title: Asbestos exposure dose-bronchoalveolar milieu response in asbestos workers and the sheep model: evidences of a threshold for chrysotile-induced fibrosis.
abstract: Epidemiological studies of asbestos workers have proposed a linear dose-response relationship between asbestos cumulative exposure indices and the incidence of asbestos-related lung diseases. However, for chrysotile, several studies have not observed such a linear relationship in low exposure workers. To further study the relationship of chrysotile exposure dose - lung tissue response, we designed in the sheep model one experiment of one exposure at variable intensity and one experiment with variable rates of individual exposures. In the first study, 6 groups of 6 sheep were exposed to either 0, 1, 10, 25, 50 or 100 mg chrysotile in 100 ml saline and lung lavage analyses carried out at day 0, 12, 24, 40 and 60 after. Histopathology was done at day 60. In the second experiment, 4 groups of 12 sheep were exposed to 100 ml saline every week or every two weeks, 100 mg chrysotile in 100 ml saline every week or every two weeks. In the second experiment, lung damage was assessed by changes in vital capacity (VC), lung compliance (Cst) and profusion of chest radiographic opacities (PO). On BAL in the control sheep, there were small and transient early increases in total cells/ml, macrophages/ml, neutrophils/ml, lactate dehydrogenase (LDH)/ml, alkaline phosphatase (AK)/ml, beta-glucuronidase (beta G)/ml and procollagen lll/ml. In the 1, 10, 25, and 50 mg asbestos sheep groups, there were no significant differences. However, in the 100 mg asbestos sheep, there were significant sustained increases in total cells/ml (3-6 times controls), macrophages/ml (2-6 times controls), neutrophils/ml (60-600 times controls), LDH/ml (5-10 times controls), AK/ml (1.5-2 times controls), beta G/ml (3-5 times controls), procollagen lll/ml (2 times controls) and IgG (1.5-3 times controls). These data were correlated with histopathological findings. In the sheep exposed weekly to chrysotile, significant changes in VC, Cst and PO occurred at mean cumulative exposure dose of 1.2 g whereas in the sheep exposed every 2 weeks, similar changes in VC, Cst and PO occurred at the cumulative exposure dose of 3.6 g (P less than 0.05). In conclusion, our data suggest that there is a threshold for chrysotile-induced fibrosis. This level cannot be considered adequately in term of cumulative exposure dose but must take into account intensity and rate of individual exposures.
authors.affiliation: Unité de recherche pulmonaire, Centre Hospitalier Universitaire, Université de Sherbrooke, Québec.
authors.forename: R
authors.initials: R
authors.lastname: Bégin
authors.forename: S
authors.initials: S
authors.lastname: Massé
authors.forename: M
authors.initials: M
authors.lastname: Rola-Pleszczynski
authors.forename: M
authors.initials: M
authors.lastname: Boctor
authors.forename: G
authors.initials: G
authors.lastname: Drapeau
mesh_terms: D000818:Animals; D001194:Asbestos / Q000633:toxicity*; D017632:Asbestos, Serpentine; D001992:Bronchoalveolar Lavage Fluid / Q000473:pathology*; D004195:Disease Models, Animal; D008168:Lung / Q000473:pathology; D008170:Lung Compliance; D008297:Male; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D012756:Sheep
chemical_list: D017632:Asbestos, Serpentine; D001194:Asbestos