114: Insecticides: Organic Chlorines, Pyrethrins/Pyrethroids, and Insect Repellents

History and Epidemiology

Until the 1940s, commonly available pesticides included highly toxic arsenicals, mercurials, lead, sulfur, and nicotine. When Nobel Prize-winning chemist Paul Müller demonstrated the insecticidal properties of dichlorodiphenyltrichloroethane (DDT) in the early 1940s, a whole new class of pesticides was introduced. The organic chlorine insecticides were inexpensive to produce, nonvolatile, environmentally stable, and had relatively low acute toxicity when compared to previous insecticides. Most organic chlorines have a negative temperature coefficient, making them more insecticidal at lower temperatures and less toxic to warm-blooded organisms (Table 114–1).¹⁶⁴ Widespread use of these xenobiotics occurred from the 1940s until the mid 1970s. They were highly effective and revolutionized modern agriculture, allowing unprecedented crop output from each acre of arable land. Because of their stability, organic chlorines were used extensively in structural protection (termites, carpenter ants) and soil treatments. Medical and public health applications of DDT and its analogues were also found in the control of typhus and eradication of malaria by eliminating the mosquito vector.³⁴ By 1953, DDT alone was credited for saving an estimated 50 million lives and with averting one billion cases of human disease. It has also been credited with eliminating malaria from the United States and Europe. It is suggested that because of this consequential impact on human health, DDT is the single most important factor in the population explosion that occurred between 1950 and 1970.⁴⁶

However, the properties that made these chemicals such effective insecticides also made them environmental hazards; they are slowly metabolized, lipid soluble, chemically stable, and environmentally persistent. In her 1962 book, Silent Spring, Rachel Carson, a biologist with the US Fish and Wildlife Service, demonstrated that organic chlorines are bioconcentrated and biomagnified up the food chain.¹⁹ She alleged that this persistence could eventually lead to increases in cancer in the future. Extensive environmental reasearch demonstrates that organic chlorine residues caused eggshell thinning and decreased reproductive success in predatory birds, most notably grebes, peregrine falcons, bald eagles, and pelicans.⁴⁵ However, conflicting results were seen when DDT-laced feedstuffs were administered in high concentrations to experimental birds. Testing on domesticated birds, such as Japanese quail^21,26,121 and chickens,¹⁶² showed little or no eggshell thinning, whereas testing on mallard ducks showed thinning.^40,41 Hearings before the Environmental Protection Agency (EPA) regarding DDT registration focused also on the uproven fear of placing future generations at risk of cancer. This fear, and the demonstration of persistent DDT residues in all humans, even those living in areas where DDT was never utilized (eg, Eskimos), led to the severe restriction or total ban of DDT and most other organic chlorines in North America and Europe.³⁴ There is considerable evidence that since DDT was banned, less-effective replacements have placed many more millions of people at risk for malaria and are responsible, at least in part, for millions of deaths from this disease.^95,118,119 Not surprisingly, DDT is still considered a highly effective mosquito control agent with a low order of acute toxicity, and it is very inexpensive compared to newer replacement insecticides. For these reasons, the World Health Organization (WHO) exempted DDT from its list of banned pesticides, and it is still widely used for malaria control programs in many countries since alternatives are more expensive and must be applied more often. Current use of DDT for indoor residual spraying is ongoing in endemic areas in Africa and has been shown to be safe and effective as a public health initiative to control malaria, even in areas with resistant strains.¹²⁷ In 2006, the EPA officially cancelled the registration for lindane and all use in agriculture ceased in 2009.¹⁵⁷

Organic chlorine pesticides are complex, cyclic polychlorinated hydrocarbons having molecular weights generally in the range of 300 to 550 Da. They are nonvolatile solids at room temperature. Most act as central nervous system stimulants. In contrast, chlorinated hydrocarbon solvents and fumigants are low molecular weight, alkyl compounds that are volatile liquids or gases and generally have CNS depressant effects (Chap. 108).

The organic chlorine pesticides can be grouped into four categories based on their chemical structures and similar toxicities: (a) DDT and related analogues; (b) cyclodienes (the related isomers aldrin, dieldrin, and endrin; and heptachlor, endosulfan), and related compounds (toxaphene, dienochlor); (c) hexachlorocyclohexane, the primary organochlorine pesticide still in clinical use as a pediculocide (more commonly termed lindane, the γ ­isomer; also referred to by the misnomer γ-benzene hexachloride). ­Specifying the exact isomer is important with this compound, because the β and δ isomers are CNS depressants and have no insecticidal ­properties,^3,32,108 and (d) mirex and chlordecone (Table 114–1; Fig. 114–1). These organic chlorine insecticide compounds differ substantially, both between and within groups, with respect to toxic doses, skin absorption, fat storage, metabolism, and elimination.³⁴ The signs and symptoms of toxicity in humans, however, are remarkably similar within each group.

Toxicokinetics

Absorption.

All the organic chlorine pesticides are well absorbed orally and by inhalation; transdermal absorption is variable, depending on the particular xenobiotic. Absorption by any route may be affected by the vehicle and the physical state (solid or liquid) of the pesticide. Organic chlorines are not water-soluble, and they are usually either dissolved in organic solvents or manufactured as powders for dusting.

DDT and its analogues, methoxychlor, dicofol, and chlorobenzilate, are very poorly absorbed transdermally, unless the pesticide is dissolved in a suitable hydrocarbon solvent.¹¹⁶ DDT has limited volatility, so air concentrations are usually low, and toxicity by the respiratory route is unlikely.

All the cyclodienes have significant transdermal absorption rates. Cutaneous absorption of dieldrin is approximately 50% of the oral route. Oral absorption of the cyclodienes is also high, and significant poisonings have occurred when foodstuffs were contaminated with these pesticides.^17,23 Toxaphene is poorly absorbed through the skin in both acute and chronic exposures.¹³²

Lindane is well absorbed after skin application, and in adults it has a documented forearm skin absorption rate of 9.3% of a topically applied dose over 24 hours.⁵⁴ Anatomic sites vary in their absorptive capacities: axillary rates are 3.6 times greater, and scrotal absorption is 42 times greater than that of forearm rates.^14,58,73,142 Animal studies and case reports suggest that the young, the malnourished, and those who receive repeated topical doses may have increased accumulation and increased toxicity.¹⁰⁹ Hot baths, occlusive clothing or bandages, the vehicle for the lindane, and a disturbed cutaneous integrity, such as eczema, fissures, and other violations of the skin, all enhance dermal penetration.^141,142 The state of hydration of the skin also affects the amounts absorbed, so bathing just prior to application can enhance absorption and increase the likelihood of toxicity.^93,142 Lindane is a stable compound and volatilizes easily when heated. It was previously used extensively in home vaporizers, and toxicity was common via inhalation and when vaporizer tablets were unintentionally ingested by children. Review of data when lindane was ingested therapeutically as an anthelmintic demonstrates that 40 mg/d for 3 to 14 days generally produced no symptoms.³⁴

Mirex and chlordecone are efficiently absorbed via skin, by inhalation, and orally.⁵³

Distribution.

All organic chlorines are lipophilic, a property that allows penetration to their sites of action.²⁸ The fat-to-serum ratios at equilibrium are high, in the range of 660:1 for chlordane;⁶²220:1 for lindane;¹³³ and 150:1 for dieldrin.³⁵ Central nervous system redistribution of the organic chlorines to the blood and then to fat may account for the apparent rapid CNS recovery despite the persistent substantial total body burden. In the rat model, there is a direct correlation between the concentration of DDT or dieldrin in the brain and the clinical signs produced after a single dose of the insecticide.^34,38

Metabolism.

The high lipid solubility and very slow metabolic disposition of DDT, DDE (dichlorodiphenyl dichloroethylene, a metabolite of DDT), dieldrin, heptachlor, chlordane, mirex, and chlordecone causes significant adipose tissue storage and increased body burdens in chronically exposed populations.⁵³ Organic chlorines that are rapidly metabolized and eliminated, such as endrin (an isomer of dieldrin), endosulfan, lindane, methoxychlor, dienochlor, chlorobenzilate, dicofol, and toxaphene tend to have less persistence in body tissues, despite being highly lipid soluble.¹¹⁶

Most organic chlorines are metabolized by the hepatic microsomal enzyme systems by dechlorination, oxidation, with subsequent conjugation. However, metabolism may result in the production of a metabolite with more toxicity than the parent compound, such as heptachlor to heptachlor epoxide, chlordane to oxychlordane, and aldrin to dieldrin.

In animals, most organic chlorine pesticides are capable of inducing the hepatic microsomal enzyme systems.^33,166 Enzyme induction changes the biodegradation of the pesticide in rodents,¹⁴⁸ and in certain animal models the acute toxicity of organic phosphorus compounds and carbamates may be reduced by the administration of organic chlorines. This protective effect is presumably induced by the hepatic microsomal metabolism of the organic phosphorus compound because this effect is ameliorated by administering piperonyl butoxide, an inhibitor of the liver microsomal enzyme system.^34,166 However, induction of hepatic enzymes has not been described in humans, except in rare cases of massive exposure with concomitant neurologic findings.^53,62

Elimination.

The half-lives of fat-stored compounds and poorly metabolized organic chlorines, such as DDT and chlordecone, are measured in months or years, compared to the elimination half-life of lindane, which is 21 hours in adults.⁹⁴ The primary route of excretion of organic chlorines is in the bile, but most also have detectable urinary metabolites. ­However, as with other compounds excreted in bile, most organic chlorines, such as mirex and chlordecone, have significant enterohepatic or enteroenteric recirculation.^12,31,53 All the lipophilic compounds are excreted in ­maternal milk.¹²²

Mechanisms of Toxicity

The same neurotoxic properties that make organic chlorines lethal to target insects make them potentially toxic to higher forms of life. Organic chlorines exert their most important effects on the central nervous system. Electrophysiologic studies demonstrate that organic chlorine insecticides affect the neuronal membrane by either interfering with repolarization, by prolonging depolarization, or by impairing the maintenance of the polarized state of the neuron. The end result is hyperexcitability of the nervous system and repetitive neuronal discharges.⁴⁶

The voltage-gated Na⁺ channel is a common site of action for neurotoxins, both natural and synthetic. There are at least 10 separate binding sites on the Na⁺ channel, including those for local anesthetics and anticonvulsants. DDT, as well as the pyrethroids (see below), bind at the same site on these channels. They preferentially bind when the channel is in the open state, allowing prolonged inward sodium conductance, repetitive action potentials, and extended tail currents. Prolonged axonal firing and repetitive stimulus eventually leads to nerve paralysis and death in target insects, whose Na⁺ channels have much greater affinity for these insecticides than those in mammals.^{98,99,143,102} In mammals, low-level stimuli cause exaggerated responses, manifested clinically as prominent tremors and abnormal startle reflexes observed in test animals.^70,155 Evidence of this as the primary mechanism of action is the amelioration of DDT-induced tremor by pretreatment with phenytoin, a Na⁺ channel blocker, which reduces the ability of voltage-dependent Na⁺ channels to recover from inactivation.^70,156

The cyclodienes and lindane act as γ-aminobutyric acid (GABA) antagonists. They inhibit GABA binding at the GABA_A receptor-chloride ionophore complex in the CNS, by interacting at the picrotoxinin binding site.^{3,9,32,61,66,101,108} In fact, the degree of binding at this site correlates well with the amount of Cl^– influx inhibited and the relative neurotoxicity of each insecticide^9,61 (Figs. 14–9, 14–10, and 114–2). Indeed, development of cyclodiene resistance seems to be related to alterations of the GABA_A-receptor-chloride ionophore complex in these affected insects.^10,99 This also explains the efficacy of GABA agonists, such as benzodiazepines and phenobarbital, in treating the seizures and neurotoxicity of the cyclodienes⁶⁷ and lindane.¹⁷⁰ Toxaphene also inhibits GABA binding at the GABA_A receptor-chloride ionophore complex.¹³²

The mechanisms of action of mirex and chlordecone are not as well understood. They inhibit Na⁺-K⁺-ATPase and Ca⁺²-ATPase. However, lindane, DDT, and the cyclodienes also inhibit these enzymes yet produce very different symptoms of toxicity, suggesting that these effects are not responsible for the clinical manifestations seen in mirex and chlordecone toxicity. Phenytoin and serotonin agonists exacerbate the prominent tremor that occurs with chlordecone intoxication, but conversely attenuate the tremors in DDT poisoning, which further supports a different mechanism than the Na⁺ channel effects of DDT.⁴⁶ Mirex and chlordecone are poor inhibitors of GABA binding at the GABA_A-receptor-chloride ionophore complex; therefore, their mechanism of action is likely not at this site,⁵³ and seizures are not described with mirex or chlordecone. Organic chlorines can predispose test animals to cardiac dysrhythmias,¹¹⁶ presumably via myocardial sensitization, similar to chlorinated hydrocarbon solvents (Chap. 108).

Drug Interactions

There are theoretical consequences of liver enzyme induction, such as enhanced metabolism of therapeutic drugs and reduced efficacy. Dysfunctional uterine bleeding was attributed to enhanced oral contraceptive metabolism induced by chlordane, but this report involved a single patient with weeks of excessive exposure to chlordane.⁶² A large group of workers poisoned by chlordecone over many months had some increased hepatic microsomal activity, but there was no evidence of drug interactions or adverse clinical effects.⁵³ Thus, induction of the hepatic microsomal enzyme system by organic chlorines probably occurs only with extended, substantial exposure.¹¹⁶ There are no definitive reports of enhanced metabolism of therapeutic drugs or adverse reactions because of microsomal enzyme induction in humans.

Clinical Manifestations

Acute Exposure.

In sufficient doses, organic chlorines lower the seizure threshold (DDT and related Na⁺ channel agents) or remove inhibitory influences (antagonism to GABA effects) and produce CNS stimulation, with resultant seizures, respiratory failure, and death.^{20,23,29,66,67,80,81,125,126} After DDT exposure, tremor may be the only initial manifestation. Nausea, vomiting, hyperesthesia of the mouth and face, paresthesias of face, tongue, and extremities, headache, dizziness, myoclonus, leg weakness, agitation, and confusion may subsequently occur. Seizures only occur after very high exposures, usually following large ingestions.^46,67 DDT has a relatively low order of acute toxicity, and high doses of DDT (>10 mg/kg or more) are usually necessary to produce symptoms.⁶⁷ However, with lindane, the cyclodienes, and toxaphene, there often are no prodromal signs or symptoms, and more often than not, the first manifestation of toxicity is a generalized seizure.^{20,23,46,45,67,81,125,145} If seizures develop, they often occur within 1 to 2 hours of ingestion when the stomach is empty, but they may be delayed as much as 5 to 6 hours when the ingestion follows a substantial meal.⁶⁷

Seizures related to dermal application of 1% lindane for treatment of ectoparasitic diseases may occur following a single inappropriate application,^86,109,153 or, more commonly, after repetitive and prolonged exposures.^83,113 The time from application to seizure onset can vary from hours to days. The seizures are often self-limited, but may recur or result in status epilepticus. Analysis of an epidemic of lindane poisoning related to the unintentional substitution of lindane powder for sugar used in coffee demonstrated a delay of 20 minutes to 3 hours before the onset of nausea, vomiting, dizziness, facial pallor, severe cyanosis of the face and extremities, collapse, convulsions, and hyperthermia. Affected patients ingested an average of 86 mg/kg of lindane in a single dose.³⁴

The cyclodienes are also notable for their propensity to cause seizures that may recur for several days following an acute exposure. If the seizures are brief and hypoxia has not occurred, recovery is usually complete. Electroencephalographic (EEG) abnormalities have been recorded before, during, and following seizures.⁸¹ Hyperthermia secondary to central mechanisms, increased muscle activity, or aspiration pneumonia is common.⁴⁶

Staus epilepticus is a common occurrence in patients with intentional endsulfan ingestions. A recent abstract summarized 25 cases of endosulfan self-poisonings with resultant status epilepticus in Nepal. More than half of the patients developed refractory status epilepticus, and eight patients died.⁸⁸

The ingestion of combinations of xenobiotics may result in significantly increased toxicity—probably the result of synergy. This has been demonstrated for DDT and lindane.⁶⁷

Lindane: Specific Risks.

Patients are at risk for developing central nervous system toxicity from improper topical therapeutic use, such as exceeding recommended application times or amounts, repeated applications, application following hot baths, and use of occlusive dressings or clothing shortly after application. Toxicity also occurs after unintentional oral ingestion of topical preparations. Young children appear at greatest risk, possibly because of greater skin permeability, increased ratio of body surface area to mass, or immature liver enzymes.^113,152,153 The elderly may also be at increased risk because of impaired hepatic metabolism, atrophic skin, and perhaps age-related increased sensitivity. Patients at increased risk also include those with preexisting conditions that cause increased risk of seizures, such as treatment with antipsychotics, which lower the seizure threshold, CNS disease, or skin absorption changes.^{4,36,55,83,86,103,109,113,141,142,152,153}

Despite the availability of safer and equally or more effective treatments such as permethrin, lindane had continued to be used because of its lower cost than permethrin and generally good safety profile, when used according to directions. However, now that permethrin products are available in less-expensive generic forms, the cost advantage of lindane is gone, and it is being used less each year.

An evaluation of published English-language case reports and those submitted to the US Food and Drug Administration (FDA) divided toxicity into those associated with concentrations of lindane greater than or less than 1%.⁸³ Only 6 of 26 cases could be considered related to 1% lindane;⁴ six of these cases were the result of ingestion or inappropriate skin application.⁴ However, a recent comprehensive review of all published adverse events associated with topical lindane (67 cases) showed that while most of the serious adverse reactions (16 deaths, 11 seizures) occurred in ingestions or excessive use, labelled use accounted for a substantial portion of serious adverse reactions (4 deaths, 11 seizures).¹⁰⁰ The sale of lindane-containing products for use in humans was banned in California in 2004 because of its toxicity and environmental concerns.¹⁷ In 1995, the FDA changed the labeling requirements for lindane, adding a black-box warning and relegating it to second line therapy for ectoparasitic skin infections, due to its toxicity and to the superior safety and efficacy of other products.¹⁵⁸

Chronic Exposure.

Chlordecone (Kepone), unlike the other organic chlorines, produces an insidious picture of chronic toxicity related to its extremely long persistence in the body. Because of poor industrial hygiene practices in a makeshift chlordecone factory in Hopewell, Virginia, 133 workers were heavily exposed for 17 months between 1974 and 1975. They developed a clinical syndrome which became known as the “Hopewell epidemic,” which consisted of a prominent tremor of the hands, a fine tremor of the head, and trembling of the entire body, known as the “Kepone Shakes.” Other findings included weakness, opsoclonus (rapid, irregular, dysrhythmic ocular movements), ataxia, altered mental status, rash, weight loss, and elevated liver enzymes..Idiopathic intracranial hypertension, oligospermia, and decreased sperm motility were also found in some of these workers. Severely affected workers even exhibited an exaggerated startle response, remarkably similar to that seen in animal studies. The exposures were so intense that some workers went home covered with chlordecone, and several workers’ wives developed neurologic symptoms, presumably from exposures while laundering their husbands’ work clothes.^53,31

There is much concern in environmental health centers on persistent organic chemicals, organic chlorine residues and PCBs being prime examples. A recent review of the world literature reveals that since being outlawed in many processes and countries, human burden appears to be decreasing.⁹⁰

DDT and Breast Cancer.

DDT and other organic chlorine insecticides have estrogenic effects.^37,144 Since breast cancer incidence rates in the United States have steadily climbed 1% per year since the 1940s, coinciding with the worldwide use of DDT, it has been postulated that women who have higher concentrations of estrogenic organic chlorines compounds (eg, DDT, polychlorinated biphenyls {PCBs}) may be at risk for developing breast cancer.^{128,129,130,130,168}

Several small case-control studies of women with breast cancer showed that women with the disease had higher average body burdens of DDT, DDE, and PCBs than their age-matched controls. These studies implicated organic chlorines as a possible cause of human breast cancer. Recently, however, larger studies have shown no increased risk of breast cancer because of exposure to organic chlorines¹⁸ and that currently accepted hereditary and lifestyle risk factors were present in the patients with cancer.^{71,84,130,129,128} In fact, other natural dietary estrogens, such as flavonoids, lignans, sterols, and fungal metabolites, are present in the human diet and have much higher estrogenic potency; the organic chlorine contribution is probably minimal by comparison.⁶⁰ One interesting report suggests age at first exposure, that is, age <14 years (prior to menarche) as having an association with later breast cancer,³⁰ but most case-control studies recently published have not supported an association between DDT and breast cancer.^{15,63,72,74,138,139} A meta-analysis of 22 studies found strong evidence to discard the putative relationship between p,p′-DDE levels and breast cancer risk.⁸⁹

Diagnostic Information

The history of exposure to an organic chlorine pesticide is the most critical piece of information because exposure is otherwise rare. By law, the package label of these products must list the ingredients, the concentrations, and the vehicle. The EPA-registered use of the insecticide may be helpful in determining which agent is involved. The presence of an unusual odor in the mouth, in the vomitus, or on the skin may be helpful. Toxaphene, a chlorinated pinene, has a mild turpentinelike odor, and endosulfan has a unique “rotten egg” sulfur odor (Table 114–1). Following ingestion, an abdominal radiograph may reveal the presence of a radiopaque chlorinated pesticide, since chlorine increases the radiopacity of the xenobiotics (Chap. 5). A large number of other xenobiotics lead to seizures as the first manifestation of toxicity and must be considered in the differential of an unknown exposure (Chaps. 14 and 24).

Laboratory Testing

Gas chromatography can detect organic chlorine pesticides in serum, adipose tissue, and urine.^35,71 If confirmation is necessary for purposes of documentation of source, it may be necessary to measure concentrations of organic chlorines. If the patient’s history and toxidrome are obvious, then laboratory evaluation is unnecessary, as this determination will not alter the course of management, and these blood tests are not available on an emergent basis. At present, there are no data correlating health effects and tissue concentrations. Routine surveillance of serum concentrations in the occupationally exposed is not currently performed.³⁵

Most humans studied have measurable concentrations of DDT in adipose tissue. In a study of a community with a very large exposure to DDT, serum DDT concentrations increased proportionally with age. These increasing concentrations were not associated with any apparent adverse health effects, but there was an association with increasing concentrations of the liver enzyme γ-glutamyltransferase (GGT), although significant hepatotoxicity did not occur. The CDC’s Third National Report on Human Exposure to Environmental Chemicals demonstrated the presence of numerous organic chlorine pesticide residues in lipid fraction of serum of US residents. These concentrations tend to increase with patient age, consistent with the bioaccumulation and fat-storing properties of the chemicals.²⁴ More recently, studies of occupationally-exposed pesticide applicators and persons living in targeted regions confirmed higher serum concentrations over those not exposed, but no ill health effects are documented.¹²⁷

Serum lindane concentrations can be used to document exposure, and clinical signs and symptoms of toxicity correlated with blood concentrations.³¹ Lindane-exposed workers with chronic neurologic symptoms showed blood lindane concentrations of 0.02 mg/L.^4,67 A limited series of patients with acute lindane ingestion suggests that a serum concentration of 0.12 mg/L correlates with sedation, and that 0.20 mg/L is associated with seizures and coma.⁴ After cutaneous application, lindane concentrations in the CNS are 3 to 12 times higher than serum concentrations.^39,142

Management

As with any patient who presents with an altered mental status, the administration of dextrose and thiamine in an adult should be considered. Skin decontamination is essential. Clothing should be removed, placed in a plastic bag, and disposed of appropriately as a biohazardous waste; the skin must be washed with soap and water. Health care providers should be protected with rubber gloves and aprons. Because these pesticides are almost invariably liquids, a nasogastric tube can be used to suction and lavage gastric contents, if clinically indicated. This is most appropriate only with very recent ingestion (Chap. 8). Activated charcoal (AC) can be used after or instead of gastric lavage, when lavage is not indicated.^67,92 However, the ability of AC to adsorb the various organic chlorines is not adequately studied, and mixtures containing petroleum distillates would obviously preclude the use of AC (Chap. 20). Because organic chlorines are all neurotoxins, the risk of complications associated with seizures probably outweighs the risk of any of the GI decontamination strategies in most acute settings. A murine model of lindane toxicity following intragastric administration showed a trend, but not a statistically significant benefit, of AC. The use of cholestyramine, a nonabsorbable bile acid-binding anion exchange resin, in the same murine model did show a statistically significant benefit by raising both the convulsive dose and the lethal dose.⁷⁸ Oil-based cathartics should never be used, as they may facilitate absorption. There is some evidence that sucrose polyester (olestra, a nonabsorbed synthetic dietary oil substitute) can increase excretion of a wide variety of fat-soluble organic chlorine chemicals.^75,96 This effect was demonstrated in dioxin-poisoned patients when administered in potato chips,⁶⁴ and was recently employed in treating Ukrainian President Viktor Yushenko.¹⁴⁶ Sucrose polyester might be an inexpensive and more palatable alternative to cholestyramine to increase excretion in patients with increased body burdens from chronic organic chlorine toxicity.

Seizures should be controlled with a benzodiazepine followed by pentobarbital or a propofol infusion and, if necessary, neuromuscular blockade to control the peripheral manifestations of seizures, thereby preventing metabolic acidosis and rhabdomyolysis. As has been shown in other toxic exposures, phenytoin is much less effective in these cases, particularly with the GABA-chloride ionophore antagonists lindane, toxaphene, and the cyclodienes.¹¹⁶ Hyperthermia should be managed aggressively with external cooling.

Cholestyramine should be administered to all patients symptomatic from chlordecone, and possibly other organic chlorines. Chlordecone undergoes both enterohepatic and enteroenteric recirculation, which can be interrupted by cholestyramine at a dosage of 16 g/d. Cholestyramine increased the fecal elimination of chlordecone 3- to 18-fold in industrial workers exposed during the Hopewell epidemic, resulting in clinical improvement.³¹ Sucrose polyester may also be an option for enhancing excretion.

The pyrethrins are the active extracts from the flower Chrysanthemum cinerariaefolium. These insecticides are important historically, having been used in China since the 1st century A.D.³⁴ and developed for commercial application by the 1800s. They are produced by organic solvent extraction from ground Chrysanthemum flowers. The resulting concentrates have greater than 90% purity. Pyrethrum, the first pyrethrin identified, consists of six esters derived from chrysanthemic acid and pyrethric acid. These insecticides are highly effective contact poisons, and their lipophilic nature allows them to readily penetrate insect chitin (exoskeleton) and paralyze the nervous system through Na⁺ channel blockade.^{28,97,143,116} When applied properly, they have essentially no systemic mammalian toxicity because of their rapid hydrolysis. Pyrethrins break down rapidly in light and in water, and therefore have no environmental persistence or bioaccumulation. This fact makes them extremely safe after human exposures, but unsuitable for commercial agriculture, since the constant reapplication would be cost prohibitive.

The pyrethroids are the synthetic derivatives of the natural pyrethrins¹⁴⁰ (Table 114–2 and Fig. 114–3). They were developed in an effort to produce more environmentally stable products for use in agriculture. Originally, the pyrethroids were divided into two groups based on the toxic syndromes they elicited in test animals. The T syndrome (for tremor seen in rats) was produced by intravenous administration of pyrethrin and most (15 of 18) of the pyrethroids that did not contain a cyano group at the central ester linkage (see below). The CS syndrome (for choreoathetosis and salivation) was produced by 12 of the 17 pyrethroids that had an α-cyano group at the ester linkage. The original studies delineating the T or CS method of classification did not test several new currently registered pyrethroid pesticides, and the testing methods involved intravenous or intracerebral administration, which are not relevant to human exposures.¹⁴⁰

The predominant classification scheme used today is based on the structure of the pyrethroid, its clinical manifestations in mammalian poisoning, its actions on insect nerve preparations, and its insecticidal activity. Type I pyrethroids have a simple ester bond at the central linkage without a cyano group. Commonly used type I pyrethroids include permethrin, allethrin, tetramethrin, and fenothrin. The type II pyrethroids have a cyano group at the carbon of this ester linkage. Type II pyrethroids in common use include cypermethrin, deltamethrin, fenpropathrin, fluvalinate, and fenvalerate. The cyano group greatly enhances neurotoxicity of the type II pyrethroids in both mammals and insects, and type II pyrethroids tend to produce the CS syndrome in test animals and are generally considered more potent and toxic than the type I pyrethroids (Fig. 114–3).^{45,91,115,116,140}

The development of the pyrethroids can also be divided into “generations,” based on efficacy and dates of introduction.¹⁶⁴ The first generation began in 1949, with the development of allethrin. The second generation began in 1965, with the introduction of tetramethrin. The major advance of the second generation was a dramatic increase in potency compared with the pyrethrins. The third generation, introduced in the 1970s and including fenvalerate and permethrin, were the first pyrethroids with practical agricultural use. They were more potent, and more environmentally stable, with efficacious crop residues lasting 4 to 7 days. The current fourth generation includes mostly type II pyrethroids, which have even greater insecticidal activity, are photostable (do not undergo photolysis, “splitting,” in sunlight), have minimal volatility, and provide extended residual effectiveness for up to 10 days under optimum conditions.^91,164

There are more than 1000 pyrethroids, of which 16 to 20 are in widespread use today.^34,13 Pyrethrins and pyrethroids are found in more than 2000 commercially available products. These insecticides have a rapid paralytic effect (“knock down”) on insects. Most mammalian species are relatively resistant because the pyrethrins can be rapidly detoxified by ester cleavage and oxidation.¹⁰⁷ Toxicity of the pyrethrins and pyrethroids is enhanced in insects by combination with microsomal enzyme inhibitors such as piperonyl butoxide (a synthetic analogue of sesamin, the methylenedioxyphenyl component of sesame oil) or N-octyl bicycloheptene dicarboximide.^8,111

Permethrin, a type I pyrethroid, is used medicinally for topical treatment of ectoparasitic conditions in humans, and it is impregnated in clothing and mosquito netting for its insect repellant properties. It has an excellent safety profile, with approximately 2% or less absorbed systemically through the skin.⁹³ Recent comprehensive reviews have confirmed that 5% permethrin is the drug of choice for scabies treatment, with the best efficacy versus safety profile of topical treatments for scabies and lice.^123,163

West Nile Virus was first identified in the United States in 1999 and rapidly spread to most of the United States by 2006. Outbreaks of encephalitis caused by West Nile virus (WNV) have occurred in the late summer and early autumn months in the United States since 1999. Although birds are the reservoirs for WNV, transmission to humans occurs via mosquito bites, and hence many states and municipalities have increased their aerial spraying in an effort to control mosquitoes vectors of this disease. Most spraying programs use pyrethroid insecticides because of their favorable safety profile and their efficacy against the adult mosquito. These widespread spraying programs have increased the potential for human exposures to these xenobiotics. A Centers for Disease Control and Prevention study of pyrethroid spraying did not reveal an increase in detectable pyrethroid metabolites in the general public living in the sprayed areas.⁷ Another study of asthma surveillance showed no increases in emergency department visits because of asthma-related conditions for the periods after pyrethroid spraying.⁷⁶

Toxicokinetics

Absorption.

Pyrethrins are well absorbed orally and via inhalation, but skin absorption is poor. Piperonyl butoxide is also well absorbed orally, but likewise has poor dermal penetration.¹¹¹ The oral toxicity of pyrethrins in mammals is extremely low because they are so readily hydrolyzed into inactive compounds. Their dermal toxicity is even lower, owing to their slow penetration and rapid metabolism.^46,107

The pyrethroids are more stable than the natural pyrethrins, and significant systemic toxicity occurs following ingestion.⁶⁸ An average of 35% (range 27%–57%) of orally administered cypermethrin is absorbed in human volunteers.¹⁶⁹ Most exposures are from dermal absorption, the rate of which may vary depending on the solvent vehicle. In the same volunteer study noted above, a mean of 1.2% (range 0.85%–1.8%) of dermally applied cypermethrin in soybean oil vehicle was absorbed systemically.¹⁶⁹ Intradermal metabolism of pyrethroids is documented in test animals and likely further limits systemic absorption.¹³ Direct absorption of pyrethroids through the skin to the peripheral sensory nerves probably accounts for the facial paresthesias that occur in these cases, as symptoms were prominent in areas of direct contact.^27,85 Absorption probably also occurs through the oral mucosa, as noted by a large study of Chinese insecticide sprayers who frequently used their mouths to clear clogged spray nozzles. The pyrethroids are also absorbed via inhalation; however, in these same sprayers, inhalation was not found to be a clinically significant route of exposure as analyzed by breathing zone assays.²⁷ The pyrethroids are not volatile compounds, so inhalation is always due to powders or sprayed mists, and mucosal and pulmonary toxicity may be due to hydrocarbon solvent vehicles. Systemic absorption and resultant effects may follow massive exposures, such as occurs in enclosed spraying or other extreme conditions.

Distribution.

The pyrethroids and pyrethrins are lipophilic and as such are rapidly distributed to the central nervous system. Because they are rapidly metabolized, there is no storage or bioaccumulation, which limits chronic toxicity.^46,45

Metabolism.

Natural pyrethrins are readily metabolized by mammalian microsomal enzymes, and hence are essentially nontoxic to humans. They can induce CYP3A and CYP2B isoforms in vitro in human cultured hepatocytes, but clinical significance is doubtful.¹¹⁰

The synthetic pyrethroids are readily metabolized in animals and humans by hydrolases and the CYP microsomal system. The metabolites are of lower toxicity than the parent compounds.¹⁴⁰ Piperonyl butoxide, a P-450 inhibitor, enhances the potency of pyrethrins and pyrethroids 10- to 300-fold to target insects. It is often added to insecticide preparations to ensure lethality, as the initial “knock down” effect of a pyrethroid alone is not always lethal to the insect.⁴⁵ Testing of piperonyl butoxide on ­antipyrine metabolism (measure of CYP enzyme function) in humans at a dose exceeding 50 times that received in all-day confined space pesticide ­spraying revealed no effect on this enzyme system in humans.¹¹¹

Elimination.

There is no evidence that the pyrethroids undergo enterohepatic recirculation. Deltamethrin disappeared from the urine of exposed workers within 12 hours, and fenvalerate disappeared within 24 hours.²⁷ Parent compounds, and metabolites of the pyrethroids, are found in the urine.¹¹⁶ The most commonly assayed metabolites are 3-PBA (3-phenoxybenzoic acid, a nonspecific metabolite of multiple pyrethroids), cis-DCCA (cis-3-{2,2-dichloroethenyl}-dimethyl cyclopropane carboxylic acid, a metabolite of cis-permethrin, cypermethrin, and cyfluthrin), trans-DCCA (trans-3-{2,2-dichloroethenyl}-dimethyl cyclopropane carboxylic acid, a metabolite of trans-permethrin, cypermethrin, cyfluthrin), and Br2CA (3-{2,2-dibromovinyl}-2,2-dimethylcyclopropanecarboxlic acid, a metabolite of deltamethrin). The metabolite CDCA (chrysanthemumdicarboxylic acid) is also a nonspecific metabolite of natural pyrethrin I and the synthetic pyrethroids allethrin, resmethrin, and tetramethrin.^87,149 Monitoring of these metabolites is used in population-based studies for pesticide exposures. However, a recent review revealed that commonly assayed pyrethroid metabolites also occur in the environment from natural degradation. Therefore, the detection of these metabolites in the urine may be from a subject’s exposure to the parent compound or from its metabolite in the environment.

Pathophysiology

Like DDT, pyrethrins and pyrethroids prolong the activation of the voltage-dependent Na⁺ channel by binding to it in the open state, causing a prolonged depolarization, as evidenced by an extended tail current seen with squid axon voltage clamp experiments.^98,99 Indeed, DDT and pyrethrin/pyrethroids bind to the same site on insect Na⁺ channels, and resistance to one class causes cross-resistance to the other class as well.¹⁰² The voltage-sensitive Na⁺ channel binding is responsible for the insecticidal activity and the toxicity of the pyrethroids to nontarget ­species. ­Natural pyrethrins and type I synthetic pyrethroids induce repetitive or “burst discharges” following a single stimulus because they hold the Na⁺ channel in its open state for shorter periods. The actual amplitude of the tail current is determined by the concentration of the pyrethroids, regardless of type. Type II pyrethroids cause the Na⁺ channel to remain open longer and allow a prolonged period of depolarization of the resting membrane potential, causing a longer duration of the tail current.^143,161 Type II pyrethroids are thus more potent and lead to significant after-potentials and eventual nerve conduction block. The mammalian voltage-dependent Na⁺ channel, unlike the insect, has many isoforms, and may help explain the relative resistance in mammalian species. Different pyrethroids have varied effects on these mammalian Na⁺ channels, and the effects are not additive, and in fact may be antagonistic. Structure-activity relationship is important as well because some pyrethroid trans isomers at the ester linkage are not insecticidal, but the cis isomers are, and some isomers are insecticidal but lack mammalian toxicity because of this isomeric specificity.¹⁴⁰

Pyrethroids also have activity at certain isoforms of the voltage-sensitive calcium channel, which may explain the neurotransmitter release that occurs in pyrethroid intoxication. Additionally, pyrethroids block voltage-sensitive chloride channels in test animals, producing the salivation as part of the CS syndrome. These effects may contribute to enhanced CNS toxicity¹⁴⁰ and are likely responsible for the choreoathetosis that occurs in animal models of severe type II poisonings.¹¹⁴ Some studies show some interference of the type II pyrethroids with the GABA_A-mediated inhibitory chloride channels, but only in high concentrations.^28,97 Antagonism of the GABA_A chloride channels likely has a significant role in human pyrethroid exposures and probably contributes to the seizures following severe poisoning by type II agents.^97,114 The pyrethroids may also act at the peripheral benzodiazepine receptor, as evidenced by decreased salivation in test animals when this receptor was blocked. The clinical significance of this is currently unknown.¹³

Natrural pyrethrins and type I pyrethroids have a negative temperature coefficient, similar to DDT, and are more selectively toxic to non–warm-blooded target species, but also less effective at warmer environmental temperatures. Type II pyrethroids have a positive temperature coefficient, which makes them more insecticidal at higher ambient temperatures, and thus more useful in agricultural applications.^97,164 However, this may also partly explain the greater toxicity of type II pyrethroids to warm-blooded species as compared to type I.⁹⁷

Clinical Manifestations

Pyrethrum probably has an LD₅₀ of well over 1 g/kg in humans, as extrapolated from animal data. Most cases of toxicity associated with the pyrethrins are the result of allergic reactions.^107,165 Theoretically, those at highest risk for allergic reactions would be patients who are sensitive to ragweed pollen, 50% of whom may cross-react with chrysanthemums (ragweed and chrysanthemum are in the same botanical family). These allergic reactions are postulated to be due to residual natural components present in the extracts.¹¹⁶ However, recent reviews have cast some doubt on this explanation. First, there have been only four cases of life-threatening respiratory reactions reported in the literature, three of which were in known asthmatics.¹¹¹ Second, the presence of residual natural proteins is unlikely, as the purification procedures would allow little, if any, residuals.⁵⁹ Third, most reported cases of contact urticaria have been erroneously classified as type I hypersensitivity reactions.⁵⁹ The synthetic pyrethroids can cause histamine release in vitro⁴² but generally do not induce IgE-mediated allergic reactions.¹⁷

In animals, type I pyrethroid poisoning most closely resembles that of DDT, with extensive tremors, twitching, increased metabolic rate, and hyperthermia. Excluding the rare possibility of skin irritation or allergy, the type I pyrethroids are unlikely to cause systemic toxicity in humans. It has been shown experimentally that pyethroids have greater than 1000-fold more affinity for insect Na⁺ channels than for those of mammals, explaining their low toxicity in higher life forms. This selectivity, along with the negative temperature coefficient and slower insect metabolism, combines to make the type I pyrethroids approximately 15,000 times more toxic in insects than humans.⁹⁹ The type II pyrethroids are generally more potent and cause profuse salivation, ataxia, coarse tremor, choreoathetosis, and seizures in animals. In humans, poisoning with type II pyrethroids can cause paresthesias (secondary to Na⁺ channels effects in cutaneous sensory nerves after topical exposure),⁸⁵ salivation, nausea, vomiting, dizziness, fasciculations, altered mental status, coma, seizures, and acute lung injury.⁶⁸ A review of more than 500 cases of acute pyrethroid poisoning from China highlights some similar manifestations between a massive acute type II pyrethroid overdose and an organic phosphorus compound overdose. However, serious atropine toxicity and death has resulted when poisoning from a type II pyrethroid was mistaken for an organic phosphorus compound, and treatment was directed at these seemingly muscarinic signs.⁶⁸ Features such as acute respiratory distress syndrome may be caused by solvents and surfactants present in the agricultural products.⁸ Although the type II pyrethroids contain a cyanide moiety, cyanide poisoning does not occur, and cyanide antidotal therapy is not indicated.

Most significant unintentional exposures are dermal, especially in occupational settings, and local symptoms predominate in the majority of these cases. Systemic effects from insecticidal sprayings have been reported from wind drift or inappropriate handling, and the more potent type II pyrethroids predominate in case reports. An exposure of workers possibly affected by wind drift from a mixture of 32 ounces of the type II pyrethroid cyfluthrin mixed with 18.5 gallons of petroleum oil and 1800 gallons of water was reported in California in 2006. Spraying occurred in a citrus grove, and 23 female workers in an adjacent vineyard were possibly exposed. These workers complained of a “chemical” odor and felt ill with headaches, nausea, eye irritation, weakness, anxiety, and shortness of breath. They were all evaluated in local EDs and discharged home. Despite the fact that no cyfluthrin was detected on these²⁵ workers’ clothing or on foliage in the field where they were alleged to have been exposed, the report concluded that cyfluthrin was the cause; no estimate of the contribution of the petroleum vehicle to the symptoms was posited.²⁵ The predominant feature after significant cutaneous exposures is local paresthesias in the areas of skin contact, due to Na⁺ channel effects on cutaneous sensory nerves. Local skin irritation was seen in up to 10% of workers spraying pyrethroid insecticides, but it is rarely seen after medicinal use of the pyrethroid creams and shampoos. Ocular contact causes more severe symptoms, including immediate pain, lacrimation, photophobia, and conjunctivitis.¹³

Intentional ingestions represent the most serious exposures, due to the higher doses involved and the greater exposures to vehicles and solvents. However, a study of 48 cases of permethrin/xylene/surfactant mixtures (38 were suicidal ingestions) revealed that mild GI signs and symptoms predominated (73%: sore throat, mouth ulcerations, dysphagia, epigastric pain, vomiting). Pulmonary signs and symptoms were documented in 29%, and eight patients (including one death) had aspiration pneumonia. Thirty three percent had CNS symptoms: confusion (13%), coma (21%), and seizures (8%). The involvement of the central nervous system and lungs were less common, but clinically more significant.¹⁷² The relative contributions of the 70% xylene and 10% surfactant were likely responsible for much of the GI and pulmonary effects, though it was not discussed in the report.

Chronic Exposures

Since the pyrethroids are rapidly metabolized and are not biopersistent compounds, they have not been shown to cause cumulative toxicity. A single case of motor neuron disease resulted from heavy daily inhalation exposure to pyrethroid mixtures in a combined space for 3 years, which resolved after exposure ceased.⁴³ Some investigators have expressed concerns regarding possible neurotoxicity of the pyrethroids. However, a recent review noted that regulatory studies in multiple species have shown no evidence supporting gross neurodevelopmental toxicity or adult neuronal loss in man.¹¹⁴ In Germany, a unique situation exists where numerous civil lawsuits allege multiple chemical sensitivity (MCS) was caused by pyrethroid exposures. Scientific study of this phenomenon yields no scientific data to support this contention,¹¹ and the controversy is fueled by civil litigation, popular media sensationalizing, and subsequent public fear.⁵

Treatment

Initial treatment should be directed toward skin decontamination, as most poisonings occur from exposures by this route. Patients with intentional oral ingestions of a type II pyrethroid should be treated with a single standard dose of AC, provided the diluent of the pyrethroid does not contain a petroleum solvent. Contact dermatitis and acute systemic allergic reactions should be treated in the usual manner, utilizing histamine blockers, corticosteroids, and β-adrenergic agonists as clinically indicated.

Treatment of systemic toxicity is entirely supportive and symptomatic because no specific antidote exists. Benzodiazepines should be used for tremor and seizures. Topical vitamin E oil (dl-α-tocopherol) is especially effective in preventing and treating cutaneous paresthesias due to topical pyrethroid exposures.^13,116

Mosquitoes transmit more diseases to humans than any other biting insect. Worldwide, more than 700 million people are infected yearly by mosquito bites that transmit such diseases as malaria, viral encephalitis, yellow fever, dengue fever, bancroftian filariasis, and epidemic polyarthritis. Novel approaches to mosquito control also includes impregnation of indoor house paints with various insecticides (organic phosphorus compounds) and insect growth regulators. The WHO estimates that in 2010 there were about 219 million malaria cases and an estimated 660,000 malaria deaths worldwide.⁶ In the United States, eight people died from West Nile Virus (WNV) in NYC in 1999, and by January 2005, the virus, carried by mosquitoes from infected birds, had spread to all lower 48 states. Therefore, mosquito repellants have become important public health tools, and DEET has been the time-tested primary weapon for the past five decades. However, much controversy continues to surround DEET despite a remarkable safety profile with over a half-century of global use by billions of people. A growing trend in the United States and many western cultures has been a chemophobia against synthetic products like DEET. Many people favor plant-based “natural” or “organic” repellents, paralleling the increasing consumer preference for natural or organic foods. Several xenobiotics are proposed, but thus far few have been shown by objective blinded studies to even approach the efficacy of DEET, much less surpass it. Numerous comprehensive reviews of the subject have demonstrated superiority of DEET in most cases, and it remains the insect repellent standard by which all others are measured (Table 114–3).

Deet

The topical insect repellent, N,N-diethyl-3-methylbenzamide (DEET, former nomenclature N,N-diethyl-meta-toluamide), was patented by the US Army in 1946 and has been commercially marketed in the United States since 1956. Currently, it is used worldwide by more than 200 million persons annually. The EPA estimates that 38% of the US population uses DEET each year. Despite the current search for alternatives, DEET is still the most effective repellent available and has the most clinical toxicity information.^56,57

DEET can be purchased without prescription in concentrations ranging from 5% to 100%, and in multiple formulations of solutions, creams, lotions, gels, and aerosol sprays. Mosquitoes are attracted to their hosts by temperature and chemical attractants, principally CO₂ and lactate. The mechanism by which DEET repels insects was thought to be due to some interference with the chemoreceptors that detect lactic acid and CO₂.^56,112 However, recent work has demonstrated that DEET itself is actually detected by the mosquito’s olfactory receptors and repels them independently of whether the normal physical or chemical attractants are present.¹⁵¹ DEET formulations can feel greasy or sticky and can dissolve or damage some plastics (eyeglass frames, watches) and synthetic fabrics.

Toxicokinetics

DEET is extensively absorbed via the gastrointestinal tract.¹⁵⁹ Skin absorption is significant, depending on the vehicle and the concentration. Transdermal absorption of 30 to 45% DEET in ethanol is significantly higher than 100% DEET solution in an in vitro human skin model.¹⁴⁷ This has led to development of microencapsulated liposphere formulas and polyethylene glycol-based solutions that reduce absorption and increase repellent time and efficacy in animal models.⁴⁴

DEET does not bind to stratum corneum, and only 0.08% or less of a dose remains in the skin 8 hours after application.¹¹² DEET is lipophilic, and skin absorption usually occurs within 2 hours, although it is eliminated from plasma within 4 hours. The volume of distribution is large, in the range of 2.7 to 6.2 L/kg in animal studies. DEET is extensively metabolized by oxidation and hydroxylation by the hepatic microsomal enzymes, primarily by the isozymes CYP2B6, 3A4, 2C19, and 2A6.¹⁵⁹ DEET is excreted in the urine within 12 hours, mainly as metabolites, with 15% or less appearing as the parent compound.^57,112

DEET toxicity reports and studies have been extensively reviewed in terms of acute and chronic toxicity. It has been found safe for use in pregnant and lactating women⁸²; it was found to have no specific target organ toxicity or oncogenicity in any observed rat, mouse, or dog studies¹³⁶; and chronic DEET exposure together with other insecticides showed no increased cancer risks.¹⁰⁶

Pathophysiology

The exact mechanism of DEET toxicity is unknown. Recent reviews of adverse reactions to DEET reported 26 cases with major morbidity including encephalopathy, ataxia, convulsions, respiratory failure, hypotension, anaphylaxis, or death, particularly after ingestion or dermal exposure to large amounts.^{22,57,104,105,154,160} These primarily neurologic adverse reactions occurred mainly in children, and most involved prolonged use and excessive dosing beyond what is currently recommended. One fatal case involved a child who was known to be heterozygous for ornithine carbamoyl transferase (OCT) deficiency, and death was because of a Reyelike syndrome with hyperammonemia. This child had experienced prior episodes of hyperammonemia unrelated to DEET use, and DEET does not appear to affect, or be affected by, OCT activity in humans.¹⁰⁴ Currently, there is no evidence that enzyme polymorphism affects DEET metabolism or influences individual susceptibility to toxicity.

Although single, large, acute oral doses (1–3 g/kg) in rats produced seizures and CNS damage,^134,135 smaller acute doses (500 mg/kg and less) and chronic multigenerational dosing in another rat study produced no obvious toxicity.¹³⁴ Teratogenicity studies in rats and rabbits failed to demonstrate toxicity except at the highest doses,^136,171 and DEET was not found to be carcinogenic.^112,136 In view of the billions of applications, the number of reports of toxicity appears exceedingly small and suggests a remarkably wide margin of safety.^{57,65,104,105,120,150,160}

Clinical Manifestations

Most calls to poison control centers regarding DEET exposures involve minor or no symptoms, and symptomatic exposures occur primarily when DEET is sprayed in the eyes or inhaled.¹⁶⁰ Except for suicidal ingestions, most serious reactions consist of seizures in children overexposed via the dermal route; in fact, some of these cannot be definitely attributed to DEET.^65,104 Most symptoms resolve without treatment, and the majority of patients with serious toxicity recover fully with supportive care. A case report of severe poisoning developed in a man with extreme exposure. He used 30% DEET on his entire body several times daily for a prolonged time period, with an entire bottle used the day prior to admission. He developed weakness and nausea which progressed to confusion and shortness of breath. Metabolic acidosis, elevated lactate concentration, acute kidney injury requiring hemodialysis, and worsening weakness requiring mechanical ventilation developed. His blood DEET concentration was 130 ppb (μg/L). No seizures developed, and he experienced a full neurological recovery after a prolonged hospitalization.¹¹⁷

Treatment

Patients with DEET exposures are treated with supportive care aimed at primarily neurologic symptoms. In cases of dermal exposures, skin decontamination should be a priority to prevent further absorption. Patients with intentional oral ingestions should receive a single dose of AC if clinically indicated.

An extensive review of the safety risk of DEET repellent use confirms its safe use for all populations when used according to labeling ­guidelines.¹⁵⁰ Despite its good safety profile, avoiding the overuse of DEET seems ­prudent. The American Academy of Pediatrics (AAP) revised its recommendations for insect repellent (IR) use due to the emergence of WNV infections (prior recommendations were for use of products with DEET <10%).¹³⁷ They found that DEET-containing products are the most effective mosquito repellents available and are also effective against a variety of other insects, including ticks. IR with a DEET concentration from 10% to 30% (the maximum recommended for children) appear to be equally safe when used according to the directions on the product labels. The safety of DEET does not appear to relate to differences in these concentrations, and higher concentrations have longer durations of effects.¹ As indicated in the AAP handbook, repellents are not recommended for children younger than 2 months of age.²

The higher concentrations prolong the repellency period, but there is a plateau at about 50% DEET concentration, and about 6 hours may be the maximum protection time from any single application. Newer, longer-­acting DEET formulations in lipids or polymers cause the DEET to evaporate more slowly, which affords protection for > 6 hours and also less systemic absorption.^79,131 Since the lower concentrations recommended for children last approximately 2 hours, frequent reapplication is usually unnecessary. Since mosquitoes are most active for a few hours preceding and following dusk, DEET should be promptly washed off the child’s skin when protection is no longer needed. Soaking the skin is not more effective and may contribute to toxicity. DEET should be applied only to exposed skin. One should avoid abraded skin or skin with rashes. Care should be taken to avoid exposure to eyes and sensitive skin areas. Avoid use on children’s hands, so that the child does not wipe on eyes, mouth, genitalia, and so on. Adults should apply DEET to their own hands and then wipe onto the child’s face, rather than spraying onto a child’s face.

DEET combination products which include sunscreen should not be used together for mosquito repellency, since these combination products mutually enhance the percutaneous absorption of each component in both a porcine in vivo study⁷⁷ and in an in vitro mouse skin model.¹²⁴ Since mosquitoes are most active near dusk, there is clearly no need for the sunscreen component when repelling mosquitoes. These new combination products may be useful for tick repellency, however. Other options for protection include mechanical means, such as mosquito netting, as well as permethrin-impregnated clothing for tick prevention.

Newer Insect Repellents

The efficacy of any drug, treatment, or repellent is directly related to compliance with the treatment. Despite its demonstrated efficacy and safety, many people view chemical insect repellents such as DEET as potentially harmful and avoid their use. Several survey results in the United States and ­Canada revealed that 56% of people believe repellents are likely to be harmful to children, and 45% believed insect repellents are likely to sicken adults.¹⁶⁷ This has led to an intense search for effective alternatives to DEET-based repellents. Although their efficacy is not superior to DEET, their safety is likely at least equivalent to that of DEET, since the most recent data from NPDS revealed out of more than 1300 reported exposures, most reported no or minor effects.¹⁶

Picaridin (Bayrepel, KBR3023; CASRN: 119515-38-7).

Picaridin (chemi­cal name: 2-{2-hydroxyethyl}-1-piperidinecarboxylic acid 1-methylpropyl ester) is also known as Bayrepel and KBR 3023 in Europe. It is a piperidine derivative and has low acute oral, dermal, and inhalation toxicity. The EPA classifies it as Toxicity Category IV for acute inhalation toxicity and primary dermal irritation, the lowest rating available (Class III for oral ingestion). It is not a dermal sensitizer, and no developmental toxicity was observed in chronic animal feeding studies. It was also not shown to be mutagenic in a battery of tests and is not considered carcinogenic.⁴⁷ Picaridin is nearly as efficacious as DEET in comparison studies of the 20% solution used in Austalia and Europe, but unfortunately no studies have compared the 7% formula marketed in the United States (Cutter Advanced; Avon Skin So Soft with Picaridin). Since duration of protection is generally related to concentrations of the repellent (clearly shown with DEET), it would be reasonable to assume the 7% US formula would not have as long a duration of effect. A comprehensive MedLine search performed in February 2013 revealed no reports of human toxicity of picaridin insect repellents.

2-Undecanone (BioUD; Methyl Nonyl Ketone; CAS#: 112-12-9).

A newly formulated natural repellent, 2-undecanone, was approved for use as an IR by the EPA in 2007 and is known by the brand name of BioUD. Its active ingredient is derived from the wild tomato plant, Lycopersicon hirsutum Dunal f. glabratum C. H. Mull.¹⁶⁷2-Undecanone (also known as methyl nonyl ketone) was originally registered in 1966 as a dog and cat repellent and training aid and as an iris borer deterrent. It received EPA approval as a topical insect repellent in 2007. The EPA RED documents that in studies using laboratory animals, methyl nonyl ketone exhibited no toxicity via the oral and inhalation routes and was placed in Toxicity Category IV. Methyl nonyl ketone was slightly toxic (Toxicity Category III) for dermal toxicity, eye irritation, and dermal irritation and was a weak dermal sensitizer. Since it has a long history of safe use, is from a natural source, and is an approved food additive, it is considered essentially nontoxic. Methyl nonyl ketone is currently found in only one insect repellent in the form of both a lotion and a spray known as HOMS BiteBlocker Insect Repellent.⁵¹ The manufacturer lists a nonpublished study on its website of a field test showing protection from mosquito bites surpassing that of a DEET 30% at 6 hours, and equivalent at 4 hours.⁶⁹ A 2008 study done by the inventors and patent holders showed it was only as efficacious as lower DEET concentration products in laboratory arm-in-cage trials, but field trials revealed efficacy equivalent to 25% to 30% DEET formulations.¹⁶⁷ A comprehensive MedLine search performed in February 2013 revealed no reports of human toxicity of 2-undecanone insect repellents.

Oil of Lemon Eucalyptus (PMD; p-menthane-3,8-diol; CAS 42822-86-6).

Oil of Lemon eucalyptus occurs naturally in the lemon eucalyptus plant (Eucalyptus cittriodora also known as Corymbia citriodor). It is marketed in the USA under the brand name “OFF! Botanicals Insect Repellent^¯”. The natural oil can be extracted from the eucalyptus leaves and twigs; commercially the active ingredient, p-menthane-3,8-diol (PMD), is chemically ­synthesized, and is structurally similar to menthol. In its pure form, it is a solid at room temperature, and has a faint mint-like odor. PMD is placed into Toxicity Category IV for acute oral toxicity, dermal toxicity and skin irritation, and Toxicity Category I for eye irritation (Toxicity Category II for the end-use product). It is not a skin sensitizer. The EPA has determined that there there is reasonable certainty of no harm to the U.S. population or subpopulations, including infants and children, as the result of the uses of PMD to formulate insect repellents.⁴⁸ This compound is not to be confused with eucalyptus oil, a toxic essential oil containing 1,8 cineole (CAS#470-82-6), which has no insect repellent properties. A comprehensive MedLine search performed February 2013 revealed no reports of human toxicity of PMD insect repellents.

Oil of Citronella.

Plant-derived essential oil products are considered minimum-risk pesticides and are exempt from Environmental ­Protection Agency registration under Section 25(b) of the Federal Insecticide ­Fungicide and Rodenticide Act. Oil of Citronella has been used for over 50 years as an insect repellent and as an animal repellent in candles and ­topical skin products. These products, which have little efficacy, are not expected to cause harm to humans, pets, or the environment when used according to the label.⁵² A comprehensive MedLine search performed in February 2013 revealed no reports of human toxicity of citronella-­containing insect ­repellents.

Legal Standards for an Insecticide Label

The Federal Insecticide, Fungicide, and Rodenticide Act of 1962 established criteria for a “signal word” on an insecticide label, which implies the degree of toxicity based on an oral LD₅₀. Also, the label on the original container of these products is usually instructive and should always be brought to the medical facility (Table CS9–1).

• Organic chlorine insecticide agricultural use has largely been eliminated in the United States and Europe but remains a problem in the developing countries. DDT remains an important tool for control of malaria vector mosquitoes. These xenobiotics classically cause neurological toxicity (tremors, seizures) when ingested.

• Pharmaceutical use of lindane for topical ectoparasitic infestations has decreased greatly in favor of less toxic permethrin preparations. Lindane is still available in most of the United States.

• Pyrethroid insecticides are the most commonly used insecticides for home use and have a lower order of toxicity than organic chlorine or organic phosphorus insecticides. The Type II pyrethroids are more potent and can cause systemic toxicity (CNS, pulmonary) when ingested, but toxicity may be due to solvents and surfactants in the formulations.

• DEET containing insect repellents are still the most efficacious formulas and have many years of safe use in billions of people worldwide when used as directed. Neurological toxicity has been described with extreme exposure situations.

• Some newer insect repellents have efficacy approaching that of DEET, and few reported toxicities. As these newer repellents become more commonly used, it is not expected that significant toxicities will be manifested.

References