Assessment of DNA adducts and the frequency of 6-thioguanine resistant T-lymphocytes in F344 rats fed 2,4-toluenediamine or implanted with a toluenediisocyanate-containing polyester polyurethane foam.
Toluenediamines have been of toxicological concern because of their industrial use as intermediates in polyurethane synthesis and because of the potential of their release from degradation of the Microthane polyesterurethane covering of some breast implants. In this study, we have assessed the extent of DNA damage in rats treated with a carcinogenic toluenediamine isomer, 2,4-toluenediamine (2,4-TDA), under conditions that result in tumor induction, and in rats implanted with Microthane polyesterurethane foam. Time and dose-dependent formation of adducts was observed in DNA from the liver and mammary gland of rats fed 10, 40, 80 and 180 ppm 2,4-TDA for up to 6 weeks. In assays conducted 1 to 32 weeks after the start of treatment, no adducts were detected in the DNA of T-lymphocytes isolated from the spleens of animals fed 40 or 180 ppm 2,4-TDA, nor was there an increase in mutations at the hprt locus in these lymphocytes. In rats fed 40 or 180 ppm, 2,4-TDA for 6 weeks, adducts were detectable in DNA isolated from liver and mammary gland for 26 to 43 weeks after termination of the treatment. No DNA damage, as assessed by both DNA adduct measurement and induction of T-lymphocyte hprt mutations, was observed in rats up to 42 weeks after receiving subcutaneous implants of polyesterurethane foam (67 or 267 mg/kg). Although 2,4-TDA is clearly capable of damaging DNA, the results of this study are consistent with the conclusion that Microthane foam-containing implants present a minimal risk of genotoxicity through release and subsequent metabolic activation of 2,4-TDA. The study also indicates that DNA adduct formation and mutation induction in lymphocytes are inadequate biomonitors for measuring exposure to toluenediamines.
Delclos
K B
KB
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Blaydes
B
B
Heflich
R H
RH
Smith
B A
BA
D000818:Animals; D018427:Breast Implants / Q000009:adverse effects; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004351:Drug Resistance; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000378:metabolism; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity; D010655:Phenylenediamines / Q000633:toxicity*; D011091:Polyesters / Q000633:toxicity*; D011140:Polyurethanes / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology*
D018736:DNA Adducts; D009153:Mutagens; D010655:Phenylenediamines; D011091:Polyesters; D011140:Polyurethanes; C081821:microthane foam; D013866:Thioguanine; C010914:2,4-diaminotoluene