In the summary table, a carcinogenic potency value
(TD50) is reported for each chemical in each species
that has a positive author’s evaluation of carcinogenicity in
at least one experiment. TD50 values for each species in
the summary table are averages calculated by taking the harmonic
mean of the most potent TD50 values from among target
sites in each positive experiment from the Carcinogenic Potency
Database (CPDB). If there is only one positive experiment on the
chemical in the species, then the most potent TD50 value from that experiment
is reported. When more than one experiment is positive in the
species, the reported TD50 value is a harmonic mean of
the most potent TD50 value from each positive
experiment, selected from the tissue-tumor combinations (target
sites) that were evaluated by he published author of the experiment
as evidence of carcinogenicity. The harmonic mean (TH)
is defined as:
The harmonic mean TD50 is a summary measure that takes into account all positive results for a chemical in each species, from experiments that may differ, for example, in animal strain, route of administration, dose levels tested, duration of experiment, and whether an author published results on survival. In contrast, use of the most potent site (lowest TD50 value in any experiment) would reflect only results from a single experiment and not take these differences into account.
The harmonic mean TD50 value, as we showed in earlier work, is similar to the most potent site from among all experiments, and more similar than the geometric or arithmetic mean (1). For various purposes one may wish to use different summary measures of TD50. It generally makes little difference in the TD50 value whether one uses the most potent target site in the CPDB or the harmonic mean of the most potent TD50 from all positive experiments (1). In the CPDB overall, for 45% of rat carcinogens and 34% of mouse carcinogens, there is only one positive experiment, and therefore the harmonic mean of TD50 is the same as the most potent site. For 99% of mouse carcinogens and 97% of rat carcinogens, the harmonic mean is within a factor of 3 of the most potent site.
To obtain the harmonic mean, TD50 values from each experiment are used only from among target sites that the published author evaluated as evidence of carcinogenicity. We use the author’s opinion to determine positivity because it often takes into account more information than statistical significance alone, such as historical control rates for particular sites, survival and latency, and/or dose-response. Generally, this designation by author’s opinion corresponds well with the results of statistical tests for the significance of the dose-response effect (p<0.01).
The most potent (lowest) TD50 value from each positive experiment is selected from among values with a statistically significant dose response (p<0.1) for tissue-tumor target sites that the published author considered to be induced by compound administration. If no target sites have a significant dose response, then the most potent (lowest TD50) is selected from among positively evaluated target sites with p≥0.1. If some experiments in a species have a positive evaluation and statistically significant results while others have only positive evaluations but statistically non-significant results (p≥0.1), the non-significant experimental results are not used in the calculation of the harmonic mean.Forty-four chemicals had an experiment for which no TD50 could be estimated because all dosed animals had the tumor of interest, and only summary data (not lifetable) on tumor incidence were available. The 99% upper confidence limit of TD50 from that experiment is used in calculating the harmonic mean, as a replacement for the TD50. These cases are marked in the table with a “P” superscript. For 9 of these chemicals, all animals had tumors at the target site in all positive experiments. The 99% upper confidence limit replaces a harmonic mean in these cases, and the reported value is marked with a “<” symbol to indicate that any TD50 value would be lower.
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Last updated: March 3, 2010