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

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.

Establishment and Validation of an Ultra-Short-Term Skin Carcinogenicity Bioassay Using Tg-rasH2 Mice

“…Recently, we have conducted a 26-week short-term carcinogenicity study of 1,2-dichloroethane, a known lung carcinogen, using dermal application to Tg-rasH2 mice. 23 This study confirmed that the evaluation of the lung carcinogenicity of at least some drugs is possible using a short-term dermal application assay. A 26-week short-term internal organ carcinogenicity study using dermal application could also represent an alternative assay for carcinogenicity testing.…”

<p>Organ accumulation and carcinogenicity of highly dispersed multi-walled carbon nanotubes administered intravenously in transgenic rasH2 mice</p>

“…Although we checked for the presence of thin- and thick-MWCNTs in cases with tumors that occurred in the lungs, we found no evidence of MWCNTs. The lung is the most common site of tumor occurrence in rasH2 mice, and we believe that these cases were spontaneous in onset, including those in the MWCNTs groups 32,33. The next common site of tumor occurrence was the spleen, and a tumor was found in a group other than the thick-MWCNTs group (high-dose).…”