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Biomedical subjects

V A Benignus

Publications and source records attributed to V A Benignus.

At least 19 recordsLinked to original sources
PubMed2002

Carbon monoxide and the nervous system.

Carbon monoxide (CO) is a colorless, tasteless, odorless, and non-irritating gas formed when carbon in fuel is not burned completely. It enters the bloodstream through the lungs and attaches to hemoglobin (Hb), the body's oxygen carrier, forming carboxyhemoglobin (COHb) and thereby reducing oxygen (O(2)) delivery to the body's organs and tissues. High COHb concentrations are poisonous. Central nervous system (CNS) effects in individuals suffering acute CO poisoning cover a wide range, depending on severity of exposure: headache, dizziness, weakness, nausea, vomiting, disorientation, confusion, collapse, and coma. At lower concentrations, CNS effects include reduction in visual perception, manual dexterity, learning, driving performance, and attention level. Earlier work is frequently cited to justify the statement that CO exposure sufficient to produce COHb levels of ca. 5% would be sufficient to produce visual sensitivity reduction and various neurobehavioral performance deficits. In a recent literature re-evaluation, however, the best estimate was that [COHb] would have to rise to 15-20% before a 10% reduction in any behavioral or visual measurement could be observed. This conclusion was based on (1) critical review of the literature on behavioral and sensory effects, (2) review and interpretation of the physiological effects of COHb on the CNS, (3) extrapolation from the effects of hypoxic hypoxia to the effects of CO hypoxia, and (4) extrapolation from rat behavioral effects of CO to humans. Also covered in this review article are effects of chronic CO exposure, the discovery of neuroglobin, a summary of the relatively new role for endogenous CO in neurotransmission and vascular homeostasis, groups which might be especially sensitive to CO, and recommendations on further research. The interested reader is directed to other published reviews of the literature on CO and historically seminal references that form our understanding of this ubiquitous gas.

Animals↗
PubMed2001

Quantitative cross-species extrapolation in noncancer risk assessment.

A procedure has been developed to extrapolate dose-effect findings across species and quantify some of the associated uncertainty via traditional statistical methods. The relationship between dose-effect curves which are known in two species can be described by a k-parameter dose equivalence equation (DEE). When a DEE is determined for as many agents of a given "family" as are known, a k-dimensional distribution of DEE parameters would obtain. When an actual extrapolation is to be made for a new agent of the same family which has not been (or cannot be) tested in the species to which results are to be extrapolated, the best estimate of the parameters of the new DEE would be some measure of central tendency and the best estimate of the uncertainty would be the variance/covariance of the k-dimensional distribution of DEE parameters. The method of extrapolation seeks to compliment the mechanistic knowledge or be a substitute for mechanistic methods in the large majority of cases where such understanding is lacking.

Dose-Response Relationship, Drug↗
PubMed1998

A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans.

The literature on behavioral effects of exposure to toluene is difficult to assess due, in part, to a wide variety of exposure conditions employed and outcomes measured. This study investigated whether previous experiments would be more consistent with each other if toluene exposure parameters were expressed not as concentration and duration, but as estimated amount of toluene in tissues. A physiologically based pharmacokinetic (PBPK) model was used to estimate concentration of toluene in arterial blood (CaTOL) from published studies in rats and humans exposed acutely to toluene vapor. Data for rats were selected from studies of avoidance behavior using both rate of responding and measures of successful responding. Data for humans were from studies of choice reaction time (CRT). Behavioral measures were converted to proportion of baseline to place them on a common scale across experiments. A meta-analysis was done to fit dose-effect curves using CaTOL and the rescaled effects. Results demonstrated that effects were an orderly function of CaTOL and were not influenced by concentration or duration of exposure, except as exposure influenced CaTOL. In rats, response rates first increased, reached a peak, and then declined as CaTOL increased. Successful avoidance in rats and CRT in humans always declined as CaTOL increased. In rats, response rates were increased by 10% at CaTOL approximately 13 ml/L. In humans, reaction times increased by 10% at CaTOL approximately 3 ml/L. Cross-species comparisons were made with the following caveats: PBPK uncertainties, few human data, and poor task comparability.

Animals↗
PubMed1997

Systematic considerations in the area of multiple chemical sensitivity.

Many workers who speculate about multiple chemical sensitivity (MCS) have devised a large number of hypothetical constructs designed to explain the phenomena. Too often these are not logically connected to the larger body of scientific thought but instead appeal to ideas not documented in accessible literature and often appearing metaphysical in nature.

Environmental Health↗
PubMed1995

A model to predict carboxyhemoglobin and pulmonary parameters after exposure to O2, CO2, and CO.

A computer-based physiological model of respiratory gas exchange, which considered variation in inhaled oxygen and carbon dioxide, was modified to include the effects of inhaled carbon monoxide. Output from the modified model consists of 60 variables, including blood, alveolar and tissue gases, ventilatory function and carboxyhemoglobin. Extensive testing demonstrated that this model produced accurate results for known problems and physiologically plausible results for situations in which the results were not empirically known. Estimates of the effects of simultaneous continuously varying exposure to carbon monoxide, oxygen and carbon dioxide cannot be practically obtained with other extant methods. The modified model receives input from two computer files containing environmental and subject physiological variables. These files allow a continuous dynamic multi-gas exposure simulation or actual exposure data profiles. Up to four outputs can be selected for plotting or stored in a file for later analysis.

Carbon Dioxide↗
PubMed1994

Carboxyhemoglobin formation due to carbon monoxide exposure in rats.

The Coburn-Forster-Kane equation (CFKE) is a well-tested model for prediction of carboxyhemoglobin (COHb) formation due to carbon monoxide (CO) exposure in humans. There have been few and relatively poorly tested attempts to implement a CFKE for rats. Such an implementation is of interest because many experiments on the effects of CO in rats were done without measuring COHb. To extrapolate from rats to humans requires a rat version of the CFKE. Rats were exposed to 150, 250, 500, and 1000 ppm CO for up to 240 min. Blood gases and COHb were measured. A CFKE was implemented for rats by using parameters found in the literature and estimating them from the data. It was deduced from the blood-gas data that rats hyperventilate slightly as COHb increases. The blood-gas data were used to estimate ventilation and alveolar capillary oxygen partial pressure. The hyperventilation required an iterative solution to the CFKE. The iterative CFKE predictions were found to differ statistically from observations, but in explainable ways and/or in small amounts.

Analysis of Variance↗
PubMed1994

Behavioral effects of carbon monoxide: meta analyses and extrapolations.

In the absence of reliable data, this work was performed to estimate the dose-effects function of carboxyhemoglobin (HbCO) on behavior in humans. Meta analysis is the quantitative analysis of the combined findings of a number of research reports. By meta analysis, an HbCO-behavior dose-effects function was estimated for rats and corrected for effects of hypothermia (which accompanies acute HbCO increases in rats but not in humans). By use of pulmonary function models and blood gas equations, equivalent HbCO values were calculated for data in the literature on hypoxic hypoxia and behavior. Another meta analysis was performed to fit a dose-effects function to the equivalent HbCO data and to correct for the behavioral effects of hypocapnia (which usually occurs during hypoxic hypoxia but not with HbCO elevation). The two extrapolations agreed closely and indicated that, for healthy sedentary persons, 18-25% HbCO would be required to produce a 10% decrement in behavior. Confidence intervals are computed to characterize the uncertainty. Frequent reports of lower-level effects are discussed.

Animals↗
PubMed1994

Prediction of carboxyhemoglobin formation due to transient exposure to carbon monoxide.

Fifteen men were exposed to 6,683 ppm C18O for 3.09-6.65 min. Arterial and antecubital vein blood samples were drawn at 1-min intervals beginning at the start of C18O inhalation and ending 10 min later. Simultaneously, alveolar ventilation was calculated from the measured values of minute ventilation and dead space. All other parameters of the Coburn-Forster-Kane equation (CFKE), except the Haldane affinity ratio, were measured separately in each subject. Means of CFKE predictions of increases in venous HbCO (delta HbCO) in samples collected approximately 2 min after cessation of exposure were accurate, but the range in errors of prediction for individual subjects was +/- 3.8% HbCO, depending on the time after exposure cessation. Increases in venous and arterial HbCO were inaccurately predicted during and immediately after HbCO formation, however. Venous blood was overestimated during CO uptake because of a delayed appearance of HbCO. Individual subjects differed markedly in the degree of delay of HbCO appearance in venous blood. Arterial delta HbCO was consistently underestimated either by the CFKE or by predictions based on venous blood samples. Thus, exposure of such organs as brain or heart to HbCO may be substantially higher than expected during transient high-level CO exposure.

Adolescent↗
PubMed1994

Effect of regional circulation patterns on observed HbCO levels.

In an earlier experiment, we briefly exposed 15 young men to high levels of CO while simultaneously monitoring arterial and peripheral venous HbCO levels. The arterial HbCO levels were considerably higher than the venous levels during the CO exposure. Furthermore, great variation in the difference between arterial and venous HbCO levels was observed, with the maximal difference for each subject ranging from 2.3 to 12.1% HbCO. In the present paper, we suggest an explanation for the observed differences between arterial and venous HbCO on the basis of the regional circulation of the forearm, where both samples were taken. Because regional circulation patterns are known to vary with physical training, the differences in physical training between subjects may account for the observed variation. An expanded model was derived from the Coburn-Forster-Kane equation, which reflects the above hypothesis. Most of the parameter values for the expanded model were measured on individual subjects. Literature values were used for other parameters. Two parameters were estimated using five of the subjects and were then used in the predictions of the expanded model for the remaining subjects.

Arteries↗
PubMed1991

Quantitative methods for cross-species mapping (CSM).

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.

Animals↗
PubMed1988

Babble and random-noise masking of speech in high and low context cue conditions.

"Perceptual" masking of speech by multitalker speech (babble) has been widely reported but poorly quantified. Furthermore, the validity of the construct of perceptual masking is questionable. This report describes an experiment using a newly standardized test of speech perception in noise (SPIN) with both babble and spectrally matched random-noise maskers. Classical psychophysical ogive curves were used to model speech recognition as a function of signal-to-noise ratio (S/N). The two maskers yielded speech recognition functions of the same steepness but different locations on the S/N axis. The high-context items of SPIN yielded speech recognition curves with steeper slope and different locations on the S/N axis than the low-context items. These data are used to argue that perceptual masking was not documented (under certain assumptions) and that the superior masking of babble may be explained in purely acoustical terms. Speculations are offered about the possible acoustical differences that could be responsible for the differences in masking effect.

Acoustics↗
PubMed1986

Unrecognized errors due to analog filtering of the brain-stem auditory evoked response.

Analog filtering of the brain-stem auditory evoked response (BAER) and synthetic wave forms using steeply sloped filters are shown to produce significant distortion even when filter cut-off frequencies are well removed from the wave form spectrum. The degree of distortion is such that it may result in erroneous identification of peaks in the BAER. Reversal of the order of peaks may occur with high pass settings at only 1/4 the lowest constituent frequency. Filter effects were identified as a major source of cross-laboratory differences in BAERs recorded from laboratory rats. Filter transfer functions of a typical analog filter set were derived for both gain and phase as a function of frequency. Filtering of synthetic wave forms was used to elucidate and highlight distortion effects. A typical Long-Evans rat BAER wave form was spectrum analyzed and conclusions were drawn with respect to appropriate bandpass frequencies.

Analog-Digital Conversion↗
PubMed1984

Toluene levels in blood and brain of rats as a function of toluene level in inspired air.

The relationship of toluene concentration in blood and brain to the concentration of toluene in inspired air has not been explicitly studied. Sixty rats were exposed by inhalation to 50, 100, 500, or 1000 ppm toluene for 3 hr. Immediately following exposure, venous blood samples and whole brains were collected and assayed for toluene levels. For several empirical reasons, the natural logarithm (log) of toluene tissue levels were predicted in a linear model from log toluene levels in air. An additional 10 rats were exposed to 550 ppm toluene for 8 hr in order to verify that the 3-hr exposure was sufficient to produce near-asymptotic levels of toluene in blood and brain. Log brain toluene concentration was significantly higher than log blood concentration by an additive constant. The ratio of brain to blood toluene level was estimated as 1.56/1. Three- and eight-hour exposure results did not differ, thus indicating that these results would hold for toluene exposures of 3 hr or greater.

Animals↗
PubMed1984

Toluene blood level following subcutaneous injection of toluene in the rat.

A model of toluene level in blood following subcutaneous injection of toluene mixed with polyoxyethylated-vegetable-oil vehicle was developed. The purpose was to provide a means of predicting dose received for subsequent toxicologic studies for any time and dose combination. The pharmacokinetics were of secondary interest. Using data from 111 rats, a four-parameter equation was devised to predict the time course of toluene blood level from 20-480 min post dosing, for dose levels of 50-1000 mg/kg. Blood concentrations rose at a rate which was independent of dose level. Maximum blood levels were uniquely determined by dose level. Blood levels fell at different rates depending upon dose level. Injection exposure, when compared to inhalation, has the advantages of (a) low expense, (b) low equipment requirements, and (c) simplicity. The disadvantage is, for some experiments, poor temporal stimulation of the normal route of administration, inhalation.

Animals↗
PubMed1984

Recommendations for appropriate statistical practice in toxicologic experiments.

Appropriate statistical practice in toxicologic research is reviewed. The problem centers on the antagonistic needs to discover toxic effects and avoid false indictments of harmless compounds. Specific problems which distort error rates include having many dependent variables, conducting many tests on a variable, data snooping, lack of statistical power and 5) violations of statistical assumptions. Solution strategies include top down planning, designing efficient experiments, balancing type I and type II error rates, selecting hypotheses and 5) using appropriate statistical analysis methods. Top down planning and the "leapfrog" design strategy are particularly emphasized.

Research Design↗
PubMed1982

Olfaction: anatomy, physiology and behavior.

The anatomy, physiology and function of the olfactory system are reviewed, as are the normal effects of olfactory stimulation. It is speculated that olfaction may have important but unobtrusive effects on human behavior.

Animals↗