Historically, naphthalene toxicity has mainly resulted from its use as an antihelminthic and an antiseptic.¹¹² In recent years, unintentional and intentional ingestions of mothballs containing naphthalene have become the major etiology of naphthalene toxicity.^{66,73,109,116,131} A single naphthalene mothball can contain between 0.5 and 5 g of naphthalene depending on its size.⁴ Toilet-bowl and diaper-pail deodorizers containing naphthalene have also caused toxicity.^28,139 Chronic exposure to naphthalene occurs in occupational setting with variable levels of exposure depending on the industry. The most common use of naphthalene is in the production of phthalic anhydride, a compound used in chemical feedstock.⁴⁷ Other industrial uses of naphthalene include carbamate insecticides, dye intermediates, synthetic resins, bathroom (urinal) air fresheners, fuel additives, plasticizers, and the manufacture of other chemicals.^47,114 Naphthalene is also generated as a by-product of combustion and is present in ambient air at low concentrations.⁴⁷

Most unintentional exposures to naphthalene-containing moth repellents occur in children and do not cause life-threatening toxicity. According to data from the AAPCC, each year there are between 1500 and 2000 exposures to naphthalene. Since 1998 there has not been a naphthalene-associated death reported to AAPCC, and reports of “major toxicity” are very unusual (Chap. 136). Mothball vapors are also intentionally inhaled as a form of inhalant abuse.^70,131

Pharmacology, Pharmacokinetics, and Toxicokinetics

Naphthalene is a white, flakey crystalline solid with a noxious odor. Synonyms include white tar and tar camphor. Naphthalene toxicity is reported following ingestion, dermal application, and inhalation.^{30,33,36,106,127} Although the absorption of naphthalene is not well studied, highly lipid-soluble compounds may increase both oral and dermal absorption. Naphthalene metabolism is complex and varies considerably among species and different anatomical regions.²² For instance, an in vitro study using human liver micro­somes showed that multiple CYP450 enzymes are involved in naphthalene metabolism: 1A1, 1A2, 1B1, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4.²⁷ On the other hand, data from animal studies showed a different group of CYP450 isoenzymes are responsible for naphthalene metabolism.⁴ Metabolic pathways involve several intermediates and generate multiple reactive metabolites: 1,2-naphthalene oxide, 1,4-naphthoquinone, 1,2-naphthoquinone, and 1,2-dihydrxy-3,4-epoxy-1,2,3,4-tetrahydronaphthalene^4,22,23 (Fig. 105–1).

Naphthalene is initially metabolized to an unstable epoxide interme­diate, 1,2-naphthalene oxide.^4,23,114 Naphthalene 1,2-oxide can react with cellular components such as DNA and protein to form covalent adducts or can be spontaneously converted to 1-naphthol and 2-naphthol, which undergo glucuronidation or sulfation to form conjugates that are subsequently eliminated in urine.^4,22,23 Glutathione-S-transferase and gluta-thione play an important role in detoxification of 1,2-naphthalene oxide by converting the reactive epoxide to nonreactive mercapturic acid meta-bolites.^22,23,76 The depletion of glutathione prior to naphthalene exposure increases acute injury in lung Clara cells, one of the target organs of naphthalene toxicity in mice.^94,95

Reactive hepatic metabolites, 1-naphthol, 1,2-naphthoquinone, and 1.4-naphthoquinone, are cytotoxins which deplete intracellular glutathione stores and generate reactive oxygen species.^4,114,138 They are responsible for the oxidative stress leading to naphthalene-induced hemolysis and methemoglobinemia.

The toxic amount of naphthalene reported in the medical literature is highly variable. As little as one naphthalene mothball has resulted in toxicity, including hemolysis in an infant.^41,139 Workplace standards include the OSHA PEL, which is 50 mg/m³ (10 ppm), ACGIH TLV, which is 52 mg/m³ (10 ppm), and the ACGIH STEL, which is 79 mg/m³ (15 ppm); NIOSH IDLH is 250 ppm (US Dept of Labor OSHA).¹²³

Pathophysiology

Naphthalene-induced (via oxidative metabolites: 1-naphthol, 1,2-naphthoquinone, and 1.4-naphthoquinone) hemolysis and methemoglobinemia result when physiologic compensatory mechanisms to oxidative stress are overwhelmed. It is important to understand how oxidant stress affects erythrocytes and the normal mechanisms erythrocytes use toprevent and reverse the effects of oxidant stress.

Oxidant stressors can cause methemoglobinemia and/or hemolysis. When oxidant stress causes an iron atom from any of the four globin chains of hemoglobin to be oxidized from the ferrous state (Fe²⁺) to the ferric state (Fe³⁺), methemoglobin is formed (Chap. 127). When oxidant stress causes hemoglobin denaturation, the heme groups and the globin chains dissociate and precipitate in the erythrocyte, forming Heinz bodies. An erythrocyte with denatured hemoglobin is more susceptible to hemolysis and removal by the reticuloendothelial system (Chap. 22).

Hemolysis and methemoglobinemia can occur independently or simultaneously in patients with either normal or deficient glucose-6-phosphate dehydrogenase (G6PD) activity.^{43,58,127,139} Patients with G6PD deficiency are at increased risk for both hemolysis and methemoglobinemia following oxidant stress. Patients with G6PD deficiency are at much greater risk of hemolysis rather than methemoglobinemia due to their decreased glutathione stores.^79,127,138 G6PD affects all races, but is most prevalent in patients of African, Mediterranean, and Asian descent. The gene that codes for G6PD is X-linked; consequently, men are affected more often than women.

Infants are also at increased risk of methemoglobinemia because fetal hemoglobin is more susceptible to the formation of methemoglobin and also because nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase activity is less well developed, impairing the reduction of methemoglobin to hemoglobin.⁶³

Injuries to other organs, eyes, lungs, and liver, have been reported in animal studies after exposure to naphthalene.^{40,89,99,114,128} However, there is a significant interspecies variation in the degree of toxicity. Human data on organ toxicity beyond hematologic effects of naphthalene are limited. A few case reports link the development of cataracts to occupational exposure; however, the causal relationship remains questionable.⁸⁹ The mechanism of cataract formation may involve oxidative destruction of lens proteins.¹¹⁴ Animal studies show that oxidative stress from naphthalene results in hepatic injury by lipid peroxidation and pulmonary epithelial necrosis.^40,99,114 However, there is no evidence to suggest that hepatotoxicity or pulmonary toxicity occurs in humans from naphthalene exposure.

Clinical Manifestations

Both acute and chronic exposures to naphthalene result in similar toxicity.^28,86,138 Ingestion and inhalational exposures to naphthalene commonly cause headache, nausea, vomiting, diarrhea, abdominal pain, fever, and altered mental status.^28,74,91 Dermal exposure results in dermatitis.⁴⁶

Hemolysis and methemoglobinemia usually become clinically evident, as early as 24 to 48 hours postexposure, but more typically on the third day postexposure because of the time necessary for the hepatic metabolism of naphthalene.^33,73 Anemia secondary to hemolysis often does not reach its nadir until 3 to 5 days postexposure.^9,119

Signs and symptoms of hemolysis and methemoglobinemia are nonspecific and include tachycardia, tachypnea, shortness of breath, generalized weakness, decreased exercise tolerance, and altered mental status. Methemoglobinemia may produce cyanosis, whereas hemolysis may produce pallor and jaundice (Chap. 127). Renal failure is reported as a complication of naphthalene-induced hemolysis and hemoglobinuria. Naphthalene or its metabolites cross the placenta.¹² Naphthalene pica during pregnancy causes both maternal and fetal toxicity. Children born to mothers who were experiencing naphthalene toxicity at the time of delivery have developed hemolytic anemia believed to be related to the maternal naphthalene exposure.¹³⁸ Although cataracts have been reported in animals following naphthalene exposure, human data are inconclusive.⁸²

Based upon animal data on carcinogenicity, naphthalene is classified by the International Agency for Cancer Research (IARC) as a Group 2B carcinogen (possibly carcinogenic to humans) and by the EPA as a Group C possible human carcinogen.^47,60 The data supporting human carcinogenicity of naphthalene are limited. There are several case reports of the associated exposure with laryngeal cancer in East Germany and colorectal cancer in Nigeria but causal relationship cannot be determined.^7,47

Diagnostic Testing

No specific diagnostic testing is indicated, although both naphthalene and its metabolites can be identified in blood and urine. Identification of 1-naphthol and 2-naphthol in the urine can confirm exposure to naphthalene. Qualitative or quantitative testing for naphthalene or its metabolites is not clinically indicated when managing a case of an acute overdose.⁹²

The presentation of naphthalene-induced hemolysis is similar to that of hemolysis from other causes. Reticulocytosis occurs as a response to restore a normal hemoglobin concentration. Hyperbilirubinemia from hemolysis is characterized by an elevation of the unconjugated bilirubin and a relatively normal conjugated fraction. Serum haptoglobin is usually low because the haptoglobin–hemoglobin complex is cleared by the kidneys. Both the direct and indirect Coombs tests are negative in naphthalene-induced hemolytic anemia. Lactate dehydrogenase is elevated due to its release from hemolyzed red blood cells. Hemoglobinuria is suggested by a urine dipstick that reacts strongly positive for hemoglobin with a paucity or absence of red blood cells on microscopic examination of the urine sediment. Hemoglobinemia should be differentiated from myoglobinuria, which has a comparable urine sediment, by measuring the serum creatine phosphokinase, which will be elevated in patients with rhabdomyolysis and myoglobinuria.

Examination of a peripheral blood smear can suggest hemolysis before a patient develops clinical or laboratory evidence of anemia. The peripheral smear may reveal red blood cell (RBC) fragmentation (schistocytes), anisocytosis, microspherocytosis, reticulocytosis, nucleated RBCs, Blister cells, and Heinz body formation (Chap. 22). Peripheral smear abnormalities and anemia may occur within the first 24 hours following ingestion.^{28,108,138,139} Testing for G6PD activity is not routinely recommended during an acute episode of hemolysis. Reticulocytes have higher G6PD activity than do older RBCs. If G6PD activity is measured during an episode of hemolysis when many of the older RBCs have already been destroyed, the G6PD activity may be falsely disproportionately elevated or normal. It is best to delay testing for G6PD activity for a few months following an episode of hemolysis. Family members of patients with life-threatening G6PD deficiency should also be tested.

Naphthalene-induced methemoglobinemia is similar in presentation to methemoglobinemia from other xenobiotics. The percentage of methemoglobin can rapidly be determined using a cooximeter (Chap. 127).

Management

Most patients with an unintentional exposure to no more than one naphthalene containing mothball do not require medical evaluation. Patients who should be evaluated in a health care facility following an acute ingestion include those who recently ingested more than one naphthalene-containing mothball equivalent, those with signs or symptoms of toxicity, especially hemolysis and/or methemoglobinemia, those with known or suspected G6PD deficiency, all intentional ingestions, and those patients with substantial inhalational exposures, particularly those occurring in an occupational setting.

Gastrointestinal decontamination is not well studied in patients who have ingested naphthalene. Most patients with unintentional exposures do not require gastrointestinal decontamination. Administration of activated charcoal, 1 g/kg, although not of proven efficacy, is reasonable because it is considered safe. Repeat doses of activated charcoal 0.5 g/kg and/or whole-bowel irrigation with polyethylene glycol electrolyte lavage solution would only be indicated for patients with large ingestions of naphthalene who are expected to have significant ongoing gastrointestinal absorption.

Diagnostic testing within the first 24 to 48 hours postexposure may detect the onset of methemoglobinemia and/or hemolysis before a patient becomes symptomatic. Most low-risk patients who are asymptomatic within the first 24 to 48 hours postexposure and who have no laboratory evidence of hemolysis or methemoglobinemia can be managed as out­patients if reevaluation within 24 to 48 hours can be arranged. Patients who are discharged should be instructed to return if they become symptomatic. High-risk patients, patients with laboratory evidence of hemolysis and/or methemoglobinemia, and patients who cannot be reliably managed as outpatients should be admitted.

Patients with life-threatening hemolysis and anemia should be transfused with packed red blood cells. However, most healthy patients will be able to compensate for the hemolysis and will not require a transfusion. Patients with symptomatic methemoglobinemia should receive methylene blue, 1 to 2 mg/kg (0.1–0.2 mL/kg of a 1% solution) intravenously. Repeat doses may be necessary (Antidotes in Depth: A42).

PARADICHLOROBENZENE

History and Epidemiology

Paradichlorobenzene (1,4-dichlorobenzene) is widely used as a deodorizer, disinfectant, repellent, fumigant, insecticide, fungicide, and industrial solvent. Today, paradichlorobenzene is the most common component of moth repellents in the United States. Low level exposure to paradichlorobenzene in the United States is extremely common due to environmental contamination from release of paradichlorobenzene to air by industrial facilities.⁹⁰ The primary route of human exposure is inhalation in either an occupational setting or from indoor air where paradichlorobenzene is used as a deodorizer or moth repellent.⁹⁰ Paradichlorobenzene is also found in both water and numerous food items, including pork and fresh vegetables, from environmental contamination.^90,103,130 In 1995, a study suggested that 2,5-dichlorophenol, a metabolite of paradichlorobenzene, was detectable in the urine in 98% of the US population.⁵⁸

Most unintentional exposures to paradichlorobenzene-containing moth repellents occur in children and do not cause toxicity. According to the AAPCC data, there were no deaths and no reports of major toxicity associated with paradichlorobenzene between 1998 and 2011.

Pharmacology, Pharmacokinetics, Toxicokinetics,and Pathophysiology

Paradichlorobenzene (C₆H₄Cl₂) is a colorless solid with a noxious odor. It is available as pure white crystals, as a solid in combination with other chemicals, or as a liquid dissolved in volatile solvents or oil.¹⁰ The mechanism of the toxicologic effect of paradichlorobenzene has not been studied. Although rare, paradichlorobenzene toxicity is reported following ingestion and inhalation.^59,81 Inhalation toxicokinetics reveal that in humans there is rapid distribution and accumulation in tissues, specifically in adipose tissue.^15,26,56,137 The major route of elimination is urinary excretion followed by hepatic metabolism, with none by exhalation.^15,137 CYP2E1, CYP1A1, and CYP1A2 convert paradichlorobenzene to its primary metabolite, 2,5-dichlorphenol, which is eliminated as either sulfated or glucuronidated conjugates.^21,54,56

Workplace standards include the OSHA PEL, which is 450 mg/m³ (75 ppm) time-weighted average (TWA), ACGIH TLV, which is 60 mg/m³ (10 ppm) TWA, and the ACGIH STEL, which is 675 mg/m³ (110 ppm); NIOSH IDLH is 150 ppm.¹²⁴

Clinical Manifestations

Paradichlorobenzene is considered to have less toxicity than camphor and naphthalene. However, cases of clinical toxicity from paradichlorobenzene are reported ranging from hemolytic anemia to toxic leukoencephalopathy following acute and/or chronic exposure.^{14,25,26,37,39,52,53,56,71,81,83,101,109,110,131} Although paradichlorobenzene can be absorbed following inhalation, ingestion and cutaneous exposures are the routes of exposure that lead to toxicity.^{37,39,56,83,101,131} Acute unintentional exposure to paradichlorobenzene may cause limited transient clinical effects such as nausea and vomiting, headache, and mucous membrane irritation.^31,59 However, significant neuropsychiatric dysfunction, specifically cerebellar dysfunction, motor weakness, and cognitive decline, is reported following chronic intentional and occupational exposure.^{37,39,56,71,81,83} In most cases, neurologic and cognitive deficits associated with paradichlorobenzene developed after several months of exposure and seldom resulted in complete resolution after cessation of paradichlorobenzene exposure.^14,56,83 Other clinical signs and symptoms from chronic exposure include pulmonary granulomatosis, hepatotoxicity, an ichthyosislike dermatosis, aplastic anemia, and dyspnea.^{37–39,53,85,115,133}

Hemolytic and aplastic anemias are reported, as well as methemoglobinemia, following acute paradichlorobenzene ingestion.^25,52,53,110

Paradicholorobenze is classified by IARC as a Group 2B, possibly carcinogenic to humans, based upon evidence of carcinogenicity from experimental animal studies. In mice and rats, chronic exposure was associated with the development of both hepatocellular carcinomas and adenomas in male and female mice, and renal tubular cell adenocarcinomas and mononuclear-cell leukemias developed in male mice.^{5,6,17,87,88,136} Evidence for carcinogenicity in humans from paradichlorobenzene exposure is limited. One case series reported five cases of leukemia that may have been associated with paradichlorobenzene exposure.^88,135 No additional epidemiologic data on human carcinogenesis from paradichlorobenzene exposure is available.

Diagnostic Testing

Both paradichlorobenzene and its primary metabolite, 2,5-dichlorophenol, can be identified in blood and urine following exposure.¹⁵ Identification of 2,5-dichlorophenol can confirm exposure to paradichlorobenzene. Quantifying the amount of paradichlorobenzene in the urine of workers may be useful for monitoring occupational exposures.⁴¹ Qualitative or quantitative testing for paradichlorobenzene or its metabolites is not generally indicated when managing a patient with an acute overdose. Structural CNS abnormalities, including toxic leukoencephalopathy, may be noted on imaging studies such as MRI.¹⁴

Management

Most unintentional exposures to paradichlorobenzene do not cause life-threatening toxicity. Asymptomatic patients with unintentional exposures can be managed as outpatients. Patients who should be evaluated in a health care facility include those with clinical signs or symptoms, suicidal patients, and patients who have had a large exposure.

Gastrointestinal decontamination has not been studied in patients who ingest paradichlorobenzene. Most patients with unintentional exposures do not require gastrointestinal decontamination. However, administration of activated charcoal, 1 g/kg, although not studied, is reasonable for patients with large, intentional ingestions. If present, GI symptoms such as nausea and vomiting should be managed with supportive care, including hydration and antiemetics. Laboratory testing is generally not helpful in the acute setting unless there is clinical evidence for hemolysis or methemoglobinemia. Transfusion of packed red blood cells should be considered for hemolysis and anemia. Methylene blue should be considered for symptomatic methemoglobinemia.

Asymptomatic patients should be referred for follow-up evaluation in 24 to 48 hours postexposure as development of hemolysis or methemoglobinemia may be delayed. Careful discharge instruction should be provided to patients should they become symptomatic.

MOTH REPELLENT RECOGNITION

Health care providers occasionally must determine whether a mothball is made of naphthalene, paradichlorobenzene, or camphor since management and prognosis for each chemical is different. When the container is unavailable, as is often the case, mothballs are difficult to distinguish based on appearance, odor, texture, or size. Most mothballs are white, crystalline, and have a noxious odor.¹³⁴ Camphor moth repellents are more oily than both naphthalene and paradichlorobenzene mothballs. If controls are available, moth repellents can often be differentiated based on their odor and texture.⁸ Although most new paradichlorobenzene moth repellents are slightly larger than most new naphthalene moth repellents, all moth repellents shrink over time when exposed to air, making size an unreliable differentiating characteristic. Identifying a moth repellent as paradichlorobenzene can often permit outpatient management, saving both hospital resources and unnecessary concern. The tests described in Table 105–1 and shown in Fig. 105–2 might allow rapid identification of the component of an unknown moth repellent. When performing these tests, it is most helpful to have camphor, naphthalene, and paradichlorobenzene controls available for comparison.

SUMMARY

• Paradichlorobenzene has largely replaced both camphor and naphthalene in the United States, but exposures to all three compounds occur, especially in immigrant communities.

• It is reasonable to consider activated charcoal administration in patients with large ingestions if no contraindication is present, such as CNS depression, active vomiting, or seizures.

• Seizures are commonly observed after camphor ingestion, and deaths are reported due to status epilepticus. Camphor induced seizures are responsive to benzodiazepines, propofol, and barbiturates.

• Hemolytic anemia and methemoglobinemia can be observed after naphthalene and, less frequently, paradichlorobenzene exposures. Appropriate supportive care, packed red blood cell transfusions, and methylene blue administration should be considered for symptomatic patients.

• Simple tests such as radiography and buoyance tests may help identify the unknown mothball.

Acknowledgment

Edward K. Kuffner, MD, contributed to this chapter in previous editions.

References