Application of short-term inhalation studies to assess the inhalation toxicity of nanomaterials.
BACKGROUND
A standard short-term inhalation study (STIS) was applied for hazard assessment of 13 metal oxide nanomaterials and micron-scale zinc oxide.


METHODS
Rats were exposed to test material aerosols (ranging from 0.5 to 50 mg/m3) for five consecutive days with 14- or 21-day post-exposure observation. Bronchoalveolar lavage fluid (BALF) and histopathological sections of the entire respiratory tract were examined. Pulmonary deposition and clearance and test material translocation into extra-pulmonary organs were assessed.


RESULTS
Inhaled nanomaterials were found in the lung, in alveolar macrophages, and in the draining lymph nodes. Polyacrylate-coated silica was also found in the spleen, and both zinc oxides elicited olfactory epithelium necrosis. None of the other nanomaterials was recorded in extra-pulmonary organs. Eight nanomaterials did not elicit pulmonary effects, and their no observed adverse effect concentrations (NOAECs) were at least 10 mg/m3. Five materials (coated nano-TiO2, both ZnO, both CeO2) evoked concentration-dependent transient pulmonary inflammation. Most effects were at least partially reversible during the post-exposure period.Based on the NOAECs that were derived from quantitative parameters, with BALF polymorphonuclear (PMN) neutrophil counts and total protein concentration being most sensitive, or from the severity of histopathological findings, the materials were ranked by increasing toxic potency into 3 grades: lower toxic potency: BaSO4; SiO2.acrylate (by local NOAEC); SiO2.PEG; SiO2.phosphate; SiO2.amino; nano-ZrO2; ZrO2.TODA; ZrO2.acrylate; medium toxic potency: SiO2.naked; higher toxic potency: coated nano-TiO2; nano-CeO2; Al-doped nano-CeO2; micron-scale ZnO; coated nano-ZnO (and SiO2.acrylate by systemic no observed effect concentration (NOEC)).


CONCLUSIONS
The STIS revealed the type of effects of 13 nanomaterials, and micron-scale ZnO, information on their toxic potency, and the location and reversibility of effects. Assessment of lung burden and material translocation provided preliminary biokinetic information. Based upon the study results, the STIS protocol was re-assessed and preliminary suggestions regarding the grouping of nanomaterials for safety assessment were spelled out.
Experimental Toxicology and Ecology, BASF SE, 67056 Ludwigshafen, Germany. robert.landsiedel@basf.com.
Robert
R
Landsiedel
Lan
L
Ma-Hock
Thomas
T
Hofmann
Martin
M
Wiemann
Volker
V
Strauss
Silke
S
Treumann
Wendel
W
Wohlleben
Sibylle
S
Gröters
Karin
K
Wiench
Bennard
B
van Ravenzwaay
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001466:Barium Sulfate / Q000633:toxicity; D001822:Body Burden; D001992:Bronchoalveolar Lavage Fluid; D049109:Cell Proliferation / Q000187:drug effects; D002563:Cerium / Q000633:toxicity; D020099:Coated Materials, Biocompatible; D008168:Lung / Q000473:pathology; D008297:Male; D008855:Microscopy, Electron, Scanning; D049329:Nanostructures / Q000008:administration & dosage / Q000633:toxicity*; D010087:Oxides / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012822:Silicon Dioxide / Q000633:toxicity; D014025:Titanium / Q000633:toxicity; D015430:Weight Gain / Q000187:drug effects; D015034:Zinc Oxide / Q000633:toxicity; D015040:Zirconium / Q000633:toxicity
D000336:Aerosols; D020099:Coated Materials, Biocompatible; D010087:Oxides; C009495:titanium dioxide; D001466:Barium Sulfate; D002563:Cerium; C030583:ceric oxide; D012822:Silicon Dioxide; D015040:Zirconium; D014025:Titanium; C028541:zirconium oxide; D015034:Zinc Oxide