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E R Nestmann

Publications and source records attributed to E R Nestmann.

At least 37 records · Page 2Linked to original sources
PubMed1988

Human mutagens: evidence from paternal exposure?

The importance of inherited mutations as a cause of human disease has been established clearly through examples of well-defined genetic anomalies, such as Down syndrome and retinoblastoma. Furthermore, it is suspected that environmental contaminants induce mutations resulting in increased risk for such defects in subsequent generations of persons exposed. The present lack of direct evidence for induced inherited genetic disorders in human beings hampers the development of risk estimation techniques for extrapolation from animal models. The most extensive prospective epidemiologic studies of inherited genetic effects have involved survivors of atomic bomb detonations and patients treated with cancer chemotherapy. In neither case has a significant elevation in inherited genetic effects or cancer been detected in the offspring of exposed individuals. Epidemiologic studies of subjects receiving chronic exposure may be confounded by the effect of maternal exposure during pregnancy. Consideration of only paternal exposure can minimize the confounding influence of teratogenicity, enhancing the resolving power of studies for inherited effects. Using this approach, retrospective (case-control) studies of childhood cancer patients have provided limited but suggestive evidence for inheritance of induced effects. Endpoints, such as congenital malformations and spontaneous abortion following paternal exposure, can also be considered as indicators of heritable mutagenic effects. For example, there is limited evidence suggesting that paternal exposure to anaesthetic gases may cause miscarriage and congenital abnormalities as a result of induced male germ cell mutations. By comparing male-exposure endpoints for which there are human data, as described above, with parallel or similar animal endpoints, such as dominant lethal, inherited cancer and "male teratogenic" effects, it is possible that suitable models for extrapolating to human risk can be developed. In order to establish a clearer relationship between induced mutation and genetic disease, the current surveillance systems should be expanded to include endpoints relevant to genetic study. The relaxation of regulations regarding access to census data could improve the chances of documenting such an association.

Abortion, Spontaneous↗
PubMed1987

The SIMULTEST: a new approach to screening chemicals with the Salmonella reversion assay.

A new Salmonella mutagenicity test method is under development to test a chemical with more than one strain simultaneously (the "SIMULTEST"), that is, different Salmonella typhimurium tester strains are used in combination on the same plate. Strains are combined in two sets: strains with plasmid pKM101 (TA97, TA98, TA100, and TA102) and strains without the plasmid (TA1535, TA1537, and TA1538). The SIMULTEST combinations successfully detect the mutagenic activity of five mutagens in different chemical classes. This approach may be useful in reducing the workload associated with mutagenicity testing with Salmonella.

Mutagenicity Tests↗
PubMed1986

Mutagenicity studies in Salmonella: residues of ozonated and/or chlorinated water fulvic acids.

Aqueous residues of ozonated, chlorinated, and ozonated/chlorinated water fulvic acids (WFA) were tested for induction of His+ reversion in Salmonella typhimurium strain TA100 in fluctuation tests for mutagenicity. The data suggest that ozonation of natural organics present in sources of drinking water can prevent subsequent formation of by-products of chlorination that are mutagenic in bacteria. Ozonation of the WFA at different pH and at varying dose levels produced residues that were not or were only weakly mutagenic. Chlorination of WFA or of previously ozonated WFA led to residues that were highly mutagenic. However, mutagen formation in the ozonated/chlorinated residues could be prevented, depending upon the pH of the WFA solutions during ozonation-mutagenicity decreased as pH increased. This decrease in mutagenicity is associated with previous observations of enhanced ozone decomposition into its highly reactive oxidant species at higher pH. Since ozonation seems to be more effective at alkaline pH, alkaline raw water sources seem to be the best candidates for water treatment that involves ozonation.

Benzopyrans↗
PubMed1986

The effect of 2-micron DNA on survival and mutagenesis in Saccharomyces cerevisiae.

Strains of Saccharomyces cerevisiae, with and without endogenous 2-microns DNA, were studied in experiments designed to determine the effect of this plasmid on survival and mutagenesis in yeast. Comparison of the two strains exposed to ultraviolet light, 4-nitroquinoline oxide, or methyl methanesulfonate (MMS), revealed that the presence of 2-microns DNA slightly enhanced survival after exposure to each agent. Spontaneous frequencies of mutations (histidine reversion, canavanine resistance, and mitochondrial petites, but not adenine auxotrophy) were reduced by the presence of 2-microns DNA. MMS-induced His+ reversion was weak, and both strains responded similarly. No difference was found between the two strains when induced forward mutation to canavanine resistance was examined. The extent of induction of mitochondrial petites was about the same in both strains. Therefore, it appears that under these experimental conditions with these mutagens, 2-microns DNA has an effect on spontaneous mutation and survival after DNA damage but not on induced mutagenesis in S. cerevisiae.

4-Nitroquinoline-1-oxide↗
PubMed1986

Contribution of chlorination to the mutagenic activity of drinking water extracts in Salmonella and Chinese hamster ovary cells.

The production of chlorinated by-products through chlorine disinfection of drinking water has been well documented. Natural organic precursors for these chemicals include fulvic and humic acids, the chlorination of which leads to the production of mutagenic compounds. Comparisons of extracts of raw versus treated waters have confirmed that clorination during water treatment produces mutagenic activity in the Salmonella (Ames) test. Present work on XAD-2 extracts of raw and chlorinated water from six municipalities in the Great Lakes region of Canada has involved a battery of mutagenicity assays for various genetic endpoints: the Salmonella test, the sister-chromatid exchange (SCE), and the micronucleus (MN) induction in Chinese hamster ovary (CHO) cells. All extracts of treated (chlorinated), but none of untreated, water were mutagenic in the Salmonella assay. On the other hand, extracts of both treated and untreated water samples showed activity in the SCE and MN assays, but no consistent pattern of response with regard to treatment (chlorination) was evident. These data show that chlorination contributes mutagens to drinking water and suggest that mammalian in vitro assays may be more sensitive for detecting mutagenicity in water samples than the Salmonella test.

Animals↗
PubMed1985

Solvent interactions with test compounds and recommendations for testing to avoid artifacts.

Reports in the literature describing artifactual results owing to interactions of test materials with solvents are becoming more frequent. The present study was initiated to examine possible interactions of 1,1,3-trichloro-, 1,1,3,3-tetrachloro-, pentachloro- and hexachloroacetones with different solvents, since certain solvent effects with the last compound have been shown previously. Quantitative differences in levels of mutagenic potency were found for tri-, tetra-, and pentachloroacetone, dissolved in acetone or dimethyl sulfoxide (DMSO). On the other hand, hexachloroacetone without solvent was mutagenic, and this activity was enhanced when it was dissolved in DMSO; in acetone it was not mutagenic. A time-dependent reaction of hexachloroacetone with DMSO was the only test material-solvent interaction found in this study. The results show clearly that DMSO is not an appropriate solvent for hexachloroacetone. On the basis of these and previous results, we recommend consideration of the following strategy to help prevent reporting of artifactual results owing to interaction with solvents: Results from initial screening experiments should be confirmed in repeat experiments using a different solvent; and a different solvent should be used in confirming the findings of other investigators. Differences in results would indicate a need for further study.

Acetone↗
PubMed1985

A rapid method for the extraction and purification of DNA from human leukocytes.

A rapid method for the extraction and purification of DNA from human leukocytes was developed. Crude nucleic acids were obtained by sodium dodecylsulfate (SDS) lysis and potassium acetate precipitation of other cellular material, and the DNA was purified by ribonuclease digestion, diethylaminoethyl (DEAE) cellulose chromatography and ethanol precipitation. DNA obtained by this method is biologically active as reflected by its ability to act as substrate for various nucleases and T4 DNA ligase. The yield was sufficiently high that DNA from less than 1 ml of blood could be used for a number of reactions.

Chromatography, DEAE-Cellulose↗
PubMed1984

Chlorination of ozonated soil fulvic acid: mutagenicity studies in Salmonella.

Samples of soil fulvic acid (SFA) were ozonated and subsequently chlorinated under acidic or slightly basic conditions. The residues were tested for His+ reversion in a fluctuation assay, using Salmonella typhimurium TA100 as the tester strain. The ozonated/chlorinated samples were mutagenic, but activity was dependent on the amount of ozone utilized and the pH of the reaction medium. Although increases in cell concentrations were also induced by some mutagenic samples, this alone did not account for the mutagenicity observed. Unchlorinated samples displayed insignificant activity.

Benzopyrans↗
PubMed1984

Mutagenicity in a modified Salmonella assay of fabric-protecting products containing 1,1,1-trichloroethane.

Methyl chloroform (1,1,1-trichloroethane) was identified as a major component in two fabric-protector spray products. Mutagenic effects were determined at several dosage levels for the two products and some of the identified components. Levels of organics in the air of sealed desiccators, used as exposure chambers in modified Salmonella reversion assays, were measured by a gas chromatographic technique. Both fabric protectors and two samples of trichloroethane were mutagenic in strain TA 1535 and one of each was mutagenic in strain TA 100. Other constituents, such as petroleum distillate and p-dioxane, were nonmutagenic at the tested exposure levels.

Aerosols↗
PubMed1983

Comparative mammalian in vitro and in vivo studies on the mutagenic activity of rhodamine WT.

Rhodamine WT, a xanthene dye used in the tracing of pollutants in water and in related studies, was tested for its mutagenicity in a battery of in vitro and in vivo mammalian assays. Using Chinese hamster ovary cells in the absence of metabolic activation mix, small dose-related increases in cytotoxicity, DNA damage (as detected by alkaline sucrose-gradient sedimentation) and sister-chromatid exchanges were detected, but an increase in the level of chromosomal damage was not seen. In the presence of metabolic activation a small, but statistically significant dose-related increase in sister-chromatid exchanges was evident, with no increase in cytotoxicity, DNA damage or chromosome aberrations. Furthermore, no increase in bone marrow micronuclei or sperm abnormalities was observed in male B6C3F1 mice. The data from all these mammalian assays, although involving different end-points, are in contrast to the mutagenic effects previously seen in Salmonella.

Animals↗
PubMed1983

Genotoxic activity of pulp mill effluent in Salmonella and Saccharomyces cerevisiae assays.

An XAD-2 resin concentrate of chlorination-stage pulp mill effluent was found to induce mutations in Salmonella typhimurium strains TA1535, TA100 and TA98 but not in strains TA1537 or TA1538. The presence of either S9 mix, S9 mix without cofactors, or heat-inactivated S9 mix, reduced the mutagenic effects. Dose-related increases in gene conversion, mitotic recombination and aberrant colony formation in Saccharomyces cerevisiae strain D7 also were found.

Canada↗
PubMed1983

Suitability of the modified fluctuation assay for evaluating the mutagenicity of unconcentrated drinking water.

Filter-sterilized, unconcentrated tap water induced mutagenic responses (p less than 0.01) in Salmonella strain TA100 in fluctuation assays, usually with dose-related increases in positive tubes. Additional experiments were performed to study possible artifacts that could lead to falsely positive results. Determinations of bacterial survival revealed that cell populations in the tubes containing tap water were larger than in the controls. Since spontaneous mutation is a function of cell generation, the increased numbers of bacteria appeared to be responsible for the higher numbers of mutants observed. Therefore, the positive responses must be regarded as artifactual. This study suggests that survival determination should be a routine part of this method, and care should be exercised in the interpretation of positive results.

Cell Division↗
PubMed1983

Mutagenicity of constituents of pulp and paper mill effluent in growing cells of Saccharomyces cerevisiae.

42 compounds identified in pulp mill effluent were screened for genetic activity in growing yeast cells using strains D7 and XV185-14C without S9. In addition to 3 of these compounds that had been shown previously to be mutagenic in Salmonella. 5 more were mutagenic in strain XV185-14C. All 8 induced 2-5-fold increases in reversion frequencies over background at the trp5 locus--5 of these induced 1.5-3-fold increases at the hom3 locus and 1 induced a doubling at his1. None of the compounds induced absolute increases of gene convertants per plate in strain D7, although 3 showed increased convertant frequencies as survival decreased.

Gene Conversion↗
PubMed1982

Differential survival as an indicator of potential mutagenicity using repair deficient strains of Saccharomyces cerevisiae and Schizosaccharomyces pombe.

A method is presented to screen chemicals for potential mutagenicity on the basis of their ability to cause more killing in cells of repair-deficient yeast than in wild type cells. Two species were chosen in the event that one might be more sensitive to certain chemicals. The strains used were RAD+ and rad6 derivatives of Saccharomyces cerevisiae and RAD+ and rad3 derivatives of Schizosaccharomyces pombe. This report describes the test system and results for 12 known, direct-acting mutagens (i.e., not requiring mammalian metabolic activation). These compounds showed more lethality in one or both of the repair-deficient strains, indicating that they induce damage to DNA which is subject to repair in wild type cells. Advantages of this system include the use of eukaryotic yeast cells which can be manipulated as easily as bacteria, and that exogenous enzymes (S9) can be added for metabolic activation. Growing yeast cells can activate certain promutagens, and preliminary experiments showed positive responses for diethylnitrosamine and 2-acetylaminofluorene without the addition of S9.

Ascomycota↗
PubMed1981

Mutagenic activity of diallate and triallate determined by a battery of in vitro mammalian and microbial tests.

Diallate and Triallate are carbamate herbicides used mainly for the pre-emergence control of wild oats in various crops. The genetic activity of these compounds was studied using a battery of microbial and mammalian in vitro tests. In the Salmonella/mammalian-microsome assay, Diallate and Triallate show dose-related increases without metabolic activation in strains TA1535, TA100 and TA98, indicating that these compounds cause both frameshift and base-substitution mutations. Mutagenicity of both herbicides was enhanced greatly by incubation with Aroclor 1254 induced rat-liver S9. Genetic activity in mammalian cells was determined using a number of in vitro tests with Chinese hamster ovary (CHO) cells combined with metabolic activation as described above. Both Diallate and Triallate caused dose-related decreases in colony-forming ability, with concomitant dose-related increases in the frequencies of cells with chromosome damage and in the number of sister-chromatid exchanges. However, only Diallate caused a reduction in DNA molecular weight as determined by alkaline sucrose gradient (ASG) sedimentation. DNA damage was negligible even at concentrations of Triallate that reduced colony-forming ability to zero. This suggests that the lesions in DNA detected by the ASG technique are not necessarily related to those that produce chromosomal damage. These data, taken together, strongly implicate both Diallate and Triallate as capable of causing mutations in mammals. However the risk to man in terms of inherited disease or cancer remains to be established by appropriate in vivo methodology.

Animals↗
PubMed1981

Mutagenicity of paint removers containing dichloromethane.

A volatile component of commercially available paint and varnish removers was mutagenic in strains of Salmonella typhimurium TA1535, TA100 and TA98. Levels of dichloromethane in exposure chambers were determined by gas chromatography and were related directly to mutational dose-effect curves observed for the products.

Environmental Exposure↗