Organochlorine Pesticide Toxicity

Chlorinated hydrocarbons can be highly toxic, and the overwhelming majority have been universally banned because of their unacceptably slow degradation and subsequent bioaccumulation and toxicity. ^[2]  Among the more notable examples is dichlorodiphenyltrichloroethane (DDT). The synthesis of DDT by the Swiss chemist Paul Müller in the late 1930s, and the subsequent demonstration of its effectiveness as an insecticide, won Müller the 1948 Nobel Prize in Physiology or Medicine, ^[3]   but DDT was banned in the United States in 1972. ^[4]

Organochlorines can be separated into 5 groups, as follows:

• DDT and analogues (eg, dicofol, methoxychlor)
• Hexachlorocyclohexane (ie, benzene hexachloride) and isomers (eg, lindane, gamma-hexachlorocyclohexane)
• Cyclodienes (eg, endosulfan, chlordane, heptachlor, aldrin, dieldrin, endrin, isobenzan)
• Chlordecone, kelevan, and mirex
• Toxaphene

Organochlorines are well absorbed orally and by inhalation. Transdermal absorption is variable. For example, DDT is poorly absorbed transdermally, whereas cyclodienes have significant transdermal absorption rates. ^[5] Cyclodienes have high absorption levels when taken orally, as in the case of food contamination with these pesticides. ^[6] Lindane is known to be absorbed after topical application, but oral ingestions are not rare. ^[7] Young age, malnourishment, and frequent exposure increases the risk for toxicity. ^[8]

Organic chlorines are strongly lipid soluble and sequester in body tissues with high lipid content, such as the brain and liver. Consequently, blood levels tend to be much lower than fatty tissue levels. ^[5] The lipophilic tendency of organochlorines accounts for prolonged systemic effects in overdose. The half-life of DDT has been measured in months or years, whereas other organic chlorines are metabolized faster; for example, lindane has a half-life of 21 hours. ^[9]

Mechanism of toxicity

Toxicity in humans is largely due to stimulation of the CNS. Cyclodienes, hexachlorocyclohexanes, and toxaphene predominantly are gamma aminobenzoic acid (GABA) antagonists and inhibit calcium ion influx, but also may inhibit calcium and magnesium adenosine triphosphatase (ATPase). The resulting accumulation of calcium ions at neuronal endplates causes sustained release of excitatory neurotransmitters. ^{[10, 11]}

DDT affects potassium and voltage-dependent sodium channels. These changes can result in agitation, confusion, and seizures. Cardiac effects have been attributed to sensitization of the myocardium to circulating catecholamines.

Some of the more volatile organochlorines can be inhaled while in vapor form or swallowed while in liquid form. Inhalation of toxic vapors or aspiration of liquid after ingestion may lead to atelectasis, bronchospasm, hypoxia, and a chemical pneumonitis. In severe cases, this can lead to acute lung injury, hemorrhage, and necrosis of lung tissue. In liquid form, they are easily absorbed through the skin and GI tract.

Highly toxic organochlorines include:

• Aldrin
• Dieldrin ^[12]
• Endrin ^[13]
• Endosulfan ^{[14, 15]}

Moderately toxic organochlorines include:

• Chlordane
• DDT
• Heptachlor
• Kepone
• Lindane
• Mirex
• Toxaphene

Organochlorine pesticides are now only rarely used in the developed world, and domestic poisonings have become correspondingly rare. Lindane is still used as a second-line topical prescription treatment for head lice and scabies. Adults are most likely to have serious intentional poisonings, and children are most likely to have unintentional poisonings.

The 2020 Annual Report of the American Association of Poison Control Centers' National Poison Data System lists pesticide exposure as the eleventh most common substance involved in human exposures in the United States. ^[16] In 2020, 70,831 single pesticide exposures were reported; 138 single explosure to chlorinated hydrocarbon insecticides and an additional 75 single exposures in combination with other insecticides were reported; 22 cases had a moderate or major effect outcome but no deaths were reported. ^[16]

Acute poisoning and fatality caused by organochlorine exposure is rare. DDT was banned by the US Environmental Protection Agency (EPA) in 1972. The EPA and manufacturers of organochlorine pesticides agreed to halt sales of organochlorine pesticides in 1987 after a partial ban in 1976. ^[4] All use of toxaphene was banned in 1990.

Despite a ban on sales, organochlorines may still be found in storage in the United States; thus, exposure is still possible. Toxaphene can be transported in the air at long distances and can persist in air, soil, and water for years.

Although widespread use of organochlorine insecticides has been banned in North America and Europe, these chemicals are used extensively in many developing nations, for example, DDT is still in indoor use in malaria-afflicted areas. ^[4] Organochlorine poisoning accounts for only a small fraction of pesticide poisoning, but the incidence varies from 1.8% of all poisonings in South Korea to 13.3% in some parts of India. ^{[17, 18]} A study of contamination in the Brazilian population showed adverse effects on hematopoietic tissue and the liver. ^[19]

The prognosis in patients exposed to organochlorine compounds depends on the amount and type of exposure. Pulmonary fibrosis can occur after significant aspiration. Acute respiratory distress syndrome (ARDS) may develop.

Toxic doses widely vary. The fatal dose in humans is unknown; data from nonfatal cases suggest that a dose of approximately 10 mg/kg can cause convulsions. An oral median lethal dose (LD50) is higher than 50 mg/kg in animal studies. The estimated approximate minimum lethal dose for humans is 2-7 g. With adequate decontamination and supportive care, patients generally recover from acute exposure to their previous functional level.

Studies have suggested a long-term risk of cancer ^{[20, 21]} , type 2 diabetes ^[22] and neurodegenerative diseases. ^{[23, 24]} However, these risks are more attributable to chronic exposure.  Analysis of National Health and Nutrition Examination Surveys (NHANES) data did find that higher exposure to beta-hexachlorocyclohexane is associated with increased all-cause mortality and higher exposure to four other organochlorine pesticides is associated with increased non-cancer, non-heart/cerebrovascular disease mortality in US adults 60 years or older. ^[25]  

Toxaphene interferes directly or indirectly with fertility and reproduction in rodents (testicular degeneration and endocrine changes). Toxaphene is teratogenic in mice and rats at doses that result in overt maternal toxicity. Also, tumors arise in the liver (eg, hepatomas) and renal tubules of chronically exposed animals.

Refer patients and their families to public health authorities for education regarding the use, storage, and proper disposal of pesticides. Educate patients about proper medical discharge instructions regarding acute and potential chronic signs and symptoms that are observed in toxaphene and organochlorine toxicity. Document this education.

Discuss possible long-term risk of breast cancer with female patients. Organochlorine pesticides and metabolites accumulate in breast tissue and milk. An experienced laboratory should analyze breast milk of pregnant or lactating women for toxic organochlorines, associated product contaminants, and their metabolites. ^[26]

For unknown pesticide exposures, information is available at the Extension Toxicology Network (EXTOX-NET). The National Pesticide Information Center is available 9:30 am to 7:30 pm Eastern Standard Time at 1-800-858-7378.

For patient education resources, see Pesticides and Child Safety Proofing.