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Pulmonary Lesions in Female Harlan Sprague-Dawley Rats Following Two-Year Oral Treatment with Dioxin-Like Compounds

¹ National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
² Toxicologic Pathology, Drug Safety Research Laboratories, Astellas Pharma Inc., Yodogawa, Osaka, Japan
³ Pathology II, Kansai Medical University, Moriguch, Osaka, Japan
⁴ Experimental Pathology Laboratories (EPL), Inc., Research Triangle Park, North Carolina, USA
⁵ Battelle, Columbus Laboratories, Columbus, Ohio, USA
⁶ Pathology Associates, Inc., A Charles River Company, Durham, North Carolina, USA
⁷ Constella Group, Research Triangle Park, North Carolina, USA
⁸ Toxicologic Pathologist, Haharuv 18, 36576, Timrat, Israel

Correspondence: Address correspondence to Nigel Walker, National Institute of Environmental Health Sciences, 111 Alexander Drive PO Box 12233, MD EC-34, Research Triangle Park, NC 27709, USA; e-mail:walker3{at}niehs.nih.gov

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.

Key Words: lung • cystic keratinizing epithelioma • bronchiolar metaplasia • carcinogenesis • mixtures • TEFs

Abbreviations: AEMB, Alveolar epithelium, metaplasia, bronchiolar • AhR, aryl hydrocarbon receptor • CKE, cystic keratinizing epithelioma • CYP, cytochrome P450 • DLC, dioxin-like compound • EROD, -ethoxyresorufin-O-deethylase • GSTPi, glutathione S-transferase Pi • H&E, 7-hematoxylin and eosin • IARC, International Agency for Research on Cancer • NTP, National Toxicology Program • PCB126, 3, 3', 4, 4', 5-pentachlorobiphenyl • PCDDs, polychlorinated dibenzodioxins • PCDFs, polychlorinated dibenzofurans • PCNA, proliferating cell nuclear antigen • PeCDF, 2, 3, 4, 7, 8-pentachloro-dibenzofuran • SCC, squamous cell carcinoma • SM, squamous metaplasia • TCDD, 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin • TEF, toxic equivalency factor • TEQ, toxic equivalent • WHO, World Health Organization

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