title: Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): determination of the elicitation threshold concentration of after inhalation sensitization.
abstract: Occupational exposure to polymeric diphenylmethane-diisocyanate (MDI), a known human asthmagen, can be attributed to two potential routes: the skin and the respiratory tract. While the skin as the route of sensitization was the focus of a previous investigation (Pauluhn, 2008), this paper describes a modified sensitization protocol using a 5-day inhalation exposure (days 0-4) of Brown Norway (BN) rats to two concentration x exposure time (C x t) relationships of 1000, 5000, and 10,000 mg MDI/m³ x min at exposure durations of either 10 or 360-min. Apart from the differences in the induction protocol, all other experimental variables remained identical. This was followed by four 30-min inhalation challenges to 40 mg MDI/m³ on target days 20, 25, 50, and 65. After the last challenge, changes in breathing patterns delayed in onset were recorded and allergic lung inflammation was probed by bronchoalveolar lavage (BAL). In a subsequent study groups of rats were sensitized using the 10-min C x t protocol and challenged 3-times at 40 mg MDI/m³. At the fourth challenge a dose-escalation regimen was used to determine the elicitation threshold on 'asthmatic' rats. Consistent with the skin-sensitization protocol, the most sensitive endpoints characterizing an allergic pulmonary inflammation were again BAL-neutrophils and physiological measurements showing respiratory changes delayed in onset. The dose-escalation challenge yielded an elicitation threshold of 5 mg MDI-aerosol/m³ at 30 min challenge duration. In topically sensitized rats this threshold was estimated to be 3mg/m³. In summary, these data suggest the C x t product of MDI-aerosol that triggers an elicitation response in 'asthmatic' rats is slightly below of that causing acute pulmonary irritation in naïve rats. The high concentration delivered to the respiratory tract during the 10-min exposure period elicited a more vigorous response than the similar C x t at 360 min. Therefore, short high-level exposure patterns appear to bear a higher sensitizing potency than equal C x t products at longer exposure periods. Taking into account the respective differences in exposure intensities, the comparison of elicitation thresholds of BN rats sensitized by inhalation or skin exposure did not demonstrate essential differences.
authors.affiliation: Institute of Toxicology, Bayer Schering Pharma AG, Building No. 514, 42096 Wuppertal, Germany. juergen.pauluhn@bayer.com
authors.forename: Jürgen
authors.initials: J
authors.lastname: Pauluhn
authors.forename: Alan
authors.initials: A
authors.lastname: Poole
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000485:Allergens / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001249:Asthma / Q000139:chemically induced*; D018893:Bronchoalveolar Lavage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019570:Inhalation Exposure; D017953:Isocyanates / Q000494:pharmacology / Q000633:toxicity*; D008168:Lung / Q000187:drug effects; D008297:Male; D008452:Maximum Allowable Concentration; D051381:Rats; D011914:Rats, Inbred BN; D001559:Benzhydryl Compounds
chemical_list: D000336:Aerosols; D000485:Allergens; D017953:Isocyanates; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds