| A wide variety of end-points have been assessed in in vitro assays of the genotoxicity of formaldehyde (see IARC, 1995, for a review).
Generally, the results of these studies have indicated that formaldehyde
is genotoxic in both bacterial and mammalian cells in vitro (inducing both point and
large-scale mutations) (IARC, 1995). Formaldehyde induces mutations in
Salmonella typhimurium and in Escherichia coli, with positive
results obtained in the presence or absence of metabolic activation systems.
Formaldehyde increases the frequency of chromatid/chromosome aberrations, sister
chromatid exchange, and gene mutations in a variety of rodent and human cell
types. Exposure to formaldehyde increased DNA damage (strand breaks) in human
fibroblasts and rat tracheal epithelial cells and increased unscheduled DNA
synthesis in rat nasoturbinate and maxilloturbinate cells.
As most formaldehyde is deposited and absorbed in regions
with which it first comes into contact, genotoxic effects at distal sites
following inhalation or ingestion might not be expected. Exposure of male
Sprague-Dawley rats to 0.5, 3, or 15 ppm (0.6, 3.6, or 18 mg/m3) formaldehyde for 6 h/day, 5 days/week, for 1 or 8 weeks had no effect upon the proportion of bone marrow cells with cytogenetic anomalies (e.g., chromatid or chromosome breaks, centric fusions) compared with unexposed controls, although animals in the group exposed to the highest concentration had a modest (1.7- to 1.8-fold), statistically significant (i.e., P < 0.05) increase in the proportion of pulmonary macrophage with chromosomal
aberrations compared with controls (approximately 7% and 4%, respectively)
(Dallas et al., 1992). However, Kitaeva et al. (1990) observed a statistically significant increase in the proportion
of bone marrow cells with chromosomal aberrations (chromatid or chromosome
breaks) from female Wistar rats exposed to low concentrations of formaldehyde
for 4 h/day for 4 months, approximately 0.7%, 2.4%, and 4% in animals exposed
to 0, 0.42, or 1.3 ppm (0, 0.5, or 1.5 mg/m3), respectively. In older studies, exposure
of male and female F344 rats to approximately 0.5, 5.9, or 14.8 ppm (0.6, 7.1,
or 17.8 mg/m3) formaldehyde for 6 h/day for 5 consecutive days had no effect upon the
frequency of sister chromatid exchange or chromosomal aberrations and mitotic
index in blood lymphocytes (Kligerman et al., 1984). Statistically significant (P < 0.05) increases in the proportion of cells with micronuclei and nuclear
anomalies (e.g., karyorrhexis, pyknosis, vacuolated bodies) were observed
in the stomach, duodenum, ileum, and colon within 30 h of administration
(by gavage) of 200 mg formaldehyde/kg body weight to male Sprague-Dawley
rats (Migliore et al., 1989). No significant evidence of genotoxicity (e.g., micronuclei, chromosomal aberrations) in bone marrow cells, splenic
cells, or spermatocytes was reported in earlier studies in which various
strains of mice were injected intraperitoneally with formaldehyde (Fontignie-Houbrechts,
1981; Gocke et al., 1981; Natarajan et al., 1983).
The mutational profile for formaldehyde varies among cell
types and concentration of formaldehyde to which the cells were exposed
in vitro
and includes both point and large-scale changes. In human lymphoblasts, about
half of the mutants at the X-linked hprt locus had
deletions of some or all of the hprt gene bands; the other half were assumed to have point mutations (Crosby
et al., 1988). In a subsequent study, six of seven formaldehyde-induced mutants
with normal restriction fragment patterns had point mutations at AT sites,
with four of these six occurring at one specific site (Liber et al., 1989). Crosby et al. (1988) also examined the mutational spectra induced by formaldehyde at
the gpt gene in E. coli (Crosby et al., 1988). A 1-h exposure to 4 mmol formaldehyde/litre induced a spectrum of mutants that included large insertions (41%), large deletions (18%), and point mutations (41%), the majority of which were transversions occurring at GC base pairs. Increasing the concentration of formaldehyde to 40 mmol/litre resulted in a much more homogeneous spectrum, with 92% of the mutants being produced by a point mutation, 62% of which were transitions at a single AT base pair. In contrast to these findings, when naked plasmid DNA containing the gpt gene was treated with formaldehyde and shuttled through E. coli, most of
the mutations were found to be frameshifts.
References
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