ToxSci Advance Access published online on July 28, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh233
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
* To whom correspondence should be addressed. E-mail: walker3{at}niehs.nih.gov.
Tg.AC mice develop epidermal papillomas in response to treatment with dermally-applied non-genotoxic and complete carcinogens. The persistent environmental contaminant 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is a multi-site rodent carcinogen and tumor promoter that induces the formation of papillomas in Tg.AC mice. To examine the dose-response relationship and compare dermal and oral routes of exposure for TCDD-induced skin papillomas, female Tg.AC mice were exposed dermally to average daily doses of 0, 2.1, 7.3, 15, 33, 52, 71, 152, and 326 ng TCDD/kg/day or 0, 75, 321, and 893 ng TCDD/kg body weight by gavage for 26 weeks. The incidence of cutaneous papillomas was increased in a dose-dependent manner and tumors developed earlier with higher exposure to TCDD regardless of route of administration. Increased incidences of cutaneous squamous cell carcinomas were observed in mice exposed to dermal (
Accepted July 26, 2004
Carcinogenicity
Oral and Dermal Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) Induces Cutaneous Papillomas and Squamous Cell Carcinomas in Female Hemizygous Tg.AC Transgenic Mice
2 Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA
3 Battelle Memorial Institute, Columbus, OH 43201, USA
4 Research Triangle Institute, Research Triangle Park, NC 27709, USA
Abstract 
51.9 ng/kg) and oral (893 ng/kg) TCDD. Higher gavage doses were required to induce papillomas and squamous cell carcinomas compared to dermal exposure. Despite a linear correlation between administered dose and terminal skin concentrations, the incidence of tumor formation was lower in the gavage study than the dermal study with respect to mean terminal skin TCDD concentrations. These studies demonstrate that although Tg.AC mice are less responsive to TCDD by gavage than by dermal exposure the induction of skin neoplasms is a response to systemic exposure and not solely a local response at the site of dermal application. Differences in response between the routes of exposure may reflect pharmacokinetic differences over the duration of the study in the delivery of TCDD to the skin.
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