Chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1982.

This paper is a chronological supplement to our earlier publication, "A Carcinogenic Potency Database of the Standardized Results of Animal Bioassays." We report here results of carcinogenesis bioassays published in Technical Reports of the National Cancer Institute/National Toxicology Program between July 1980 and December 1982, and the general literature between July 1981 and December 1982. This supplement includes results of 280 long-term, chronic experiments of 114 test compounds, and reports the same information about each experiment in the same plot format as the earlier paper: e.g., the species and strain of test animal, the route and duration of compound administration, dose level and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion about carcinogenicity, and literature reference. While a number of appendices are provided to facilitate use of this supplement, we have not duplicated here the material published earlier. Instead, we refer the reader to the earlier publications (Peto et al. and Gold et al.) for a thorough description of the numerical index of carcinogenic potency (TD50), a guide to the plot of the database, and a discussion of the sources of data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. For 44 of the 114 chemicals reported in this second plot, results of earlier experiments are also given in the first plot; since only 1981-1982 results are reported here, the first plot is required for these repeated compounds. In this paper we also give corrections for errors that appeared in the earlier publication.


Background
The Carcinogenic Potency Database of long-term, chronic carcinogenesis bioassays was first presented in two papers in 1984, Peto et al. (1) and Gold et al. (2). Peto et al. (1) described our numerical index of carcinogenic potency, the TD50, and the statistical procedures adopted for estimating it from experimental data. Briefly, TD50 may be defined as follows: for a given target site(s), if there are no tumors in control animals, then TD50 is that chronic dose rate in milligrams per kilogram body weight/day which would induce tumors in half the test animals at the end of a standard lifespan for the species. Since the tumor(s) of interest often does occur in control animals, TD50 is more precisely defined as that chronic dose rate which will halve the probability of remaining tumor-free throughout the standard lifespan of the species.
Gold et al. (2) presented a plot of the Carcinogenic Potency Database with an accompanying guide describing the contents, field by field, as well as a discussion of the sources of data, the criteria for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. We have developed the Carcinogenic Potency Database in an effort to improve the use of animal bioassay data in both the study of chemical carcinogenesis and the estimation of the potential health risks of chemicals to humans. The database quantifies and standardizes a very diverse body of literature, organizes it systematically, and applies an index of carcinogenic potency, the TD50, to the results of experiments on hundreds of test compounds. The range of TD50 values for carcinogens in the database is more than 10 million-fold (2).
The plot of the database provides a variety of information about each experiment, including: the species, strain, and sex of test animal; features of the experimental protocol such as route of administration, duration of dosing, dose level(s) in mg/kg body weight/day, and duration of experiment; histopathology and tumor incidence; carcinogenic potency and its statistical significance; shape of the dose response curve; author's opinion as to carcinogenicity; and literature reference. A word of caution is necessary about the limitations of the database. We have included only long-term tests of individual compounds which fit a set of criteria compatible with calculating potency; many animal cancer tests are excluded. Moreover, we have not attempted to evaluate whether or not a compound is a carcinogen; rather, we report the published opinions of the investigators whose data we present, as well as the statistical significance of the TD50 calculated from their results. Further discussion of the criteria for the database and the limitations can be found in Gold et al. (2).

Supplement to the Carcinogenic Potency Database
In this paper we present a chronological supplement to the plot, which updates the results for the literature published through December 1982. Rather than repeat the material published earlier, we refer the reader to the complete discussion and the plot in the earlier publication (2). The format of this new plot is identical to that of the first plot. It is our intention that the two plots be used together and that readers who are not familiar with the database will read the earlier papers first.
The plot of the database below includes results of 280 long-term, chronic experiments with 114 chemicals. It presents results for 32 compounds from Technical Reports of the National Cancer Institute/National Toxicology Program (NCI/NTP) published between July 1980 and December 1982, as well as results for 82 compounds published in the general literature between July 1981 and December 1982. The database as presented in the previous publication (2) covered the literature and the NCI/NTP Technical Reports published prior to these dates and included 2944 experiments of 770 test compounds. Results for several experiments that were published during the time frame of this supplementary plot were included in the first plot because of our ongoing analyses. We have not repeated those results here.
Experiments in rats, mice, hamsters, and rhesus monkeys are reported here for 114 compounds representing a variety of chemical classes (e.g., aromatic amines, nitroso compounds, hydrazines) with a variety of uses. Some are naturally occurring substances which are constituents of foods (e.g., caffeine, quercetin dihydrate, allyl isothiocyanate); food additives (e.g., bu-tylated hydroxytoluene, cinnamyl anthranilate, gum arabic); industrial compounds (e.g., vinyl chloride, ethylene oxide, 1,2-propylene oxide); and drugs (e.g., phenacetin, phenobarbital, norlestrin). Ofthe 114 chemicals, 44 were also included in the first plot, and we have flagged these in the plot below with a triple asterisk (***) after the chemical name. For some of these substances only one experiment is reported here, but large numbers of experiments were previously reported (2), e.g., 2-acetylaminofluorene and isoniazid. We have not duplicated the earlier results here, and thus, for complete results on these chemicals, both publications are necessary.
As in the first database, the TD50 values for the NCI/ NTP bioassays have been estimated using full lifetable information. For the TD50 values from the general literature the estimates use the final proportions of animals with tumors, since only this summary information is consistently published (3). The TD50 values for the compounds in this supplementary plot fall within the range of values reported earlier [ Figure 1 in (2)]. In a few cases no TD50 could be calculated because all dosed animals had the tumor of interest, and only summary incidence data were available (4).
The appendices provide the same types ofinformation as given in the earlier publication and are given the same appendix numbers. Appendix 1 lists alphabetically the compounds included in this plot and their common synonyms; Appendix 2 provides the same information ordered by Chemical Abstracts Service (CAS) Registry number. The next several appendices provide codes and definitions required for using the plot: strains of test animal (Appendix 3); routes of administration (Appendix 4); site (Appendix 5); histopathology (Appendix 6); notecodes (Appendix 7); dose-response curve symbols (Appendix 8); reference codes (Appendix 9); NCI/NTP bioassays evaluated as inadequate (Appendix 10); and species (Appendix 11). Appendices 12 and 13 give full bibliographic information for all experiments reported in this plot: the bibliography for the general literature (Appendix 12); and a list of the NCI/NTP Technical Reports (Appendix 13).
We are continuing to update the Carcinogenic Potency Database with papers published after 1982, and are also attempting to add earlier papers which we overlooked in our literature search. Therefore, we would appreciate information about any tests which the reader notices are missing.

Analyses of the Database
Our group has been using the results of the database published in Gold et al. (2) for several analyses, some still in progress. The good correlation of carcinogenic potency found between rats and mice and some tautologous aspects of this comparison have been examined using the chemicals tested by the NCI/NTP Bioassay Program (4). Two methods for estimating carcinogenic potency (TD50) from animal bioassays have been compared, one based on lifetable data and one based on summary incidence data (5). We have described the potencies of compounds which induce tumors at particular target sites in rats and mice and have examined other indicators of a chemical's hazard including: whether tumors were induced at more than one site in a single sexspecies group of test animal, whether tumors may have caused the death ofthe animal or were found at sacrifice, and whether metastases of induced tumors occurred (6). We have identified "near-replicate" carcinogenesis bioassays by selecting from the entire database those cases in which a single compound was tested more than once in a particular species, strain, and sex of rodent by the same route of administration, and have examined the extent of reproducibility of the results for these tests (7).
Other work in progress using the results of the Carcinogenic Potency Database includes a description of the extent to which compounds tested for carcinogenicity are positive-using various data sources, routes of administration, and frequency of testing; the predictive value of target sites in rats and mice is also examined. Various methods are being investigated for summarizing the potency of a single compound when several experiments have been conducted and a number of different TD50 values have been estimated for this same chemical. We are also exploring methods for comparing current human exposure levels to a substance, with the tumorigenic dose rate (TD50) estimated from the results of carcinogenesis bioassays (8).

Errata in the Earlier Publication
Since the earlier publication (2), a few errors have come to our attention. In three cases the database reports results for a single experiment as two different experiments because slightly different information had been published in two separate papers. The following corrections should be made: For ethylene thiourea, lines 1270 and 1271 are one experiment in female Charles River CD rats, and lines 1272 and 1273 are one experiment in males.
For N-nitrosodiethylamine, lines 2027 and 2030 are one experiment in female Fischer F344 rats.
For nitrosopyrrolidine, lines 2087 and 2088 are one experiment in female MRC rats, and lines 2088 and 2089 are one experiment in males.
In one other case, carrageenan (acid-degraded), two separate experiments are reported in Sprague-Dawley rats-one in which the compound was administered by gavage and one in the diet. However, the plot incorrectly assigned only one experiment number, line 482, to the two of them.
In the text, page 17, column 2, line 35, the number 5.55 mg/kg body weight/day should be 6.93 mg/kg body weight/day.
We would appreciate hearing about any additional errors which are discovered as the database is used.