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Nonpolar narcosis, also known as baseline toxicity, has been described as the minimal toxicity that an organic chemical may elicit based on its lipophilicity. Although lethal effects of narcosis‐inducing chemicals (NICs) have been thoroughly investigated, knowledge of sublethal effects is still very limited. We investigated the effects of 3 well‐known NICs (phenanthrene, 1,3,5‐trichlorobenzene, and pentachlorobenzene) on a variety of organismal endpoints (malformations, swim bladder inflation, respiration, heart rate, swimming activity, and turning angles), which can be plausibly linked to narcosis in zebrafish embryos. Baseline toxicity recorded as mortality is typically observed in similar exposure ranges in a wide variety of species including fish, corresponding to a chemical activity range between 0.01 and 0.1. In the present study, we found that sublethal effects occurred at concentrations approximately 5 times below lethal concentrations. Altered swimming activity and impaired swim bladder inflation were the most sensitive endpoints occurring at exposure levels below the generally accepted threshold for baseline toxicity for 2 out of 3 compounds. Overall, most effective exposure levels across the sublethal endpoints and compounds did fall within the range typically associated with baseline toxicity, and deviations were generally limited to a factor 10. Although there could be benefit in adding sublethal endpoints to toxicity tests, such as the fish embryo acute toxicity (FET) test, based on the present sublethal endpoints and available evidence from our and other studies, the underestimation of toxicity as a result of the sole assessment of mortality as an endpoint in an FET test may be limited for narcosis. Environ Toxicol Chem 2021;40:2802–2812. © 2021 SETAC [ABSTRACT FROM AUTHOR]

Ionizable organic chemicals (IOCs) such as organic acids and bases are an important substance class requiring aquatic hazard evaluation. Although the aquatic toxicity of IOCs is highly dependent on the water pH, many toxicity studies in the literature cannot be interpreted because pH was not reported or not kept constant during the experiment, calling for an adaptation and improvement of testing guidelines. The modulating influence of pH on toxicity is mainly caused by pH‐dependent uptake and bioaccumulation of IOCs, which can be described by ion‐trapping and toxicokinetic models. The internal effect concentrations of IOCs were found to be independent of the external pH because of organisms' and cells' ability to maintain a stable internal pH milieu. If the external pH is close to the internal pH, existing quantitative structure–activity relationships (QSARs) for neutral organics can be adapted by substituting the octanol–water partition coefficient by the ionization‐corrected liposome–water distribution ratio as the hydrophobicity descriptor, demonstrated by modification of the target lipid model. Charged, zwitterionic and neutral species of an IOC can all contribute to observed toxicity, either through concentration‐additive mixture effects or by interaction of different species, as is the case for uncoupling of mitochondrial respiration. For specifically acting IOCs, we recommend a 2‐step screening procedure with ion‐trapping/QSAR models used to predict the baseline toxicity, followed by adjustment using the toxic ratio derived from in vitro systems. Receptor‐ or plasma‐binding models also show promise for elucidating IOC toxicity. The present review is intended to help demystify the ecotoxicity of IOCs and provide recommendations for their hazard and risk assessment. Environ Toxicol Chem 2020;39:269–286. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Abstract: Fish early life stage (ELS) tests (Organisation for Economic Co‐operation and Development test guideline 210) are widely conducted to estimate chronic fish toxicity. In these tests, fish are exposed from the embryonic to the juvenile life stages. To analyze whether certain modes of action are related to high toxic ratios (i.e., ratios between baseline toxicity and experimental effect) and/or acute‐to‐chronic ratios (ACRs) in the fish ELS test, effect concentrations (ECs) for 183 compounds were extracted from the US Environmental Protection Agency's ecotoxicity database. Analysis of ECs of narcotic compounds indicated that baseline toxicity could be observed in the fish ELS test at similar concentrations as in the acute fish toxicity test. All nonnarcotic modes of action were associated with higher toxic ratios, with median values ranging from 4 to 9.3 × 104 (uncoupling < reactivity < neuromuscular toxicity < methemoglobin formation < endocrine disruption < extracellular matrix formation inhibition). Four modes of action were also found to be associated with high ACRs: 1) lysyl oxidase inhibition leading to notochord distortion, 2) putative methemoglobin formation or hemolytic anemia, 3) endocrine disruption, and 4) compounds with neuromuscular toxicity. For the prediction of ECs in the fish ELS test with alternative test systems, endpoints targeted to the modes of action of compounds with enhanced toxic ratios or ACRs could be used to trigger fish ELS tests or even replace these tests. Environ Toxicol Chem 2018;37:955–969. © 2018 SETAC [ABSTRACT FROM AUTHOR]

A comparative hazard assessment of the antiparasitics ivermectin, albendazole, and morantel was performed, with a particular focus on bioavailability and uptake into biological membranes. The experimentally determined liposome-water distribution ratio at pH 7 (Dlipw (pH 7)) of the positively charged morantel was 100 L/kg lipid. The Dlipw (pH 7) of albendazole was 3,000 L/kg lipid. The membrane permeability determined with the parallel artificial membrane permeability assay was consistent with predictions from a quantitative structure-activity relationship (QSAR) for morantel but 14-fold lower than predicted for albendazole, which can be rationalized because neutral albendazole is, in fact, zwitterionic and the large dipole moment hinders permeation through hydrophobic membranes. An unusually large molecule, ivermectin was suspected to show decreased bioaccumulation because of its bulkiness, but experimental determination of solubility showed that it was 40-fold less soluble than expected from a QSAR between solubility and the octanol-water partition coefficient. In contrast, its membrane permeability appeared to be typical for a compound of the given hydrophobicity, but it was not possible to determine the membrane-water partition coefficient because of its low solubility and high affinity to the dialysis membrane of the experimental device. The Dlipw (pH 7) for ivermectin of 2,700 L/kg lipid was calculated with a QSAR model. Morantel and albendazole were baseline toxicants in the bioluminescence inhibition test with Vibrio fischeri and a test for inhibition of photosynthesis in green algae. Only ivermectin exhibited a specific effect toward algae, but the excess toxicity was not very pronounced and might be biased by the uncertainty of the estimated hydrophobicity descriptor. Overall, we did not find any unexpected effect on nontarget endpoints. [ABSTRACT FROM AUTHOR]

Effect concentrations for aquatic baseline toxicity generally decrease with increasing log octanol-water partition coefficient (Kow) values of up to 5 to 6, whereas less is known about the baseline toxicity of organic chemicals with log Kow values above 6. A physicochemical analysis of the dissolution process for organic chemicals was combined with reported baseline toxicity data, leading to the following conclusions. First, no absolute hydrophobicity cutoff exists for baseline toxicity at a log Kow value of 6, because aquatic baseline toxicity for fish and algae was observed for chemicals with log Kow values greater than 6.5 and with effect concentrations less than 10 μg/L. Second, the baseline toxicity of hydrophobic organic substances was exerted at a relatively constant chemical activity of 0.01 to 0.1. Finally, organic chemicals with high melting points cannot provide sufficient chemical activity to exert baseline toxicity when considered as individual, pure chemicals. However, such substances are still expected to contribute to baseline toxicity when part of a complex mixture. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-mm 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. [ABSTRACT FROM AUTHOR]

Algal growth inhibition tests were performed with the unicellular green alga Selenastrum capricornutum and three 14C labeled polychlorinated biphenyl (PCB) congeners. Toxicity was related to external aqueous concentrations and additionally to internal algal boundPCB concentrations. Estimates of the concentrations at 50% effectiveness (EC50s) for the three PCB congeners ranged within a factor of 17(14-241 nmol/L) when based on measured aqueous concentrations. When based on internal toxicant concentrations (toxic cell concentrations,TCC50) the corresponding range was 6.7 to 14.3 mmol/kg wet weight. Thus, changing the basis from external to internal concentrations reduced the range by almost one order of magnitude. Additional toxic cellconcentrations of five monoaromatic compounds and S. capricornutum were calculated from literature data to be in the same order of magnitude as the experimental toxic cell concentrations for the PCBs, whereas EC50 values for all substances ranged by more than four orders of magnitude. The experimental and calculated data indicate that observed differences in the estimated EC50 values were mainly due to differences in bioconcentration behavior rather than to different intrinsic toxicities. These findings are in agreement with the concept of baseline toxicity, meaning that a number of hydrophobic organics exerts their acute toxicity by one relatively nonspecific mode of action. [ABSTRACT FROM AUTHOR]