Biomedical subjects

W K Boyes

Publications and source records attributed to W K Boyes.

At least 19 recordsLinked to original sources

PubMed2002

A comparison of Haber's rule at different ages using a physiologically based pharmacokinetic (PBPK) model for chloroform in rats.

Haber's rule as commonly interpreted in inhalation toxicology, can be stated as exposure concentration times duration equals a constant biological effect, or C x t=k. In other words, identical products of concentration and duration lead to the same effect. The goals of this paper are to develop a biological and pharmacokinetic modeling approach for chloroform, and to evaluate Haber's rule for different ages by taking into account the physiological changes due to growth and aging in rats. Three-dimensional dose-response surfaces for liver toxicity were generated for each age group of interest: adolescent, adult, and senescent rats. The three-dimensional surfaces were then characterized with a generalized description of Haber's rule for each age group. The simulations suggest that adolescent rats need higher exposure levels in order to achieve similar levels of liver damage compared to adults or senescent rats, if the comparison is made using the same exposure length. In summary, a pharmacokinetic modeling approach with a biological framework including the chemical's mode of action, was used to relate concentration, exposure duration and effect. Major advantages of this approach include: the potential ability to extrapolate to humans, the inclusion of aging in the simulations, and the ability to summarize the results using a generalized form of Haber's rule.

Administration, Inhalation↗

PubMed2002

A physiologically based pharmacokinetic model for trichloroethylene in the male long-evans rat.

A physiologically based pharmacokinetic (PBPK) model for trichloroethylene (TCE) in the male Long-Evans (LE) rat was needed to aid in evaluation of neurotoxicity data collected in this rodent stock. The purpose of this study was to develop such a model with the greatest possible specificity for the LE rat. The PBPK model consisted of 5 compartments: brain, fat, slowly perfused tissue, rapidly perfused viscera, and liver. Partition coefficients (blood, fat, muscle, brain, liver) were determined for LE rats. The volumes of the brain, liver, and fat compartments were estimated for each rat, with tissue-specific regression equations developed from measurements made in LE rats. Vapor uptake data from LE rats were used for estimation of Vmaxc. As blood flow values for LE rats were not available, values from Sprague-Dawley (SD) and Fischer-344 (F344) rats were used in separate simulations. The resulting values of Vmaxc were used to simulate tissue (blood, liver, brain, fat) TCE concentrations, which were measured during (5, 20, 60 min) and after (60 min of TCE followed by 60 min of air) flow-through inhalation exposures of LE rats to 200, 2000, or 4000 ppm TCE. Simulation of the experimental data was improved by use of F-344 blood-flow values and the corresponding Vmaxc (8.68 mg/h/kg) compared to use of SD flows and the associated Vmaxc (7.34 mg/h/kg). Sensitivity analysis was used to determine those input parameters with the greatest influence on TCE tissue concentrations. Alveolar ventilation consistently (across exposure concentration, exposure duration, and target tissue) had the greatest impact on TCE tissue concentration. The PBPK model described here is being used to explore the relationship between measures of internal dose of TCE and neurotoxic outcome.

Adipose Tissue↗

PubMed2000

Retinal degeneration in licensed pesticide applicators.

BACKGROUND: Retinal degeneration is the leading cause of visual impairment in older adults, but little is known about its relationship to neurotoxic exposures. METHODS: The Agricultural Health Study is a cohort study of licensed pesticide applicators from Iowa and North Carolina. We used cross-sectional data from self-administered questionnaires given at enrollment in 1994-1996 to compare pesticide use in 154 applicators who reported retinal degeneration and 17,804 controls. RESULTS: Retinal degeneration was associated with fungicide use (odds ratio = 1.8, 95% confidence interval = 1.3-2.6). This relationship was seen in subgroups defined by state, demographic characteristics, or medical history, as well as in the entire group. Risk increased with cumulative days of fungicide use (P for trend = 0.011) and was greater when application methods involving greater personal exposure were used. Retinal degeneration was also related to use of organochlorine or carbamate insecticides, but these associations were less consistent. Since nearly all applicators used organophosphate insecticides and herbicides, these exposures could not be effectively evaluated. CONCLUSIONS: These results suggest that exposure to some fungicides and insecticides may increase risk of retinal degeneration.

Adolescent↗

PubMed2000

Neurotoxic and pharmacokinetic responses to trichloroethylene as a function of exposure scenario.

Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concentrations and durations. The goal of this project was to describe the relationship between the concentration and duration of exposure to inhaled trichloroethylene (TCE), a representative volatile organic chemical, tissue dose as predicted by a physiologically based pharmacokinetic model, and neurotoxicity. Three measures of neurotoxicity were studied: hearing loss, signal detection behavior, and visual function. The null hypothesis was that exposure scenarios having an equivalent product of concentration and duration would produce equal toxic effects, according to the classic linear form of Haber's Rule ((italic)C(/italic) times t = k), where C represents the concentration, t, the time (duration) of exposure, and k, a constant toxic effect. All experiments used adult male, Long-Evans rats. Acute and repeated exposure to TCE increased hearing thresholds, and acute exposure to TCE impaired signal detection behavior and visual function. Examination of all three measures of neurotoxicity showed that if Haber's Rule were used to predict outcomes across exposure durations, the risk would be overestimated when extrapolating from shorter to longer duration exposures, and underestimated when extrapolating from longer to shorter duration exposures. For the acute effects of TCE on behavior and visual function, the estimated concentration of TCE in blood at the time of testing correlated well with outcomes, whereas cumulative exposure, measured as the area under the blood TCE concentration curve, did not. We conclude that models incorporating dosimetry can account for differing exposure scenarios and will therefore improve risk assessments over models considering only parameters of external exposure.

Animals↗

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↗

PubMed1998

The organophosphate pesticide chlorpyrifos affects form deprivation myopia.

PURPOSE: The effects of the anti-cholinesterase organophosphate pesticide chlorpyrifos (CPF) on the refractive development of the eye were examined. Form deprivation was used to induce eye growth to address the previously reported relationship between organophosphate pesticide use and the incidence of myopia. METHODS: Chickens, a well-established animal model for experimental myopia and organophosphate neurotoxicity, were dosed with chlorpyrifos (3 mg/kg per day, orally, from day 2 to day 9 after hatching) or corn oil vehicle (VEH) with or without monocular form deprivation (MFD) over the same period. The set of dependent measures included the refractive state of each eye measured using retinoscopy, axial dimensions determined with A-scan ultrasound, and intraocular pressure. RESULTS: Dosing with CPF yielded an inhibition of 35% butyrylcholinesterase in plasma and 45% acetylcholinesterase in brain. MFD resulted in a significant degree of myopia in form-deprived eyes resulting from significant lengthening of the vitreal chamber of the eye. CPF significantly reduced the effect of MFD, resulting in less myopic eyes (mean refraction: VEH-MFD = -16.2 +/- 2.3 diopters; CPF-MFD = -11.1 +/- 1.8 diopters) with significantly shorter vitreal chambers. Nonoccluded eyes were, on average, slightly hyperopic. Treatment with CPF for 1 week in the absence of MFD led to no significant change in ocular dimensions or refraction relative to controls. CONCLUSIONS: The use of form deprivation as a challenge suggests that CPF treatment interferes with the visual regulation of eye growth.

Animals↗

PubMed1997

A comparison of the acute neuroactive effects of dichloromethane, 1,3-dichloropropane, and 1,2-dichlorobenzene on rat flash evoked potentials (FEPs).

Previous research showed that acute exposure to dichloromethane (DCM) produced a selective reduction in peak N30 of flash evoked potentials (FEPs) in rats. In contrast, acute exposures to p-xylene or toluene selectively reduced FEP peak N160. The present experiments compared the effects of DCM (log P = 1.25; oil:water partition coefficient), 1,3-dichloropropane (DCP; log P = 2.00), and 1,2-dichlorobenzene (DCB; log P = 3.38) on FEPs recorded from adult Long-Evans rats. Before administration of test compounds, FEPs were recorded for five daily sessions to develop FEP peak N160. Test compounds were dissolved in corn oil and administered i.p. at doses based on proportions of their LD50 values. The doses were: DCM, 0, 57.5, 115, 230, or 460 mg/kg; DCP, 0, 86, 172, 343, or 686 mg/kg; and DCB, 0, 53, 105, 210, or 420 mg/kg. Testing times after dosing varied among compounds and were based on pilot studies to measure both the times of peak effect and recovery. Each solvent produced significant changes in the latency and amplitude of multiple components of the FEP waveforms. However, the predominant effect of DCM was to reduce the amplitude of peak N30 (ED50 = 326.3 mg/kg), that of DCP was to reduce both peaks N30 (ED50 = 231.0 mg/kg) and N160 (ED50 = 136.8 mg/kg), and that of DCB was to reduce peak N160 (ED50 = 151.6 mg/kg). There was no consistent relationship between log P values and the potency of the compounds to alter FEP peaks N30 and N160. The results suggest that organic solvents have multiple acute effects on the function of the central nervous system, which are not predictable solely by the compound's lipid solubility.

Animals↗

PubMed1997

EPA's neurotoxicity risk assessment guidelines.

The proposed Neurotoxicity Risk Assessment Guidelines (U.S. EPA, 1995c Fed. Reg. 60(192), 52032-52056) of the U.S. Environmental Protection Agency (EPA) were the subject of a workshop at the 1997 Meeting of the Society of Toxicology. The workshop considered the role of guidelines in the risk assessment process, the primary features, scientific basis, and implications of the guidelines for EPA program offices, as well as for industrial neurotoxicologists from the perspectives of both pesticides and toxic substances regulation. The U.S. National Academy of Sciences (NAS, 1983, Risk Assessment in the Federal Government: Managing the Process) established a framework for distinguishing risk management from risk assessment, the latter being the result of integrating hazard identification, hazard characterization, and exposure assessment data. The guidelines are intended to establish operating principles that will be used when examining data in a risk assessment context. The proposed neurotoxicity risk assessment guidelines provide a conceptual framework for deciding whether or not a chemically induced effect can be considered to be evidence of neurotoxicity. Topics in the proposed guidelines include structural and functional effects, dose-response and -duration considerations, and relationships between effects. Among the issues that must be considered are the multiplicity of chemical effects, the levels of biological organization in the nervous system, and the tests, measurements, and protocols used. Judgment of the adversity of an effect depends heavily on the amount and types of data available. The attribution of a chemically induced effect to an action on the nervous system depends on several factors such as the quality of the study, the nature of the outcome, dose-response and time-response relationships, and the possible involvement of nonneural factors. The guidelines will also serve as a reference for those conducting neurotoxicity testing, as well as establish a consistent approach to neurotoxicity risk assessment by regulators. Extending this approach through international harmonization would be advantageous to the development of products for a worldwide market. Thus, both risk assessors and regulated industries have a large stake in the guidelines to provide a framework that will lead to accurate risk assessment decisions.

Data Collection↗

PubMed1996

Possible confounding effects of strobe "clicks" on flash evoked potentials in rats.

Flash evoked potentials (FEPs) undergo within- and between-session changes and are modified by auditory white noise (26). We examined whether an auditory potential produced by the "click" associated with the strobe discharge could be recorded, and if alterations in an auditory response could explain the within- and between-session changes in FEPs. We also examined differences between a frontal cortex or a nasal reference electrode location on FEPs and auditory potentials. An auditory potential associated with the strobe discharge could be clearly recorded. This response was eliminated by the presence of 80 dB SPL masking white noise. However, the within- and between-session changes in FEPs could not be explained by modifications of the auditory potential. Animals whose ear drums were ruptured did not exhibit an auditory response, and their FEPs were similar to those of controls tested in the presence of masking white noise. A nasal reference electrode decreased the impact of auditory potentials on FEPs, but allow visual potentials (electroretinogram and optic tract activity) to influence FEPs. The data show that auditory potentials associated with the strobe discharge can be recorded from the visual cortex of rats, and that these auditory responses represent a possible confounding factor in the interpretation of toxicological studies employing FEPs.

Acoustic Stimulation↗

PubMed1995

Combined effects of paired solvents on the rat's auditory system.

A number of volatile organic solvents have been shown to be ototoxic to rats, but there is little information regarding how solvents might act in this way when encountered in combination. To examine this issue, male Long Evans rats were exposed by inhalation to pairs of solvents known to be ototoxic when administered individually; those reported on here are trichloroethylene+toluene, mixed xylenes+trichloroethylene, xylenes+chlorobenzene, and chlorobenzene+toluene. Rats were exposed 8 h/day for 5 consecutive days, using complementary proportions of isoeffective concentrations of the solvents alone. Hearing was assessed by brainstem-evoked response audiometry. The effects were as predicted by a linear dose-addition model, indicating additive rather than synergistic or antagonistic interactions at the concentrations studied.

Administration, Inhalation↗

PubMed1995

Work-site clinical and neurobehavioral assessment of solvent-exposed microelectronics workers.

Twenty-five workers, five currently and 20 formerly involved in the manufacture of hybrid microcircuits, underwent clinical evaluations at the request of a management-union committee concerned about chronic solvent exposures in a research and development laboratory. A battery of neurobehavioral tests was administered to compare the solvent-exposed group with 32 age-, gender-, ethnicity-, and education-matched controls. The tests included: MMPI-I, hand grip strength, tactile sensitivity, dexterity, color discrimination, visual acuity and contrast sensitivity, and tests selected from the computerized Neurobehavioral Evaluation System (NES2). Clinical narratives and retrospective exposure assessments in the study group suggested chronic low-level exposure to solvents, with intermittent acute excursions. Work-related diagnoses included upper respiratory mucosal irritation and sinusitis (44%), lower respiratory reactive airway disease (12%), and dermatitis (5%). Three workers (12%) had findings consistent with a solvent-induced encephalopathy. Significant differences (after Bonferroni correction) were found between the two groups on 5 of 11 NES subtests: symptom scale, mood scale, finger tapping, simple reaction time, and symbol-digit substitution. Differences also reached significance for overall vibration sensitivity thresholds, visual contrast sensitivity, and grip strength. The MMPI average clinical scale elevation was significantly higher in the exposed group than controls. These results support an association between chronic low-dose solvent exposure and measurable neurobehavioral changes.

Adult↗

PubMed1995

Assessment of offspring development and behavior following gestational exposure to inhaled methanol in the rat.

The prospect of widespread human exposure associated with its use as an alternative fuel has sparked concern about the toxic potential of inhaled methanol (MeOH). Previous studies have revealed congenital malformations in rats following inhaled MeOH (Nelson et al. (1985). Fundam. Appl. Toxicol. 5, 727-736) but these studies did not include postnatal behavioral assessment. In the present study, pregnant Long-Evans rats were placed in exposure chambers containing 15,000 ppm MeOH or air for 7 hr/day on Gestational Days (GD) 7-19. The total alveolar dose of methanol was estimated at about 6.1 g/kg/day, for a total dose of about 42.7 g/kg for the entire study. Maternal body weights were recorded daily and blood methanol concentrations were determined at the end of exposure on GD 7, 10, 14, and 18. Following birth (Postnatal Day 0 [PND 0]), a number of tests were performed at various points in development, including: offspring mortality and body wt (PND 1,3), motor activity (PND 13-21, 30, 60), olfactory learning (PND 18), behavioral thermoregulation (PND 20-21), T-maze learning (PND 23-24), acoustic startle response (PND 24, 60), reflex modification audiometry (PND 60), pubertal landmarks (PND 31-56), passive avoidance (PND 72), and visual-evoked potentials (PND 160). Maternal blood MeOH levels, measured from samples taken within 15 min after removal from the exposure chamber, declined from about 3.8 mg/ml on the first day of exposure to 3.1 mg/ml on the 12th day of exposure. MeOH transiently reduced maternal body wt (4-7%) on GD 8-10, and offspring BW (5%) on PND 1. No other test revealed significant effects of MeOH. Prenatal exposure to high levels of inhaled MeOH appears to have little effect on this broad battery of tests beyond PND 1 in the rat.

Administration, Inhalation↗

PubMed1994

Within-session changes in peak N160 amplitude of flash evoked potentials in rats.

The negative peak occurring approximately 160 ms after stimulation (peak N160) of flash evoked potentials (FEPs) of rats changes with repeated testing. Habituation, sensitization, and arousal have all been invoked to explain these changes, but few studies have directly tested these explanations. We examined within-session changes in peak N160 amplitude with repeated testing, and the modulatory effects of stimulus intensity and auditory white noise. Peak N160 amplitude increased with daily testing (between-session changes), and was larger at greater stimulus intensities. In contrast, peak N160 amplitude underwent within-session increases on early days and within-session decreases on later days. The within-session changes were not affected by stimulus intensity. In rats previously tested in a quiet environment, exposure to acoustic white noise increased motor activity and transiently decreased peak N160 amplitude, which then increased and subsequently decreased with continued photic and acoustic stimulation. Repeated testing in the presence of noise did not alter the within-session changes in peak N160 amplitude. Heart rate showed both within- and between-session decreases, but was unaffected by noise. The data suggest that the within-session changes in peak N160 amplitude may reflect a habituation-like response to the test environment.

Acoustic Stimulation↗

PubMed1994

Rat and human sensory evoked potentials and the predictability of human neurotoxicity from rat data.

The development of comprehensive quantitative models as alternatives to risk assessment based on uncertainty factors will require many steps, among them consideration of the relationships between the health endpoints which are measured in laboratory animals and humans. Sensory evoked potentials are measures of sensory function which can be recorded from many species, including humans, and as such provide an opportunity for examining the extrapolation of neurotoxicity data from laboratory animals to humans. Our research strategy for investigating how well laboratory rat data predict human neurotoxic risk involves comparing parametric stimulus manipulations and drug treatments in both species. Finally, we are comparing results in humans with neurodegenerative conditions, including those induced by neurotoxicant exposure, with animal models. To date, we have focused on pattern-elicited visual evoked potentials (VEPs) recorded from pigmented rats and humans. Parametric manipulations of spatial frequency, temporal frequency and stimulus contrast revealed parallel functions, displaced for differences in absolute sensitivity. Additionally, diazepam produced similar effects in rats and human volunteers. A quantitative cross-species map was developed to illustrate the prediction of human effects from rat data. Exposure to carbon disulfide produced changes in rat VEP-derived contrast sensitivity functions, which resembled psychophysically-measured loss of visual contrast sensitivity in human workers exposed to organic solvents. The results of these continuing efforts should help indicate how well animal electrophysiological measures predict human neurotoxicity.

Animals↗

PubMed1993

Assessing the neurotoxic potential of chemicals--a multidisciplinary approach.

Since 1981, the development of methodology to assess the neurotoxic potential of chemicals has been a high priority within the International Programme on Chemical Safety (IPCS). Following the completion of an in-depth review of the scientific principles and methods for the assessment of neurotoxicity associated with chemical exposures, IPCS started to develop a multidisciplinary and comprehensive approach for neurotoxicity testing of chemicals. In view of the complexity of the nervous system and the variety of effects caused by chemicals, no single test or approach will be appropriate. Initially, IPCS evaluated neurobehavioral tests as well as in vitro procedures as screening tests, and an international collaborative study of neurobehavioral tests appropriate for screening chemicals for neurotoxicity is now in progress. Possible integration of higher level neurobehavioral tests with neurophysiological, biochemical, and pathological procedures in future testing strategies are discussed.

Hazardous Substances↗

PubMed1993

Prolonged neurobehavioral and visual effects of short-term exposure to 3,3'-iminodipropionitrile (IDPN) in rats.

Strategies for neurotoxicity testing often include initial screening tests, such as a functional observational battery (FOB) and motor activity assessment, followed by detailed characterization studies. In this study, a neurobehavioral screening battery (FOB and motor activity) was used to evaluate the effects of 3-day repeated exposure to 0, 100, 200, or 400 mg/kg/day IDPN. Adult Long-Evans rats (males and females) were tested before dosing and 1, 14, 28, 56, and 91 days after the third dose. IDPN initially produced generalized CNS depression, weakness, and hypothermia. Thereafter, marked hyperactivity, increased excitability, decreased reactivity to visual and auditory stimuli, neuromuscular weakness, equilibrium changes, and a "waltzing syndrome" (vertical and lateral head movements, circling, and retropulsion) emerged and persisted for 3 months. Males were more severely affected than females. Following neurobehavioral testing, the rats were examined for visual function using flash (three intensities) and pattern (three pattern sizes by three contrast levels)-elicited visual evoked potentials (VEPs). IDPN produced changes in pattern- and flash-elicited VEPs, thus verifying predictions made from the screening tests. However, the extent of the VEP changes produced by IDPN was insufficient to account for some of the deficits detected in the FOB, which are dependent on sensory, integrative, and motor functions. Thus, profound neurological effects of IDPN were detected using this screening battery and visual effects were confirmed using VEPs. These effects, following only three doses of IDPN, lasted for at least 3 months and thus may be permanent.

Animals↗

PubMed1993

Acute effects of ethanol on pattern reversal and flash-evoked potentials in rats and the relationship to body temperature.

The effects of acute ethanol treatment on flash and pattern reversal visual evoked potentials (FEPs and PREPs, respectively) were examined in three experiments using Long-Evans rats. The relationships of evoked potential parameters with blood ethanol concentration and body temperature were examined. In Experiment 1, rats were treated i.p. with vehicle or 0.5, 1.0 or 2.0 g ethanol/kg body weight, and tested 30 min later. The 2.0 g/kg group had prolonged latencies of PREP peaks, no changes in PREP peak-to-peak amplitudes, and lower body temperatures than saline-treated controls. The peak latency shifts were significantly correlated with both blood ethanol concentration and body temperature, and were of a magnitude to be expected from similar changes in body temperature alone. Experiment 2 measured both PREPs and paired-flash FEPs in rats 30 min after injection of either 0, 0.5 or 2.0 g/kg ethanol. PREP changes were found following treatment with the high dose which were similar to those of Experiment 1. Some FEP peak latencies were prolonged and peak-to-peak amplitudes were reduced by both doses of ethanol, despite the fact that body temperatures were reduced at only the high dose. At 2.0 g/kg ethanol, the FEP changes in latency, but not amplitude, were in accordance with what would be expected from body temperature changes alone. The third study attempted to investigate the role of reduced body temperature in producing the visual evoked potential changes by testing at room temperatures of 22 or 30 degrees C. Contrary to expectations, the rats receiving 2 g/kg ethanol were approx. 1 degree C cooler than controls at both room temperatures. Evoked potential latencies were greater in ethanol-treated rats than controls at both room temperatures. There were no significant effects of ethanol on FEP amplitudes. Overall, the effects of low doses of ethanol were independent of temperature changes, but the effects of higher doses of ethanol (2.0 g/kg) could not be distinguished from those produced by differences in body temperature alone.

Analysis of Variance↗

PubMed1993

Combined effects of solvents on the rat's auditory system: styrene and trichloroethylene.

Because exposures to toxic agents typically involve more than one substance, it is necessary to know if combined exposures pose different risks than those to single agents. Many solvents have been implicated in central nervous disorders and some of them are known to produce hearing loss, probably mediated by damage to cochlear hair cells. Hearing loss was studied by recording the brainstem auditory evoked response (BAER) in male Long Evans rats exposed 8 h/day for 5 days to mixtures of styrene (STY) and trichloroethylene (TCE). Dose groups included air or solvent pairs (STY/TCE) in the following concentrations (ppm): (0:3000), (250:2250), (500:1500), (750:750) and (1000:0). Decreased BAER amplitude, indicative of hearing loss, was correlated with blood levels of total solvent. The effects were as predicted by a linear dose-addition model, indicating neither synergistic nor antagonistic interactions at the concentrations studied.

Acoustic Stimulation↗