Evaluation of the oncogenic potential of man-made vitreous fibres: the inhalation model.

A rodent inhalation model has been developed for the evaluation of the eoncogenic potential of man-made vitreous fibres. It is successful in delivering a quantified dose of well-characterized fibres to the lungs of rodents, and with it sufficiently high fibre aerosol concentrations were lofted to enable a maximum tolerated dose to be achieved. Fischer 344 male rats were exposed to a well-defined rat-respirable aerosol at concentrations for MMVF of 30, 16 or 3 mg m-3, 6 h per day, 5 days per week for 104 weeks with final sacrifice at 20% survival. A control group was exposed to filtered air. The high dose was chosen based upon a 28-day maximum tolerated dose study with refractory ceramic fibres (RCF). The fibre aerosol generation system lofted fibres without breaking, grinding or contaminating the bulk material. Exposure was by flow-past nose-only systems which provided fresh fibre in a laminar stream to each animal individually. The study was performed according to the Good Laboratory Practice regulations. Fibre count, fibre diameter and length distribution, aerosol mass and chemical composition were determined throughout the study. Interim sacrifices were performed at 3 or 6 month intervals for 24 months. At each sacrifice, full necropsy was performed, the accessory lobe removed for subsequent digestion to determine the fibre lung burden and the remaining lobes inflated with fixative for histopathological evaluation. The lungs were evaluated by a pathologist and graded for the degree of macrophage infiltration, bronchiolization, fibrosis and pleural thickening, and were also scored according to the Wagner scale. Lesions were evaluated according to the number of adenomas, carcinomas and mesotheliomas. The accessory lobe was digested by low-temperature plasma ashing and the number, size distribution and chemical composition of the fibres determined. This model provides a sensitive and reproducible method for evaluating existing and new fibres. A variety of different of ceramic, glass, rockwool and slagwood fibres have been evaluated with this model.