phosphorus-radioisotopes and 4-4--diphenylmethane-diisocyanate

Tissues obtained from female Wistar rats exposed to a 0.9 microm aerosol of 4,4'-methylenediphenyl diisocyanate (MDI) for 17 h per day, 5 days per week, for one year, at levels of 0, 0.3, 0.7 and 2.0 mg/m(3), were analyzed for DNA adducts. A 32P-postlabeling method was used to detect (i), adducts formed by the reaction of the isocyanate group(s) of MDI with DNA; and a 32P-postlabeling method was adapted to detect (ii), a DNA adduct formed by 4,4'- methylenedianiline (MDA), a hydrolysis/decarboxylation product of MDIV. In the lung, neither isocyanate adducts nor the arylamine adduct were detectable. The same negative result was seen in the liver, the bladder, the kidney, the respiratory epithelium and in peripheral lymphocytes. In the olfactory epithelium, on the other hand, the arylamine-derived DNA adduct was detected, at the very low levels of 5,9 and 10 adduct-nucleotides per 10(10) nucleotides, for the three dose groups, respectively. The adduct co-chromatographed with the one formed in the liver of rats after oral gavage of MDA. The results are discussed in terms of the importance of genotoxic versus nongenotoxic aspects of carcinogenesis.

Topics: Administration, Inhalation; Aniline Compounds; Animals; Carcinogens; DNA Adducts; Female; Isocyanates; Male; Nasal Mucosa; Phosphorus Radioisotopes; Rats; Rats, Inbred F344; Rats, Wistar

The 32P-postlabeling method was adapted for the detection of DNA adducts formed by methylenediphenyl-4,4'-diisocyanate (MDI). Incubation of the 3'-phosphates of the deoxyribosides of cytosine (C), adenine (A), guanine (G) and thymine (T) with MDI in Tris buffer resulted in the formation of 5, 7, 8, and 2 reaction products, respectively. Incubation of DNA with MDI resulted in detectable levels of 5, 2, and 1 adducts attributable to C, A, and G. Analysis of DNA isolated from the epidermis of rats treated dermally with 9 mg MDI showed an adduct pattern similar to the one seen in the in vitro DNA incubation. A total adduct level of 7 per 10(8) nucleotides was measured, the limit of detection was 2 adducts per 10(10) nucleotides. The data indicate that a minute fraction of MDI can reach DNA in vivo in a chemically reactive form. In comparison with the genotoxic skin carcinogen 7,12-dimethylbenz[a]anthracene on the other hand, the DNA-binding potency of MDI was more than 1000-fold lower.

Topics: Animals; Autoradiography; DNA Adducts; Female; In Vitro Techniques; Isocyanates; Phosphorus Radioisotopes; Rats; Rats, Wistar; Skin