Lung Tumor Induction by 26-week Dermal Application of 1,2-Dichloroethane in CB6F1-Tg rasH2 Mice.

Mayuko Suguro,Mayumi Kawabe,Seiko Tamano,Yuko Doi,Takamasa Numano,Norio Imai,Yukinori Mera

doi:10.1177/0192623317701003

Abstract

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. Recently, a 26-week short-term carcinogenicity study using CB6F1-Tg rasH2@Jcl (rasH2) mice has become a worldwide standard for the evaluation of chemical carcinogenesis. However, an acceptable short-term carcinogenic study model for dermally applied products is still lacking. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks. As a positive control, 10 mice of each sex received a single intraperitoneal injection of 75 mg/kg of N-methyl- N-nitrosourea. Bronchiolo-alveolar adenomas and adenocarcinomas were significantly increased in 1,2-DCE-treated rasH2 mice of both sexes, and bronchiolo-alveolar hyperplasias were significantly increased in female mice. Overall, almost all mice of each sex developed adenomas and/or adenocarcinomas with 100% of female rasH2 mice developing bronchiolo-alveolar adenocarcinomas.

Highlights

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued
Incidence and multiplicity of both bronchiolo-alveolar adenomas and adenocarcinomas were significantly increased in 1,2-DCE-treated rasH2 mice of both sexes, and bronchiolo-alveolar hyperplasias were significantly increased in female mice
In the present 26-week carcinogenicity study using rasH2 transgenic mice, 1,2-DCE was demonstrated to be a lung carcinogen after dermal application to the dorsal skin. 1,2-DCE has previously been demonstrated to be carcinogenic in mice in long-term carcinogenicity studies (Weisburger 1977; NTP 1978; Van Duuren et al 1979; Nagano et al 2006)

Summary

Introduction

Short-term alternatives to traditional 2-year carcinogenic studies in rodents are being actively pursued. To investigate the suitability of using the rasH2 mouse to test carcinogenic potential, 1,2-dichloroethane (1,2-DCE) was dermally applied to rasH2 mice: 1,2-DCE is a known carcinogen that causes lung bronchiolo-alveolar adenomas and adenocarcinomas when administered topically, orally, or by inhalation exposure; 1,2-DCE at a dose level of 126 mg/mouse in 200 μl acetone or acetone alone (vehicle control) was applied to the dorsal skin of 10 mice of each sex 3 times a week for 26 weeks. We employed 1,2-dichloroethane (1,2-DCE) to investigate the suitability of using the transgenic rasH2 mouse model to assess the carcinogenic potential of dermally applied compounds. In long-term 78-week carcinogenicity tests, oral administration caused bronchiolo-alveolar adenomas and lung tumors in mice of both sexes and caused endometrial tumors and mammary adenocarcinomas in female mice. Repeated application of 1,2-DCE to the skin of female Ha: ICR Swiss mice induced lung tumors (Van Duuren et al 1979)

Objectives

Methods

Results

Conclusion