Evaluation of the dose-response and fate in the lung and pleura of chrysotile containing brake dust compared to chrysotile or crocidolite asbestos in a 28 day inhalation toxicology study

This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust (from brakes manufactured with chrysotile) in a 28-day repeated multi-dose inhalation toxicology study (6 h/d, 5 d/wk. 4 wk) followed by 28-days of exposure free recovery and served as a range finding study for a subsequent ongoing 90-day repeated dose inhalation toxicology study with lifetime recovery. Comparative fiber control groups were included of a similar grade commercial chrysotile as used in the brakes and a commercial crocidolite asbestos sample. The aerosol fiber distribution of the chrysotile (chry) and crocidolite (croc) asbestos were similar (Fibers L > 20 μm/cm3: Chry-LD 42, Chry-HD 62; Croc-LD 36, Croc-HD 55; WHO fibers/cm3 Chry-LD 192, Chry-HD 219; Croc-LD 211, Croc-HD 255). The total number of particles in the aerosol of the brake dust groups was similar to that in the chrysotile groups (Part/cm3: B-D 710 - 1065; Chry 532 - 1442). A macrophage dose-response to the brake dust groups was observed with no fiber related effects. In the fiber control groups, the study differentiated between similar exposures to chrysotile and crocidolite asbestos. The chrysotile exposure resulted in a dose-dependent particle laden macrophage response characterised as Wagner Grade 1 to 3. In contrast, following crocidolite exposure there was a dose-response accumulation of fiber laden macrophages and interstitial fibrosis during exposure (Wagner score Grades 3 to 4) which increased in incidence following exposure (Wagner score Grade 4). Confocal microscopy images (determined following deep freezing of the chest wall at sacrifice) revealed no difference between the air control, brake dust and chrysotile high-dose exposure groups and no difference in the visceral or parietal pleura thickness at 28 or 56 days. The crocidolite exposure resulted in more than double the thickness of the visceral pleura and parietal pleura, with associated extensive inflammatory response and collagen development observed including adhesions between the visceral and parietal surfaces. These results provided a basis for the design of the 90 day study. (Study funded by Honeywell International Inc)