32P-postlabelling analysis of DNA adducts of 4,4'-methylenebis(2- chloroaniline) in target and nontarget tissues in the dog and their implications for human risk assessment.
Segerback-D; Kaderlik-KR; Talaska-G; Dooley-KL; Kadlubar-FF
Carcinogenesis 1993 Oct; 14(10):2143-2147
Induction of DNA adducts by 4,4'-methylenebis(2-chloroaniline) (101144) (MOCA) in the urinary bladder and the liver was studied in dogs. Female Beagle-dogs were orally administered 8.0mg/kg MOCA once or daily, 5 days a week for 2 weeks. The dogs were killed 2 days after the single dose or 3 to 7 days after the last multiple dose. DNA was extracted from the liver and bladder epithelium and analyzed for adducts using phosphorus-32 postlabeling/thin layer chromatography. Adduct concentrations in the bladder and liver DNA following the single 8mg/kg dose averaged 1.1 and 1.7 adducts per 10(6) nucleotides, respectively. The bladder and liver DNA adduct concentrations 3 days after the last of the multiple doses were 3.2 and 9.1 adducts/10(6). The bladder and liver DNA adduct concentrations measured 7 days after the last multiple MOCA dose were 4.4 and 8.2 adducts/10(6). At least two peaks were found in the chromatograms. The major peak was chromatographically identical to the 3',5'-bisphosphate of N-(deoxyadenosin-8-yl)-4-amino- chlorobenzyl-alcohol. The minor peak cochromatographed with the 3',5'-bisphosphate of N-(deoxyadenosin-8-yl)-4-amino-3- chlorotoluene. The hepatic and bladder MOCA/DNA adduct concentrations were comparable to those induced by 4ABP and AAF and somewhat higher than those induced by benzidine and 2NA when compared on a per unit exposure dose basis. The authors conclude that MOCA is as effective at inducing DNA adducts in the urinary bladder (target tissue) and liver (nontarget tissue) as most other potent bladder carcinogens. These data indicate that MOCA has a high potential for carcinogenicity.
NIOSH-Publication; NIOSH-Contract; Contract-224-88-0003; Chlorinated-anilines; DNA-adducts; In-vivo-studies; Laboratory-animals; Bladder-tissue; Liver-tissue; Risk-analysis; Molecular-biology; Bladder-cancer