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M D Waters

Publications and source records attributed to M D Waters.

At least 55 records · Page 3Linked to original sources
PubMed1989

Strategies for the use of computational SAR methods in assessing genotoxicity.

The relationship between computational SAR studies and relevant data gathering and generation activities is complex. First, the chemical class to be studied is selected on the basis of information requirements for hazard identification and assessment. Membership in the class is determined by consideration of chemical structure and reactivity. Compilation of the existing bioassay data for this chemical class follows immediately from the specification of the class. Bioassay data, qualitative knowledge of general chemical reactivities in this class, and knowledge concerning potential interactions with biomolecular targets all contribute to the derivation of possible mechanisms for biological activity. Computational studies based on modeling the proposed mechanism of action and/or the existing data base can provide a quantitative basis for the differentiation between chemicals. There is the opportunity for continuing feedback between the quantitative computational studies and the development of a relevant bioassay data base for this chemical class. The qualitative and quantitative information on the potential biological responses obtained will provide a rational basis for extrapolation from the extant data base to the chemicals of interest, and to biological responses significant to the assessment for which complete data are unavailable. Knowledge concerning possible mechanisms of action and preexisting data determine the type of computational study that will be most useful.

Animals↗
PubMed1987

An approach to identifying specialized batteries of bioassays for specific classes of chemicals: class analysis using mutagenicity and carcinogenicity relationships and phylogenetic concordance and discordance patterns. 1. Composition and analysis of the overall data base. A report of phase II of the U.S. Environmental Protection Agency Gene-Tox Program.

This report of the Gene-Tox Assessment Panel is a compilation of data that documents the chemical testing efforts in genetic toxicology through mid-1979. It thus provides an historical perspective of the major efforts in this field and the utility of test models. The total number of chemicals tested in assays reflects chemical availability, commercial interest in specific structural types, the ease or difficulty in assay performance, as well as methodological development resulting from testing experience. Other factors that have been important in assay selection and utility are the perceptions of relevance to hazard evaluation of chemicals and the role that genetic factors may have in other disease states as well as in heritable defects. The phylogenetic diversity of test systems attests to the tremendous effort that has been applied to the testing and evaluation of the effect chemicals can have on genetic structure. The data also illustrate the fact that certain chemicals have an intrinsic capability to alter the genetic structure of cells of diverse biological origin in an heritable manner, whereas others do not. Any attempt to summarize and analyze a data base of this magnitude is a formidable task that would be almost impossible without a computer capability. A computerized system of analysis has been developed at the Environmental Mutagen Information Center (EMIC) that makes it possible to examine the performance of any particular assay in any of 30 chemical classes and to make comparisons with all the other assays individually or in designated groupings. Components of this system include: A distribution of the 2622 chemicals into 30 chemical classes with results of testing in each class. A tabulation of assay results showing the total numbers of chemicals tested, with their definitive and nondefinitive results. A subdivision of assays and results of testing into four major groups: gene mutation, chromosomal aberrations, other genotoxic effects, and in vitro cell transformation assays. These major groups are further subdivided into phylogenetic categories and type of assay. A system of analysis of results utilizing mutagenicity and carcinogenicity comparisons and phylogenetic concordance and discordance. The major utility and/or benefit of this compilation will be derived from a chemical class by chemical class comparative analysis of individual assay performance. Obviously, the data base will serve as a resource for safety evaluation of chemicals through structural correlations and biological end point analyses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Evaluation of the genetic activity profiles of 65 pesticides.

We have previously reported the qualitative results of a major study on 65 pesticides (Waters et al., 1982). Dose information from this investigation (either lowest effective or highest ineffective dose tested) has now been incorporated into a computerized data management system. This report focuses on the qualitative profiles of genetic activity produced by these pesticides and our efforts to classify them according to their genotoxic effects and chemical structures. Three main categories may be distinguished based on the qualitative results: Category 1 pesticides were active in most of the in vitro and in vivo assays employed. These 9 compounds include the structurally similar organophosphate insecticides, acephate, demeton, monocrotophos and trichlorfon; the phthalimide fungicide analogues, captan and folpet; and the thiocarbamate herbicide analogues, diallate, sulfallate and triallate. The 26 Category 2 compounds demonstrated fewer positive results and may be subdivided into two parts, one of which contains 12 halogenated aromatic or heterocyclic ring compounds, including the phenoxy herbicides, 2,4-D, 2,4-DB and 2,4,5-T. The remaining part of Category 2 (14 compounds) consists of structurally similar organophosphate insecticides, azinphos-methyl, crotoxyphos, disulfoton, methyl parathion; three similar ethylenebisdithiocarbamate fungicides, maneb, mancozeb, and zineb; three similar pyrethroid insecticides, allethrin, chrysanthemic acid, and ethyl chrysanthemate; and four structurally diverse compounds, cacodylic acid, dinoseb, sec.-butylamine and benomyl. The third category of 30 pesticides gave negative results in all tests and represents structurally diverse compounds. Using the computerized profile matching methodology, from 2080 possible pairwise chemical combinations of the 65 pesticides, 20 statistically significant pairs were selected, 6 groups of pesticides were identified which were substantially similar to groups of pesticides we had formed previously (Waters et al., 1982) based on genetic activity and chemical structure. The matches showed excellent qualitative and, in most cases, excellent quantitative agreement. Hence it appears that specific patterns of test results present in the genetic activity profiles are related directly to chemical structure. Conversely, the data suggests that certain groups of compounds may be recognized by a well defined series of concordant tests results. As additional data is added, comparison of test results for new chemicals with existing data for known genotoxicants should aid in the evaluation of potential genetic health hazards.

Animals↗
PubMed1985

Evaluation of the genotoxic potential of certain pesticides used in Pakistan.

The mutagenicity of fifteen insecticides, five fungicides, four herbicides, and an acaricide commonly used in Pakistan was evaluated by employing thirteen short-term bioassays. The genetic endpoints used included point or gene mutation, primary DNA damage, and chromosomal effects. Initially, all pesticides were tested in a "core" battery of four in vitro bioassays. A carefully selected group among these chemicals was retested in higher level test systems to confirm the results obtained in the initial phase. Of the pesticides tested, only a small portion consistently displayed mutagenicity across test systems. The Saccharomyces cerevisiae bioassays detected mutagenicity for the largest number of pesticides. The Salmonellaces typhimurium strain, TA100, was able to detect genetic activity in all of the pesticides that produced positive results in this bioassay. The cytogenetic effects observed from the Vicia faba root assay were consistent with those obtained in mammalian cells in culture. All pesticides which displayed mutagenicity were not carcinogenic in animal bioassays but, in general, mutagenicity in a battery of short-term bioassays was a reliable indicator of the carcinogenic potential in animals. A simple test battery is proposed for evaluating the genetic potential of agricultural pesticides.

Animals↗
PubMed1985

Structure-genotoxic activity relationships of pesticides: comparison of the results from several short-term assays.

The Computer-Automated Structure Evaluation (CASE) program has been applied to the analysis of the genotoxic activity of 54 pesticides (31 insecticides, 15 herbicides and 8 fungicides) in 5 different short-term test systems measuring gene mutation and DNA damage. The database contains compounds presenting diverse structures including carbamates, thiocarbamates, organophosphates, halo-aromatics and other functionalities. Some significant relationships between common structural features and the genotoxic activity displayed by these chemicals have been found. Among the most relevant fragments, automatically selected by the program, a methoxyphosphinyl and a chlorovinyl group appear as the common structural subunits responsible for the activities detected in the battery composed of the Salmonella typhimurium histidine reversion assay, the mouse lymphoma gene mutation assay and recombination in the yeast Saccharomyces cerevisiae.

Animals↗
PubMed1985

Mutagenicity of selected organic solvents.

For certain organic solvents, such as benzene, vinyl chloride, styrene, technical grade trichloroethylene, and acrylonitrile, the available studies provide convincing evidence to demonstrate activity in short-term genetic assays. For a few solvents, such as phenol, vinyl toluene, ethanol, and tetrachloroethylene, the evidence is limited to a certain test system and/or test organism. For most of the solvents reviewed, studies are either lacking or they are so inadequate that no final evaluation on the mutagenic activity of the solvents can be made.

Animals↗
PubMed1984

Evaluation of diallate and triallate herbicides for genotoxic effects in a battery of in vitro and short-term in vivo tests.

Commercial-grade preparations of two thiocarbamate herbicides, diallate and triallate, were evaluated for their mutagenic potential in a battery of short-term bioassays. All in vitro bioassays were performed with and without mammalian metabolic activation, and all such tests were repeated after an interval of at least 1 week. Diallate and triallate were tested in the Salmonella/microsome assay over dose ranges of 0.59 to 118.0 micrograms/plate and 6.37 to 1273 micrograms/plate, respectively. Both diallate and triallate gave positive results in S. typhimurium strains TA1535, TA98, and TA100 only in the presence of a rat-liver metabolic activation system. In Saccharomyces cerevisiae strain D7, diallate was tested at concentrations from 1.18 to 29.50 micrograms/ml, and triallate was tested at 0.955 to 9.548 micrograms/ml. Both diallate and triallate gave negative results for mitotic gene conversion, mitotic crossing-over, and reverse mutation. In the mouse lymphoma L5178Y TK+/- assay, diallate was tested at concentrations ranging from 1 to 72 micrograms/ml, and triallate was tested at 0.5 to 60 micrograms/ml. Both herbicides produced mutagenic responses in the mouse lymphoma assay in the presence of metabolic activation. In the Drosophila sex-linked recessive lethal test, flies were exposed to 0.0004% diallate and 0.001% triallate. In this assay, diallate was considered mutagenic, whereas triallate did not produce a detectable mutagenic response.

Animals↗
PubMed1983

Two methods to induce 6-thioguanine resistance in human fibroblasts in the presence of rat-liver microsomes.

7,12-Dimethylbenz[a]anthracene and 4-aminobiphenyl induced dose-dependent 6-thioguanine-resistant mutations in normal human fibroblasts in the presence of rat S9 microsomes. With each chemical, mutations were induced by two different methods: single treatment of synchronized cells, and multiple treatment of nonsynchronized cells. Multiple treatment of nonsynchronized cells gave higher mutation frequencies at lower doses, and appears to be the more sensitive method.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Use of prolonged treatment and the fluctuation test to detect mutations in human fibroblasts treated with methyl methanesulfonate.

The methyl methanesulfonate (MMS) induction of 6-thioguanine-resistant (6TGr) mutants in non-synchronized human fibroblasts has been quantitatively characterized. A 24-h MMS treatment failed to induce mutations in non-synchronized cultures. However, exposure of growing cells to MMS for 3 days caused a significant increase in the mutation frequencies. The mutation induction was dose-dependent. The fluctuation test was also useful in detecting the mutagenic activity of MMS in human fibroblasts. Prolonged treatment of cultures made the human cell mutagenesis testing system more sensitive.

Cells, Cultured↗
PubMed1981

Development of a toxicity test system using primary rat liver cells.

A model in vitro rat liver parenchymal cellular toxicity system employing cells obtained by the in situ collagenase perfusion technique has been developed to detect potential liver toxicants. The initial evaluation of this test system was accomplished using cadmium chloride, chromium chloride, cobalt chloride, mercuric chloride, nickelous chloride, sodium arsenite, sodium selenite, and ammonium vanadate. Linear regression analysis of the dose response curves was used to determine the effective concentration at which the viability was reduced to 50% (EC50). The relative toxicity of the compounds was as follows: Cd greater than V = As greater than Se greater than Hg greater than Cr = Co greater than Ni. Since several of the compounds with very similar EC50s had significantly different dose response slopes, an additional parameter, lowest effective concentration tested (LECT) was employed to assess the relative toxicity. The LECT was determined using the Williams test and the relative toxicity of the compounds was found to be Cd = Se greater than V greater than As = Hg greater than Co greater than Cr = Ni. The primary objective in developing this rat liver cellular toxicity test system was to employ an in vitro test system utilizing metabolically active primary cells from a potential target organ. This study demonstrates the utility of this test system in determining the relative liver cell toxicity of a series of inorganic agents of differing toxicity.

Animals↗