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© 1991 Oxford University Press

research-article

4,4'-Methylenebis(2-chloroaniline) (MOCA): The Effect of Multiple Oral Administration, Route, and Phenobarbital Induction on Macromolecular Adduct Formation in the Rat

KENNETH L. CHEEVER, D. GAYLE DEBORD and TERRI F. SWEARENGIN

Department of Health and Human Services, Public Health Service Centers for Disease Control, National Institute for Occupational Safety and Health, Division of Biomedical and Behavioral Science 4676 Columbia Parkway, Cincinnati, Ohio 45226

Received February 12, 1990; accepted August 15, 1990

The effect of multiple oral administration of MOCA, a suspect human carcinogen, was studied in the adult male rat. As many as 28 consecutive daily doses of [14C]MOCA at 28.1µmol/kg body wt (5 µC1/day) were administered and rats were euthanized at weekly intervals for 7 weeks. MOCA adduct formation for globin and serum albumin was evaluated by determination of [14C]MOCA covalent binding. The covalent binding associated with globin showed a linear increase over the 28-day exposure period with 342 fmol/mg globin 24 hr after the final dose. More extensive covalent binding was detected for albumin with 443 fmol/mg albumin after the final dose, but increases were not linear. After cessation of dosing, the albumin adduct levels decreased rapidly (t 1/2 =4.6 days) in relation to globin adduct levels (t 1/2 =16.1 days). The MOCA-globin adduct t 1/2 is consistent with that determined after a single 281 µmol/kg oral dose of MOCA. Significant differences related to route of administration were detected for 24-hr globin covalent binding with ip > po > dermal. Distribution of undifferentiated [14C]MOCA was highest in the liver at 24 hr with tissue levels for liver > kidney > lung > spleen > testes > urinary bladder. Induction of cytochrome P450 enzymes by administration of phenobarbital (100 mg/kg/day/3 days) resulted in a significant (p < 0.05) increase in MOCA-globin adduct formation detected with 33.5 pmol/ mg globin for induced rats versus 13.6 pmol/mg globin for control rats. Although MOCA-globin and albumin adducts show differing stability, quantification of such MOCA adducts may be useful for long-term industrial biomonitoring of MOCA.


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