title: Respiratory sensitization to diphenyl-methane-4,4'-diisocyanate (MDI) in guinea pigs: impact of particle size on induction and elicitation of response.
abstract: The impact of particle size of aerosolized polymeric diphenylmethane-4,4'-diisocyanate (MDI) for the induction and elicitation of respiratory sensitization was evaluated. Four groups of 16 female guinea pigs each received either the vehicle, repeated intradermal (id) injections (3 x 0.3% MDI), one high-level inhalation exposure of 15 min to 135 mg MDI/m(3) air using a small aerosol (MMAD approximately 1.7 microm) or large aerosol (MMAD approximately 3.8 microm). Three weeks later, animals were challenged subsequently with two ramped concentrations of MDI aerosol (average concentrations 16 and 49 mg/m(3) air, each for 15 min) and two different particle sizes, i.e., the MMAD was either approximately 1.6 microm or approximately 5.1 microm for the small- and large-size aerosol, respectively. Respiratory sensitization was assessed by two endpoints: the measurement of respiratory rate, and examination of influx of eosinophilic granulocytes into the mucosa and submucosa of the trachea, bronchi, and lung-associated lymph nodes (LALN). The recruitment of eosinophilic granulocytes into bronchial tissues was subdivided as follows: muscularis mucosae, submucosa, and perivascular. From measurements of respiratory rate, it would appear that guinea pigs sensitized by id injections or by inhalation exposure with the large aerosol tended to display a higher responsiveness than naive controls when challenged with the small aerosol. The recruitment of eosinophilic granulocytes in the bronchial tissue was greater in both inhalation induction groups as compared to the vehicle control. It appears that there was a somewhat greater response in animals sensitized by id injections or by inhalation exposure with the large aerosol and challenged with the small aerosol. Topographically, this difference was apparent only at the bronchial perivascular level and lung-associated lymph nodes (LALN), whereas at the submucosal and muscularis mucosae level the impact on particle size tended to be less pronounced. In summary, this study suggests that a brief, high-level inhalation exposure of MDI aerosol caused a sensitization of bronchial tissues in guinea pigs. The higher sensitization potency of the large aerosol may possibly be related to a dosimetric phenomenon because of the greater fraction of deposition of large particles within the upper respiratory tract. Overall, challenge exposures with this type of irritant aerosol appear to evoke more consistent effects when the MMAD is in the range of approximately 2 rather than approximately 5 microm.
authors.affiliation: Institute of Toxicology, Bayer AG, Building No. 514, 42096 Wuppertal, Germany. juergen.pauluhn.jp@bayer-ag.de
authors.forename: J
authors.initials: J
authors.lastname: Pauluhn
authors.forename: A
authors.initials: A
authors.lastname: Thiel
authors.forename: M
authors.initials: M
authors.lastname: Emura
authors.forename: U
authors.initials: U
authors.lastname: Mohr
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000485:Allergens; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000139:chemically induced / Q000473:pathology; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005260:Female; D006168:Guinea Pigs; D007074:Immunoglobulin G / Q000096:biosynthesis; D007271:Injections, Intradermal; D017953:Isocyanates / Q000276:immunology / Q000633:toxicity*; D010316:Particle Size; D012119:Respiration / Q000187:drug effects; D012130:Respiratory Hypersensitivity / Q000139:chemically induced* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D001559:Benzhydryl Compounds
chemical_list: D000336:Aerosols; D000485:Allergens; D007074:Immunoglobulin G; D017953:Isocyanates; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds