Genetic Toxicity, Reproductive and Development Toxicity, and Carcinogenicity Database

The US Food and Drug Administration Center for Drug Evaluation and Research (FDA/CDER) is charged with assuring that safe and effective drugs are available to the American people. The safety of drugs is assessed using in vitro and in vivo animal toxicology studies, and with human volunteers in clinical trials conducted by pharmaceutical industry and evaluated by FDA scientists. The clinical trials are conducted to identify efficacy and the potential adverse effects of pharmaceuticals in patients. Toxicology studies are used to assess three broad categories of chemical toxicities that cannot be appropriately assessed in humans, genetic toxicity (genetox), reproductive and developmental toxicity (reprotox), and carcinogenicity. Reprotox and carcinogenicity are assessed in standard rodent studies; genetox is assessed using a standard battery of in vitro and in vivo tests that identify potential chemical induced gene mutations, clastogenic damage, and direct DNA damage.

We have published a research article (Matthews, E.J., Kruhlak, N.L., Cimino, M.C., Benz, R.D., and Contrera, J.F. An Analysis of Genetic Toxicity, Reproductive and Developmental Toxicity, and Carcinogenicity Data: I. Identification of Carcinogens Using Surrogate Endpoints. Regulatory and Toxicology and Pharmacology, 2006 (in press)) describing research designed to see how well a very large database of genetic toxicity and reproductive and developmental toxicity study results predict the results of rodent bioassays. The abstract for this article is as follows:

A retrospective analysis of standard genetic toxicity (genetox) tests, reproductive and developmental toxicity (reprotox) studies, and rodent carcinogenicity bioassays (rcbioassay) was performed to identify the genetox and reprotox endpoints whose results best correlate with rcbioassay observations. A database of 7205 chemicals with genetox (n=4961), reprotox (n=2173), and rcbioassay (n=1442) toxicity data was constructed; 1112 of the chemicals have both genetox and rcbioassay data and 721 chemicals have both reprotox and rcbioassay data. This study differed from previous studies by using conservative weight of evidence criteria to classify chemical carcinogens, data from 63 genetox and reprotox toxicological endpoints, and a new statistical parameter of correlation indicator (CI, the average of specificity and positive predictivity) to identify good surrogate endpoints for predicting carcinogenicity. Among 63 endpoints, results revealed that carcinogenicity was well correlated with certain tests for gene mutation (n=8), in vivo clastogenicity (n=2), unscheduled DNA synthesis assay (n=1), and reprotox (n=3). The current FDA regulatory battery of four genetox tests used to predict carcinogenicity includes two tests with good correlation (gene mutation in Salmonella and in vivo micronucleus) and two tests with poor correlation (mouse lymphoma gene mutation and in vitro chromosome aberrations) by our criteria.

The majority of the genetox study data considered for the investigation described in this paper was obtained from the US Environmental Protection Agency (EPA). This database of genetox studies is a super-set of the US EPA GENE-TOX Program database[external link]. The EPA database is a comprehensive historical collection of genetox studies from the literature and genetox reports received by government agencies and government sponsored programs [e.g., Organization for Economic Cooperation and Development (OECD), Screening Information Data Sets (SIDS)]. The EPA database also contains information on chemicals tested in standard and transgenic mouse carcinogenicity studies and a small number of reproductive toxicity studies. This database includes 203 different types of genetox, reprotox, and carcinogenicity studies, which are subdivided into four broad categories of lesions (gene mutation, clastogenicity, DNA damage, and cell transformation). The remaining portion of the ICSAS genetic toxicity database consists of data acquired from genetox studies reported in drug labeling and other FDA archives, NTP technical reports, literature citations, large genetox endpoint-specific data sets in the literature, and genetox data received from MultiCASE, Inc.[external link] through a Cooperative Research and Development Agreement (CRADA).

The ICSAS reproductive and developmental toxicity database contains data records from FDA segment I (reproductive toxicity in male and female animals), segment II (teratology, organ toxicity, and non-specific toxicity to the fetus), and segment III (behavioral toxicity in newborn pups) studies in Glires (primarily rats, mice, rabbits, and hamsters) and other animals. The data were acquired from publicly available sources, such as Shepard’s Catalog of Teratogenic Agents, TERIS, REPROTOX, and RTECS, as well as studies reported in drug labeling, and other reproductive toxicity studies obtained from the EPA Toxdata-1g database.

The ICSAS carcinogenicity database contains data records from chemicals tested in long-term (generally two-year) studies in rodents (rats, mice, and hamsters). The data were acquired from five different sources: Agency archives, NTP technical reports, IARC monographs, the L. Gold Carcinogenic Potency Database, and the published literature.

Genetic Toxicity, Reproductive and Developmental Toxicity, and Carcinogenicity Database (7067 chemicals)
[Please note that this database is in the form of a 10MB Excel spreadsheet.]
Link to free Excel Viewer 2003 [external link]
PDF Version

Comments or corrections of these data should be sent to: R.Daniel.Benz@fda.hhs.gov.

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Date created: 1/23/2006

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