There is an extensive database on the genotoxicity of chloral
hydrate and its metabolites. A complete summary of these results is provided
in US EPA (2000). Chloral hydrate did not induce mutation in most strains
of Salmonella typhimurium, but did in some studies with S. typhimurium
TA100 and in a single study with S. typhimurium TA104. The latter response was inhibited by free-radical scavengers alpha-tocopherol
and menadione (Ni et al., 1994). Chloral hydrate did not induce mitotic crossing-over in Aspergillus nidulans in the absence of metabolic activation. Chloral
hydrate caused weak induction of meiotic recombination in the presence
of metabolic activation and gene conversion in the absence of
metabolic activation in Saccharomyces cerevisiae. It did not induce
reverse mutation in S. cerevisiae. Chloral hydrate clearly induced aneuploidy in various fungi in the absence
of metabolic activation.
Chloral hydrate induced somatic and germ cell mutations
in Drosophila melanogaster.
Chloral hydrate did not produce DNA-protein cross-links in rat
liver nuclei, DNA single-strand breaks/alkaline-labile sites in
primary hepatocytes in vitro, or DNA repair in Escherichia coli.
One study showed induction of single-strand breaks in liver DNA of
both rats and mice treated in vivo; another study in both species
using higher concentrations of chloral hydrate found no such effect.
Chloral hydrate was weakly mutagenic, but did not induce
micronuclei in mouse lymphoma cells in vitro. Chloral hydrate
increased the frequency of micronuclei in Chinese hamster cell lines.
Although a single study suggested that chloral hydrate induces
chromosomal aberrations in Chinese hamster CHED cells in vitro, the micronuclei produced probably contained whole chromosomes and not chromosome fragments, as the micronuclei could all be labelled with antikinetochore antibodies. In kangaroo rat kidney epithelial cells, chloral hydrate inhibited spindle elongation and broke down mitotic microtubuli, although it did not inhibit pole-to-pole movement of chromosomes. It produced multipolar spindles, chromosomal dislocation from the mitotic spindle, and a total lack of mitotic spindles in Chinese hamster DON:Wg.3h cells.
Chloral hydrate weakly induced sister chromatid exchange
in cultures of human lymphocytes. It induced micronuclei, aneuploidy, C-mitosis,
and polyploidy in human lymphocytes in vitro. Micronuclei were induced in studies with human whole blood cultures but
not in one study with isolated lymphocytes. The differences seen in the
micronucleus test have been attributed to differences between whole blood
and purified lymphocyte cultures (Vian et al., 1995), but this hypothesis has not been tested. Chloral hydrate increased
the frequency of chromosomal aberrations in mouse bone marrow, spermatogonia,
and primary and secondary spermatocytes, but not in oocytes, after in vivo
treatment. Chloral hydrate induced chromosomal aberrations in mouse
bone marrow erythrocytes after treatment in vivo. In one of these
studies, the use of antikinetochore antibodies suggested induction of
micronuclei containing both whole chromosomes and fragments. Chloral
hydrate induced micronuclei in the spermatids of mice treated in vivo in some studies.
Chloral hydrate induced aneuploidy in the bone marrow of mice
treated in vivo. It increased the rate of aneuploidy
in mouse secondary spermatocytes. It did not produce polyploidy in
bone marrow, oocytes, or gonosomal or autosomal univalents in primary
spermatocytes of mice treated in vivo. Chloral hydrate, however,
induced polyploidy and meiotic delay when a synchronized population of
mouse oocytes was exposed in vitro prior to the resumption of maturation.
Trichloroethanol, a reduction product of chloral hydrate,
did not induce lambda prophage in E. coli or mutation in S. typhimurium
TA100. Trichloroethanol caused spindle aberrations when mouse oocytes
were treated in vitro.
Trichloroacetic acid did not induce lambda prophage in E. coli
and was not mutagenic to S. typhimurium in the presence or absence
of metabolic activation. Trichloroacetic acid was weakly positive in
the mouse lymphoma assay with metabolic activation. Trichloroacetic
acid also did not induce chromosomal damage in human lymphocytes or
micronuclei in bone marrow in vitro. It is unclear whether
trichloroacetic acid can induce chromosomal damage in vivo, because
some studies have been positive and others negative.
Dichloroacetic acid did not induce differential toxicity in DNA
repair-deficient strains of S. typhimurium but did induce lambda
prophage in E. coli. Dichloroacetic acid gave equivocal results for
gene mutation in S. typhimurium TA100 and TA98. Dichloroacetic acid
was weakly mutagenic in the in vitro mouse lymphoma assay and
induced chromosomal aberrations but not micronuclei or aneuploidy in
that test system. Dichloroacetic acid induced micronuclei in mouse
polychromatic erythrocytes in vivo and mutations at the lacI locus
in the transgenic B6C3F1 mouse (the Big Blue Mouse) in vivo at an exposure that induces liver tumours in male mice. It is unclear whether
dichloroacetic acid can induce primary DNA damage, as some assays are positive
and others negative.
References
・US EPA (2000) Toxicological review on chloral hydrate. Available from US Environmental Protection Agency's Risk Assessment Hotline
[513-569-7254 (phone), 513-569-7159 (fax), rih.iris@epa.gov (e-mail address),
or www.epa.gov/iris (Website)].
・Ni Y-C, Wong T-Y, Kadlubar FF, Fu PP (1994) Hepatic metabolism of chloral
hydrate to free-radical(s) and induction of lipid peroxidation. Biochemical and biophysical research communications, 204: 937-943.
・Vian L, Van Hummelen P, Bichet N, Gouy D, Kirsch-Volders M (1995) Evaluation
of hydroquinone and chloral hydrate on the in vitro
micronucleus test on isolated lymphocytes. Mutation research, 334: 1-7.
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