lindane

Lindane
Systematic (IUPAC) name
(1r,2R,3S,4r,5R,6S)-1,2,3,4,5,6-hexachlorocyclohexane
Identifiers
CAS number	58-89-9
ATC code	P03AB02 QP53AB02 QS02QA01
PubChem	727
DrugBank	APRD01072
ChemSpider	10481896
Chemical data
Formula	C6H6Cl6
Mol. mass	290.83 g/mol
SMILES	eMolecules & PubChem
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	Listed in 2009 under the Stockholm Convention on Persistent Organic Pollutants, which bans lindane in ratified countries, with a specific exemption for use of lindane as a human health pharmaceutical for the control of head lice and scabies as second-line treatment [1] In the U.S., pharmaceutical lindane FDA approved for second-line treatment of scabies and head lice; agricultural uses cancelled by the EPA in 2006 (use of stockpiles allowed through 2009) [2]
Routes	Topical
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Lindane, also known as gamma-hexachlorocyclohexane, (γ-HCH), gammaxene, Gammallin and erroneously known as benzene hexachloride (BHC),^[3] is an organochlorine chemical variant of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for infestations of lice and scabies.^[4]

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. In humans, lindane primarily affects the nervous system, liver and kidneys, and may be a carcinogen and/or endocrine disruptor.^[5][6]

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.^[7] It is presently banned in more than 50 countries, and in 2009 was included in the Stockholm Convention on persistent organic pollutants, which bans its production and use worldwide. ^[8]

History

In the United States, lindane pesticide products are regulated by the U.S. Environmental Protection Agency (EPA), while lindane-based medications are regulated by the Food and Drug Administration (FDA). In the 1940s, lindane was registered as an agricultural insecticide, and in 1951 it was approved 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.^[9][10]

In 2006, the 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.^[2] Lindane medications continue to be available in the US,^[11] and Canada and other countries have similarly banned agricultural use while allowing its use in medicine to continue.

Lindane medications

Lindane is a prescription topical treatment for head lice and scabies, and it is formulated as a shampoo and a lotion. Since 1995 it has been designated a "second-line" treatment, meaning it should be used only when other "first-line" treatments have failed.^[11][12][13] 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.^[14][15]

In December 2007, the FDA sent a warning letter to Morton Grove Pharmaceuticals, the sole U.S. manufacturer of lindane products,^[16] 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."^[17]

The State of California banned the pharmaceutical use of lindane, effective 2002. The Michigan House of Representatives passed House Bill 4402 in March 2009 to restrict the use of pharmaceutical lindane to doctors' offices. ^[18] 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."^[19]

Human health effects

The EPA and WHO both classify lindane as "moderately" acutely toxic. It has an oral LD₅₀ of 88 mg/kg in rats and a dermal LD₅₀ of 1000 mg/kg. Most of the adverse human health effects reported for lindane have been related to agricultural uses and chronic, occupational exposure of seed treatment workers.^[20]

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.^[5][21] THe FDA reports one death from repeated topical applications for scabies treatment.^[22]. The most common side effects associated with the use of lindane medications are burning sensations, itching, dryness and rash.^[23] Lindane has not been shown to affect the immune system in humans and, it is not considered to be genotoxic.^[5] Prenatal exposure to β-HCH, an isomer of lindane and production byproduct, has been associated with altered thyroid hormone levels and could affect brain development.^[24]

Cancer risk

Based primarily on evidence from animal studies, most evaluations of the carcinogenicity of lindane have concluded that lindane may cause cancer. In 1987, the International Agency for Research on Cancer (IARC) classified lindane as a group 2B "possible" human carcinogen,^[25] and in 2001 the EPA concluded there was “suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential.”^[26] 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,"^[5] however the World Health Organization concluded in 2004 that “lindane is not likely to pose a carcinogenic risk to humans.”^[27]

Adverse reactions to lindane pharmaceuticals

A variety of adverse reactions to lindane pharmaceuticals have been reported, ranging from skin irritation to seizures to, in rare instances, death. While serious effects are rare and have most often resulted from misuse, adverse reactions have occurred when used properly.^{[11][28][29][30]} The FDA therefore requires a so-called black box warning on lindane products, which explains the risks of lindane products and its proper use.^[23][31]

The black box warning emphasizes that lindane should not be used on 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., dermatitis, psoriasis) and people who weigh less than 110 lbs (50 kg) as they may be at risk of serious neurotoxicity. ^[28][29]

Environmental contamination

Lindane is a persistent organic pollutant: it is relatively long-lived in the environment, it is transported long distances by natural processes like global distillation, and it can bioaccumulate in food chains.^[20]

The production and agricultural use of lindane are the primary causes of environmental contamination,^[32] and levels of lindane in the environment have been decreasing in the U.S., consistent with decreasing agricultural usage patterns.^[33] 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."^[34]

When lindane is used in agriculture, an estimated 12-30% of it volatilizes into the atmosphere, where it is subject to long-range transport and can be deposited by rainfall. Lindane in soil can leach to surface and even ground water and can bioaccumulate in the food chain.^[2] 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.^[5] The ecological impact of lindane’s environmental persistence continues to be debated.

The US EPA has determined that lindane does not contaminate drinking water in excess of the Agency's level of concern.^[5] U.S. Geologic Survey teams in 1999 and 2000.^[35] With regard to lindane medications, the EPA conducted “down-the-drain” estimates of the amount of lindane reaching public water supplies and concluded that lindane levels from pharmaceutical sources were “extremely low” and not of concern.^[10]

Isomers

Lindane is the gamma isomer of hexachlorocyclohexane ("γ-HCH"). In addition to the issue of lindane pollution are concerns related to the other isomers of HCH, namely alpha-HCH and beta-HCH, which are notably more toxic than lindane, lack its insecticidal properties, and are byproducts of lindane production.^[5] 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.^{[36][dead link]} Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic industrial chemicals, a process known as “cracking.”^[33][36] Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs.^[9] Lindane has not been manufactured in the U.S. since the mid-1970s but continues to be imported.

α-hexachlorocyclohexane

β-hexachlorocyclohexane

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.^[9][32] The latter includes the U.S. and Canada, which support public health uses of pharmaceutical lindane but no longer allow agricultural applications.^[9][2] It is banned by the Stockholm Convention On Persistent Organic Pollutants.^[8][37][38] but is still used in agriculture in India,^[39] Nigeria,^[40] and elsewhere.

Lindane is banned in California, and 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.^[41][42] Michigan passed the lindane bill through the House on May 2008, and again in March, 2009. ^[43]

In May 2009 the Fourth Conference of signers of the Stockholm Convention on Persistent Organic Pollutants added lindane and its alpha and beta isomers to the list of globally banned chemicals.^[44]

Morton Grove lawsuit

In the face of negative publicity concerning its lindane products, in 2006 Morton Grove Pharmaceuticals filed a lawsuit against the National Pediculosis Association, the Michigan Ecology Center, and two physicians, alleging that statements they 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.”^[45] The defendants considered the legal action to be SLAPP suit.

Morton Grove and the Ecology Center settled in 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.^[42][46][47] 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.^{[48][verification needed]}

Morton Grove Pharmaceuticals and the National Pediculosis Association have agreed to dismiss their respective lawsuits with no admission of wrongdoing and no payment of any damages.

See also

• Pesticide toxicity to bees

References

External links

Government and organizations

• FDA Information on Lindane
• EPA Information on Lindane
• Gamma Hexachlorocyclohexane Fact Sheet
• Agency for Toxics and Disease Registry: Toxicological Profile for Hexachlorocyclohexane
• World Health Organization Background Document on Lindane for Drinking-Water Quality Guidelines
• PAN Pesticides Database: Lindane
• Lindane Chemistry and Uses
• World Health Organization: Lindane (EHC 124)
• "Lindane Facts" - Website run by Morton Grove Pharmaceuticals
• headlice.org - Website of the National Pediculosis Association
• Michigan Ecology Center website
• Morton Grove Pharmaceuticals homepage - US producer of Lindane Medications

News stories and opinion articles

• "Mom and Pros Tackle Lice" - NPR story from 2006
• Pepsi and Coca-Cola - Lindane in drinks in India - news story from 2004
• India - Pesticides in Coke & Pepsi drinks - news story from 2003