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The carbohydrate in the toxic glycoprotein ricin was chemically modified by simultaneous treatment with sodium metaperiodate and sodium cyanoborohydride. This treatment causes oxidative cleavage of the sugar residues and reduction of the aldehyde groups which are formed to primary alcohols. The modification markedly decreased the rapid removal of ricin from the blood by hepatic non-parenchymal cells with only a relatively small increase in accumulation of the toxin by parenchymal cells. Binding, uptake and toxicity of the modified ricin in primary monolayer cultures of hepatic non-parenchymal cells were all decreased to a much greater extent than in parenchymal cells. The results indicate that native ricin binds to non-parenchymal cells by a dual recognition process which involves both interaction of cell receptors with the mannose-containing oligosaccharides of the toxin and binding of ricin to galactose-containing glycoproteins and glycolipids on the cells. However, uptake and toxicity of native ricin in non-parenchymal cells appears to result principally from entry of the toxin through the mannose recognition pathway. By contrast, uptake and toxicity of the expressed essentially through the galactose-recognition route.
Mixtures of chemicals with different target organs or the same target organ but different target sites or different modes of action did not appear to be distinctly more hazardous than the individual chemicals, provided the dose level of each chemical in the mixture did not exceed its own 'No-Observed-Adverse-Effect Level'. Clearly, for such mixtures and exposure conditions the additivity assumption did not hold. However, the additivity rule appeared to be applicable to mixtures of chemicals with the same target organ and the same mechanism of action or receptor. Fractional 2-factorial study designs were found to be promising tools for examining possible combined actions or interactions of chemicals in a mixture.
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Industrial chemicals are seldom used as pure substances; hazards resulting from exposure to mixtures have, however not been solved. Our study deals with chronic inhalation toxicity of a mixture of benzene and toluene; few studies have been completed on this subject. Our results show: - leucopenia with benzene alone, at a concentration of 50 p.p.m., that is not detectable in the presence of toluene; - metabolic variations consisting in: a decrease in the phenol urinary rate versus time with benzene alone; a sharp decrease of this rate from the third month of exposure on, in presence of toluene.
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Polycyclic aromatic hydrocarbons (PAHs) typically contaminate the environment as complex assemblages of different chemical compounds. Modeling approaches provide a means of estimating the toxicity of these PAH mixtures. In the present study, we tested the hypothesis that the joint effects of four PAHs: pyrene, phenanthrene, fluoranthene and naphthalene, on the growth rate of the crustacean Daphnia magna during sub-chronic exposure could be accurately predicted using a mathematical algorithm for concentration addition based upon the assumption that these PAHs impact growth by a common mode of action. Assessment of the individual toxicity of the four PAHs confirmed that these compounds elicited the common effect of retarding growth of daphnids at concentrations below those that were lethal to the organisms. Using the experimentally derived toxicity parameters for the individual chemicals, the toxicity of multiple mixtures of these four PAHs was modeled. These mixtures were based on concentrations reported in the environment and on equi-toxic concentrations. The effects of over 140 combinations of four mixture formulations on the growth rate of daphnids were experimentally determined and compared to model predictions. The concentration addition models tended to over predict the joint toxicity of these PAH mixtures and experimental data was better represented by an alternative model based upon the concept of independent joint action. Mixtures at environmentally relevant concentrations were predicted and experimentally demonstrated to have no effect on daphnid growth rates. Results indicate that PAHs elicit toxicity to daphnids by multiple mechanisms and demonstrate an appropriate modeling approach to assess the toxicity of these mixtures.
OBJECTIVES: Potentiation, inhibition, antagonism, synergism or other interactions of chemicals in an organism may significantly affect the toxicity of chemical mixtures. Therefore, a suitable physicochemical parameter is sought as a predictor of these effects. METHODS: Acute toxicity EC50 (mol/l) was used as an index of toxic hazard. The EC50 was defined here as the concentration inhibiting movement of 50% of Tubifex tubifex worms in a standardised short-term test. The EC50 for the mixture benzene/ethanol was measured over the whole range of molar fractions between 0 and 1. The determined EC50 values were compared with those calculated by the effect-addition and concentration-addition models. The distribution of benzene and ethanol between the aqueous and gaseous phases was determined by gas chromatography. RESULTS: The determined EC50 of the benzene/ethanol mixtures exhibited deviations from the values predicted using the EC50 of the single compounds. The magnitude of this deviation depended on the composition of the mixture, and could be as high as 80% if the effect-addition model is used or 20% if the concentration-addition model is applied. The air/water distribution coefficients of benzene and ethanol measured in aqueous solutions of their mixtures exhibit unobservable to slight deviations from those obtained by simple summation. CONCLUSION: The determined values of the EC50 of benzene/ethanol mixtures calculated by either the concentration-addition or effect-addition model differ from the true values due to interactions among chemicals. The deviations depend on a quantitative composition of a mixture. The air/water distribution coefficient of chemicals in a mixture is not the most suitable predictor of the interactions.