Lindane: Difference between revisions

Lindane

Clinical data
Pregnancy category	C
Routes of administration	Topical
ATC code	P03AB02 (WHO) QP53AB02 (WHO) QS02QA01 (WHO)
Legal status
Legal status	US: WARNING[1] In 2009, the Stockholm Convention banned agricultural uses but permitted pharmaceutical uses for 5 more years.[2] There are 152 ratified countries to the treaty[3].
Pharmacokinetic data
Protein binding	91%
Metabolism	Hepatic cytochrome P-450 oxygenase system
Elimination half-life	18 hours
Identifiers
IUPAC name (1r,2R,3S,4r,5R,6S)-1,2,3,4,5,6-hexachlorocyclohexane
CAS Number	58-89-9
PubChem CID	727
DrugBank	APRD01072
ChemSpider	10481896
CompTox Dashboard (EPA)	DTXSID2020686
ECHA InfoCard	100.000.365
Chemical and physical data
Formula	C6H6Cl6
Molar mass	290.83 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES Cl[C@H]1[C@H](Cl)[C@H](Cl)[C@@H](Cl)[C@H](Cl)[C@@H]1Cl
(verify)

Lindane, also known as gamma-hexachlorocyclohexane, (γ-HCH), gammaxene, Gammallin and erroneously known as benzene hexachloride (BHC),^[4] is an organochlorine chemical variant of hexachlorocyclohexane that has been used both as an agricultural insecticide and as a pharmaceutical treatment for lice and scabies.^[5][6]

Lindane works as a neurotoxin by interfering with GABA neurotransmitter, specifically 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.^[7][8] Lindane is not a mutagenic and data regarding carcinogenic potential have been conflicting.^{[7][9][10][11][12]} It is unclear whether lindane is an endocrine disruptor.^[9][10][11]

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.^[13] In 2009 the production and agricultural use of lindane was banned under the Stockholm Convention on persistent organic pollutants in ratified countries. A specific exemption to that ban allows for its continued use as a second-line pharmaceutical treatment for lice and scabies. ^[14]

History and use

The use of lindane as an insecticide began in the 1940s. It has been used to treat food crops and forestry products, as a seed treatment, a soil treatment, and to treat livestock and pets. It has also been used as a pharmaceutical treatment for lice and scabies, formulated as a shampoo and lotion.^[15][16][17] Notably, lindane-based agricultural products generally contain much higher concentrations of lindane compared with pharmaceutical treatments, often in combination with other agricultural chemicals. ^[18] It is estimated that roughly 600,000 tonnes of lindane were produced globally between 1950 and 2000; the vast majority of uses -- greater than 99% -- have been agricultural. ^[15] It has been manufactured in several countries, including the United States, China, Brazil, and several European countries, but as of 2007 only India and possibly Russia are still producing it.^[15]

By 2006, the use lindane had been banned in 52 countries and restricted in 33. Seventeen countries, including the US and Canada, allow either limited agricultural or pharmaceutical use.^[15] In 2009, a ban on the agricultural uses of lindane in agriculture was implemented under the Stockholm Convention on Persistent Organic Pollutants in ratified countries. A specific exemption to this treaty allows for the continued use of lindane-based medications for the second-line treatment of head lice and scabies for 5 more years. The production of the lindane isomers a- and ß-hexachlorocyclohexane, which are notably more toxic than lindane, was also banned.^[19] Although the US has not ratified the Convention, it has similarly banned agricultural uses while allowing public health uses for the second-line treatment of lice and scabies.^{[19][14][20][21]}

United States

In the US, lindane pesticide products were regulated by the U.S. Environmental Protection Agency (EPA), while lindane medications are regulated by the Food and Drug Administration (FDA). It was registered as an agricultural insecticide in the 1940s and as a pharmaceutical in 1951.^[15] The EPA gradually began restricting its agricultural use in the 1970s due to concerns over its effects on human health and the environment.^[22] By 2002, its use was limited to seed treatments for just 6 crops,^[15] and in 2007 these last uses were cancelled.^[23] The FDA continues to support approved medical uses.^[24][25]

Pharmaceutical uses

Lindane medications are approved in the US for the treatment of scabies, head lice and pubic lice (“crabs”) and formulated as a 1% lotion and 1% shampoo for topical use. They are available by prescription only and were designated as second-line treatments in 1995, which means they are indicated when other "first-line" treatments have failed or cannot be used.^{[26] [26][27][28][29]}

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. ^{[27] [28] [30][31] [32] [33] [34] [35][36] [37][38]} The actual rate of clinical resistance to lindane and other scabicides and pediculicides in the US is not known but varies geographically. ^[39] 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. ^{[40] [41]} To this point, the most recent authoritative review of head lice treatments by a group of international experts ("The Cochrane Review") was withdrawn in 2007 for lack of current evidence of the comparative effectiveness of head lice treatments, noting that " The 'best' choice will now depend on local resistance patterns." ^[42]

In December 2007, the FDA sent a warning letter to Morton Grove Pharmaceuticals^[43], requesting that the company correct misleading information about its lindane shampoo product that appeared on two websites developed by Alliant Pharmaceuticals as part of a contract marketing agreement, which the FDA believed minimized serious risks while over stating product benefits.^[44] Morton Grove responded with corrective actions and the contract with Alliant Pharmaceuticals terminated in May 2007. ^[45]

The State of California banned pharmaceutical lindane, effective 2002, and there are bills pending in the New York and Michigan state legislatures.^{[46] [47]} The Michigan bill, which would restrict its use to doctors’ offices, passed the House on May 2008 and again in March 2009, but has not passed the Senate. ^{[48] [49]}

An analysis of the California ban concluded that the majority of pediatricians responding to a mail-in survey--78% of 135 respondents-- had not experienced problems treating lice or scabies since the ban took effect. By comparison, 22% of respondents did express concerns and cited resistance as the primary challenge following the ban. The study also documented a decrease in lindane wastewater contamination (i.e., water entering purification plants) and a decline in lindane poisoning incidents reported to Poison Control Centers. The report noted, however, that significant and steady declines in lindane poisonings had already occurred prior to the ban from 1998 to 2002. In addition, it is relevant to note that the study did not measure lindane levels in purified water released from treatment plants nor did it measure lindane in water sources used for drinking. ^[50] Regardless of these limitations, the authors stated 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." ^[50]

By contrast, the EPA published in 2002 the results of their own analysis, based in part on data from California water treatment plants, and concluded that lindane levels from use of pharmaceutical lindane was extremely low and not of concern.^[17]

Morton Grove lawsuit

In 2006 Morton Grove Pharmaceuticals, the sole US manufacturer of lindane pharmaceuticals, sued the National Pediculosis Association, the Michigan Ecology Center, and two physicians, alleging that they disseminated defamatory materials regarding lindane and other charges. Morton Grove alleged more than $9.3 million in damages.^[51] The defendants considered the legal action to be SLAPP suit and settled in 2008. The settlement did not require them 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.^{[46][52][53][54]}

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.^[55]

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.^[7][56] Lindane has not been shown to affect the immune system in humans and, it is not considered to be genotoxic.^[7] Limited data suggest that lindane may be an endocrine disruptor but the CDC has noted that additional research is needed to determine if there is any relevance to public health. ^[7]

Cancer risk

Assessments on the carcinogenic risk of lindane derived primarily from animal toxicology studies have been conflicting, though the most recent review of available evidence in 2004 by 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.”^[11] In 2001, the Cancer Assessment Review Committee of the EPA issued a report on lindane in which they found “major deficiencies” with some of the earlier studies, 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 “quantification of human cancer risk is not required” because the evidence was limited to the finding of benign tumors in one species of female mice.^[10] In 1987, the International Agency for Research on Cancer (IARC) classified the broader chemical class of hexachlorocyclohexanes (HCH) to which lindane belongs 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.^[9] Likewise, the U.S. Department of Health and Human Services (DHHS) determined that hexachlorocyclohexanes, including lindane, "may reasonably be anticipated to cause cancer in humans but similarly noted that “evidence for carcinogenicity in humans was inadequate.” The DHHS position was based on experimental animal studies reported by the IARC in 1979, 1982, 1987 and the National Cancer Institute in 1977.^[10][11][57]

Adverse reactions to lindane pharmaceuticals

A variety of adverse reactions to lindane pharmaceuticals have been reported. The most common are nonserious reactions of the skin such as burning sensations, itching, dryness and rash. ^[58][59] Systemic effects have also been reported, including headache and dizziness and in rare instances seizures, and even more rarely death.^[60] While serious effects are rare and have most often resulted from misuse, adverse reactions have occurred when used properly.^{[26][24][25][61]} The FDA therefore requires a so-called black box warning on lindane products, which explains these risks and details proper use instructions.^[60][62]

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. ^[24][25]

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.^[55]

The production and agricultural use of lindane are the primary causes of environmental contamination,^[63] and levels of lindane in the environment have been decreasing in the U.S., consistent with decreasing agricultural usage patterns.^[12] 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."^[64] Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic molecules, a process known as "cracking." ^{[12] [65]}

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. ^[22] However, biotransformation and elimination are relatively rapid when exposure is discontinued. ^[15] 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 ).^[66] 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%. ^[22][15]

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.^[7] 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.^[7] U.S. Geologic Survey teams concluded the same in 1999 and 2000.^[67] 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.^[17]

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).^[68] By comparison, the state of California imposes a lower MCL for lindane of 19 ppt.^[50] 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. ^{[10][69][70][68]} 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." ^[68] 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. ^[68] Today, the legally enforceable MCL standard for lindane is 200 ppt while the national water criterion for lindane is 980 ppt. ^[68]

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.^[7] 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.^{[65][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."^[7][65] Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs.^[15] Lindane has not been manufactured in the U.S. since the mid-1970s but continues to be imported.

• 
  a-hexachlorocyclohexane
• 
  ß-hexachlorocyclohexane

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