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2,3, 7,8-Tetrachlorodibenzo-P-Dioxin, Steven P. Bradbury Jan 1996

2,3, 7,8-Tetrachlorodibenzo-P-Dioxin, Steven P. Bradbury

Steven P. Bradbury

Since 1985, the United States Environmental Protection Agency (USEPA) has classified 2,3,7,8-tetrachloro-p-dioxin (TCDD) as a probable human carcinogen; subsequently, sources of TCDD in the environment have been regulated on the basis of animal cancer rates extrapolated to doses associated with human exposures. Two major activities have prompted the decision to reassess this approach for evaluating TCDD toxicity and its associated risks. First, an epidemiological study of cancer mortality in U.S. chemical workers by the National Institute of Occupational Safety and Health provided evidence of TCDD-mediated human carcinogenicity (Fingerhut et al. 1991 ). Second, at a 1990 Banbury conference a consensus …


Ecological Risk Assessment For Chemical Stressors: Challenges In Predictive Ecotoxicology Research, Steven P. Bradbury Jan 1995

Ecological Risk Assessment For Chemical Stressors: Challenges In Predictive Ecotoxicology Research, Steven P. Bradbury

Steven P. Bradbury

Environmental management decisions are increasingly based on the results of ecological risk assessments that require data and models to establish the likelihood of adverse ecological effects that may occur or are occurring as a result of exposure to one or more stressors .. Research to support ecological risk assessments for chemical stressors must include a predictive capability.. The great number of chemicals, species and habitats (exposure conditions) associated with prospective and retrospective management decisions precludes the use of empirical testing as the sole means to fill data gaps .. Therefore, strategic laboratory and field testing must be undertaken in the …


Sar Models For Futile Metabolism: One-Electron Reduction Of Quinones, Phenols And Nitrobenzenes, Steven P. Bradbury, Ovanes Mekenyan, G. D. Veith, N. Zaharieva Jan 1995

Sar Models For Futile Metabolism: One-Electron Reduction Of Quinones, Phenols And Nitrobenzenes, Steven P. Bradbury, Ovanes Mekenyan, G. D. Veith, N. Zaharieva

Steven P. Bradbury

Benzoquinones, naphthoquinones and aziridinylbenzoquinones, can be reduced by flavoproteins to semiquinones that react with molecular oxygen to form superoxide anion with the subsequent regeneration of the parent compounds. This redox cycling, a form of futile metabolism, produces reactive oxygen species and depletes the reducing equivalents of cells without concomitant energy production. The ability of a toxicant to redox cycle is related to its one-electron reduction potential, and this study attempted to estimate reduction potential from structure using semi-empirical quantum chemical models for a diverse set of chemicals. The results of this study suggest that one-electron reduction potentials, within structural classes …


Quantitative Structure-Activity Relationships And Ecological Risk Assessment: An Overview Of Predictive Aquatic Toxicology Research, Steven P. Bradbury Jan 1995

Quantitative Structure-Activity Relationships And Ecological Risk Assessment: An Overview Of Predictive Aquatic Toxicology Research, Steven P. Bradbury

Steven P. Bradbury

In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence, 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. In this review, techniques to assess modes of toxic action from …


Use Of Knowledge Bases And Qsars To Estimate The Relative Ecological Risk Of Agrichemicals: A Problem Formulation Exercise, Steven P. Bradbury, C. L. Russom, A. R. Carlson Jan 1995

Use Of Knowledge Bases And Qsars To Estimate The Relative Ecological Risk Of Agrichemicals: A Problem Formulation Exercise, Steven P. Bradbury, C. L. Russom, A. R. Carlson

Steven P. Bradbury

Ecological risk assessments can be used to establish the likelihood that an adverse effect will result from exposure to one or more chemicals. When evaluating contaminated sites with many chemicals present, risk assessors must grapple with the problem of quickly identifying the chemicals that are most likely to be of concern, based on effect and exposure assessment information. Many times data gaps exist and the risk assessor is left with decisions on which models to use to estimate the parameter of concern. In the present paper, a procedure is presented for ranking agrichemicals, utilizing the ASTER (ASsessment Tools for the …


Predicting Modes Of Toxic Action From Chemical Structure: An Overview, Steven P. Bradbury Jan 1994

Predicting Modes Of Toxic Action From Chemical Structure: An Overview, Steven P. Bradbury

Steven P. Bradbury

In the field of environmental toxicology, and especially aquatic toxicology, quantitative structure activity relationships (QSARs) have developed as scientifically-credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A basic and fundamental understanding of toxicological principles has been considered crucial to the continued acceptance and application of these techniques as biologically relevant. As a consequence, 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 assessment of a compound’s likely mode of toxic action …


Interim Report On Data And Methods For Assessment Of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin Risks To Aquatic Life And Associated Wildlife, Steven P. Bradbury, Philip M. Cook, Russell J. Erickson, Robert L. Spehar, Gerald T. Ankney Mar 1993

Interim Report On Data And Methods For Assessment Of 2,3,7,8-Tetrachlorodibenzo-P-Dioxin Risks To Aquatic Life And Associated Wildlife, Steven P. Bradbury, Philip M. Cook, Russell J. Erickson, Robert L. Spehar, Gerald T. Ankney

Steven P. Bradbury

In April, 1991 the Administrator of the U.S. Environmental Protection Agency (EPA) announced that the Agency would conduct a scientific reassessment of the risk of 2,3,7,8-tetrachlorodibenzo-p-dioxin (hereafter referred to as TCDD), and similar chemicals, to human health and the environment. Since 1985, EPA has classified TCDD, which it considers the most potent known animal carcinogen, as a probable human carcinogen. Sources of TCDD in the environment were subsequently regulated on the basis of animal cancer rates extrapolated to doses associated with human exposures. Recently, consensus has developed that the toxic effects of TCDD appear to be mediated by its binding …


Toxicokinetics And Metabolism Of Aniline And 4-Chloroaniline In Medaka (Oryzias Latipes), Steven P. Bradbury, Julia M. Dady, Patrick N. Fitzsimmons, Michelle M. Voit, Dean E, Hammermeister, Russell J. Erickson Jan 1993

Toxicokinetics And Metabolism Of Aniline And 4-Chloroaniline In Medaka (Oryzias Latipes), Steven P. Bradbury, Julia M. Dady, Patrick N. Fitzsimmons, Michelle M. Voit, Dean E, Hammermeister, Russell J. Erickson

Steven P. Bradbury

The in vivo toxicokinetics and in vitro hepatic microsomal metabolism of (14C)aniline and (14C)4-chloroaniline in medaka (Oryzias latipes) were investigated to provide a basis upon which to interpret the toxicological responses of small aquarium fish to aniline derivatives. During static aqueous exposures of up to 320 min, parent equivalents failed to reach steady state and results from depuration studies clearly demonstrated biphasic elimination. Due to low elimination rates, 40 to 20% of absorbed aniline and 4-chloroaniline doses, respectively, remained within the fish through 330 min postexposure. Based on an analysis of excreted metabolites, N-acetylation was the dominant route of in …


A Non-Invasive Neurotoxicity Assay Using Larval Medaka, Steven P. Bradbury, Dave Featherstone, Charles D. Drewes, Joel R. Coats Jan 1993

A Non-Invasive Neurotoxicity Assay Using Larval Medaka, Steven P. Bradbury, Dave Featherstone, Charles D. Drewes, Joel R. Coats

Steven P. Bradbury

We present a method for non-invasive electrophysiological analysis of rapid escape responses in intact, freely behaving larval medaka (Oryzias latipes) before and after short-term exposure to environmental toxicants. Recordings are obtained as a larval medaka swims in a small chamber of water above pairs of recording electrodes etched onto a printed circuit board. When the chamber is briefly vibrated by a sinusoidal pulse from a speaker attached to the grid, a stereotyped Mauthner cell-initiated escape response is evoked. The following parameters were quantified from recordings: 1) Mauthner axon conduction velocity, 2) delay between Mauthner axon spike and motoneuron spike in …


Hepatic Microsomal N-Hydroxylation Of Aniline And 4-Chloroaniline By Rainbow Trout (Onchorhyncus Mykiss), Steven P. Bradbury, J. M. Dady, A. D. Hoffman, M. M. Voit, D. L. Olson Dec 1991

Hepatic Microsomal N-Hydroxylation Of Aniline And 4-Chloroaniline By Rainbow Trout (Onchorhyncus Mykiss), Steven P. Bradbury, J. M. Dady, A. D. Hoffman, M. M. Voit, D. L. Olson

Steven P. Bradbury

N-Hydroxylation of aniline and 4-chloroaniline was quantified in rainbow trout microsomal preparations using h.p.l.c.-liquid scintillation methods. Radioactive phenylhydroxylamine and 4-chlorophenylhydroxylamine metabolites were identified by co-elution with non-labelled standards. The method provided resolution of metabolite standards, and quantification of both N-hydroxylated metabolites was achieved without derivatization. The maximum velocities at 25 degrees C were 33.8 +/- 1.40 and 22.0 +/- 0.98 pmol/min per mg for aniline and 4-chloroaniline N-hydroxylation, respectively. The Km values were 1.0 +/- 0.11 and 0.8 +/- 0.11 mM for aniline and 4-chloroaniline N-hydroxylation, respectively. These activities were not induced by treatment of the trout with Aroclor 1254 …


Inhibition Of Alcohol Dehydrogenase Activity By Acetylenic And Allylic Alcohols: Concordance With In Vivo Electrophile Reactivity In Fish, Steven P. Bradbury, Glenn M. Christensen Jan 1991

Inhibition Of Alcohol Dehydrogenase Activity By Acetylenic And Allylic Alcohols: Concordance With In Vivo Electrophile Reactivity In Fish, Steven P. Bradbury, Glenn M. Christensen

Steven P. Bradbury

Acetylenic and al!ylic alcohols have been reported to be 20 to 5,000 times more acutely toxic to fathead minnows (Pimephales promelas) than would be expected from a narcosis-based mechanism of action. The greater-than-expected toxicity of these alcohols has been proposed to be a result of metabolic activation to the corresponding reactive a ,)3-unsaturated aldehydes or allene derivatives. Using purified horse liver and rainbow trout (Oncorhynchus mykiss) hepatic cytosol alcohol dehydrogenase (ADH) preparations, the propensity of a series of acetylenic and allylic alcohols to inhibit enzyme activity, in both the presence and the absence of reduced glutathione, was ascertained. Those alcohols …


Use Of Respiratory-Cardiovascular Responses Of Rainbow Trout (Oncorhynchus Mykiss) In Identifying Acute Toxicity Syndromes In Fish: Part 4. Central Nervous System Seizure Agents, Steven P. Bradbury, Richard W. Carlson, Gerald J. Niemi, Tala R. Henry Jan 1991

Use Of Respiratory-Cardiovascular Responses Of Rainbow Trout (Oncorhynchus Mykiss) In Identifying Acute Toxicity Syndromes In Fish: Part 4. Central Nervous System Seizure Agents, Steven P. Bradbury, Richard W. Carlson, Gerald J. Niemi, Tala R. Henry

Steven P. Bradbury

The respiratory-cardiovascular responses of spinally transected rainbow trout to acutely lethal concentrations of chlorpyrifos, cypermethrin, fenvalerate, endosulfan, endrin, and strychnine were examined. Common to all six toxicants, the most striking change in respiratory-cardiovascular parameters was an increased cough frequency. Ventilation frequency and volume dropped in strychnine-exposed trout, but both remained near predose levels (frequency) or elevated (volume) in the pyrethroid- and cyclodiene-exposed trout. In chlorpyrifos-intoxicated trout, ventilation frequency decreased while volume increased. Oxygen consumption remained near predose levels in the chlorpyrifos-, pyrethroid-, and strychnine-exposed trout, but increased dramatically in the cyclodiene-exposed trout. Arterial oxygen, carbon dioxide, and pH declined in …


Introduction: Structural Properties For Determining Mechanisms Of Toxic Action, Steven P. Bradbury, Robert L. Lipnick Jan 1990

Introduction: Structural Properties For Determining Mechanisms Of Toxic Action, Steven P. Bradbury, Robert L. Lipnick

Steven P. Bradbury

The U.S. Environmental Protection Agency (EPA), under a variety of Federal legislation, is charged with the responsibility of assessing the hazards of chemicals to human health and the environment. In some cases EPA incorporates predictive techniques in its decisionmaking processes. In the context of some statutes, predictive toxicological methods can be cost-effective components in an overall approach for prioritizing chemicals for in-depth toxicological investigation. Predictive approaches are also used where empirical toxicological data are either unavailable or not required under a specific statute. For example, under Section 5 of the Toxic Substances Control Act (TSCA), EPA's Office of Toxic Substances …


Influence Of Cytochrome P450 Mixed-Function Oxidase Induction On The Acute Toxicity To Rainbow Trout (Salmo Gairdneri) Of Primary Aromatic Amines, Steven P. Bradbury, Joop L. M. Hermens, Steven J. Broderius Jan 1990

Influence Of Cytochrome P450 Mixed-Function Oxidase Induction On The Acute Toxicity To Rainbow Trout (Salmo Gairdneri) Of Primary Aromatic Amines, Steven P. Bradbury, Joop L. M. Hermens, Steven J. Broderius

Steven P. Bradbury

The influence of enzyme induction on the acute toxicity of aniline and 4-chloroaniline to rainbow trout (Salmo gairdneri) was investigated. For these two xenobiotics, bioactivation reactions are known to occur in mammals. Induction of cytochrome P450 mixed-function oxidase was obtained by intraperitoneal (ip) injection of trout with a mixture of polychlorinated biphenyls (Aroclor 1254). Five days after ip injection with three different doses of Aroclor 1254 (50. 100. and 200 mg/kg). benzo[a)pyrene hydroxylase activity in trout liver microsomes increased five- to sixfold. Cytochrome P450 concentrations in the microsomes were slightly. but significantly. enhanced in two of the three dose levels. …


Toxicology Of Synthetic Pyrethroids In Aquatic Organisms: An Overview, Steven P. Bradbury, Joel R. Coats, D. M. Symonik, S. D. Dyer, L. K. Timson, G. J. Atchison Aug 1989

Toxicology Of Synthetic Pyrethroids In Aquatic Organisms: An Overview, Steven P. Bradbury, Joel R. Coats, D. M. Symonik, S. D. Dyer, L. K. Timson, G. J. Atchison

Steven P. Bradbury

The aquatic toxicology of the photostable synthetic pyrethroid insecticides as it affects two important groups of susceptible organisms — fish and aquatic insects — is discussed. The sensitivity of these aquatic species to the pyrethroids is dependent on several factors, including toxicokinetics, target site (nervous system), sensitivity and possible secondary mechanisms of action, as well as chemical and physical properties of the aquatic medium that influence toxicity and bioavailability. Uptake rates and routes of fenvalerate greatly affected the toxicity of fenvalerate to mosquito larvae. LD50 values were determined for cuticular and dietary exposure routes by utilizing radiolabeled fenvalerate at the …


Toxicokinetics And Toxicodynamics Of Pyrethroid Insecticides In Fish, Steven P. Bradbury, Joel R. Coats May 1989

Toxicokinetics And Toxicodynamics Of Pyrethroid Insecticides In Fish, Steven P. Bradbury, Joel R. Coats

Steven P. Bradbury

The pyrethroid insecticides are extremely toxic to fish, with 96—h LC50 values generally below 10 μg/L and i.p. and i.v. LD50 values below 20 mg/kg. Corresponding LD50 values in mammals and birds are in the range of several hundred to several thousand milligrams per kilogram. This review examines pyrethroid toxicokinetics and toxicodynamics in fish as critical factors associated with species selectivity. Studies with permethrin, cypermethrin and fenvalerate have established that rates of metabolism and elimination in rainbow trout are significantly lower than those reported for birds and mammals. Comparatively low lethal brain pyrethroid concentrations and nonneural aspects of pyrethroid intoxication …


Use Of Respiratory-Cardiovascular Responses Of Rainbow Trout (Salmo Gairdneri) In Identifying Acute Toxicity Syndromes In Fish: Part 3. Polar Narcotics, Steven P. Bradbury, Tala R. Henry, Gerald J. Niemi, Richard W. Carlson, Virginia M. Snarski Mar 1989

Use Of Respiratory-Cardiovascular Responses Of Rainbow Trout (Salmo Gairdneri) In Identifying Acute Toxicity Syndromes In Fish: Part 3. Polar Narcotics, Steven P. Bradbury, Tala R. Henry, Gerald J. Niemi, Richard W. Carlson, Virginia M. Snarski

Steven P. Bradbury

The physiological responses of rainbow trout to acutely lethal aqueous concentrations of the suspected polar narcotics phenol, 2,4-dimethylphenol, aniline, 2-chloroaniline and 4-chloroaniline were examined. Visible signs of intoxication included tremors that progressed to whole-organism clonic seizures, followed by general depression and respiratory-cardiovascular collapse. Tremors and seizures were usually initiated with coughs. The most striking changes in the respiratory-cardiovascular parameters for all five toxicants included elevated cough frequency (coincident with seizures), ventilation frequency and hematocrit, and depressed gill oxygen uptake efficiency, arterial pH, total arterial oxygen and total arterial carbon dioxide. The physiological responses noted were attributed to the initial muscular …


Polar Narcosis In Aquatic Organisms, Steven P. Bradbury, Richard W. Carlson, Tala R. Henry Jan 1989

Polar Narcosis In Aquatic Organisms, Steven P. Bradbury, Richard W. Carlson, Tala R. Henry

Steven P. Bradbury

The majority of industrial organic chemicals lack identifiable structural characteristics that result in specific biological activity. These nonpolar-nonelectrolytes are acutely toxic to aquatic organisms via a nonspecific mode of action termed narcosis. The toxicity of industrial chemicals eliciting nonpolar narcosis can be reliably predicted by log P (baseline toxicity models). Using single chemical and joint toxic action models, several research groups have reported classes of polar compounds (for example, esters, phenols, and anilines) that elicit a narcosis-like syndrome; however, they are more acutely toxic than what is predicted using baseline toxicity models. An assessment of rainbow trout (Salmo gairdneri) in …


Comparative Toxicology Of The Pyrethroid Insecticides, Steven P. Bradbury, Joel R. Coats Jan 1989

Comparative Toxicology Of The Pyrethroid Insecticides, Steven P. Bradbury, Joel R. Coats

Steven P. Bradbury

The toxic effects elicited by synthetic pyrethroids in animals are varied in degree and nature. Their relative safety to birds and mammals contrasts sharply with their acute effects on fish and arthropods. Explantation of their differences in toxicity depends on examination of all factors of their comparative toxicology. Routes of exposure are important, as are metabolism and elimination rates, especially for mammals and birds with their considerable capabilities for biotransformation. Significant differences in sensitivity at the sites of toxic action may also play a role in differential responses to these insecticides. Finally, physical properties that influence the environmental disposition and …


Fish Acute Toxicity Syndromes And Their Use In The Qsar Approach To Hazard Assessment, Steven P. Bradbury, James M. Mckim, Gerald J. Niemi Jan 1987

Fish Acute Toxicity Syndromes And Their Use In The Qsar Approach To Hazard Assessment, Steven P. Bradbury, James M. Mckim, Gerald J. Niemi

Steven P. Bradbury

Implementation of the Toxic Substances Control Act of 1977 creates the need to reliably establish testing priorities because laboratory resources are limited and the number of industrial chemicals requiring evaluation is overwhelming. The use of quantitative structure activity relationship (QSAR) models as rapid and predictive screening tools to select more potentially hazardous chemicals for in-depth laboratory evaluation has been proposed. Further implementation and refinement of quantitative structure-toxicity relationships in aquatic toxicology and hazard assessment requires the development of a "mode-of-action" database. With such a database, a qualitative structure-activity relationship can be formulated to assign the proper mode of action, and …


Physiological Response Of Rainbow Trout (Salmo Gairdneri) To Acute Fenvalerate Lntoxication, Steven P. Bradbury, James M. Mckim, Joel R. Coats Jan 1987

Physiological Response Of Rainbow Trout (Salmo Gairdneri) To Acute Fenvalerate Lntoxication, Steven P. Bradbury, James M. Mckim, Joel R. Coats

Steven P. Bradbury

The physiological responses of rainbow trout (Salmo gairdneri) to fenvalerate intoxication during aqueous exposure were examined to provide information about the pyrethroid mode of action in fish. Trout (n = 4) were exposed to 412 ± 50 μg/liter fenvalerate and died in 10.9 ± 1.5 hr. Brain, liver, and carcass fenvalerate concentrations associated with mortality were 0.16 ± 0.05, 3.62 ± 0.57, and 0.25 ± 0.05 mg/kg, respectively. Visible signs of intoxication included elevated cough rate, tremors, and seizures. Histopathological examination of gill tissue showed damage consistent with irritation. An evaluation of respiratory-cardiovascular and blood chemistry responses indicated an elevated …