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History and Epidemiology
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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
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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 quail21,26,121 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
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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).
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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.
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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.
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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.
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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
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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
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Mirex and chlordecone are efficiently absorbed via skin, by inhalation, and orally.53
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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
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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
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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.
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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
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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
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Mechanisms of Toxicity
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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
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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
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The cyclodienes and lindane act as γ-aminobutyric acid (GABA) antagonists. They inhibit GABA binding at the GABAA 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 insecticide9,61 (Figs. 14–9, 14–10, and 114–2). Indeed, development of cyclodiene resistance seems to be related to alterations of the GABAA-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 GABAA receptor-chloride ionophore complex.132
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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 GABAA-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).
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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.
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Clinical Manifestations
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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
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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
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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
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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
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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
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Lindane: Specific Risks.
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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
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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.
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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
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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
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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
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DDT and Breast Cancer.
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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
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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
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Diagnostic Information
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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).
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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
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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
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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
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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.
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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.
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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.