Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black.
Chronic inhalation of carbon black can produce carcinomas in rat lungs. At present the mechanisms underlying the rat lung tumor response to carbon black are unknown, although a significant role for inflammation and cell proliferation has been postulated. To investigate the processes which may contribute to development of rat lung tumors after carbon black exposure, we characterized the effects of subchronic inhalation of carbon black by rats on mutagenesis in alveolar epithelial cells, pulmonary inflammation, inflammatory cytokine/growth factor expression, and lung histopathology. Briefly, rats were exposed for 6 hr/day, 5 days/week for up to 13 weeks to 1.1, 7.1, and 52.8 mg/m3 carbon black and the effects on the lung were characterized after 6.5 and 13 weeks of exposure and 3 and 8 months of recovery. Endpoints characterized after carbon black exposure included mutation in the hprt gene of alveolar epithelial cells, changes in bronchoalveolar lavage fluid markers of lung injury and inflammation, expression of mRNA for the chemokines, MIP-2 and MCP-1, and lung histopathology. Lung burdens of carbon black were also determined. After 13 weeks of exposure to 1.1, 7.1, and 52.8 mg/m3 carbon black, lung burdens were 354, 1826, and 7861 micrograms carbon black, respectively. The lung clearance of carbon black appeared impaired after exposure to 7.1 and 52.8 mg/m3 carbon black, with the effects being more pronounced at the higher exposure level. Subchronic inhalation of 1.1 mg/m3 carbon black did not elicit any detectable adverse lung effects. A significant increase in hprt mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to 7.1 and 52.8 mg/m3 carbon black as well as after 3- and 8-month recovery periods for the group exposed to 52.8 mg/m3. No increase in hprt mutation frequency was observed for epithelial cells obtained from rats exposed to 1.1 mg/m3 carbon black. The observation that genotoxic effects (i.e., mutations) on alveolar epithelial cells occurred only after carbon black exposures which resulted in significant inflammation and epithelial hyperplasia supports the hypothesis that inflammatory cell-derives oxidants and increased cell proliferation play a role in the pathogenesis of rat lung tumors in response to carbon black.
Driscoll
K E
KE
Procter & Gamble Company, Cincinnati, Ohio 45253, USA.
Carter
J M
JM
Howard
B W
BW
Hassenbein
D G
DG
Pepelko
W
W
Baggs
R B
RB
Oberdörster
G
G
D000280:Administration, Inhalation; D000818:Animals; D001483:Base Sequence; D001822:Body Burden; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002244:Carbon / Q000008:administration & dosage / Q000633:toxicity*; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D054426:Chemokine CXCL2; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D007249:Inflammation / Q000209:etiology; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008969:Molecular Sequence Data; D015846:Monokines / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D016133:Polymerase Chain Reaction; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D015846:Monokines; D012333:RNA, Messenger; D002244:Carbon; D007041:Hypoxanthine Phosphoribosyltransferase