Narcotic Mode Of Action Research Articles

Accurate prediction of acute fish toxicity of fragrance chemicals with the RTgill-W1 cell assay.

Testing for acute fish toxicity is an integral part of the environmental safety assessment of chemicals. A true replacement of primary fish tissue was recently proposed using cell viability in a fish gill cell line (RTgill-W1) as a means of predicting acute toxicity, showing good predictivity on 35 chemicals. To promote regulatory acceptance, the predictivity and applicability domain of novel tests need to be carefully evaluated on chemicals with existing high-quality in vivo data. We applied the RTgill-W1 cell assay to 38 fragrance chemicals with a wide range of both physicochemical properties and median lethal concentration (LC50) values and representing a diverse range of chemistries. A strong correlation (R2 = 0.90-0.94) between the logarithmic in vivo LC50 values, based on fish mortality, and the logarithmic in vitro median effect concentration (EC50) values based on cell viability was observed. A leave-one-out analysis illustrates a median under-/overprediction from in vitro EC50 values to in vivo LC50 values by a factor of 1.5. This assay offers a simple, accurate, and reliable alternative to in vivo acute fish toxicity testing for chemicals, presumably acting mainly by a narcotic mode of action. Furthermore, the present study provides validation of the predictivity of the RTgill-W1 assay on a completely independent set of chemicals that had not been previously tested and indicates that fragrance chemicals are clearly within the applicability domain. Environ Toxicol Chem 2018;37:931-941. © 2017 SETAC.

Toxicity of oil sands acid-extractable organic fractions to freshwater fish: Pimephales promelas (fathead minnow) and Oryzias latipes (Japanese medaka)

The Alberta oil sands are one of the largest global petroleum deposits and, due to non-release practices for oil sands process-affected waters, produced tailings are stored in large ponds. The acid extractable organic (AEO) compounds in oil sands process-affected water are of greatest concern due to their persistence and toxicity to a variety of aquatic biota. The present study evaluated the toxicity of the five AEO fractions to two fish species: Oryzias latipes (Japanese medaka) and Pimephales promelas (fathead minnow). The fractions (F1-F5) were comprised of AEO with increasing mean molecular weight and subsequent increases in cyclicity, aromaticity, degree of oxygenation, and heteroatom content. The lowest molecular weight fraction, F1, displayed the lowest acute toxicity to both fish species. For fathead minnow, F5 displayed the greatest toxic potency, while F2 to F4 displayed intermediate toxicities. For Japanese medaka, F2 and F3 displayed the greatest acute toxicities and F1, F4 and F5 were significantly less potent. Overall, fathead minnow were more acutely sensitive to AEO than Japanese medaka. The present study indicates that AEO toxicity may not be solely driven by a narcotic mode of action, but chemical composition such as aromaticity and heteroatom content and their relation to toxicity suggest other drivers indicative of additional modes of toxic action.

ECOSM-a new joint project for assessing environmental risks of poorly soluble compounds used in cosmetics-project presentation

'Personal Care Products' contain a multitude of substances which introduce certain functions to the product and show a great variability in physicochemical properties. 'Poorly soluble substances', characterised by a low water solubility (< 1 mg/l), may constitute a substantial proportion of these products. Their production volume causes the need for aquatic risk assessment, as requested e.g. by the European Regulation on Registration, Evaluation, Authorisation and Restriction of Chemicals. As it is difficult to conduct toxicity tests at the threshold of the substance's water solubility a high lipophilicity complicates the performance of standardised ecotoxicological tests. For these substances, standard tests mostly provide insufficient results and are often not suitable to assess the risk appropriately. One promising approach to address this problem is the 'poorly solubles approach'. It assumes that highly lipophilic and poorly soluble substances have a low water concentration and consequently might cause low exposure to aquatic organisms. However, as these substances may bioaccumulate high internal exposure might be reached leading to long-term effects. The poorly solubles approach defines an 'ecotoxicological threshold of no concern'. According to the theory, below this concentration, neither acute nor long-term adverse effects on aquatic organisms are expected to occur. This threshold is derived from a comprehensive compilation of experimental data for inert substances with a narcotic mode of action and therefore currently restricted to such substances. Hence, considering this threshold concentration combined with the water solubility of a substance, derived by, e.g. quantitative structure-activity relationships methods, may allow a risk assessment without the need of further experiments. The 'poorly solubles approach' may also become relevant regarding the verification of potential persistent + bioaccumulative + toxic properties. The aim of the project ECOtoxicity investigations of COSMetic ingredients is to develop the 'poorly solubles approach' into a pragmatic tool for risk assessment of the important and environmentally relevant group of highly lipophilic substances with a narcotic mode of action. This project will adapt existing aquatic ecotoxicological test methods using lipophilic compounds to check whether the 'poorly solubles approach' may be useful for risk assessment of such substances.

A new concept for the environmental risk assessment of poorly water soluble compounds and its application to consumer products

Many consumer products contain lipophilic, poorly soluble ingredients representing large-volume substances whose aquatic toxicity cannot be adequately determined with standard methods for a number of reasons. In such cases, a recently developed approach can be used to define an aquatic exposure threshold of no concern (ETNCaq; i.e., a concentration below which no adverse affects on the environment are to be expected). A risk assessment can be performed by comparing the ETNCaq value with the aquatic exposure levels of poorly soluble substances. Accordingly, the aquatic exposure levels of substances with water solubility below the ETNCaq will not exceed the ecotoxicological no-effect concentration; therefore, their risk can be assessed as being negligible. The ETNCaq value relevant for substances with a narcotic mode of action is 1.9 microg/L. To apply the above risk assessment strategy, the solubility in water needs to be known. Most frequently, this parameter is estimated by means of quantitative structure/activity relationships based on the log octanol-water partition coefficient (log Kow). The predictive value of several calculation models for water solubility has been investigated by this method with the use of more recent experimental solubility data for lipophilic compounds. A linear regression model was shown to be the most suitable for providing correct predictions without underestimation of real water solubility. To define a log Kow threshold suitable for reliably predicting a water solubility of less than 1.9 microg/L, a confidence limit was established by statistical comparison of the experimental solubility data with their log Kow. It was found that a threshold of log Kow = 7 generally allows discrimination between substances with solubility greater than and less than 1.9 microg/L. Accordingly, organic substances with a baseline toxicity and log Kow > 7 do not require further testing to prove that they have low environmental risk. In applying this concept, the uncertainty of the prediction of water solubility can be accounted for. If the predicted solubility in water is to be below ETNCaq with a probability of 95%, the corresponding log Kow value is 8.

Chronic toxicity of unresolved complex mixtures (UCM) of hydrocarbons in marine sediments

Background, Aim and Scope Unresolved complex mixtures (UCM) of hydrocarbons, containing many thousands of compounds which cannot be resolved by conventional gas chromatography (GC), are common contaminants of sediments but little is known of their potential to affect sediment-dwelling organisms. Evidence exists for reduced health status in mussels, arising from aqueous exposure to aromatic UCM components acting through a narcotic mode of action. However, UCM contaminants in sediments may not be sufficiently bioavailable to elicit toxic effects. The aim of our study was therefore to measure the sublethal effects of chronic exposure to model UCM-dominated oils at environmentally realistic concentrations and compare this to effects produced by a UCM containing weathered crude oil. A further aim was to determine which, if any, fractions of the oils were responsible for any observed toxicity.

Baseline toxicity of a chlorobenzene mixture and total body residues measured and estimated with solid-phase microextraction.

Body residues of compounds with a narcotic mode of action that exceed critical levels result in baseline toxicity in organisms. Previous studies have shown that internal concentrations in organisms also can be estimated by way of passive sampling. In this experiment, solid-phase microextraction (SPME) fibers were used as a tool to estimate the body residues, which were then compared to measured levels. Past application of SPME fibers in the assessment of toxicity risk of samples has focused on separate exposure of fibers and organisms, often necessitated by the amount of agitation needed in order to achieve steady state in the fibers within a convenient time period. Uptake kinetic studies have shown that in SPME fibers with thin coatings, equilibrium concentrations can be reached without agitation within the time frame of a toxicity test. In contrast to toxicity experiments to date, the SPME fibers in the current study were exposed concomitantly to the test water with the organisms, ensuring an exposure under the exact same conditions. Fibers and two aquatic invertebrate species were exposed to a mixture of four chlorobenzenes with a narcotic mode of action. The total body residue of these compounds in the organisms was determined, as was the acute toxicity resulting from the accumulation. The total body residues of both species were correlated to the total concentrations in SPME fibers. It was concluded that toxicity could be predicted based on total body residue (TBR) estimates from fiber concentrations.

Biomimetic solid‐phase microextraction to predict body residues and toxicity of chemicals that act by narcosis

AbstractA biomimetic extraction technique using solid‐phase microextraction (SPME) fibers has been developed for the risk assessment of contaminants with a narcotic mode of action. Our goal is to apply this technique in the future for the prediction of total baseline toxicity of environmental water and effluent samples. Validation of this method requires establishing the relationship between contaminant accumulation and toxicity in biota and accumulation in the surrogate solid phase (the SPME fiber coating). For this purpose, we determined the median lethal concentration (LC50) values for Chironomus riparius midge larvae exposed to two halogenated aromatic compounds separately and measured body residues in the exposed larvae. Solid‐phase microextraction fibers with an 85‐μm polyacrylate (PA) coating served as the surrogate hydrophobic phase, mimicking the uptake of the compounds by midge larvae. The toxicant concentrations in SPME fibers measured directly by gas chromatography/mass spectrometry (GCMS) or calculated from the SPME fiber—water partition coefficient, KSPME, were related to the toxicant concentrations found in midge larvae. Our results demonstrated that the biomimetic SPME method enables the estimation of body residues in biota and prediction of the degree of baseline toxicity of a water medium.

Biomimetic solid-phase microextraction to predict body residues and toxicity of chemicals that act by narcosis.

A biomimetic extraction technique using solid-phase microextraction (SPME) fibers has been developed for the risk assessment of contaminants with a narcotic mode of action. Our goal is to apply this technique in the future for the prediction of total baseline toxicity of environmental water and effluent samples. Validation of this method requires establishing the relationship between contaminant accumulation and toxicity in biota and accumulation in the surrogate solid phase (the SPME fiber coating). For this purpose, we determined the median lethal concentration (LC50) values for Chironomus riparius midge larvae exposed to two halogenated aromatic compounds separately and measured body residues in the exposed larvae. Solid-phase microextraction fibers with an 85-microm polyacrylate (PA) coating served as the surrogate hydrophobic phase, mimicking the uptake of the compounds by midge larvae. The toxicant concentrations in SPME fibers measured directly by gas chromatography/mass spectrometry (GC-MS) or calculated from the SPME fiber-water partition coefficient, K(SPME) were related to the toxicant concentrations found in midge larvae. Our results demonstrated that the biomimetic SPME method enables the estimation of body residues in biota and prediction of the degree of baseline toxicity of a water medium.

Phototoxicity of azaarene isomers to the marine flagellate Dunaliella tertiolecta

Many studies have shown that narcosis or baseline toxicity of polycyclic aromatic hydrocarbons (PAHs) is strongly related to their lipophilicity. For azaarenes, such relationships have also been demonstrated, but for some compounds, deviations from these relationships have been observed, even for closely related compounds such as isomers. In the present study, the toxicity of four azaarene isomer pairs to the marine flagellate Dunaliella tertiolecta was determined. For quinoline, isoquinoline, acridine, phenanthridine, benz[a]acridine, and benz[c]acridine, the 72-h median effective concentrations for growth were 571, 464, 2.10, 14.7, 0.50, and 0.11 microM, respectively. For the five-ringed isomers dibenz[a,i]acridine and dibenz[c,h]acridine, no effects were observed at the highest concentration tested (0.1 and 0.005 microM, respectively). Growth inhibition by the two-, three-, and four-ringed isomer pairs to D. tertiolecta was well described by molecular volume and log Kow, indicating a narcotic mode of action. However, the toxicity of acridine and benz[c]acridine was much higher than that of their respective isomers, phenanthridine and benz[a]acridine, suggesting an additional specific mode of action. Based on the differences in energies between the highest occupied molecular orbital and the lowest unoccupied molecular orbital, acridine and benz[c]acridine are susceptible to ultraviolet (UV) radiation, in contrast to the other tested compounds. Because UV was present, it is therefore argued that the toxicity of both compounds was photoenhanced. Photoenhanced toxicity may increase the environmental hazard of azaarenes, indicating the importance of enlarging the present monitoring of PAHs with phototoxic N-heterocyclic PAHs and incorporating this mode of action in water-quality criteria.

Distribution of a novel serine protease (motopsin) mRNA in the mouse brain

The Alberta oil sands are one of the largest global petroleum deposits and, due to non-release practices for oil sands process-affected waters, produced tailings are stored in large ponds. The acid extractable organic (AEO) compounds in oil sands process-affected water are of greatest concern due to their persistence and toxicity to a variety of aquatic biota. The present study evaluated the toxicity of the five AEO fractions to two fish species: Oryzias latipes (Japanese medaka) and Pimephales promelas (fathead minnow). The fractions (F1-F5) were comprised of AEO with increasing mean molecular weight and subsequent increases in cyclicity, aromaticity, degree of oxygenation, and heteroatom content. The lowest molecular weight fraction, F1, displayed the lowest acute toxicity to both fish species. For fathead minnow, F5 displayed the greatest toxic potency, while F2 to F4 displayed intermediate toxicities. For Japanese medaka, F2 and F3 displayed the greatest acute toxicities and F1, F4 and F5 were significantly less potent. Overall, fathead minnow were more acutely sensitive to AEO than Japanese medaka. The present study indicates that AEO toxicity may not be solely driven by a narcotic mode of action, but chemical composition such as aromaticity and heteroatom content and their relation to toxicity suggest other drivers indicative of additional modes of toxic action.

Effects of narcotic industrial pollutants on behaviour of midge larvae ( Chironomus riparius (Meigen), Diptera): a quantitative structure-activity relationship

Fourth-instar larvae of the midge Chironomus riparius were exposed for 96–98 h in a semistatic substrate-water system to nine industrial pollutants with a narcotic mode of action. Effects on the behaviour of the larvae were registered by means of the impedance conversion technique. Despite the common mode of action of the tested chemicals, different behavioural responses were observed. No-observed-effect concentrations (NOECs), based on aqueous concentrations, were derived. Correlation of these NOECs with octanol-water partition coefficients ( K ow), ranging from −0.77 to 4.64, demonstrated a very accurate quantitative structure-activity relationship (QSAR). The results indicate that behaviour of chironomids is one of the most sensitive parameters in aquatic toxicity tests with narcotic chemicals.