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.
4,4'-Methylenebis(2-chloroaniline) (MOCA) has considerable human occupational exposure and it induces urinary bladder tumors in the dog, a species that has been often used as a model for aromatic amine-induced urinary bladder carcinogenesis in humans. Metabolic activation and formation of DNA adducts are considered to be critical steps in this process; and two major C8-adenine adducts have been shown to be formed in vitro by reaction with the proximate carcinogenic metabolite N-hydroxy-MOCA. MOCA-DNA adducts have also been detected in vivo in treated rats and in exfoliated urothelium of a worker accidentally exposed to MOCA. Thus, the aim of this study was to detect and quantify DNA adducts in the urinary bladder of dogs exposed to MOCA and thereby provide data that could be useful for risk assessment after human exposure to MOCA. Beagle dogs were treated with single and multiple doses of MOCA and DNA adduct levels were determined in liver and bladder epithelium. After a single dose, adduct levels in the liver were 1.5-fold higher than that in the bladder epithelium. Adduct levels in these two organs increased 3- to 5-fold after 10 doses and adducts in the liver were then 2.8-fold higher than that in the bladder epithelium. The levels found in these two organs after single exposures were compared, per unit exposure dose, with that reported for other carcinogenic aromatic amines. The comparison showed that MOCA was as effective in DNA adduct formation as most other potent urinary bladder carcinogens. These results suggest that MOCA may have high carcinogenic potential in humans and are consistent with the recent classification of MOCA as a probable human carcinogen.
Segerbäck
D
D
National Center for Toxicological Research, Jefferson, AR 72079.
Kaderlik
K R
KR
Talaska
G
G
Dooley
K L
KL
Kadlubar
F F
FF
D000818:Animals; D001345:Autoradiography; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000032:analysis* / Q000378:metabolism; D004285:Dogs; D005260:Female; D008099:Liver / Q000737:chemistry; D008753:Methylenebis(chloroaniline) / Q000032:analysis* / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D001743:Urinary Bladder / Q000737:chemistry*
D010761:Phosphorus Radioisotopes; D008753:Methylenebis(chloroaniline); D004247:DNA