105: Camphor and Moth Repellents

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.

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.

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).

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.

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.

• 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