Pulmonary lesions in female Harlan Sprague-Dawley rats following two-year oral treatment with dioxin-like compounds

Abstract

Dioxin and dioxin-related compounds have been associated with high incidences of pulmonary dysfunctions and/or cancers in humans. To evaluate the relative potencies of effects of these compounds, the National Toxicology Program completed a series of two-year bioassays which were conducted using female Harlan Sprague-Dawley rats. The rats were treated orally for up to 2 years with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB126), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and a ternary mixture of TCDD, PCB126 and PeCDF. In addition to treatment-related effects reported in other organs, a variety of pulmonary lesions were observed that were related to exposure. Pulmonary CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was increased in all dosed groups. The most common non-neoplastic lesions, which occurred in all studies, were bronchiolar metaplasia and squamous metaplasia of the alveolar epithelium. Cystic keratinizing epithelioma was the most commonly observed neoplasm which occurred in all studies. A low incidence of squamous cell carcinoma was associated only with PCB126 treatment. Potential mechanisms leading to altered differentiation and/or proliferation of bronchiolar and alveolar epithelia may be through CYP1A1 induction or disruption of retinoid metabolism.

Figure 1

Bronchiolar metaplasia of alveolar epithelium is present at the junction of terminal bronchioles (*) and alveolar ducts throughout lung. Alveolar type I cells have been replaced by cuboidal to columnar ciliated cells. Scattered among these cells are cells that lack cilia and have a smooth apical surface that protrudes into alveolar duct space. TEF Mixture study, H&E, x20.

Figure 2

Bronchiolar metaplasia of alveolar epithelium. In alveolar lumens abundant Periodic acid-Schiff (PAS)-positive materials, consistent with mucus, can be seen. PCB126 study, PAS staining, X100.

Figure 3

Squamous metaplasia of alveolar epithelium. This lesion is located in small to large foci where the normal alveolar epithelial structure was changed to a stratified squamous epithelium with keratinization. PCB126 study, H&E, X66. Reprinted with permission from Toxicologic Pathology from Sells et al. 2007.

Figure 4

Cystic keratinizing epithelioma. The mass is located in the lung below the thoracic serosa and has a center filled with keratin. TCDD study, H&E, X5.

Figure 5

Cystic keratinizing epithelioma. Cystic structures consists of a highly irregular wall of highly keratinized stratified squamous epithelium, with a center filled with keratin. The wall has a thick complex proliferation of squamous epithelial outgrowths into surrounding alveolar spaces. PCB126 study, H&E, X33. Reprinted with permission from Toxicologic Pathology from Sells et al. 2007.

Figure 6

Squamous cell carcinoma. Invasion of the surrounding lung parenchyma (arrows), increased cellular atypia and pleomorphism can be seen. PCB126 study. H&E, X60.