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The effect of multiple oral administration on the formation and disappearance of 4,4'-methylene-bis(2-chloroaniline)-DNA adducts in rat liver.

Debord-DG; Cheever-KL; Werren-DM; Swearengin-TF; Savage-RE
Toxicologist 1997 Mar; 36(1)(Part 2):116
The p postlabeling assay using nuclease PI enhancement procedures as utilized to investigate the formation and disappearance of DNA adducts in rats after multiple oral administration of 4,4' -methylene-bis(2-chloroaniline) [MOCA], a probable human carcinogen. Adult male rats were dosed with 7.5 mg MOCA/kg body weight for up to 28 days. Groups of rats were sacrificed every 7 days for the 4-week treatment period and for an additional three weeks after treatment cessation. Two adducts, A and E, were observed in liver DNA of the rats from all treatment groups. The major adduct, A, had similar chromatographic properties to N-(deoxyadenosin-8-yl)-4-amino3-chlorobenzyl alcohol, which is the same adduct that has been previously identified in target site DNA from both human uroepithelial cells treated with MOCA and in exfoliated urothelial cells from a worker accidentally exposed to MOCA. The minor adduct, E, has not been identified. Levels of both A and E increased in a dose-dependent manner over the 28-day treatment period. After 7 days, adduct levels were 7,627 +/- 2,585 and 1,279 +/- 354 (relative adduct level +/- SE x 107 nuc1eotides) for A and E, respectively. By 28 days, the levels of A and E had increased to 13,071 +/- 3,585 and 4,423 +/-1,238, respectively. Adduct levels for A- and E rapidly decreased after the cessation of dosing. Seven days after the treatment period had ended, the levels of A and E were 3,134 +/-638 and 319 +/-77, respectively. However, detectable adduct levels remained 21 days after the dosing period had been completed. The half-life of the adducts were determined to be 4 days for A and 2 days for E. The development of a mathematical model to assess exposure based on DNA adduct levels has been initiated. In summary, this study shows that relatively high levels of DNA adducts are formed with repeated low level exposure to MOCA and that quantifiable levels of these adducts remain at the target site for at least 3 weeks following the exposure period. In addition, this study provides additional evidence that the major adduct, A, may be useful for occupational biomonitoring.
Toxic-dose; Toxic-materials; Toxins; Exposure-assessment; Exposure-levels; Exposure-limits; Laboratory-animals; Animal-studies; Animals; Liver-tissue; Liver-disorders; Liver-cells
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The Toxicologist. Society of Toxicology 36th Annual Meeting, March 9-13, 2006, Cincinnati, Ohio