* Department of Molecular and Cell Biology, University of California, Berkeley, California 94720; Life Sciences Division, E.O. Lawrence Berkeley National Laboratory, Berkeley, California 94720; and
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 |
---|
![]() ![]() ![]() ![]() ![]() |
---|
Key Words: carcinogenic potency; TD50; database; chronic animal cancer test.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() |
---|
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., 1984; Sawyer et al., 1984
), 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., 1984
). 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 19971998. For the general literature, about 60% of experiments are from papers published in 19951997. 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, 1997). 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:
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:
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., 2001).
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, 2004); 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, 2002
), 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, 2003
). (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, 1990, 2000
; Gold et al., 1998
, 2002
).
|
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.
![]() |
SUPPLEMENTAL PLOT OF THE CARCINOGENIC POTENCY DATABASE |
---|
![]() ![]() ![]() ![]() ![]() |
---|
|
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() |
---|
Ames, B. N., and Gold, L. S. (2000). Paracelsus to parascience: The environmental cancer distraction. Mutat. Res. 447, 313.[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, 9319.[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, 161200.[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, 237329.[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, 215286.[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, 65135.[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 19891990 and by the National Toxicology Program 19901993. Environ. Health Perspect. 103(Suppl. 8), 3122.[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. 1605. 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, 359404.[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), 527600.
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, 639652.[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, 15761577.
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, 18.[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, 2740.[ISI][Medline]
|