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• W1560874561 abstract "A quantitative structure property relationship (QSPR) for a,b-unsaturated carboxylates(mainly acrylates and methacrylates) was established in chapter 2. Chemical reaction rateconstants were measured for 12 different chemicals with three different nucleophiles, namelyH 2 O, OH - and glutathione (GSH). Relatively small differences were found in hydrolysisrates (reaction with H 2 O and OH - ). At an elevated pH (8.8) the hydrolysis half-life of thecompound ranged between 7 and 40 days, with exception of diethyl fumarate (0.4 day). Aseparation in two groups was observed for the reaction with GSH (Michael addition), whereacrylates reacted approximately 100 times as fast as methacrylates. This difference was con-sistent with differences found in electronic structure, which was determined by quantum-chemical calculations. Because no single parameter could describe the electrophilic charac-ter of the unsaturated carboxylates satisfactory, four descriptors were pooled, using amultivariate correlation (partial least squares regression, PLS). The resulting QSPR forMichael addition was able to predict the reactivity of structurally related, unsaturatedcarboxylates.Acute fish toxicity of a set of acrylates and methacrylates was evaluated in chapter 3.Published four-day LC 50 data for fathead minnow were compared to the chemical reactivityof the compounds towards GSH, because Michael addition was expected to be the mecha-nism that causes harmful binding to essential biological thiol-sites in the fish (e. g. proteinsand enzymes). A simple equation was used to model the interaction of electrophilic chemi-cals with GSH. The degree of GSH depletion, which was used to estimate the toxic effect,was found to be related to the product of aqueous exposure concentration and chemicalreaction rate of the reactive compound. Although, all acrylates and methacrylates poten-tially could react with GSH, narcosis was judged to be an alternative mode of toxic actionresponsible for the observed acute toxicity. Potencies for GSH depletion and narcosis werecompared on the bases of critical body residues and critical depletion rates. Five out of 12compounds were thereby identified as narcosis chemicals on the bases of their high calcu-lated lethal body burden. It was concluded that, although the tested chemicals all containeda similar functional group, their mode of action regarding acute fish toxicity was not thesame. Therefore, a correlation between chemical reaction rate and LC 50 for the whole test setof chemicals would not be meaningful.The results from chapter 3 indicated, that narcosis was an interfering mode of action inQSAROs for fish toxicity of reactive chemicals. To evaluate this hypothesis, data of reactivechemicals from three different classes (unsaturated carboxylates, organophosphorus esters?126 Chapter 8 Summary and General Discussionand nitrobenzenes) were taken from the literature and subjected to an analysis for multiplemodes of action (chapter 4). The Toxic ratio, being the ratio between the observed LC 50 andthe LC 50 , predicted for the same compound by a narcosis QSAR was used to estimate theprobability of a compound to act by narcosis. In total, 40 % of the 61 compounds tested wereidentified as Oprobably acting by narcosisO. For these compounds, a narcosis QSAR usingthe octanol/water partitioning coefficient (K OW ) as sole descriptor was found to describethe toxicity. QSAROs using reactivity descriptors, which in earlier work had been foundinsufficient to describe the toxicity of these classes of compounds improved considerably, ifthe Onarcotic chemicalsO were excluded from the data sets. It was concluded, that narcosisshould always be considered as a possible alternative cause of death in acute fish toxicitytest, even if the chemicals seem to have a very specific mode of action. Additionally, it wasshown, that QSAROs should only be established for sets of chemicals with an identical modeof action. Modes of action clearly should not be confused with functional groups.The toxic effect of acrylates and methacrylates on a cellular level were investigated inchapter 5. Cellular glutathione (GSH) concentrations were recorded in isolated cells of ratlivers. These cells have a continuous high expression of GSH and a broad range of metabo-lism. Potentially toxic metabolites of the acrylates and methacrylates were therefore likelyto be produced in these cells. Furthermore, the additivity of the toxic effect of these chemi-cals was investigated in this in-vitro test. For each chemical, an EC 50 for GSH depletion wasdetermined and used as an effect equivalent to compare their potencies. By testing twomixtures, each containing six individual chemicals, it could be shown that the depletion ofGSH was dose-additive. This means that in a mixture of acrylates and methacrylates eachindividual chemical will contribute to the total toxic effect of the mixture. As expected, thecompounds were metabolized by the hepatocytes. For one of them, allyl methacrylate, thevery toxic metabolic product acrolein could be identified in the cell-culture medium. Theproduction of this metabolite is most probably responsible for the high toxicity of this spe-cific compound towards the liver cells as well as towards fish (chapter 3).A preliminary physiologically based pharmacokinetic and -dynamic model (PBPK-PD)for ethyl acrylate (EA) was presented in chapter 6. It was based on an existing PBPK modelfor inert compounds in fish, which had been established by the US-EPA in Duluth, MN ( 1,2). The model was adapted to be used with EA by adding elimination processes in severaltissue compartments. Elimination rates of EA, which had been measured in-vitro, wereextrapolated to whole organs. The turnover of GSH in the gills was modeled separately andwas used to describe the toxic effect of EA on biological targets. Once the model was estab-?lished, several aspects of an aqueous exposure scenario were investigated. The uptake ofEA in different organs of the fish was predicted to occur very rapidly (steady state concen-trations reached in minutes to a few hours) with exception of the fat tissue. The metabolicelimination of EA in the gills was not sufficient to cause a notable first pass effect. Conse-quently, the EA concentration in the gill tissue was predicted to be almost instantaneouslyat equilibrium with the aqueous exposure concentration. The EA concentration in the gillswas subsequently used in the biological effect sub-model to describe the depletion of GSH.For a simulated exposure scenario close to a lethal aqueous concentration, the GSH concen-tration in the gills decreased by 60 % during the first 6 hours. This forecast was in agree-ment with experimental observations. In contrast to an existing rat model for EA, the troutmodel did not predict a first pass elimination of EA and therefore a systemic distributioncan be expected in the fish. In both models, however, a local depletion of the GSH level atthe site of adsorption was evident.In chapter 7, several findings from the previous chapters were combined to postulate anelementary approach to model toxic effects of reactive chemicals in aquatic organisms. Themost important simplification of this approach was, to disregard the pharmacokinetics ofmoderately hydrophobic reactive chemical in aquatic organisms. This resulted in a elemen-tary pharmacodynamic model (EPD), which describes a target and the interaction of a reac-tive chemical with this target. This approach can be used to describe time and concentrationdependent toxicological effects. Models, based on this approach were found to give excel-lent description of experimental data on acetylcholine-esterase inhibition due to OP-estersin several aquatic animals. The approach was also able to predict time dependent effectconcentrations (e. g. LC 50 ). Under certain conditions, the EPD model can be reduced to anequivalent of HaberOs Law, which states that the product of concentration and exposuretime will be constant. In addition to this, the EPD model can give a rational interpretation ofthreshold concentration, which are often observed in toxicity experiments." @default.
• W1560874561 created "2016-06-24" @default.
• W1560874561 creator A5027338923 @default.
• W1560874561 date "2000-05-31" @default.
• W1560874561 modified "2023-09-23" @default.
• W1560874561 title "Models for risk assessment of reactive chemicals in aquatic toxicology" @default.
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