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Metabolism of Lindane

HCH (lindane) breaks down into many other substances. One of these substances is pentachlorophenal which is known to be harmful. Another substance, called chlorinated hydrocarbon epoxide, may cause cancer in animals.

Angerer et al. (1983) determined that chlorophenals were the primary urinary metabolites of γ-HCH excreted by workers involved in γ-HCH production. The metabolites 2,3,5-, 2,4,5- and 2,4,6-trichlorophenal accounted for almost 57.7% of the γ-HCH metabolites identified in the urine collected during the last 2 hours of the workers' shifts. Other urinary metabolites included other trichlorophenols, dichlorophenols, tetrachlorophenols, and dihydroxychlorobenzenes. Pentachlorophenol has also been identified as a urinary metabolite in humans following occupational exposure (Engst et al. 1979). In vitro investigations indicate that human liver microsomes convert γ-HCH by dechlorination, dehydrogeneration, dehydrochlorination, and hydroxylation to five primary metabolites: 3,6/4,5-hexachlorocyclohexane, pentachlorocyclohexane, 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol, and pentachlorobenzene (Fitzloff et al. 1982). Simular in vitro studies have demonstrated  that an epoxide forms during the metabolism of pentachlorocyclohexane. This stable halogenated hydrocarbon epoxide metabolite may be responsible for the mutagenic and carcinogenic effects of γ-HCH (Fitzloff and Pan 1984).

In animals, γ-HCH appears to be transformed by hepatic enzymes to form chlorophenols, chlorobenzene, chlorocyclohexanes, chlorocyclohexanals, and conjugates of mercapturic acid, glucuronide, and sulfate (Chadwick and Freal 1972a; Chadwick et al. 1978a; Engst et al. 1979; Kujawa et al. 1977). Thes metabolites have been identified in various tissues and in the urine of laboratory animals. Metabolites found in the liver of rats following intermediate exposure of γ-HCH via gavage or diet include di-, tri-, tetra-, and pentachlorobenzenes; pentachlorocyclohexanes; and pentachloro-2-cyclohexen-1-ol (Chadwick and Freal 1972a; Kujawa et al. 1977). Metabolites identified in the blood of these rats include di-, tri-, tetra-, and pentachlorophenols and pentachloro-2-cyclohexen-1-ol (Kujawa et al. 1977) Di-, tri-, and tetrachlorophenols; pentachlorocyclohexenes; and pentachloro-2-cyclohexen-1-ol have been identified in samples of kidney, spleen, heart, and brain tissue from rats fed γ-HCH (Kujawa et al. 1977). Metabolites found in the urine include tri-, tetra-, and pentachlorophenol; pentachloro-2-cyclohexen-1-ol; and isomers of tetrachloro-2-cyclohexen-1-ol (Chadwick and Freal 1972a; Chadwick et al. 1978a; Kujawa et al. 1977) The metabolism of γ-HCH in the intestine was reported to be very minor, or the metabolites were completely absorbed. No metabolites were detected in the feces or in the adrenal gland (Kujawa et al. 1977). In vitro preparations using rat liver slices have also found that γ-HCH is converted to hexachlorobenzene (Gopalaswamy and Aiyar 1984).

Excerpt from:
 
ATSDR Toxilogical Profile for ALPHA-, BETA-, GAMMA-, AND DELTA-HEXACHLOROCYCLOHEXANE (ATSDR, 1997)


Many of the symptoms noted on this site are also associated with exposure to many of the chemicals (metabolites), which lindane has been found to degrade into in humans, animals and the environment.

metabolism : The total of all chemical changes that take place in a cell or an organism. These changes produce energy and basic materials that are needed for important life processes.

metabolism
(Gr. metaballein to turn about, change, alter) the sum of all the physical and chemical processes by which living organized substance is produced and maintained (anabolism), and also the transformation by which energy is made available for the uses of the organism (catabolism).
metabolite
any substance produced by metabolism or by a metabolic process.
metabolization
the chemical process by which matter is broken down into simpler substances, said especially of food processed by the human body.

Multilingual Glossary of technical and popular medical terms in nine European Languages

metabolismestofskifte

Metabolismus, Umwandlung,  Stoffwechsel

metabolismo (nm), conjunto de reacciones bioquímicas dentro del organismo

métabolisme (m), transformations qui s'accomplissent dans l'organisme

metabolismo, complesso dei processi fisici e chimici dell'organismo

metabolisme, stofwisseling

metabolismo/conjunto de reacções bioquímicas dentro do organismo


Metabolism/Metabolites:

METABOLISM OF GAMMA-BHC WAS STUDIED IN 21 WORKERS PRODUCING THIS INSECTICIDE. USING GC WITH ECD & MASS SPECTROMETRY 14 MONO-, DI-, TRI-, & TETRACHLOROPHENOLS WERE IDENTIFIED IN URINE. SEVEN DIHYDROXYCHLOROBENZENES OF UNKNOWN CONFIGURATION WERE DETECTED. 2,4,6-, 2,3,5-, & 2,4,5-TRICHLOROPHENOL WERE MAIN METABOLITES & WERE EXCRETED IN NEARLY EQUAL QUANTITIES.
[ANGERER J ET AL; INT ARCH OCCUP ENVIRON HEALTH 52 (1): 59-68 (1983)]**PEER REVIEWED**

HUMAN LIVER MICROSOMES METABOLIZED LINDANE TO 4 PRIMARY METABOLITES, GAMMA-1,2,3,4,5,6-HEXACHLOROCYCLOHEX-1-ENE; GAMMA-1,3,4,5,6-PENTACHLOROCYCLOHEX-1-ENE; BETA-1,3,4,5,6-PENTACHLOROCYCLOHEX-1-ENE; & 2,4,6-TRICHLOROPHENOL. THE SECONDARY METABOLITES, 2,3,4,6-TETRACHLOROPHENOL & PENTACHLOROBENZENE WERE ALSO FORMED.
[FITZLOFF JF ET AL; XENOBIOTICA 12 (3): 197-202 (1982)]**PEER REVIEWED**

IN MICE, URINARY METABOLITES OF SINGLE IP INJECTION ... ACCOUNTED FOR 57% OF DOSE ... & CONSISTED MOSTLY OF GLUCURONIDE & SULFATE CONJUGATES OF 2,4,6-TRICHLOROPHENOL & 2,4-DICHLOROPHENOL. NO MERCAPTURIC ACID CONJUGATES WERE DETECTED. WHEN ... ADMIN IP TO RATS, 2,3,5- & 2,4,5-TRICHLOROPHENOL WERE IDENTIFIED IN URINE ... FREE OR AS CONJUGATES WITH GLUCURONIC &/OR SULFURIC ACID. WHEN WEANLING SPRAGUE-DAWLEY RATS WERE FED 400 MG/KG DIET LINDANE, 3,4-DICHLOROPHENOL, 2,4,6-TRICHLOROPHENOL, 2,3,4,5- & 2,3,4,6-TETRACHLOROPHENOL & 2,3,4,5,6-PENTACHLORO-2-CYCLOHEXENE-1-OL WERE IDENTIFIED IN URINE. PENTACHLOROBENZENE, 2,3,4,6- & 2,3,5,6-TETRACHLOROPHENOL & 2,4,6-TRICHLOROPHENOL WERE EXCRETED IN URINE OF RATS GIVEN ORAL DOSES ... PRETREATMENT OF RATS WITH OTHER ORGANOCHLORINE PESTICIDES MODIFIED LINDANE METABOLISM.
[IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer,1972-PRESENT. (Multivolume work).,p. V20 218 (1979)]**PEER REVIEWED**

... /In vitro studies using rat liver homogenates to determine/ mechanism involved in formation of phenols ... indicated three pathways of formation ... from lindane: 1) Direct hydroxylation of lindane/derivatives & formation of gem-chlorohydrins. Subsequent decomposition to pentachlorocyclohexanones & dehydrochlorinations of tautomers give rise to 2,4,6-TCP. 2) Formation of HCCH (hexachlorocyclohexene) & PCCH (pentachlorocyclohexene) which give rise to gem-chlorohydrins through an ene-like reaction with activated oxygen. These products spontaneously form enones, tautomerize, & yield 2,4,5-TCP & 2,3,4,6-TeCP from PCCH & HCCH, respectively. 3) Direct hydroxylation of benzene analogs which form.
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 72]**PEER REVIEWED**

Laying hen pheasants were admin (14)C-lindane in gelatin capsules & with seed treated with labeled lindane. Residues were determined in eggs & in tissues of hatched chicks. Residues in eggs from birds given treated seed showed greater variation in total (14)C than from capsule-fed birds. Egg yolks were analyzed by ECGC on 3 columns & by use of Coulson conductivity detector on 2 columns. Confirmation was by GC/MS. Chick tissue contained: 1,2-DCB; 1,2,4-TCB; 1,2,3,4-TeCB; 1,2,3,5-/or 1,2,4,5,-TeCB; Gamma-PCCH; PCB. Yolks contained these metabolites plus 1,3,5-TCB & 1,2,3-TCB.
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 75]**PEER REVIEWED**

IN INSECTS MAJOR METABOLITE OF GAMMA-BHC IS S-(2,4-DICHLOROPHENYL)-GLUTATHIONE.
[Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 198]**PEER REVIEWED**

In vitro studies with fly homogenates showed that deuteriated lindane breakdown was 6-fold slower than non-deuteriated lindane. Lindane treated houseflies produced gamma-1,2,3,4,5,6-hexachlorocyclohexene (HCCH), gamma-pentachlorocyclohexene (PCCH), pentachlorobenzene (PCB) & tri- & tetrachlorobenzenes. PCB was identified as in vivo metabolite of gamma-HCCH but not from gamma- ... /or other/ isomers of PCCH. In presence of housefly microsomal fraction & NADPH, lindane produced gamma-HCCH & -PCCH, & alpha-PCCH. The latter was not observed in in vivo studies. ... Other in vitro observations showed no PCB from lindane but small amt from gamma-HCCH. Formation of S-(2,4-dichlorophenyl)glutathione indicated conjugation probably occurred at position 6 of gamma-PCCH ... A similar mechanism would occur with alpha-PCCH or gamma-HCCH. From this it appears that cis-dehydrogenation & cis-dehydrochlorination leads to gamma-HCCH & alpha-PCCH, respectively, & that trans-dehydrochlorination leads to gamma-PCCH. PCB was derived from gamma-HCCH. Thus, glutathione conjugation is believed to occur at the PCCH or HCCH stage.
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 78]**PEER REVIEWED**

gamma-HCH was added to culture soln of ... algae Chlorella vulgaris ... & Chlamydomonas reinhardtii ... in axenic culture. Chromatographic analyses indicated formation of cmpd identified as PCCH. In mold culture containing lindane, gamma-PCCH & PCB/or HCB were observed. In other studies with mold cultures, lindane metabolites were identified by use of 5 different GC columns & mass spectrometry. Sixteen cmpd were observed ... there were also at least 4 unidentified metabolites, one of which is believed to be 2,3,4,5,6-pentachlorocyclohexen-2-ol-1 (PCCOL).
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 78]**PEER REVIEWED**

Of 354 microorganisms isolated from the environment, 71 were capable of metabolizing gamma-HCH. Using Pseudomonas putida, it was shown that there were 2 patterns of metabolism of gamma-HCH & that in measure they were related to the nutritional properties of the medium. ... Studies also indicated that the 1st step of gamma-HCH metabolism was oxidative & required NAD; & that the 2nd step was stimulated by FAD. The NAD requiring route produced gamma-BTC & alpha-HCH whereas the other route was one of non-specific metabolism of gamma-HCH to gamma-PCCH.
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 79]**PEER REVIEWED**

Lindane was applied to beans (Phaseolus vulgaris) & maize (Zea mays). Analyses of bean plants indicated presence of gamma-PCCH & 1,2,4-TCB. In addn to these ... cmpd, 1,2,3-TCB was observed in maize extracts. When maize plants were exposed to gamma-PCCH in aqueous soln, metabolites observed with GC & MS were m-DCB; 1,2,4-TCB; 1,2,4,5-TeCB; 1,2,3,4-TeCB; 2,4,5-TCP; & 2,3,5-TCP. When plants were used, in addn to m-DCB, 1,2,4,5-TeCB, & 2,4,5-TCB, compounds identified as 1,2,3-TCB & 2,4,6-TCP were observed.
[Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 77]**PEER REVIEWED**

Bacterial metabolites of lindane include the following: gamma-2,3,4,5,6-pentachloro-1-cyclohexene, gamma-3,4,5,6-tetrachloro-1-cyclohexene, beta-3,4,5,6-tetrachloro-1-cyclohexene, pentachlorobenzene, 1,2,4,5-tetrachlorobenzene, and 1,2,3,5-tetrachlorobenzene.
[Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S.Environmental Protection Agency, December 1979.,p. 32-7]**PEER REVIEWED**
TOXNET


MAMMALIAN BIOTRANSFORMATION OF BHC ISOMERS INVOLVES FORMATION OF CHLOROPHENOLS (TRICHLOROPHENOL, TETRACHLOROPHENOL & PENTACHLOROPHENOL), WHICH ARE EXCRETED FREE & AS CONJUGATES OF SULFURIC & GLUCURONIC ACIDS.
[National Research Council. Drinking Water & Health Volume 1. Washington, DC: National Academy Press, 1977. 585]**PEER REVIEWED**

14 mono-, di-, tri- & tetrachlorophenols were identified in the urine of 21 workers producing gamma-hexachlorocyclohexane (HCH), & 7 dihydroxychlorobenzenes of unknown configuration were detected. The main metabolites of gamma-HCH, 2,4,6-, 2,3,5- & 2,4,5-trichlorophenol, were excreted in nearly equal quantities.
[Angerer J et al; International Archives of Occupational and Environmental Health 52 (1): 59-67 (1983)]**PEER REVIEWED**

Although alpha, beta, and gamma isomers of hexachlorocyclohexane are biotransformed at significantly different rates in vivo by dehydrochlorination, glutathione conjugation, and aromatic ring hydroxylation to produce a variety of excretable phenolic products, the beta isomer is much more slowly metabolized and is found as the predominant tissue residue.
[Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. 579]**PEER REVIEWED**
TOXNET


gamma-Hexachlorocyclohexane degradation - Standard metabolic pathway


Occupational exposure to hexachlorocyclohexane. V. Gas chromatographic determination of monohydroxychlorobenzenes (chlorophenols) in urine.

Angerer J, Heinrich R, Laudehr H

A sensitive and specific gas chromatographic method is described for the simultaneous determination of ten chlorinated phenols that appear in the urine of persons exposed to hexachlorocyclohexane (HCH). The phenolic compounds in the urinary samples are hydrolysed in an acidic medium and derivatised with acetic anhydride. This sample treatment permits routine application. The stationary phase (8% DC 200 on Chromosorb G AW-DMCS) possesses a high separating capability for the acetic esters of the chlorophenols. The detection limits lie between 4.9 and 18.6 micrograms/l and allow determinations even in the environmentally interesting concentration range. The recoveries determined using aqueous standards range between 87 and 119% and the relative standard deviations are between 4.4 and 10.1%.
PMID: 6170587, UI: 82052085


The urinary and biliary excretion of (14)C-labeled o-chlorophenol were investigated in 12 species of freshwater fish when immersed in sublethal concentrations of the cmpd in the aquarium water for 48 hr. o-Chlorophenol sulfate and o-chlorophenol glucuronide were detected in both the aquarium water and the bile of all the fish species. [R33] ... Various chlorophenols are formed as intermediate metabolites during the microbiological degradation of the herbicides 2,4-D & 2,4,5-T and the pesticides Silvex, Ronnel, lindane, and benzene hexachloride. /Chlorophenols/ [R34] Mammalian metabolism of chlorobenzene yields 2-chlorophenol as /one of/ the major products. [R35]

Spectrum Laboratories Inc.


Isolation and characterization of Tn5-induced mutants of Pseudomonas paucimobilis UT26 defective in gamma-hexachlorocyclohexane dehydrochlorinase (LinA).
1-Chlorocyclohexene oxide
beta-Pentachlorocyclohexene
gamma-Pentachlorocyclohexene
Octafluorodichlorocyclohexene


Metabolites

 

 

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