Environment and Breast Cancer: Science Review
AboutCancer studies: Experimental details
National Toxicology Program Technical Report 452, 1996
Notes
Increased benign mammary tumors in male and female rats. Increased malignant mammary tumors in female mice. Rats: 0, 2500, 5000, 10,000 ppm in feed for 104-105 wks. male rats: 0/51, 4/53, 7/51, 7/55 fibroadenoma or adenoma female rats: 25/50, 45/51, 46/53, 45/52 fibroadenoma Mice: 0, 312, 625, 1250 ppm in feed for 104-105 wks female mice: 0/52, 0/50, 1/51, 3/50 carcinoma
Increased benign mammary tumors in male and female rats. Increased malignant mammary tumors in female mice. Rats: 0, 2500, 5000, 10,000 ppm in feed for 104-105 wks. male rats: 0/51, 4/53, 7/51, 7/55 fibroadenoma or adenoma female rats: 25/50, 45/51, 46/53, 45/52 fibroadenoma Mice: 0, 312, 625, 1250 ppm in feed for 104-105 wks female mice: 0/52, 0/50, 1/51, 3/50 carcinoma
Route
Route of chemical administration: dermal, inhalation, gavage (delivery directly into the
stomach), in feed, subcutaneous injection (under the skin), or intraperitoneal injection (into the
cavity that contains the abdominal organs).
in diet
Doses
Dosage, frequency, and duration of treatment; the sizes of the groups of animals
involved and what age the animals were at the beginning of the study.
Rats: 0, 2500, 5000, 10,000 ppm in feed for 104-105 wks. Dosed groups included 60 animals of each sex, except controls which had 60 females and 70 males. An additional group of 70 males were treated with 20,000ppm for 3 months. Interim kills were performed.
Mice: 0, 312, 625, 1250 ppm in feed for 104-105 wks. Group sizes were 60 of each sex.
Animals were 6 wks old at beginning of study.
Time after cessation of dosing
How long the animals were observed after the chemical was no
longer being administered and before death of the animals.
First experiment: none
Second experiment: remainder of 2 yrs
Mammary tumors, benign
Development of benign mammary tumors, reported as a series of
fractions. The numerators represent the number of animals that developed benign mammary
tumors and the denominators represent the total number of animals receiving the particular
dose of chemical. Where available, the denominator will reflect the number of animals alive
when the first tumor developed. Otherwise, it will reflect the number of animals examined. The
order of the fractions reflects the level of chemical treatment, from no dose (controls) on the left
to the highest dose on the right. Where available, the histological type of the tumors will be
indicated, i.e. adenoma or fibroadenoma.
Additional information, in development, includes statistical significance and trend information.
We plan to indicate whether a particular treatment group’s ratio of mammary tumors related to
the control is statistically significantly elevated, as determined by the author. This is indicated
with an asterisk (*). We will also include information indicating whether there was an
increasing, statistically significant dose response trend reported by CPDB. Results that are
statistically significant at p < 0.05 are labeled "T+" and statistical significance between 0.05 and
1.0 is labeled "T~". Where there is no dose-related effect or the trend is identified as decreasing
with dose, results are labeled here as "Tna."
female rats: 25/50, 45/51, 46/53, 45/52 fibroadenoma
male rats: 0/51, 4/53, 7/51, 7/55, 5/60 fibroadenoma or adenoma
male rats-stop exposure: 0/51, 5/60 fibroadenoma
male rats-104 wks: 0/51, 4/53, 6/51, 6/55 fibroadenoma
0/51, 0/53, 1/51, 1/55 adenoma
Mammary tumors, malignant
Development of malignant mammary gland tumors follows the
same format as for benign, as described above.
female mice: 0/52, 0/50, 1/51, 3/50 carcinoma
Comments
This field contains information on the survival rates of the animals and the body
weight trends in order to evaluate whether these factors were likely to have affected the
generation of mammary gland tumors. Mammary gland tumors tend to develop later in an
animal’s life, so studies with lowered survival could mean that animals died before mammary
gland tumors could develop. Decreased weight (perhaps due to toxicity of the chemical) can
decrease the development of tumors. This field may also contain other comments about the
design or outcome of the study.
For the top two exposure levels of both sexes in rats and the stop-exposure study, survival was diminished. The highest exposure level in mice of both sexes also had reduced survival. Body weight was also reduced in both sexes in the top exposure category and for the stop-report study. Mice dosed groups were similar to controls. Performed adjusted incidence rates due to high mortality in rat groups, but reviewers questioned their usefulness. Reviewers questioned the use of dosed feed administration instead of dermal or inhalation. NIEHS researchers defended the chosen route, explaining that it was chosen for maximum exposure. Female rat multiplicity of mammary tumors increased significantly from control: 6/50, 37/51, 40/53, 37/52
Other tumors
A list of other tumors that developed in the study that were treatment related.
skin, Zymbal gland, oral, esophagus, forestomach, intestines, bladder, lung, thyroid, leukemia, seminal vesicles, harderian gland, kidney, mesothelium
Endocrine related toxicities
This field reports endocrine related toxicities that appeared in the
study such as testicular atrophy.
hyperplasia of seminal vesicle
CPDB TD50 (mg/kg-d)
Data excerpted from the CPDB database that is defined as the "dose-rate in
mg/kg body wt/day which, if administered chronically for the standard lifespan of the species,
will halve the probability of remaining tumorless throughout that period". The CPDB
calculated values for all tumor endpoints listed as well as for total tumors. The range of
mammary gland tumors TD50s is provided, as well as an overall range.
Mammary: 78.3-1480, Overall: 5.94- 16000