Registration Dossier

Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
biochemical or cellular interactions
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented study.

Data source

Reference
Reference Type:
publication
Title:
Cytokine and growth factor release by alveolar macrophages: potential biomarkers of pulmonary toxicity
Author:
Driscoll, K.E.; Maurer, J.K.
Year:
1991
Bibliographic source:
Toxicol. Pathol. 19, 398-405

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study only reports on isolated mechanistic investigations.
Investigation of pulmonary response to TiO2 and SiO2.
GLP compliance:
no
Type of method:
in vivo
Endpoint addressed:
carcinogenicity

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: nanomaterial
Details on test material:
- Name of test material (as cited in study report): titanium dioxide (TiO2-F), ultrafine titanium dioxide (TiO2-D)
- Particle size: 0.3 µm (TiO2-F), 0.02 µm (TiO2-D)
- Surface area: 8.8 m^2/g
No further details are given.

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
No further details are given.

Administration / exposure

Route of administration:
intratracheal
Vehicle:
other: saline
Details on exposure:
All instillations were performed using a dosing volume of 1.0 ml/kg body weight.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
single instillation
Frequency of treatment:
no
Post exposure period:
up to 90 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
5 mg dust/kg body weight
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
10 mg dust/kg body weight
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
50 mg dust/kg body weight
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
100 mg dust/kg body weight
Basis:
nominal conc.
No. of animals per sex per dose:
no data
Control animals:
yes
Details on study design:
Rats instilled with suspensions of SiO2 or TiO2 (5, 10, 50 and 100mg dust/kg bw), the alveolar macrophages were analysed for the presence of IL-1, TNF and/or fibronectin

Examinations

Examinations:
Histopathology: On days 28 and 90 (at 100 mg/kg, day 60) after instillation, 5 animals/treatment (at 100 mg/kg, 3 rats/treatment) were sacrificed. The lungs were infused to 25 cm H2O with 10% formalin. paraffin embedded sections from both lungs were stained for light microscopic examinations.
Bronchoalveolar lavage (BAL) and cell culture: At 1, 7, 14 and 28 days after exposure 5-6 animals/treatment were sacrificed. BAL and cell culture was performed. The alveolar macrophage (AM) conditioned media samples were analysed for the presence of IL-1, TNF and/or fibronectin.

Pulmonary dust retention: 5 animals/group were sacrificed 1, 7 and 28 days after treatment, the lungs removed, weighed and lyophilised. Titanium level in lung tissues were determined.
Positive control:
no data

Results and discussion

Details on results:
AM release of tumour necrosis factor (TNF) positively correlated with the degree of neutrophil recruitment after TiO2-F exposure. A persistent increase in Am fibronectin release consistently correlated with the development of pulmonary fibrosis after SiO2 or TiO2-F exposure. Studies comparing pulmonary response to ultrafine TiO2 with TiO2-F demonstrated that ultrafine particles have a relatively greater toxicity on a mass/lung basis. Exposure to TiO2-D resulted in a persistent increase in AM TNF and fibronectin release which was associated with neutrophil recruitment and firosis, respectively. TiO2-D did not stimulate AM IL-1 release and this was consistent with the absence of a granulomatous response to TiO2-D. In light of the known bioactivities of IL-1, TNF and fibronectin, these correlative findings suggest that these mediators play significant roles in pulmonary responses to mineral dust exposure and may serve as potential early biomarkers of pulmonary toxicity.

Applicant's summary and conclusion

Conclusions:
AM release of tumour necrosis factor (TNF) positively correlated with the degree of neutrophil recruitment after TiO2-F exposure. A persistent increase in Am fibronectin release consistently correlated with the development of pulmonary fibrosis after SiO2 or TiO2-F exposure. Studies comparing pulmonary response to ultrafine TiO2 with TiO2-F demonstrated that ultrafine particles have a relatively greater toxicity on a mass/lung basis. Exposure to TiO2-D resulted in a persistent increase in AM TNF and fibronectin release which was associated with neutrophil recruitment and firosis, respectively. TiO2-D did not stimulate AM IL-1 release and this was consistent with the absence of a granulomatous response to TiO2-D. In light of the known bioactivities of IL-1, TNF and fibronectin, these correlative findings suggest that these mediators play significant roles in pulmonary responses to mineral dust exposure and may serve as potential early biomarkers of pulmonary toxicity.