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	In 2009, the Stockholm Convention banned agricultural uses globally in 166 countries, but permitted pharmaceutical use for 5 more years.[1]
Routes	Topical
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Lindane, also known as gamma-hexachlorocyclohexane, (γ-HCH), gammaxene, Gammallin and erroneously known as benzene hexachloride (BHC),^[2] 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.^[3][4]

Lindane works as a neurotoxin by interfering with GABA neurotransmitter function, specifically by interacting with the GABA_A receptor-chloride channel complex at the picrotoxin binding site. In humans, exposure to toxic amounts of lindane primarily affects the nervous system.^[5][6] Limited data suggest that lindane may be an endocrine disruptor but additional research is needed to determine the relevance to public health. Data regarding carcinogenicity have been conflicting, though the most recent assessments indicate that lindane is not likely to pose a major cancer risk to humans.^[7][8][9]

The World Health Organization classifies lindane as "Moderately Hazardous," based on acute animal toxicity studies and its international trade is restricted and regulated under the Rotterdam Convention on Prior Informed Consent.^[10] 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 for agricultural purposes in participating (ratified) countries but with a specific exemption for use as a human health pharmaceutical for the control of head lice and scabies as second-line treatment. ^[11] While the US is not currently a member country to the Stockholm Convention, it similarly called for the voluntary cancellation of registered agricultural products but continues to support FDA-approved medical uses of pharmaceutical lindane.

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.^[12][13] 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.^[14] Lindane medications continue to be available in the US,^[15] and Canada and other countries have similarly banned agricultural use while allowing its use in medicine to continue. Notably, lindane-based agricultural products generally contain much higher concentrations of lindane compared with pharmaceutical treatments, often in combination with other agricultural chemicals.^[16]

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 with more favorable risk profiles have failed, cannot be tolerated or are otherwise contraindicated.^{[15][17][18][19]}

Resistance to lindane and other agents used to treat scabies and lice has been reported in the US and elsewhere, and is an important cause of treatment failure in areas where resistance has emerged. ^{[20][21][22][23][24][25][26][27][28][29][30]} The actual rate of clinical resistance to lindane and other scabicides and pediculicides in the US is not known but varies geographically.^[31]Moreover, because there are no recent controlled clinical studies evaluating the efficacy of lindane versus other approved treatments in the US, it is not known how lindane would compare with these agents today. Resistance to permethrin, in particular, is a growing concern because of its extensive use and availability as an over-the-counter first-line treatment. ^[32][33] To this point, the most recent authoritative review of head lice treatments by international experts ("The Cochrane Review") was withdrawn in 2007 for lack of direct contemporary evidence of the comparative effectiveness of head lice treatments, noting that " The 'best' choice will now depend on local resistance patterns."^[34]

In December 2007, the FDA sent a warning letter to Morton Grove Pharmaceuticals, the sole U.S. manufacturer of lindane products,^[35] requesting that the company correct misleading advertising information contained in two websites developed by Alliant Pharmaceuticals. 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."^[36] Morton Grove responded with corrective actions and the contract with Alliant Pharmaceuticals terminated in May 2007.^[37]

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. ^[38] A recent analysis^[39] of the California ban found that 78% of 135 pediatricians responding to a mail-in survey had not experienced problems treating lice or scabies since that ban took effect. By contrast, 22% expressed difficulty in managing these infections, which they most often attributed to the development of resistance. The authors noted that calls to the California Poison Control System relating to lindane exposure had already been declining gradually in the years prior to the ban (1998-2002) but went to near zero after the ban took effect (2004-2006). No comparative data from poison control centers in other states were provided as part of the California analysis. ^[39]

The study also documented a decrease in the amount of lindane in California wastewater entering water treatment plants. The level of lindane in purified water discharged from California water treatment works was not measured in this study, nor was lindane assessed in sources of California drinking water. ^[39] Nonetheless, it was in the authors’ opinion that the "California experience" suggests that elimination of pharmaceutical lindane reduced reported unintentional exposures, did not adversely affect head lice and scabies treatment and produced environmental benefits. ^[39]

In 2002, however, the US Environmental Protection Agency (EPA) concluded to the contrary that the amount of lindane in public water supplies resulting from the use of lindane-based medications was "extremely low" and not of concern. ^[13] (See also Environmental Contamination)

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.^[40]

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][41] The most common side effects associated with the use of lindane medications are burning sensations, itching, dryness and rash.^[42]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 hexachlorocyclohexane and production byproduct, has been associated with altered thyroid hormone levels and could affect brain development.^[43] Prior to 1974, technical-grade HCH—a mixture of HCH isomers including the β form—was used agriculturally in the US.

Cancer risk

Assessments of the carcinogenicity of lindane have been conflicting, though more recent authoritative reviews of the available data have found that lindane is not likely to pose a major cancer risk to humans. In 2004, the Joint Commission of Pesticide Residues (JMPR) of the World Health Organization (WHO) and Food Agricultural Organization (FAO) of the United Nations concluded that "lindane is not likely to pose a carcinogenic risk to humans" based on the weight of scientific evidence from carcinogenicity studies. ^[9] In 2001, the Cancer Assessment Review Committee of the EPA issued a report on lindane in which they found "major deficiencies" with many of the experimental animal studies that had been conducted previously, prompting additional research and subsequent reclassification of lindane from "possibly carcinogenic" into the lesser category of "Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential." The expert Committee further recommended that additional assessment of cancer risk in humans was not necessary.^[8]

In 1987, the International Agency for Research on Cancer (IARC) classified the broader chemical class of hexachlorocyclohexanes (HCH) that lindane belongs to as group 2B "possible" human carcinogens, with the caveat that human evidence relating specifically to lindane was inadequate and that findings from animal cancer studies were equally limited.^[7] Likewise, the U.S. Department of Health and Human Services determined that hexachlorocyclohexanes, including lindane, "may reasonably be anticipated to cause cancer in humans" based on earlier experimental animal studies reported by the IARC (1979, 1982, 1987) and the National Cancer Institute (1977), but similarly noting that "evidence for carcinogenicity in humans was inadequate."^{[5] [7][44]}

Adverse reactions to lindane pharmaceuticals

A variety of adverse reactions to lindane pharmaceuticals have been reported, though the most common are nonserious reactions of the skin. ^[45][46][47] However, systemic effects have been reported, including dizziness and headache and in rare instances seizures, and even more rarely death. ^[48] While rare serious effects have most often resulted from misuse, such as oral ingestions and excessive applications, adverse reactions have occurred when used properly.^{[49][50][15][48]} The FDA therefore requires a so-called black box warning on lindane products, which explains the risks of lindane products and their proper use.^{[3] [51]} Likewise, the FDA limited lindane medications to small 2 oz. bottles to minimize the risk of product misuse and accidental poisoning.^[19]

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. ^[49][50]

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, though it is rapidly eliminated when exposure is discontinued.^[40]

The production and agricultural use of lindane are the primary causes of environmental contamination,^[52] and levels of lindane in the environment have been decreasing in the U.S., consistent with decreasing agricultural usage patterns.^[53] 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."^[54] Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic molecules, a process known as "cracking." ^{[53] [55]}

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. ^[14] However, biotransformation and elimination are relatively rapid when exposure is discontinued. ^[12] Most exposure of the general population to lindane has resulted from agricultural uses and the intake of foods, such as produce, meats and milk, produced from treated agricultural commodities. Human exposure has decreased significantly since the cancellation of agricultural uses in 2006. Even so, the CDC published in 2005 its Third National Report on Human Exposures to Environmental Chemicals, which found no detectable amounts of lindane in human blood taken from a random sampling of about 5,000 people in the US as part of the NHANES study (National Health and Nutrition Examination Survey at: http://www.cdc.gov/nchs/nhanes/about_nhanes.htm ).^[56] The lack of detection of lindane in this large human "biomonitoring" study likely reflects the increasingly limited agricultural uses of lindane over the last two decades. The cancellation of agricultural uses in the U.S. will further reduce the amount of lindane introduced into the environment by more than 99%. ^[14][12]

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 determined in 2002 that the Agency does not believe that lindane contaminates drinking water in excess of levels considered safe.^[5] U.S. Geologic Survey teams concluded the same in 1999 and 2000.^[57] 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.^[13]

Note that the EPA has set the maximum contaminant level or "MCL" for lindane allowed in public water supplies and considered safe for drinking at 200 parts per trillion (ppt).^[58] By comparison, the state of California imposes a lower MCL for lindane of 19 ppt.^[39] However, the California standard is based on a dated 1988 national water criterion that was subsequently revised by the EPA in 2003 to 980 ppt. ^{[8][59][60][58]} The EPA stated that the change resulted from "significant scientific advances made in the last two decades particularly in the areas of cancer and noncancer risk assessments." ^[58] While the EPA considered raising the MCL standard for lindane to 980 ppt at that time, the change was never implemented because states had little difficultly in maintaining lindane levels below the 200 ppt MCL limit already in place. ^[58] Today, the legally enforceable MCL standard for lindane is 200 ppt while the national water criterion for lindane is 980 ppt. ^[58]

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.^{[55][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."^[5][55] Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs.^[12] 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.^[12][52] The latter includes the U.S. and Canada, which support public health uses of pharmaceutical lindane but no longer allow agricultural applications. ^[14][12] In May 2009, lindane (as well as the alpha- and beta-isomers of hexachlorocyclohexane) was listed in Annex A of the Stockholm Convention On Persistent Organic Pollutants, which bans agricultural uses of 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. ^[61] Although the US is not a member country to the Stockholm Convention, it has similarly abandoned agricultural uses of lindane while supporting approved public health applications. ^{[61][11][62][63]} Lindane is still used in agriculture in India,^[64] Nigeria,^[65] 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.^[66][67] The Michigan bill which would require use of lindane in physician offices only, passed the House on May 2008, and again in March, 2009 but has not passed the Senate. ^[68]

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."^[69] 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.^[67][70][71] 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.^{[72][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