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.
(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).
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.
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.
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.
... /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.
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.
IN INSECTS MAJOR METABOLITE OF GAMMA-BHC IS
S-(2,4-DICHLOROPHENYL)-GLUTATHIONE.
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.
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).
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.
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.
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. TOXNET
MAMMALIAN BIOTRANSFORMATION OF BHC ISOMERS INVOLVES
FORMATION OF CHLOROPHENOLS (TRICHLOROPHENOL, TETRACHLOROPHENOL &
PENTACHLOROPHENOL), WHICH ARE EXCRETED FREE & AS CONJUGATES OF SULFURIC
& GLUCURONIC ACIDS.
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.
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. TOXNET
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