Supplement to the Carcinogenic Potency Database (CPDB): Results of Animal Bioassays Published in the General Literature through 1997 and by the National Toxicology Program in 1997–1998

Lois Swirsky Gold*,{dagger},1, Neela B. Manley{dagger}, Thomas H. Slone*, Lars Rohrbach{ddagger} and Georganne Backman Garfinkel{dagger}

* Department of Molecular and Cell Biology, University of California, Berkeley, California 94720; {dagger} Life Sciences Division, E.O. Lawrence Berkeley National Laboratory, Berkeley, California 94720; and {ddagger} Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, California 94720

1 To whom correspondence should be addressed: Fax: (510) 547-7073. E-mail: lois{at}potency.berkeley.edu. Web Site: http://potency.berkeley.edu/.

Received January 31, 2005; accepted March 23, 2005


    ABSTRACT
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 INTRODUCTION
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The Carcinogenic Potency Database (CPDB) is a systematic and unifying resource that standardizes the results of chronic, long-term animal cancer tests which have been conducted since the 1950s. The analyses include sufficient information on each experiment to permit research into many areas of carcinogenesis. Both qualitative and quantitative information is reported on positive and negative experiments that meet a set of inclusion criteria. A measure of carcinogenic potency, TD50 (daily dose rate in mg/kg body weight/day to induce tumors in half of test animals that would have remained tumor-free at zero dose), is estimated for each tissue-tumor combination reported. This article is the ninth publication of a chronological plot of the CPDB; it presents results on 560 experiments of 188 chemicals in mice, rats, and hamsters from 185 publications in the general literature updated through 1997, and from 15 Reports of the National Toxicology Program in 1997–1998. The test agents cover a wide variety of uses and chemical classes. The CPDB Web Site (http://potency.berkeley.edu/) presents the combined database of all published plots in a variety of formats as well as summary tables by chemical and by target organ, supplemental materials on dosing and survival, a detailed guide to using the plot formats, and documentation of methods and publications. The overall CPDB, including the results in this article, presents easily accessible results of 6153 experiments on 1485 chemicals from 1426 papers and 429 NCI/NTP (National Cancer Institute/National Toxicology program) Technical Reports. A tab-separated format of the full CPDB for reading the data into spreadsheets or database applications is available on the Web Site.

Key Words: carcinogenic potency; TD50; database; chronic animal cancer test.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 SUPPLEMENTAL PLOT OF THE...
 REFERENCES
 
The Carcinogenic Potency Database (CPDB) is a systematic and unifying analysis of the published results of the diverse literature of chronic, long-term animal cancer tests on individual chemicals. A detailed set of inclusion rules is designed to restrict the database to reasonably thorough experiments for evaluating carcinogenic activity and carcinogenic potency. The CPDB standardizes the experimental results and creates an easily accessible resource that has been widely used to address a variety of research and regulatory issues in carcinogenesis. The CPDB is expanded chronologically, and the present article is a supplement that reports bioassay results that were published in the general literature through 1997 and in Technical Reports of the National Toxicology Program in 1997–1998. Our analyses are presented in the same plot format as earlier publications (Gold et al., 1984Go, 1986Go, 1987Go, 1990Go, 1993Go, 1995Go, 1997Go, 1999Go). Data are reported here for 560 experiments on 188 chemicals. When added to the data published earlier, the CPDB now includes results of 6153 experiments on 1485 chemicals that have been reported in 1426 published papers and 429 NCI/NTP Technical Reports.

In this article, as in earlier publications of the CPDB, a plot format is used to report detailed information on each experiment (whether positive or negative for carcinogenicity), which is important in the interpretation of bioassays including qualitative data on strain, sex, target organ, histopathology and author's opinion as to carcinogenicity, as well as quantitative information on average daily dose rate, duration of dosing, carcinogenic potency, statistical significance, tumor incidence, dose response curve, and length of experiment. Each set of experimental results references the original published paper. A series of appendices describes the fields in the plot and defines the codes in each field.

A numerical description of carcinogenic potency, the TD50 (Peto et al., 1984Go; Sawyer et al., 1984Go), is estimated for each set of tumor incidence data reported in the CPDB, thus providing a standardized quantitative measure for comparisons. In a simplified way, TD50 may be defined as that dose-rate in mg/kg body weight/day which, if administered chronically for the standard lifespan of the species, will halve the probability of remaining tumorless throughout that period. Put differently, TD50 is the daily dose-rate that will induce tumors in half of test animals that would have remained tumor-free at zero dose. We estimate TD50 using a one-hit model (Peto et al., 1984Go). TD50 is analogous to LD50, and a low value of TD50 indicates a potent carcinogen, whereas a high value indicates a weak one. TD50 is often within the range of doses tested, and does not indicate anything about carcinogenic effects at low doses because bioassays are usually conducted at or near the maximum tolerated dose (MTD). Among the 751 rodent carcinogens in the overall CPDB, the range of TD50 values (mg/kg/day) is at least 10-million-fold in each sex of rat or mouse.

The CPDB is exhaustive in that it includes all published results of experiments that meet a set of inclusion criteria designed to include reasonably thorough tests and to measure carcinogenic potency; however, since many tests do not meet the criteria, not all cancer tests are included. No attempt has been made to perform an evaluation of whether or not a compound induced tumors in any given experiment; rather, the opinion of the published authors is presented as well as the statistical significance of the TD50 calculated from the experimental results. The CPDB augments the published literature because we have had correspondence with about half the authors of published papers and have obtained tumor incidence data in addition to what has been published and have confirmed opinions about carcinogenicity at particular target sites.

There is great diversity in the extent of testing of the chemicals reported in the database; while most chemicals have been tested in rats or mice, some have been tested in hamsters, dogs, prosimians, or monkeys. Among the 1485 chemicals in the CPDB, 52% have been tested in only a single species, 44% in two species, and 4% in more than two. Experiments with 120 different mouse strains and 91 rat strains are included. For a given chemical, the database may have only a single experiment or several experiments. For example, among the 1165 chemicals tested in rats, 26% have only one rat test and 51% have two tests; however, 26 chemicals have more than 10 tests. For the 957 chemicals tested in mice, the parallel numbers are 11% with 1 test, 59% with 2 tests, and 18 chemicals with more than 10 tests. Chronologically, the CPDB reflects trends in bioassay design; for example, in the 1990s compared to earlier decades, fewer experiments have only a single dose level and a higher proportion have three or more groups in addition to controls. Seventy-two percent of the experiments in the CPDB are from papers in the general literature, and 28% are from NCI/NTP Technical Reports.

The CPDB is readily amenable to analyses ranging from large-scale investigations of the literature of chronic cancer bioassays to studies of individual chemicals or target organs or routes of administration. One major goal of the CPDB is to facilitate the use of bioassay results in carcinogenesis research. We, as well as hundreds of other researchers and agencies, have used the CPDB to address important issues in toxicology. The widely accessed CPDB Web Site presents the database in a variety of formats and also gives the text of papers using the database that our group has published since the 1980s.

Plot in This Supplement
The supplement to the CPDB presented in this article includes results on 188 chemicals and 560 long-term, chronic experiments in rats, mice, and hamsters. NTP Technical Reports are from 1997–1998. For the general literature, about 60% of experiments are from papers published in 1995–1997. The rest of the papers are from earlier years but were not included in the CPDB earlier because they were identified recently, mainly from two sources we had not used previously in our extensive literature searches: the Japanese Science and Technology Database (JICST-EPlus) and the U.S. FDA database on Food Additives: Toxicology, Regulation and Properties (Clydesdale, 1997Go). This supplement, like the overall CPDB, is exhaustive in that it includes all published results of experiments that meet a set of inclusion criteria. In the general literature, experimental designs as well as the author's choice of information to report are quite diverse, and bioassays have been included only if they meet all of the following conditions:

  1. Animals on test were mammals.
  2. Administration was begun early in life (100 days of age or less for rats, mice, and hamsters).
  3. Route of administration was diet, water, gavage, inhalation, iv or ip injection (i.e., where the whole body was more likely to have been exposed rather than only a specific site, as with sc injection or skin painting).
  4. Test agent was administered alone, rather than in combination with other chemicals.
  5. Exposure was chronic, with not more than seven days between administrations.
  6. Duration of exposure was at least one-fourth the standard lifespan for that species. For rodents the standard lifespan is two years.
  7. Duration of experiment was at least half the standard lifespan for that species.
  8. Research design included a concurrent control group.
  9. Research design included at least five animals per group.
  10. Surgical intervention was not performed.
  11. Pathology data were reported for the number of animals with tumors rather than the total number of tumors.
  12. Results reported were original data, rather than secondary analyses of experiments already reported by other authors.
  13. For studies with interim sacrifices, data are reported as a separate experiment for each sacrifice time.

Because we have adhered strictly to the standard inclusion criteria, bioassays of particulate or fibrous matters are not in the CPDB, e.g., asbestos, cigarette smoke, and dusts. There are no studies using a single administration of a test agent, no experiments by skin painting, sc injection, or in utero exposure, and no co-carcinogenesis experiments.

The selection of tissue-tumor combinations to report in the CPDB for each experiment is determined by a set of rules used throughout the database. Whenever the published paper has the following information, it is included:

  1. Each target site evaluated by the author as evidence of a carcinogenic effect
  2. Liver for all species, and lung for mice, whenever reported
  3. The category "all tumor-bearing animals"
  4. For completeness, the CPDB also includes sites with a statistically significant increase in tumors that the author of the published paper did not consider treatment-related.

The plot format in this article is designed to facilitate use of the data. Appendix 1 describes each of the fields in the plot. Other Appendices define codes, e.g., tissue, tumor, note codes. Appendices 12 and 13 provide a bibliography of papers that are the source of data reported in the plot. Further details and a guide to using the plot, are given on our Web Site. For 67 of the 188 chemicals in this plot, additional bioassay results were reported earlier in the CPDB, and these are indicated with *** following the chemical name. In the plot, experiments are ordered alphabetically by chemical name. Within each chemical, the experiments are ordered alphabetically by species, within a species by strain, and within strain by sex. Each line of the plot reports results for a particular tissue-tumor combination. Each experiment is assigned a consecutive number, and within an experiment each tissue-tumor combination is assigned a letter.

In the field of carcinogenicity bioassays, over time fewer experiments have only a single dose group in addition to controls, and in this plot only 25% of experiments have a single dose group, 15% have two dose groups, and 60% have more than two dose groups. NTP bioassays now routinely use three dose groups. As in the CPDB overall, the chemicals in this plot induce tumors in a variety of target sites. Liver is the most frequent target site for both rats and mice, as in the CPDB overall (Gold et al., 2001Go).

Naturally occurring and synthetic compounds from a variety of chemical classes and with a variety of uses are included in this supplement to the CPDB. A few examples follow: (1) In inhalation bioassays of three genotoxic synthetic, industrial chemicals (chloroprene, tetrafluorethylene, and vinyl fluoride) tumors were induced at multiple target sites in both sexes of rats and mice. (2) Arsenic in drinking water is a human carcinogen (International Agency for Research on Cancer, 2004Go); most arsenic in groundwater is the result of natural occurrence. We report here the first positive results for arsenic compounds in the CPDB. Two methylated arsenic compounds that are urinary metabolites of ingested inorganic arsenic induced tumors in male rats when administered in drinking water: dimethylarsinic acid induced bladder tumors, and trimethylarsine oxide induced hepatocellular adenomas. Another urinary metabolite, monomethylarsonic acid, gave negative results in both sexes of rats and mice when administered in the diet, and in male rats when administered in water. (3) Results are also reported here for another human carcinogen, aristolochic acid (AA) (International Agency for Research on Cancer, 2002Go), which is a naturally occurring constituent of plants commonly used in traditional Chinese herbal medicine. We recently showed that despite FDA warnings and an import alert for aristolochic acid under the Dietary Supplement Safety and Health Act (DSHEA), two years later more than 100 U.S. web sites were selling products listing botanical ingredients known or suspected to contain AA (Gold and Slone, 2003Go). (4) Two by-products of water chlorination, dichloroacetic acid and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), are also carcinogenic. (5) About 30% of the chemicals in this supplement are pharmaceuticals; examples of some that are positive for carcinogenicity are lovastatin, AZT, and salicylazosulfapyridine. (6) Bioassays of three food additives found no evidence of carcinogenicity: olestra, monosodium glutamate, and aspartame. (7) Acrylamide is a genotoxic, industrial chemical that was recently identified as a product of cooking; it is widespread in the food supply. Acrylamide is also a constituent of cigarette smoke. The plot reports positive results at multiple target sites in male and female rats for acrylamide administered by drinking water.

The range of TD50 values (mg/kg/day) for carcinogens in this plot is 2-million fold across chemicals. At the two extremes in female rats, for example, are the most potent TD50 values for aristolochic acid (TD50 = 14.1 µg/kg/day), and hydrochlorofluorocarbon 123 (TD50 = 22.7 gm/kg/day).

Analyses That Use the CPDB
During the past 20 years we have published many papers based on results in the CPDB, including methodological analyses of bioassay results such as reproducibility of results and methods for summarizing potency of a chemical; species comparisons in positivity, target site, and potency; frequency and type of target organs in each species; constraints on potency estimation; mechanism of carcinogenesis; carcinogenicity of natural vs. synthetic chemicals and comparisons of possible cancer hazards; permitted occupational exposures and possible cancer hazards; disparities in cancer risk estimates of pesticide residues in food; and comparison of cancer risk assessments based on a variety of methodologies. The text of these papers is given on our Web Site.

One persistent finding has been that half or more of the chemicals tested in chronic, long-term tests are carcinogenic in at least one experiment. Results are similar for a variety of subsets of the data, including naturally occurring chemicals in the diet and synthetic chemicals (Table 1). Human exposures to rodent carcinogens are thus ubiquitous. We have discussed in several papers the plausible explanations for this high positivity rate, including a variety of high dose effects (Ames and Gold, 1990Go, 2000Go; Gold et al., 1998Go, 2002Go).


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TABLE 1 Proportion of Chemicals in the CPDB That Are Evaluated as Carcinogenic

 
The CPDB Web Site
One goal of the CPDB has been to facilitate the use of bioassay results in carcinogenesis research and regulatory policy. Our highly accessed Web Site (http://potency.berkeley.edu/) is designed to provide user-friendly access to CPDB results for 6153 experiments on 1485 chemicals. The Web Site can be searched for results on a particular chemical, a particular target organ, or a particular published paper or experiment. A plot of the full CPDB is on the Web in the format presented in this paper and is suitable for printing. A compact format is designed for viewing on a single computer screen, and a tab-separated format is designed for reading into spreadsheets or database applications.

Two tables on the Web Site summarize each chemical using all experiments in the CPDB. Separate tables summarize the results of NCI/NTP bioassays only.

The Summary Table by Chemical (http://potency.berkeley.edu/chemicalsummary.html) is an alphabetical index of chemicals in the CPDB and a tabular compilation of positivity, target sites, and carcinogenic potency on each chemical based on data from all experiments. It can be used to investigate associations between carcinogenic potency or target sites and other factors such as mutagenicity, teratogenicity, chemical structure, and human exposure. It is readily downloadable to spreadsheets or other databases.

The Summary Table by Target Organ (http://potency.berkeley.edu/pathology.table.html) is a compendium of bioassay results organized by target site in each species for chemicals with a positive result. It lists, for example, each chemical that induces tumors in the lung or liver or hematopoietic system, and superscripts indicate whether the chemical is tested in both rats and mice and whether it is positive in both species. Target organs are also summarized for hamsters, dogs, and nonhuman primates.

Additional information on the Web Site for each chemical includes mutagenicity in Salmonella, chemical structure, and SMILES code. A supplementary database reports details of dosing and survival in each experiment. Documentation is provided on the methods used to develop the CPDB, a detailed guide to each field in the plot, and details of the tab-separated database for reading into spreadsheets.


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    ACKNOWLEDGMENTS
 
We thank the hundreds of scientists who have assisted us in developing the CPDB over the past 20 years by providing additional information on their experiments. We thank Bruce N. Ames and Jerrold Ward for their many years of advice. This work was supported by the National Institute of Environmental Health Sciences through the E.O. Lawrence Berkeley National Laboratory (LBNL) Interagency Agreement (YIES101901) with the U.S. Department of Energy (DOE) DE-AC-03-76SFO0098, and through the University of California, Berkeley by a grant for research in disease prevention through the Dean's Office of the College of Letters and Science.


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Ames, B. N., and Gold, L. S. (1990). Perspective: Too many rodent carcinogens: Mitogenesis increases mutagenesis. Science 249, 970–971.[ISI][Medline]

Ames, B. N., and Gold, L. S. (2000). Paracelsus to parascience: The environmental cancer distraction. Mutat. Res. 447, 3–13.[ISI][Medline]

Clydesdale, F. M., Ed. (1997). Food Additives: Toxicology, Regulation, and Properties. CRC Press, Boca Raton, FL.

Gold, L. S., Sawyer, C. B., Magaw, R., Backman, G. M., de Veciana, M., Levinson, R., Hooper, N. K., Havender, W. R., Bernstein, L., Peto, R., Pike, M. C., and Ames, B. N. (1984). A Carcinogenic Potency Database of the standardized results of animal bioassays. Environ. Health Perspect. 58, 9–319.[ISI][Medline]

Gold, L. S., de Veciana, M., Backman, G. M., Magaw, R., Lopipero, P., Smith, M., Blumenthal, M., Levinson, R., Bernstein, L., and Ames, B. N. (1986). Chronological supplement to the Carcinogenic Potency Database: Standardized results of animal bioassays published through December 1982. Environ. Health Perspect. 67, 161–200.[ISI][Medline]

Gold, L. S., Slone, T. H., Backman, G. M., Magaw, R., Da Costa, M., Lopipero, P., Blumenthal, M., and Ames, B. N. (1987). 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. Environ. Health Perspect. 74, 237–329.[ISI][Medline]

Gold, L. S., Slone, T. H., Backman, G. M., Eisenberg, S., Da Costa, M., Wong, M., Manley, N. B., Rohrbach, L., and Ames, B. N. (1990). Third chronological supplement to the Carcinogenic Potency Database: Standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987. Environ. Health Perspect. 84, 215–286.[ISI][Medline]

Gold, L. S., Manley, N. B., Slone, T. H., Garfinkel, G. B., Rohrbach, L., and Ames, B. N. (1993). The fifth plot of the Carcinogenic Potency Database: Results of animal bioassays published in the general literature through 1988 and by the National Toxicology Program through 1989. Environ. Health Perspect. 100, 65–135.[ISI][Medline]

Gold, L. S., Manley, N. B., Slone, T. H., Garfinkel, G. B., Ames, B. N., Rohrbach, L., Stern, B. R., and Chow, K. (1995). Sixth plot of the Carcinogenic Potency Database: Results of animal bioassays published in the general literature 1989–1990 and by the National Toxicology Program 1990–1993. Environ. Health Perspect. 103(Suppl. 8), 3–122.[ISI][Medline]

Gold, L. S., Slone, T. H., Ames, B. N., Manley, N. B., Garfinkel, G. B., and Rohrbach, L. (1997). Carcinogenic Potency Database. In Handbook of Carcinogenic Potency and Genotoxicity Databases (L. S. Gold and E. Zeiger, Eds.), pp. 1–605. CRC Press, Boca Raton, FL.

Gold, L. S., Slone, T. H., and Ames, B. N. (1998). What do animal cancer tests tell us about human cancer risk? Overview of analyses of the Carcinogenic Potency Database. Drug Metab. Rev. 30, 359–404.[ISI][Medline]

Gold, L. S., Manley, N. B., Slone, T. H., and Rohrbach, L. (1999). Supplement to the Carcinogenic Potency Database (CPDB): Results of animal bioassays published in the general literature in 1993 to 1994 and by the National Toxicology Program in 1995 to 1996. Environ. Health Perspect. 107(Suppl. 4), 527–600.

Gold, L. S., Manley, N. B., Slone, T. H., and Ward, J. M. (2001). Compendium of chemical carcinogens by target organ: Results of chronic bioassays in rats, mice, hamsters, dogs and monkeys. Toxicol. Pathol. 29, 639–652.[CrossRef][ISI][Medline]

Gold, L. S., Slone, T. H., Manley, N. M., and Ames, B. N. (2002). Misconceptions about the Causes of Cancer. Fraser Institute, Vancouver, British Columbia.

Gold, L. S., and Slone, T. H. (2003). Aristolochic acid, an herbal carcinogen, sold on the Web after FDA alert. N. Engl. J. Med. 349, 1576–1577.[Free Full Text]

International Agency for Research on Cancer (2002). Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene. IARC, Lyon, France.

International Agency for Research on Cancer (2004). Some Drinking-water Disinfectants and Contaminants, Including Arsenic. IARC, Lyon, France.

Peto, R., Pike, M. C., Bernstein, L., Gold, L. S., and Ames, B. N. (1984). The TD50: A proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments. Environ. Health Perspect. 58, 1–8.[ISI][Medline]

Sawyer, C., Peto, R., Bernstein, L., and Pike, M. C. (1984). Calculation of carcinogenic potency from long-term animal carcinogenesis experiments. Biometrics 40, 27–40.[ISI][Medline]





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