IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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increase in the induction of micronuclei in human lymphocytes treated in vitro. These
results are consistent with those previously reviewed.
Three recent studies have reported that DNA strand breaks and alkali-labile sites are
induced in multiple tissues (lung, liver, kidney, bone marrow and lymphocytes) of mice
exposed to styrene 7,8-oxide by a single intraperitoneal injection at doses of 100–400
mg/kg bw. Results from previously evaluated studies of induction of cytogenetic damage
in rodents exposed to styrene 7,8-oxide in vivo were predominately negative. Two of
three studies reported some evidence of exposure-related sister chromatid exchange
induction and two of four studies reported that styrene 7,8-oxide induced chromosomal
aberrations. Neither of the two micronucleus studies previously evaluated reported
increases in the frequency of micronuclei following exposures to styrene 7,8-oxide via
intraperitoneal injection (IARC, 1994b).
4.5 Mechanistic considerations
IARC MONOGRAPHS VOLUME 82
Following chronic exposure to styrene, a carcinogenic response has been observed
only in mouse lung, but not in tissues of rats.
Studies in humans and experimental animals and with tissues from both rodents and
humans in vitro using a variety of experimental approaches have attempted to determine
the mode of action for the styrene toxicity and carcinogenicity observed in experimental
animals. In general, the objectives of many of these studies have been (1) to explore the
basis for the observed interspecies differences in tumour response between rats and mice,
(2) to determine the critical steps in styrene carcinogenicity and (3) to identify the most
likely chemical species responsible for the initiation of tumour development.
At least two plausible modes of action, which are not mutually exclusive, for styrene
carcinogenicity are suggested by the existing data. One involves a DNA-reactive mode
of action initiated by the metabolic conversion of styrene to styrene 7,8-oxide, a
genotoxic metabolite of styrene, and the subsequent induction of DNA damage in target
tissues; the other involves cytotoxic effects in lungs of mice exposed to styrene. For
either mode of action, interspecies differences in the metabolism and toxicokinetics of
styrene and styrene 7,8-oxide that exist between rats and mice are likely to play a key
role.
4.5.1 Interspecies differences in toxicokinetics and metabolism
A number of studies in human volunteers and in workers occupationally exposed to
styrene by inhalation (summarized by Bond, 1989) have shown that styrene toxicokinetics
and metabolic pathways are qualitatively similar in humans and experimental
animals, although there are quantitative differences. In humans, between 60 and 70% of
inhaled styrene is absorbed and more than 85% of the absorbed styrene is eliminated in
the urine as mandelic and phenylglyoxylic acids. These metabolites are formed following
hydrolysis of styrene 7,8-oxide, which indicates that humans metabolize styrene to