In the absence of cytotoxicity, acrolein induces gene mutations in both bacteria (with or without metabolic activation) (Hemminki et al., 1980; Lijinsky & Andrews, 1980; Hales, 1982; Lutz et al., 1982; Haworth et al., 1983; Marnett et al., 1985; Foiles et al., 1989; Parent et al., 1996) and mammalian cells in culture (Smith et al., 1990), as well as structural chromosomal aberrations in Chinese hamster
ovary (CHO) cells (Au et al., 1980) and sister chromatid exchanges in CHO cells (Au et al., 1980; Galloway et al., 1987) and cultured human lymphocytes (Wilmer et al., 1986). The mode of induction of the genotoxicity of acrolein appears to
involve the induction of DNA damage. Acrolein binds to DNA, forms DNA-protein
cross-links (Grafstrom et al., 1988), and induces DNA single strand breaks in human fibroblasts (Dypbukt et al., 1993) and bronchial epithelial cells (Grafstrom et al., 1988). In human fibroblasts, acrolein induces mutations at the HPRT
locus in DNA repair-deficient cells from xeroderma pigmentosum patients
but not in normal cells (Curren et al., 1988), supporting DNA damage as the primary mechanism for acrolein-induced
mutagenesis. The results of in vitro studies suggest that intracellular glutathione (or other free sulfhydryl
groups) may protect against the DNA-damaging effects of acrolein (Eisenbrand
et al., 1995).
Although the results of in vitro studies indicate that acrolein
can react directly with DNA and proteins to form stable adducts, an increased
formation of DNA-protein cross-links was not observed in the nasal mucosa
of male F344 rats exposed in vivo (by inhalation) to 5 mg acrolein/m3 (2 ppm) for 6 h (Lam et al., 1985).
Although less relevant to the assessment of genotoxicity at the site of initial contact (i.e., where critical effects occur), in vivo studies of the genotoxicity of acrolein at systemic sites are not extensive.
In a dominant lethal study in male ICR/Ha Swiss mice, acrolein (administered
by intraperitoneal injection) at doses up to 2.2 mg/kg body weight had
no effect upon the numbers of pregnancies, implants, or fetal deaths (Epstein et al., 1972). Increases in the frequency of chromosomal aberrations in peripheral
blood lymphocytes or bone marrow cells were not observed in studies in
which F344 rats were exposed (by inhalation) to concentrations up to 9.2
mg acrolein/m3 (4.0 ppm) for 6 h/day, 5 days/week, for 62 days (Kutzman,
1981) or in which Sprague-Dawley rats were administered (by intraperitoneal
injection) single doses of up to 4.1 mg acrolein/kg body weight (BSC, 1982b),