Strong nasal carcinogenicity and genotoxicity of 1-nitroso-4-methylpiperazine after low dose inhalation in rats.
Sprague-Dawley rats were exposed by inhalation to 1-nitroso-4-methylpiperazine (NMPz) vapor at 2.4 p.p.m. for 15 h/day for 74 days over a 7.5 month period. After a dose of 1.1 mg/day NMPz (total dose 340 mg/kg body wt) 10/10 animals developed tumors of the nasal cavity, mostly invasive muco-epidermoidal carcinomas; no such tumors were observed in sham-exposed controls. This high tumor yield was seen at an 80 times lower dose and a shorter latency period when compared with rat carcinogenicity studies reported earlier. The single cell microgel electrophoresis (Comet) assay was used to determine genotoxicity in target tissues. Short-term in vitro exposure of rat and human nasal epithelial tissues to NMPz caused genotoxic effects in cells of both species. Short-term in vivo exposure of rats to NMPz vapor for 1 h induced DNA damage in nasal epithelial cells. Our results revealed NMPz as a potent genotoxic nitrosamine in rat and human nasal cells, the carcinogenicity of inhaled NMPz vapor in rats being remarkably higher as compared with oral uptake.
Klein
R G
RG
Deutsches Krebsforschungszentrum, Division of Toxicology and Cancer Risk Factors, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Schmezer
P
P
Hermann
R
R
Waas
P
P
Spiegelhalder
B
B
Bartsch
H
H
D002288:Adenocarcinoma, Mucinous / Q000139:chemically induced / Q000473:pathology; D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000818:Animals; D015197:Carcinogenicity Tests; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009152:Mutagenicity Tests; D009602:Nitrosamines / Q000008:administration & dosage / Q000633:toxicity*; D009669:Nose Neoplasms / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D009602:Nitrosamines; C014710:N-nitroso-N'-methylpiperazine