Lindane
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Lindane
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Clinical data
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C
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Topical
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Legal status
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Production and
agricultural use is banned the 169 countries that are parties to the Stockholm Convention, but pharmaceutical use is allowed as a
second-line treatment for scabies and lice[1]
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Pharmacokinetic data
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91%
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Hepatic cytochrome
P-450 oxygenase system
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18 hours
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Identifiers
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Chemical and physical data
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C6H6Cl6
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290.83 g/mol
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3D model (JSmol)
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Lindane,
also known as gamma-hexachlorocyclohexane, (γ-HCCH), gammaxene, Gammallin and
sometimes incorrectly called 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 lice and scabies.[3][4]
Lindane is a neurotoxin that interferes
with GABA neurotransmitter function by
interacting with the GABAA receptor-chloride channel complex at the picrotoxinbinding site. In humans, lindaffects
the nervous system, liver, and kidneys, and may well be a carcinogen.[5][6] Whether lindane is an endocrine disruptor is unclear.[7][8][9]
The World Health
Organization classifies
lindane as "moderately hazardous", and its international trade is
restricted and regulated under the Rotterdam Conventionon Prior Informed Consent.[10] In 2009, the production and agricultural use of lindane
was banned under the Stockholm Convention on persistent organic
pollutants. A specific exemption
to that ban allows it to continue to be used as a
In 2009, the production and agricultural use of lindane
was banned under the Stockholm Convention on persistent organic pollutants. A
specific exemption to that ban allows it to continue to be used as a
second-line pharmaceutical treatment for lice and scabies.[11]
Contents
[hide]
History
and use[edit]
The chemical was originally synthesised in 1825 by Faraday. It is
named after the Dutch chemist Teunis van der Linden (1884–1965), the first to
isolate and describe γ-hexachlorcyclohexane in 1912. Its pesticidal action was
discovered only in 1942, after which lindane production, by Imperial Chemical Industries Ltd
(ICI), and use started up in the United Kingdom. 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 pharmaceutical treatment for lice and scabies, formulated as
a shampoo or
lotion.[12][13][14] Between
1950 and 2000, an estimated 600,000 tonnes of lindane were produced globally, and the
vast majority of which was used in agriculture. It has been manufactured by
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.[12]
By November 2006, the use of lindane had been banned in 52
countries and restricted in 33 others. Seventeen countries, including the US
and Canada, allowed either limited agricultural or pharmaceutical use.[12] In
2009, an international ban on the use of lindane in agriculture was implemented
under the Stockholm
Convention on Persistent Organic Pollutants. A specific exemption
allows for it to continue to be used in second-line treatments for the head
lice and scabies for five more years. The production of the lindane isomers α-
and β-hexachlorocyclohexane was also banned.[15] Although
the US has not ratified the Convention, it has similarly banned agricultural
uses while still allowing its use a second-line lice and scabies treatment.[11][15][16][17]
United States[edit]
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 pharmaceutical in 1951.[12] The
EPA gradually began restricting its agricultural use in the 1970s due to
concerns over its effects on human health and the environment.[18] By
2002, its use was limited to seed treatments for just six crops,[12]and in 2007, these last uses
were cancelled.[19]
Pharmaceutical uses[edit]
Lindane medications continue to be available in the US,[20] though since 1995, they
have been designated "second-line" treatments, meaning they should be
prescribed when other "first-line" treatments have failed or cannot
be used.[20][21][22][23] In
December 2007, the FDA sent a Warning Letter to Morton Grove Pharmaceuticals, the
sole U.S. manufacturer of lindane products,[24] requesting
that the company correct misleading information on two of its lindane websites.
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."[25]
California banned the pharmaceutical lindane,
effective 2002, and the Michigan House of
Representatives passed a bill in 2009 to restrict its use to doctors'
offices.[26] 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, "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."[27][non-primary source needed]
The Persistent Organic Pollutants Review Committee of the Stockholm
Convention on Persistent Organic Pollutants considers the use
of lindane in agriculture as largely redundant, with other, less toxic and less
persistent pesticides. In the case of pharmaceutical use, the committee noted,
"alternatives for pharmaceutical uses have often failed for scabies and
lice treatment and the number of available alternative products for this use is
scarce. For this particular case, a reasonable alternative would be to use
lindane as a second-line treatment when other treatments fail, while potential
new treatments are assessed."[28]
Human
health effects[edit]
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.[28]
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][29] 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.[30][non-primary source needed]
The Occupational Safety and
Health Administration and National
Institute for Occupational Safety and Health have set
occupational exposure limits (permissible exposure and recommended exposure,
respectively) for lindane at 0.5 mg/m3 at
a time-weighted average of eight hours for skin exposure. People can be exposed
to lindane in the workplace by inhaling it, absorbing it through their skin,
swallowing it, and eye contact. At levels of 50 mg/m3,
lindane is immediately
dangerous to life and health.[31]
It is classified as an extremely hazardous
substance in the United States as defined in section 302 of the
U.S. Emergency
Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is
subject to strict reporting requirements by facilities which produce, store, or
use it in significant quantities.[32]
Cancer risk[edit]
Based primarily on evidence from animal studies, most
evaluations of lindane have concluded that it may possibly cause cancer. In 2015,
the International Agency for
Research on Cancer classified lindane as a known human carcinogen,[33][34] and
in 2001 the EPA concluded there was "suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic
potential."[8] 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] and
in 1999, the EPA characterized the evidence carcinogenicity for lindane as
"suggestive ... of carcinogenicity, but not sufficient to assess human
carcinogenic potential."[14] Lindane
and its isomers have also been on California's Proposition
65 list of known carcinogens since 1989.[35] In
contrast, the World Health Organization concluded
in 2004 that "lindane is not likely to pose a carcinogenic risk to
humans."[36]India's
BIS considers Lindane a "confirmed carcinogen".[37]
Adverse reactions to lindane[edit]
A variety of adverse reactions to lindane pharmaceuticals have
been reported, ranging from skin irritation to seizures, and,
in rare instances, death. The most common side effects are burning sensations,
itching, dryness, and rash.[38] While
serious effects are rare and have most often resulted from misuse, adverse
reactions have occurred when used properly.[20][39][40][41]The
FDA, therefore, requires a so-called black box
warning on lindane products, which explains the risks of lindane
products and their proper use.[38][42]
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.[39][40]
Environmental
contamination[edit]
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.[28]
The production and agricultural use of lindane are the primary
causes of environmental contamination,[43] and levels of lindane in
the environment have been decreasing in the U.S., consistent with decreasing
agricultural usage patterns.[44] The
production of lindane generates large amounts of waste hexachlorocyclohexane
isomers, and "every ton of lindane manufactured produces about 9 tons of
toxic waste."[45] Modern
manufacturing standards for lindane involve the treatment and conversion of
waste isomers to less toxic molecules, a process known as "cracking".[44][46]
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.[18] 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: https://www.cdc.gov/nchs/nhanes/about_nhanes.htm ).[47] 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 United
States will further reduce the amount of lindane introduced into the
environment by more than 99%.[12][18]
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] Lindane
residues in honey and beeswax are reported to be the highest of any historical
or current pesticide and to continue to pose a threat to honeybee health.[48] 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. Geological Survey teams concluded the same
in 1999 and 2000.[49] 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.[14]
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).[50] By
comparison, the state of California imposes a lower MCL for lindane of 19 ppt.[27] 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][50][51][52] 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."[50] 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.[50] Today,
the legally enforceable MCL standard for lindane is 200 ppt, while the national
water criterion for linda
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