Sixth Plot of the Carcinogenic Potency Database

Environmental Health Perspectives Volume 103, Supplement 8, November 1995

Sixth Plot of the Carcinogenic Potency Database: Results of Animal Bioassays Published in the General Literature 1989 to 1990 and by the National Toxicology Program 1990 to 1993

Lois Swirsky Gold,^1,2 Neela B. Manley,²Thomas H. Slone,^1,2 Georganne Backman Garfinkel,² Bruce N. Ames,² Lars Rohrbach,² Bonnie R. Stern,¹ and Kenneth Chow¹

¹Life Sciences Division, Lawrence Berkeley Laboratory, Berkeley, California; ²Division of Biochemistry and Molecular Biology, University of California, Berkeley, California

Main Article

Background
Plot in this Supplement
Analyses of Bioassays in Nonhuman Primates
Addenda and Errata to Earlier Plots

Carcinogenic Potency Database

A, B, C, D, E-F, G-H-I, L-M, N, O-P-Q-R, S-T-U-V

Appendicies

Appendix 1. Chemical Names and Synonyms in This Plot
Appendix 2. Chemical Names in This Plot Listed by CAS Number
Appendix 3. Strain Codes and Definitions
Appendix 4. Route of Administration Codes and Definitions
Appendix 5. Site Codes and Definitions
Appendix 6. Histopathology Codes and Definitions
Appendix 7. Note Codes and Definitions
Appendix 8. Dose-Response Curve Symbols and Definitions
Appendix 9. Reference Codes and Definitions
Appendix 10. Species Codes and Definitions
Appendix 11. Author's Opinion Codes and Definitions
Appendix 12. Bibliography: General Literature
Appendix 13. Bibliography: National Cancer Institute/National Toxicology Program Technical Reports
Appendix 14. Index to All Chemicals in the Six Plots of the Carcinogenic Potency Database and Results for Potency (TD50) and Positivityncy (TD50) and Positivity

Abstract

This paper presents two types of information from the Carcinogenic Potency Database (CPDB): (a) the sixth chronological plot of analyses of long-term carcinogenesis bioassays, and (b) an index to chemicals in all six plots, including a summary compendium of positivity and potency for each chemical (Appendix 14). The five earlier plots of the CPDB have appeared in this journal, beginning in 1984 (1-5). Including the plot in this paper, the CPDB reports results of 5002 experiments on 1230 chemicals. This paper includes bioassay results published in the general literature between January 1989 and December 1990, and in Technical Reports of the National Toxicology Program between January 1990 and June 1993. Analyses are included on 17 chemicals tested in nonhuman primates by the Laboratory of Chemical Pharmacology, National Cancer Institute. This plot presents results of 531 long-term, chronic experiments of 182 test compounds and includes the same information about each experiment in the same plot format as the earlier papers: 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 (1,6,7) for a detailed guide to the plot of the database, a complete description of the numerical index of carcinogenic potency, 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 six plots of the CPDB are to be used together since results of individual experiments that were published earlier are not repeated. Appendix 14 is designed to facilitate access to results on all chemicals. References to the published papers that are the source of experimental data are reported in each of the published plots. For readers using the CPDB extensively, a combined plot is available of all results from the six separate plot papers, ordered alphabetically by chemical; the combined plot in printed form or on computer tape or diskette is available from the first author. A SAS database is also available. For further information, our World Wide Web URL is http://potency.berkeley.edu/cpdb.html -- Environ Health Perspect 103(Suppl 8):3-123 (1995)

Key words: carcinogenic potency, TD50, database, animal cancer test, monkeys, dose response

We thank the many researchers who provided additional experimental results for the CPDB, sometimes by having to go back to earlier pathology reports. Susan Sieber and Unnur Thorgeirsson were enormously helpful with data and suggestions for the analyses on nonhuman primates. We thank Jerrold Ward and Leslie Bernstein for advice on pathology and statistics throughout the project. This work was supported through the University of California, Berkeley by National Institute of Environmental Health Sciences Center grant ESO1896, and through the Lawrence Berkeley Laboratory by U.S. Department of Energy, contract DE-AC-03-76SFO0098.

Address correspondence to Dr. Lois Gold, 433 Barker Hall, University of California, Berkeley, CA 94720. Telephone: (510)486-7080. Fax: (510)486-6773.E-mail: cpdb@potency.berkeley.edu

Background

The Carcinogenic Potency Database (CPDB) is a standardized resource of results of chronic, long-term carcinogenesis bioassays (1-5). It provides an easily accessible resource with sufflcient information on each experiment to permit investigations in many research areas of carcinogenesis. Both qualitative and quantitative information on positive and negative tests are reported. All experiments in the CPDB meet a speciflc set of inclusion criteria designed to permit the estimation of carcinogenic potency; therefore, reasonable consistency of experimental protocols is assured. Bioassays are included in the database only if the test agent was administered alone, rather than in combination with other substances; if the bioassay included a control group; if the route of administration was diet, water, gavage, inhalation, iv injection or ip injection; and if the length of experiment was at least half the standard lifespan for the species and the duration of dosing one-fourth the standard lifespan. Many cancer tests do not meet these rules and are not included, e.g., if a rodent test was shorter than 1 year or the duration of dosing was shorter than 6 months, if dosing was not chronic, or if the compound was administered by skin painting or sc injection.

The CPDB is exhaustive because it includes all published tests that meet a set of experimental criteria. There is great diversity in the testing of 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. Experiments with 107 different mouse strains and 76 rat strains are included. For a given chemical, the database may have only a single experiment or several experiments. For example, among the 952 chemicals tested in rats, 26% have only one rat test and 53% have two tests; however, 18 chemicals have more than 10 tests. Among the 1230 chemicals in the CPDB, 52% have been tested in only a single species, 45% in two species, and 3% in more than two.

In the CPDB we do not ourselves evaluate whether the results in each experiment provide evidence for carcinogenicity; rather, we report the published opinions of the investigators and the statistical signiflcance of the dose response. We have corresponded with many researchers to clarify their evaluations of particular target sites as well as to obtain additional experimental results; this is indicated in the plot by "pers. comm." in the reference fleld. The CPDB includes results of all National Cancer Institute/National Toxicology Program (NCI/NTP) Technical Reports published through June 1993, except for a few bioassays of particulates or where the compound was administered by skin painting. Thirty percent (370/1230) of the chemicals included in the CPDB have been tested in NCI/NTP bioassays.

A detailed guide to the plot of the database was included in the flrst published plot in 1984 (1). It described the contents, fleld by fleld, and discussed the sources of data, the criteria for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Therefore, readers who are not familiar with the CPDB should read the 1984 paper before using the plot in this paper.

The TD₅₀, our numerical index of carcinogenic potency, has been fully described (1,6,7) and may be briefly deflned as follows: for a given target site(s), if there are no tumors in control animals, then TD₅₀ is the chronic dose rate in mg/kg body weight/day that 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 deflned as the chronic dose rate that will halve the probability of remaining tumor-free throughout the standard lifespan. One reason for choosing TD₅₀ is that it is easy to understand the concept, particularly because of the analogy to LD₅₀. Importantly, TD₅₀ is often within the range of doses tested; thus the experimental results do not have to be extrapolated far to estimate TD₅₀. The TD₅₀ does not indicate anything about carcinogenic effects at low doses, since carcinogenesis bioassays are generally conducted at doses at or near the maximum tolerated dose (MTD). In the CPDB, TD₅₀ values for NCI/NTP bioassays have been estimated using lifetable data, whereas summary analyses have been used for the general literature. [See (8) for a comparison of methods.] The range of statistically signiflcant TD₅₀ values for chemicals in the CPDB that are carcinogenic in rodents is more than 10 millionfold.

In each of the six plot papers, Appendices 1 through 13 are in the same format and provide information for the data in that publication. Appendices 1 through 13 below apply only to the plot presented here. Appendix 1 lists alphabetically the compounds included in the current plot, their common synonyms, and Chemical Abstracts Service (CAS) registry numbers; Appendix 2 provides a list of those same compounds ordered by CAS number. The next several appendices provide codes and deflnitions required for using the plot: strains of test animal (Appendix 3); routes of administration (Appendix 4); sites of tumor induction (Appendix 5); histopathology of tumors (Appendix 6); notes about the experiment, e.g., survival problems (Appendix 7); dose-response curve symbols (Appendix 8); journal reference codes (Appendix 9); species of test animal (Appendix 10); and author's opinion codes (Appendix 11). Appendices 12 and 13 give full bibliographic information for experiments reported in this plot: a bibliography for the general literature (Appendix 12); and a list of NTP Technical Reports (Appendix 13). Appendix 14 provides an index to chemicals in all six plots of the CPDB, and evaluations of positivity and carcinogenic potency in rats and mice for each chemical.

In the flfth plot paper of the CPDB (5) we updated several analyses reported earlier, in order to reflect data in the CPDB at that time: i.e., the proportion of chemicals that are positive for several datasets, the association between mutagenicity and carcinogenicity, prediction of positivity between species, reproducibility of results in "near-replicate" experiments, and carcinogen identiflcation on the basis of two vs four sex-species groups. When data from this sixth plot are added, results in each of these analyses are similar to those reported in plot 5 (within two percentage points); therefore, we have not presented the updated tables in this paper.

We have used the CPDB to address many issues relevant to chemical carcinogenesis and interspecies extrapolation (8-24). Papers published since the flfth plot discuss: how tautological are interspecies correlations of carcinogenic potencies (25); three key factors in mutagenesis and carcinogenesis: DNA lesions, inducible DNA repair, and cell division (26); comparison of target organs of carcinogenicity for mutagenic and nonmutagenic chemicals (27); prediction of carcinogenicity from two instead of four sex-species groups (28); the importance of data on mechanism of carcinogenesis in efforts to predict low-dose human risk (29); comparison of results for heterocyclic amines with other chemicals in the CPDB (30); setting priorities among possible carcinogenic hazards in the workplace (31); causes and prevention of human cancer (32); and quick estimation of the regulatory, virtually safe dose based on the MTD (33).

Plot in this Supplement

This sixth plot of the CPDB includes results of 531 long-term, chronic experiments on 182 chemicals. It reports on 50 compounds published in Technical Reports of the NTP between January 1990 and June 1993, and 139 compounds published in the general literature between January 1989 and December 1990. Experiments are reported in rats, mice, hamsters, prosimians, and monkeys. Eighty-seven of the 182 chemicals in this plot were also included in an earlier plot, and we have flagged the chemical names on the plot with a triple asterisk (***). Whereas only a few experiments may be reported here for a given chemical, several experiments may have been reported in earlier plots (e.g. 2-acetylaminofluorene, BHT, formaldehyde, and lead acetate). By using Appendix 14, the reader can identify the earlier plot publications that include data on each chemical as well as information on whether the chemical was tested and evaluated as carcinogenic in each sex of rat and mouse; the most potent TD₅₀ value in rats and mice from all six plots is also reported in Appendix 14.

Chemicals from a variety of sources and with a variety of uses are included in this sixth plot: for example, industrial chemicals (e.g. cadmium chloride, glycidol, rhodamine 6G, and tetranitromethane); food additives (e.g., sodium benzoate and polysorbate 80); agricultural chemicals (e.g., methyl bromide, ethylene thiourea, mirex, and 1,1-dimethylhydrazine [UDMH]); and pharmaceuticals (e.g., acetaminophen, doxefazepam, probenecid, and sulfamethazine). Some are naturally occurring substances in the human diet that we have discussed and ranked in possible carcinogenic hazard and compared to synthetic chemicals (24,30) (e.g., caffeic acid, furfural, sesamol, IQ, PhIP.HCl and MeIQx). Some experiments reported in this plot have extensive dose-response data, with more than four dose groups (e.g., 1,3-butadiene, diethylstilbestrol, N-nitrosopyrrolidine, and sulfamethazine). The TD₅₀ values for the compounds in this plot fall within the 10 millionfold range reported earlier (1).

For several recent bioassays in which NTP suspected a potential for chemically induced renal tubule neoplasms, multiple additional sections were taken of the kidneys. This is the flrst CPDB plot to include results on these step sections. For bioassays with kidney step sections in which NTP evaluated the evidence for carcinogenicity as "clear" "some" or "equivocal," we have estimated one TD₅₀ value using data from the standard protocol and one that includes the step section data. On the plot the TD₅₀ including step sections is indicated by the words "with step." Whereas TD₅₀ values for NTP bioassays throughout the CPDB are estimated with lifetable methods, only summary data were available for the kidney step sections. The confldence limits of the summary TD₅₀ value for the step sections are therefore indicated on the plot by the symbol "." (as for all summary values in the CPDB). For example, see TD₅₀ values for kidney tubule adenoma in male mice for tris(2-chloroethyl)phosphate.

Analyses of Bioassays in Nonhuman Primates

A series of lifetime studies of 30 chemicals in cynomolgus and rhesus monkeys have been conducted at the Laboratory of Chemical Pathology, National Cancer Institute (NCI) [SM Sieber and UP Thorgeirsson, personal communication; (34-36)]. Included in this plot of the CPDB, are lifetable analyses of results on 17 completed studies, 16 of which are rodent carcinogens. The duration of experiments is up to 27 years. We have relaxed some of our standard CPDB rules in order to report these results, for example, because there were often fewer than five animals per sex-species, because controls are from a colony rather than concurrent, and because some positive experiments were shorter than half the standard lifespan. We describe our methods of analysis below, and details of each experiment appear on the plot including exposure and experiment length, special notecodes, and tumor incidence for each site. The first plot of the CPDB included interim results for 7 of these studies, using summary incidence data to estimate TD₅₀ (1). These 7 are indicated with the notecode "j" in this plot.

The published authors evaluated 10 of the test agents as carcinogenic in monkeys: aflatoxin B₁, N-nitrosopiperidine, procarbazine.HCl, urethane, IQ, sterigmatocystin, cycasin and methylazoxymethanol acetate, N-methyl-N-nitrosourea, N-nitrosodipropylamine, and N-nitrosodiethylamine. Seven were not considered carcinogenic: 2-acetylaminofluorene, sodium arsenate, N,N-dimethyl-4-aminoazobenzene, 3´-methyl-4-dimethylaminoazobenzene, 3-methylcholanthrene, N-methyl-N´-nitro- N-nitrosoguanidine, and N-nitrosodimethylamine. We note that the protocol for most of the negative studies differed from that of all but one of the positive studies in that exposure to the test agent was stopped early in the experiment rather than being administered to death or nearly to death. Three other negative compounds are not included here because they did not meet the inclusion rules of the CPDB: cigarette smoke condensate (a mixture administered by implant); 2,4,9,10-dibenzopyrene and copper chelate of N-OH- acetylaminofluorene (administered sc).

Studies are ongoing at NCI for 10 additional compounds; many animals are still alive, and few or no tumors have been observed in those that have died. These studies will be added to the CPDB when completed: adriamycin, melphalan, azathioprine, cyclophosphamide, cyclamate, saccharin, MeIQx, PhIP, DDT, and 2,7-acetylaminofluorene.

Special Considerations

(i) Generally, few animals of each sex of either cynomolgus or rhesus monkeys were on test for each chemical, and there was usually only one dose group per experiment. Even combining results for males and females of each species, about half the experiments had 10 or fewer dosed animals, and never more than 22 in a dose group. Therefore, we have combined males and females of each species in our analyses; this results in having at least 5 dosed animals in all experiments but one (in which all of the 4 dosed animals developed tumors). (ii) Whereas experiments with surgical intervention are excluded from the CPDB, laparoscopic examination of the liver was performed every 3 to 6 months, followed by wedge or needle biopsies of observed liver lesions. (iii) We have included experiments that were shorter than our rule of one-half the standard lifespan, when tumors were induced in nearly all animals (cycasin, N-nitrosodipropylamine, IQ); these are indicated on the plot by the symbol "(+)". (iv) A few experiments have been included in which animals were put on test as adults (4 years of age). (v) Control monkeys for all analyses are from the colony at NCI, which includes breeders, offspring, and some feral monkeys. At any given time, the age of colony control animals ranged from neonate to greater than 25 years. In our lifetable analyses, control animals of each species are included if they lived longer than 8 months of age, the age of the first tumor in any group in these experiments. [For one ongoing study, IQ in cynomolgus, only summary data were available and concurrent vehicle controls were used in our analyses (37).] We note that, compared to rodent bioassays, the tumor incidence rate in control monkeys in this colony is low: for all tumor-bearing animals, whether benign or malignant, the tumor rate is 3% (3/99) in dead cynomolgus controls, and 10% (11/108) in rhesus.

Estimation of Average Daily Dose Level

In the CPDB for standard rodent bioassays the dose rate used to estimate TD₅₀ is the daily dose rate for each group (in mg/kg body weight); if dosing is less than the experiment length, then the dose rate is obtained by averaging over the duration of the experiment. For this series of monkey studies we use the same averaging over experiment length; however, the dose rate for the group is calculated based on the average rate for individual animals. We obtained from NCI the total cumulative dose for each animal in mg/kg body weight. Using the age at death, we calculate an average daily dose rate for each animal, and the dose rate for the group (mg/kg/day) is the mean of these individual daily dose rates. This value can be considerably lower than the administered dose level reported by Thorgeirsson et al. (35) because the duration of dosing is often less than the experiment length (sometimes less than one-fourth the experiment length) and because dosing schedules ranged from once every 2 weeks to 5 times per week.

Lifetable Analyses

Estimates of TD₅₀ are based on lifetable analysis, which adjusts for the differential effects of toxicity among dose groups and for differences between groups in the time pattern of tumor incidence.

On the plot, a TD₅₀ is reported for each site at which a benign or malignant tumor was diagnosed in dosed monkeys. The denominators in each group, whether control or dosed, represent the number of animals alive at the age of the flrst death with the tumor of interest in any group. The numerator on the plot for control animals excludes tumors found at death in animals that lived to be older than the last dosed animal, and such cases are indicated by the notecode "W" on the plot.

Since individual animal pathology reports were made available to us, we were able to calculate a TD₅₀ for combined tumors, just as we do in the CPDB for lifetable analyses of the NCI/NTP rodent bioassays; these are signified in the plot by the code MXB for "Berkeley Mix". For each experiment in monkeys, we estimated a TD₅₀ for "all tumor-bearing animals" ("tba" on the plot) for all benign tumors, for all malignant tumors, and for any animal with either a benign or malignant tumor. The denominators in the tumor incidence flelds of the plot for "all tumor-bearing animals" represent the maximum number of animals used in any TD₅₀ in the experiment, and indicate the number alive at the flrst tumor in any group. As for NCI/NTP bioassays, we also estimate a composite TD₅₀ value for all sites that were evaluated as target sites by the published authors (35) This composite value (denoted on the plot by MXB MXB), is reported for four chemicals that were evaluated as having more than one target site in a monkey experiment.Further analyses are in progress which compare results in rodents and monkeys. For example, the liver is the most frequent target site in monkeys, just as it is in mice and rats.

Addenda and Errata to Earlier Plots

A few changes have been made to earlier plots. In plot 1 the chemical name "ethylene glycol" should have been "ethylene glycol, cyclic sulfate."

Two code changes are necessary in previously reported results due to typographical errors. The code "cca" (c-cell adenoma) in the flfth plot was used with adrenal gland when the code should have been "coa" (cortical-cell adenoma) for the following chemicals: acetaldoxime, acrolein, acrolein diethylacetal, acrolein oxime, allyl alcohol, cyclohexanone, N-methyldopamine,O,O´-diisobutyroyl ester.HCl and 3-nitro-4-hydroxyphenylarsonic acid. In the flrst plot for N,N-dimethyl-4-aminoazobenzene, the tumor code for liver cell carcinoma should have been "lcc" but was reported as "cca". The author's opinion for urinary bladder papilloma in a test of sodium saccharin in plot 4 (Hasegawa et al., Cancer Research 45:1469-1473, 1985) has been changed from + (positive) to blank (none) following recent personal communication with the author.

Kidney step section data in the CPDB for NTP bioassays are reported for the flrst time in this publication. Below we plot step section results for furosemide and nitrofurantoin, which were included in an earlier plot without this data. The previously published results are included for comparison.

REFERENCES

1. Gold LS, Sawyer CB, Magaw R, Backman GM, de Veciana M, Levinson R, Hooper NK, Havender WR, Bernstein L, Peto R, Pike MC, Ames BN. A Carcinogenic Potency Database of the standardized results of animal bioassays. Environ Health Perspect 58:9-319 (1984).

2. Gold LS, de Veciana M, Backman GM, Magaw R, Lopipero P, Smith M, Blumenthal M, Levinson R, Bernstein L, Ames BN. Chronological supplement to the Carcinogenic Potency Database: Standardized results of animal bioassays published through December 1982. Environ Health Perspect 67:161-200 (1986).

3. Gold LS, Slone TH, Backman GM, Magaw R, Da Costa M, Lopipero P, Blumenthal M, Ames BN. 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 (1987).

4. Gold LS, Slone TH, Backman GM, Eisenberg S, Da Costa M, Wong M, Manley NB, Rohrbach L, Ames BN. 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 (1990).

5. Gold LS, Manley NB, Slone TH, Garflnkel GB, Rohrbach L, Ames BN. The flfth 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 (1993).

6. Peto R, Pike MC, Bernstein L, Gold LS, Ames BN. 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 (1984).

7. Sawyer C, Peto R, Bernstein L, Pike MC. Calculation of carcinogenic potency from long-term animal carcinogenesis experiments. Biometrics 40:27-40 (1984).

8. Gold LS, Bernstein L, Kaldor J, Backman G, Hoel D. An empirical comparison of methods used to estimate carcinogenic potency in long-term animal bioassays: lifetable vs. summary incidence data. Fundam Appl Toxicol 6:263-269 (1986).

9. Bernstein L, Gold LS, Ames BN, Pike MC, Hoel DG. Some tautologous aspects of the comparison of carcinogenic potency in rats and mice. Fundam Appl Toxicol 5:79-86 (1985).

10. Gold LS, Ward JM, Bernstein L, Stern B. Association between carcinogenic potency and tumor pathology in rodent carcinogenesis bioassays. Fundam Appl Toxicol 6:677-690 (1986).

11. Gold LS, Wright C, Bernstein L, de Veciana M. Reproducibility of results in 'near-replicate' carcinogenesis bioassays. J Natl Cancer Inst 78:1149-1158 (1987).

12. Gold LS, Backman GM, Hooper NK, Peto R. Ranking the potential carcinogenic hazards to workers from exposures to chemicals that are tumorigenic in rodents. Environ Health Perspect 76:211-219 (1987).

13. McCann J, Gold LS, Horn L, McGill R, Graedel TE, Kaldor J. Statistical analysis of Salmonella test data and comparison to results of animal cancer tests. Mutat Res 205:183-195 (1988).

14. Gold LS, Slone TH, Bernstein L. Summary of carcinogenic potency (TD₅₀) and positivity for 492 rodent carcinogens in the Carcinogenic Potency Database. Environ Health Perspect 79:259-272 (1989).

15. Gold LS, Bernstein L, Magaw R, Slone TH. Interspecies extrapolation in carcinogenesis: prediction between rats and mice. Environ Health Perspect 81:211-219 (1989).

16. Ames BN. Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun 7:121-128 (1989).

17. Ames BN, Gold LS. Dietary carcinogens, environmental pollution, and cancer: some misconceptions. Med Oncol Tumor Pharmacother 7:69-85 (1990).

18. Ames BN, Gold LS. Perspective: too many rodent carcinogens: mitogenesis increases mutagenesis. Science 249:970-971 (1990). Letters: 250:1498 (1990); 250:1645-1646 (1990); 251:12-13 (1991); 251:607-608 (1991); 252:902 (1991).

19. Ames BN, Gold LS. Chemical carcinogenesis: too many rodent carcinogens. Proc Natl Acad Sci USA 87:7772-7776 (1990).

20. Ames BN, Profet M, Gold LS. Dietary pesticides (99.99% all natural). Proc Natl Acad Sci USA 87:7777-7781 (1990).

21. Ames BN, Profet M, Gold LS. Nature's chemicals and synthetic chemicals: comparative toxicology. Proc Natl Acad Sci USA 87:7782-7786 (1990).

22. Gold LS, Slone TH, Manley NB, Bernstein L. Target organs in chronic bioassays of 533 chemical carcinogens. Environ Health Perspect 93:233-246 (1991).

23. Ames BN, Gold LS. Animal cancer tests and the prevention of cancer. J Natl Cancer Inst Monogr 12:125-132 (1992).

24. Gold LS, Slone TH, Stern BR, Manley NB, Ames BN. Rodent carcinogens: setting priorities. Science 258:261-265 (1992).

25. Freedman DA, Gold LS, Slone TH. How tautological are inter-species correlations of carcinogenic potency? Risk Anal 13:265-272 (1993).

26. Ames BN, Shigenaga MK, Gold LS. DNA lesions, inducible DNA repair and cell division: three key factors in mutagenesis and carcinogenesis. Environ Health Perspect 101 (Suppl 5):35-44 (1993).

27. Gold LS, Slone TH, Stern BR, Bernstein L. Comparison of target organs of carcinogenicity for mutagenic and non-mutagenic chemicals. Mutat Res 286:75-100 (1993).

28. Gold LS, Slone TH. Prediction of carcinogenicity from 2 vs. 4 sex-species groups in the carcinogenic potency database. J Toxicol Environ Health 39:147-161 (1993).

29. Gold LS. The importance of data on mechanism of carcinogenesis in efforts to predict low-dose human risk. Risk Anal 13:399-401 (1993).

30. Gold LS, Slone TH, Manley NB, Ames BN. Heterocyclic amines formed by cooking food: comparison of bioassay results with other chemicals in the Carcinogenic Potency Database. Cancer Lett 83:21-29 (1994).

31. Gold LS, Garflnkel GB, Slone TH. Setting priorities among possible carcinogenic hazards in the workplace. In: Chemical Risk Assessment and Occupational Health: Current Applications, Limitations, and Future Prospects (Smith CM, Christiani DC, Kelsey KT, eds). Westport, CT:Auburn House, 1994;91-103.

32. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci USA 92 (1995).

33. Gaylor, DW and Gold LS. Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays. Regul Toxicol Pharmacol 22:57-63 (1995).

34. Adamson RH, Sieber SM. Chemical carcinogenesis in nonhuman primates. In: Organ and Species Speciflcity in Chemical Carcinogenesis (Langenbach R, Nesnow S, Rice JM, eds). New York:Plenum Press, 1982;129-156.

35. Thorgeirsson UP, Dalgard DW, Reeves J, Adamson RH. Tumor incidence in a chemical carcinogenesis study in nonhuman primates. Regul Toxicol Pharmacol 19:130-151 (1994).

36. Dalgard DW. Induction, biological markers and therapy of tumors in primates. Annual Report of Contract No. N01-CP-05622 Study No. 421-156, Vienna, VA:National Cancer Institute, 1991.

37. Adamson RH, Takayama S, Sugimura T, Thorgeirsson UP. Induction of hepatocellular carcinoma in nonhuman primates by the food mutagen 2-amino-3methylimidazo[4,5-f]quinoline. Environ Health Perspect 102(2):190-193 (1994).

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Last Update: September 8, 1998