Female F344/N rats, approximately 2 years old

SIGNALMENT: (age, breed, sex, species, and scientific name) 

Female F344/N rats, approximately 2 years old.

HISTORY:

The photomicrographs are from rats with chronic, lifetime, whole body aerosol exposure to cosmetic grade, non-asbestiform talc (2.5 to 3.5 痠 diameter, 18 mg/m3, 6 hours/day, 5 days/week, for 2 years).

GROSS PATHOLOGY:
There were multiple, small, round, pale foci visible from the pleural surface.

LABORATORY RESULTS: none provided

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:
• Lung: Chronic, multifocal interstitial fibrosis with alveolar type II hypertrophy and hyperplasia, lymphohistiocytic interstitial infiltrates.
• Lung: Chronic, multifocal, histiocytic and neutrophilic alveolitis with intrahistiocytic particulate material.
• Lung: Bronchioloalveolar adenoma, papillary pattern.
• Lung: Bronchioloalveolar carcinoma, alveolar pattern

CONTRIBUTOR: Anonymous

CONTRIBUTOR'S COMMENTS:
These tissues were part of a chronic inhalation study examining the toxicity and carcinogenicity of non-asbestiform cosmetic grade talc, a finely powdered, hydrous magnesium silicate (NTP 421, 1993). Talc, along with carbon black, titanium dioxide and coal dust, are considered non-genotoxic, poorly soluble particles (PSP) of low acute toxicity, which have been shown to cause cancer in rats after chronic, high dose inhalation exposure (see Nikula, 2000 for review). In contrast, talc and other PSPs are not carcinogenic in mice and other rodent species.

High doses of PSPs are thought to contribute to pulmonary carcinogenesis in rats by overloading the macrophage based pulmonary clearance mechanisms. PSPs contribute to chronic inflammatory changes in both mice and rats. However, rats exhibit fibrotic and type II hyperplastic changes in addition to infiltration by inflammatory cells. These hyperplastic changes are thought to be precursors to neoplastic transformation. Species differences in macrophage and pulmonary epithelial cell function and interactions, perhaps involving oxidant quenching ability or ability to repair oxidative damage, are hypothesized to underlie the observed species differences in PSP tumorigenicity (see Donaldson, Mossman 2000 for review).

Interestingly, PSPs appear to be more tumorigenic in female than in male rats. Female rats had higher levels of glutathione reductase in bronchoalveolar lavage fluid than did males, suggesting greater oxidative stress in the lungs of the female rats. This observation led to the proposal that the gender differences in PSP tumorigenicity were due to greater antioxidant activity in the lungs of male rats.

REFERENCES:
1. Donaldson K. Nonneoplastic lung responses induced in experimental animals by exposure to poorly soluble nonfibrous particles. Inhal Toxicol 2000 Jan-Feb;12(1-2):121-39.

2. Mossman BT. Mechanisms of action of poorly soluble particulates in overload-related lung pathology. Inhal Toxicol 2000 Jan-Feb;12(1-2):141-148.

3. National Toxicology Program Technical Report No. 421 (1993). Toxicology and carcinogenesis studies of talc (CAS No. 14807-96-6) in F344/N rats and B3C3F1 mice (inhalation studies). USDHHS, Public Health Service, National Institutes of Health, National Toxicology Program, Research Triangle Park, NC. (see NTP website for abstract: http://ntp-server.niehs.nih.gov/htdocs/LT-studies/tr421.html, viewed 10-28-02)

4. Nikula KJ. Rat lung tumors induced by exposure to selected poorly soluble nonfibrous particles. Inhal Toxicol 2000 Jan-Feb;12(1-2):97-119.


 

r140a.jpg

4X, H&E. Alveoli. There are multiple foci of interstitial fibrosis with lymphohistiocytic interstitial infiltrates and type II alveolar epithelial hypertrophy and hyperplasia. Scattered areas of alveolar macrophage hyperplasia are evident, and there are intra-alveolar accumulations of granular to fibrillar protein rich debris and occasional neutrophils.


r140b.jpg

40X, H&E. Higher power view of alveoli. Grayish-brown granular material is present within the cytoplasm of many interstitial and alveolar macrophages. Note the formation of cholesterol clefts within an aggregate of alveolar macrophages.


 
r140c.jpg

10X, H&E, Polarized light. Birefringent particulate material (talc) is evident within macrophages.


 
r140d.jpg

2X, H&E. Bronchioloalveolar adenoma, papillary pattern. Neoplastic cells grow as papillary projections on a thin fibrovascular stroma. The tumor is well demarcated and grows by expansion, with compression of adjacent parenchyma.


 
r140e.jpg

20X, H&E. Higher power view of adenoma. The cuboidal to low columnar cells are uniform in appearance, with small, round, basally oriented nuclei.


 
r140f.jpg

2X, H&E. Bronchioloalveolar carcinoma, alveolar pattern. Neoplastic cells grow along alveoli giving the mass a less well circumscribed appearance. Aggregates of neutrophils with lesser numbers of macrophages are present within the mass.


 
r140g.jpg

20X, H&E. Higher power view of carcinoma. The neoplastic cells exhibit mild to moderate atypia, with a higher nuclear to cytoplasmic ratio, mild anisokaryosis, and loss of polarity.


 

 

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