Threshold effects in genetic toxicity: perspective of chemicals regulation in Germany

In the regulation of chemical substances, it is generally agreed that there are no thresholds for genotoxic effects of chemicals, i.e. , that there are no doses without genotoxic effects. When classifying and labelling chemicals, dangerous properties of chemicals are to be identified. In this context, in general, the mode of action (threshold or not) is not considered for genotoxic substances. In the process of quantitative risk assessment, however, determination of the type of dose-effect relationships is decisive for the outcome and the type of risk management. The presence of a threshold must be justified specifically in each individual case. Inter alia, the following aspects may be discussed in this respect: aneugenic activity, indirect modes of action, extremely steep dose-effect relationships in combination with strong toxicity, specific toxicokinetic conditions which may lead to 'metabolic protection' prior to an attack of DNA. In the practice of the regulation of chemical substances with respect to their genotoxic effects, the discussion of thresholds has played a minor role. For notified new substances, there are, in general, no data available that would allow a reasonable discussion. Concerning substances out of the European programme on existing substances, so far 29 have been assessed in our institute with respect to genetic toxicity. Eight out of these have shown considerable evidence for genotoxicity. For two of them, a possible threshold is discussed: one substance is an aneugen, the other one is metabolised to an endogenic compound with genotoxic potential. In the practice of risk assessment of genotoxic substances, the discussion of the mode of action for genotoxicity is frequently associated with the evaluation of potential carcinogenic effects. Here, tissue-specific genotoxic effects in target organs for carcinogenicity are to be discussed. Moreover, the contribution of genotoxicity to the multifactorial process of tumour development should be assessed.     

Inhibition of Nitrification in the Activated Sludge Process of Sewage Disposal

S ummary . A simple method is described for determining the short term effects of sewages, effluents and individual substances on the nitrifying ability of activated sludge and the results of screening many substances are listed. The effects of mixtures of inhibitors and the possibility of formation of complexes between some of those inhibitors were investigated. The long term effects of inhibitors often differ from their immediate effects, one of the most important factors being the ability of activated sludge to become adapted to the inhibitor.     

Development of multifunctional foods

Foods contain various biologically active substances with extent physiological effects. Among them, some substances, such as dietary fibers, polyunsaturated fatty acids, and antioxidants, exert multiple activities. In addition, combinational uses of some components, such as sesamin and α-tocopherol, enhance their biological effects each other. The expression of multiple effect leads to the production of multifunctional foods which prevent the occurrence of various diseases. Furthermore, synergic effects between biologically active substances allow us to decrease the dose of each component, which lead to the improvement of safety and reduction of production cost of multifunctional foods. To use these active components for human health, studies on their adsorption and transportation are important, since distribution of some components, such as tocotrienols, is limited to some tissues. In addition, extent safety studies are essential to use artificially synthesized substances such as 10t, 12c derivative of conjugated linoleic acid for human health.     

Antioxidative and Prooxidative Abilities of some Biological Substances and Physiologically Active Substances on the Oxidation of Unsaturated Fatty Acids

Some biological substances and physiologically active substances such as amino acids, hormones, vitamins, medicines and the other substances were added into the linoleic acid solution; and antioxidative and prooxidative abilities of these substances, the abilities to act as electron donors or acceptors, were tested. Many substances were effective as the antioxidant and some others showed prooxidative effects. These facts suggested the possibility of the occurrence of many reactions involving the transfer of an electron among biological processes.     

植物抗虫性次生物质的研究概况

综述了国内外与植物抗虫性有关的次生物质的主要类型和植物次生物质对昆虫的寄主选择、取食和产卵等作用的研究进展,对次生物质在生态系统中的作用也作了介绍,并展望了植物次生物质的应用前景。     

The effect of ecoestrogens on the development of the mammalian reproductive system

Recently, it has been shown that the environment contains a large variety of chemical substances possessing estrogenic activity (ecoestrogens/environmental estrogens). In this connection, the problem of estrogenic effects exerted by the environment on animal ontogenesis is very important. Here, we review the available data concerning the effects of ecoestrogens on the development of the reproductive system in mammals. We discuss issues of reproductive toxicology related to the effects of these substances during prenatal and postnatal development, with special attention to the effect of ecoestrogens and modern reproductive technologies on preimplantation embryonic development.     

The phenolic compounds in <Emphasis Type="Italic">Cladonia</Emphasis> lichens are not antimicrobial in soils

According to classic text books on lichen biology, the phenolic secondary chemicals in lichens have antibiotic effects on soil microorganisms and mycorrhizal fungi in ecosystems. However, the experimental evidence for this under natural conditions is still relatively scarce. We examined some of the assumptions behind the concept of antimicrobial effects of lichen secondary substances: (1) the secondary substances of Cladonia stellaris, usnic and perlatolic acids, are leached out from the lichens by rainwater; (2) these substances inhibit the microbial activity of soil, and; (3) since they are extremely resistant to microbial decomposition, the soil underneath a continuous lichen mat is enriched in usnic and perlatolic acids. Our results did not support any of these assumptions. The evidence for the antimicrobial activity of lichen secondary substances seems to be weak in comparison to other suggested functions such as light filtering and herbivore protection. We suggest that it is time to re-evaluate the evidence for the antimicrobial ecological role of lichen secondary substances in natural systems.     

Hygienic examination of the stimulating effect on the organism of a complex of natural substances

No exhaustive hygienic studies have been conducted yet of the natural substances present in the atmosphere. A complex of natural substances was shown to affect EEG parameters, subjective perception of one's health and general perception. The concentration of the vapours of a mixture of substances was kept at 0.1 mg/m3 which is characteristic of mountainous air. The inhalation of the natural substances was shown to alter the EEG indicators and subjective perception of tested subjects, suggesting a stimulatory effect on the central nervous system. The natural substances proved to stimulate the efficiency of mental and manual work, self-perception and mood. These effects can be accounted for by the positive biological influence of the mountainous atmosphere.     

植物抗虫性次生物质的研究概况

综述了国内外与植物抗虫性有关的次生物质的主要类型和植物次生物质对昆虫的寄主选择、取食和产卵等作用的研究进展,对次生物质在生态系统中的作用也作了介绍,并展望了植物次生物质的应用前景。     

Influence of waste water from the paper industry and UV-B radiation on the photosynthetic efficiency of Euglena gracilis

The green flagellate Euglena gracilis has been used as a model organism to elucidate the possible large-scale and short-term effects of waste substances from the pulp and paper industry on photosynthetic efficiency (PE). Different concentrations of waste substances before and after treatment in a cleaning system were studied. The uncleaned sample at concentrations up to 1:10 and the cleaned sample at concentrations up to 1:5 showed stimulating effects on the PE after 7 days of incubation compared to the control. The effects of waste substances on the PE of E. gracilis were also studied in combination with short-term studies (20 and 40 min) of ultraviolet-B radiation (UV-B, 280–320 nm). It was shown that increasing concentrations of the uncleaned sample had continuously stimulating effects on the PE and worked protectively against UV-B radiation. The cleaned sample exhibited no effects, or negative effects, on the PE of E. gracilis together with UV-B radiation compared to the experiments with only UV-B radiation. At the concentration 1:1 of the cleaned sample an increase in the PE was detected due to the high concentration of the coloured substances and a decrease in the UV-B penetration. PE revealed itself to be highly sensitive for detecting toxic effects on E. gracilis and is thus very promising for use in regular toxicity tests of waste water from pulp and paper industry. This revised version was published online in July 2006 with corrections to the Cover Date.     

Liposomes as model for taste cells: receptor sites for bitter substances including N-C=S substances and mechanism of membrane potential changes

Various bitter substances were found to depolarize liposomes. The results obtained are as follows: (1) Changes in the membrane potential of azolectin liposomes in response to various bitter substances were monitored by measuring changes in the fluorescence intensity of 3,3'-dipropylthiocarbocyanine iodide [diS-C3(5)]. All the bitter substances examined increased the fluorescence intensity of the liposome-dye suspension, which indicates that the substances depolarize the liposomes. There existed a good correlation between the minimum concentrations of the bitter substances to depolarize the liposomes and the taste thresholds in humans. (2) The effects of changed lipid composition of liposomes on the responses to various bitter substances vary greatly among bitter substances, suggesting that the receptor sites for bitter substances are multiple. The responses to N-C=S substances and sucrose octaacetate especially greatly depended on the lipid composition; these compounds depolarized only liposomes having certain lipid composition, while no or hyperpolarizing responses to these compounds were observed in other liposomes examined. This suggested that the difference in "taster" and "nontaster" for these substances can be explained in terms of difference in the lipid composition of taste receptor membranes. (3) It was confirmed that the membrane potential of the planar lipid bilayer is changed in response to bitter substances. The membrane potential changes in the planar lipid bilayer as well as in liposomes in response to the bitter substances occurred under the condition that there is no ion gradient across the membranes. These results suggested that the membrane potential changes in response to bitter substances stem from the phase boundary potential changes induced by adsorption of the substances on the hydrophobic region of the membranes.     

The effect of ecoestrogens on the development of the mammalian reproductive system

Recently, it has been shown that the environment contains a large variety of chemical substances possessing estrogenic activity (ecoestrogens/environmental estrogens). In this connection, the problem of estrogenic effects exerted by the environment on animal ontogenesis is very important. Here, we review that available data concerning the effects of ecoestrogens on the development of the reproductive system in mammals. We discuss issues of reproductive toxicology related to the effects of these substances during prenatal and postnatal development, with special attention to the effect of ecoestrogens and modern reproductive technologies on preimplantation embryonic development.     

On the use of morphactin and triiodobenzoic acid in apical dominance studies

Summary Application of either CFM or TIBA to bean plants caused four main effects: (i) inhibition of main shoot and leaf growth; (ii) abscission of young leaflets and internodes; (iii) limited outgrowth of lateral buds below the point of application of the substances followed by abscission of these buds; (iv) abscission of all other lateral buds. Although the chemical pruning effects of CFM and TIBA may be the result of their action in blocking auxin transport, the use of these substances for analysing auxin effects in apical dominance is questionable.     

Record linkage and the identification of long-term environmental hazards.

The long-term effects of toxic substances in man that have been discovered so far have involved gross relative risks or bizarre effects, or have stumbled upon by chance or because of special circumstances. These facts and some recent epidemiological evidence together suggest that a systematic approach with better methods would reveal the effects of many more toxic substances, particularly in manufacturing industry. Record linkage is a powerful tool because it makes possible the correlation of indicators of exposure with indicators of the biological effect of such exposure in the same persons or in their progeny even after considerable periods of time have elapsed. A system of linked records exists in England and Wales which is at present used by research workers to follow up samples of persons defined in various ways, e.g. in respect of exposure to a suspected toxic factor. In this way hypotheses about substances causing cancer or other lethal effects can be tested. It is suggested that there are two additional ways in which record linkage techniques could be used to identify substances with long-term toxic effects: the first would be by setting up a register of women employed in industry during pregnancy and linking this register to records of the occurrence of congenital malformations and of stillbirth or death in their children; the second would be to follow samples of workers in manufacturing industry, notably those engaged in the manufacture of products from raw materials including the chemical industry, to death and to the development of cancer. Regular analyses of material from these two systems of linked records would provide the basis for a monitoring system for certain gross effects of long-term toxic substances in man. There are two principal obstacles to further progress in this field. The first is the lack of a clear statement of public policy concerning the issues of confidentiality and informed consent in the use of identifiable personal records for medical research. A settlement is needed which defines the proper limits of their use in the interests of health with safeguards to privacy. The second obstacle is a lack of resources to improve the quality, accessibility and organization of the appropriate data.     

Further Evidence that Humic Substances Have the Potential to Modulate the Reproduction of the Nematode Caenorhabditis elegans

Humic isolates have previously been shown to modulate the reproduction of the nematode, Caenorhabditis elegans Maupas . The aim of this study was to find out if a hormone‐like effect is an intrinsic feature of humic substances. Therefore, the same nematode bioassay was used with ten humic substances (XAD and/or reverse osmosis isolates). The results confirmed the hormone‐like effect of humic substances, nine isolates significantly increased the numbers of offspring per worm, one isolate did not modulate the reproduction of C. elegans. This effect occurred with XAD isolates and with reverse osmosis isolates as well. Thus, this effect is an intrinsic feature of humic substances. This reproduction modulating potential of humic substances may be due to alkylaromatics that are major structural and photo stable structural components, rather than to sterols that are only minor structural components. This is a new view about the direct interactions of humic with aquatic organisms. The effects haven been mathematically modeled by a simple approach, considering a hormone‐like effect (β) and a non‐hormone like effect, such as nutrient effect (α) on growth. The different effects observed can be interpreted in terms of trade‐offs between these two competing mode of actions.     

In vitro measurement of pollen tube growth inhibition

A method for estimating inhibition of pollen tube growth was developed. Pollen is placed in straight lines on an agar surface where it responds uniformly and predictably to aqueous solutions of germination-inhibiting substances located in wells at the ends of the lines. A scale of ratings, roughly corresponding to serial, doubled concentrations of inhibiting substances, was devised. Water-soluble organic solvents are relatively noninhibitory, salts are variable, and metabolic inhibitors have strong inhibitory effects. Pollens differ in their susceptibility to inhibition and in their response to particular substances.     

The physiological activity of volatile substances of plants in air and water media

Physiological effects of volatile substances released by the overground as well as by the underground organs of higher plants were studied. The activity of the volatile substances was tested both when these substances were allowed to act directly in the air and when they were dissolved in water in the form of solutions. Plants which do not contain essential oils or which are not rich in them as well as those abounding in essential oils and other volatiles were used in the experiments. The physiological activity of the volatile substances was tested on rye seedlings. The overground as well as underground mature organs of the tested plants were found to release volatile substances causing, when acting directly, in the majority of cases an inhibition of the growth in length and of the formation of dry matter in rye seedlings. A pronounced inhibition of the growth of rye seedlings was brought about especially by the volatile substances of “aromatic” plants such as common dill, wild thyme, yarrow milfoil, garden thyme, marjoram, etc. The volatile substances released by the organs of “non-aromatic” plants like sugar-beet, common sunflower, quackgrass, etc., were found to bring about a significant inhibition of the growth of rye seedlings, too. The volatile substances released by the plant organs were found to be altogether absorbable in water and physiologically active also in the form of water solutions. With the exception of volatile substances from hemp and quackgrass leaves, which brought about a mild stimulation of the dry matter formation in rye seedlings, inhibitory effects of these solutions were found to prevail in all cases. Most effective were the solutions of the volatiles from some of the “aromatic plants”. An assay for olefines in the atmosphere of the experimental vessels demonstrated that in almost all cases ethylene is being released by the plant organs.     

Interactions in enzymatic reactions

The paper deals with interactions of substances via an enzymatic reaction (Bull. Math. Biophysics,25, 141–154, 1963). The substances are the activators, inhibitors and/or substrates of the reaction. Due to the bimolecularity of the processes in the reaction, the quantitative relation between the steady state amount of complexes and the amounts of the substances assumes a typical form. In multiple enzymatic reactions this form is more complicated, though basically similar. Because the substances may influence the steady state amounts of the complexes in opposite directions, the compensation and blocking effects are the properties of enzymatic reactions. The substances with the same direction of influence may potentiate each other. In the enzymatic reaction here considered, the potentiation is always non-negative.