Search PubMed⌕ Search

Biomedical subjects

M D Waters

Publications and source records attributed to M D Waters.

81 records · Page 5Linked to original sources
PubMedDate not supplied

An analysis of the spectra of genetic activity produced by known or suspected human carcinogens.

For 24 agents classified by the International Agency for Research on Cancer as known or suspected human carcinogens, we previously catalogued the qualitative genetic bioassay data available in the literature. In the present analysis, dose information, where available, was added to this data base: either the lowest effective dose (LED) or the highest ineffective dose (HID) was recorded for each agent and bioassay system. Bioassay systems were organized according to classes of genetic activity and subdivided by the phylogenetic level of the test organism. For each compound, the quantitative results in the test systems were represented by computer-generated bar graphs ('genetic activity spectra'). The x-axis unit values corresponded to the 100 different test systems, and the y-axis values were the logarithmically transformed LED or HID values. Statistical methods and pattern-recognition techniques were used to evaluate the genetic activity spectra. Spectra were compared among agents grouped according to target-organ specificity. In addition, the spectra of all possible pairs of compounds were compared to identify compounds displaying qualitatively or quantitatively similar genetic activity. Chemically similar compounds frequently produced similar spectra of genetic activity, and it was possible to identify the most appropriate test systems for some classes of compounds. As the data base for human carcinogens is enlarged, analysis of genetic activity spectra may contribute to our understanding of the structure-activity relationships and mechanisms of action of these agents.

Animals↗
PubMedDate not supplied

An introduction to a series of U.S. Environmental Protection Agency special committee reports on testing approaches for the detection of chemically induced aneuploidy.

A committee of scientists was established by the U.S. Environmental Protection Agency to appraise the current state of aneuploidy test methodology, to compile and analyze published data on the chemical induction of aneuploidy, and to provide guidance for additional test development and validation. The reports that follow in this special issue of Mutation Research, document the urgent need for test method development and validation in this important area of environmental mutagenesis, and provide directions for further research.

Aneuploidy↗
PubMedDate not supplied

The parallelogram approach in studies of genotoxic effects.

Over the past two decades mutagenicity tests have been used for the identification of potential human mutagens and have had an ancillary role, as supportive evidence in the assessment of human carcinogens. The demonstration of human germinal mutagens has been beyond the main scope of short-term testing strategies. However, just as mutagenicity tests have been useful in detecting potential carcinogens so should carcinogenicity tests assist the identification of presumptive germ cell mutagens. Cancer is an easily observable phenotype of mutation for genotoxic carcinogens and multi-site carcinogens or gonadal carcinogens logically could be germ cell mutagens. Thus carcinogenicity and mutagenicity data for a given genotoxic chemical should be considered together in the identification of putative germinal mutagens. Clearly, most classified human carcinogens are genotoxic thus helping to build the case for human germ cell mutagenicity. This paper describes the issues involved in such thinking and suggests an enhanced parallelogram approach incorporating the cancer endpoint. The enhanced parallelogram is explored using 1,3-butadiene and ethylene oxide as examples. The obvious lack of data for extrapolations using the parallelogram method suggests the need for targeted studies specifically designed for use in this approach.

Animals↗
PubMedDate not supplied

Genetic activity profiles and pattern recognition in test battery selection.

Computer-generated genetic activity profiles and pairwise matching procedures may aid in the selection of the most appropriate short-term bioassays to be used in test batteries for the evaluation of the genotoxicity of a given chemical or group of chemicals. Selection of test batteries would be based on a quantitative comparative assessment of the past performance of similar tests applied to other chemicals of the same structural group. The information potentially available for test-battery selection through the use of this pattern-recognition technique is considerably greater than the qualitative results obtained from individual short-term tests. Application of the method should further our understanding of the relationships between chemical properties and genotoxic responses obtained in short-term bioassays and also may contribute to our knowledge of the mechanisms of complex processes such as carcinogenesis. This approach to battery selection should be augmented by careful consideration of established principles of genetic toxicity testing; that is, a chemical should be evaluated in a battery of tests representing the full range of relevant genetic endpoints.

Animals↗
PubMedDate not supplied

The genetic toxicology of Gene-Tox non-carcinogens.

The Gene-Tox Program has identified 61 chemicals that have been tested in chronic rodent carcinogenesis bioassays and found to be inactive. The genetic toxicology data of these 61 non-carcinogens is reviewed and summarized. A large proportion of these chemicals have been tested to a limited extent in genetic toxicity bioassays: 32 in 2 tests or less. Of the remaining 29 chemicals, 28% have been tested in 9 or more tests which encompass a range of genetic endpoints: gene mutation, chromosomal effects, other genetic endpoints, and cell transformation. The genetic toxicity of 12 chemicals with sufficient data is discussed in detail: benzoin, caffeine caprolactam, ethanol, halothane, hycanthone methanesulfonate, malathion, maleic hydrazide, methotrexate, 1-naphthylamine, 4-nitro-o-phenylenediamine, and p-phenylenediamine. A new technique for the evaluation of multiple test data, the "genetic activity profile", has been applied to 6 of these chemicals, allowing the qualitative and quantitative information to be compared collectively. In the evaluation of the genotoxicity effects of these non-carcinogens, a number of discrepancies between the results from genetic toxicity bioassays and chronic rodent bioassays have been uncovered. These discrepancies are discussed in light of current knowledge on the strengths and weaknesses of both genetic toxicity bioassays and chronic rodent bioassays.

Animals↗
PubMedDate not supplied

Use of computerized data listings and activity profiles of genetic and related effects in the review of 195 compounds.

Computer-generated listings of data from short-term tests for genetic and related effects (activity profile listings) were prepared for 195 compounds that included for each compound, the test system (identified by a three-letter code word), qualitative results and the lowest effective dose (LED) or highest ineffective dose (HID) tested. A corresponding bar or line graph (activity profile) was also generated, in which test systems are displayed along the x-axis and the LED or HID values along the y-axis. The listings were reviewed and the data summarized by an IARC Working Group. The methodology used to generate these listings and plots is described, and results are given for one compound, benzene. The entire data base contains approximately 7000 entries from 4000 references.

Animals↗
PubMedDate not supplied

Multiple-endpoint mutagenesis with Chinese hamster ovary (CHO) cells: evaluation with eight carcinogenic and non-carcinogenic compounds.

Previously, we have shown that Chinese hamster ovary (CHO) cells are useful for quantifying chemical-induced gene mutations. We have defined the conditions of a Multiplex CHO System which permits determination of mutagen-induced chromosome aberration, and sister chromatid exchange (SCE) in addition to cytotoxicity and gene mutation in the same treated culture. This allows us to extend the spectrum of quantitative mutagenesis to include clastogenic endpoints. In the present study, we used four carcinogenic/noncarcinogenic pairs to validate the relative utility and sensitivity of each endpoint, and to study the interrelationship of these four distinct biological effects. These compounds include the direct-acting carcinogens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), ICR 170 and their noncarcinogenic analogue N-methyl-N'-nitroguanidine (MNG) and ICR 170-OH, and the procarcinogens benzo[a]pyrene (B[a]P) and dimethylnitrosamine (DMN) and their noncarcinogenic analogues pyrene and dimethylamine (DMA) respectively. A rat liver homogenate preparation (S9) was used to assay for the biological activities of procarcinogens. Under our experimental conditions, we observed that carcinogens DMN, B[a]P, MNNG and ICR 170, but not their noncarcinogenic counterparts, showed all four biological effects. Our studies with these chemicals showed that cytotoxicity does not necessarily correlate with any of the genetic endpoints. On a molar basis, noncarcinogens, pyrene and ICR 170-OH show similar toxicity to carcinogens B[a]P and ICR 170, respectively. The other two non-carcinogenic analogues, DMA and MNG, exhibit minimal toxicity at concentrations 10-1,000 times higher than cytotoxic concentrations of the corresponding carcinogens, DMN and MNNG. In general, gene mutation and SCE are more sensitive than chromosome aberration assay. The gene mutation assay is more specific than SCE and chromosome aberration assays since none of the noncarcinogens exhibit a detectable response in the gene mutational assay. ICR 170 and MNNG are much more active than B[a]P and DMN as ranked on a molar basis. These results indicate that the Multiplex CHO System is capable of discriminating divergent structural classes of carcinogenic and noncarcinogenic compounds, such as the eight chemicals chosen for our study.

Animals↗