William Boyes - Academia.edu (original) (raw)

Papers by William Boyes

Neurotoxicology and Teratology

Inhalation Toxicology, 2014

Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and development... more Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.

Toxicology and Applied Pharmacology, 2012

Titanium dioxide nanoparticles (nano-TiO(2)) catalyze reactions under UV radiation and are hypoth... more Titanium dioxide nanoparticles (nano-TiO(2)) catalyze reactions under UV radiation and are hypothesized to cause phototoxicity. A human-derived line of retinal pigment epithelial cells (ARPE-19) was treated with six samples of nano-TiO(2) and exposed to UVA radiation. The TiO(2) nanoparticles were independently characterized to have mean primary particle sizes and crystal structures of 22nm anatase/rutile, 25nm anatase, 31nm anatase/rutile, 59nm anatase/rutile, 142nm anatase, and 214nm rutile. Particles were suspended in cell culture media, sonicated, and assessed for stability and aggregation by dynamic light scattering. Cells were treated with 0, 0.3, 1, 3, 10, 30, or 100μg/ml nano-TiO(2) in media for 24hrs and then exposed to UVA (2hrs, 7.53J/cm(2)) or kept in the dark. Viability was assessed 24hrs after the end of UVA exposure by microscopy with a live/dead assay (calcein-AM/propidium iodide). Exposure to higher concentrations of nano-TiO(2) with UVA lowered cell viability. The 25nm anatase and 31nm anatase/rutile were the most phototoxic (LC(50) with UVA<5μg/ml), while the 142nm anatase and 214nm rutile were the least phototoxic. An acellular assay ranked TiO(2) nanoparticles for their UVA photocatalytic reactivities. The particles were found to be capable of generating thiobarbituric acid reactive substances (TBARS) under UVA. Flow cytometry showed that nano-TiO(2) combined with UVA decreased cell viability and increased the generation of reactive oxygen species (ROS, measured by Mitosox). LC(50) values under UVA were correlated with TBARS reactivity, particle size, and surface area.

Toxicological Sciences, 2008

These experiments sought to establish a dose-effect relationship between the concentration of per... more These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE in the brains of adult Long-Evans rats following inhalation exposure. The model was evaluated for performance against tissue concentrations from exposed rats (n 5 40) and data from the published scientific literature. Visual function was assessed using steady-state pattern-elicited visualevoked potentials (VEPs) recorded from rats during exposure to air or PCE in two experiments (total n 5 84) with concentrations of PCE ranging from 250 to 4000 ppm. VEP waveforms were submitted to a spectral analysis in which the major response component, F2, occurring at twice the visual stimulation rate, was reduced in amplitude by PCE exposure. The F2 amplitudes were transformed to an effect-magnitude scale ranging from 0 (no effect) to 1 (maximum possible effect), and a logistical function was fit to the transformed values as a function of estimated concurrent brain PCE concentrations. The resultant function described a dose-response relationship between brain PCE concentration and changes in visual function with an ED 10 value of approximately 0.684 mg/l and an ED 50 value of approximately 46.5 mg/l. The results confirmed that visual function was disrupted by acute exposure to PCE, and the PBPK model and logistic model together could be used to make quantitative estimates of the magnitude of deficit to be expected for any given inhalation exposure scenario.

Toxicological Sciences, 1997

Toxicological Sciences, 1985

A series of neurophysiological tests was performed on Long-Evans hooded rats treated with either ... more A series of neurophysiological tests was performed on Long-Evans hooded rats treated with either 2-, 3-, or 4-methylpyridine at dosages of 100 mg/kg, approximately one-half the ip LD50. The tests contained measures of sensory function (paired pulse flash evoked potentials, pattern reversal evoked potentials, and brainstem auditory evoked responses) and cerebral excitability (pentylenetetrazol seizures and hippocampal afterdischarges). In general, rats treated with 2- and 3-methylpyridine were more affected than those treated with 4-methylpyridine. The changes observed were in many ways similar to those seen following administration of depressant compounds: increased latency of evoked potentials and increased latency to PTZ seizures. Not all findings, however, were consistent with previously observed patterns of central nervous system depression.

Cytometry Part A, 2010

Evaluation of the potential hazard of man-made nanomaterials has been hampered by a limited abili... more Evaluation of the potential hazard of man-made nanomaterials has been hampered by a limited ability to observe and measure nanoparticles in cells. In this study, different concentrations of TiO 2 nanoparticles were suspended in cell culture medium. The suspension was then sonicated and characterized by dynamic light scattering and microscopy. Cultured human-derived retinal pigment epithelial cells (ARPE-19) were incubated with TiO 2 nanoparticles at 0, 0.1, 0.3, 1, 3, 10, and 30 lg/ml for 24 hours. Cellular reactions to nanoparticles were evaluated using flow cytometry and dark field microscopy. A FACSCalibur TM flow cytometer was used to measure changes in light scatter after nanoparticle incubation. Both the side scatter and forward scatter changed substantially in response to the TiO 2. From 0.1 to 30 lg/ml TiO 2 , the side scatter increased sequentially while the forward scatter decreased, presumably due to substantial light reflection by the TiO 2 particles. Based on the parameters of morphology and the calcein-AM/propidium iodide viability assay, TiO 2 concentrations below 30 lg/ml TiO 2 caused minimal cytotoxicity. Microscopic analysis was done on the same cells using an E-800 Nikon microscope containing a xenon light source and special dark field objectives. At the lowest concentrations of TiO 2 (0.1-0.3 lg/ml), the flow cytometer could detect as few as 5-10 nanoparticles per cell due to intense light scattering by TiO 2. Rings of concentrated nanoparticles were observed around the nuclei in the vicinity of the endoplasmic reticulum at higher concentrations. These data suggest that the uptake of nanoparticles within cells can be monitored with flow cytometry and confirmed by dark field microscopy. This approach may help fulfill a critical need for the scientific community to assess the relationship between nanoparticle dose and cellular toxicity Such experiments could potentially be performed more quickly and easily using the flow cytometer to measure both nanoparticle uptake and cellular health. Published 2010 Wiley-Liss, Inc. y Key terms nanoparticles; side scatter; titanium dioxide; flow cytometry; darkfield microscopy THE rapid development and commercialization of man-made nanomaterials have outpaced information regarding the potential hazards of these materials to the environment, humans, or other organisms (1). This situation has prompted the US federal government to form a National Nanotechnology Initiative, which is focused on promoting the safe and responsible development of these promising new technologies (2). The US Environmental Protection Agency (EPA) has developed an overall approach for addressing man-made nanomaterials and a research strategy for the EPA Office of Research and Development (3,4). Nanoparticles may pose unique health risks beyond those posed by larger particles of the same material due to their compositions, reactivity, small sizes, and increased surface areas (3,5,6). Research on potential hazards of manufactured nanomaterials presents many technical challenges, one of which is a limited ability to detect and quantify nanoparticles in environmental media, tissues, or cells that may have been exposed to nanomaterials. The development of techniques to identify and characterize nanoparticles in cells and various

FUNDAMENTAL AND APPLIED …, 1997

Page 1. FUNDAMENTAL AND APPLIED TOXICOLOGY 40, 175-184 (1997) ARllClE NO. F A972388 WORKSHOP OVER... more Page 1. FUNDAMENTAL AND APPLIED TOXICOLOGY 40, 175-184 (1997) ARllClE NO. F A972388 WORKSHOP OVERVIEW William K. Boyes,.,3 Michael L. Dourson, t Jacqueline Patterson, t Hugh A. Tilson,. William F. Sette,:!: Robert C. MacPhail,. ...

Inhalation Toxicology, 2012

Neurotoxicology and Teratology, 2014

Ethanol-blended gasoline entered the market in response to demand for domestic renewable energy s... more Ethanol-blended gasoline entered the market in response to demand for domestic renewable energy sources, and may result in increased inhalation of ethanol vapors in combination with other volatile gasoline constituents. It is important to understand potential risks of inhalation of ethanol vapors by themselves, and also as a baseline for evaluating the risks of ethanol combined with a complex mixture of hydrocarbon vapors. Because sensory dysfunction has been reported after developmental exposure to ethanol, we evaluated the effects of developmental exposure to ethanol vapors on neurophysiological measures of sensory function as a component of a larger project evaluating developmental ethanol toxicity. Pregnant Long-Evans rats were exposed to target concentrations 0, 5000, 10,000, or 21,000 ppm ethanol vapors for 6.5h/day over GD9-GD20. Sensory evaluations of male offspring began between PND106 and PND128. Peripheral nerve function (compound action potentials, nerve conduction velocity (NCV)), somatosensory (cortical and cerebellar evoked potentials), auditory (brainstem auditory evoked responses), and visual evoked responses were assessed. Visual function assessment included pattern elicited visual evoked potentials (VEPs), VEP contrast sensitivity, and electroretinograms recorded from dark-adapted (scotopic), light-adapted (photopic) flashes, and UV flicker and green flicker. No consistent concentration-related changes were observed for any of the physiological measures. The results show that gestational exposure to ethanol vapor did not result in detectable changes in peripheral nerve, somatosensory, auditory, or visual function when the offspring were assessed as adults.

Critical reviews in toxicology, Jan 29, 2017

Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sus... more Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sustainable development, use, and eventual disposal requires the capability to forecast and avoid potential problems. This review provides a framework to evaluate the health and safety implications of ENM releases into the environment, including purposeful releases such as for antimicrobial sprays or nano-enabled pesticides, and inadvertent releases as a consequence of other intended applications. Considerations encompass product life cycles, environmental media, exposed populations, and possible adverse outcomes. This framework is presented as a series of compartmental flow diagrams that serve as a basis to help derive future quantitative predictive models, guide research, and support development of tools for making risk-based decisions. After use, ENM are not expected to remain in their original form due to reactivity and/or propensity for hetero-agglomeration in environmental media. Ther...

NeuroToxicology, 2016

Studies of humans chronically exposed to volatile organic solvents have reported impaired visual ... more Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000 ppm toluene by inhalation (6 hr/d, 5 d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not

ACS Nano, 2015

For nanotechnology to meet its potential as a game-changing and sustainable technology, it is imp... more For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future.

Environment International, 1981

Nida Research Monograph, Feb 1, 1993

... 1981; Apkarian and Spekreijse 1986 Coben et al. 1983; Smith et al. 1990 Levi and Manny 1986 C... more ... 1981; Apkarian and Spekreijse 1986 Coben et al. 1983; Smith et al. 1990 Levi and Manny 1986 Cosi et al. ... 1978). Recently, the formamidines have been shown to enhance susceptibility to amygdaloid kindling through local anesthetic-like properties (Gilbert and Mack 1989). ...

Journal of Econometrics, 1989

Most credit assessment models used in practice are based on simple credit scoring functions estim... more Most credit assessment models used in practice are based on simple credit scoring functions estimated by discriminant analysis. These functions are designed to distinguish whether or not applicants belong to the population of 'would be' defaulters. We suggest that the ...

Neurotoxicology, Mar 31, 2007

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relati... more Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Neurosci Biobehav Rev, 1991

Cross-species extrapolation will be defined as prediction from one species to another without emp... more Cross-species extrapolation will be defined as prediction from one species to another without empirical vetification. Cross-species mapping (CSM) is the same except empirical vetification is performed. CSM may be viewed as validation of methods for extrapolation. Algorithms for CSM may originate from theory, from empirical observations or a combination of the two. Regardless of their origins, CSM algorithms must be explicated and confidence intervals given around their predictions. This paper offers a quantitative method for constructing CSM equations which is useful in evaluation of the CSM and as an aid in the design of new experiments in CSM and extrapolation. The method requires fitting mathematical models for the physiological or behavioral phenomena to be mapped across species. A CSM equation can then be derived from the models in each species and approximate confidence limits may be obtained for predictions from the equation. The method is useful even when the models in the two species differ in form, implying differences in physiology or behavioral principles between species. The method proposed has a number of remaining uncertainties and possible problems.

Neurotoxicology and Teratology

Inhalation Toxicology, 2014

Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and development... more Ethanol (EtOH) exposure induces a variety of concentration-dependent neurological and developmental effects in the rat. Physiologically-based pharmacokinetic (PBPK) models have been used to predict the inhalation exposure concentrations necessary to produce blood EtOH concentrations (BEC) in the range associated with these effects. Previous laboratory reports often lacked sufficient detail to adequately simulate reported exposure scenarios associated with BECs in this range, or lacked data on the time-course of EtOH in target tissues (e.g. brain, liver, eye, fetus). To address these data gaps, inhalation studies were performed at 5000, 10 000, and 21 000 ppm (6 h/d) in non-pregnant female Long-Evans (LE) rats and at 21 000 ppm (6.33 h/d) for 12 d of gestation in pregnant LE rats to evaluate our previously published PBPK models at toxicologically-relevant blood and tissue concentrations. Additionally, nose-only and whole-body plethysmography studies were conducted to refine model descriptions of respiration and uptake within the respiratory tract. The resulting time-course and plethysmography data from these in vivo studies were compared to simulations from our previously published models, after which the models were recalibrated to improve descriptions of tissue dosimetry by accounting for dose-dependencies in pharmacokinetic behavior. Simulations using the recalibrated models reproduced these data from non-pregnant, pregnant, and fetal rats to within a factor of 2 or better across datasets, resulting in a suite of model structures suitable for simulation of a broad range of EtOH exposure scenarios.

Toxicology and Applied Pharmacology, 2012

Titanium dioxide nanoparticles (nano-TiO(2)) catalyze reactions under UV radiation and are hypoth... more Titanium dioxide nanoparticles (nano-TiO(2)) catalyze reactions under UV radiation and are hypothesized to cause phototoxicity. A human-derived line of retinal pigment epithelial cells (ARPE-19) was treated with six samples of nano-TiO(2) and exposed to UVA radiation. The TiO(2) nanoparticles were independently characterized to have mean primary particle sizes and crystal structures of 22nm anatase/rutile, 25nm anatase, 31nm anatase/rutile, 59nm anatase/rutile, 142nm anatase, and 214nm rutile. Particles were suspended in cell culture media, sonicated, and assessed for stability and aggregation by dynamic light scattering. Cells were treated with 0, 0.3, 1, 3, 10, 30, or 100μg/ml nano-TiO(2) in media for 24hrs and then exposed to UVA (2hrs, 7.53J/cm(2)) or kept in the dark. Viability was assessed 24hrs after the end of UVA exposure by microscopy with a live/dead assay (calcein-AM/propidium iodide). Exposure to higher concentrations of nano-TiO(2) with UVA lowered cell viability. The 25nm anatase and 31nm anatase/rutile were the most phototoxic (LC(50) with UVA<5μg/ml), while the 142nm anatase and 214nm rutile were the least phototoxic. An acellular assay ranked TiO(2) nanoparticles for their UVA photocatalytic reactivities. The particles were found to be capable of generating thiobarbituric acid reactive substances (TBARS) under UVA. Flow cytometry showed that nano-TiO(2) combined with UVA decreased cell viability and increased the generation of reactive oxygen species (ROS, measured by Mitosox). LC(50) values under UVA were correlated with TBARS reactivity, particle size, and surface area.

Toxicological Sciences, 2008

These experiments sought to establish a dose-effect relationship between the concentration of per... more These experiments sought to establish a dose-effect relationship between the concentration of perchloroethylene (PCE) in brain tissue and concurrent changes in visual function. A physiologically based pharmacokinetic (PBPK) model was implemented to predict concentrations of PCE in the brains of adult Long-Evans rats following inhalation exposure. The model was evaluated for performance against tissue concentrations from exposed rats (n 5 40) and data from the published scientific literature. Visual function was assessed using steady-state pattern-elicited visualevoked potentials (VEPs) recorded from rats during exposure to air or PCE in two experiments (total n 5 84) with concentrations of PCE ranging from 250 to 4000 ppm. VEP waveforms were submitted to a spectral analysis in which the major response component, F2, occurring at twice the visual stimulation rate, was reduced in amplitude by PCE exposure. The F2 amplitudes were transformed to an effect-magnitude scale ranging from 0 (no effect) to 1 (maximum possible effect), and a logistical function was fit to the transformed values as a function of estimated concurrent brain PCE concentrations. The resultant function described a dose-response relationship between brain PCE concentration and changes in visual function with an ED 10 value of approximately 0.684 mg/l and an ED 50 value of approximately 46.5 mg/l. The results confirmed that visual function was disrupted by acute exposure to PCE, and the PBPK model and logistic model together could be used to make quantitative estimates of the magnitude of deficit to be expected for any given inhalation exposure scenario.

Toxicological Sciences, 1997

Toxicological Sciences, 1985

A series of neurophysiological tests was performed on Long-Evans hooded rats treated with either ... more A series of neurophysiological tests was performed on Long-Evans hooded rats treated with either 2-, 3-, or 4-methylpyridine at dosages of 100 mg/kg, approximately one-half the ip LD50. The tests contained measures of sensory function (paired pulse flash evoked potentials, pattern reversal evoked potentials, and brainstem auditory evoked responses) and cerebral excitability (pentylenetetrazol seizures and hippocampal afterdischarges). In general, rats treated with 2- and 3-methylpyridine were more affected than those treated with 4-methylpyridine. The changes observed were in many ways similar to those seen following administration of depressant compounds: increased latency of evoked potentials and increased latency to PTZ seizures. Not all findings, however, were consistent with previously observed patterns of central nervous system depression.

Cytometry Part A, 2010

Evaluation of the potential hazard of man-made nanomaterials has been hampered by a limited abili... more Evaluation of the potential hazard of man-made nanomaterials has been hampered by a limited ability to observe and measure nanoparticles in cells. In this study, different concentrations of TiO 2 nanoparticles were suspended in cell culture medium. The suspension was then sonicated and characterized by dynamic light scattering and microscopy. Cultured human-derived retinal pigment epithelial cells (ARPE-19) were incubated with TiO 2 nanoparticles at 0, 0.1, 0.3, 1, 3, 10, and 30 lg/ml for 24 hours. Cellular reactions to nanoparticles were evaluated using flow cytometry and dark field microscopy. A FACSCalibur TM flow cytometer was used to measure changes in light scatter after nanoparticle incubation. Both the side scatter and forward scatter changed substantially in response to the TiO 2. From 0.1 to 30 lg/ml TiO 2 , the side scatter increased sequentially while the forward scatter decreased, presumably due to substantial light reflection by the TiO 2 particles. Based on the parameters of morphology and the calcein-AM/propidium iodide viability assay, TiO 2 concentrations below 30 lg/ml TiO 2 caused minimal cytotoxicity. Microscopic analysis was done on the same cells using an E-800 Nikon microscope containing a xenon light source and special dark field objectives. At the lowest concentrations of TiO 2 (0.1-0.3 lg/ml), the flow cytometer could detect as few as 5-10 nanoparticles per cell due to intense light scattering by TiO 2. Rings of concentrated nanoparticles were observed around the nuclei in the vicinity of the endoplasmic reticulum at higher concentrations. These data suggest that the uptake of nanoparticles within cells can be monitored with flow cytometry and confirmed by dark field microscopy. This approach may help fulfill a critical need for the scientific community to assess the relationship between nanoparticle dose and cellular toxicity Such experiments could potentially be performed more quickly and easily using the flow cytometer to measure both nanoparticle uptake and cellular health. Published 2010 Wiley-Liss, Inc. y Key terms nanoparticles; side scatter; titanium dioxide; flow cytometry; darkfield microscopy THE rapid development and commercialization of man-made nanomaterials have outpaced information regarding the potential hazards of these materials to the environment, humans, or other organisms (1). This situation has prompted the US federal government to form a National Nanotechnology Initiative, which is focused on promoting the safe and responsible development of these promising new technologies (2). The US Environmental Protection Agency (EPA) has developed an overall approach for addressing man-made nanomaterials and a research strategy for the EPA Office of Research and Development (3,4). Nanoparticles may pose unique health risks beyond those posed by larger particles of the same material due to their compositions, reactivity, small sizes, and increased surface areas (3,5,6). Research on potential hazards of manufactured nanomaterials presents many technical challenges, one of which is a limited ability to detect and quantify nanoparticles in environmental media, tissues, or cells that may have been exposed to nanomaterials. The development of techniques to identify and characterize nanoparticles in cells and various

FUNDAMENTAL AND APPLIED …, 1997

Page 1. FUNDAMENTAL AND APPLIED TOXICOLOGY 40, 175-184 (1997) ARllClE NO. F A972388 WORKSHOP OVER... more Page 1. FUNDAMENTAL AND APPLIED TOXICOLOGY 40, 175-184 (1997) ARllClE NO. F A972388 WORKSHOP OVERVIEW William K. Boyes,.,3 Michael L. Dourson, t Jacqueline Patterson, t Hugh A. Tilson,. William F. Sette,:!: Robert C. MacPhail,. ...

Inhalation Toxicology, 2012

Neurotoxicology and Teratology, 2014

Ethanol-blended gasoline entered the market in response to demand for domestic renewable energy s... more Ethanol-blended gasoline entered the market in response to demand for domestic renewable energy sources, and may result in increased inhalation of ethanol vapors in combination with other volatile gasoline constituents. It is important to understand potential risks of inhalation of ethanol vapors by themselves, and also as a baseline for evaluating the risks of ethanol combined with a complex mixture of hydrocarbon vapors. Because sensory dysfunction has been reported after developmental exposure to ethanol, we evaluated the effects of developmental exposure to ethanol vapors on neurophysiological measures of sensory function as a component of a larger project evaluating developmental ethanol toxicity. Pregnant Long-Evans rats were exposed to target concentrations 0, 5000, 10,000, or 21,000 ppm ethanol vapors for 6.5h/day over GD9-GD20. Sensory evaluations of male offspring began between PND106 and PND128. Peripheral nerve function (compound action potentials, nerve conduction velocity (NCV)), somatosensory (cortical and cerebellar evoked potentials), auditory (brainstem auditory evoked responses), and visual evoked responses were assessed. Visual function assessment included pattern elicited visual evoked potentials (VEPs), VEP contrast sensitivity, and electroretinograms recorded from dark-adapted (scotopic), light-adapted (photopic) flashes, and UV flicker and green flicker. No consistent concentration-related changes were observed for any of the physiological measures. The results show that gestational exposure to ethanol vapor did not result in detectable changes in peripheral nerve, somatosensory, auditory, or visual function when the offspring were assessed as adults.

Critical reviews in toxicology, Jan 29, 2017

Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sus... more Engineered nanomaterials (ENM) are a growing aspect of the global economy, and their safe and sustainable development, use, and eventual disposal requires the capability to forecast and avoid potential problems. This review provides a framework to evaluate the health and safety implications of ENM releases into the environment, including purposeful releases such as for antimicrobial sprays or nano-enabled pesticides, and inadvertent releases as a consequence of other intended applications. Considerations encompass product life cycles, environmental media, exposed populations, and possible adverse outcomes. This framework is presented as a series of compartmental flow diagrams that serve as a basis to help derive future quantitative predictive models, guide research, and support development of tools for making risk-based decisions. After use, ENM are not expected to remain in their original form due to reactivity and/or propensity for hetero-agglomeration in environmental media. Ther...

NeuroToxicology, 2016

Studies of humans chronically exposed to volatile organic solvents have reported impaired visual ... more Studies of humans chronically exposed to volatile organic solvents have reported impaired visual functions, including low contrast sensitivity and reduced color discrimination. These reports, however, lacked confirmation from controlled laboratory experiments. To address this question experimentally, we examined visual function by recording visual evoked potentials (VEP) and/or electroretinograms (ERG) from four sets of rats exposed repeatedly to toluene. In addition, eyes of the rats were examined with an ophthalmoscope and some of the retinal tissues were evaluated for rod and M-cone photoreceptor immunohistochemistry. The first study examined rats following exposure to 0, 10, 100 or 1000 ppm toluene by inhalation (6 hr/d, 5 d/wk) for 13 weeks. One week after the termination of exposure, the rats were implanted with chronically indwelling electrodes and the following week pattern-elicited VEPs were recorded. VEP amplitudes were not

ACS Nano, 2015

For nanotechnology to meet its potential as a game-changing and sustainable technology, it is imp... more For nanotechnology to meet its potential as a game-changing and sustainable technology, it is important to ensure that the engineered nanomaterials and nanoenabled products that gain entry to the marketplace are safe and effective. Tools and methods are needed for regulatory purposes to allow rapid material categorization according to human health and environmental risk potential, so that materials of high concern can be targeted for additional scrutiny, while material categories that pose the least risk can receive expedited review. Using carbon nanotubes as an example, we discuss how data from alternative testing strategies can be used to facilitate engineered nanomaterial categorization according to risk potential and how such an approach could facilitate regulatory decision-making in the future.

Environment International, 1981

Nida Research Monograph, Feb 1, 1993

... 1981; Apkarian and Spekreijse 1986 Coben et al. 1983; Smith et al. 1990 Levi and Manny 1986 C... more ... 1981; Apkarian and Spekreijse 1986 Coben et al. 1983; Smith et al. 1990 Levi and Manny 1986 Cosi et al. ... 1978). Recently, the formamidines have been shown to enhance susceptibility to amygdaloid kindling through local anesthetic-like properties (Gilbert and Mack 1989). ...

Journal of Econometrics, 1989

Most credit assessment models used in practice are based on simple credit scoring functions estim... more Most credit assessment models used in practice are based on simple credit scoring functions estimated by discriminant analysis. These functions are designed to distinguish whether or not applicants belong to the population of 'would be' defaulters. We suggest that the ...

Neurotoxicology, Mar 31, 2007

Synthesizing information about the acute neurotoxicity of organic solvents into predictive relati... more Synthesizing information about the acute neurotoxicity of organic solvents into predictive relationships between exposure and effect in humans is difficult because (1) data are usually derived from experimental animals whose sensitivity to the chemical relative to humans is unknown; (2) the specific endpoints measured in laboratory animals seldom translate into effects of concern in humans; and (3) the mode of action of the chemical is rarely understood. We sought to develop approaches to estimate the hazard and cost of exposure to organic solvents, focusing on the acute behavioral effects of toluene in rats and humans. Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data suggested that a 10% change in rat avoidance behavior occurs at a blood concentration of toluene 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. In contrast, our in vitro studies of nicotinic acetylcholine receptors indicated that human and rat receptors do not differ in sensitivity to toluene. Analysis of other dose-response relationships for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific endpoints measured in the two species rather than by inherent differences in sensitivity to toluene. We also explored the hypothesis that dose-equivalence relationships may be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs are estimatable, may be used as a benchmark effect for estimating the monetary benefits of controlling exposure to organic solvents. This dose-equivalence method is applicable for solvents because this set of data fulfills three important assumptions about equivalence relationships based on a single effect: (1) a common dose metric (concentration of the chemical in the brain); (2) a common effect to provide a linking variable (choice reaction time); and (3) a common mode of action (interference with neuronal ion channel function).

Neurosci Biobehav Rev, 1991

Cross-species extrapolation will be defined as prediction from one species to another without emp... more Cross-species extrapolation will be defined as prediction from one species to another without empirical vetification. Cross-species mapping (CSM) is the same except empirical vetification is performed. CSM may be viewed as validation of methods for extrapolation. Algorithms for CSM may originate from theory, from empirical observations or a combination of the two. Regardless of their origins, CSM algorithms must be explicated and confidence intervals given around their predictions. This paper offers a quantitative method for constructing CSM equations which is useful in evaluation of the CSM and as an aid in the design of new experiments in CSM and extrapolation. The method requires fitting mathematical models for the physiological or behavioral phenomena to be mapped across species. A CSM equation can then be derived from the models in each species and approximate confidence limits may be obtained for predictions from the equation. The method is useful even when the models in the two species differ in form, implying differences in physiology or behavioral principles between species. The method proposed has a number of remaining uncertainties and possible problems.