Chronic pulmonary effects of respirable methylene diphenyl diisocyanate (MDI) aerosol in rats: combination of findings from two bioassays

Two independent bioassays are available which have examined the potential c arcinogenicity of monomeric and polymeric methylene diphenyl diisocyanate ( MDI) following long-term inhalation exposure in rats. These studies are not directly comparable, however, due to differences in design and conduct of the in-life phase, and differences in nomenclature used for some of the his topathological findings. This paper presents a definitive overview of the p ulmonary toxicity of MDI developed following a thorough review of both inve stigations. As part of this process, the test materials and the designs of the studies were compared, and an in-depth review of lung lesions was condu cted by an independent reviewing pathologist. This included the reexaminati on of the original lung slides, supported by an analysis of the exposure re gimens, the results of which were used to develop an accurate profile of th e doses received by the animals in the two studies. Histopathological findi ngs were then combined with this information to give an overall dose-respon se curve for both studies as a whole. The range of total inhalation exposur es to MDI was calculated as 559, 1972, 2881, 6001, 17,575 and 17,728 mgh/m( 3). Major pulmonary effects included increased lung weights together with b ronchiolo-alveolar adenomas and hyperplasia, and interstitial fibrosis whic h occurred consistently in both studies, indicating a very similar qualitat ive response of the lungs to polymeric and monomeric MDI. The quantitative response of the lung was clearly dose-related in each study, and when the s tudies were considered as a whole a reasonable overall dose-response relati onship was apparent for major lung lesions. Lung tumours tin low incidences ) only occurred at the highest dose level in both studies (17,575 and 17,72 8 mgh/m(3)). For inflammatory and other non-neoplastic pulmonary changes, t he lowest dose examined (559 mgh/m(3)) was regarded as a no-observed-advers e-effect-level for both polymeric and monomeric MDI. It was concluded that the results of the two studies could be combined to serve as a basis for hu man risk assessment of MDI.