||Serial sacrifice experiments of aristolochic acid in the same
paper were evaluated as positive at additional sites by the author
but did not meet inclusion rules of the CPDB. Full data are
reported in the Table at the end of this appendix.
||The exposure time reported on the plot is an average of the
different exposure times of the individual dose groups in the
experiment. For NCI/NTP, both exposure and experiment times have
been averaged because of differential survival among the dose
groups. (In the TD50 calculation for the NCI/NTP
bioassays, full lifetable data have been used.)
||Diet was specially prepared to be deficient in one or more
||Quantitative data are reported in the paper on cell division in
this tissue in dosed and control animals (e.g., labeling index). C
does not indicate whether or not there was an association between
cell division and tumorigenesis.
||Diet was specially prepared to be low in lipotropes.
||A cyclic dosing schedule was followed for part of the exposure
time, with at least one week between cycles, e.g., 3 weeks dosed,
one week not dosed. (NCI only)
||For the general literature we have used an effective number of
animals in a group whenever possible. This effective number is
either: (1) the number of animals alive at the time of appearance
of the first tumor, or (2) if that is not reported, then the number
of animals examined.
||Diet was specially prepared to have a lower than average
||Some or all of the animals were used as breeders during the
course of the experiment.
||Occasionally, when there is a “c”, “p”,
“a”, or “e” in the opinion column for an
NCI/NTP bioassay, or a “+” for a test from the general
literature, the evaluation was made because the incidence among
dosed animals was high in comparison to historical control
incidences; this occurs, for example, when there is a rare tumor
among dosed animals. The actual numbers of animals bearing such
tumors may be quite low, thus making the estimate of
TD50 unreliable. In such cases, we have indicated that
the author’s opinion was based on historical control
comparisons withn an “h” notecode.
||Control and dosed animals received isocaloric diets.
||Dosing in this test was intermittent; it was stopped for more
than one week at some point in the experiment.
||Data for this test have been previously published in the CPDB.
The experimental results have been revised either because of a
later publication by the same authors or because of a personal
communication. In the CPDB, we give the same reference number to
the experiment in all plot publications.
||For interim and serial sacrifice experiments, we have reported,
as a separate experiment with a k notecode, each sacrifice time
that otherwise met the inclusion rules of the database. We have
included unscheduled deaths with the terminal sacrifice data, and
when this has been done, there is no k notecode for the terminal
||Female mouse strain was mammary tumor virus positive (MTV+)
with a high spontaneous incidence of mammary tumors; histopathology
was restricted to mammary gland. The study was designed to measure
tumor latency, and no author”s opinion about carcinogenicity
is given in the CPDB.
||The calculated dose rate for a group is an average of either
(1) different doses administered to individual animals, or (2) a
narrow range of doses administered.
||NTP considered one dose group inadequate for detecting a
||Chemical was administered as an aerosol.
||Restricted site analysis; the authors either examined or
reported results for only one or a couple of tissues.
||Authors noted that survival was decreased due to toxicity,
disease, or accidental death.
||The NCI Technical Report indicated that tumors were
“associated” with compound administration, and the NTP
assigned a “positive” evaluation, while noting that
“these experiments were particularly difficult to evaluate
based on the wording in the Technical Report Summaries”
(Haseman et al., Environ. Health Perspect. 74: 229-235,
||Variable or irregular dosing schedules have been used, e.g.
dose level changed during the experiment.
||Tumors in control monkeys that lived longer than the last dosed
animal in the experiment are deleted from the analysis. See
Species Appendix for details on monkey
||For nonhuman primates, denominators for tumor incidence on the
plot represent the number alive at the age of the first tumor of
that type; since that age varies for different tumor types,
denominators on the plot for control and dosed animals can vary
widely from one site to another within an experiment. Only a few
chemicals were tested at more than one dose level; we use the
symbol “–/–” to indicate that for one of
the dose groups all animals were dead before the occurrence of
tumors of that type in another group. The maximum number of animals
used in any TD50 for an experiment is indicated by the
denominator of the tumor incidence for “all tumor-bearing
animals” (“tba” on the plot) and represents the
number alive at the first tumor in any group.
||Exposure began before the animals were weaned.
||Animals were dosed for only 25 weeks; one week short of the
standard criterion. Due to rounding, 6 months is reported as the
exposure time on the plot.
||In a report of these vinyl chloride experiments (Maltoni,
1977), the author notes “All the animals exposed to the
highest doses (30,000 and 10,000 ppm for 52 weeks), with or without
tumors, were examined radiologically during treatment and/or at
death; moreover, radiologic examinations have also been made on
several animals bearing tumors even though these animals had been
exposed to the lower doses.” The experiment at the highest
dose (30,000 ppm) is not included in the database. The reported
data include the 10,000 ppm or lower doses.
||For NTP bioassays evaluated as having no evidence of
carcinogenicity, a statistically significant increase in tumors
occurred in one or more sites (p<0.05). We have indicated
this by placing a “–” in the opinion column and
flagging the TD50 with a “#” sign in the
plot just to the left of the TD50 value.
For the test of aristolochic acid (AA) in Wistar
rats (Mengs, 1982), the CPDB includes only results of the chronic,
69 week experiment in which AA was administered at 0.1 mg/kg/day
for 52 weeks (daily dose-rate in CPDB=0.075 mg/kg/day). Other
groups of rats were administered 1.0 or 10 mg/kg/day for only 13
weeks and were sacrificed at various times shown in the table
below; this short dosing period and the short times to sacrifice do
not meet the inclusion rules of the CPDB (at least 26 weeks dosing
and 52 weeks experiment length). In the 69-week experiment that
meets the inclusion rules, the only target site was forestomach.
Kidney and bladder were additional target sites in the groups that
were administered higher doses for 13 weeks; tumor incidence data
are given in the table below for each sacrifice time. The table
reports the dose as administered for 13 weeks and not the CPDB
daily dose-rate or a TD50 value, because the serial
sacrifice experiments do not meet the CPDB inclusion rules.