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The genotoxicity of ethylene oxide has been reviewed extensively
(IARC, 1994). Owing to the consistency of the results, only a brief summary
of studies conducted with in vitro systems or with Labouratory animals is provided here. Ethylene oxide is
a potent alkylating agent that has been genotoxic in virtually all studies
in which it was examined (reviewed in IARC, 1994). In in vitro testing, it induced DNA damage and gene mutations in bacteria, yeast,
and fungi and gene conversion in yeast. In mammalian cells, observed effects
include gene mutations, micronucleus formation, chromosomal aberrations,
cell transformation, unscheduled DNA synthesis, sister chromatid exchange,
and DNA strand breaks. Notably, Hallier et al. (1993) observed that the frequency of sister chromatid exchange in human
peripheral blood lymphocytes exposed in
vitro to ethylene oxide was higher in cells isolated from individuals
expressing low levels of GSTT1 than in cells from subjects expressing higher
levels of this enzyme.
The results of in vivo studies on the genotoxicity of ethylene oxide
have also been consistently positive (see IARC, 1994) following ingestion,
inhalation, or injection. In vivo exposure to ethylene oxide induced gene
mutation at the hypoxanthine phosphoribosyl transferase (Hprt) locus in
mouse and rat splenic T-lymphocytes; sister chromatid exchange was induced in
lymphocytes from rabbit, rat, and monkey, in bone marrow cells from mouse and
rat, and in rat spleen. Increases in the frequency of gene mutations in the lung
(lacI locus) (Sisk et al., 1997) and in T-lymphocytes (Hprt locus) (Walker et al., 1997a) have been observed in transgenic mice exposed to ethylene oxide
via inhalation, at concentrations similar to those in carcinogenesis bioassays
with this species (NTP, 1987).
In male Big BlueR (lacI transgenic) B6C3F1 mice
exposed to 0, 92, 183, or 366 mg ethylene oxide/m3 for 6 h/day, 5
days/week, for 4 weeks, the observed mean (}SE) frequency of mutation at the
Hprt locus in splenic T-lymphocytes was 2.2 (}0.03) ~ 10?6,
3.8 (}0.5) ~ 10?6 (P = 0.009), 6.8 (}0.9) ~ 10?6
(P = 0.001), and 14.1 (}1.1) ~ 10-6 (P < 0.001), respectively (Walker et al., 1997). The frequency of Hprt mutations in
splenic T-lymphocytes was increased (compared with unexposed controls) 5.0- to
5.6-fold in male F344 rats and (non-transgenic) male B6C3F1 mice
exposed to 366 mg ethylene oxide/m3 for 6 h/day, 5 days/week, for 4 weeks (Walker et al., 1997b). Similarly, the frequency of lacI mutations
in the lungs, bone marrow, and spleen, but not in germ cells, was increased in
male Big BlueR (lacI transgenic) B6C3F1 mice
exposed to 0 or 366 mg ethylene oxide/m3 (Sisk et al., 1997; Recio et al., 1999).
In vivo exposure to ethylene oxide also induced heritable mutations or effects
in germ cells in rodents (IARC, 1994). Ethylene oxide induced dominant
lethal effects in mice and rats and heritable translocations in mice. There
were dominant visible and electrophoretically detectable mutations in the
offspring of male mice exposed (by inhalation) to 366 mg ethylene oxide/m3 for 6 h/day, 5 days/week, for 7 weeks and then mated. This exposure regimen
was adopted to ensure that all progeny originated from sperm exposed during
the entire spermatogenic process (Lewis et al., 1986). In a study in which male (C3H ~ 101)F1 mice were exposed by inhalation to 0, 302, 373, 458, or 549
mg ethylene oxide/m3, 6 h/day, 5 days/week, for 6 weeks, then daily
for an additional 2.5 weeks, and subsequently mated to T-stock (or [SEC ~
101]F1) females, the percent dominant lethals (P < 0.01 at
concentrations >373 mg/m3, compared with controls) was 0 (0), 6 (8), 14 (13), 23 (24), and 60 (45),
respectively (Generoso et al., 1990). The frequency of translocation carriers (P < 0.01 at all
concentrations, compared with controls) among the progeny of these groups of
ethylene oxide-exposed male mice mated to T-stock (or [SEC ~
C57BL]F1) females (data combined) was 1/2068 (0.05%), 32/1143 (2.8%), 52/1021 (5.1%),
88/812 (10.8%), and 109/427 (25.5%), respectively (Generoso et al., 1990).
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