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Scott E Belanger - One of the best experts on this subject based on the ideXlab platform.
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on the impact of sample size on median lethal concentration estimation in acute Fish Toxicity testing is n 7 group enough
Environmental Toxicology and Chemistry, 2018Co-Authors: Gregory J Carr, Jane M Rawlings, John A Bailer, Scott E BelangerAbstract:The Fish acute Toxicity test method is foundational to aquatic Toxicity testing strategies, yet the literature lacks a concise sample size assessment. Although various sources address sample size, historical precedent seems to play a larger role than objective measures. We present a novel and comprehensive quantification of the effect of sample size on estimation of the median lethal concentration (LC50), covering a wide range of scenarios. The results put into perspective the practical differences across a range of sample sizes, from n = 5/concentration up to n = 23/concentration. We also provide a framework for setting sample size guidance illustrating ways to quantify the performance of LC50 estimation, which can be used to set sample size guidance given reasonably difficult (or worst-case) scenarios. There is a clear benefit to larger sample size studies: they reduce error in the determination of LC50s, and lead to more robust safe environmental concentration determinations, particularly in cases likely to be called worst-case (shallow slope and true LC50 near the edges of the concentration range). Given that the use of well-justified sample sizes is crucial to reducing uncertainty in Toxicity estimates, these results lead us to recommend a reconsideration of the current de minimis 7/concentration sample size for critical studies (e.g., studies needed for a chemical registration, which are being tested for the first time, or involving difficult test substances). Environ Toxicol Chem 2018;37:1565-1578. © 2018 SETAC.
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oecd validation study to assess intra and inter laboratory reproducibility of the zebraFish embryo Toxicity test for acute aquatic Toxicity testing
Regulatory Toxicology and Pharmacology, 2014Co-Authors: Francois Busquet, Gregory J Carr, Jane M Rawlings, Scott E Belanger, T Braunbeck, Ruben Strecker, P H Cenijn, Przemyslaw Fochtman, Anne Gourmelon, Nicole HublerAbstract:Abstract The OECD validation study of the zebraFish embryo acute Toxicity test (ZFET) for acute aquatic Toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebraFish eggs (20/concentration and control) were exposed for 96 h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96 h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV 30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute Fish Toxicity and Fish embryo acute Toxicity data, the ZFET is ready to be considered for acute Fish Toxicity for regulatory purposes.
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investigating alternatives to the Fish early life stage test a strategy for discovering and annotating adverse outcome pathways for early Fish development
Environmental Toxicology and Chemistry, 2014Co-Authors: Daniel L Villeneuve, Scott E Belanger, Kristin Schirmer, Marc Leonard, David C Volz, Michelle R Embry, Gerald T Ankley, Robert L Tanguay, Lisa Truong, Leah C WehmasAbstract:The Fish early-life stage (FELS) test (Organisation for Economic Co-operation and Development [OECD] test guideline 210) is the primary test used internationally to estimate chronic Fish Toxicity in support of ecological risk assessments and chemical management programs. As part of an ongoing effort to develop efficient and cost-effective alternatives to the FELS test, there is a need to identify and describe potential adverse outcome pathways (AOPs) relevant to FELS Toxicity. To support this endeavor, the authors outline and illustrate an overall strategy for the discovery and annotation of FELS AOPs. Key events represented by major developmental landmarks were organized into a preliminary conceptual model of Fish development. Using swim bladder inflation as an example, a weight-of-evidence–based approach was used to support linkage of key molecular initiating events to adverse phenotypic outcomes and reduced young-of-year survival. Based on an iterative approach, the feasibility of using key events as the foundation for expanding a network of plausible linkages and AOP knowledge was explored and, in the process, important knowledge gaps were identified. Given the scope and scale of the task, prioritization of AOP development was recommended and key research objectives were defined relative to factors such as current animal-use restrictions in the European Union and increased demands for Fish Toxicity data in chemical management programs globally. The example and strategy described are intended to guide collective efforts to define FELS-related AOPs and develop resource-efficient predictive assays that address the toxicological domain of the OECD 210 test. Environ Toxicol Chem 2014;33:158–169. © 2013 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited.
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use of Fish embryo Toxicity tests for the prediction of acute Fish Toxicity to chemicals
Environmental Toxicology and Chemistry, 2013Co-Authors: Scott E Belanger, Jane M Rawlings, Gregory J CarrAbstract:The Fish embryo test (FET) is a potential animal alternative for the acute Fish Toxicity (AFT) test. A comprehensive validation program assessed 20 different chemicals to understand intra- and interlaboratory variability for the FET. The FET had sufficient reproducibility across a range of potencies and modes of action. In the present study, the suitability of the FET as an alternative model is reviewed by relating FET and AFT. In total, 985 FET studies and 1531 AFT studies were summarized. The authors performed FET-AFT regressions to understand potential relationships based on physical-chemical properties, species choices, duration of exposure, chemical classes, chemical functional uses, and modes of action. The FET-AFT relationships are very robust (slopes near 1.0, intercepts near 0) across 9 orders of magnitude in potency. A recommendation for the predictive regression relationship is based on 96-h FET and AFT data: log FET median lethal concentration (LC50) = (0.989 × log Fish LC50) - 0.195; n = 72 chemicals, r = 0.95, p < 0.001, LC50 in mg/L. A similar, not statistically different regression was developed for the entire data set (n = 144 chemicals, unreliable studies deleted). The FET-AFT regressions were robust for major chemical classes with suitably large data sets. Furthermore, regressions were similar to those for large groups of functional chemical categories such as pesticides, surfactants, and industrial organics. Pharmaceutical regressions (n = 8 studies only) were directionally correct. The FET-AFT relationships were not quantitatively different from acute Fish-acute Fish Toxicity relationships with the following species: fathead minnow, rainbow trout, bluegill sunFish, Japanese medaka, and zebraFish. The FET is scientifically supportable as a rational animal alternative model for ecotoxicological testing of acute Toxicity of chemicals to Fish.
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baseline characteristics and statistical implications for the oecd 210 Fish early life stage chronic Toxicity test
Environmental Toxicology and Chemistry, 2012Co-Authors: James T Oris, Scott E Belanger, John A BailerAbstract:The Fish Toxicity assay most commonly used to establish chronic effects is the Organisation for Economic Co-operation and Development (OECD) 210, Fish early-life stage test. However, the authors are not aware of any systematic analysis of the experimental design or statistical characteristics of the test since the test guideline was adopted nearly 20 years ago. Here, the authors report the results of an analysis of data compiled from OECD 210 tests conducted by industry labs. The distribution of responses observed in control treatments was analyzed, with the goal of understanding the implication of this variability on the sensitivity of the OECD 210 test guideline and providing recommendations on revised experimental design requirements of the test. Studies were confined to fathead minnows, rainbow trout, and zebraFish. Dichotomous endpoints (hatching success and posthatch survival) were examined for indications of overdispersion to evaluate whether significant chamber-to-chamber variability was present. Dichotomous and continuous (length, wet wt, dry wt) measurement endpoints were analyzed to determine minimum sample size requirements to detect differences from control responses with specified power. Results of the analysis indicated that sensitivity of the test could be improved by maximizing the number of replicate chambers per treatment concentration, increasing the acceptable level of control hatching success and larval survival compared to current levels, using wet weight measurements rather than dry weight, and focusing test efforts on species that demonstrate less variability in outcome measures. From these analyses, the authors provide evidence of the impact of expected levels of variability on the sensitivity of traditional OECD 210 studies and the implications for defining a target for future animal alternative methods for chronic Toxicity testing in Fish.
Stefan Scholz - One of the best experts on this subject based on the ideXlab platform.
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meta analysis of Fish early life stage tests association of toxic ratios and acute to chronic ratios with modes of action
Environmental Toxicology and Chemistry, 2018Co-Authors: Stefan Scholz, Rene Schreiber, James M Armitage, Philipp Mayer, Beate I Escher, Annegret Lidzba, Marc Leonard, Rolf AltenburgerAbstract: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.
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applicability of the Fish embryo acute Toxicity fet test oecd 236 in the regulatory context of registration evaluation authorisation and restriction of chemicals reach
Environmental Toxicology and Chemistry, 2018Co-Authors: Marta A Sobanska, Stefan Scholz, Annamaija Nyman, Romanas Cesnaitis, Simon Gutierrez Alonso, Nils Kluver, Ralph Kuhne, Henrik Tyle, Joop De Knecht, Zhichao DangAbstract:In 2013 the Organisation for Economic Co-operation and Development (OECD) test guideline (236) for Fish embryo acute Toxicity (FET) was adopted. It determines the acute Toxicity of chemicals to embryonic Fish. Previous studies show a good correlation of FET with the standard acute Fish Toxicity (AFT) test; however, the potential of the FET test to predict AFT, which is required by the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) regulation (EC 1907/2006) and the Classification, Labelling and Packaging (CLP) Regulation (EC 1272/2008), has not yet been fully clarified. In 2015 the European Chemicals Agency (ECHA) requested that a consultant perform a scientific analysis of the applicability of FET to predict AFT. The purpose was to compare the Toxicity of substances to Fish embryos and to adult Fish, and to investigate whether certain factors (e.g., physicochemical properties, modes of action, or chemical structures) could be used to define the applicability boundaries of the FET test. Given the limited data availability, the analysis focused on organic substances. The present critical review summarizes the main findings and discusses regulatory application of the FET test under REACH. Given some limitations (e.g., neurotoxic mode of action) and/or remaining uncertainties (e.g., deviation of some narcotic substances), it has been found that the FET test alone is currently not sufficient to meet the essential information on AFT as required by the REACH regulation. However, the test may be used within weight-of-evidence approaches together with other independent, relevant, and reliable sources of information. The present review also discusses further research needs that may overcome the remaining uncertainties and help to increase acceptance of FET as a replacement for AFT in the future. For example, an increase in the availability of data generated according to OECD test guideline 236 may provide evidence of a higher predictive power of the test. Environ Toxicol Chem 2018;37:657-670. © 2017 SETAC.
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Fish embryo Toxicity test identification of compounds with weak Toxicity and analysis of behavioral effects to improve prediction of acute Toxicity for neurotoxic compounds
Environmental Science & Technology, 2015Co-Authors: Nils Kluver, Ralph Kuhne, Julia Ortmann, Riccardo Massei, Albrecht Paschke, Maria Konig, Stefan ScholzAbstract:The Fish embryo Toxicity test has been proposed as an alternative for the acute Fish Toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute Toxicity in the Fish embryo. In order to better define the applicability domain and improve the predictive capacity of the Fish embryo test, we performed a systematic analysis of existing Fish embryo and acute Fish Toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no Toxicity in the Fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo Toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating Fish embryo Toxicity. Published Fish embryo LC50 values were confirmed by experimental analysis of zebraFish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of Fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute Fish Toxicity LC50. Our data provided the first evidence that the applicability domain of the Fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute Fish Toxicity LC50 using behavioral assays in Fish embryos may not yet be possible, the identification of neuroToxicity could trigger the conduction of a conventional Fish acute Toxicity test or application of assessment factors while considering the very good Fish embryo-acute Fish Toxicity correlation for other compounds.
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Fish Embryo Toxicity Test: Identification of Compounds with Weak Toxicity and Analysis of Behavioral Effects To Improve Prediction of Acute Toxicity for Neurotoxic Compounds
2015Co-Authors: Nils Klüver, Maria König, Julia Ortmann, Riccardo Massei, Albrecht Paschke, Ralph Kühne, Stefan ScholzAbstract:The Fish embryo Toxicity test has been proposed as an alternative for the acute Fish Toxicity test, but concerns have been raised for its predictivity given that a few compounds have been shown to exhibit a weak acute Toxicity in the Fish embryo. In order to better define the applicability domain and improve the predictive capacity of the Fish embryo test, we performed a systematic analysis of existing Fish embryo and acute Fish Toxicity data. A correlation analysis of a total of 153 compounds identified 28 compounds with a weaker or no Toxicity in the Fish embryo test. Eleven of these compounds exhibited a neurotoxic mode of action. We selected a subset of eight compounds with weaker or no embryo Toxicity (cyanazine, picloram, aldicarb, azinphos-methyl, dieldrin, diquat dibromide, endosulfan, and esfenvalerate) to study toxicokinetics and a neurotoxic mode of action as potential reasons for the deviating Fish embryo Toxicity. Published Fish embryo LC50 values were confirmed by experimental analysis of zebraFish embryo LC50 according to OECD guideline 236. Except for diquat dibromide, internal concentration analysis did not indicate a potential relation of the low sensitivity of Fish embryos to a limited uptake of the compounds. Analysis of locomotor activity of diquat dibromide and the neurotoxic compounds in 98 hpf embryos (exposed for 96 h) indicated a specific effect on behavior (embryonic movement) for the neurotoxic compounds. The EC50s of behavior for neurotoxic compounds were close to the acute Fish Toxicity LC50. Our data provided the first evidence that the applicability domain of the Fish embryo test (LC50s determination) may exclude neurotoxic compounds. However, neurotoxic compounds could be identified by changes in embryonic locomotion. Although a quantitative prediction of acute Fish Toxicity LC50 using behavioral assays in Fish embryos may not yet be possible, the identification of neuroToxicity could trigger the conduction of a conventional Fish acute Toxicity test or application of assessment factors while considering the very good Fish embryo–acute Fish Toxicity correlation for other compounds
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predicting adult Fish acute lethality with the zebraFish embryo relevance of test duration endpoints compound properties and exposure concentration analysis
Environmental Science & Technology, 2012Co-Authors: Melanie Knobel, Kristin Schirmer, Katrin Tanneberger, Nynke I Kramer, Christoph Hafner, Joop L M Hermens, Frans J M Busser, Angeles Ricorico, Stefan ScholzAbstract:The zebraFish embryo Toxicity test has been proposed as an alternative for the acute Fish Toxicity test, which is required by various regulations for environmental risk assessment of chemicals. We investigated the reliability of the embryo test by probing organic industrial chemicals with a wide range of physicochemical properties, toxicities, and modes of toxic action. Moreover, the relevance of using measured versus nominal (intended) exposure concentrations, inclusion of sublethal endpoints, and different exposure durations for the comparability with reported Fish acute Toxicity was explored. Our results confirm a very strong correlation of zebraFish embryo to Fish acute Toxicity. When Toxicity values were calculated based on measured exposure concentrations, the slope of the type II regression line was 1 and nearly passed through the origin (1 to 1 correlation). Measured concentrations also explained several apparent outliers. Neither prolonged exposure (up to 120 h) nor consideration of sublethal eff...
Gregory J Carr - One of the best experts on this subject based on the ideXlab platform.
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on the impact of sample size on median lethal concentration estimation in acute Fish Toxicity testing is n 7 group enough
Environmental Toxicology and Chemistry, 2018Co-Authors: Gregory J Carr, Jane M Rawlings, John A Bailer, Scott E BelangerAbstract:The Fish acute Toxicity test method is foundational to aquatic Toxicity testing strategies, yet the literature lacks a concise sample size assessment. Although various sources address sample size, historical precedent seems to play a larger role than objective measures. We present a novel and comprehensive quantification of the effect of sample size on estimation of the median lethal concentration (LC50), covering a wide range of scenarios. The results put into perspective the practical differences across a range of sample sizes, from n = 5/concentration up to n = 23/concentration. We also provide a framework for setting sample size guidance illustrating ways to quantify the performance of LC50 estimation, which can be used to set sample size guidance given reasonably difficult (or worst-case) scenarios. There is a clear benefit to larger sample size studies: they reduce error in the determination of LC50s, and lead to more robust safe environmental concentration determinations, particularly in cases likely to be called worst-case (shallow slope and true LC50 near the edges of the concentration range). Given that the use of well-justified sample sizes is crucial to reducing uncertainty in Toxicity estimates, these results lead us to recommend a reconsideration of the current de minimis 7/concentration sample size for critical studies (e.g., studies needed for a chemical registration, which are being tested for the first time, or involving difficult test substances). Environ Toxicol Chem 2018;37:1565-1578. © 2018 SETAC.
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oecd validation study to assess intra and inter laboratory reproducibility of the zebraFish embryo Toxicity test for acute aquatic Toxicity testing
Regulatory Toxicology and Pharmacology, 2014Co-Authors: Francois Busquet, Gregory J Carr, Jane M Rawlings, Scott E Belanger, T Braunbeck, Ruben Strecker, P H Cenijn, Przemyslaw Fochtman, Anne Gourmelon, Nicole HublerAbstract:Abstract The OECD validation study of the zebraFish embryo acute Toxicity test (ZFET) for acute aquatic Toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebraFish eggs (20/concentration and control) were exposed for 96 h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96 h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV 30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute Fish Toxicity and Fish embryo acute Toxicity data, the ZFET is ready to be considered for acute Fish Toxicity for regulatory purposes.
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use of Fish embryo Toxicity tests for the prediction of acute Fish Toxicity to chemicals
Environmental Toxicology and Chemistry, 2013Co-Authors: Scott E Belanger, Jane M Rawlings, Gregory J CarrAbstract:The Fish embryo test (FET) is a potential animal alternative for the acute Fish Toxicity (AFT) test. A comprehensive validation program assessed 20 different chemicals to understand intra- and interlaboratory variability for the FET. The FET had sufficient reproducibility across a range of potencies and modes of action. In the present study, the suitability of the FET as an alternative model is reviewed by relating FET and AFT. In total, 985 FET studies and 1531 AFT studies were summarized. The authors performed FET-AFT regressions to understand potential relationships based on physical-chemical properties, species choices, duration of exposure, chemical classes, chemical functional uses, and modes of action. The FET-AFT relationships are very robust (slopes near 1.0, intercepts near 0) across 9 orders of magnitude in potency. A recommendation for the predictive regression relationship is based on 96-h FET and AFT data: log FET median lethal concentration (LC50) = (0.989 × log Fish LC50) - 0.195; n = 72 chemicals, r = 0.95, p < 0.001, LC50 in mg/L. A similar, not statistically different regression was developed for the entire data set (n = 144 chemicals, unreliable studies deleted). The FET-AFT regressions were robust for major chemical classes with suitably large data sets. Furthermore, regressions were similar to those for large groups of functional chemical categories such as pesticides, surfactants, and industrial organics. Pharmaceutical regressions (n = 8 studies only) were directionally correct. The FET-AFT relationships were not quantitatively different from acute Fish-acute Fish Toxicity relationships with the following species: fathead minnow, rainbow trout, bluegill sunFish, Japanese medaka, and zebraFish. The FET is scientifically supportable as a rational animal alternative model for ecotoxicological testing of acute Toxicity of chemicals to Fish.
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is the Fish embryo Toxicity test fet with the zebraFish danio rerio a potential alternative for the Fish acute Toxicity test
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2009Co-Authors: E Lammer, Gregory J Carr, K Wendler, Jane M Rawlings, Scott E Belanger, T BraunbeckAbstract:The Fish acute Toxicity test is a mandatory component in the base set of data requirements for ecoToxicity testing. The Fish acute Toxicity test is not compatible with most current animal welfare legislation because mortality is the primary endpoint and it is often hypothesized that Fish suffer distress and perhaps pain. Animal alternative considerations have also been incorporated into new European REACH regulations through strong advocacy for the reduction of testing with live animals. One of the most promising alternative approaches to classical acute Fish Toxicity testing with live Fish is the Fish embryo Toxicity (FET) test. The FET has been a mandatory component in routine whole effluent testing in Germany since 2005 and has already been standardized at the international level. In order to analyze the applicability of the FET also in chemical testing, a comparative re-evaluation of both Fish and Fish embryo Toxicity data was carried out for a total of 143 substances, and statistical approaches were developed to evaluate the correlation between Fish and Fish embryo Toxicity data. Results confirm that Fish embryo tests are neither better nor worse than acute Fish Toxicity tests and provide strong scientific support for the FET as a surrogate for the acute Fish Toxicity test.
Jane M Rawlings - One of the best experts on this subject based on the ideXlab platform.
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on the impact of sample size on median lethal concentration estimation in acute Fish Toxicity testing is n 7 group enough
Environmental Toxicology and Chemistry, 2018Co-Authors: Gregory J Carr, Jane M Rawlings, John A Bailer, Scott E BelangerAbstract:The Fish acute Toxicity test method is foundational to aquatic Toxicity testing strategies, yet the literature lacks a concise sample size assessment. Although various sources address sample size, historical precedent seems to play a larger role than objective measures. We present a novel and comprehensive quantification of the effect of sample size on estimation of the median lethal concentration (LC50), covering a wide range of scenarios. The results put into perspective the practical differences across a range of sample sizes, from n = 5/concentration up to n = 23/concentration. We also provide a framework for setting sample size guidance illustrating ways to quantify the performance of LC50 estimation, which can be used to set sample size guidance given reasonably difficult (or worst-case) scenarios. There is a clear benefit to larger sample size studies: they reduce error in the determination of LC50s, and lead to more robust safe environmental concentration determinations, particularly in cases likely to be called worst-case (shallow slope and true LC50 near the edges of the concentration range). Given that the use of well-justified sample sizes is crucial to reducing uncertainty in Toxicity estimates, these results lead us to recommend a reconsideration of the current de minimis 7/concentration sample size for critical studies (e.g., studies needed for a chemical registration, which are being tested for the first time, or involving difficult test substances). Environ Toxicol Chem 2018;37:1565-1578. © 2018 SETAC.
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oecd validation study to assess intra and inter laboratory reproducibility of the zebraFish embryo Toxicity test for acute aquatic Toxicity testing
Regulatory Toxicology and Pharmacology, 2014Co-Authors: Francois Busquet, Gregory J Carr, Jane M Rawlings, Scott E Belanger, T Braunbeck, Ruben Strecker, P H Cenijn, Przemyslaw Fochtman, Anne Gourmelon, Nicole HublerAbstract:Abstract The OECD validation study of the zebraFish embryo acute Toxicity test (ZFET) for acute aquatic Toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebraFish eggs (20/concentration and control) were exposed for 96 h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96 h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV 30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute Fish Toxicity and Fish embryo acute Toxicity data, the ZFET is ready to be considered for acute Fish Toxicity for regulatory purposes.
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use of Fish embryo Toxicity tests for the prediction of acute Fish Toxicity to chemicals
Environmental Toxicology and Chemistry, 2013Co-Authors: Scott E Belanger, Jane M Rawlings, Gregory J CarrAbstract:The Fish embryo test (FET) is a potential animal alternative for the acute Fish Toxicity (AFT) test. A comprehensive validation program assessed 20 different chemicals to understand intra- and interlaboratory variability for the FET. The FET had sufficient reproducibility across a range of potencies and modes of action. In the present study, the suitability of the FET as an alternative model is reviewed by relating FET and AFT. In total, 985 FET studies and 1531 AFT studies were summarized. The authors performed FET-AFT regressions to understand potential relationships based on physical-chemical properties, species choices, duration of exposure, chemical classes, chemical functional uses, and modes of action. The FET-AFT relationships are very robust (slopes near 1.0, intercepts near 0) across 9 orders of magnitude in potency. A recommendation for the predictive regression relationship is based on 96-h FET and AFT data: log FET median lethal concentration (LC50) = (0.989 × log Fish LC50) - 0.195; n = 72 chemicals, r = 0.95, p < 0.001, LC50 in mg/L. A similar, not statistically different regression was developed for the entire data set (n = 144 chemicals, unreliable studies deleted). The FET-AFT regressions were robust for major chemical classes with suitably large data sets. Furthermore, regressions were similar to those for large groups of functional chemical categories such as pesticides, surfactants, and industrial organics. Pharmaceutical regressions (n = 8 studies only) were directionally correct. The FET-AFT relationships were not quantitatively different from acute Fish-acute Fish Toxicity relationships with the following species: fathead minnow, rainbow trout, bluegill sunFish, Japanese medaka, and zebraFish. The FET is scientifically supportable as a rational animal alternative model for ecotoxicological testing of acute Toxicity of chemicals to Fish.
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is the Fish embryo Toxicity test fet with the zebraFish danio rerio a potential alternative for the Fish acute Toxicity test
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2009Co-Authors: E Lammer, Gregory J Carr, K Wendler, Jane M Rawlings, Scott E Belanger, T BraunbeckAbstract:The Fish acute Toxicity test is a mandatory component in the base set of data requirements for ecoToxicity testing. The Fish acute Toxicity test is not compatible with most current animal welfare legislation because mortality is the primary endpoint and it is often hypothesized that Fish suffer distress and perhaps pain. Animal alternative considerations have also been incorporated into new European REACH regulations through strong advocacy for the reduction of testing with live animals. One of the most promising alternative approaches to classical acute Fish Toxicity testing with live Fish is the Fish embryo Toxicity (FET) test. The FET has been a mandatory component in routine whole effluent testing in Germany since 2005 and has already been standardized at the international level. In order to analyze the applicability of the FET also in chemical testing, a comparative re-evaluation of both Fish and Fish embryo Toxicity data was carried out for a total of 143 substances, and statistical approaches were developed to evaluate the correlation between Fish and Fish embryo Toxicity data. Results confirm that Fish embryo tests are neither better nor worse than acute Fish Toxicity tests and provide strong scientific support for the FET as a surrogate for the acute Fish Toxicity test.
William H Gerwick - One of the best experts on this subject based on the ideXlab platform.
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structure and biosynthesis of the jamaicamides new mixed polyketide peptide neurotoxins from the marine cyanobacterium lyngbya majuscula
Chemistry & Biology, 2004Co-Authors: Daniel J Edwards, Brian L Marquez, Lisa M Nogle, Kerry L Mcphail, Douglas E Goeger, Mary Ann Roberts, William H GerwickAbstract:Abstract A screening program for bioactive compounds from marine cyanobacteria led to the isolation of jamaicamides A–C. Jamaicamide A is a novel and highly functionalized lipopeptide containing an alkynyl bromide, vinyl chloride, β-methoxy eneone system, and pyrrolinone ring. The jamaicamides show sodium channelblocking activity and Fish Toxicity. Precursor feeding to jamaicamide-producing cultures mapped out the series of acetate and amino acid residues and helped develop an effective cloning strategy for the biosynthetic gene cluster. The 58 kbp gene cluster is composed of 17 open reading frames that show an exact colinearity with their expected utilization. A novel cassette of genes appears to form a pendent carbon atom possessing the vinyl chloride functionality; at its core this contains an HMG-CoA synthase-like motif, giving insight into the mechanism by which this functional group is created.
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structure and biosynthesis of the jamaicamides new mixed polyketide peptide neurotoxins from the marine cyanobacterium lyngbya majuscula
Chemistry & Biology, 2004Co-Authors: Daniel J Edwards, Brian L Marquez, Lisa M Nogle, Kerry L Mcphail, Douglas E Goeger, Mary Ann Roberts, William H GerwickAbstract:A screening program for bioactive compounds from marine cyanobacteria led to the isolation of jamaicamides A-C. Jamaicamide A is a novel and highly functionalized lipopeptide containing an alkynyl bromide, vinyl chloride, beta-methoxy eneone system, and pyrrolinone ring. The jamaicamides show sodium channelblocking activity and Fish Toxicity. Precursor feeding to jamaicamide-producing cultures mapped out the series of acetate and amino acid residues and helped develop an effective cloning strategy for the biosynthetic gene cluster. The 58 kbp gene cluster is composed of 17 open reading frames that show an exact colinearity with their expected utilization. A novel cassette of genes appears to form a pendent carbon atom possessing the vinyl chloride functionality; at its core this contains an HMG-CoA synthase-like motif, giving insight into the mechanism by which this functional group is created.