4,4'-Methylenebis(2-chloroaniline) (MOCA): the effect of multiple oral administration, route, and phenobarbital induction on macromolecular adduct formation in the rat.
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 28.1 mumol/kg body wt (5 microCi/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 (t1/2 = 4.6 days) in relation to globin adduct levels (t1/2 = 16.1 days). The MOCA-globin adduct t1/2 is consistent with that determined after a single 281 mumol/kg oral dose of MOCA. Significant differences related to route of administration were detected for 24-hr globin covalent binding with ip greater than po greater than dermal. Distribution of undifferentiated [14C]MOCA was highest in the liver at 24 hr with tissue levels for liver greater than kidney greater than lung greater than spleen greater than testes greater than urinary bladder. Induction of cytochrome P450 enzymes by administration of phenobarbital (100 mg/kg/day/3 days) resulted in a significant (p less than 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.
Cheever
K L
KL
Department of Health and Human Services, National Institute for Occupational Safety and Health, Cincinnati, Ohio 45226.
DeBord
D G
DG
Swearengin
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TF
D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects*; D005914:Globins / Q000302:isolation & purification / Q000378:metabolism; D006207:Half-Life; D008297:Male; D008753:Methylenebis(chloroaniline) / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012306:Risk; D012709:Serum Albumin / Q000378:metabolism; D014018:Tissue Distribution
D012709:Serum Albumin; D008753:Methylenebis(chloroaniline); D005914:Globins; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital