Environment and Breast Cancer: Science Review
AboutCancer studies: Experimental details
National Toxicology Program Technical Report 306, 1986
Notes
"Clear evidence" in rats is based on the mammary tumors. Rats: 0, 1000, 2000, 4000 ppm:benign mammary tumors in female rats: 5/50, 11/50, 13/50, 22/50. In male rats, they looked at the combined benign mammary tumors and the integumentary ones, for significant increase. In Discussion, for mammary tumors they note Burek 1980 and 1984 for mammary tumors, Nitschke 1982. For"negative" they note National Coffee Association studies of 1982 and 1983 in which much lower levels were used (highest was 250 mg/kg).
"Clear evidence" in rats is based on the mammary tumors. Rats: 0, 1000, 2000, 4000 ppm:benign mammary tumors in female rats: 5/50, 11/50, 13/50, 22/50. In male rats, they looked at the combined benign mammary tumors and the integumentary ones, for significant increase. In Discussion, for mammary tumors they note Burek 1980 and 1984 for mammary tumors, Nitschke 1982. For"negative" they note National Coffee Association studies of 1982 and 1983 in which much lower levels were used (highest was 250 mg/kg).
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).
inhalation
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, 1000, 2000, 4000ppm, Mice: 0, 2000, 4000ppm; for 6 hrs/day, 5 days/wk for 102 weeks. 50 animals in each group. Age exposure started 8-9 weeks for rats, 7-8 weeks for mice.
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.
1 week
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."
male rat: 0/50, 0/50, 2/50, 5/50; female rat: 5/50, 11/50, 13/50, 22/50. None in mice.
Fibroadenomas
Mammary tumors, malignant
Development of malignant mammary gland tumors follows the
same format as for benign, as described above.
male rat:none; female rat 2/50, 2/50, 2/50, 0/50 malignant mammary gland neoplasms; male rats subcutaneous tissue fibroma or sarcoma in area of mammary chain: 1/50, 1/50, 2/50, 5/50. None in mice.
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.
Body weight gains similar between dosed and control. Survival for rats a problem at high dose for females (all groups for males) because of rampant leukemia, liver, and lung tumors. All male groups had survival problems. Reviewers (with industry affiliation) challenged the "clear evidence" determination based on the mammary tumors because they are benign, even though this falls under the description developed by NTP in 1983. They also unsuccessfully challenged the increase rate for being not "a substantially increased incidence" based on comparisons to historical controls. However, the dosed animals did have a substantial increase of benign mammary tumors in comparison to the concurrent control, which NTP weighs most heavily. A compromise was made to add 'benign' before neoplasm in the summary.
Other tumors
A list of other tumors that developed in the study that were treatment related.
liver,hematopoietic, nasal, kidney, spleen, prostate,kidney, spleen, parathyroid, lung,
Endocrine related toxicities
This field reports endocrine related toxicities that appeared in the
study such as testicular atrophy.
"Dose related increases were observed in the incidences of testicular atrophy in male mice and uterine and ovarian atrophy in female mice; these effects are considered to be secondary responses to neoplasia."
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: 598- 1770; other: 501-1580