title: Pulmonary toxicity screening studies in male rats with M5 respirable fibers and particulates.
abstract: M5 fiber is a high-strength, high-performance organic fiber type that is a rigid rod material and composed of heterocyclic polymer fibers of type PIPD. The aim of this study was to evaluate the acute lung toxicity of intratracheally instilled M5 respirable fibers and particulates in rats. Using a pulmonary bioassay and bridging methodology, the acute lung toxicity of intratracheally instilled M5 particulates and that of its fibers were compared with a positive control particle type, quartz, as well as a negative control particle type, carbonyl iron particles. Moreover, the results of these instillation studies were bridged with data previously generated from inhalation studies with quartz and carbonyl iron particles, using the quartz and iron particles as the inhalation/instillation bridge material. For the bioassay experimental design, in the bronchoalveolar lavage studies, the lungs of rats were intratracheally instilled with 0.5 or 0.75 mg/kg of M5 particulate or 1 or 5 mg/kg of the following control or particle types: (1) M5 long fiber preparation, (2) silica-quartz particles, and (3) carbonyl iron particles. Phosphate-buffered saline (PBS)-instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were assessed using bronchoalveolar lavage (BAL) fluid biomarkers, cell proliferation methods, and histopathological evaluation of lung tissue at 24 h, 1 wk, 1 mo and 3 mo post instillation exposure. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to M5 particulate and M5 long fiber preparation produced transient inflammatory and cell injury effects at 24 h postexposure (pe) as well as at 24 h and 1 wk pe, respectively, but these effects were not sustained when compared to quartz-silica effects. Exposures to carbonyl iron particles and PBS resulted in only minor short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to M5 particulate and in particular, the M5 long fiber preparation in rats produced some inflammatory responses, observed up to 1 wk postexposure. These responses were often associated with the presence of M5 long fiber in the airways or in the proximal alveolar regions but appeared to be reversible at 1 and 3 mo postexposure. In contrast, pulmonary exposures to silica-quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation and evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: (1) It was very difficult to produce M5 fibers into a respirable fibrous form; these findings suggest that aerosol exposure concentrations of respirable fibrous M5 in the workplace are likely to be rather low. (2) The particulate and long fiber preparations of M5 that were tested produced a moderate amount of pulmonary inflammatory activity, more active than our negative control, carbonyl iron particles, but substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle type, silica-quartz particles. Thus, based on the results of this study, we would expect that inhaled M5 respirable fibers have a low risk potential for producing adverse pulmonary effects.
authors.affiliation: DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware 19714-0050, USA. david.b.warheit@usa.dupont.com
authors.forename: David B
authors.initials: DB
authors.lastname: Warheit
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Reed
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019570:Inhalation Exposure / Q000009:adverse effects; D007442:Intubation, Intratracheal; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced* / Q000175:diagnosis* / Q000473:pathology; D008297:Male; D019016:Mineral Fibers / Q000633:toxicity*; D052638:Particulate Matter / Q000633:toxicity*; D011108:Polymers / Q000633:toxicity; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D019016:Mineral Fibers; D052638:Particulate Matter; D011108:Polymers