Lindane

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Lindane
Systematic (IUPAC) name
1,2,3,4,5,6-hexachlorocyclohexane
Identifiers
CAS number	58-89-9
ATC code	P03AB02
PubChem	727
DrugBank	APRD01072
Chemical data
Formula	C6H6Cl6
Mol. mass	290.828 g/mol
Pharmacokinetic data
Bioavailability	?
Protein binding	91%
Metabolism	Hepatic cytochrome P-450 oxygenase system
Half life	18 hours
Excretion	?
Therapeutic considerations
Pregnancy cat.	C
Legal status	FDA-approved for the second-line treatment of scabies, pubic lice (crabs) and head lice
Routes	Topical

Lindane, also known as gamma-hexachlorocyclohexane (γ-HCH), benzene hexachloride (BHC), and Gammallin, is an organochlorine insecticide that has been used in agriculture and as a treatment for headlice and scabies.

Lindane is a neurotoxin that interferes with GABA neurotransmitter function by interacting with the GABA_A receptor-chloride channel complex at the picrotoxin binding site. It has an oral LD₅₀ of 88 mg/kg in rats and a dermal LD₅₀ of 1000 mg/kg. In humans, lindane primarily affects the nervous system, liver and kidneys, and may be a carcinogen and/or endocrine disruptor.^[1][2]

The World Health Organization classifies lindane as "Moderately Hazardous," and its international trade is restricted and regulated under the Rotterdam Convention on Prior Informed Consent.^[3] It is presently banned in more than 50 countries, and is being considered for inclusion in the Stockholm Convention on persistent organic pollutants, which would ban its production and use worldwide.

Contents 1 History 1.1 Lindane medications 2 Human health effects 2.1 Cancer risk 2.2 Adverse reactions to lindane pharmaceuticals 3 Environmental contamination 4 Non-gamma isomers 5 Regulatory status 6 Morton Grove lawsuit 7 See also 8 References 9 External links 9.1 Toxicology links

[edit] History

In the 1940s, lindane was registered as an agricultural insecticide with the U.S. Department of Agriculture (USDA), and in 1951 it was approved by the U.S. Food and Drug Administration (FDA) for medical use in the treatment of scabies and lice. Since this time, the vast majority of lindane use―more than 99%―has been in agriculture and much of the safety and environmental concerns have related to this application.^[4][5]

In 2006, the U.S. Environmental Protection Agency (EPA) called for the voluntary cancellation of all agricultural uses of lindane, which in recent years had already been limited to pre-planting seed treatments.^[6] Lindane remains registered with the FDA, which has concluded that lindane medications provide public health benefits at an acceptable level of risk, stating that “The risk of occupational/environmental exposure should be assessed separately and independent of the risk related to the therapeutic use of a medication to treat a medical condition where there is direct benefit to the patient.”^[7] Canada and other countries have similarly allowed lindane to remain available as a prescription drug even though they no longer permit its broader use in agricultural.

[edit] Lindane medications

Lindane is available by prescription only, and since 1995 it has been designated a "second-line" treatment, meaning it should be used only when other "first-line" treatments have failed.^[7][8][9] The efficacy of lindane has decreased in recent years because of increasing resistance, and lindane is generally not as effective as other treatments or as safe.^[10][11]

In December 2007, the FDA sent a warning letter to Morton Grove Pharmaceuticals, Inc. (the sole U.S. manufacturer of lindane products)^[12] requesting that the company correct misleading advertising information it had distributed. The letter said, in part, that the materials "are misleading in that they omit and/or minimize the most serious and important risk information associated with the use of Lindane Shampoo, particularly in pediatric patients; include a misleading dosing claim; and overstate the efficacy of Lindane Shampoo."^[13]

The State of California banned the pharmaceutical use of lindane, effective 2002, and a bill has been introduced in the Michigan legislature that would restrict its use there.^[14] A recent analysis of the California ban concluded that a majority of pediatricians had not experienced problems treating lice or scabies since that ban took effect. The study also documented a marked decrease in lindane wastewater contamination and a dramatic decline in lindane poisoning incidents reported to Poison Control Centers. The authors concluded that "The California experience suggests elimination of pharmaceutical lindane produced environmental benefits, was associated with a reduction in reported unintentional exposures and did not adversely affect head lice and scabies treatment."^[15]

[edit] Human health effects

Most of the adverse human health effects reported for lindane have been related to agricultural uses and chronic, occupational exposure of seed treatment workers to agricultural-grade lindane.^[16]

Exposure to large amounts of lindane can harm the nervous system, producing a range of symptoms from headache and dizziness to seizures, convulsions and more rarely death.^[1] Adverse hematologic effects have also been reported with chronic occupational exposures and excessive dermal applications; however, a direct cause and effect has not been established.^[1] Vomiting and nausea are usual symptoms associated with oral ingestions of lindane but serious neurologic effects can occur, albeit less frequently.^[1][17] The most common side effects with topical use of lindane medications are nonserious reactions of the skin, including burning, itching, dryness and rash.^[18] Lindane has not been shown to alter immunocompetence in humans and is not considered to be genotoxic.^[1] Prenatal exposure to β-HCH, an isomer of lindane and production byproduct, has been associated with altered thyroid hormone levels and could effect brain development.^[19]

[edit] Cancer risk

Based primarily on evidence from animal studies, most evaluations of the carcinogenicity of lindane have concluded that lindane might cause cancer. For example, in 1987 the International Agency for Research on Cancer (IARC) classified lindane as a possible human carcinogen.^[20] In 2001, the EPA concluded there was “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential,”^[21] and the U.S. Department of Health and Human Services determined that all isomers of hexachlorocyclohexane, including lindane, "may reasonably be anticipated to cause cancer in humans."^[1] However, the World Health Organization concluded in 2004 that “lindane is not likely to pose a carcinogenic risk to humans.”^[22]

Studies of the carcinogenic effects of lindane in humans have been inconclusive and often limited by study design and no major carcinogenic effects have been noted in human studies to date.^[1] For example, a meta-analysis of studies looking at the association between occupational exposure to agricultural lindane and non-Hodgkin’s lymphoma among U.S. farmers found that lindane was not a primary factor in the development of the disease.^[23] The majority of studies of the general population have also shown no association between serum or breast tissue levels of lindane and breast cancer.^[1][22] Similarly, no increased cancer risk was noted in a large epidemiologic study of lindane medications involving a 143,594-patient database with up to 21 years of follow up, which concluded that “There is still no persuasive evidence from studies of humans that lindane, as ordinarily used clinically, is carcinogenic in humans.” ^[24]

[edit] Adverse reactions to lindane pharmaceuticals

While adverse reactions can occur with use of low-dose topical pharmaceutical formulations, serious effects are rare and have most often resulted from the misuse of medication.^{[7][25][26][27]}

The most common side effects associated with topical use of lindane medications are nonserious reactions of the skin, including burning, itching, dryness and rash.^[18] Central nervous system stimulation ranging from dizziness to seizures to death has also been reported, although these serious effects have almost always resulted from misuse of medication (e.g., repeated treatments, prolonged applications, or oral ingestion).^[27] However, on rare occasions, seizures and even more rarely fatalities have been reported when lindane medications were used according to directions.^[7][25][26]

In 2003, the FDA published a safety analysis of adverse events reported in association with the use of lindane medications received through its adverse event monitoring system (“AERS” database) between from 1974 through 2002.^[27] The vast majority (85%) of these reports―488 total―were classified as nonserious, while serious events most often resulted from product misuse (80% of serious cases). The most common reports to the FDA were "drug ineffective," followed by convulsions, dermatitis and dizziness. (Note: These events represent the most common reported to the FDA and do not represent the most common events associated with the use of lindane lotion and lindane shampoo overall).

A review of the most serious cases described 15 deaths of which two were confirmed related to lindane misuse including a suicidal ingestion. The direct causes of death for the other cases were attributed to reasons other than lindane. In addition, there were 46 hospitalizations, and seven life-threatening outcomes—five from the same household. Six cases of congenital anomaly were also described–five for infants "possibly" exposed to lindane in utero and one paternal exposure—but no characteristic pattern of effect was noted.^[7][27]

In all age groups, reported adverse events occurred mainly in patients with contraindications to the use of lindane or in those who appeared to have misapplied or orally ingested medication.^[7]

Based on these findings, lindane lotion and lindane shampoo were limited to small unit-dose bottles in 2003 by the FDA to mitigate the risk of misuse and further enhance product safety. At the same time, a boxed warning was added to the prescription label to highlight to healthcare providers appropriate use criteria and rare treatment risks. A medication guide, written in plain English, was also developed and is now required by law to be dispensed with every lindane prescription dispensed in the U.S. to better educate patients and caregivers on safe application technique.^[7][28] When used properly, lindane medications are safe and effective for the diseases they are approved. The most common side effects are nonserious reactions of the skin (e.g., burning, itching, dryness and rash).^[18]

The current FDA-approved product labeling emphasizes that lindane medications are contraindicated for use in premature infants and individuals with known uncontrolled seizure disorders and should be used with caution in infants, children, the elderly, and individuals with other skin conditions (e.g., atopic dermatitis, psoriasis) and in those who weigh less than 110 lbs (50 kg) as they may be at risk of serious neurotoxicity. It also notes that careful consideration should be given before prescribing lindane medications to patients with conditions that may increase the risk of seizure, such as HIV infection, history of head trauma or a prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, excessive use of alcohol, abrupt withdrawal from alcohol or sedatives, as well as concomitant use of medications known to lower seizure threshold.^[25][26]

[edit] Environmental contamination

The production and use of lindane in agricultural (both of which have declined significantly in the last 20 years) are the primary causes of environmental contamination,^[29] and levels of lindane in the environment have waned in the U.S. from 1986 through 2003, consistent with decreasing agricultural usage patterns.^[30] The production of lindane generates large amounts of waste hexachlorocyclohexane isomers, and it is estimated that "every ton of lindane manufactured produces about 9 tons of toxic waste."^[31]

Lindane is released into the environment during and after agricultural application through volatilization into the atmosphere (estimated at 12-30%), where it has long-range transport potential and can be deposited by rainfall. Lindane in soil can leach to surface and even ground water and can bioaccumulate in the food chain.^[6] Most exposure of the general population to lindane results from agricultural uses and the intake of contaminated foods, such as produce, meats and milk. Over time, lindane is broken down in soil, sediment and water into less harmful substances by algae, fungi and bacteria; however, the process is relatively slow and dependent on ambient environmental conditions.^[1] The ecological impact of lindane’s environmental persistence continues to be debated.^{[citation needed]}

The US EPA has determined that lindane does not contaminant drinking water in excess of the Agency's level of concern.^[1] In 2003, the EPA reported on the results of large-scale water contaminant testing of 16,000 water systems serving 100 million people across the U.S. and found that none contained lindane levels above the maximum contaminant level standard considered safe.^[32] Similar findings were noted by U.S. Geologic Survey teams in 1999 and 2000.^[33] More specifically, the EPA conducted “down-the-drain” estimates of the amount of lindane reaching public water supplies from the use of lindane medications using data from California water treatment facilities, concluding that lindane levels from pharmaceutical sources were “extremely low” and not of concern.^[5]

[edit] Non-gamma isomers

Larger than the issue of lindane toxicity are concerns related to the non-gamma isomers of HCH, namely alpha-HCH and beta-HCH, which are notably more toxic than lindane.^[1] Alpha- and beta-HCH were used agriculturally in the U.S. in the form of technical-grade HCH until 1976 and are also produced as manufacturing by-products but are void of insecticidal properties and have little to no use.^[1] In the 1940s and 1950s lindane producers stockpiled these isomers in open heaps, which led to ground and water contamination. The International HCH and Pesticide Forum has since been established to bring together experts to address the clean-up and containment of these sites.^[34] Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic industrial chemicals, a process known as “cracking.”^[30][34] Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs.^[4] Lindane has not been manufactured in the U.S. since the mid-1970s but continues to be imported and formulated for pharmaceutical use.

[edit] Regulatory status

As of November 2006, Lindane was banned in 52 countries, restricted in 33 countries, not registered in 10 countries, and registered in 17 countries.^[4][29] The latter includes the U.S. and Canada, which support public health uses of pharmaceutical lindane but no longer allow agricultural applications.^[4][6] It is banned in more than 50 countries and the state of California, and is under review for addition to the Stockholm Convention On Persistent Organic Pollutants.^[35][36] It is still used in agriculture in India,^[37] Nigeria,^[38] and elsewhere.

Canada’s Pest Management Regulatory Agency phased out of all agricultural uses of lindane between 2000 and 2005 due to concerns of chronic occupational exposure and risks to workers during seed treatment and planting. However, lindane medications remain available in Canada for public health purposes as non-prescription therapies.^[29] In 2002, the EPA concluded that lindane agricultural products were eligible for re-registration given industry compliance with certain data and labeling requirements to mitigate occupational risks to workers.^[5] However, in 2006, the Agency published an addendum to its initial decision and called for the voluntary cancellation of all agricultural uses by registered manufacturers (effective July 2007), citing a significant change in the costs and benefits of agricultural uses due to the recent introduction of seed-treatment alternatives to lindane. The EPA has approved the use of lindane stockpiles through 2009^{[citation needed]} Mexico has committed to a structured, voluntary phase out of lindane through the North American Regional Action Plan (NARAP) but currently authorizes agricultural, veterinary and healthcare uses.^[4]

There are currently bills pending in the New York and Michigan state legislatures that would further restrict its medical uses on children in the those states.^[39][14] Michigan passed the lindane bill through the House on 5/15/08.^[40]

[edit] Morton Grove lawsuit

In the face of negative publicity concerning its lindane pharmaceutical products, in July of 2006 Morton Grove Pharmaceuticals filed a lawsuit against the National Pediculosis Association, the Ecology Center, Inc., and two physicians, alleging that statements they made and disseminated to healthcare providers and consumers constituted defamation, tortious interference, trade disparagement, and deceptive trade practices. Morton Grove alleged more than $9.3 million in damages. The case pled that “[d]efendants swap agricultural and pharmaceutical research selectively quoting and/or misstating findings from studies relating to the agricultural use of lindane, and widely disseminate false, misleading, and defamatory statements about the safety profile and effectiveness of lindane.”^[41] The defendants considered the legal action to be SLAPP suit.

Morton Grove and the Ecology Center settled in February 2008. The settlement did not require the defendants to admit liability or make any payments to Morton Grove, but the Ecology Center did agree to clarify 7 of the statements it had published in its lindane factsheet.^[14][42][43]

In March 2008, Morton Grove re-filed its complaint against the National Pediculosis Association, seeking a permanent injunction and corrective advertising under the Lanham Act and companion Illinois' statutes. This case remains ongoing.^{[44][verification needed]}

[edit] See also

• Pesticide toxicity to bees

[edit] References

[edit] External links

• "Mom and Pros Tackle Lice" - NPR story
• FDA Information on Lindane
• EPA Information on Lindane
• World Health Organization Background Document on Lindane for Drinking-Water Quality Guidelines
• Pepsi and Coca-Cola - Lindane in drinks in India - news story
• India - Pesticides in Coke & Pepsi drinks - news story
• Lindane Chemistry and Uses
• Time for the FDA to ban Lindane
• Gamma Hexachlorocyclohexane Fact Sheet
• Morton Grove Pharmaceuticals homepage - US producer of Lindane Medications
• "Lindane Facts" - Website run by Morton Grove
• headlice.org - Website of the National Pediculosis Association
• Michigan Ecology Center website

[edit] Toxicology links

• PAN Pesticides Database: Lindane
• World Health Organization: Lindane (EHC 124)
• Agency for Toxics and Disease Registry: Toxicological Profile for Hexachlorocyclohexane

v • d • e Human lice and pediculosis Species Head louse · Crab louse · Body louse Infestation Pediculosis · Phthiriasis Treatment Treatment of human head lice · Nitpicking · Lindane · Permethrin · Delphinium Other terms of interest Cooties · Sucking louse · Louse

v • d • e Ectoparasiticides (P03) Sulfur-containing products Disulfiram Chlorine-containing products Lindane Pyrethrines, including synthetic compounds Pyrethrum · Phenothrin · Permethrin Other ectoparasiticides, including scabicides Benzyl benzoate · Malathion · Quassia