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Pharmacology, Toxicology and Environmental Health Commons™
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- Aquatic toxicology (7)
- Ecological risk assessment (5)
- Rainbow trout (5)
- Quantitative structure–activity relationships (4)
- Carbofuran (3)
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- Daphnia magna (3)
- Estrogen receptor (3)
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Articles 1 - 30 of 53
Full-Text Articles in Pharmacology, Toxicology and Environmental Health
Advancing Computational Toxicology In A Regulatory Setting: A Selected Review Of The Accomplishments Of Gilman D. Veith (1944–2013), Steven P. Bradbury, Christine L. Russom, Patricia K. Schmieder, Terry W. Schultz, Robert Diderich, Charles M. Auer
Advancing Computational Toxicology In A Regulatory Setting: A Selected Review Of The Accomplishments Of Gilman D. Veith (1944–2013), Steven P. Bradbury, Christine L. Russom, Patricia K. Schmieder, Terry W. Schultz, Robert Diderich, Charles M. Auer
Steven P. Bradbury
With the passing of Dr. Gilman D. Veith on August 18, 2013, the research community lost one of its true visionaries in the development and implementation of alternative in silico and in vitro toxicology models in human health and ecological risk assessment. His career spanned more than four decades, during which he repeatedly demonstrated vision and leadership to advance alternative testing and assessment research and to guide the adoption of research accomplishments into U.S. and international chemical regulatory programs. His ability to advance toxicological and environmental exposure research, and associated quantitative structure– activity relationships (QSARs), for application in environmental regulatory …
Predicting Modes Of Toxic Action From Chemical Structure, Steven P. Bradbury, Christine L. Russom, Steven J. Broderius, Dean J. Hammermeister, Robert A. Drummond, Gilman D. Veith
Predicting Modes Of Toxic Action From Chemical Structure, Steven P. Bradbury, Christine L. Russom, Steven J. Broderius, Dean J. Hammermeister, Robert A. Drummond, Gilman D. Veith
Steven P. Bradbury
Like many of the papers in the Environmental Toxicology and Chemistry “Top 100” list, the development of the fathead minnow database [1] and the assignment of modes of action to the 617 chemicals therein resulted from a comprehensive research effort by a multidisciplinary team of researchers with expertise in quantitative structure–activity relationship (QSAR) modeling, chemistry, toxicokinetics, joint toxicity of chemical mixtures, and behavioral and aquatic toxicology. The fathead minnow database was the culmination of the US Environmental Protection Agency’s (USEPA) QSAR research program, which spanned nearly 20 yr, a rare program because many research planning efforts typically run within a …
Application Of The Tissue Residue Approach In Ecological Risk Assessment, Steven P. Bradbury, Keith G. Sappington, Todd S. Bridges, Russell J. Erickson, A. Jan Hendriks, Roman P. Lanno, James P. Meador, David R. Mount, Mike H. Salazar, Doug J. Spry
Application Of The Tissue Residue Approach In Ecological Risk Assessment, Steven P. Bradbury, Keith G. Sappington, Todd S. Bridges, Russell J. Erickson, A. Jan Hendriks, Roman P. Lanno, James P. Meador, David R. Mount, Mike H. Salazar, Doug J. Spry
Steven P. Bradbury
The objective of this work is to present a critical review of the application of the tissue residue approach (TRA) in ecological risk and/or impact assessment (ERA) of chemical stressors and environmental criteria development. A secondary goal is to develop a framework for integrating the TRA into ecological assessments along with traditional, exposure concentration-based assessment approaches. Although widely recognized for its toxicological appeal, the utility of the TRA in specific applications will depend on numerous factors, such as chemical properties, exposure characteristics, assessment type, availability of tissue residue-response data, and ability to quantify chemical exposure. Therefore, the decision to use …
Meeting The Common Needs Of A More Effective And Efficient Testing And Assessment Paradigm For Chemical Risk Management, Steven P. Bradbury, Vicki Dellarco, Tala Henry, Phil Sayre, Jennifer Seed
Meeting The Common Needs Of A More Effective And Efficient Testing And Assessment Paradigm For Chemical Risk Management, Steven P. Bradbury, Vicki Dellarco, Tala Henry, Phil Sayre, Jennifer Seed
Steven P. Bradbury
Significant advances have been made in human health and ecological risk assessment over the last decade. Substantial challenges, however, remain in providing credible scientific information in a timely and efficient manner to support chemical risk assessment and management decisions. A major challenge confronting risk managers is the need for critical information to address risk uncertainties in large chemical inventories such as high- and medium-production-volume industrial chemicals or pesticide inert ingredients. From a strategic and tactical viewpoint, an integrated approach that relies on all existing knowledge and uses a range of methods, including those from emerging and novel technologies, is needed …
Application Of Genomics To Regulatory Ecological Risk Assessments For Pesticides, Steven P. Bradbury, Sigmund J. Degitz, Robert A. Hoke, Richard Brennan, Lee Ferguson, Rebecca Klaper, Laszlo Orban, David Spurgeon, Susan Tilton
Application Of Genomics To Regulatory Ecological Risk Assessments For Pesticides, Steven P. Bradbury, Sigmund J. Degitz, Robert A. Hoke, Richard Brennan, Lee Ferguson, Rebecca Klaper, Laszlo Orban, David Spurgeon, Susan Tilton
Steven P. Bradbury
Substantial advances in human health and ecological risk assessment have been achieved by the risk assessment community; however, challenges remain, such as providing credible scientific information on a timely, efficient basis to support decisions for industrial chemicals and pesticides. Current risk assessment data generation requirements-including animal welfare concerns and the volume, appropriateness, and cost of required data-and the large number of chemicals requiring evaluation are a challenge confronting the chemical industry, national and international regulatory agencies, and associated stakeholders (Bradbury et al. 2004). The lack of hazard data for many chemicals and the need to improve the efficiency and quality …
Toxic Responses Of The Fish Nervous System, Steven P. Bradbury, Richard W. Carlson, Tala R. Henry, Stephanie Padilla, John Cowden
Toxic Responses Of The Fish Nervous System, Steven P. Bradbury, Richard W. Carlson, Tala R. Henry, Stephanie Padilla, John Cowden
Steven P. Bradbury
Few of the approximately 70,000 chemicals on the Toxic Substances Control Act inventory or the 1000 to 1600 new chemicals introduced each year in the United States have been tested for neurotoxicity to support risk assessments (NRC, 1992), even though it is estimated that 5 to 10% of them are likely to be neurotoxic. Neurotoxicity has been defined as adverse effects of physical, biological, or chemical agents on the structure or function of the nervous system in developing or adult organisms (Philbert et al., 2000). From a human health risk assessment perspective, the potential for neurotoxic effects associated with synthetic …
Meeting The Scientific Needs Of Ecological Risk Assessment In A Regulatory Context, Steven P. Bradbury, Tom C. Feitel, Cornelis J. Van Leeuwen
Meeting The Scientific Needs Of Ecological Risk Assessment In A Regulatory Context, Steven P. Bradbury, Tom C. Feitel, Cornelis J. Van Leeuwen
Steven P. Bradbury
During the past decade, the field of ecological risk assessment has progressed considerably. Advances have come from such international bodies as the Organisation for Economic Co-operation and Development (OECD), the World Health Organisation (WHO), the European and Mediterranean Plant Protection Organisation (EPPO), and the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) (1–8). Risk assessments have played a critical role in the development of various regulations within the European Commission (EC) as well as in other parts of the world, including the United States, Canada, and Japan (9–17). But scientists and regulators are faced with three significant challenges: streamlining …
Single-Cell Microbiology: Tools, Technologies, And Applications, Byron F. Brehm-Stecher, Eric A. Johnson
Single-Cell Microbiology: Tools, Technologies, And Applications, Byron F. Brehm-Stecher, Eric A. Johnson
Byron F. Brehm-Stecher
The field of microbiology has traditionally been concerned with and focused on studies at the population level. Information on how cells respond to their environment, interact with each other, or undergo complex processes such as cellular differentiation or gene expression has been obtained mostly by inference from population-level data. New appreciation for the existence and importance of cellular heterogeneity, coupled with recent advances in technology, has driven the development of new tools and techniques for the study of individual microbial cells. As a result, scientists have been able to characterize microorganisms and their activities at unprecedented levels of detail.
Sensitization Of Staphylococcus Aureus And Escherichia Coli To Antibiotics By The Sesquiterpenoids Nerolidol, Farnesol, Bisabolol, And Apritone, Byron F. Brehm-Stecher, Eric A. Johnson
Sensitization Of Staphylococcus Aureus And Escherichia Coli To Antibiotics By The Sesquiterpenoids Nerolidol, Farnesol, Bisabolol, And Apritone, Byron F. Brehm-Stecher, Eric A. Johnson
Byron F. Brehm-Stecher
The sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone were investigated for their abilities to enhance bacterial permeability and susceptibility to exogenous antimicrobial compounds. Initially, it was observed by flow cytometry that these sesquiterpenoids promoted the intracellular accumulation of the membrane-impermeant nucleic acid stain ethidium bromide by live cells of Lactobacillus fermentum, suggesting that enhanced permeability resulted from disruption of the cytoplasmic membrane. The ability of these sesquiterpenoids to increase bacterial susceptibility to a number of clinically important antibiotics was then investigated. In disk diffusion assays, treatment with low concentrations (0.5 to 2 mM) of nerolidol, bisabolol, or apritone enhanced the susceptibility …
Overview Of Data And Conceptual Approaches For Derivation Of Quantitative Structure-Activity Relationships For Ecotoxicological Effects Of Organic Chemicals, Steven P. Bradbury, Christine L. Russom, Gerald T. Ankley, T. Wayne Schultz, John D. Walker
Overview Of Data And Conceptual Approaches For Derivation Of Quantitative Structure-Activity Relationships For Ecotoxicological Effects Of Organic Chemicals, Steven P. Bradbury, Christine L. Russom, Gerald T. Ankley, T. Wayne Schultz, John D. Walker
Steven P. Bradbury
The use of quantitative structure–activity relationships (QSARs) in assessing potential toxic effects of organic chemicals on aquatic organisms continues to evolve as computational efficiency and toxicological understanding advance. With the everincreasing production of new chemicals, and the need to optimize resources to assess thousands of existing chemicals in commerce, regulatory agencies have turned to QSARs as essential tools to help prioritize tiered risk assessments when empirical data are not available to evaluate toxicological effects. Progress in designing scientifically credible QSARs is intimately associated with the development of empirically derived databases of well-defined and quantified toxicity endpoints, which are based on …
Qsar Prioritization Of Chemical Inventories For Endocrine Disruptor Testing, Steven P. Bradbury, Patricia Schmeider, Ovanes Mekenyan, Gilman Veith
Qsar Prioritization Of Chemical Inventories For Endocrine Disruptor Testing, Steven P. Bradbury, Patricia Schmeider, Ovanes Mekenyan, Gilman Veith
Steven P. Bradbury
Binding affinity between chemicals and the estrogen receptor (ER) serves as an indicator of the potential to cause endocrine disruption through this receptor-mediated endocrine pathway. Estimating ER-binding affinity is, therefore, one strategic approach to reducing the costs of screening chemicals for potential risks of endocrine disruption. While measuring ER binding with in vitro assays may be the first choice in prioritizing chemicals for additional in vitro or in vivo estrogenicity testing, the time and costs associated with screening thousands of chemicals is prohibitive. Recent advances in 3D modeling of the reactivity of flexible structures make in silico methods for estimating …
An Overview Of The Use Of Quantitative Structure-Activity Relationships For Ranking And Prioritzing Large Chemical Inventories For Environmental Risk Assessments, Steven P. Bradbury, Christine L. Russom, Roger L. Breton, John D. Walker
An Overview Of The Use Of Quantitative Structure-Activity Relationships For Ranking And Prioritzing Large Chemical Inventories For Environmental Risk Assessments, Steven P. Bradbury, Christine L. Russom, Roger L. Breton, John D. Walker
Steven P. Bradbury
Ecological risk assessments for chemical stressors are used to establish linkages between likely exposure concentrations and adverse effects to ecological receptors. At times, it is useful to conduct screening risk assessments to assist in prioritizing or ranking chemicals on the basis of potential hazard and exposure assessment parameters. Ranking of large chemical inventories can provide evidence for focusing research and/or cleanup efforts on specific chemicals of concern. Because of financial and time constraints, data gaps exist, and the risk assessor is left with decisions on which models to use to estimate the parameter of concern. In this review, several methods …
Influence Of Suspended Solids On Acute Toxicity Of Carbofuran To Daphnia Magna: Ii. An Evaluation Of Potential Interactive Mechanisms, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
Influence Of Suspended Solids On Acute Toxicity Of Carbofuran To Daphnia Magna: Ii. An Evaluation Of Potential Interactive Mechanisms, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
Steven P. Bradbury
It has been demonstrated that simultaneous exposure of Daphnia magna to suspended solids and a carbamate pesticide potentiates the toxic response to the pesticide. The toxicodynamics between these stressors were investigated to determine possible mechanisms of interaction. Three experimental series were conducted with D. magna to determine: the effect of food availability on carbofuran toxicity; the effect of food availability on jointly administered carbofuran and suspended solids; and changes in the magnitude of effects which can occur with suspended solids of different composition. These experiments demonstrated that both carbofuran toxicity and the joint toxicity of carbofuran and suspended solids to …
Quantitative Structure-Activity Relationship Models For Prediction Of Estrogen Receptor Binding Affinity Of Structurally Diverse Chemicals, Steven P. Bradbury, Patricia K. Schmeider, Gerald Ankley, Ovanes Mekenyan, John D. Walker
Quantitative Structure-Activity Relationship Models For Prediction Of Estrogen Receptor Binding Affinity Of Structurally Diverse Chemicals, Steven P. Bradbury, Patricia K. Schmeider, Gerald Ankley, Ovanes Mekenyan, John D. Walker
Steven P. Bradbury
The demonstrated ability of a variety of structurally diverse chemicals to bind to the estrogen receptor has raised the concern that chemicals in the environment may be causing adverse effects through interference with nuclear receptor pathways. Many structure–activity relationship models have been developed to predict chemical binding to the estrogen receptor as an indication of potential estrogenicity. Models based on either two-dimensional or three-dimensional molecular descriptions that have been used to predict potential for binding to the estrogen receptor are the subject of the current review. The utility of such approaches to predict binding potential of diverse chemical structures in …
Influence Of Suspended Solids On Acute Toxicity Of Carbofuran To Daphnia Magna: I. Interactive Effects, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
Influence Of Suspended Solids On Acute Toxicity Of Carbofuran To Daphnia Magna: I. Interactive Effects, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
Steven P. Bradbury
This study explored the effects on Daphnia magna from exposure to the pesticide carbofuran in combination with stress from suspended solids exposure. Our objective was to assess whether suspended solids affects the toxicodynamic response of D. magna to carbofuran. A series of laboratory experiments was performed where animals were exposed to carbofuran concentrations ranging from 0 to 160 mg/l in combination with suspended solids concentrations ranging from 0 to 10,000 mg/l. In the absence of suspended solids, effects of carbofuran were dose dependent and resulted in an EC(sub)50 of 92 mg/l. Exposure to suspended solids, up to extreme levels that …
Reactivity Profiles Of Ligands Of Mammalian Retinoic Acid Receptors: A Preliminary Corepa Analysis, Steven P. Bradbury, G. T. Ankley, O. G. Mekenyan, V. . Kamenska, P. K. Schmieder
Reactivity Profiles Of Ligands Of Mammalian Retinoic Acid Receptors: A Preliminary Corepa Analysis, Steven P. Bradbury, G. T. Ankley, O. G. Mekenyan, V. . Kamenska, P. K. Schmieder
Steven P. Bradbury
Retinoic acid and associated derivatives comprise a class of endogenous hormones that bind to and activate different families of retinoic acid receptors (RARs, RXRs), and control many aspects of vertebrate development. Identification of potential RAR and RXR ligands is of interest both from a pharmaceutical and toxicological perspective. The recently developed COREPA (COmmon REactivity PAttern) algorithm was used to establish reactivity profiles for a limited data set of retinoid receptor ligands in terms of activation of three RARs (a, b, g) and an RXR (a). Conformational analysis of a training set of retinoids and related analogues in terms of thermodynamic …
A Computationally Based Identification Algorithm For Estrogen Receptor Ligands: Part 2. Evaluation Of A Herα Binding Affinity Model, Steven P. Bradbury, O. G. Mekenyan, V. Kamenska, P. K. Schmieder, G. T. Ankley
A Computationally Based Identification Algorithm For Estrogen Receptor Ligands: Part 2. Evaluation Of A Herα Binding Affinity Model, Steven P. Bradbury, O. G. Mekenyan, V. Kamenska, P. K. Schmieder, G. T. Ankley
Steven P. Bradbury
The objective of this study was to evaluate the capability of an expert system described in the previous paper (S. Bradbury et al., Toxicol. Sci. 58, 253–269) to identify the potential for chemicals to act as ligands of mammalian estrogen receptors (ERs). The basis of the expert system was a structure activity relationship (SAR) model, based on relative binding affinity (RBA) values for steroidal and nonsteroidal chemicals derived from human ERa (hERa) competitive binding assays. The expert system enables categorization of chemicals into (RBA ranges of < 0.1, 0.1 to 1, 1 to 10, 10 to 100, and >150% relative to 17b-estradiol. In the current analysis, the algorithm was evaluated with respect …
A Computationally Based Identification Algorithm For Estrogen Receptor Ligands: Part 1. Predicting Herα Binding Affinity, Steven P. Bradbury, V. Kamenska, P. Schmieder, G. Ankley, O. Mekenyan
A Computationally Based Identification Algorithm For Estrogen Receptor Ligands: Part 1. Predicting Herα Binding Affinity, Steven P. Bradbury, V. Kamenska, P. Schmieder, G. Ankley, O. Mekenyan
Steven P. Bradbury
The common reactivity pattern (COREPA) approach is a 3-dimensional, quantitative structure activity relationship (3-D QSAR) technique that permits identification and quantification of specific global and local stereoelectronic characteristics associated with a chemical’s biological activity. It goes beyond conventional 3-D QSAR approaches by incorporating dynamic chemical conformational flexibility in ligand-receptor interactions. The approach provides flexibility in screening chemical data sets in that it helps establish criteria for identifying false positives and false negatives, and is not dependent upon a predetermined and specified toxicophore or an alignment of conformers to a lead compound. The algorithm was recently used to screen chemical data …
New Developments In A Hazard Identification Algorithm For Hormone Receptor Ligands, Steven P. Bradbury, Ovanes Mekenyan, Nina Nikolova, Stoyan Karabunarliev, Gerald T. Ankley, Bjorn Hansen
New Developments In A Hazard Identification Algorithm For Hormone Receptor Ligands, Steven P. Bradbury, Ovanes Mekenyan, Nina Nikolova, Stoyan Karabunarliev, Gerald T. Ankley, Bjorn Hansen
Steven P. Bradbury
Recently we described the Common REactivity PAttern (COREPA) technique to screen data sets of diverse structures for their ability to serve as ligands for steroid hormone receptors [1]. The approach identi®es and quanti®es similar global and local stereoelectronic characteristics associated with active ligands through a comparison of energeticallyreasonable conformer distributions for selected descriptors. For each stereoelectronic descriptor selected, discrete conformer distributions from a training set of ligands are evaluated and parameter ranges common for conformers from all the chemicals in the training set are identi®ed. The use of discrete partitions of parameter ranges to de®ne common reactivity patterns can, however, …
Biotransformation Of 4-Methoxyphenol In Rainbow Trout (Oncorhynchus Mykiss) Hepatic Microsomes, Steven P. Bradbury, R. Kolanczyk, P. Schmieder, T. Spizzo
Biotransformation Of 4-Methoxyphenol In Rainbow Trout (Oncorhynchus Mykiss) Hepatic Microsomes, Steven P. Bradbury, R. Kolanczyk, P. Schmieder, T. Spizzo
Steven P. Bradbury
Rainbow trout liver microsomes were used to study the O-demethylation and ring hydroxylation of 4-methoxyphenol (4-MP) (4-hydroxyanisole) at 11 and 25°C by directly measuring the production of the primary metabolite hydroquinone (HQ), 4-methoxycatechol (4-MCAT), and additional metabolites. An HPLC method with integrated ultraviolet (UV) and electrochemical detection (ECD) was developed for metabolite identification and quantification at low concentrations. Sample handling with appropriate buffers, solvents, low temperature and light prevented loss of extremely labile metabolites. Saturation kinetics for the production of HQ via O-demethylation of 4-MP (0.66–40 mM) was never achieved, with substrate solubility being the limiting factor. The linear rate …
Temporal Changes In Purity And Specific Activity Of Tritium-Labeled 2,3,7,8-Tetrachlorodibenzo-Ρ-Dioxin: Radiopurity Model For Toxicology, Steven P. Bradbury, Joseph D. Fernandez, Philip M. Cook, Brian C. Butterworth
Temporal Changes In Purity And Specific Activity Of Tritium-Labeled 2,3,7,8-Tetrachlorodibenzo-Ρ-Dioxin: Radiopurity Model For Toxicology, Steven P. Bradbury, Joseph D. Fernandez, Philip M. Cook, Brian C. Butterworth
Steven P. Bradbury
The specific activity (S) and radiopurity (R) of tritium labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin, [3H]TCDD, were measured by gas chromatography/mass spectrometry (GC/ MS) while attempting to accurately characterize TCDD doses received by invertebrates, fish, and fish embryos during several toxicology studies conducted over a 3 year period. The [3H]TCDD sample was found to consist of six TCDD analogues involving hydrogen, deuterium, and tritium substitution at the 1,6-dibenzo-p-dioxin carbon positions and a complex mixture of impurities (with and without tritium labels). Planar aromatic impurities were identified as tolyl- TCDD adducts and appeared to result from the decay of 3H radiolabels to produce TCDD carbocations …
Derivation Of Wildlife Values For Mercury, Steven P. Bradbury, John Nichols, Jeff Swartout
Derivation Of Wildlife Values For Mercury, Steven P. Bradbury, John Nichols, Jeff Swartout
Steven P. Bradbury
A procedure has been developed to estimate surface water concentrations of toxicants (“wildlife values”) that will protect the viability of wildlife populations associated with aquatic resources. This procedure was designed primarily to protect piscivorous birds and mammals from compounds that bioaccumulate in fish and was used in the Great Lakes Water Quality Initiative (GLI) to calculate wildlife values (WV) for mercury, DDT/DDE, total polychlorinated biphenyls (PCBs), and 2,3,7,8-tetrachlorodibenzodioxin (TCDD). Published in 1995, and expressed as total mercury in unfiltered water, the final wildlife value (WVf) for mercury derived in the GLI was 1300 pg Hg/L. This value was selected as …
New Testing Apparatus For Assessing Interactive Effects Of Suspended Solids And Chemical Stressors On Plankton Invertebrates, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
New Testing Apparatus For Assessing Interactive Effects Of Suspended Solids And Chemical Stressors On Plankton Invertebrates, Steven P. Bradbury, Carl Herbrandson, Deborah L. Swackhamer
Steven P. Bradbury
To better predict and interpret the responses of aquatic organisms to environmentally relevant chemical exposures, it is necessary to investigate the combined effects of physical (e.g., suspended solids) and chemical stressors. One of the limitations in investigating suspended solids–chemical interactions has been the lack of an appropriate testing system. The specific objective of the current study was to develop and assess a suspended solids testing apparatus (SSTA) for studies on the combined effects of suspended solids and chemicals on aquatic invertebrates. The SSTA was designed to permit the assessment of varying suspended solids concentrations on Daphnia magna at a constant …
A Kinetic Analysis Of The Conformational Flexibility Of Steroid Hormones, Steven P. Bradbury, Julian Ivanov, Ovanes Mekenyan, Gerritt Schüürmann
A Kinetic Analysis Of The Conformational Flexibility Of Steroid Hormones, Steven P. Bradbury, Julian Ivanov, Ovanes Mekenyan, Gerritt Schüürmann
Steven P. Bradbury
For a set of 10 androgen steroids and estradiol (E2), the kinetic feasibility of conformation flexibility of the cyclic moieties was studied under the constraint of maintaining the B/C trans and C/D trans ring fusion of the natural and biologically active enantiomer. To this end, the conformational energy surface was quantified using the semiempirical quantum chemical AM1 model. The computational analysis included the location of Conformational transition states with associated barriers, and intrinsic reaction coordinate (IRC) calculations to characterize the trajectories of the rotations and the relationships of the transition states to neighbouring chair and twist conformations. Conformational transformations were …
Neurological Effects On Startle Response And Escape From Predation By Medaka Exposed To Organic Chemicals, Steven P. Bradbury, Richard W. Carlson, Robert A. Drummond, Dean E. Hammermeister
Neurological Effects On Startle Response And Escape From Predation By Medaka Exposed To Organic Chemicals, Steven P. Bradbury, Richard W. Carlson, Robert A. Drummond, Dean E. Hammermeister
Steven P. Bradbury
Simultaneous electrophysiological and behavioral studies were performed on 21–32 day old juvenile medaka (Oryzias latipes) exposed at sublethal concentrations to organic chemicals representing various modes of action. Non-invasive recordings were made of the electrical impulses generated within giant neuronal Mauthner cells, associated interneurons and motoneurons, and axial musculature, all of which initiate the startle or ‘escape’ response in fish. Timing in ms between these electrical sequelae was measured for each fish before and after 24 and 48 h exposure to a chemical. Carbaryl and phenol affected Mauthner cell to motoneuron transmission while chlorpyrifos, carbaryl, phenol and 2,4-dinitrophenol (DNP) showed neuromuscular …
A Comparative Study Of Molecular Similarity, Statistical, And Neural Methods For Predicting Toxic Modes Of Action, Steven P. Bradbury, Subhash C. Basak, Gregory D. Grunwald, George E. Host, Gerald J. Niemi
A Comparative Study Of Molecular Similarity, Statistical, And Neural Methods For Predicting Toxic Modes Of Action, Steven P. Bradbury, Subhash C. Basak, Gregory D. Grunwald, George E. Host, Gerald J. Niemi
Steven P. Bradbury
Quantitative structure–activity relationship (QSAR) models are routinely used in predicting toxicologic and ecotoxicologic effects of untested chemicals. One critical factor in QSAR-based risk assessment is the proper assignment of a chemical to a mode of action and associated QSAR. In this paper, we used molecular similarity, neural networks, and discriminant analysis methods to predict acute toxic modes of action for a set of 283 chemicals. The majority of these molecules had been previously determined through toxicodynamic studies in fish to be narcotics (two classes), electrophiles/proelectrophiles, uncouplers of oxidative phosphorylation, acetylcholinesterase inhibitors, and neurotoxicants. Nonempirical parameters, such as topological indices and …
The Role Of Ligand Flexibility In Predicting Biological Activity: Structure–Activity Relationships For Aryl Hydrocarbon, Estrogen, And Androgen Receptor Binding Affinity, Steven P. Bradbury, Ovanes G. Mekenyan, Gerald T. Ankley
The Role Of Ligand Flexibility In Predicting Biological Activity: Structure–Activity Relationships For Aryl Hydrocarbon, Estrogen, And Androgen Receptor Binding Affinity, Steven P. Bradbury, Ovanes G. Mekenyan, Gerald T. Ankley
Steven P. Bradbury
Recent studies indicate that the potency and agonist or antagonist activity of steroid hormone ligands are dependent, in part, on ligand–receptor binding affinity as well as the conformation of the ligand–receptor complex. The binding of ligands to hormone receptors is thought to involve interactions by which shapes of both the receptor and ligand are modified in the formation of the ligand–receptor complex. As a consequence, it is essential to explore the significance of ligand flexibility in the development of screening-level structure–activity relationships. In this review, examples are provided of techniques used to generate and screen ligand conformers in the development …
Predicting Modes Of Toxic Action From Chemical Structure: Acute Toxicity In The Fathead Minnow (Pimephales Promelas), Steven P. Bradbury, Christine L. Russom, Steven J. Broderius, Dean E. Hammermeister, Robert A. Drummond
Predicting Modes Of Toxic Action From Chemical Structure: Acute Toxicity In The Fathead Minnow (Pimephales Promelas), Steven P. Bradbury, Christine L. Russom, Steven J. Broderius, Dean E. Hammermeister, Robert A. Drummond
Steven P. Bradbury
In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible models for predicting the toxicity of chemicals when little or no empirical data are available. In recent years, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The objective of this research was to develop procedures that relate modes of acute toxic action in the fathead minnow (Pimephales promelas) to chemical structures and properties. An empirically derived database for diverse chemical structures of acute toxicity …
Acute Toxicity And Behavioral Effects Of Chlorpyrifos, Permethrin, Phenol, Strychnine, And 2,4-Dinitrophenol To 30-Day-Old Japanese Medaka (Oryzias Latipes), Steven P. Bradbury, Patricia J. Rice, Charles D. Drewes, Theresa M. Klubertanz, Joel R. Coats
Acute Toxicity And Behavioral Effects Of Chlorpyrifos, Permethrin, Phenol, Strychnine, And 2,4-Dinitrophenol To 30-Day-Old Japanese Medaka (Oryzias Latipes), Steven P. Bradbury, Patricia J. Rice, Charles D. Drewes, Theresa M. Klubertanz, Joel R. Coats
Steven P. Bradbury
Five chemicals with different modes of action were evaluated in laboratory studies to determine their acute toxicity (48-h median lethal concentration [LC50]) and behavioral effects on 30-d-old Japanese medaka (Oryzias latipes). The order of toxicity for these xenobiotics was permethrin > chlorpyrifos > 2,4-dinitrophenol (2,4-DNP) > strychnine > phenol. The 48-h LC50s were significantly different and ranged from 0.011 to 24.1 mg/L. In addition, chlorpyrifos and permethrin accumulated in the tissues of juvenile O. latipes. Observations of five behavioral/morphological responses, including changes in equilibrium, general activity, startle response, and morphology (e.g., hemorrhage and deformities) were used as indicators of sublethal toxicity. Each chemical, with …
A Computationally-Based Hazard Identification Algorithm That Incorporates Ligand Flexibility. 1. Identification Of Potential Androgen Receptor Ligands, Steven P. Bradbury, Ovanes Mekenyan, Julian Ivanov, Stoyan Karabunarliev, Gerald T. Ankley, Walter Karcher
A Computationally-Based Hazard Identification Algorithm That Incorporates Ligand Flexibility. 1. Identification Of Potential Androgen Receptor Ligands, Steven P. Bradbury, Ovanes Mekenyan, Julian Ivanov, Stoyan Karabunarliev, Gerald T. Ankley, Walter Karcher
Steven P. Bradbury
To advance techniques for screening large data sets of diverse structures for toxicologically active compounds, an algorithm was developed that is not dependent upon a predetermined and specified toxicophore or an alignment of conformers to a lead compound. Instead, the approach provides the means to identify and quantify specific global and local stereoelectronic characteristics associated with active compounds through a comparison of energeticallyreasonable conformer distributions for specific descriptors. To illustrate the algorithm, the stereoelectronic requirements associated with the binding affinity of 28 steroidal and non-steroidal ligands to the androgen receptor were defined. Common ranges of interatomic distances, atomic charges, and …