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Styrene respiratory tract toxicity and mouse lung tumors are mediated by CYP2F-generated metabolites
George Cruzan1, Gary P Carlson, Keith A Johnson
1ToxWorks, Bridgeton, New Jersey 08302-6640, USA.
Abstract:
Mice are particularly sensitive to respiratory tract toxicity following styrene exposure. Inhalation of styrene by mice results in cytotoxicity in terminal bronchioles, followed by increased incidence of bronchioloalveolar tumors, as well as degeneration and atrophy of nasal olfactory epithelium. In rats, no effects on terminal bronchioles are seen, but effects in the nasal olfactory epithelium do occur, although to a lesser degree and from higher exposure concentrations. In addition, cytotoxicity and tumor formation are not related to blood levels of styrene or styrene oxide (SO) as measured in chronic studies. Whole-body metabolism studies have indicated major differences in styrene metabolism between rats and mice. The major differences are 4- to 10-fold more ring-oxidation and phenylacetaldehyde pathways in mice compared to rats. The data indicate that local metabolism of styrene is responsible for cytotoxicity in the respiratory tract. Cytotoxicity is seen in tissues that are high in CYP2F P450 isoforms. These tissues have been demonstrated to produce a high ratio of R-SO compared to S-SO (at least 2.4 : 1). In other rat tissues the ratio is less than 1, while in mouse liver the ratio is about 1.1. Inhibition of CYP2F with 5-phenyl-1-pentyne prevents the styrene-induced cytotoxicity in mouse terminal bronchioles and nasal olfactory epithelium. R-SO has been shown to be more toxic to mouse terminal bronchioles than S-SO. In addition, 4-vinylphenol (ring oxidation of styrene) has been shown to be highly toxic to mouse terminal bronchioles and is also metabolized by CYP2F. In human nasal and lung tissues, styrene metabolism to SO is below the limit of detection in nearly all samples, and the most active sample of lung was approximately 100-fold less active than mouse lung tissue. We conclude that styrene respiratory tract toxicity in mice and rats, including mouse lung tumors, are mediated by CYP2F-generated metabolites. The PBPK model predicts that humans do not generate sufficient levels of these metabolites in the terminal bronchioles to reach a toxic level. Therefore, the postulated mode of action for these effects indicates that respiratory tract effects in rodents are not relevant for human risk assessment.
Insights
Styrene causes respiratory toxicity and tumors in mice via local metabolism, but humans are unlikely to experience these effects due to lower metabolic activity. Rodent respiratory tract effects are not relevant for human risk assessment.
Area of Science:
- Toxicology
- Metabolism
- Carcinogenesis
Background:
- Mice exhibit high sensitivity to styrene-induced respiratory tract toxicity, including cytotoxicity and tumor formation in terminal bronchioles and nasal olfactory epithelium.
- Rats show less severe effects, primarily in the nasal olfactory epithelium, and these are not linked to blood styrene or styrene oxide (SO) levels.
- Significant differences in styrene metabolism exist between mice and rats, with mice showing higher activity in ring-oxidation and phenylacetaldehyde pathways.
Purpose of the Study:
- To investigate the role of local styrene metabolism in respiratory tract toxicity observed in rodents.
- To determine if specific cytochrome P450 (CYP) isoforms, particularly CYP2F, are responsible for styrene-induced cytotoxicity.
- To assess the relevance of rodent respiratory tract toxicity findings for human risk assessment.
Main Methods:
- Comparative analysis of styrene metabolism in mice and rats, focusing on CYP2F activity and metabolite ratios (R-SO vs. S-SO).
- Inhibition studies using 5-phenyl-1-pentyne to block CYP2F and assess its effect on styrene-induced cytotoxicity.
- Measurement of styrene metabolism in human nasal and lung tissues and comparison with rodent data.
- Physiologically based pharmacokinetic (PBPK) modeling to predict human exposure levels and toxicological outcomes.
Main Results:
- Mice exhibit higher CYP2F activity and a greater R-SO to S-SO ratio (≥2.4:1) in sensitive tissues compared to rats.
- Inhibition of CYP2F prevented styrene-induced cytotoxicity in mice, implicating CYP2F-generated metabolites.
- 4-vinylphenol, a CYP2F-metabolized product, was highly toxic to mouse terminal bronchioles.
- Human tissues showed minimal styrene metabolism to SO, with lung activity ~100-fold lower than in mice.
Conclusions:
- Styrene respiratory tract toxicity and lung tumors in rodents are mediated by CYP2F-generated metabolites, including R-SO and 4-vinylphenol.
- Humans are predicted to have insufficient CYP2F activity in the respiratory tract to produce toxic levels of these metabolites.
- The mode of action for styrene-induced respiratory tract effects in rodents is not relevant for human risk assessment.