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.
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
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
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
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
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.