Second chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1984 and by the National Toxicology Program through May 1986.

This paper is the second chronological supplement to the Carcinogenic Potency Database, published earlier in this journal (1,2,4). We report here results of carcinogenesis bioassays published in the general literature between January 1983 and December 1984, and in Technical Reports of the National Cancer Institute/National Toxicology Program between January 1983 and May 1986. This supplement includes results of 525 long-term, chronic experiments of 199 test compounds, and reports the same information about each experiment in the same plot format as the earlier papers: 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 (carcinogenic potency) and its statistical significance, dose response, author's opinion about carcinogenicity, and literature citation. We refer the reader to the 1984 publications for a 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. The three plots of the database are to be used together, since results of experiments published in earlier plots are not repeated. Taken together, the three plots include results for more than 3500 experiments on 975 chemicals. Appendix 14 is an index to all chemicals in the database and indicates which plot(s) each chemical appears in.


Background
This is the third paper in which a portion of the Carcinogenic Potency Database (CPDB) is published in plot format. We have developed the CPDB in an effort to improve the use of animal bioassay data in the study of chemical carcinogenesis, and in the assessment of potential health hazards to humans. Together the three plots quantify and standardize the very diverse literature of long-term, chronic carcinogenesis bioassays pub-*A computer tape of the plot of the database and appendices can be obtained from the first author. (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 mg/kg 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 (1,3). The range of TD50 values for carcinogens in the CPDB is more than 10 million-fold.
Gold et al. (2) presented a guide to the plot of the database 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. The second plot (4) covered the literature published in 1981 and 1982. The present paper is a chronological supplement for 1983 and 1984. It is our intention that the three plots be used together, and that readers who are not familiar with the database will read the earlier papers when using the plot. We have not duplicated earlier results, and thus for complete data on chemicals in more than one plot, all of the publications are necessary.
Each plot of the database provides the same set of information about each experiment in the same format, 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 citation. 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).
The TD50 values in the CPDB 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 (1,3). In a few cases, no TD50 could be calculated because all dosed animals had the tumor ofinterest, and only summary incidence data were available (5). The TD50 values for the compounds in this supplementary plot fall within the range of values reported earlier (2).
In 1983 the NTP adopted a new set of categories for their interpretive conclusions. In the "author's opinion" column on our plot, we report these evaluations using the same codes as in our earlier plots with the addition of "e" to denote "equivocal evidence of carcinogenicity." The "author's opinion" column for the general literature is the same as in earlier plots. Appendix 11 in this publication lists the codes and definitions used for the author's opinion, and full details are given in Gold et al. (2).
The appendices to each of the three plots provide the same types of information for the data in that publication, and are given the same appendix numbers. Appendix 1 lists alphabetically the compounds included in the plot and their common synonyms; Appendix 2 provides a list of the compounds sorted 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); sites of tumor induction (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 author's opinion codes (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 have added a new Appendix in this publication, Appendix 14, that indicates which plot contains results of experiments on each of the 975 chemicals in the database; it is sorted alphabetically by chemical name or common synonym. We are continuing to update the Carcinogenic Potency Database with papers published after 1984, 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.

Plot in This Supplement
The plot of the database includes results of 525 longterm, chronic experiments with 199 chemicals. It presents results for 35 compounds from Technical Reports of the National Cancer Institute/National Toxicology Program (NCI/NTP) published between January 1983 and May 1986, as well as results for 167 compounds published in the general literature between January 1983 and December 1984. Several experiments which have been identified from earlier years are also included.
Experiments in rats, mice, and hamsters are reported here for 199 compounds representing a variety of chemical classes, (e.g., nitroso compounds and halogenated hydrocarbons) with a variety of uses. Some are naturally occurring substances which are constituents of foods (e.g., safrole, quercetin, and estragole); food additives (e.g., D,L-monosodium glutamate and butylated hydroxyanisole); industrial compounds (e.g., ethylene oxide and 1,2-propylene oxide); and drugs (e.g., phenobarbital and primodolol). Of the 199 chemicals, 66 were also included in the first or second plot, and we have flagged these with a triple asterisk (***) after the chemical name in the plot. For some substances, only a few experiments are reported here, but large numbers of experiments were previously reported (2,3), e.g., 2-acetylaminofluorene and DDT.

Analyses of the Database
The three plots of the CPDB include more than 3500 experiments on 975 chemicals which meet the inclusion Table 1. Correct CAS numbers for eleven chemicals in earlier CPDB plots.
Most of the chemicals have been tested in rats or mice; however, some have been tested in hamsters, dogs, or monkeys. Experiments with 95 different mouse strains and 72 rat strains are included. For a given chemical, the database may contain only a single experiment, or a great many experiments. For example, among the 706 chemicals tested in rats, 33% have only one rat test and 52% have two tests; however, 11 chemicals have more than 10 tests. Overall, about half of the 975 chemicals in the database are positive in at least one experiment according to the opinion of the published author. This proportion is similar for rats and mice and for each of the three plots of the database. There is generally good concordance between authors' opinions as to carcinogenicity and the statistical significance of the experimental results.
Of the 975 chemicals in the CPDB, 392 have been tested in both rats and mice. Among these, 130 (33%) are positive in both species, 166 (43%) are negative in both, 56 (14%) are positive only in mice, and 40 (10%) are positive only in rats. We are currently examining these results and some possible explanations for differences between the species.
Our group has used the CPDB to address several issues relevant to interspecies extrapolation and chemical carcinogenesis. The good correlation of carcinogenic potency found between rats and mice has been described using the chemicals tested by the NCI/NTP Bioassay Program and some tautologous aspects of this comparison have been examined (5). 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 (6). 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 sex-species group oftest animal, whether tumors may have caused the death of the animal or were found at sacrifice, and whether metastases of induced tumors occurred (7). Reproducibility of results has been investigated in 70 "near-replicate" comparisons consisting of two or more tests of the same chemical ad-ministered by the same route and using the same sex and strain of rodent. Overall, there was good reproducibility of positivity, target site, and TD50 in rats, mice, and hamsters (8).
We have proposed a rough index of possible carcinogenic hazards to humans from exposures to chemicals that are carcinogenic in rodents, the HERP (human exposure dose/rodent potency dose). The HERP expresses each human exposure (mg/kg/day) as a percentage of the rodent TD50. We have computed HERP values for a variety of man-made and naturally occurring substances to which people may be exposed and have constructed a scale to rank possible hazards, although not to estimate absolute risks directly (9). In a separate analysis using a similar index, we rank the potential carcinogenic hazards permitted to U.S. workers from exposures to 41 rodent carcinogens that are regulated with Permissible Exposure Levels (PELs) by the U.S. Occupational, Safety, and Health Administration. For some substances, exposures at the PEL would be close to the dose rate that produces tumors in 50% of test animals (10)(11)(12).

Errata in the Earlier Publication
A few omissions and errors in earlier plots of the CPDB (2,4) have come to our attention.
Definitions for two codes were omitted from the appendices: the site code "sbg" stands for sebaceous gland, and the strain code "ssa" stands for S strain, albino.
The strain code "sds" should have been "sss." The chemical listed as mercury (II) acetate is actually phenylmercuric acetate. The CAS number is correct. For eleven chemicals in the earlier plots, the CAS numbers were reported incorrectly. The correct numbers for these substances, sorted alphabetically, are listed in Table 1.
We would appreciate hearing about any additional errors that the reader may discover. R m lev eat liv mix 56w56 s a R m Lev eat ski mix 56w56 s b R m lev eat mgl tum 56w56 s no dre P-I. 9.09mg Z P<.0005+ 7.65mg P<. 0005+ 13.5mg P< gann,74,8-20; Murasaki ;carc,4, 97-99;1983 Cohen;canr, 39, 1207-1217; 1979 Fukushima;gann, 74,8-20; 1983        Definition number of animals in a group whenever possible. This effective number is either: (1) the number of animals examined, or (2) the number of animals alive at the time of appearance of the first tumor. f Diet was specially prepared to have a lower than average protein level. g Some or all of the animals were used as breeders during the course of the experiment. i Dosing in this test was intermittent; it was stopped for more than one week at some point in the experiment. j The data for this test have been previously published in the database. The experimental results have been revised and re-published by the authors. In the database, we give the same reference number to the test in both publications. k For interim and serial sacrifice experiments, we have reported, as a separate experiment, each sacrifice time that otherwise met the inclusion rules of the database. The k notecode identifies these sacrificed groups. Wherever possible, we have included unscheduled deaths with the terminal sacrifice data, and when this has been done, there is no k notecode for that experiment.
r Restricted site analysis; the authors either examined or chose to report data for only a few selected tissues. s Authors noted that survival was decreased due to toxicity or disease.
v Variable or irregular dosing schedules have been used, e.g., dose level changed during the experiment. y 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.