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Biomedical subjects

J P Seiler

Publications and source records attributed to J P Seiler.

At least 19 recordsLinked to original sources
PubMed1991

Pentachlorophenol.

Pentachlorophenol (PCP) is a substance whose widespread use, mainly in wood protection and pulp and paper mills, has led to a substantial environmental contamination. This in turn accounts for a significant exposure of the general human population, with rather high exposure levels being attained in occupational settings. Investigations on the genotoxic activity of PCP have given rise to divergent results which would seem to make an evaluation difficult. By grouping them into 3 categories a somewhat clearer picture, allowing finally an (admittedly tentative) assessment, can be obtained. PCP does seem to be at most a weak inducer of DNA damage: it produces neither DNA-strand breaks nor clear differential toxicity to bacteria in rec-assays in the absence of metabolic activation. Also in SCE induction no increase can be observed in vivo, while PCP is found marginally active in a single in vitro experiment. Metabolic activation, however, leads to prophage induction and to DNA strand breaks in human lymphocytes, presumably through the formation of oxygen radicals. A possible further exception in this area might be the positive results in the yeast recombination tests, although their inadequate reporting makes a full evaluation difficult. PCP does not seem to induce gene (point) mutations, as most bacterial assays, the Drosophila sex-linked recessive lethal test and in vitro assays with mammalian cells did not demonstrate any effects. Marginally positive results were obtained in the mammalian spot test in vivo and in one bacterial test; the positive result in the yeast assay for cycloheximide resistance is fraught somewhat with its questionable genetic basis. PCP does, however, induce chromosomal aberrations in mammalian cells in vitro and in lymphocytes of exposed persons in vivo. Those in vivo results that were unable to provide evidence of chromosomal damage are hampered either by methodological inadequacies or by too low exposure levels. The (rodent) metabolite tetrachlorohydroquinone might be a real genotoxic agent, capable of binding to DNA and producing DNA strand breaks; this activity is probably due to semiquinone radical formation and partly mediated through active oxygen species. Since this compound has not been tested in the common bacterial and mammalian mutagenicity assays, the few ancillary results on this substance cannot be used in a meaningful human risk assessment of PCP. Furthermore, this metabolite has only been produced by human liver microsomes in vitro, but has not been detected in exposed humans in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Chirality-dependent DNA reactivity as the possible cause of the differential mutagenicity of the two components in an enantiomeric pair of epoxides.

Chemical compounds containing an epoxy group are very reactive substances and, in many cases, they therefore exhibit strong mutagenic properties. Very often such epoxides contain an asymmetric C atom and thus exist as racemic mixtures of optical isomers, the so-called R- and S-enantiomers. It is well known that in many cases a biological activity resides completely in one of the two enantiomeric forms of a molecule. Also, the R- and S-enantiomeric forms of epoxystyrene exhibit different mutagenic activities in Salmonella typhimurium TA100, although their chemical reactivity does not differ to a recognizable extent. Neither could the higher mutagenic activity of the R-epoxystyrene be attributed to a slower enzymatic hydrolysis reaction. Thus, the intrinsic potential for eliciting mutagenic responses may not be the same for the two enantiomers, as there is evidence of qualitative differences in the binding to DNA, pointing strongly to an intrinsic difference in mutagenic activity of the two enantiomers.

DNA, Bacterial↗
PubMed1989

The mutagenic activity of sodium perborate.

Sodium perborate (CAS No. 1333-73-9, 10486-00-7, or 13517-20-9, depending on the structural formula given) is produced in huge amounts mainly for its use as a bleaching agent in laundry detergents. Its action involves the liberation of active oxygen species at elevated temperatures. In view of the widespread use of this compound it is surprising to note that no mutagenicity test data yet exist. The investigations reported in this paper have shown that sodium perborate is indeed capable of producing mutagenic changes in a number of in vitro test systems. Its potential for inflicting damage to DNA could be demonstrated in an assay which is tailored to probe for oxidative damage induced by a chemical agent. As expected, sodium perborate proved to be able to oxidize thymidine to an appreciable extent at an incubation temperature of 80 degrees C, but even at 40 degrees C thymidine oxidation was measurable. The compound induced point mutations in the Salmonella typhimurium strains TA100 and TA102, while TA98 did not respond. Also, incubation in the presence of a mammalian auxiliary metabolic system (rat liver S9) abolished the mutagenic activity completely. Finally, Chinese hamster ovary cells (strain CHO-K1) were shown to undergo extensive chromosomal damage when treated with sodium perborate. The rather unusual prevalence of chromosome rearrangements was especially noted. Sodium perborate is thus to be regarded as a direct-acting in vitro mutagen.

Animals↗
PubMed1985

Chemical impurity as the possible cause of nitrofen mutagenicity.

The results of Salmonella mutagenicity tests with the herbicide nitrofen (2,4-dichlorophenyl-4-nitrophenyl ether, CAS 1836-75-5) reported in the literature seem to vary according to source or lot of the technical product. This behaviour could be reproduced in our experiments, and it could be traced to the varying content of bis(4-nitrophenyl) ether in nitrofen. Nitrofen samples with the highest bis(4-nitrophenyl) ether concentrations proved to exhibit also the highest mutagenic activities, while the one containing no bis(4-nitrophenyl) ether was also devoid of mutagenic activity towards Salmonella typhimurium TA 100.

Herbicides↗
PubMed1979

Dose and effect of methyl-2-benzimidazolylcarbamate in the "mammalian spot test", an in vivo method for the detection of genetic alterations in somatic cells of mice.

In the spot test, mouse embryos which are heterozygous for four different recessive coat-colour genes are treated in utero by injection of a mutagen into the peritoneal cavity of the mother or by other appropriate routes of administration. If this treatment leads in a pigment precursor cell to an alteration of the wild type allele of one of the genes under study or to its loss, a colour spot in the adult coat may be seen. Peroral application of 100-300 mg methyl-2-benzimidazolylcarbamate (MBC)/kg to the mother during the tenth day postconception led to an increase in the frequency of colour spots in the coats of offspring. The data are consistent with the hypothesis that MBC is a point mutagen.

Alleles↗
PubMed1978

Herbicidal phenylalkylureas as possible mutagens I. Mutagenicity tests with some urea herbicides.

Substituted phenylalkylureas are widely used as herbicides. In the assay system of Friedman and Staub, which measures the inhibition of testicular DNA synthesis (DSI test), most of these substances showed a positive reaction, i.e. they depressed tnymidine incorporation significantly. Bacterial tests demonstrated a weak mutagenic activity, too; but in the micronucleus test the compounds were almost inactive. As one member of this group of chemicals--the herbicide monuron--is a recognized carcinogen, these results seem to indicate a possible hazard, but more investigations are needed to quantify this danger.

DNA↗
PubMed1977

Nitrosation in vitro and in vivo by sodium nitrite, and mutagenicity of nitrogenous pesticides.

37 nitrogenous pesticides, belonging to the chemical groups of amides, carbamates and ureas, were nitrosated with sodium nitrite in vitro. The nitrosated compounds were tested for mutagenic activity in the bacterial spot test with Salmonella typhimurium his G 46. Those pesticides reacting positively in this test after nitrosation were then fed to mice in combination with sodium nitrite in order to assess the formation and mutagenicity of these nitroso compounds in vivo. With the already known exception of ethylenethiourea (ETU), no pesticide produced enhanced numbers of micronuclei in mouse bone-marrow erythrocytes when fed together with nitrite. Dose-response experiments with intraperitoneal injection of N-nitroso-ETU revealed an apparent no-effect level of about 15--18 mg/kg. The findings are correlated with the pesticide residues actually present in the environment.

Animals↗
PubMed1976

The mutagenicity of benzimidazole and benzimidazole derivatives. VI. Cytogenetic effects of benzimidazole derivatives in the bone marrow of the mouse and the Chinese hamster.

Methyl benzimidazole-2-ylcarbamate (MBC) was mutagenic in mice by the micro-nucleus test. Other benzimidazole derivatives, with the exception of the parent compound of MBC, benomyl, and the very closely related substance 2-benzimidazolylurea, did not produce micro-nuclei in mouse bone marrow. Evidence is presented that MBC acts through inhibition of mitosis and that for this action the carbamoyl group is a necessary but not a sufficient condition. It is also demonstrated that for this particular type of mutagenic activity a threshold limit exists, which seems to be in the order of less than 10 mug MBC per ml blood.

Animals↗
PubMed1975

The molecular mechanism of benzimidazole mutagenicity: in vitro studies on transcription and translation.

Benzimidazoles are weak mutagens acting through base substitutions; they are incorporated into nucleic acids. Experiments with deoxyribohomopolymers as templates demonstrated that benzimidazole nucleoside triphosphate is polymerized by RNA polymerase only in the presence of poly dC, i.e., instead of guanine. In plasmolyzed Escherichia coli cells, benzimidazole ribonucleoside diphosphate is polymerized by polynucleotide phosphorylase and can, after blocking of the normal mRNA synthesis with actinomycin D, be used as a messenger for polypeptide formation. The addition of radioactive amino acids to this system showed that benzimidazole is not read preferentially as guanine, as would have been expected from the RNA polymerase results. Instead, the reading was position dependent and brnzimidazole is recognized (1) in the first codon position as adenine, (2) in the second as purine, and (3) in the third possibly only as base. Benzimidazole mutagenicity is thus explained as a G in equilibrium A transition.

Adenine↗