Male Fisher 344 rats, ~ 2 years old

SIGNALMENT: (age, breed, sex, species, and scientific name) 
Male Fisher 344 rats, approximately 2 years old

HISTORY:

The photomicrographs are from rats exposed chronically (lifetime) to diluted whole diesel exhaust for 7 hr/day, 5 days/week at a target concentration of 7 mg/m3

GROSS PATHOLOGY: 

LABORATORY RESULTS: (clinical pathology, microbiology, etc…)
N/A 

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:

Marked, widespread alveolar macrophage hyperplasia with moderate multifocal alveolar epithelial (Type II cell) hyperplasia and abundant intra- and extracellular black particulate material.  Abundant granular to dense/hyaline proteinaceous material is present within alveoli. 

Ciliated cuboidal-columnar cell metaplasia of alveolar ducts (a.k.a.“bronchiolar-alveolar metaplasia”). 

Multifocal alveolitis characterized by histiocytic and neutrophilic infiltrates with associated focal fibrosis, cholesterol clefts, and epithelial hypertrophy and hyperplasia. 

Pulmonary keratin cyst (or squamous cyst). 

Bronchioloalveolar adenoma. 

Etiology:  Chronic whole body exposure to diesel exhaust. 

CONTRIBUTOR'S COMMENTS: 

These tissues were part of a study examining the pulmonary toxicity and carcinogenicity of inhaled diesel exhaust in F344 rats (Mauderly 1987).  Diesel exhaust is a known pulmonary carcinogen in rats.  It has been suggested that particulate associated organic compounds have genotoxic effects resulting in initiation.  However, this study and others have demonstrated increased rates of lung cancer in rats exposed to several types of poorly soluble particles in the lung, including carbon black (Nikula 1995, Heinrich 1995), titanium dioxide (Heinrich 1994), and nonasbestiform talc (NTP,1994).  These findings suggest that the contribution of organic fractions to carcinogenesis by particulates can be minor or negligible (an organic fraction is essentially absent in TiO2 and talc).  DE with the soot removed was also shown not to increase lung tumor incidence in rats--although this filtered DE did increase tumor rates in mice (Heinrich, 1986).

In a similar study comparing DE with carbon black, Nikula et al documented moderate alveolar macrophage hyperplasia by 3 months, with progressive accumulation of particle-laden macrophages and eventually the other lesions shown.  Lesions similar in severity and extent to those shown were present beginning at 12 to 18 months.  Lung tumors first occurred at about 18 to 24 months of exposure in both groups.

Lung cancer in  response to DE in rats apparently requires levels high enough to cause progressive accumulation of soot and the accompanying inflammatory, fibrotic and proliferative lesions (see Mauderly 2000 for a comprehensive review of diesel exhaust health effects). 

Note on estimates of human exposures (various sources--see Mauderly 2000.   The rats shown were exposed to

7.0 mg/m3):

Most of U.S. population:  probably range from 1-3 mg/m3

Truck drivers:  Approximately 7 mg/m3

Some mine workers:  Up to 1700 mg/m3 

REFERENCES: (Please submit a photocopy of each reference.)

Heinrich U, Muhle H, Takenaka S, Ernst H, Fuhst R, Mohr U, Pott F, Stober W.  1986.  Chronic effects on the respiratory tract of hamsters, mice and rats after long-term inhalation of high concentrations of filtered and unfiltered diesel engine emissions.  J Appl Toxicol. 6:383-95. 

Heinrich, U. 1994.  Toxic and carcinogenic effects of solid particles in the respiratory tract, pp. 57-73.  ILSI Press, Washington, DC. 

Heinrich U ; Fuhst R ; Rittinghausen S ; Creutzenberg O ; Bellmann B ; Koch W ; Levsen K.  1995.  Chronic Inhalation Exposure of Wistar Rats and Two Different Strains of Mice to Diesel Engine Exhaust, Carbon Black, and Titanium DioxideInhalation Toxicology.  7:533-556. 

Mauderly JL, Jones RK, Griffith WC, Henderson RF, McClellan RO. 1987.  Diesel exhaust is a pulmonary carcinogen in rats exposed chronically by inhalation.  Fundam Appl Toxicol. 9:208-21. 

Mauderly JL.  2000.  Diesel exhaust, pp 193-241 in Environmental toxicants:  human exposures and their health effects, 2ed.  M. Lippmann.  J Wiley & Sons, Inc.  New York, NY. 

National Toxicology Program Technical Report (NTP).  1994.  Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).  U.S. Dept. of Health and Human Services, Public Health Service, National Institutes of Health. 

Nikula KJ, Snipes MB, Barr EB, Griffith WC, Henderson RF, Mauderly JL.  1995.  Comparative pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black in F344 rats.  Fundam Appl Toxicol. 25:80-94. 

IMAGES: 

Legend:  (Objective of the microscope or the magnification of the Electron Microscope when each photograph is taken, type of stain used, and descriptive legend you would suggest for the submitted image.) 

4X, H&E.  Junction of terminal bronchiole and alveolar duct.  There is widespread alveolar macrophage hyperplasia with mild to moderate multifocal alveolar epithelial (Type II cell) hyperplasia and abundant intra- and extracellular black particulate material.  Abundant granular to dense/hyaline proteinaceous material is present within alveoli.  Note metaplasia of some alveolar duct and alveolar epithelium to cuboidal, ciliated cells. 

40X, H&E.  Higher power view of ciliated, metaplastic cells in above image. 

10X, H&E.  Multifocal alveolitis characterized by histiocytic and neutrophilic infiltrates with associated focal fibrosis, cholesterol clefts, and epithelial hypertrophy and hyperplasia. 

20X, H&E.  Higher power view within above image.  Note neutrophilic component, epithelial cell hypertrophy/hyperplasia. 

2X, H&E.  Pulmonary keratin cyst or squamous cyst.  Not considered neoplastic, but rather a metaplastic lesion which grows by keratin accumulation and extension of the squamous metaplasia.  This lesion is most common in rats and is associated with a variety of inhaled insults, including particulates and radioisotopes.

2X, H&E.  Bronchioloalveolar adenoma, characterized by loss of normal alveolar architecture, relatively uniform epithelium with minimal atypia, and occasionally compression/distortion of adjacent tissues.  Note that periphery grades into epithelial hyperplasia with essentially normal underlying alveolar architecture.

 

r085a.jpg

4x H&E 

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40x H&E

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10x H&E

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20x H&E

 

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2x H&E

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2x H&E 

 

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