Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance.
Evidence suggests that short-term inhalation studies may provide comparable prediction of respiratory tract toxicity to 90-day studies, presenting the opportunity to save time and resources in screening inhalation toxicity of test substances. The aim of this study was to develop a short-term inhalation test that could be employed to provide early evidence on respiratory tract effects which might occur from long-term exposure to aerosols of nano-materials. Male Wistar rats were exposed to aerosols of 0 (control), 2, 10 and 50 mg/m(3) nano-titanium dioxide (TiO2) by inhalation for 6 h/day for 5 days. Necropsies were performed either immediately after the last exposure or after 3 and 16 days post exposure (study days 5, 8 and 21, respectively). Treatment with nano-TiO2 resulted in morphological changes in the lung, with 50 mg/m(3) nano-TiO2 producing an increase in lung weight. Lung inflammation was associated with dose-dependent increases in bronchoalveolar lavage fluid (BALF) total cell and neutrophil counts, total protein content, enzyme activities and levels of a number of cell mediators. No indications of systemic effects could be found by measurement of appropriate clinical pathology parameters. Cell replication (determined by incorporation of 5-bromo-2'-deoxyuridine) was increased at all nano-TiO2 dose levels in large/medium bronchi and terminal bronchioles. The effects on the parameters measured were most prominent either on study day 5 or 8, with some endpoints returning to control levels by day 21. Overall, the pulmonary effects of nano-TiO2 observed in this short-term study were comparable to those previously reported in subchronic inhalation studies.
Ma-Hock
Lan
L
Department of Product Safety, BASF SE, Ludwigshafen, Germany.
Burkhardt
Silke
S
Strauss
Volker
V
Gamer
Armin O
AO
Wiench
Karin
K
van Ravenzwaay
Bennard
B
Landsiedel
Robert
R
D000336:Aerosols; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D049109:Cell Proliferation / Q000187:drug effects; D019570:Inhalation Exposure / Q000009:adverse effects* / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity*; D009929:Organ Size / Q000187:drug effects; D009928:Organ Specificity; D010316:Particle Size; D010865:Pilot Projects; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013499:Surface Properties; D013997:Time Factors; D014018:Tissue Distribution; D014025:Titanium / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D036401:Toxicity Tests, Chronic / Q000295:instrumentation / Q000379:methods*
D000336:Aerosols; D015415:Biomarkers; C009495:titanium dioxide; D014025:Titanium