Occurrence of styrene-7,8-oxide and styrene glycol in mouse after the administration of styrene.

A, Lof; Gullstrand, E; Lundgren, Ewa; Mb, Nordqvist

doi:10.5271/sjweh.2345

Cited by 24 publications

(5 citation statements)

References 12 publications

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“…Löf et al (1984) also analyzed blood and tissue samples from the liver and the whole lung for ST and SO in mice, 2 h after ip dose of 1.1, 2.3, 3.4, and 5.1 mmol/kg 14 C-ST, and determined the exposure-dose relationship for ST and SO in the liver and lung tissues (Lof et al, 1984). The PBPK model simulations predict a similar trend and provide a good fit to the data ( Figure 10).…”

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confidence: 98%

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

Sarangapani

Teeguarden

Cruzan

et al. 2002

Inhalation Toxicology

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Styrene (ST) is widely used to manufacture resins, glass-reinforced plastics, and a number of commercially important polymers (Miller et al., 1994). Chronic ST inhalation studies in rodents have demonstrated unique species specificity in the resulting pulmonary toxicity and carcinogenicity. Increased incidences of pulmonary bronchioloalveolar tumors have been observed in mice, but not in rats. No other tumor type was increased significantly in either species. Clara cells lining the respiratory epithelium metabolize ST to styrene 7,8-oxide (SO), which is cytotoxic and weakly genotoxic. Rodent species show marked differences in the distribution and regional density of Clara cells within the respiratory tract, as well as in their capacity to produce and eliminate SO. A mode of action-based physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of ST and SO in blood, liver, and the respiratory-tract tissues, particularly in terminal bronchioles (target tisue), in order to conduct interspecies extrapolations and determine the extent to which there is a pharmacokinetic basis for the observed species specificity. This PBPK model has a multicompartment description of the respiratory tract and incorporates species-specific quantitative information on respiratory-tract physiology, cellular composition, and metabolic capacity. The model is validated against multiple data sets, including blood, liver, and whole lung tissue concentration of ST and SO following multiple routes of exposure. The trend in neoplastic incidences in mice correlated well with model-estimated SO concentration in the terminal bronchioles. The PBPK model predicts a 10-fold lower SO concentration in the terminal bronchioles in rats compared to mice, which is consistent with the observed species sensitivity to the development of respiratory-tract neoplasms. The model-based analysis suggests that humans would be expected to be 100-fold less sensitive to ST-inducted lung tumors than mice, based on pharmacokinetic differences. Pharmacodynamic factors are also expected to contribute to species sensitivity, potentially augmenting pharmacokinetics-based differences.

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confidence: 98%

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

Sarangapani

Teeguarden

Cruzan

et al. 2002

Inhalation Toxicology

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“…The major urin ary excretion products, mandelic acid, phenylgl yoxylic acid and hippuric acid, are rel ated to styrene gl ycol, indicating the intermediate formation of styrene oxide. Styrene oxide has been detected in the blood of animal s experime nta lly expo sed to styre ne (2) . Low levels of this epoxide have also been indicated in human vo luntee rs exposed to styrene and in occ upation ally exposed workers (3).…”

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confidence: 99%

Monitoring occupational exposure to styrene from hemoglobin adducts and metabolites in blood.

Christakopoulos¹,

Bergmark²,

Zorcec³

et al. 1993

Scand J Work Environ Health

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“…However, in the lung, the entrance organ for vaporous ST, the SO burden of ST-inhaling rodents might be considerably higher than is to be expected from systemic concentrations, because lungs of rats and mice have been demonstrated to be able to form SO from ST (Cantoni et al, 1978;Carlson, 1997;Hynes et al, 1999;Mendrala et al, 1993;Nakajima et al, 1994;Oberste-Frielinghaus et al, 1999;Salmona et al, 1976). Although the occurrence of SO has been qualitatively shown in lungs of mice after dosing 14 Clabeled ST intraperitoneally (Lo ¨f et al, 1984), quantitatively reliable data on the SO burden in the lungs at steady state were not available so far. Assuming the SO lung burden to be most relevant for ST-induced tumorigenicity and considering lung tumorigenicity occurring only in mice, one might speculate the SO levels to be considerably higher in lungs of ST-exposed mice than in those of rats.…”

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confidence: 99%

Styrene-7,8-Oxide Burden in Ventilated, Perfused Lungs of Mice and Rats Exposed to Vaporous Styrene

Hofmann¹,

Pütz²,

Semder³

et al. 2005

Toxicological Sciences

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Styrene (ST) is an important industrial chemical. In long-term inhalation studies, ST-induced lung tumors in mice but not in rats. To test the hypothesis that the lung burden by the reactive metabolite styrene-7,8-oxide (SO) would be most relevant for the species-specific tumorigenicity, we investigated the SO burden in isolated lungs of male Sprague-Dawley rats and in-situ prepared lungs of male B6C3F1 mice ventilated with air containing vaporous ST and perfused with a modified Krebs-Henseleit buffer (37 degrees C). Styrene vapor concentrations were determined in air samples collected in the immediate vicinity of the trachea. They were almost constant during each experiment. Styrene exposures ranged from 50 to 980 ppm (rats) and from 40 to 410 ppm (mice). SO was quantified from the effluent perfusate. Lungs of both species metabolized ST to SO. After a mathematical translation of the ex-vivo data to ventilation and perfusion conditions as they are occurring in vivo, a species comparison was carried out. At ST concentrations of up to 410 ppm, mean SO levels in mouse lungs ranged up to 0.45 nmol/g lung, about 2 times higher than in rat lungs at equal conditions of ST exposure. We conclude that the species difference in the SO lung burden is too small to consider the genotoxicity of SO as sufficient for explaining the fact that only mice developed lung tumors when exposed to ST. Another cause is considered as driving force for lung tumor development in the mouse.

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Occurrence of styrene-7,8-oxide and styrene glycol in mouse after the administration of styrene.

Cited by 24 publications

References 12 publications

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

Physiologically Based Pharmacokinetic Modeling of Styrene and Styrene Oxide Respiratory-Tract Dosimetry in Rodents and Humans

Monitoring occupational exposure to styrene from hemoglobin adducts and metabolites in blood.

Styrene-7,8-Oxide Burden in Ventilated, Perfused Lungs of Mice and Rats Exposed to Vaporous Styrene

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