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Hexachlorocyclohexanes Including Lindane
Hexachlorocyclohexanes Including Lindane G Chen, Oklahoma State University, Stillwater, OK, USA Ó 2014 Elsevier Inc. All rights reserved.
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Name: Hexachlorocyclohexanes Chemical Names: 1,2,3,4,5,6-Hexachlorocyclohexane (mixed isomers), CAS 608-73-1; 1a,2a,3b,4a,5b,6a-Hexachlorocyclohexane (a-isomer), CAS 319-84-6; 1a,2b,3a,4b,5a,6b-Hexachlorocyclohexane (b-isomer), CAS 319-85-7; 1a,2a,3b,4a,5a,6b-Hexachlorocyclohexane (gisomer); Lindane, CAS 58-89-9; 1a,2a,3a,4b,5a,6b-Hexachlorocyclohexane (d-isomer), CAS 319-86-8; 1a,2a,3a,4b,5b,6b-Hexachlorocyclohexane (ε-isomer), CAS 6108-10-7; 1a,2a,3a,4a,5a,6a-Hexachlorocyclohexane (z-isomer), CAS 6108-11-8; 1a,2a,3a,4a,5b,6b-Hexachlorocyclohexane (Z-isomer), CAS 6108-12-9; 1a,2a,3a, 4a,5a,6b-Hexachlorocyclohexane (j-isomer), CAS 6108-13-0 Synonyms: Benzene hexachloride; 1,2,3,4,5,6Hexachlorocyclohexane; Lindane Chemical/Pharmaceutical/Other Class: Organochlorine pesticides Molecular Formula: C6H6Cl6 Chemical Structure:
were banned for agriculture uses in most countries. The large dumps of unused HCHs now create a major hazard because of their long residence times in soil. HCHs are still used for medical purposes in some countries. HCH has not been produced in the United States since 1976. However, imported lindane is available as a prescription medicine for the treatment of scabies and body lice in humans.
Environmental Fate and Behavior HCHs are highly stable and persist in the environment, and have been detected in the environment worldwide. In air, the different forms of HCH can be present as a vapor or adsorbed to small particles. HCH can remain in the air for long periods of time and residues can travel great distances, depending on environmental conditions. HCH is degraded to less toxic substances by algae, fungi, and bacteria.
Exposure and Exposure Monitoring CI CI
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CI
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Oral exposure through diet is the primary pathway for the general population. HCHs can also be distributed in air and can be absorbed through inhalation. Dermal exposure can occur through pharmaceutical use of lindane for head lice. HCH isomers can be measured in the blood, urine, and semen of exposed persons. HCH metabolites can also be measured to determine whether a person has been exposed to HCH. However, this method cannot be used to determine exposure to HCH alone, that is, other environmental contaminants may also produce the same metabolites.
CI
Toxicokinetics Background Hexachlorocyclohexane (HCH) is also known as benzene hexachloride (BHC). It is a synthetic chemical. HCH is a white solid substance that may evaporate under suitable conditions. HCH has eight isomeric forms. The four common isomers are a-, b-, g-, and d-HCHs. The most common of these is g-HCH (also known as lindane), which is usually the predominant isomer. It is used as an insecticide on fruit, vegetables, and animals. As worldwide use of HCH declines, the frequency of detection and the levels detected in the environment is continuing to decrease.
HCHs are readily absorbed through the gastrointestinal tract. Inhaling air contaminated with isomers of HCH can also lead to systemic absorption. HCHs can also be absorbed through the skin when used as a lotion, cream, or shampoo for the treatment or control of ectoparasites. In general, HCH isomers and their metabolites can be temporarily stored in body fat. Absorbed HCHs are mainly excreted via the urine. Lesser amounts are excreted in feces. In rats, the highest concentrations have been found in liver, kidneys, body fat, brain, and muscles, with substantial deposition occurring in fatty tissue. Whole-body elimination half-lives may be 1–2 months but varies by isomer.
Uses Mechanism of Toxicity HCHs are potent insecticides. HCHs were widely used as commercial insecticides in the last half of the twentieth century. Because HCHs cause serious environmental problems, they
874
The g isoform (g-HCH; lindane) and a isoform are potent neurostimulants and convulsants, whereas the b and d forms
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00152-4
Hexachlorocyclohexanes Including Lindane
are primarily depressants. g-HCH mediated neurotoxicity is primarily the result of blockade of Cl influx through ionotropic g-aminobutyric acid receptors, resulting in depolarization and hyperexcitation of the postsynaptic neuronal membrane. g-HCH has been shown to enhance both spontaneous and evoked release of neurotransmitters from nerve terminals. These actions have been correlated with the ability of g-HCH to elevate Ca2þ in brain synaptosomes. g-HCH has also been shown to alter contractility in skeletal myocytes. d-HCH is particularly potent toward disrupting Ca2þ homeostasis in a variety of excitable and nonexcitable cells and altering contractility of cardiac muscle. d-HCH has been shown to stereoselectively mobilize Ca2þ from intracellular stores in cultured neural cells, which appears mediated by interaction with ryanodine receptors. g-HCH and b-HCH have been reported to have estrogenic actions.
Acute Toxicity In animals, g- and a-HCH can cause convulsions, and b-HCH can cause coma. All isomers can damage liver, including altered enzyme function, degeneration, and cancer, as well as kidney toxicity. The g-isomer is most potent acutely, but b-HCH is metabolized more slowly and becomes more toxic with repeated exposures. Exposure to large amounts of HCHs can harm the nervous system, producing a range of symptoms from headache and dizziness to seizures, and convulsions. The onset of signs and symptoms following exposure to HCH insecticides vary. HCHs can result in blood disorders, dizziness, headaches, and possible changes in the levels of sex hormones in the blood. The time interval between high dose exposure and the onset of symptoms is generally less than 12 h. The symptoms produced by these agents may last for weeks to months and patients often experience periodic relapses despite adequate therapy because of the initial lipid storage and subsequent redistribution of these chemicals.
875
reproductive parameters in adult offspring. g-HCH and b-HCH were reported to damage the ovaries and testes in animals.
Genotoxicity Technical grade HCHs produce dominant lethal mutations in mice, but studies of specific isomers mostly do not indicate mutagenicity.
Carcinogenecity Long-term oral administration of HCHs to laboratory rodents has been reported to result in liver cancer. The Department of Health and Human Services (DHHS) has determined that HCHs may cause cancer in humans. The International Agency for Research on Cancer (IARC) has classified HCHs as carcinogenic to animals and evidence in humans is inadequate.
Clinical Management When a large amount of HCH has been swallowed, emetics have been used to induce vomiting. Activated charcoal can also be used to decrease gastrointestinal absorption. To avoid skin absorption after exposure, clothing should be removed, and the skin should be washed. In case of eye contact, irrigate eyes immediately with water or saline. There are no known methods for reducing absorption following inhalation exposure. In the nervous system, g-HCH is thought to interfere with the gamma-Aminobutyric acid (GABA) system by interacting with the gamma-Aminobutyric acid type A (GABAA) receptor–ionophore complex at the picrotoxin binding site. The seizures caused by g-HCH can be antagonized by GABAA-mimetics. Use of anticonvulsants should include careful monitoring of hypotension, respiratory depression, and the need for endotracheal intubation. In the liver, g-HCH produces oxidative stress and increased lipid metabolism. Interfering with these mechanisms can decrease the toxicity of HCH.
Chronic Toxicity Exposure Standards and Guidelines In animals, chronic exposures to HCHs produce liver and kidney toxicity.
Immunotoxicity In rodents, HCH isomers produce immunotoxicity in adult repeated-dose studies, and in offspring following developmental exposures. There is evidence that HCHs affect the human immune system.
The JMPR (Joint FAO/WHO Meeting on Pesticide Residues) acceptable daily intake value for lindane is 0.005 mg kg day1. Minimal risk levels set by the US Agency for Toxic Substances and Disease Registry range from 0.05 to 0.0001 mg kg day1 for acute to chronic exposures to different isomers. There are no exposure standards for technical HCHs.
See also: Organochlorine Insecticides.
Further Reading Reproductive Toxicity HCHs are passed to the developing organism through the placenta and breast milk. HCHs do not cause birth defects. However, neurological and hormonal effects have been reported resulting in neurobehavioral alterations and altered
Lal, R., Dogra, C., Malhotra, S., et al., 2006. Diversity, distribution and divergence of lin genes in hexachlorocyclohexane-degrading sphingomonads. Trends Biotechnol. 24 (3), 121–130. Lal, R., Pandey, G., Sharma, P., et al., 2010. Biochemistry of microbial degradation of hexachlorocyclohexane and prospects for bioremediation. Microbiol. Mol. Biol. Rev. 74 (1), 58–80.
876
Hexachlorocyclohexanes Including Lindane
Nagata, Y., Endo, R., Ito, M., et al., 2007. Aerobic degradation of lindane (gammahexachlorocyclohexane) in bacteria and its biochemical and molecular basis. Appl. Microbiol. Biotechnol. 76 (4), 741–752. Nagata, Y., Tsuda, M., 2005. Metabolic pathway, genes, and enzymes for the degradation of chlorinated pesticide, gamma-hexachlorocyclohexane. Tanpakushitsu Kakusan Koso 50 (12), 1511–1518. Sauviat, M.P., Pages, N., 2002. Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane. J. Soc. Biol. 196 (4), 339–348. Singh, B.K., Kuhad, R.C., Singh, A., et al., 2000. Microbial degradation of the pesticide lindane (gamma-hexachlorocyclohexane). Adv. Appl. Microbiol. 47, 269–298. Vijgen, J., Abhilash, P.C., Li, Y.F., et al., 2011. Hexachlorocyclohexane (HCH) as new stockholm convention POPs – a global perspective on the management of Lindane and its waste isomers. Environ. Sci. Pollut. Res. Int. 18 (2), 152–162. Vizcaino, P., Pistocchi, A., 2010. A GIS model-based assessment of the environmental distribution of gamma-hexachlorocyclohexane in European soils and waters. Environ. Pollut. 158 (10), 3017–3027.
Zhulidov, A.V., Robarts, R.D., Headley, J.V., et al., 2003. A review of riverine fluxes of hexachlorocyclohexane and DDT to the Azov and Black seas from the former USSR and Russian Federation. J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. 38 (5), 753–769.
Relevant Websites http://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid¼138 – Agency for Toxic Substances & Disease Registry. http://www.inchem.org/documents/pims/chemical/pim257.htm – International Programme on Chemical Safety. http://www.drrichardhall.com/Articles/lindaine.pdf – Long-Term Psychological and Neurolgical Complications of Lindane Poisoning.
l l
l l l l
Name: Hexachlorocyclohexanes Chemical Names: 1,2,3,4,5,6-Hexachlorocyclohexane (mixed isomers), CAS 608-73-1; 1a,2a,3b,4a,5b,6a-Hexachlorocyclohexane (a-isomer), CAS 319-84-6; 1a,2b,3a,4b,5a,6b-Hexachlorocyclohexane (b-isomer), CAS 319-85-7; 1a,2a,3b,4a,5a,6b-Hexachlorocyclohexane (gisomer); Lindane, CAS 58-89-9; 1a,2a,3a,4b,5a,6b-Hexachlorocyclohexane (d-isomer), CAS 319-86-8; 1a,2a,3a,4b,5b,6b-Hexachlorocyclohexane (ε-isomer), CAS 6108-10-7; 1a,2a,3a,4a,5a,6a-Hexachlorocyclohexane (z-isomer), CAS 6108-11-8; 1a,2a,3a,4a,5b,6b-Hexachlorocyclohexane (Z-isomer), CAS 6108-12-9; 1a,2a,3a, 4a,5a,6b-Hexachlorocyclohexane (j-isomer), CAS 6108-13-0 Synonyms: Benzene hexachloride; 1,2,3,4,5,6Hexachlorocyclohexane; Lindane Chemical/Pharmaceutical/Other Class: Organochlorine pesticides Molecular Formula: C6H6Cl6 Chemical Structure:
were banned for agriculture uses in most countries. The large dumps of unused HCHs now create a major hazard because of their long residence times in soil. HCHs are still used for medical purposes in some countries. HCH has not been produced in the United States since 1976. However, imported lindane is available as a prescription medicine for the treatment of scabies and body lice in humans.
Environmental Fate and Behavior HCHs are highly stable and persist in the environment, and have been detected in the environment worldwide. In air, the different forms of HCH can be present as a vapor or adsorbed to small particles. HCH can remain in the air for long periods of time and residues can travel great distances, depending on environmental conditions. HCH is degraded to less toxic substances by algae, fungi, and bacteria.
Exposure and Exposure Monitoring CI CI
CI
CI
CI
Oral exposure through diet is the primary pathway for the general population. HCHs can also be distributed in air and can be absorbed through inhalation. Dermal exposure can occur through pharmaceutical use of lindane for head lice. HCH isomers can be measured in the blood, urine, and semen of exposed persons. HCH metabolites can also be measured to determine whether a person has been exposed to HCH. However, this method cannot be used to determine exposure to HCH alone, that is, other environmental contaminants may also produce the same metabolites.
CI
Toxicokinetics Background Hexachlorocyclohexane (HCH) is also known as benzene hexachloride (BHC). It is a synthetic chemical. HCH is a white solid substance that may evaporate under suitable conditions. HCH has eight isomeric forms. The four common isomers are a-, b-, g-, and d-HCHs. The most common of these is g-HCH (also known as lindane), which is usually the predominant isomer. It is used as an insecticide on fruit, vegetables, and animals. As worldwide use of HCH declines, the frequency of detection and the levels detected in the environment is continuing to decrease.
HCHs are readily absorbed through the gastrointestinal tract. Inhaling air contaminated with isomers of HCH can also lead to systemic absorption. HCHs can also be absorbed through the skin when used as a lotion, cream, or shampoo for the treatment or control of ectoparasites. In general, HCH isomers and their metabolites can be temporarily stored in body fat. Absorbed HCHs are mainly excreted via the urine. Lesser amounts are excreted in feces. In rats, the highest concentrations have been found in liver, kidneys, body fat, brain, and muscles, with substantial deposition occurring in fatty tissue. Whole-body elimination half-lives may be 1–2 months but varies by isomer.
Uses Mechanism of Toxicity HCHs are potent insecticides. HCHs were widely used as commercial insecticides in the last half of the twentieth century. Because HCHs cause serious environmental problems, they
874
The g isoform (g-HCH; lindane) and a isoform are potent neurostimulants and convulsants, whereas the b and d forms
Encyclopedia of Toxicology, Volume 2
http://dx.doi.org/10.1016/B978-0-12-386454-3.00152-4
Hexachlorocyclohexanes Including Lindane
are primarily depressants. g-HCH mediated neurotoxicity is primarily the result of blockade of Cl influx through ionotropic g-aminobutyric acid receptors, resulting in depolarization and hyperexcitation of the postsynaptic neuronal membrane. g-HCH has been shown to enhance both spontaneous and evoked release of neurotransmitters from nerve terminals. These actions have been correlated with the ability of g-HCH to elevate Ca2þ in brain synaptosomes. g-HCH has also been shown to alter contractility in skeletal myocytes. d-HCH is particularly potent toward disrupting Ca2þ homeostasis in a variety of excitable and nonexcitable cells and altering contractility of cardiac muscle. d-HCH has been shown to stereoselectively mobilize Ca2þ from intracellular stores in cultured neural cells, which appears mediated by interaction with ryanodine receptors. g-HCH and b-HCH have been reported to have estrogenic actions.
Acute Toxicity In animals, g- and a-HCH can cause convulsions, and b-HCH can cause coma. All isomers can damage liver, including altered enzyme function, degeneration, and cancer, as well as kidney toxicity. The g-isomer is most potent acutely, but b-HCH is metabolized more slowly and becomes more toxic with repeated exposures. Exposure to large amounts of HCHs can harm the nervous system, producing a range of symptoms from headache and dizziness to seizures, and convulsions. The onset of signs and symptoms following exposure to HCH insecticides vary. HCHs can result in blood disorders, dizziness, headaches, and possible changes in the levels of sex hormones in the blood. The time interval between high dose exposure and the onset of symptoms is generally less than 12 h. The symptoms produced by these agents may last for weeks to months and patients often experience periodic relapses despite adequate therapy because of the initial lipid storage and subsequent redistribution of these chemicals.
875
reproductive parameters in adult offspring. g-HCH and b-HCH were reported to damage the ovaries and testes in animals.
Genotoxicity Technical grade HCHs produce dominant lethal mutations in mice, but studies of specific isomers mostly do not indicate mutagenicity.
Carcinogenecity Long-term oral administration of HCHs to laboratory rodents has been reported to result in liver cancer. The Department of Health and Human Services (DHHS) has determined that HCHs may cause cancer in humans. The International Agency for Research on Cancer (IARC) has classified HCHs as carcinogenic to animals and evidence in humans is inadequate.
Clinical Management When a large amount of HCH has been swallowed, emetics have been used to induce vomiting. Activated charcoal can also be used to decrease gastrointestinal absorption. To avoid skin absorption after exposure, clothing should be removed, and the skin should be washed. In case of eye contact, irrigate eyes immediately with water or saline. There are no known methods for reducing absorption following inhalation exposure. In the nervous system, g-HCH is thought to interfere with the gamma-Aminobutyric acid (GABA) system by interacting with the gamma-Aminobutyric acid type A (GABAA) receptor–ionophore complex at the picrotoxin binding site. The seizures caused by g-HCH can be antagonized by GABAA-mimetics. Use of anticonvulsants should include careful monitoring of hypotension, respiratory depression, and the need for endotracheal intubation. In the liver, g-HCH produces oxidative stress and increased lipid metabolism. Interfering with these mechanisms can decrease the toxicity of HCH.
Chronic Toxicity Exposure Standards and Guidelines In animals, chronic exposures to HCHs produce liver and kidney toxicity.
Immunotoxicity In rodents, HCH isomers produce immunotoxicity in adult repeated-dose studies, and in offspring following developmental exposures. There is evidence that HCHs affect the human immune system.
The JMPR (Joint FAO/WHO Meeting on Pesticide Residues) acceptable daily intake value for lindane is 0.005 mg kg day1. Minimal risk levels set by the US Agency for Toxic Substances and Disease Registry range from 0.05 to 0.0001 mg kg day1 for acute to chronic exposures to different isomers. There are no exposure standards for technical HCHs.
See also: Organochlorine Insecticides.
Further Reading Reproductive Toxicity HCHs are passed to the developing organism through the placenta and breast milk. HCHs do not cause birth defects. However, neurological and hormonal effects have been reported resulting in neurobehavioral alterations and altered
Lal, R., Dogra, C., Malhotra, S., et al., 2006. Diversity, distribution and divergence of lin genes in hexachlorocyclohexane-degrading sphingomonads. Trends Biotechnol. 24 (3), 121–130. Lal, R., Pandey, G., Sharma, P., et al., 2010. Biochemistry of microbial degradation of hexachlorocyclohexane and prospects for bioremediation. Microbiol. Mol. Biol. Rev. 74 (1), 58–80.
876
Hexachlorocyclohexanes Including Lindane
Nagata, Y., Endo, R., Ito, M., et al., 2007. Aerobic degradation of lindane (gammahexachlorocyclohexane) in bacteria and its biochemical and molecular basis. Appl. Microbiol. Biotechnol. 76 (4), 741–752. Nagata, Y., Tsuda, M., 2005. Metabolic pathway, genes, and enzymes for the degradation of chlorinated pesticide, gamma-hexachlorocyclohexane. Tanpakushitsu Kakusan Koso 50 (12), 1511–1518. Sauviat, M.P., Pages, N., 2002. Cardiotoxicity of lindane, a gamma isomer of hexachlorocyclohexane. J. Soc. Biol. 196 (4), 339–348. Singh, B.K., Kuhad, R.C., Singh, A., et al., 2000. Microbial degradation of the pesticide lindane (gamma-hexachlorocyclohexane). Adv. Appl. Microbiol. 47, 269–298. Vijgen, J., Abhilash, P.C., Li, Y.F., et al., 2011. Hexachlorocyclohexane (HCH) as new stockholm convention POPs – a global perspective on the management of Lindane and its waste isomers. Environ. Sci. Pollut. Res. Int. 18 (2), 152–162. Vizcaino, P., Pistocchi, A., 2010. A GIS model-based assessment of the environmental distribution of gamma-hexachlorocyclohexane in European soils and waters. Environ. Pollut. 158 (10), 3017–3027.
Zhulidov, A.V., Robarts, R.D., Headley, J.V., et al., 2003. A review of riverine fluxes of hexachlorocyclohexane and DDT to the Azov and Black seas from the former USSR and Russian Federation. J. Environ. Sci. Health A Tox. Hazard Subst. Environ. Eng. 38 (5), 753–769.
Relevant Websites http://www.atsdr.cdc.gov/substances/toxsubstance.asp?toxid¼138 – Agency for Toxic Substances & Disease Registry. http://www.inchem.org/documents/pims/chemical/pim257.htm – International Programme on Chemical Safety. http://www.drrichardhall.com/Articles/lindaine.pdf – Long-Term Psychological and Neurolgical Complications of Lindane Poisoning.