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CHLORINATED HYDROCARBON INSECTICIDES

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This discussion refers to the management of toxicity related to chlorinated hydrocarbon insecticides such as DDT, cyclodiene, toxaphene, and related compounds. Simple chlorinated solvents are NOT included and can be found under the specific solvent.
    B) Lindane, one of the four main categories of organochlorine pesticides, and endosulfan, a chlorinated hydrocarbon insecticide of intermediate toxicity, are covered in separate managements.

Specific Substances

    A) HIGHEST TOXICITY
    1) Endrin
    2) Dieldrin
    3) Aldrin
    4) Chlordane
    5) Toxaphene
    INTERMEDIATE TOXICITY
    1) Kepone
    2) Heptachlor
    3) Mirex
    4) DDT
    LOWEST TOXICITY
    1) Methoxychlor
    2) Perthane
    3) Kelthane
    4) Chlorobenzilate
    5) Hexachlorobenzene
    GENERAL TERMS
    1) ENDRIN MIXTURE, DRY OR LIQUID
    2) CHLORDANE (TECHNICAL MIXTURE AND
    3) ------- METABOLITES)
    4) CHLORDANE, TECHNICAL
    5) CHLORDANE MIXTURE
    6) CHLORDANE METABOLITES
    7) CHLORDANE, LIQUID
    8) 4-PYRIMIDINAMINE, 2-CHLORO-4-(DIMETHYL
    9) ------AMINO)-6-METHYL-
    10) DCB (ORTHODICHLOROBENZENE)
    11) DIANISYLTRICHLOROETHANE
    12) HCBD (HEXACHLOROBUTADIENE)
    13) 2-CHLOR-4-DIMETHYLAMINO-
    14) ------6-METHYLPYRIMIDINE (GERMAN)
    15) ENDREX
    16) 2-CHLORO-4-(DIMETHYLAMINO)-6-
    17) -----METHYLPYRIMIDINE
    18) CRISTOXO
    19) GOLDENLEAF TOBACCO SPRAY
    20) HYDROCARBONS, CHLORINATED
    21) METOX K
    22) NENDRIN
    23) PERFLUOROBUTADIENE
    24) SECURITY TOX-MP
    25) THIOFUR

Available Forms Sources

    A) FORMS
    1) Commercial preparation of organochlorines are commonly dissolved in petroleum distillates which form emulsions when added to water.
    2) ENDRIN: In the United States, endrin was withdrawn in 1984. Supplies of endrin may remain in this country as documented by the occurrence of endrin poisoning associated with Taquito snack food in California in 1988 (Prendergast et al, 1989).
    B) USES
    1) The use of DDT, aldrin, dieldrin, endrin, BHC, mirex, kepone, hexachlorobenzene, chlorbenzilate, chlordane, chlordecone, heptachlor, and TDE have been sharply curtailed by the U.S. Environmental Protection Agency (EPA). The USFDA has published action levels for residues of certain pesticides in food and feed (Anon, 1990).
    2) Chlordane is rarely available in home and garden sprays and dusts.
    3) Orthodichlorobenzene is a colorless liquid used as an herbicide, insecticide, soil fumigant, and solvent.
    4) Chloropropylate and chlorobenzilate are available for control of mites on plants (Prod Info Acaraben(R), Acaralate(R), and Acarol(R), 1972).
    5) Isopropyl-4,4-dibromobenzilate is an experimental acaracide (Prod Info Acaraben(R), Acaralate(R), and Acarol(R), 1972).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Chlorinated hydrocarbon insecticides are a class of agents used as insecticides that includes endrin, chlordane, toxaphene, kepone, DDT, mirex, endosulfan, hepatachlor, lindane, and perthane. The use of many of these agents is either banned or restricted in the United States. Lindane and endosulfan are covered in separate managements.
    B) PHARMACOLOGY: These insecticides are neurotoxic to insects.
    C) TOXICOLOGY: Chlorinated hydrocarbon insecticides are likely to primarily act as "axon poisons", interfering with movement of ions across membranes resulting in CNS excitation and repetitive neuronal firing. Some of the agents are GABA antagonists as well. They may also sensitize myocardial tissue to catecholamines and predispose one to dysrhythmias in a similar manner as chlorinated hydrocarbon solvents.
    D) EPIDEMIOLOGY: Rare exposure. While inadvertent exposures are rarely toxic, large or deliberate exposures have resulted in significant morbidity and death.
    E) WITH THERAPEUTIC USE
    1) Many of these agents can induce hepatic enzymes, although the clinical significance is unclear. Chronic exposure to some agents has produced liver necrosis. There is a questionable increased risk of cancer from chronic exposure to these agents. Blood dyscrasias have been reported with chronic exposure.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, tremor, paresthesias, headache, and dizziness.
    2) SEVERE TOXICITY: Seizures, myoclonus, agitation, ataxia, confusion, hypotension, dysrhythmias, respiratory failure, metabolic acidosis, and coma. Elevated liver enzymes, renal failure, and thrombocytopenia are rare effects. Cellulitis and tissue necrosis have been reported after intravenous injection of these agents.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Hypotension may occur following oral ingestions of chlorinated hydrocarbons.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Aspiration of insecticide containing petroleum distillate may result in pneumonitis.
    0.2.9) HEPATIC
    A) WITH POISONING/EXPOSURE
    1) DDT, toxaphene, and chlordane are hepatic enzyme inducers. Chronic absorption may cause hepatomegaly and centrilobular hepatic necrosis in man and animals. Hexachlorobutadiene (HCBD) and trichloroethylene (TCE) have been associated with significant increases in individual and summed bile acid blood concentrations. These bile acid elevations in blood may reflect early and small disturbances of hepatic function.
    0.2.20) REPRODUCTIVE
    A) Organochlorine pesticides such as DDT pass through the placenta, with an average level in the newborn blood reaching around a third of that in maternal blood. They can also be found in breast milk. Excessive absorption of kepone (chlordecone) has depressed sperm counts and sperm motility in exposed workers.

Laboratory Monitoring

    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Adequate decontamination of dermal exposures and supportive care are the mainstays of treatment for mild to moderate exposures. Seizures, respiratory depression, and CNS depression indicate a more severe poisoning.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Perform endotracheal intubation and mechanical ventilation in patients with coma, respiratory depression, or recurrent seizures. Treat hypotension with intravenous fluids (10 to 20 mL/kg NS). If hypotension persists, vasopressors may be added, with the precaution that cardiac monitoring is necessary as chlorinated hydrocarbons may sensitize the myocardium to catecholamines and predispose patient to dysrhythmias. Treat seizures with benzodiazepines as a first-line therapy followed by phenobarbital if seizures persist. Propofol infusions and/or neuromuscular blockade (with continuous EEG monitoring) may be necessary in refractory cases. Phenytoin should not be used as it is likely to be of minimal effectiveness, especially with agents that are GABA antagonists (ie, lindane, toxaphene, endrin, hepatachlor, and endosulfan). Hyperthermia may result from neuromuscular agitation and should be aggressively managed with active cooling measures and liberal use of benzodiazepines. Severe metabolic acidosis can be treated with sodium bicarbonate.
    C) DECONTAMINATION
    1) PREHOSPITAL: Because of the risk of seizures and subsequent aspiration, prehospital gastrointestinal decontamination should be avoided.
    2) HOSPITAL: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. These procedures should only be used in a patient who presents soon after an ingestion and who have adequate airway protection. If the ingestion was very recent and a liquid formulation, nasogastric suction of gastric contents can be considered.
    D) AIRWAY MANAGEMENT
    1) Patients who are comatose or with altered mental status may need endotracheal intubation and mechanical ventilation.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) Dialysis is unlikely to be of benefit because of the large volume of distribution. Cholestyramine may enhance elimination of these compounds, especially chlordecone, but there is no evidence that it affects clinical outcome.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Adults who intentionally ingest one of these agents or any child with an ingestion should be referred to a healthcare facility. Patients with prolonged or repeated dermal applications or inhalational exposures should be referred to a healthcare facility if they become symptomatic.
    2) OBSERVATION CRITERIA: If patients are asymptomatic after 6 hours of observation, they can be discharged after appropriate psychiatric clearance.
    3) ADMISSION CRITERIA: Patients with persistently altered mental status, abnormal vital signs, or recurrent seizures should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    H) PITFALLS
    1) Phenytoin is likely to be of minimal effectiveness for seizure control.
    I) TOXICOKINETICS
    1) Oral absorption is generally very good. Dermal absorption is variable. Some agents (ie, DDT) are poorly absorbed dermally, while other agents (ie, lindane and kepone) are well absorbed dermally. While these agents are not very volatile, they may be absorbed via inhalation of sprays and dusts.
    2) All agents are lipophilic which can result in storage in fat tissues. Metabolism varies. DDT is slowly metabolized and can persist for months. Other agents (ie, endrin, lindane, toxaphene) have more rapid metabolism and have less persistence in body tissues.
    J) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis is broad and would include anything that can cause seizures.
    0.4.3) INHALATION EXPOSURE
    A) Move patient to fresh air. Monitor for respiratory distress. if cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with inhaled beta-2 agonist and oral or parenteral corticosteroids.
    0.4.4) EYE EXPOSURE
    A) Irrigate exposed eyes with copious amounts of room temperature water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist, the patient should be seen in a health care facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Remove contaminated clothing. Wash skin and hair thoroughly; do two soap and water washings. Leather absorbs pesticides. Hence, leather should not be worn in the presence of pesticides and all contaminated leather should be discarded.

Range Of Toxicity

    A) The toxic dose varies by compound and is not well established for humans. For example, endrin, chlordane, and toxaphene are believed to have the highest hazard potential. Kepone, endosulfan, hepatachlor, mirex, and DDT are believed to have intermediate hazard potential. Methoxychlor and perthane are believed to have the lowest hazard potential.
    B) An adult died after ingesting 100 mL of endosulfan.

Clinical Effects

Summary Of Exposure

    A) USES: Chlorinated hydrocarbon insecticides are a class of agents used as insecticides that includes endrin, chlordane, toxaphene, kepone, DDT, mirex, endosulfan, hepatachlor, lindane, and perthane. The use of many of these agents is either banned or restricted in the United States. Lindane and endosulfan are covered in separate managements.
    B) PHARMACOLOGY: These insecticides are neurotoxic to insects.
    C) TOXICOLOGY: Chlorinated hydrocarbon insecticides are likely to primarily act as "axon poisons", interfering with movement of ions across membranes resulting in CNS excitation and repetitive neuronal firing. Some of the agents are GABA antagonists as well. They may also sensitize myocardial tissue to catecholamines and predispose one to dysrhythmias in a similar manner as chlorinated hydrocarbon solvents.
    D) EPIDEMIOLOGY: Rare exposure. While inadvertent exposures are rarely toxic, large or deliberate exposures have resulted in significant morbidity and death.
    E) WITH THERAPEUTIC USE
    1) Many of these agents can induce hepatic enzymes, although the clinical significance is unclear. Chronic exposure to some agents has produced liver necrosis. There is a questionable increased risk of cancer from chronic exposure to these agents. Blood dyscrasias have been reported with chronic exposure.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, tremor, paresthesias, headache, and dizziness.
    2) SEVERE TOXICITY: Seizures, myoclonus, agitation, ataxia, confusion, hypotension, dysrhythmias, respiratory failure, metabolic acidosis, and coma. Elevated liver enzymes, renal failure, and thrombocytopenia are rare effects. Cellulitis and tissue necrosis have been reported after intravenous injection of these agents.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Hypotension may occur following oral ingestions of chlorinated hydrocarbons.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypotension may occur following oral ingestions of chlorinated hydrocarbons (Blanco-Coronado et al, 1992).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Intraperitoneal injection of 2.5 mg/kg of hexachlorocyclohexane (HCH) or 5 mg/kg of endosulfan to male albino rabbits twice weekly for 15 months resulted in ocular toxicity (Anand et al, 1987).
    a) Two of six animals exposed to HCH developed unilateral corneal opacity by the end of the experiment.
    b) Fundal changes associated with marked pallor of the optic disc, papilledema, and attenuation of the blood vessels and retinal tissue degeneration with reduction in ganglionic cell population were noted.
    c) It was also noted that pesticide-treated rabbits had reduced vitamin A levels in plasma and liver after 15 months' exposure.
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) MOUTH: Foaming at the mouth was observed in a 20-year-old man one hour after ingestion of 200 mL of 30% endosulfan (Shemesh et al, 1988).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ISCHEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Two cases of myocardial ischemia were reported and associated with chlorinated hydrocarbon exposure (Bailey et al, 1997).
    1) A 37-year-old non-obese and nonsmoking woman collapsed at work after an inhalational exposure to 30% 1,1,1-trichloroethane. She sustained a myocardial infarction (by CK-MB and ECG). Cardiac enzymes peaked at 25 hours and the patient remained asymptomatic; she was treated medically and released.
    2) The second case involved a 33-year-old woman who intentionally ingested 15 mg clonazepam, 5 mg alprazolam and 4 g chloral hydrate (a chlorinated hydrocarbon and a metabolite of trichloroethylene) and developed almost immediate epigastric and retrosternal chest pain. The symptoms resolved spontaneously, the ECG and ST returned to baseline. , No further symptoms were reported.
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) METHOXYCHLOR: A 62-year-old man (95 kg) ingested approximately 100 to 150 mL of a product that contained 120 mg/L of methoxychlor and was found unresponsive and severely hypotensive (58/40 mmHg). The patient was given IV fluids and became more alert. Blood pressure stabilized at 110/70; pulse rate and rhythm remained stable. The patient recovered with no apparent permanent sequelae (Thompson & Vorster, 2000).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Aspiration of insecticide containing petroleum distillate may result in pneumonitis.
    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) WITH POISONING/EXPOSURE
    a) Aspiration of petroleum distillate solvent is likely to cause a hydrocarbon pneumonitis.
    B) INJURY OF UPPER RESPIRATORY TRACT
    1) WITH POISONING/EXPOSURE
    a) Irritation of respiratory membranes may result from inhalation of hexachlorobenzene (Dreisbach, 1983).
    C) HYPOVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Aldrin, dieldrin, endrin, chlordane, toxaphene, and DDT are respiratory depressants.

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) Aldrin, dieldrin, endrin (Clinical Note, 1984), chlordane, endosulfan, lindane, heptachlor, strobane, toxaphene, and DDT cause CNS excitation and seizures.
    2) Seizures are characteristic of acute poisoning (Wells & Milhorn, 1983).
    b) Convulsions are characteristic of acute camphechlor poisoning and consist of tonic-clonic motions due to diffuse stimulation of the brain and spinal cord (Wells & Milhorn, 1983).
    c) CASE REPORTS
    1) A 47-year-old man and his 15-year-old son ingested DDT powder by mistake and developed tonic-clonic seizures. They both recovered with intensive support and benzodiazepine administration (Ozucelik et al, 2004).
    2) Grand mal seizures and dysconjugate eye movements were seen in a patient who had ingested camphechlor. Intermittent seizure activity continued throughout the night, and the patient was recovered by the next morning (Wells & Milhorn, 1983).
    d) CASE SERIES
    1) Five cases of multiple generalized seizures occurring within one hour after eating taquitos (a corn tortilla with meat filling) contaminated with endrin. The concentration of endrin in the food was found to be approximately 100 ppm (Waller et al, 1992).
    2) In Pakistan following endrin contamination of foodstuffs; there was an epidemic of seizures with 194 cases and 19 deaths (Clinical Note, 1984; Rowley et al, 1987).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Kelthane, perthane, methoxychlor and hexachlorobenzene have little CNS toxicity, and, at extreme dosages, CNS depression is often more evident than stimulation.
    b) Severe global encephalopathy was reported in a 46-year-old woman after the ingestion of 6 to 8 ounces of chlordane and 10 to 12 paroxetine tablets (Stipetic & Hobbs, 1998).
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH POISONING/EXPOSURE
    a) SUMMARY
    1) INGESTION OF LARGE AMOUNTS of hexachlorobenzene may result in central nervous system stimulation which may include headache, dizziness, nausea, vomiting, numbness of hands and arms, apprehension, partial paralysis of extremities, loss of equilibrium and vibratory sense, coma, and seizures.
    b) CHLORDANE
    1) Neurobehavioral impairment in 9 symptomatic patients exposed to chlordane was evaluated. Abnormal balance (with eyes closed in 7), abnormal color discrimination (in 6), verbal recall deficit (in 5), prolonged blink reflex latency (in 4), prolonged choice reaction time (in 4), and decreased Culture Fair scores (in 4) were reported (Kilburn, 1997).
    c) METHOXYCHLOR
    1) A 62-year-old man (95 kg) ingested approximately 100 to 150 mL of a product that contained 120 mg/L of methoxychlor and was found unresponsive and severely hypotensive (58/40 mmHg). The patient was given IV fluids and became more alert. The only neurologic abnormality noted was an increased tone in the lower extremities; however, no long term sequelae was reported (Thompson & Vorster, 2000).
    D) NEURITIS
    1) WITH POISONING/EXPOSURE
    a) OPSOCLONUS: When workers are exposed to chlordecone, they developed overt neurologic manifestations, which included postural and intention tremor and opsoclonus. This latter condition appears to be a unique manifestation of chlordecone intoxication (Taylor, 1985).
    E) SECONDARY PERIPHERAL NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Occasional reports have associated peripheral neuropathy with exposure to organochlorines (reviewed in Goldfrank, 1994).
    F) AMNESIA
    1) WITH POISONING/EXPOSURE
    a) Amnesia following toxaphene ingestion has been reported (Dreisbach, 1983; Wells & Milhorn, 1983). Confusion and agitation may occur prior to or independent of seizures (reviewed in Goldfrank, 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROENTERITIS
    1) WITH POISONING/EXPOSURE
    a) When ingested, these agents may cause nausea, vomiting, and diarrhea, especially when contained in petroleum distillates. In the case of toxaphene, nausea and vomiting may be absent (Karatas et al, 2006; Wells & Milhorn, 1983).
    B) PANCREATITIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Pancreatitis with elevated amylase levels were reported in a 46-year-old woman following an intentional ingestion of 6 to 8 ounces chlordane and 10 to 12 paroxetine tablets. The patient died 4 days later from multisystem failure (Stipetic & Hobbs, 1998).

Hepatic

    3.9.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) DDT, toxaphene, and chlordane are hepatic enzyme inducers. Chronic absorption may cause hepatomegaly and centrilobular hepatic necrosis in man and animals. Hexachlorobutadiene (HCBD) and trichloroethylene (TCE) have been associated with significant increases in individual and summed bile acid blood concentrations. These bile acid elevations in blood may reflect early and small disturbances of hepatic function.
    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) DDT, toxaphene (Wells & Milhorn, 1983), and chlordane (Garrettson et al, 1984-85; (Stipetic & Hobbs, 1998) are hepatic enzyme inducers. This probably is the basis for an estrogenic effect of DDT in rodents.
    b) CASE REPORT: Elevated liver enzymes, bilirubin, and amylase occurred in a 46-year-old woman after intentionally ingesting 6 to 8 ounces of chlordane and 10 to 12 paroxetine tablets in a suicide attempt. Hepatic failure worsened and the patient died after developing irreversible asystole (Stipetic & Hobbs, 1998).
    B) LARGE LIVER
    1) WITH POISONING/EXPOSURE
    a) Chronic absorption may cause hepatomegaly and centrilobular hepatic necrosis in man and animals.
    C) GALLBLADDER FINDING
    1) WITH POISONING/EXPOSURE
    a) BILE ACIDS: One study of workers exposed to hexachlorobutadiene (HCBD) and trichloroethylene (TCE) revealed significant increases in individual and summed bile acid blood concentrations. The authors concluded that these blood bile acid elevations might reflect early and small disturbances of hepatic function. No association was found between the chlorinated hydrocarbon exposures and standard liver function tests. The significance and mechanism for the bile acid elevations was not determined (Driscoll et al, 1992).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC NECROSIS
    a) Orthodichlorobenzene produced marked centrilobular liver necrosis in rats exposed to 539 ppm for 3 hours (Hollingsworth, 1956). Liver damage was also seen in animals after exposure to 50 to 800 ppm for several hours (ACGIH, 1981).
    2) GAMMA GT INCREASED
    a) Studies in rats have shown increased GGTP activity with acute exposure to DDT or toxaphene. Subchronic exposure resulted in increased GGTP levels after 2 months of exposure (Garcia & Mourelle, 1984).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DISORDER OF TESTIS
    1) WITH POISONING/EXPOSURE
    a) Excessive absorption of kepone (chlordecone) has depressed sperm counts and sperm motility in exposed workers (Taylor, 1985).
    B) ACUTE RENAL FAILURE SYNDROME
    1) WITH POISONING/EXPOSURE
    a) A 15-year-old boy developed acute oliguric renal failure with a BUN of 47 mg/dL and a creatinine of 6.4 mg/dL 2 days after an unintentional ingestion of DDT. The acute renal failure, which was thought to be due to the rhabdomyolysis, resolved. Approximately 2 months after the ingestion, the patient's serum BUN and creatinine were within normal limits (Ozucelik et al, 2004).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Severe metabolic acidosis (pH 7.0, pCO2 31 mmHg, and HCO3 7.8 mEq/L) secondary to seizures was reported in a 46-year-old woman following the ingestion of 6 to 8 ounces chlordane and 10 to 12 paroxetine tablets. Acidosis was persistent, and the following day dropped (pH 6.97). Despite aggressive therapy, she died of cardiac arrest on day 4 (Stipetic & Hobbs, 1998).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH POISONING/EXPOSURE
    a) Chlordane may have induced rare cases of megaloblastic anemia.
    b) A number of case reports are available implicating prolonged exposures to organochlorines as possible causal agents for a variety of blood dyscrasias, including aplastic anemia (Infante et al, 1978; Sharp et al, 1986; Epstein & Ozonoff, 1987).
    B) LEUKEMIA
    1) WITH POISONING/EXPOSURE
    a) Six cases of leukemia associated with home termite treatment with chlordane or heptachlor have been reported (Epstein & Ozonoff, 1987).
    C) DISSEMINATED INTRAVASCULAR COAGULATION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Disseminated intravascular coagulation (DIC) was reported in a 46-year-old woman following an ingestion of 6 to 8 ounces chlordane and 10 to 12 paroxetine tablets. The following laboratory values were reported: platelets 10,000, PT 27.1, PTT 33.5, INR 4.94, and fibrinogen 99 mg/dL. DIC was refractory to therapy with packed red blood cells and fresh frozen plasma transfusions. The patient died on day 4 (Stipetic & Hobbs, 1998).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATITIS
    1) WITH POISONING/EXPOSURE
    a) Some skin irritation results from extensive contact with these agents or with petroleum distillates in which they are contained.
    B) PORPHYRIA CUTANEA TARDA
    1) WITH POISONING/EXPOSURE
    a) PORPHYRIA CUTANEA TARDA: Hexachlorobenzene food contamination resulted in an outbreak in Turkey of porphyria cutanea tarda consisting of blistering and epidermolysis which caused the skin to be unusually light-sensitive. Hypertrichosis was also present. The skin lesions healed poorly and formed pigmented scars (Teske, 1986).
    C) SKIN NECROSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORTS: Buchman (2000) reported on 2 adults who intravenously injected household insecticides (reportedly Raid Roach Killer(R) in one case) into their upper extremities. Each developed inflammation, swelling, cellulitis, and necrosis of the tissue, subcutaneous fat, and muscle. The only systemic toxicity reported was fever. In each case, wound care consisted of multiple debridements which were eventually closed with a flap procedure. Despite ongoing joint stiffness, full range of motion was present on follow-up in both patients (Buchman, 2000).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) INCREASED ESTROGEN LEVEL
    1) WITH POISONING/EXPOSURE
    a) PROESTROGENS/ESTROGENS: It has been demonstrated that purified methoxychlor and MDDE (methoxychlor metabolite) are proestrogens and that monohydroxymethoxychlor and monohydroxy-MDDE are estrogens (Kupfer & Bulger, 1987).
    b) Windham et al studied 50 Southeast Asian women of reproductive age from 1997-1999 and found that all of the women had higher levels of DDT and its metabolite DDE in their urine than typical US counterparts. The woman with the highest concentrations had a menstrual cycle length that was 4 days shorter than the women with the lowest concentrations. This effect was lost after adjustment for age, parity, lipid profiles, tubal ligation, and the exclusion of a patient with long menstrual cycle. The clinical significance of this finding is uncertain, although the authors concluded that DDE affected ovarian function (Windham et al, 2005).
    B) DISORDER OF MENSTRUATION
    1) WITH POISONING/EXPOSURE
    a) A study of nulliparous female Chinese textile workers 20 to 34 years of age reported that exposure to DDT resulted in an earlier age at menarche and an increased risk of shortened menstrual cycles (Ouyang et al, 2005).
    C) LACK OF EFFECT
    1) WITH POISONING/EXPOSURE
    a) Mean concentrations of organochlorines were compared in a case control study of 86 women with endometriosis and 70 controls, matched for the indication of laparoscopy. No significant differences were found between cases and controls in crude geometric mean concentrations for any of the organochlorine compounds (Lebel et al, 1998).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) WITH POISONING/EXPOSURE
    a) AUTOIMMUNITY: Chlordane exposed persons appear to have a significantly increased frequency of cortical thymocytes in the circulation and a decreased frequency of the suppressor-inducer phenotype CD45RA/T4. Eleven out of 12 persons tested for evidence of autoimmunity demonstrated some increased titer of a form of autoantibody (Mcconnachie & Zahalsky, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Organochlorine pesticides such as DDT pass through the placenta, with an average level in the newborn blood reaching around a third of that in maternal blood. They can also be found in breast milk. Excessive absorption of kepone (chlordecone) has depressed sperm counts and sperm motility in exposed workers.
    3.20.3) EFFECTS IN PREGNANCY
    A) PLACENTAL BARRIER
    1) Organochlorine pesticides such as DDT pass through the placenta, with an average level in the newborn blood reaching around a third of that in maternal blood.
    a) Although DDT levels have been shown to be elevated in the cord blood of infants delivered prematurely or in fetuses spontaneously aborted, the DDT levels in their mothers are not consistently elevated.
    b) A number of theories attempt to explain the elevated DDT levels seen in preterm infants or aborted fetuses. One group proposed that organochlorine pesticides are known to have weak estrogenic effects, and may precipitate labor.
    c) Others suggested that preterm infants may have an increased placental permeability to DDT; or, more DDT is found in the blood because preterm infants have less adipose tissue (Sharp et al, 1986).
    d) Hexachlorobenzene is transferred from mother to fetus via the placenta, and it has been shown that a significant linear correlation exists between the placental concentration and that in cord blood. Placental concentration is an accurate indicator of hexachlorobenzene contamination in pregnant females and newborns (Ando et al, 1985).
    B) PRETERM BIRTH
    1) A case-cohort study showed a positive association between maternal serum levels of organochlorine pesticides and the occurrence of preterm birth. Maternal serum levels of p,p'-DDE, measured at the time of delivery, showed approximately a two-fold increased risk for preterm birth (adjusted OR=1.87 {95%CI=0.95-3.68} for 111.6-228.8 ng/g and adjusted OR=1.67 {95%CI=0.84-3.31} for >228.8 ng/g). Maternal serum levels of beta-hexachlorocyclohexane (beta-HCH) also indicated an increased risk of preterm birth (adjusted OR=1.58 {95%CI=0.80-3.10} for 23.96-76.53 ng/g and adjusted OR=1.85 {95%CI=0.94-3.66} for >76.53 ng/g). Limitations of this study include a possibility of a confounding factor, such as another toxicant or other organochlorine compound, or the simultaneous measurement of beta-HCH levels which may be correlated with p,p'-DDE levels (Torres-Arreola et al, 2003).
    C) COGNITIVE DEVELOPMENT
    1) A study was conducted to determine the impact of prenatal organochlorine pesticide exposure on the cognitive development of children 4 years later. Two study populations were analyzed (Ribera d'Ebre and Menorca cohorts), involving children who were prenatally exposed to DDT and DDE and had measurable organochlorine concentrations in their serum cord blood (n=70, Ribera d'Ebre; n=405, Menorca). Neuropsychological testing of the children at age 4 was conducted using the McCarthy Scales of Children's Abilities (MCSA) for measurement of cognitive development. The results of this testing showed that there was a decrease in general cognitive function, verbal and memory skills in children who were exposed to DDT or DDE, with statistically significant associations in the DDT-exposed group. For infants with a serum cord blood DDT concentration greater than 0.20 ng/mL, the general cognitive function, verbal skills, and memory skills (at 4 years of age) decreased by 5.87, 7.86, and 10.86 points, respectively, as compared with infants whose DDT serum cord blood concentrations were less than 0.05 ng/mL (Ribas-Fito et al, 2006).
    D) SOCIAL BEHAVIOR
    1) The social behavior of 4-year-old children, who were prenatally exposed to hexachlorobenzene, was assessed utilizing the California Preschool Social Competence Scale (CPSCS) and the Attention Deficit Hyperactivity Disorder (ADHD) checklist. Two birth cohorts were analyzed (Ribera d'Ebre and Menorca cohorts) involving children who were prenatally exposed to hexachlorobenzene (HCB) and had measurable organochlorine concentrations in their serum cord blood (Ribera d'Ebre n=70; Menorca n=405). The results of the assessment showed that children with HCB serum cord blood concentrations greater than 1.5 ng/mL had a statistically significant increased risk of having poor social competence (relative risk (RR) = 4.04; 95% confidence interval (CI) 1.76 to 9.58) and an increased risk of developing symptoms (RR=2.71; 95% CI 1.05 to 6.96) (Ribas-Fito et al, 2007).
    E) LACK OF EFFECT
    1) BIRTH WEIGHT: Prenatal exposure to organochlorine pesticides, including p,p'-DDT, p,p'-DDE, beta-hexachlorocycloxane, hexachlorobenzene, trans-nonachlor, oxychlordane, and heptachlor epoxide, did not appear to impact birth weight, according to a study conducted in the Ukraine from 1993 to 1994, which included 197 infants (Gladen et al, 2003). Another study, evaluating infants born between 1993 and 1998 who were prenatally exposed to organochlorine pesticides, yielded similar results, demonstrating no impact on birth size measurements (including birth weight, birth length, and head circumference) following prenatal exposure to hexachlorobenzene and p,p'-DDE (Sagiv et al, 2007).
    F) ANIMAL STUDIES
    1) The effects of perinatal exposure to methoxychlor on reproductive function after maturation was studied in rats. In females, irregular estrous cycles, and significant depression in lordosis quotient and LH surge were observed. In mature males, serum concentrations of gonadotropins were significantly decreased, but testosterone levels were not altered (Suzuki et al, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Peters et al (1982) report that HCB (hexachlorobenzene) was found in the breast milk of mothers with and without porphyria who had been exposed to HCB (Peters et al, 1982).
    2) Ramakrishnan et al (1985) and Siddiqui & Saxena (1985) have found alpha HCH, p,p'-DDE, p,p'-DDT, alpha, beta, and gamma-isomers of benzene hexachloride (BHC), and aldrin in the milk of nursing mothers in India (Ramakrishnan et al, 1985; Siddiqui & Saxena, 1985).
    3) Bouwman et al (1990) found significantly higher mean levels of DDT and metabolites in breast milk from mothers living in DDT-treated dwellings compared to controls (Bouwman et al, 1990).
    a) Parity, infant age, and maternal age were evaluated as a predictor of DDT in breast milk of the exposed group. Parity was the best predictor. Significantly higher levels of DDT were found in breast milk of primiparous mothers of the exposed group than multiparous mothers of the exposed group.
    b) Determined levels were not analyzed for correlation of percentage milk fat.
    4) The daily intake of total organochlorine pesticides residues calculated for the suckling infant was significantly higher when compared with the acceptable daily intake (ADI) as recommended by FAO/WHO (FAO/WHO, 1970).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS143-50-0 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Chlordecone (Kepone)
    b) Carcinogen Rating: 2B
    1) The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    3.21.3) HUMAN STUDIES
    A) SUMMARY
    1) With few exceptions, the delayed effects of pesticides on human health have been difficult to detect. Perhaps the health risks are sufficiently small that they are below the power of epidemiologic studies to detect (Sharp et al, 1986).
    2) The results of the Agricultural Health Study, conducted as a prospective cohort study and involving 24, 384 pesticide applicators who used a chlorinated hydrocarbon insecticide from 1993 to 1997, showed that there was no clear association between the overall use of chlorinated hydrocarbon pesticides and an increased incidence of cancer, although, in some instances, there were statistically significant associations between specific agents and the development of some cancers (Purdue et al, 2007).
    B) SPECIFIC AGENT
    1) DDT: The International Agency for Research on Cancer (IARC) has listed some of these agents (eg, DDT) as "possibly carcinogenic to humans", although it also categorizes them as being inadequately assessed for human carcinogenic potential. For other agents (e.g., aldrin), carcinogenicity has been demonstrated in animal studies, but insufficient data has accrued from human studies (IARC, 1987).
    a) Chronic lymphocytic leukemia has been associated with occupations of farming and painting as well as occupational contacts with horses, DDT, and fresh wood (Flodin et al, 1987).
    b) In humans, there is a reported association between DDT and malignant lymphoma (Hardell et al, 1981).
    c) A 10-year prospective follow-up study of cancer mortality in 919 subjects found no relation between either overall mortality or cancer mortality and increasing serum DDT concentrations (Austin et al, 1989). The authors concluded that the evidence does not support the opinion that DDT is a human carcinogen.
    d) Key & Reeves (1994) provide a statistical analysis providing information on lack of evidence for an association of breast cancer risk with polychlorinated biphenyls.
    e) An epidemiologic study evaluated mortality from various cancers in workers exposed to various pesticides at one plant, over a median 29 year period, and found no excess cancers due to occupational exposures (Amoateng-Adjepong et al, 1995).
    f) A follow-up study of 4,552 male workers exposed to DDT in Sardinia, Italy between 1946 and 1950 was performed to determine cancer mortality. For those exposed before 31 years of age, cancer mortality (RR 0.8; 95% CI 0.6 to 0.9) and lung cancer mortality (RR 0.5; 95% CI 0.4 to 0.8) were significantly decreased. When subjects born in Sardinia were compared with those born elsewhere, those not born in Sardinia had an increased risk of mortality from prostate cancer (RR 1.8; 95% CI 0.6 to 5.2), stomach cancer (RR 2.0; 95% CI 0.7 to 5.7), and leukemia (RR 5.7; 95% CI 2.0 to 16.3). The authors did not find a link between occupational exposure to DDT and mortality from any of these cancers (Cocco et al, 2005).
    2) CHLORDANE: The EPA has characterized chlordane as a probable human carcinogen, based on animal studies (category IIB) (Mcconnachie & Zahalsky, 1992).
    a) According to the Agricultural Health Study of pesticide applicators (n=51,011), there was a statistically significant association between chlordane exposure and an increased risk of rectal cancer (relative risk (RR) 1.7; 95% Confidence Interval (CI) 1 to 2.8) (Purdue et al, 2007).
    3) HEPTACHLOR: Hawaiian children born between 1980 and 1982 were studied to determine the incidence of cancer or mortality after being exposed to heptachlor in milk at concentrations exceeding the federal action level. All dairy products were recalled in 1982. Overall, the study reported no indication of higher cancer incidence or mortality in children born during the heptachlor contamination period, compared with unexposed children. They did report, however, a slightly higher occurrence of cancer for the heptachlor-exposed children when they were 15 to 19 years of age (Maskarinec, 2005).
    a) According to the Agricultural Health Study of pesticide applicators (n=51,011), there was a statistically significant association between heptachlor exposure and an increased risk of leukemia (relative risk (RR) 2.1; 95% Confidence Interval (CI) 1.1 to 3.9) (Purdue et al, 2007).
    4) TOXAPHENE: According to the Agricultural Health Study of pesticide applicators (n=51,011), there was a statistically significant association between toxaphene exposure and an increased risk of rectal cancer (relative risk (RR) 2; 95% Confidence Interval (CI) 1.1 to 3.5) (Purdue et al, 2007).
    C) BREAST CARCINOMA
    1) Hunter et al (1997) conducted a nested case-control study (240 patients with breast cancer and 240 age-matched controls) testing the hypothesis that hormonally active organochlorine chemicals may be responsible for increased incidences of breast cancer. No significant correlation between breast cancer and plasma levels of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p-DDE) and polychlorinated biphenyls (PCBs) 2 to 3 years before diagnosis was found (Hunter et al, 1997).
    a) Vom Saal et al (1998) point out that estrogenic chemicals in pesticides, plastics, and other products, which may contribute to the burden of environmental body estrogens, were not taken into consideration in the above study. These authors also suggest that exposure to estrogenic chemicals during crucial developmental periods may predispose organs to disease (vom Saal et al, 1998).
    b) Talbott et al (1998) point out that a highly exposed population sample of women was not chosen for the study by Hunter et al (1997) (Talbott et al, 1998; vom Saal et al, 1998).
    c) Another flaw in the above study may be the lipid-weight basis calculations that were not addressed. Fat-tissue levels of organochlorines may be 250 to 1000 times higher than blood levels, and may be released from fat stores (Bigsby & Steinmetz, 1998; Gammon et al, 1998).
    2) During a prospective study of women in Denmark, dieldrin was associated with a significantly increased dose-related risk of breast cancer (adjusted odds ratio 2.05 [95% CI 1.17-3.57]) (Hoyer et al, 1998).
    3) In another study, Bagga et al (2000) were not able to find an association between organochlorines exposure and a risk of breast cancer (Bagga et al, 2000).
    4) A meta-analysis was conducted to determine the association between dichlorodiphenyldichloroethane (DDE) exposure (the main metabolite of dichlorodiphenyltrichloroethane (DDT)) and breast cancer risk. The meta-analysis included 22 studies, all of which were case-control studies and 9 of the 22 studies were prospective case-control studies. The overall results showed a summary odds ratio of 0.97 (95% CI 0.87-1.09), indicating no association between exposure to DDE and an increased risk of breast cancer (Lopez-Cervantes et al, 2004). It has been suggested that the lack of a positive association between DDE exposure and breast cancer risk may be due to the low estrogenicity of DDE as compared with other metabolites of DDT (p,p'-DDT and o,p'-DDT).
    5) O'Leary et al conducted a nested case-control study that found an increased risk of breast cancer in women residing within one mile of a hazardous waste site containing organochlorine pesticides. The limitation of this study was that the risk was restricted to nulliparous women or women whose first birth was at age 26 or older, both known to be independent risk factors for breast carcinoma. The study was also limited by small numbers and wide confidence intervals. The clinical relevance of this finding remains unclear since the multiple other studies listed above show no association between organochlorine exposure and breast cancer(O'Leary et al, 2004)
    D) PROSTATE CARCINOMA
    1) A pilot study, conducted to determine the association between chlorinated hydrocarbon insecticides and the development of prostate cancer and involving 58 prostate cancer patients and 99 controls, suggested an association between higher lipid adjusted serum levels of oxychlordane and prostate cancer (serum oxychlordane levels 0.020 to 0.032 micrograms/g adjusted odds ratio of 3.1 {95% CI 1.3-7.6}; serum oxychlordane levels above 0.032 micrograms/g adjusted OR 1.23 {CI 0.42-3.55}). Due to the small sample size of this study, further investigation is warranted (Ritchie et al, 2003).
    E) OCCUPATIONAL EXPOSURE
    1) MORTALITY OF WORKERS: A significant increase in liver and biliary tract cancer among workers was noted at one plant, manufacturing primarily aldrin and dieldrin, in a study of mortality of workers employed at organochlorine pesticide manufacturing plants (Brown, 1992).
    a) Mortality for all malignant neoplasms and all causes at each of the plants was noted to be lower than expected.
    b) The plants studied manufactured chlordane; heptachlor and endrin; aldrin, dieldrin, and endrin; and DDT.
    c) Study limitations included lack of exposure data, small number of deaths with which to assess adequately mortality from rare diseases, and the potential for confounding exposures to other chemical compounds.
    d) Undoubtedly, however, the need continues for surveillance and assessment of delayed human health effects from pesticide exposure.
    3.21.4) ANIMAL STUDIES
    A) SPECIFIC AGENT
    1) DDT - has demonstrated significant liver, lymphatic, and lung neoplastic activity in rodents (Sharp et al, 1986).
    a) In mice, DDT has been reported to cause leukemia, lymphomas, and lung neoplasms (Terjan & Kemeny, 1969; IARC, 1982).
    2) Endrin, lindane, dieldrin, aldrin, kepone, toxaphene, and chlordane induced neoplasms of the liver, as well as carcinomas and sarcomas in other organs, in rats, and induced high incidences of carcinoma of the liver in mice (Reuber, 1987; NCI, 1979).
    3) HEPTACHLOR: In a chronic rat and mouse feeding study, heptachlor was hepatocarcinogenic at higher doses in mice, but not in rats. Heptachlor induced a statistically significant increase in proliferative lesions of thyroid follicular cells in rats (NCI, 1977).
    4) CHLORDANE: A 24-month tumorigenicity and chronic toxicity study in mice found no evidence that chlordane induced tumors in ICR mice (Khasawinah & Grutsch, 1989).
    5) HEXACHLOROBENZENE: Rat studies have shown dose-related increase in pituitary and subcutaneous tumors, which were the most commonly seen. Also seen were parathyroid adenomas, adrenal pheochromocytoma, cortical adenomas, and neoplastic liver nodules (Arnold & Krewski, 1988).
    6) ORGANOCHLORINE COMPOUNDS (p,p'-DDT, PCBs): may have a role in the development of exocrine pancreatic cancer in humans (Porta et al, 1999). The authors suggested that further studies are required.

Genotoxicity

    A) Refer to specific chemicals in this group for genotoxicity data.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Blood chlorinated hydrocarbon levels are not clinically useful following acute exposure. For most compounds they reflect cumulative exposure over a period of months or years rather than recent exposure (Coye et al, 1986). Chlorinated hydrocarbons can be measured with gas chromatography, if needed for forensic documentation.
    2) BACKGROUND SERUM LEVELS: Serum concentrations of pesticide residues generally increased with age, with females having slightly lower concentrations than males (Stehr-Green et al, 1988; Frank et al, 1988).
    3) In one study it was concluded that adipose tissues and human milk reflected historical pesticide exposure (in particular organochlorine exposure), and blood appeared to be a better indicator of recent pesticide exposure (Frank et al, 1988).
    4) Obtain serum chemistries, renal function tests, liver enzymes, and complete blood count in patients who are symptomatic or those with deliberate or large exposures.
    5) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    4.1.3) URINE
    A) MONITORING
    1) Measurement of organic halogen compounds in urine is suggested as an indicator of exposure (Salkinoja-Salonen & Jokela, 1991). Sensitivity is as low as 1 microgram of organic halogen per 100 milliliters of urine.

Methods

    A) CHROMATOGRAPHY
    1) ORGANOCHLORINE PESTICIDES: There are excellent gas-liquid chromatographic methods for measuring organochlorine pesticides in serum at levels above and below those likely to be associated with acute poisoning.
    2) CHLORINATED HYDROCARBON PESTICIDES: A simplified, quantitative method for the determination of chlorinated hydrocarbon pesticides in serum by solid-phase extraction and capillary gas chromatography with electron capture detection has been described (Saady & Poklis, 1990).
    3) BROMOCYCLEN: A gas chromatographic (GC) method interfaced to a Mass Selective Detector (MSD) for determination of bromocyclen concentrations in various animal tissues has been used (Quick, 1992).
    4) ENDRIN: Gas chromatography coupled to mass spectrometry (GC/MS), described by Kintz et al (1992), was used to quantify endrin in biological fluids in a suicide case. Due to lack of significant UV absorption of endrin, HPLC combined with diode array would not be effective for quantification of endrin (Kintz et al, 1992).
    5) METHOXYCHLOR: Gas chromatography-mass spectrometry was used to quantify methoxychlor serum concentrations in an attempted suicide ingestion. The authors noted that methoxychlor is rapidly metabolized and eliminated from the body and should, therefore, be collected shortly after exposure (i.e., within 24 hours) (Thompson & Vorster, 2000).
    B) OTHER
    1) In the case of some organochlorines, sufficient information is presently available to judge whether a specific serum concentration is toxicologically significant. For other agents, experience is too limited to permit a definitive judgement.
    2) MONITORING HUMAN EXPOSURE: A method to measure organic halogen compounds in urine as an indicator of exposure has been described (Salkinoja-Salonen & Jokela, 1991).
    3) The advice of professionals having access to this type of information should be sought in evaluating blood organochlorine concentrations.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistently altered mental status, abnormal vital signs, or recurrent seizures should be admitted to an intensive care setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Adults who intentionally ingest one of these agents or any child with an ingestion should be referred to a healthcare facility. Patients with prolonged or repeated dermal applications or inhalational exposures should be referred to a healthcare facility if they become symptomatic.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) If patients are asymptomatic after 6 hours of observation, they can be discharged after appropriate psychiatric clearance.

Monitoring

    A) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    B) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    C) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    D) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) SUMMARY: Activated charcoal and orogastric lavage should be used with caution because of the risk of seizures and subsequent risk of pulmonary aspiration. These procedures should only be used in a patient who presents soon after an ingestion and who have adequate airway protection. If the ingestion was very recent and a liquid formulation, nasogastric suction of gastric contents can be considered.
    2) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    3) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) No specific laboratory markers can identify poisoning with a chlorinated hydrocarbon pesticide.
    2) Obtain serum chemistries, renal function tests, liver enzymes, complete blood count, and urinalysis in patients who are symptomatic or those with deliberate or large exposures.
    3) Obtain creatinine kinase in patients with recurrent seizures or prolonged coma.
    4) Serum or urine concentrations can be obtained to confirm exposure, but will not be useful to guide therapy.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    7) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).
    8) In one series of 18 cases of endosulfan poisoning, hydantoins were not effective in controlling seizures, but phenobarbitone was (Chugh et al, 1998).
    C) CONTRAINDICATED TREATMENT
    1) Do NOT give oils by mouth. They tend to increase intestinal absorption of these lipophilic toxicants.
    2) Do NOT administer adrenergic amines, which further increase myocardial irritability and produce refractory ventricular arrhythmias (Dreisbach, 1983; Bryson, 1986).
    D) CHOLESTYRAMINE
    1) Cholestyramine (4 grams every 8 hours) accelerated excretion of kepone and chlordane in excessively exposed workers, and probably would have a similar effect on other slowly excreted organochlorines which are trapped in the enterohepatic circulation (Cohn et al, 1978) Garrettson et al, 1984, 1985; (Boylan et al, 1978).
    E) PULMONARY ASPIRATION
    1) Evaluate the patient for pulmonary complications, especially if the ingested product contained a petroleum solvent.
    F) EXPERIMENTAL THERAPY
    1) Peters et al (1982) report that symptoms of chronic exposure to hexachlorobenzene improved following treatment with intravenous and oral edetic acid therapy (Peters et al, 1982).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. Rescue personnel and bystanders should avoid direct contact with contaminated skin, clothing, or other objects (Burgess et al, 1999). Since contaminated leather items cannot be decontaminated, they should be discarded (Simpson & Schuman, 2002).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) HEMODIALYSIS has not been proven effective.
    2) HEMOPERFUSION: Effectiveness not been determined due to limited experience.
    3) Exchange transfusion, extracorporeal, and peritoneal dialysis have not proven effective in management of these poisonings. There has been little or no experience with charcoal hemoperfusion in organochlorine poisonings.

Abstracts

Case Reports

    A) SPECIFIC AGENT
    1) ENDRIN: Runhaar et al (1985) reported that a 49-year-old man ingested 60 mL of Endrex (containing 12 g of endrin dissolved in aromatic hydrocarbons-Shellsol A). The ingestion caused seizures which persisted for 4 days, hypersalivation, hyperthermia, renal insufficiency, thrombocytopenia and recurrent hypotension. Death followed after 11 days, due to pulmonary complications (infection and hemorrhage) and hypoxemia causing bradycardia and cardiac arrest (Runhaar et al, 1985).
    2) TOXAPHENE: Wells & Milhorn (1983) reported one case of Tox-Sol(R) (toxaphene, major component) ingestion. The patient was in status epilepticus which resolved by the next day (Wells & Milhorn, 1983).
    3) CHLORDECONE: Taylor (1985) reported that twenty-three workers chronically exposed to chlordecone developed overt neurologic manifestations, including postural and intention tremor, gait difficulty, and opsoclonus (Taylor, 1985).
    a) Blood levels of chlordecone ranged from 2 to 33 ppm. A low sperm count was also noted at 33 ppm. Absorption sites are uncertain in the workers because they were exposed by way of skin, gastrointestinal tract, and lungs. The manifestations slowly cleared in all but one worker (no apparent explanation).
    B) ROUTE OF EXPOSURE
    1) INJECTION: Goldberg et al (1982) reported 2 cases of patients who injected (subcutaneously and intravenously) commercially available household spray insecticides and presented with a chemical cellulitis and abscess at and around the injection site (Goldberg et al, 1982).
    a) The commercially available household insecticides contain chlorinated hydrocarbons, piperonyl butoxide, pyrethrins, carbamates, and hydrocarbons (petroleum distillates).

Range Of Toxicity

Summary

    A) The toxic dose varies by compound and is not well established for humans. For example, endrin, chlordane, and toxaphene are believed to have the highest hazard potential. Kepone, endosulfan, hepatachlor, mirex, and DDT are believed to have intermediate hazard potential. Methoxychlor and perthane are believed to have the lowest hazard potential.
    B) An adult died after ingesting 100 mL of endosulfan.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) ENDOSULFAN
    a) CASE REPORT: A 48-year-old male ingested 100 milliliters of endosulfan and developed almost immediate seizure activity that was unresponsive to treatment. The EEG showed status epilepticus(Boereboom et al, 1998). On hospital day 4, the patient died of cerebral herniation.
    2) METHOXYCHLOR
    a) The estimated lethal dose of methoxychlor is approximately 6400 milligrams/kilogram for humans (Thompson & Vorster, 2000).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxic doses of these compounds vary enormously with route and rate of absorption. Based on reports of poisonings and laboratory studies, their acute hazard potentials may be ranked approximately as follows:
    a) HIGHEST: Endrin, dieldrin, aldrin, chlordane, toxaphene
    b) INTERMEDIATE: Kepone, endosulfan, heptachlor, mirex, DDT
    c) LOWEST: Methoxychlor, perthane, kelthane, chlorobenzilate, hexachlorobenzene. (NOTE - Despite many years of use, acute human poisonings by the compounds listed in the "lowest" category have been extremely rare).
    B) SPECIFIC SUBSTANCE
    1) ENDOSULFAN: A 20-year-old survived an ingestion of approximately 200 milliliters of 30 percent endosulfan. At one year follow-up his mentation was severely impaired and he required carbamazepine to prevent seizures (Shemesh et al, 1988).
    2) HEPTACHLOR: No acute and/or subacute hepatic effects were noted in a study of 45 dairy farm family members who had consumed raw milk products contaminated with heptachlor residues at concentrations as high as 89.2 parts per million when compared with 94 unexposed persons in the same geographic area (Stehr-Green et al, 1988a). Some related compounds are neurotoxins. This study did not evaluate exposed dairy farm families for neurotoxicity.
    3) METHOXYCHLOR: A 62-year-old male (95 kg) ingested approximately 100 to 150 milliliters of a product that contained 120 milligrams/liter of methoxychlor and was found unresponsive and severely hypotensive (58/40 mmHg). The patient was given IV fluids and became more alert. Neurological activity following treatment included hypertonic lower extremities; however, no long-term sequelae was reported (Thompson & Vorster, 2000).
    4) ORTHODICHLOROBENZENE: Eye irritation is noticeable at concentrations of 25 to 30 parts per million and painful at 60 to 100 parts per million. Workers exposed to 1 to 44 (mean 15) parts per million showed no harmful effects (Hollingsworth, 1956).
    5) OTHER: There have been no cases of toxicity in humans from ingestion of chlorobenzilate, chloropropylate, or isopropyl-4,4-dibromobenzilate (Prod Info Acaraben(R), Acaralate(R), and Acarol(R), 1972).
    C) ANIMAL DATA
    1) CHLORDANE
    a) Khasawinah & Grutsch (1989) reported a long-term no-observed-effect level (NOEL) of 1 part per million chlordane in diet from a 24-month tumorigenicity and chronic toxicity study in mice (Khasawinah & Grutsch, 1989).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) ENDRIN - Postmortem blood concentration of 544.9 milligrams/liter was measured by GC/MS analysis in a 21-year-old female following an ingestion of endrin in a xylene solvent (Kintz et al, 1992).
    b) HEPTACHLOR - The mean levels of heptachlor epoxide and oxychlordane were 0.84 +/- 1 and 0.71 +/- 0.8 part per billion, respectively, in a group of 45 dairy farm family members who had consumed raw milk products known to be contaminated with residues of heptachlor at concentrations as high as 89.2 parts per million (Stehr-Green et al, 1988a).
    c) METHOXYCHLOR - A serum concentration (at time of admission) of 0.67 micrograms/milliliter of methoxychlor was reported in a 62-year-old male who was found unconscious following ingestion of between 100 to 150 milliliters of a product containing 120 milligrams/liter methoxychlor. The patient made a complete recovery (Thompson & Vorster, 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS143-50-0 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS143-50-0 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Kepone
    2) REL:
    a) TWA: 0.001 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Ca) NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix A
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS143-50-0 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): B2 ; Listed as: Chlordecone (Kepone)
    a) B2 : Probable human carcinogen - based on sufficient evidence of carcinogenicity in animals.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 2B ; Listed as: Chlordecone (Kepone)
    a) 2B : The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Ca ; Listed as: Kepone
    a) Ca : NIOSH considers this substance to be a potential occupational carcinogen (See Appendix A in the NIOSH Pocket Guide to Chemical Hazards).
    5) MAK (DFG, 2002): Category 3B ; Listed as: Chlordecone (Kepone)
    a) Category 3B : Substances for which in vitro or animal studies have yielded evidence of carcinogenic effects that is not sufficient for classification of the substance in one of the other categories. Further studies are required before a final decision can be made. A MAK value can be established provided no genotoxic effects have been detected. (Footnote: In the past, when a substance was classified as Category 3 it was given a MAK value provided that it had no detectable genotoxic effects. When all such substances have been examined for whether or not they may be classified in Category 4, this sentence may be omitted.)
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): R ; Listed as: Kepone (Chlordecone)
    a) R : RAHC = Reasonably anticipated to be a human carcinogen

    D) OSHA PEL Values for CAS143-50-0 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) DIELDRIN-
    1) LD50- (ORAL)MOUSE:
    a) 38 mg/kg (RTECS, 2000)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 35 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 38300 mcg/kg (RTECS, 2000)
    4) LD50- (SKIN)RAT:
    a) 56 mg/kg (RTECS, 2000)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) 49 mg/kg (RTECS, 2000)
    B) ENDOSULFAN-
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 7 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 7360 mcg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 18 mg/kg (RTECS, 2000)
    4) LD50- (SKIN)RAT:
    a) 34 mg/kg (RTECS, 2000)
    C) METHOXYCHLOR-
    D) TOXAPHENE-
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 42 mg/kg (RTECS, 2000)
    2) LD50- (ORAL)MOUSE:
    a) 112 mg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 50 mg/kg (RTECS, 2000)
    4) LD50- (SKIN)RAT:
    a) 600 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Toxicologic Mechanism

    A) The principal neurotoxic action of these compounds is that of "axon poison," affecting primarily the CNS nerve cells. Essentially, the organochlorines interfere with the normal flux of Na+ and K+ ions across the axon membrane as nerve impulses pass. This results in irritability, altered mental status, dysesthesias, and seizures (Morgan, 1982).
    1) Effects of DDT include lengthening the time the sodium channel is open, thus affecting sodium conductance (reviewed in Goldfrank, 1994).
    B) Depression of the medullary respiratory center drive often occurs concurrently, leading to asphyxia. Depending on dosage, these effects may be fatal, or entirely reversible within minutes or hours.
    C) The organochlorines do not affect cholinesterase enzymes.
    D) An important property of the chlorinated hydrocarbons, particularly toxaphene, chlordane, DDT, and lindane is their capacity to induce the drug-metabolizing enzymes of the liver (Wells & Milhorn, 1985; Garretson et al, 1984-1985; (Klaasen, 1985).
    1) Evidence suggests an important role of benzoquinones in the hepatotoxicity of chlorinated hydrocarbons as opposed to traditional epoxides. Cytochrome P-450 appears to be associated with covalent protein binding of reactive metabolites (den Besten et al, 1994).
    E) Chronic hexachlorobenzene exposure can cause porphyria cutanea tarda and may be unique property of this compound, among the organochlorines. Metabolic activation appears to be involved in porphyria, but reactive benzoquinones appear not to be involved in porphyria (den Besten et al, 1994).
    F) The neurotoxic mechanism of endosulfan involves inhibition of the calmodulin-dependent Ca2+ -ATPase activity, alterations in the serotoninergic system, and inhibition of GABA receptors (Blanco-Coronado et al, 1992).

Physicochemical

Physical Characteristics

    A) These compounds typically posses a strong penetrating odor.

Molecular Weight

    A) Hexachlorobenzene: 284.80
    B) Orthodichlorobenzene: 147.01

Animal Toxicology

Clinical Effects

    11.1.1) AVIAN/BIRD
    A) RAPTORS - Emaciation, tonic-clonic seizures, anemia, abnormal posture, and inability to stand have been noted in Great Horned Owls from acute organochlorine poisoning (Porter & Snead, 1990). Owls may appear to be blind; pupils may react to light.
    B) PIGEON & LOVE BIRDS - Topical organochlorine poisoning resulted in staggering, dullness, and death (Quick, 1992).
    11.1.2) BOVINE/CATTLE
    A) Calves poisoned from aldrin contamination of their food exhibited sudden onset of neurologic dysfunctions, including ataxia, tremors, hypersalivation, diarrhea, disorientation, lateral recumbency, and intermittent tonoclonic seizures (Casteel et al, 1993).
    11.1.3) CANINE/DOG
    A) Dogs may demonstrate extreme agitation and apprehension, vomiting, and diarrhea. Mucous membranes may appear brick-red in color (Staley & Edwards, 1990).
    11.1.6) FELINE/CAT
    A) Apprehension, belligerence, hyperesthesia, hypersalivation, vomiting, diarrhea, seizures, and death may occur immediately or several weeks following exposure (Staley & Edwards, 1990; Boothe, 1990).
    B) Respiratory distress, seizures, and death have occurred in a Persian cat treated topically for ectoparasites with an organohalogen (bromocyclen) dusting powder (Quick, 1992).
    11.1.11) REPTILE
    A) REPTILE
    1) INDIAN PYTHON - Three days after topical treatment with bromocyclen for mites, an Indian python developed aggressive fits and was ill for 3 weeks before dying (Quick, 1992).
    11.1.13) OTHER
    A) OTHER
    1) SIGNS - CNS stimulation, violent excitation, muscle fasciculations, and cranial to caudal seizures.
    2) GUINEA PIG - Two guinea pigs developed hyperexcitability one week after topical treatment with bromocyclen for mites. Both subsequently died (Quick, 1992).

Treatment

    11.2.1) SUMMARY
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water.
    11.2.2) LIFE SUPPORT
    A) GENERAL
    1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.
    11.2.4) DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) Induce emesis with Syrup of Ipecac, 10 to 30 mL orally or hydrogen peroxide 5 to 25 mL orally repeated in 5 to 10 minutes if there is no response. DOGS ONLY may receive apomorphine 0.05 to 0.10 mg/kg IV, IM, or subcutaneously.
    b) Gastric lavage may be performed using tap water or normal saline.
    c) Administer activated charcoal, 5 to 50 grams, orally, as a slurry in water.
    d) Then administer Milk of Magnesia 1 to 15 mL orally, mineral oil 2 to 15 mL orally, sodium sulfate 20%, 2 to 25 grams orally or magnesium sulfate 20% 2 to 25 grams orally, for catharsis.
    2) LARGE ANIMALS
    a) Give 250 to 500 grams of activated charcoal in a water slurry, orally, to adsorb the toxic agent.
    b) Administer an oral cathartic: mineral oil (1 to 3 liters), 20% sodium sulfate (25 to 10,000 grams), 20% magnesium sulfate (25 to 1,000 grams), or milk of magnesia (20 to 30 mL).
    c) Ruminants (cattle and sheep) cannot be made to vomit. Horses should not be made to vomit.
    11.2.5) TREATMENT
    A) SMALL ANIMALS
    1) Induce emesis or gastric lavage. Administer activated charcoal. Use pentobarbital to control seizures. Give 10% calcium gluconate 5 to 50 mL IV, slowly.
    2) Clinical improvement was rapid in two dogs administered two treatments of cholestyramine 9 grams once daily beginning on the third day after exposure to chlordane. Symptomatic treatment consisting of subcutaneous atropine sulfate, IV fluids, and oral activated charcoal twice daily controlled the signs only temporarily during the first two days after exposure (Staley & Edwards, 1990).
    3) Place small animal in a quiet environment and ensure adequate renal function since chlorinated hydrocarbon insecticide products are excreted primarily through the urine (Boothe, 1990).
    B) LARGE ANIMALS
    1) Barbiturates or chloral hydrate to control seizures. Administer a saline cathartic. Administer activated charcoal, 1 kg daily, to absorb and reduce residues. For external exposure, decontaminate thoroughly with soap and water.
    C) RAPTOR
    1) Treatment of chlorinated hydrocarbon insecticide poisoning is supportive (Porter & Snead, 1990).
    2) Administer intravenous fluids, oral hyperalimentation formula, and B-complex (Porter & Snead, 1990).
    3) Transfusion may be necessary to manage anemia. Benzodiazepines or barbiturates are used to control seizures.
    4) The effectiveness of cholestyramine has not been tested in birds.
    D) POULTRY
    1) CHICKENS - The body burden of hexachlorobenzene in chickens has been shown to decrease significantly when treated with 5% mineral oil or 5% colestipol added to chicken feed and fed as desired (Polin et al, 1986).

Range Of Toxicity

    11.3.1) THERAPEUTIC DOSE
    A) CAT
    1) Use of chlorinated hydrocarbon insecticides are not recommended in cats (Boothe, 1990).
    11.3.2) MINIMAL TOXIC DOSE
    A) LACK OF INFORMATION
    1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

    11.4.1) SUMMARY
    11.4.1.2) DECONTAMINATION/TREATMENT
    A) GENERAL TREATMENT
    1) Begin treatment immediately.
    2) Keep animal warm.
    3) Sample vomitus, blood, urine, and feces for analysis.
    4) If skin exposure has occurred, wash animal thoroughly with a mild detergent and flush with copious amounts of water.
    11.4.2) DECONTAMINATION
    11.4.2.2) GASTRIC DECONTAMINATION
    A) GASTRIC DECONTAMINATION
    1) SMALL ANIMALS
    a) Induce emesis with Syrup of Ipecac, 10 to 30 mL orally or hydrogen peroxide 5 to 25 mL orally repeated in 5 to 10 minutes if there is no response. DOGS ONLY may receive apomorphine 0.05 to 0.10 mg/kg IV, IM, or subcutaneously.
    b) Gastric lavage may be performed using tap water or normal saline.
    c) Administer activated charcoal, 5 to 50 grams, orally, as a slurry in water.
    d) Then administer Milk of Magnesia 1 to 15 mL orally, mineral oil 2 to 15 mL orally, sodium sulfate 20%, 2 to 25 grams orally or magnesium sulfate 20% 2 to 25 grams orally, for catharsis.
    2) LARGE ANIMALS
    a) Give 250 to 500 grams of activated charcoal in a water slurry, orally, to adsorb the toxic agent.
    b) Administer an oral cathartic: mineral oil (1 to 3 liters), 20% sodium sulfate (25 to 10,000 grams), 20% magnesium sulfate (25 to 1,000 grams), or milk of magnesia (20 to 30 mL).
    c) Ruminants (cattle and sheep) cannot be made to vomit. Horses should not be made to vomit.

Kinetics

    11.5.1) ABSORPTION
    A) LACK OF INFORMATION
    1) There was no specific information on absorption at the time of this review.
    11.5.3) METABOLISM
    A) SPECIFIC TOXIN
    1) ALDRIN
    a) Aldrin is biotransformed in cattle to dieldrin, which is stored in adipose tissues. Dieldrin in fat is slowly biotransformed to hydroxydieldrin, which can be conjugated and excreted in urine (Casteel et al, 1993).
    11.5.4) ELIMINATION
    A) RUMINANT
    1) Ovines eliminate heptachlor more rapidly than bovines (Smith et al, 1989).
    2) The biological half-life of dieldrin in adipose tissue of heifers and steers is approximately 85 and 245 days, respectively (Casteel et al, 1993).

Other

    A) OTHER
    1) GENERAL
    a) LABORATORY
    1) Definitive diagnosis of chlorinated hydrocarbon insecticide toxicity is made postmortem. Findings are non-specific except for emaciation (Porter & Snead, 1990).
    2) Submit tissues for analysis by gas chromatography (Porter & Snead, 1990).

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