Disposition of [Ring-U-14C]styrene in Rats and Mice Exposed by Recirculating Nose-Only Inhalation

Abstract

The disposition of styrene was studied in a group of 12 Sprague Dawley rats and two groups of 30 CD1 mice exposed separately to 160 ppm [ring-U-(14)C]styrene of high specific radioactivity of 1.92 TBq x mol(-1) (52 Ci x mol(-1)) for 6 h. A nose-only exposure system was successfully adapted to (1) recirculate a portion of the flow to limit the amount of (14)C-styrene required, and (2) avoid any polymerization of the compound. The mean uptake of styrene in rats was 113 +/- 7 micromol x kg(-1) x h(-1) and stable over time. The mean uptake in mice was higher, 189 +/- 53 and 183 +/- 76 micromol x kg(-1) x h(-1), for the first and second mouse inhalation experiment, but decreased steadily over time. Some of the mice, but none of the rats, showed signs of overt toxicity. The overall excretion of styrene and its metabolites was quantitatively similar in rats and mice. Urinary excretion was the primary route of excretion while fecal excretion accounted for only a very small part of the radioactivity. There was, however, a significant difference between mice and rats in the exhalation of (14)CO(2), which must have resulted from opening and subsequent breakdown of the aromatic ring. In mice the exhalation of (14)CO(2) accounted for 6.4 +/- 1.0 and 8. 0 +/- 0.5% of the styrene retained during the first and second mouse inhalation experiment. In rats, exhalation of (14)CO(2) accounted for only 2.0 +/- 0.7% of the retained styrene. Together with the results from the quantitative whole-body autoradiography (showing significantly higher binding in mouse lung and nasal passages compared to rat) the larger production of (14)CO(2) might be indicative of the formation of reactive ring-opened metabolites in the mouse lung, which, in turn, might be related to the observed development of bronchioalveolar tumors and nasal effects in mice exposed to styrene.

Effects of styrene and its metabolites on different lung compartments of the mouse—cell proliferation and histomorphology

“…No evidence of DNA adduct formation was measured in either the mouse or rat lung samples at a limit of detection of 3 and 5 adduct/10 7 nucleotides for the -and -isomers, respectively. Other studies including Boogaard et al (2000) and Otteneder et al (2002) have also indicated that mouse lung tumor formation is not associated with DNA adduct formation. Moreover, styrene did not cause mutations when tested in vivo (Speit and Henderson, 2005).…”

Evaluation of nose-only aerosol inhalation chamber and comparison of experimental results with mathematical simulation of aerosol deposition in mouse lungs

“…The disadvantage with these systems is a large deposition of the aerosolized drug all over the animal's Alternatively, nose-only inhalation chambers were developed to avoid the above problems for small animals like rats and mice. 23,24 Validation of these nose-only inhalation chambers is an important step towards their suitable use in inhalation studies. 25,26 Unfortunately, little data is available in the literature on the fraction of drug that deposits in the mice and their lungs using such chambers.…”

Effects of Pregnancy, Age and Sex in the Metabolism of Styrene in Rat Liver in Relation to the Regulation of Cytochrome P450 Enzymes

“…4-VP is a more potent toxicant in mice than either styrene or SO. Approximately 95% of the styrene retained upon inhalation was excreted as urinary metabolites by rats 12) .…”