![Study Results & Research Projects Study Results & Research Projects](https://webarchive.library.unt.edu/web/20090202032531im_/http://ntp.niehs.nih.gov/images/template/subMastHead_studyResults.gif)
NTP Study Reports
NTP Study Reports
Home » Study Results & Research Projects » NTP Study Reports » All Long-Term Reports » Abstract for TR-59 - Estradiol Mustard
Chemical Formula: | C42H50Cl4N2O4 | - | 3D Structure* |
---|---|---|---|
*To view structure, download free Chemscape Chime Plug-in | |||
A bioassay of the experimental anticancer drug estradiol mustard for possible carcinogenicity was conducted by administering the chemical by gavage to Sprague-Dawley rats and B6C3F1 mice.
Groups of 35 rats and 34-36 mice of each sex were administered estradiol mustard at one of the following doses, either 0.62 or 1.25 mg/kg body weight for rats and either 15 or 30 mg/kg body weight for mice. The vehicle used for the test chemical consisted of 0.05% polysorbate 80 in phosphate-buffered saline. The rats and mice were dosed three times per week for 52 weeks, then observed for an additional 30-34 weeks. Controls consisted of groups of 10 rats and 15 mice of each sex that were not administered the chemical (untreated controls) and also of groups of 10 rats of each sex, 14 male mice, and 16 female mice administered the vehicle alone (vehicle controls). Pooled controls were also used. All surviving rats were killed at 84-86 weeks and all surviving mice at 82-86 weeks.
Mean body weights of male rats and male and female mice administered estradiol mustard were lower throughout the greater part of the study than those of corresponding vehicle or untreated controls; mean body weights of dosed female rats were unaffected. Administration of the test chemical had no significant effect on the survival of either male or female rats. A large number of dosed mice died prior to the end of the study. The numbers of dosed male mice which were at risk as long as 52 weeks were sufficient, however, for development of tumors appearing up to that time. Time-adjusted analysis and life-table analyses were applied to data obtained with the mice.
In rats, no tumors were observed in a statistically significant incidence in the animals administered estradiol mustard.
In mice, lymphoma or lymphocytic leukemia occurred at significant incidences in low-dose (P=0.018) and high-dose (P<0.001) groups of males compared with those in the pooled vehicle controls (controls 0/28, low-dose 6/32, high-dose 17/29) and at significant incidences in low-dose (P=0.020) and high-dose (P=0.002) groups of females compared with those in the corresponding vehicle controls (controls 0/14, low-dose 9/30, high-dose 11/23). In addition, the incidences of lymphoma were statistically significant for dose-related trend for both the males (P<0.001) and the females (P=0.003). Since lymphoma was observed in male mice as early as 25 weeks, life-table analyses of the incidence in each sex were performed. The results indicated a dose association (P=0.001) between the administration of estradiol mustard and the time of observation of lymphoma in either sex of mice.
In mice, alveolar/bronchiolar adenoma or carcinoma occurred at a significant incidence (P=0.004) in the low-dose group of males compared with the pooled vehicle controls (controls 2/28, low-dose 12/30, high-dose 5/24) and at a significant incidence (P=0.022) in the low-dose group of females compared with the pooled vehicle controls (controls 1/28, low-dose 7/27, high-dose 1/18). Sarcoma of the myocardium similarly occurred at a significant incidence (P=0.015) in the low-dose group of males compared with the pooled vehicle controls (controls 0/28, low-dose 6/30, high-dose 2/24) and at a significant incidence (P=0.002) in the low-dose group of females compared with the pooled vehicle controls (controls 0/28, low-dose 8/27, high-dose 1/12). The survival of both high-dose males and high-dose females was slightly lower than that of the respective low-dose groups and may account for the higher numbers of pulmonary tumors and myocardial sarcomas among low-dose mice of both sexes. The association of myocardial sarcoma with administration of the chemical in both dosed groups of each sex is strengthened by the fact that these tumors of the myocardium have not occurred in the more than 500 male and 500 female historical-control mice of this strain at the laboratory.
Squamous cell carcinoma of the stomach occurred in the dosed male mice (high-dose 2/29) and in the dosed female mice (low-dose 2/26, high-dose 2/14) but was absent in all controls. Although the incidences in this bioassay were too low to be statistically significant, the fact that no squamous-cell carcinomas of the stomach have occurred in the more than 500 male and 500 female historical-control mice of this strain at this laboratory indicates that these gastric tumors were related to the administration of the estradiol mustard.
It is concluded that under the conditions of this bioassay, estradiol mustard administered in a buffered saline vehicle was not carcinogenic in Sprague-Dawley rats. Estradiol mustard was carcinogenic in both male and female B6C3F1 mice, inducing lymphoma, sarcoma of the myocardium, alveolar adenoma or carcinoma, and squamous-cell carcinoma of the stomach.
Synonym: estradiol, bis((p-bis(2-chloroethyl)-amino)phenyl)acetate
Levels of Evidence of Carcinogenicity:
Male Rats: Negative
Female Rats: Negative
Male Mice: Positive
Female Mice: Positive
Report Date: 1978
Target Organs from 2-year Studies
You may link to the full technical report in pdf format ( Note: A print ready copy of the document is presented in Portable Document Format (pdf) which requires the Acrobat Reader plug-in -- download a free copy of the reader.)
Web page last updated on October 15, 2007
The National Institute of Environmental Health Sciences is one of the National Institutes of Health within the U.S. Department of Health and Human Services. The National Toxicology Program is headquartered on the NIEHS campus in Research Triangle Park, NC.