The role of cytochromes P-450 in styrene induced pulmonary toxicity and carcinogenicity.
Exposure of CD-1 mice to atmospheres of 40 and 160 ppm styrene, daily for up to 10 days, caused pulmonary toxicity characterised by focal loss of cytoplasm and focal crowding of non-ciliated Clara cells, particularly in the terminal bronchiolar region. The toxicity was accompanied by an increase in cell replication rates in terminal and large bronchioles of mice exposed for 3 days or longer. The toxicity and increased cell replication were no longer apparent after a 2-day break in exposure, but re-occurred when exposure was resumed. Similar effects were seen in mice given oral doses of 10, 100 or 200 mg/kg styrene, daily for 5 days. Increases in cell replication rates were seen in the terminal bronchioles in mice dosed with 100 and 200 mg/kg styrene, but not 10 mg/kg. Toxicity was limited to 3 to 10 animals in the 200 mg/kg group. Neither morphological nor cell proliferation effects were seen in the alveolar region of the mouse lung in any of these studies, nor were any effects observed in the lungs of CD rats exposed to 500 ppm styrene for up to 10 days. The pulmonary toxicity and increased cell division seen in mice, but not rats, correlates with the known species differences in pulmonary carcinogenicity of styrene, suggesting that the acute and chronic responses are causally related. 5-Phenyl-1-pentyne was shown to inhibit the pulmonary cytochrome P-450 metabolism of styrene in vivo. Cell replication rates in the lungs of mice treated with this inhibitor and exposed to styrene were comparable with controls demonstrating that the pulmonary effects of styrene on the mouse lung are caused by a metabolite of styrene, probably styrene oxide. The risks associated with exposure to styrene appear to correlate well with the metabolic capacity of the lung.
Green
T
T
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, SK10 4TJ, Cheshire, UK. trevor.green@syngenta.com
Toghill
A
A
Foster
J R
JR
D000280:Administration, Inhalation; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects; D012727:Sex Characteristics; D020058:Styrene / Q000008:administration & dosage / Q000633:toxicity*
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D020058:Styrene