ToxSci Advance Access originally published online on May 20, 2008
Toxicological Sciences 2008 104(2):320-331; doi:10.1093/toxsci/kfn098
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Brown Norway Rat Asthma Model of Diphenylmethane-4,4'-Diisocyanate (MDI): Analysis of the Elicitation Dose-Response Relationship
Institute of Toxicology, Bayer HealthCare, 42096 Wuppertal, Germany
1 To whom correspondence should be addressed at Institute of Toxicology, Bayer HealthCare, Building no. 514, 42096 Wuppertal, Germany. Fax. +49-202-364589. E-mail: juergen.pauluhn{at}bayerhealthcare.com.
Received March 10, 2008; accepted May 11, 2008
 |
Abstract |
|---|
The known human asthmagen polymeric diphenylmethane-diisocyanate (MDI) was investigated in the Brown Norway rat skin asthma model. Two types of dose-response relationships are addressed with the following focus: (1) does sensitization dose and surface area influence the subsequent elicitation response and (2) is the elicitation response more dependent on previous elicitation doses or more on skin sensitizing dose? These two aims are investigated in two elaborated experiments, using inflammatory (bronchoalveolar lavage, BAL) and physiologic (Penh) endpoints to characterize asthma-like responses in rats. Postchallenge measurements of Penh focused on responses delayed in onset. Inflammatory endpoints in BAL were performed one day after the fourth challenge. Both protocols utilized a dermal sensitization phase with two administrations on days 0 and 7 followed by four inhalation challenges with 
38 mg MDI/m3 in intervals of 2 weeks. In the first protocol three groups of rats were topically dosed with 40, 10, and 2.5 µl of MDI per rat. Each dose group consisted of three subgroups with dosed surface areas of 3.1–12.6 cm2, 0.8–3.1 cm2, and 0.4–0.8 cm2, respectively. In the second protocol groups of rats were topically dosed with 40 µl of MDI per rat followed by three challenges with 37 mg MDI/m3. At the fourth challenge subgroups of rats were either challenged with 8, 18, or 39 mg MDI/m3. Independent of the protocol used, response was characterized by increased influx of neutrophilic granulocytes in BAL and delayed respiratory response. All groups from the first study sensitized to and challenged with MDI elicited a distinct response relative to similarly challenged naïve rats. A sensitization dose dependence of the elicitation response was not found. The second protocol revealed that the elicitation dose correlates with increased neutrophils in BAL and delayed-onset respiratory responses. In summary, these data suggest that the vigor of asthma-like responses appear to be more dependent on the inhalation elicitation dose of previously challenged rats rather than the dermal induction dose.
Key Words: diphenylmethane-diisocyanate; MDI; respiratory allergy; diisocyanate asthma; lung function; delayed responses; Penh; neutrophilic inflammation; dose metric; dose-response.