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Toxicological information

Acute Toxicity: other routes

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Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
COMPARISON OF GENE EXPRESSION OF CYTOKINES mRNA IN LUNGS OF RATS INDUCED BY INTRATRACHEAL INSTILLATION AND INHALATION OF MINERAL FIBERS
Author:
Yasuo Morimoto, Tohru Tsuda, Hiroshi Yamato, Takako Oyabu,
Toshiaki Higashi, Isamu Tanaka, Takahiko Kasai, Sumiyo Ishimatsu, Hajime Hori and Masamitsu Kido.
Year:
2001
Bibliographic source:
Inhalation Toxicology. 2001. (13): 589–601.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The Authors compared pathological changes in the pulmonary tissue and the expression of typical fibrosis-related cytokines after intratracheal instillation or long-term inhalation of two types of mineral fibers to determine whether intratracheal installation studies can predict the results obtained using long-term inhalation.
GLP compliance:
not specified
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: fibres
Details on test material:
no data
Specific details on test material used for the study:
Fibers used in this study were potassium octatitanate whisker (PT1); the geometric mean diameter (SD) and the geometric mean length were 0.085 (1.4) μm and 0.7 (0.19) μm, respectively.
fibers were provided by Japan Fibrous Material Research Association (JFMRA) (Kohyama et al., 1996, 1997).

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
no data

Administration / exposure

Route of administration:
other: intratracheal
Vehicle:
not specified
Details on exposure:
single intratracheal instillation of fibers
Doses:
only one dose administered: PT1 suspension (2 mg/0.2 ml)
Mass concentration (mg/m3): 2.2 ± 0.7
Fiber concentration(fibers/cm3): 111.2 ± 33.7
MMAD (mass median aerodynamic diameter) (GSD) (μm): 1.7 (2.4)
A dose of 2 mg was used in the present intratracheal instillation study.
The dose instilled in the present study was therefore the upper limit of the amount physiologically deposited in the lungs. The volume of instillate for injection was 0.2 ml/rat, and was approximate 1 ml/kg. It is reported that an injection volume of 1–2 ml/kg avoids distributing dust, limits potential dust effects, and loosens instilled dust (Driscoll et al., 2000).
As the volume for intratracheal injection in our experiment is within this limit, we think that fibers may be distributed in rat lungs
No. of animals per sex per dose:
no data
Control animals:
other: yes: saline suspension
Details on study design:
Male Wistar rats (10 wk old) were used in this study. Saline PT1 suspension (2 mg/0.2 ml) suspension was administered to the rats intratracheally. Then rats were housed in an exposure chamber for 4 wk. Each animal was anaesthetized by an intraperitoneal injection of phenobarbital.
Statistics:
Values were expressed as the mean ± SD. The difference between values was assessed using a Mann–Whitney U test.

Results and discussion

Effect levels
Sex:
male
Dose descriptor:
other: instilled dose
Effect level:
2 other: mg
Based on:
test mat.
Remarks on result:
not measured/tested
Remarks:
no lethal dose measured/tested
Mortality:
not examined
Clinical signs:
not examined
Body weight:
not examined
Gross pathology:
not examined
Other findings:
In intratracheal instillation study,
(i) exposure to PT1 increased the gene expression of TNF-a , IL-6, and TGF-b 1 mRNA in lungs of rats
(ii) mild fibrotic changes were observed in PT-1 exposed rats, and no significant changes were obtained in control rats.
The pulmonary findings for PT1 were abnormal.

Any other information on results incl. tables

A 4-wk recovery period after intratracheal instillation of the mineral fibers was allowed because previous investigators reported nonspecific responses in the acute phase after intratracheal instillation (Morimoto et al., 1993, 1996).

The Authors also previously reported that the transient increase in alveolar macrophages induced by intratracheal instillation of crocidolite and potassium titanate whiskers was no longer observed at 1 mo after instillation (Tsuda et al., 1997).

Applicant's summary and conclusion

Conclusions:
There were similarities not only in the pathology findings but also in the patterns of gene expression induced by mineral fiber irritation in the inhalation and instillation models.
Executive summary:

To investigate whether the results of intratracheal instillation studies on mineral fibers reflect the findings obtained by long-term inhalation data on mineral fibers, we have examined gene expression of cytokines and pathological features in lungs induced by intratracheal instillation and inhalation of mineral fibers. Male Wistar rats were given a single intratracheal instillation of 2 mg alumina silicate refractory fiber (RF1) or potassium octatitanate whisker (PT1) , and were sacrificed 4 wk after the fiber instillation. Longterm inhalation studies were also performed. In these, animals were exposed to fiber aerosol of RF1 or PT1 for 5 days/wk for 1 yr, and sacrificed after 1 yr of inhalation. Expression of tumor necrosis factor-a (TNF-a ), interleukin-6 (IL-6) , and transforming growth factor-b 1 (TGF-b 1) from lungs was observed by reverse-transcription polymerase chain reaction (RT-PCR) . The expression of TNF-a , IL-6, and TGF-b 1 mRNA in PT1-exposed lung was significantly higher than for those exposed to RF1 in both intratracheal instillation and inhalation studies. Pathological findings revealed that mild pulmonary fibrosis was seen in the lungs after intratracheal instillation and inhalation of PT1 but not RF1. Similarities were observed not only in gene expression of cytokines but in pathological features between both studies. These data suggested that the results of intratracheal instillation reflect the findings obtained from long-term inhalation data.