Nonpolar Narcotics Research Articles

Quantitative aquatic toxicity prediction: using group contribution and classification methods on polar and non-polar narcotics

A model based on a Group Contribution Method (GCM) approach developed to correlate aquatic toxicity to fathead minnow ( Pimephales promelas) has been applied to an external set containing 190 organic chemicals. This set was also previously partitioned into polar and non-polar toxicants using a different classification model. The application of the GCM approach to develop specific models both of the entire set and of its partitions permits to discuss the importance of the subclassification in order to improve the result.

Assessment of baseline toxicity of mono-cyclic aromatic compounds by pseudomonas initial oxygen uptake assay

The objective of this study was to develop quantitative structure-activity relationships (QSARs) for the toxicity of mono-cyclic aromatic compounds in the Pseudomonas putida initial oxygen uptake assay. The QSARs were developed using response-surface based on descriptors for chemical hydrophobicity and electrophilicity (LUMO). The model ; led us to conclude that the polar and non-polar narcotics were statistically indistinguishable. Pentafluorophenol, pentachlorophenol and most dinitrophenols classified as weak acid respiratory uncouplers in literature fit well into this model when they were treated as their corresponding phenoxides. This latter result suggests that the action mechanism of these phenols should be reevaluated.

Artificial Neural Network for Predicting the Toxicity of Organic Molecules

Abstract Structure–activity relationships for aquatic toxicity were studied using neural networks and linear regression analysis. The structural features contributing to toxicity were identified in molecules exhibiting a level of toxicity greater than that of non-reactive organic molecules. A neural network was trained for the toxicity of non-polar narcotics, polar narcotics, or reactive toxicants. Quantitative structure–activity relationships (QSARs) were developed, relating a molecular aquatic toxicity to its log P and to a set of 16 structural descriptors based upon the presence of selected structural features. The inclusion of these structural descriptors into a QSAR was found to enhance the correlation of the equation, and thus to improve its ability for predicting aquatic toxicity.

Reproductive Impairment in the Zebrafish, Danio rerio, upon Chronic Exposure to 1,2,3-Trichlorobenzene

Most organic pollutants are supposed to act via the mechanism of nonpolar narcosis upon acute exposure. Because the chronic effects of these compounds are still relatively unknown, in this study a chronic toxicity experiment was performed with zebrafish, Danio rerio, exposed to 1,2,3-trichlorobenzene (123TCB), a nonpolar narcotic. Fish were exposed in a flow-through system for 68 and 147 days. Parameters measured are survival, growth, reproduction, and glycogen and protein content. The only parameter which was influenced was the number of eggs produced per female, resulting in an EC50 of 40 μg/L. Using this value and acute toxicity data for 123TCB, an acute to chronic ratio (ACR) of 80 was calculated, which is larger than ACRs for other species exposed to nonpolar narcotics. This finding might indicate that compounds acting by nonpolar narcosis in acute tests can have completely different effects upon chronic exposure.

Dimyristoyl Phosphatidylcholine/water Partitioning-dependent Modeling of Narcotic Toxicity toTetrahymena pyriformis

Regression-type structure-toxicity relationships have been developed between Tetrahymena pyriformis population growth impairment toxicity data (log 1/IGC50) and the dimyristoyl phosphatidylcholine/water partition coefficient (log KDMPC) or the 1-octanol/water partition coefficient (log Kow). A statistically robust model [log(1/ IGC50)= 0.73 log (KDMPC)−1.62; n=23, r2=0.926, s=0.24, F=263, Pr/gt F=0.0001] was found for non-polar narcotics, polar narcotics, as well as esters with the DMPC partition coefficient. The above model was statistically better than the model [log(1/IGC50) = 0.71 (log Kow) − 1.60; n = 23, r2 = 0.828, s = 0.39, F = 101, Pr> F = 0.0001] developed for the same compounds with 1-octanol/water partitioning as the independent variable. The former equation does not explain the difference in the acute mechanisms of toxic action known to exist in fish for non-polar and polar narcotics. However, log KDMPC appears to correct for differences in the concentration of toxicant reaching the site of toxic action between narcotic mechanisms. Outliers to the log KDMPC model were primary aliphatic amines.

Variation in Sensitivity of Aquatic Species to Toxicants: Practical Consequences for Effect Assessment of Chemical Substances.

/ This study addresses the relation between the sensitivity of aquatic species and mode of action of different classes of organic chemicals. We analyzed large data sets of ecotoxicological information to reveal the interspecies variation in sensitivity, to relate this variation to the compounds' mode of action, and to explain the observed patterns using general biological information. Here we present a general framework and recommendations for risk assessment procedures. We recommend the use of toxicologically based classification schemes at an early stage of the risk assessment procedure. Screening programs are most efficiently run when only one species per compound is tested to prioritize substances. The toxicity of compounds belonging to the class of nonpolar narcotics is highly predictable and shows little interspecies variation. For these compounds quantitative structure-activity relationships (QSARs) can be used to estimate effect levels. Most effort should be put into testing reactive compounds and compounds with a specific mode of action as toxicity to some species can be 10(5)-10(6) times higher compared with less sensitive species. The use of assessment factors in effect assessment procedures may lead to an underestimation of effects on the more sensitive species.For many priority pollutants there is little information on their ecotoxicity. Predictive techniques are needed to compensate for this lack of data. Knowledge of the relation between modes of action of compounds and interspecies variation in sensitivity should be integrated in risk assessment procedures in order to make more efficient use of the limited financial resources available.

Ratios between acute aquatic toxicity and effects on population growth rates in relation to toxicant mode of action

AbstractEnvironmental risk assessment of chemicals is mostly based on the results of standardized toxicity tests. To obtain environmental quality criteria, extrapolation factors are used that depend on the amount and quality of available data. These extrapolation factors do not, however, take into account the mode of action of the compound tested or the life history of the test organism. In this study, we analyzed the variability in acute‐to‐chronic ratios (ACRs) for various chemicals in relation to their mode of action. Chemicals were classified as nonpolar narcotics, polar narcotics, specifically acting compounds, and heavy metals. As an acute endpoint, the LC50 was used; as a chronic endpoint, the lowest test concentration at which the natural rate of population increase (r) is affected, or LOEC(r), was used. Data were derived from the on‐line literature. Nonpolar narcotic chemicals demonstrate the smallest variation in ACRs, and acute tests can be used to derive chronic endpoints for this class. For the other classes, the variation in ACRs is larger. Fish species especially show a relatively large ACR. For heavy metals, differences in the mode of action may play an important role in explaining differences in ACRs. For the other three classes, however, it is less reliable to predict chronic toxicity using the results of acute tests. In general, differences in species sensitivity rather than in mode of action for the chemical seem to determine differences in ACRs.

QSAR Studies of Compounds Acting by Polar and Non-polar Narcosis: an Examination of the Role of Polarisability and Hydrogen Bonding

The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.

QSAR Studies of Compounds Acting by Polar and Non-polar Narcosis: an Examination of the Role of Polarisability and Hydrogen Bonding

The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.

RATIOS BETWEEN ACUTE AQUATIC TOXICITY AND EFFECTS ON POPULATION GROWTH RATES IN RELATION TO TOXICANT MODE OF ACTION

Environmental risk assessment of chemicals is mostly based on the results of standardized toxicity tests. To obtain environmental quality criteria, extrapolation factors are used that depend on the amount and quality of available data. These extrapolation factors do not, however, take into account the mode of action of the compound tested or the life history of the test organism. In this study, we analyzed the variability in acute-to-chronic ratios (ACRs) for various chemicals in relation to their mode of action. Chemicals were classified as nonpolar narcotics, polar narcotics, specifically acting compounds, and heavy metals. As an acute endpoint, the LC50 was used; as a chronic endpoint, the lowest test concentration at which the natural rate of population increase (r) is affected, or LOEC(r), was used. Data were derived from the on-line literature. Nonpolar narcotic chemicals demonstrate the smallest variation in ACRs, and acute tests can be used to derive chronic endpoints for this class. For the other classes, the variation in ACRs is larger. Fish species especially show a relatively large ACR. For heavy metals, differences in the mode of action may play an important role in explaining differences in ACRs. For the other three classes, however, it is less reliable to predict chronic toxicity using the results of acute tests. In general, differences in species sensitivity rather than in mode of action for the chemical seem to determine differences in ACRs.

Application of Quantitative Structure–Activity Relationships for Assessing the Aquatic Toxicity of Phthalate Esters

Phthalate esters (PEs) are an important class of industrial chemicals for which an extensive aquatic toxicity database is available. The objectives of this study were to use these data to develop quantitative structure–activity relationships (QSARs) that describe aquatic toxicity for different freshwater and marine species, gain insights into toxicity mechanisms, and calculate PE water quality criteria using statistical extrapolation procedures. Results for low-molecular-weight PEs with log Kow<6 indicate that toxicity data conform to a simple log Kow-dependent QSAR. Fish were found to be more sensitive than algae while invertebrates spanned a wide range in toxicological response. Freshwater and marine species demonstrated a similar distribution of sensitivities. Comparison of species-dependent QSARs supports the hypothesis that biotransformation plays an important role in explaining toxicity differences observed between species. Estimated critical body residues (CBRs) for parent PE in fish were in the range reported for other polar organic chemicals while CBRs for parent PE plus associated metabolites were in the range reported for nonpolar narcotics (i.e., baseline toxicity) suggesting a possible putative role of PE metabolites. Depending on extrapolation procedure and assumptions, predicted no-effect concentrations (PNECs) for dimethyl, diethyl, dibutyl, and butybenzyl phthalate ranged from 3109 to 4780, 865 to 1173, 43 to 62, and 38 to 60 μg l−1, respectively. PNECs derived using this approach provide a transparent technical basis to support aquatic risk assessment for low-molecular-weight PEs. Results for high-molecular-weight PEs (log Kow>6) indicate that these chemicals are not acutely or chronically toxic to freshwater or marine organisms due to the combined role of low water solubility and limited bioconcentration potential which precludes attainment of internal concentrations that are required to elicit adverse effects. It is concluded that attempts to establish aquatic PNECs for high-molecular-weight PEs are not scientifically defensible.

An LC50 vs Time Model for the Aquatic Toxicity of Reactive and Receptor-Mediated Compounds. Consequences for Bioconcentration Kinetics and Risk Assessment

For aquatic toxicants that act by so-called nonpolar narcosis, it is generally acknowledged that the Critical Body Residue (CBR) at death, as a surrogate dose metric for the amount of target that has interacted with the toxicant, is constant. This constancy is not only maintained across exposure times but also across different (narcosis) compounds as well as species. We present here an alternative model, applicable to reactive and receptor-mediated toxicants, that implies that for these compounds there is no constant CBR. The model also shows that for each single species-compound combination, the Critical Area Under the Curve (CAUC) is constant and independent of exposure time. These findings can have profound consequences for the interpretation of experimental toxicity data (such as 96 h LC50 values) in risk assessment. Among other things, it shows us that for compounds other than nonpolar narcotics, LC50 vs time values may decrease significantly even after bioconcentration steady state has been achieved...

Quantitative structure-activity relationships and volume fraction analysis for nonpolar narcotic chemicals to the australian cladoceran ceriodaphnia cf. dubia

The toxicity of eleven nonpolar narcotic chemicals to the cladoceran Ceriodaphnia cf. dubia was determined. C. cf. dubia was found to be approximately four times more sensitive to these narcotic chemicals than Daphnia magna tested under virtually identical conditions. The toxicity data were also used to develop and validate quantitative structure-activity relationships (QSARs) using a range of physicochemical properties of the chemicals. The three best QSARs, based on octanol-water partition coefficients and two lipid-water partition coefficients, were able to explain 98% of the variation in toxicity. The mean absolute percentage errors between the predicted and experimental EC50 values for these three QSARs were 17.3%, 20.6%, 24.6%. Neither the critical concentration (CC) nor the critical volume (CV) hypotheses validly modeled the toxicity data when octanol-water and triolein-water partition coefficients were used although the CV hypothesis was the better of the two. When a phospholipid-water partition coefficient was used the CV hypothesis was valid. The mean toxic membrane volume fraction of 0.48 x 10(-2) m3/m3 derived in this study agreed with published values for nonpolar narcotics and supports the use of this property to determine the mode of action of chemicals.

Toxicokinetics of fluoranthene to the amphipod, Leptocheirus plumulosus, in water-only and sediment exposures

The ability of the equilibrium partitioning (EqP) and critical body residue (CBR) approaches to predict the toxicity of the polycyclic aromatic hydrocarbon, fluoranthene, to a standard sediment toxicity test organism, the amphipod Leptocheirus plumulosus was examined in a series of water-only and sediment exposures. Concentrations of fluoranthene in water that resulted in 50% mortality (10-d LC 50) were 39.2 (35.1–43.8, 95% C.I.) and 39.2 (34.1-– 45.1, 95% C.I.) μg / liter in replicate tests. CBR or tissue concentrations that produced 50% mortality after replicate 8-d water-only exposures (LD 50) were 0.694 (0.596–0.876, 95% C.I.) and 2.44 (1.83–3.68, 95% C.I.) mmol total fluoranthene-equivalents/kg wet wt tissue, values somewhat lower than the range of CBR established for nonpolar narcotics in other organisms ( 2–8 mmol kg ). No significant mortality of L. plumulosus was observed over 26-d sediment toxicity tests, even though estimated interstitial water concentrations (up to 212 μg/liter) exceeded the average water-only LC 50 (39.2 μg/liter) by more than a factor of five, suggesting that the EqP approach over-estimated toxicity to this species. Average tissue concentrations attained in sediment tests ( 0.30 mmol kg ) were substantially lower than the CBR for nonpolar narcotics in other organisms, and in the water-only tests. Thus, lack of mortality in sediment exposures agrees with CBR predictions. The CBR approach appears to be a useful complement to the EqP approach for predicting the toxicity of sediment-associated contaminants.

Population growth kinetics of Tetrahymena pyriformis exposed to selected nonpolar narcotics.

This study describes effects of selected nonpolar narcotics of varying hydrophobicity (quantified by the 1-octanol-water partition coefficient, log Kow) and molecular structure on the population growth kinetics of the freshwater ciliate Tetrahymena pyriformis. The response of Tetrahymena exposed to different nonpolar narcotics varied from a change in generation time to a change in lag phase with similar generation time compared to control. Two narcotics with high (>3.00), intermediate (>0.00 and <3.00), and low log Kow (<0. 00) values were tested. Growth of Tetrahymena inhibited up to 85% by the high log Kow toxicants (2-decanone and butylbenzene) grew with similar rates as the control, but exhibited increased lag time, suggesting that the protozoan became acclimated to toxicant stress. Results from growth of Tetrahymena in the low log Kow toxicants (ethanol and acetone) indicate an increased generation time with increasing concentration. Cells inhibited by the intermediate log Kow chemicals, 1-pentanol and anisole, exhibited a response that was a combination of the previously mentioned two contrary responses. Cells inhibited <35% with 1-pentanol and <50% with anisole grew with similar generation times as control flasks, whereas in cells inhibited >35% or >50%, respectively, the doubling times were longer than control growth.

Variation in the sensitivity of aquatic species in relation to the classification of environmental pollutants

Differences in species sensitivity to toxicants can be substantial. In this study this among-species variation in sensitivity was analyzed in relation to chemical's mode of action. Chemicals were classified as: non-polar narcotics, polar narcotics, reactive compounds and specifically acting compounds. Acute toxicity data of aquatic species were derived from the literature. Levels of enhanced toxicity, averaged over all species, and interspecies variation in sensitivity were analyzed for 35 chemicals, with data ranging from 12 to 62 aquatic species per compound. Non-polar and polar narcotic chemicals demonstrate the smallest variation in sensitivity and have levels of toxicity, which are highly predictable on the basis of their hydrophobicity. Reactive and specifically acting compounds can be much more toxic than predicted and variation in species sensitivity can be as large as 105 to 10 6. In general, the larger this interspecies variation the more asymmetric is the toxicity distribution due to extremely sensitive species. Reactive and specifically acting compounds pose a potentially larger risk for species in ecosystems than polar and non-polar narcotic compounds. They will need more testing to derive precisely equal estimates of safe environmental concentrations.

Validation of Vibrio fisheri acute toxicity data: mechanism of action-based QSARs for non-polar narcotics and polar narcotic phenols

Quantitative structure-activity relationships (QSARs) have been utilized to validate toxicity data to Vibrio fisheri (the acute Microtox test) at each of the 5-, 15- and 30-min endpoints. Statistically robust QSARs were found for chemicals acting by a non-polar narcosis mechanism of action (MOA). The baseline, non-polar narcosis QSARs were similar to those found in other aquatic organisms, thus indicating that for this MOA, the acute V. fisheri assay makes a suitable surrogate for higher test species. For the toxicity of phenols, previously modeled in other species with parameters describing membrane transport (i.e. hydrophobicity) and soft electrophilicity or ionization, no significant relationships were obtained. The use of acute V. fisheri toxicity data is not recommended for extrapolation to higher species for these compounds. Despite this recommendatio, it was noted, however, that a ‘minimal’ phenolic toxicity was apparent that was analogous to polar narcosis in other species. This confirmed that a polar narcosis MOA does operate in the acute V. fisheri system analogous to other species. For all the compounds considered, there were highly significant correlations between the toxicities at each endpoint, indicating that data from different time endpoints were effectively interchangeable.

Pattern analysis of the variation in the sensitivity of aquatic species to toxicants

Our aim in this study was to identify groups of species showing a similar pattern in their sensitivity to toxicants and to relate the patterns to the mode of toxic action and biological species characteristics. A data matrix was composed of acute toxicity data for 26 aquatic species and 21 compounds. Most of the variation in the toxicological data was due to differences in toxicity of compounds and not intrinsic differences between species, so that practically every species can be used to order compounds with respect to average toxicity. Compounds with high overall toxicity also had large interspecies variation in sensitivity. The toxicity of non-polar narcotics correlated well with the log K OW. Compounds with a specific or reactive mode of action were more than a factor 10 toxic than predicted by their log K OW. Patterns in species sensitivity were more diffuse because only part of the variance in species sensitivity could be explained. Fishes and amphibians were more sensitive to dieldrin, lindane and pentachlorophenol than were invertebrates. Among the arthropods, the Phyllopoda (daphnids) were the most sensitive species. They were very sensitive to aniline, the heavy metals, malathion and parathion.

Growth Kinetics of Preexposed and Naive Populations of Tetrahymena pyriformisto 2-Decanone and Acetone

The growth kinetics of preexposed and naive Tetrahymena pyriformisgrown in the presence of one hydrophilic and one hydrophobic nonpolar narcotic (acetone and 2-decanone, respectively) have been evaluated. The response of naive Tetrahymenaexposed to nonpolar narcotics varied from a change in generation time upon exposure to hydrophilic chemical to a change in lag phase with similar generation time compared to control upon exposure to hydrophobic compounds. Tetrahymenagrown in the presence of low concentrations of 2-decanone and then transferred to higher concentrations acclimated to the presence of the toxicant. Acclimation was demonstrated by reduced lag phases compared to naive cells. Results of population growth studies of Tetrahymenagrown in the presence of low concentrations of acetone and then transferred to higher concentrations of acetone exhibit the same pattern, an increased generation time with increasing concentration with no lag time, as naive populations. Additionally, the observed generation times in acetone were cumulative relative to the transfer concentration as well as the acclimation concentration. The most feasible explanation for this phenomenon is the interaction of the toxicants with the plasma membrane.

Structure‐activity relationships for Pimephales and Tetrahymena: A mechanism of action approach

AbstractThe toxicity data of 74 chemicals tested in both the 96‐h fathead minnow (Pimephales promelas) mortality assay and the 2‐d Tetrahymena pyriformis (a protozoan) growth inhibition assay were evaluated using quantitative structure‐activity relationships (QSARs). Each chemical was a priori assigned a mechanism of acute toxic action from either nonpolar narcosis, polar narcosis, weak acid respiratory uncoupling, soft electrophilicity, or proelectrophilicity. The polar narcotics were further split into a phenol group and an aniline group. The relationship between bioreactivity and the importance of penetration to the site of action in both systems was studied. Bioreactivity showed a trend to be inversely proportional to the value of the hydrophobicity term. The data were examined to investigate how different molecular descriptors modeled the mechanisms of action. Models were produced for nonpolar narcotics and anilines for both species with the 1‐octanol/water partition coefficient (log Kow) alone. Soft electrophiles were best predicted by the average acceptor superdelocalizability (Snav), whereas proelectrophiles were modeled by log Kow and Snav. The weak acid uncouplers modeled with either log Kow or log Kow plus the ionization constant (pKa) for Pimephales and Tetrahymena, respectively. Phenols yielded predictive models using a either a combination of log Kow with Snav or lowest unoccupied molecular orbital, for fathead minnow and protozoan, respectively.