title: Micronuclei, hemoglobin adducts and respiratory tract irritation in mice after inhalation of toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI).
abstract: Toluene diisocyanate (TDI) and 4,4'-methylenediphenyl diisocyanate (MDI), used in the production of polyurethane foam, are well known for their irritating and sensitizing properties. Contradictory results have been obtained on their genotoxicity. We investigated the genotoxicity and protein binding of inhaled TDI and MDI in mice by examining micronucleated polychromatic erythrocytes (PCEs) in bone marrow and peripheral blood and TDI- and MDI-derived adducts in hemoglobin. Male C57Bl/6J mice (8 per group) were exposed head-only to TDI vapour (mean concentrations 1.1, 1.5, and 2.4mg/m(3); the mixture of isomers contained, on the average, 63% 2,4-TDI and 37% 2,6-TDI) or MDI aerosol (mean concentrations 10.7, 20.9 and 23.3mg/m(3)), during 1h/day for 5 consecutive days. Bone marrow and peripheral blood were collected 24h after the last exposure. Inhalation of TDI caused sensory irritation (SI) in the upper respiratory tract, and cumulative effects were observed at the highest exposure level. Inhalation of MDI produced SI and airflow limitation, and influx of inflammatory cells into the lungs. Hemoglobin adducts detected in the exposed mice resulted from direct binding to globin of 2,4- and 2,6-TDI and MDI, and dose-dependent increases were observed especially for 2,4-TDI-derived adducts. Adducts originating from the diamines of TDI (toluene diamine) or MDI (methylene dianiline) were not observed. No significant increase in the frequency of micronucleated PCEs was detected in the bone marrow or peripheral blood of the mice exposed to TDI or MDI. The ratio of PCEs and normochromatic erythrocytes (NCEs) was reduced at the highest concentration of MDI, and a slight reduction of the PCE/NCE ratio, dependent on cumulative inhaled dose, was also seen with TDI. Our results indicate that inhalation of TDI or MDI (1h/day for 5 days), at levels that induce toxic effects and formation of TDI- or MDI-specific adducts in hemoglobin, does not have detectable genotoxic effects in mice, as studied with the micronucleus assay.
authors: Safe New Technologies, Work Environment Development, Finnish Institute of Occupational Health, FI-00250 Helsinki, Finland.
authors: Hanna K
authors: HK
authors: Lindberg
authors: Anne
authors: A
authors: Korpi
authors: Tiina
authors: T
authors: Santonen
authors: Kirsi
authors: K
authors: Säkkinen
authors: Merja
authors: M
authors: Järvelä
authors: Jarkko
authors: J
authors: Tornaeus
authors: Niina
authors: N
authors: Ahonen
authors: Hilkka
authors: H
authors: Järventaus
authors: Anna-Liisa
authors: AL
authors: Pasanen
authors: Christina
authors: C
authors: Rosenberg
authors: Hannu
authors: H
authors: Norppa
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D006454:Hemoglobins / Q000378:metabolism*; D017953:Isocyanates / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015162:Micronucleus Tests; D009153:Mutagens / Q000008:administration & dosage / Q000633:toxicity*; D012130:Respiratory Hypersensitivity / Q000139:chemically induced*; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage / Q000633:toxicity*; D001559:Benzhydryl Compounds
chemical_list: D000336:Aerosols; D006454:Hemoglobins; D017953:Isocyanates; D009153:Mutagens; D014051:Toluene 2,4-Diisocyanate; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds