The genetic toxicity database of the National Toxicology Program: evaluation of the relationships between genetic toxicity and carcinogenicity.

The database of the U.S. National Toxicology Program has been developed over approximately two decades, principally focused on substances evaluated for carcinogenicity in rodent bioassays.

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. National Toxicology Program.

This paper is an extension of compilations published previously in this journal. (Ashby and Tennant, 1988; Ashby et al., 1989).

Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP.

An analysis is presented in which are evaluated correlations among chemical structure, mutagenicity to Salmonella, and carcinogenicity to rats and mice among 301 chemicals tested by the U.S. NTP.

Evidence that toxic injury is not always associated with induction of chemical carcinogenesis.

Long-term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty-one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty-two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity.

A perspective on measurement of mutations in vivo.

The development of transgenic mouse lines with target genes that are suitable for tissue-specific mutagenesis studies is an important contribution to the field of environmental mutagenesis. These models can accommodate many of the questions relating to metabolism, distribution and relative potency of mutagens as well as providing a more comprehensive system for the identification of mutagens. However, the lesions that the field has learned about methods, development and validation from the use of in vitro systems must be applied to the development and validation of transgenic models.

Prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 44 chemicals by the National Toxicology Program.

This paper was written to enable evaluation of the concept that knowledge about chemical structure combined with limited short-term genotoxicity and toxicity test results can be used to predict potential carcinogens. Previous attempts have been potentially biased by prior knowledge about the tumorigenicity of chemicals in animals or humans, but the 44 chemicals that are currently being bioassayed for carcinogenicity by the National Toxicology Program provide an opportunity prospectively to evaluate factors that may be predictive of chemical carcinogenicity. Predictions of rodent carcinogenicity for these 44 agents are presented as an example of what we believe is the best available approach at this time.

Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals.

The effectiveness of four in vitro short-term tests (STT) for genetic toxicity, induction of mutations in Salmonella (SAL) and mouse lymphoma L5178Y cells (MLA), and induction of sister chromatid exchanges (SCE) and chromosome aberrations (ABS) in Chinese hamster ovary cells that are used for predicting rodent carcinogenicity were examined. The in vitro results were compared with the results from 41 rodent carcinogenicity studies performed by the National Toxicology Program. The predictive values of, and interrelationships among, the STT for these 41 chemicals were similar to those previously reported for 73 chemicals and confirm those earlier results [Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R (1987): Science 236:933-941].

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicity by the U.S. National Toxicology Program.

This paper is an extension and update of an earlier review published in this journal (Ashby and Tennant, 1988). A summary of the rodent carcinogenicity bioassay data on a further 42 chemicals tested by the U.S.

Comparison of the Magill and Lack anaesthetic breathing systems in anaesthetized patients.

The Magill and Lack anaesthetic breathing systems were compared by measuring inspired and expired carbon dioxide concentrations and expired minute volumes in lightly anaesthetized, unstimulated subjects. There were no significant differences between the two breathing systems at fresh gas flow rates of approximately 50 and 70 ml kg-1 min-1. Inspired carbon dioxide concentrations increased in one of six subjects at the higher fresh gas flow rate using the Magill system and in two using the Lack system.

An interlaboratory evaluation of the Syrian hamster embryo cell transformation assay using eighteen coded chemicals.

Eighteen coded chemicals were evaluated in the Syrian hamster embryo (SHE) cell transformation assay in three different laboratories using the same basic experimental protocol with minor modifications. In addition, individual cell and serum sources were selected. Major factors influencing intra-and interlaboratory reproducibility were the source of cells and serum, the toxicity of the chemicals, and the dose-range selected for transformation evaluation.

Relationships between in vitro genetic toxicity and carcinogenicity studies in animals.

In vitro genetic toxicity assays currently in use cannot be used to unambiguously define all potential carcinogens. The relationship between the various in vitro endpoints (mutation, cytogenetic effects, transformation) and the patterns of tumorigenicity is quite complex. Additional data, particularly for noncarcinogens, are needed to better understand the inconsistencies and to define the limits of predictability.

Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP.

A survey has been conducted of 222 chemicals evaluated for carcinogenicity in mice and rats by the United States NCI/NTP. The structure of each chemical has been assessed for potential electrophilic (DNA-reactive) sites, its mutagenicity to Salmonella recorded, and the level of its carcinogenicity to rodents tabulated. Correlations among these 3 parameters were then sought.

Comparative evaluation of genetic toxicity patterns of carcinogens and noncarcinogens: strategies for predictive use of short-term assays.

The results of a recent comprehensive evaluation of the relationship between four measures of in vitro genetic toxicity and the capacity of the chemicals to induce neoplasia in rodents carry some important implications. The results showed that while the Salmonella mutagenesis assay detected only about half of the carcinogens as mutagens, the other three in vitro assays (mutagenesis in MOLY cells or induction of aberrations or SCEs in CHO cells) did not complement Salmonella since they failed to effectively discriminate between the carcinogens and noncarcinogens found negative in the Salmonella assay. The specificity of the Salmonella assay for this group of 73 chemicals was relatively high (only 4 of 29 noncarcinogens were positive).

Management of endoscopically removed malignant colon polyps.

The medical records of 87 patients with 89 malignant colorectal polyps removed endoscopically between 1971 and 1983 were reviewed retrospectively. Fifty-five polyps contained carcinoma-in-situ. Four polyps had "pseudo-invasion" by displaced mucosal glands.

Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays.

Four widely used in vitro assays for genetic toxicity were evaluated for their ability to predict the carcinogenicity of selected chemicals in rodents. These assays were mutagenesis in Salmonella and mouse lymphoma cells and chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells. Seventy-three chemicals recently tested in 2-year carcinogenicity studies conducted by the National Cancer Institute and the National Toxicology Program were used in this evaluation.

Oxygen analysers. An evaluation of five fuel cell models.

Five currently available fuel cell oxygen analysers were studied with a view to their use in anaesthesia. The accuracy, response time and safety features of these analysers are discussed. Fuel cell analysers appear to be suitable oxygen monitors for routine anaesthetic use.

A method for accelerating progression to a malignant phenotype in rodent cells.

This report describes a system of suspension culturing that enhances the expression of transformed cells in carcinogen-treated rodent cells and decreases the time required to observe clear evidence of the neoplastic or malignant phenotype by 2-8 wk or more. Retrovirus-infected Fischer rat embryo cells, uninfected Balb/c 3T3 mouse cells and Syrian hamster embryo cells in monolayer culture were treated with the chemical carcinogens, dimethylbenzanthracene, benzo[a]pyrene or N-methyl-N'-nitro-N-nitrosoguanidine, following a protocol appropriate to each cell type. The cultures were divided into two groups, one seeded directly onto a plastic surface, and the other suspended in liquid medium over agar before seeding onto a plastic surface.

Chemical carcinogens. A review and analysis of the literature of selected chemicals and the establishment of the Gene-Tox Carcinogen Data Base. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The literature on 506 selected chemicals has been evaluated for evidence that these chemicals induce tumors in experimental animals and this assessment comprises the Gene-Tox Carcinogen Data Base. Three major sources of information were used to create this evaluated data base: all 185 chemicals determined by the International Agency for Research on Cancer to have Sufficient evidence of carcinogenic activity in experimental animals, 28 selected chemicals bioassayed for carcinogenic activity by the National Toxicology Program/National Cancer Institute and found to induce tumors in mice and rats, and 293 selected chemicals which had been evaluated in genetic toxicology and related bioassays as determined from previous Gene-Tox reports. The literature data on the 239 chemicals were analyzed by the Gene-Tox Carcinogenesis Panel in an organized, rational and consistent manner.