Regulatory agencies have mandated that certain classes of chemicals to which humans will be exposed must be evaluated for their carcinogenic potential. Over the years, thousands of long-term carcinogenesis bioassays have been conducted in rodents, and thousands of in vitro tests have been performed to assess genetic toxicity. The Department of Molecular and Cell Biology, Division of Biochemistry and Molecular Biology, University of California, Berkeley, under the leadership of Bruce N. Ames, has been studying carcinogenesis for many years in a highly productive and provocative manner.
Drs. Gold and Zeiger are associates of Dr. Ames and have been advocating that scientists should utilize all of the animal and in vitro data available in the literature as they relate to the carcinogenic process. This Handbook is designed as a general reference source for genetic toxicity and carcinogenicity test results, bringing together 2 databases that present experimental results by individual chemical entity. Easily accessible formats allow the reader quick entry into the databases, and citations to the original experiments are provided. The 2 databases are the Carcinogenic Potency Database (CPDB), developed at Berkeley and the Lawrence Berkeley National Laboratory, and the Genetic Toxicity database (GT), developed by the U.S. National Toxicology Program (NTP). Results on 2,300 chemicals are reported, including cancer tests on 1,298 and genetic toxicity tests on 1,525. For 523, results are given in both the carcinogenicity and genetic toxicity databases.
While subsets of the CPDB and the GT have been published in journal articles, this is the first time all results on all chemicals in each database are presented together along with data on 300 new cancer tests. The GT systems are described and summary data are presented so as to allow qualitative comparisons among test systems. In keeping with the concept of a useful laboratory handbook, the chapters are organized by database. Chapter 1 presents the inclusion rules and methods of the CPDB and a guide to facilitate use of the plot of cancer test results. There are 5,152 cancer tests presented in the CPDB, including for each qualitative information on strain, sex, target organ, histopathology, and the authors' opinion about carcinogenicity, as well as quantitative information on carcinogenic potency (TD50), statistical significance, tumor incidence, dose-response curve shape, length of experiment, dose rate, and duration of dosing. Data are included for mice, rats, hamsters, nonhuman primates, and dogs.
This leads to Chapter 2, which is a compendium of CPDB results organized by target organ for 684 chemicals that are positive in at least 1 species. I found Chapter 3 to be most useful. Here is an overview of CPDB results on each chemical, including the sex-species groups that have been tested, the strongest level of evidence for carcinogenicity based on the opinion of a published author, carcinogenic potency, target organs in each species, and mutagenicity in S. typhimurium. This chapter is followed by an overview and update of analyses reported in earlier publications that include the data most recently added to the database. This would include reproducibility and validity, positivity rates, comparisons of carcinogenicity between rats and mice and between mutagens and nonmutagens, and ranking possible carcinogenic hazards to humans from rodent carcinogens. Chapter 5 describes and presents the in vitro genetic toxicity database of the NTP, which contains qualitative results of experiments on the effects of chemicals on cellular DNA and chromosomes. Chapter 6 is an index to all chemicals in the CPDB and GT by Chemical Abstract Services (CAS) registry number.
The CPDB is an attempt to systematize and unify animal cancer test data in an analytical manner. This approach serves to standardize the published literature and creates an easily accessible research resource that can be used to address a wide variety of research and regulatory issues in carcinogenesis. A word of caution is necessary about the limitations of the database. No attempt has been made to evaluate 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 their results. Of equal importance, the database contains only long-term tests, which fit the criteria designed to measure potency and, therefore, does not cover all cancer tests.
What is carcinogenic potency and can it be quantified in a manner acceptable to biologists? The authors believe that this can be done and, therefore, will allow for a more rational approach to understanding carcinogenesis. This in turn may provide insights into human cancer induction. A numerical description of carcinogenic potency, the TD50, is estimated for each set of tumor incidence data reported in the CPDB, thus providing a standardized quantitative measure for comparisons and analyses of many important issues in carcinogenesis. Simply, TD50 may be defined as follows: for a given target site, if there are no tumors in control animals, then TD50 is that chronic dose rate in mg/kg body wt/day which would induce tumors in half the test animals at the end of a standard life span for the species. However, because-the tumor of interest often does occur in control animals, TD50 is more precisely defined as that dose rate in mg/kg body wt/day that, if administered chronically for the standard life span of the species, will halve the probability of remaining tumorless throughout that period. TD50 is analogous to LD50, and a low value of TD50 indicates a potent carcinogen.
As our knowledge of carcinogenesis changes due to advances in molecular biology and genetics, it is important to test the assumptions currently underlying the rodent carcinogenicity bioassays. Cancer tests at high doses have given us a plethora of rodent carcinogens that may be irrelevant for human experience. This Handbook is an important milestone in the ongoing process to make the detection of potential human carcinogens more specific and sensitive. It is an interim product that the authors will modify and change as valid new data appear. All toxicologic pathologists, regulatory agency personnel. and basic cancer researchers should have a copy in their library. The book is easy to use, and the large (8-1/4 x 11 in.) format spread across adjacent pages when necessary facilitates finding data. If you are really interested in the . process of improving the current situation regarding animal tests predicting human carcinogens, then this book is a must.
Bernard M. Wagner, M.D.
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Last updated: May 21, 1998