Biomedical subjects

S G Gilbert

Publications and source records attributed to S G Gilbert.

At least 19 recordsLinked to original sources

PubMed1995

Effects of developmental methylmercury exposure or lifetime lead exposure on vibration sensitivity function in monkeys.

Paresthesias are a frequently reported symptom of methylmercury exposure in adults, while peripheral neuropathy has long been known to result from high-level lead exposure. Despite this, no objective determination of somatosensory function has been performed in either humans or animals for either toxicant. Somatosensory function was assessed following developmental methylmercury exposure or lifetime lead exposure in monkeys (Macaca fascicularis) by determination of sensitivity to vibration applied to the fingertip. Vibration thresholds were determined over a number of frequencies, from 25 to 250 Hz, by means of a behavioral procedure. The underside of the tip of the monkey's middle finger was precisely positioned over a blunt probe attached to a vibrator. The monkey signaled detection of the vibration by breaking contact with a stainless steel bar with the free hand. At each of the five frequencies tested, the amplitude of the vibration was manipulated systematically to determine the monkey's threshold of detection. Four of five monkeys dosed with methylmercury from birth to 7 years of age, with blood mercury levels during dosing of 0.8-1.1 micrograms/g, exhibited elevated thresholds when tested at 18 years of age. Two monkeys dosed in utero through 4 years of age, with blood mercury levels of 0.35 micrograms/g during dosing, were impaired when tested at 15 years of age, while two monkeys with histories of blood mercury levels of 0.70 were relatively unimpaired. Lifetime exposure to lead resulting in stable blood lead levels of 20-25 micrograms/dl resulted in elevated vibration sensitivity only at the highest frequency in all four individuals tested. However, only two of six individuals with high lead levels (60-130 micrograms/dl) exhibited impairment. These results represent severe impairment in methylmercury-exposed monkeys 11 years after cessation of dosing and extend previous research documenting visual and auditory impairment in these monkeys. While effects of lifetime lead exposure on vibration sensitivity observed in the present study are suggestive, there is clearly a need for further research.

Animals↗

PubMed1995

Neurobehavioral effects of developmental methylmercury exposure.

Methylmercury (MeHg) is a global environmental problem and is listed by the International Program of Chemical Safety as one of the six most dangerous chemicals in the world's environment. Human exposure to MeHg primarily occurs through the consumption of contaminated food such as fish, although catastrophic exposures due to industrial pollution have occurred. The fetus is particularly sensitive to MeHg exposure and adverse effects on infant development have been associated with levels of exposure that result in few, if any, signs of maternal clinical illness or toxicity. High levels of prenatal exposure in humans result in neurobehavioral effects such as cerebral palsy and severe mental retardation. Prenatal exposure to MeHg in communities with chronic low-level exposure is related to decreased birthweight and early sensorimotor dysfunction such as delayed onset of walking. Neurobehavioral alterations have also been documented in studies with nonhuman primates and rodents. Available information on the developmental neurotoxic effects of MeHg, particularly the neurobehavioral effects, indicates that the fetus and infant are more sensitive to adverse effects of MeHg. It is therefore recommended that pregnant women and women of childbearing age be strongly advised to limit their exposure to potential sources of MeHg. Based on results from human and animal studies on the developmental neurotoxic effects of methylmercury, the accepted reference dose should be lowered to 0.025 to 0.06 MeHg microgram/kg/day. Continued research on the neurotoxic effects associated with low level developmental exposure is needed.

Animals↗

PubMed1994

In utero caffeine exposure affects feeding pattern and variable ratio performance in infant monkeys.

Adult female monkeys (Macaca fascicularis) were exposed via their drinking water to 0.0, 0.15, or 0.35 mg/ml of caffeine prior to and throughout pregnancy. Caffeine exposure resulted in a dose-related increase in the number of infant deaths at parturition. Additional females were added to the control group and the original groups were rebred, which resulted in 16, 13, and 9 live infants in control, low-dose, and high-dose groups, respectively. During pregnancy the mean serum caffeine levels were 3.4 and 10.3 micrograms/ml and the mean serum theophylline levels were 6.6 and 12.9 micrograms/ml for the low-dose and high-dose groups, respectively. Infants were separated from their mothers at birth and reared in a primate nursery to facilitate evaluation of infant performance on a variety of behavioral tasks. Infant formula consumption was monitored by a computer-based system 19 hr per day until 30 days of age. At 30 days of age infants were trained to press a button for a formula reward, after which they performed on a variable ratio schedule for a 14-day period. Monitoring of feeding pattern revealed that the treated infants spent significantly more time feeding than controls. On the variable ratio schedule, the high-dose group had consistently longer pause times and longer interresponse times than the control group. The results from this study indicate that in utero exposure to caffeine and its metabolites results in altered behavioral patterns in infant monkeys.

Animals↗

PubMed1993

Effects of in utero methylmercury exposure on a spatial delayed alternation task in monkeys.

Adult female monkeys (Macaca fascicularis) were exposed to 0, 50, 70, or 90 micrograms/kg/day of methylmercury prior to and throughout pregnancy and produced 11, 9, 2, and 2 infants, respectively. At birth, blood mercury levels of treated infants ranged from 1.04 to 2.46 ppm. At approximately 7 to 9 years of age, the monkeys were trained by successive approximation to respond on a lit button for a small amount of apple juice. The monkeys were then trained on a 0.1-sec spatial delayed alternation task to a specified criterion of performance. This was followed by 10 sessions each of fixed delay times of 0.5, 1, 3, 5, and 10 sec, followed by 20 sessions containing variable delay times of 0.1 to 15 sec. Data from all treated monkeys were combined. There were no differences between treated and control monkeys in initial button training or number of sessions to reach criterion on 0.1-sec delay procedure. On the fixed delay sessions, the treated monkeys had significantly more correct trials, and fewer incorrect responses, perseverative responses, and delay responses than controls. There were no differences between the treated and control monkeys on performance on the variable delay schedule. Results from this study indicate that in utero methylmercury exposure did not adversely affect the spatial memory of adult monkeys when tested on a delayed alternation task and may have facilitated performance on this task.

Animals↗

PubMed1993

Relation of vertebral bone screw axial pullout strength to quantitative computed tomographic trabecular bone mineral content.

Noninvasive prediction of the maximum axial load that a spinal bone screw will be able to withstand after anterior surgical placement would be highly useful. To investigate if this is feasible, we first performed preliminary experiments to distinguish the trabecular and cortical contributions to overall stiffness; the trabecular component was found to dominate. We then used a commercial computed tomography bone mineral package to determine the mineral density of the trabecular region of 41 porcine vertebrae in terms of equivalent K2HPO4 concentration; values ranged from 104 to 343 mg/cm3. A 6.5-mm diameter cancellous bone screw was then inserted laterally in each vertebra, and the ultimate tensile strength (UTS) of the screw/bone interface was measured using a tensile testing machine. The UTS values ranged from 589 to 2,620 Newtons. A superlinear relation was found between UTS and the projected K2HPO4 concentration in the direction of the screw axis, expressed in units of mg/cm2.

Animals↗

PubMed1992

Exposure to methyl mercury from birth to adulthood impairs high-frequency hearing in monkeys.

Hearing deficits are a frequent consequence of both developmental and adult methyl mercury exposure in humans. However, a detailed characterization of these deficits has not been performed in either humans or animals. Cynomolgus monkeys (Macaca fascicularis) were dosed from birth to 7 years of age with 50 micrograms/kg/day of mercury as methyl mercuric chloride. Steady-state blood mercury levels during dosing were 0.6-0.9 ppm. When monkeys were 14 years old, pure tone detection thresholds were determined by a psychophysical procedure. Control monkeys exhibited thresholds at frequencies between 125 and 31,500 Hz comparable to previously published values for macaques. One methyl mercury-treated monkey exhibited normal detection thresholds at all frequencies. Three treated monkeys were impaired at the second highest frequency tested (25,000 Hz) and therefore were not tested at 31,500 Hz. The fifth treated monkey displayed severely elevated thresholds at middle frequencies (10,000-12,500 Hz), precluding testing at higher frequencies. These results indicate a selective high-frequency deficit in monkeys exposed to methyl mercury from birth to adulthood and not exposed to methyl mercury in the 7 intervening years before auditory testing. These findings extend previous results in this group of monkeys in which deficits in spatial and temporal visual function were observed.

Animals↗

PubMed1991

Water diffusivity in starch-based systems.

The objective of this study was to investigate the influence of structure, and component interactions, on the sorption and transport properties of water in starch-based systems. We compared the effective diffusivity (Deff) of water in two starches, with differing amylose-amylopectin ratios, using either kinetics of water adsorption or analysis of drying curves (water desorption) to estimate Deff. The effect of incorporating small sugar molecules into the granular or gelatinized starch matrices on Deff was measured by drying curve analysis. To investigate the possible mechanisms of water transport, the porosity and microscopic appearance of the samples at different stages of drying were determined. In a complementary study, sorption isotherms and the number of accessible "binding" sites in the starch and starch-sugar systems were determined using gravimetric analysis and inverse gas chromatography (IGC) 'probe analysis'. In the case of the starch-sugar systems, the measurements were made after the components had been 'mechanically mixed', or after more intimate mixing had been achieved by a co-freeze-drying process. The Deff of the starches was found to depend, in a complex way, on the moisture content of the samples. At relatively high moisture contents, the predominant mode of water transport was by liquid diffusion. As the samples became drier, their porosity increased, and the predominant mode of moisture transport was by vapor phase diffusion. As the samples became very dry (less than 10% water content), Deff fell significantly. Incorporation of sugars, in general, led to a reduction of Deff, which was correlated with a corresponding fall in porosity. In agreement with the findings of other workers, for the starches studied, the value of Deff determined from water adsorption measurements was significantly less than Deff determined from water desorption (drying curve analysis). The form of the Deff versus moisture content relationship was, however, independent of the method of measurement (adsorption or desorption). The water sorption and IGC probe analysis results indicated that some physicochemical interaction was expedited by the freeze-drying process. This interaction was manifested by a reduction in water sorption at a given relative vapor pressure, and by major changes in the accessibility of the co-freeze-dried samples to organic probe molecules. Taken together, the results indicate that water transport (diffusion) in starches and in starch-sugar mixtures is dependent significantly on gross structural features (development of porosity during drying), but that specific molecular, physico-chemical interactions must also be considered.

Adsorption↗

PubMed1991

Effects of chronic caffeine consumption in pregnant monkeys (Macaca fascicularis) on blood and urine clinical chemistry parameters.

Pregnancy requires a variety of physiological adaptations to create an environment for the optimal development of the fetus. The widespread consumption of the methylxanthines especially caffeine and to a lesser extent theophylline by pregnant women suggests that it is important to determine whether these methylxanthines may influence maternal physiology during pregnancy. Forty female monkeys (Macaca fascicularis), randomly divided into three groups, were exposed to caffeine in their drinking water (0, 0.15, or 0.35 mg/ml) before, during, and after pregnancy. This exposure resulted in a dose-related increase in reproductive failure in the form of stillbirths, miscarriages, and decreased maternal weight gain. Blood and 24-hr urine samples were collected every 2 weeks for clinical chemistry analysis. There were a number of both pregnancy-related changes and treatment-related effects on the clinical chemistry measures. As expected, serum cholesterol and triglyceride levels declined during pregnancy for all dose groups but there were no treatment-related effects. Serum and urine creatinine levels were increased in both treated groups. Serum glucose levels, which usually decline during pregnancy, remained elevated in the high-dose group. Serum estrogen levels in the high-dose groups were depressed compared to those of the other two groups. These changes indicate that elevated serum levels of caffeine and its metabolites, particularly theophylline, may influence maternal physiology during pregnancy in the monkey.

Animals↗

PubMed1991

Somatic development of the infant monkey following in utero exposure to caffeine.

Caffeine has been associated with a number of reproductive and developmental effects in animals and humans. In an effort to characterize the potential effects of caffeine on the developing infant, 40 adult female monkeys (Macaca fascicularis) were randomly divided into three groups and exposed at 0, 0.15, and 0.35 mg/ml (equivalent to 0, 10-15, and 25-30 mg/kg/day, respectively) of caffeine via their drinking water, before, during, and after pregnancy. Maternal blood and milk samples were collected following parturition. Infants were separated from their mothers within 12 hr of birth and were reared in a primate nursery. Blood samples were collected during the first week of life, and body weight, somatic measurements, and food consumption data were collected throughout the first 3 years. Maternal blood and milk concentrations and infant blood concentrations of caffeine and theophylline (the major blood metabolite of caffeine in the monkey) were similar to one another. Infant half-life of these methylxanthines was longer than that of the adult but not as long as that observed in human infants. Body weights and somatic measurements of male infants were significantly reduced over the first 30 days, as were a number of initial somatic measurements in both male and female infants. These deficits were not evident after 1 year of age. There were no treatment-related effects on infant tooth eruption or milk consumption. Results from this study support previously published results from this group of monkeys as well as studies by other researchers in rodents indicating that caffeine consumption during pregnancy can alter infant somatic development.

Animals↗

PubMed1990

Methods for predicting migration to packaged pharmaceuticals.

The compatibility of the pharmaceutical product with packaging materials is an important parameter which must be evaluated during the product development process. This paper discusses the possibility that pertinent FDA methodology can be modified in a more efficient way using currently available analytical techniques. Several studies on potential migrants from packaging materials, such as heat-seal adhesives, amber polyethylene terephthalate (PET) containers, and rubber gaskets of aerosol valves, are presented to show that commonly encountered questions with regard to packaging materials used during product stability studies can also be answered in the same way.

Chemical Phenomena↗

PubMed1990

Sensitive periods for lead-induced behavioral impairment (nonspatial discrimination reversal) in monkeys.

A total of 52 nursery-reared monkeys (Macaca fascicularis) were dosed orally with 1.5 mg/kg/day of lead on one of four dosing regimens (13 monkeys/group): Group 1, vehicle only; Group 2, dosed with lead continuously from birth; Group 3, dosed with lead from birth to 400 days of age and vehicle thereafter; and Group 4, dosed with vehicle from birth to 300 days of age and lead thereafter. This dosing regimen allowed evaluation of differential infant vulnerability as well as reversibility of the behavioral toxicity of lead. Blood lead concentrations averaged 3-6 micrograms/dl when monkeys were not being exposed to lead, 32-36 micrograms/dl when being dosed with lead and having access to infant formula, and 19-26 micrograms/dl during lead exposure after weaning from infant formula. When monkeys were 5-6 years old, they were tested on a series of nonspatial discrimination reversal tasks: form, form with irrelevant color cues, color with irrelevant form cues, and alternating form and color. Group 2 exhibited the greatest degree of impairment compared to controls. Group 4 also exhibited impaired performance, although less marked than that of Group 2. Group 3 was not impaired on this series of tasks. These results confirm findings observed in other monkeys exposed continuously to lead and suggest that while exposure beginning after infancy produces impairment, exposure during infancy as well exacerbates the effect.

Aging↗

PubMed1990

Effects of developmental exposure to methyl mercury on spatial and temporal visual function in monkeys.

Detailed characterization of several aspects of visual function was made in two groups of monkeys exposed developmentally to methyl mercury. One group of monkeys (Macaca fascicularis) was dosed from birth onward with 50 micrograms/kg/day of mercury as methyl mercury. Another group was exposed in utero by dosing the mother with 10, 25, or 50 micrograms/kg/day of mercury as methyl mercury, and postnatally until 4.0-4.5 years of age with the same dose the mother had received. Spatial and temporal visual function was tested in both groups. Spatial visual deficits observed in the group dosed beginning postnatally were reported previously (Rice and Gilbert, 1982, Science, 216, 759-761). Monkeys exposed in utero plus postnatally exhibited impaired high- and low-luminance spatial vision. They also exhibited deficits in low-frequency high-luminance temporal vision, while low-luminance temporal vision was superior to that of control monkeys. Monkeys in which exposure began at birth displayed superior low-luminance temporal vision, while high-luminance temporal vision was not impaired. These effects were observed in the absence of constriction of visual fields. These data suggest that the pattern of visual deficits produced by developmental exposure to methyl mercury may be different from that in the adult, and that the developing visual system may be able to remodel as a result of early insult by a neurotoxic agent.

Animals↗

PubMed1990

Lack of sensitive period for lead-induced behavioral impairment on a spatial delayed alternation task in monkeys.

A total of 52 monkeys (Macaca fascicularis) were dosed orally with vehicle or 1.5 mg/kg/day of lead on one of four dosing regimens (13 monkeys/group): vehicle only; dosed with lead from birth onward; dosed with lead from birth to 400 days of age and vehicle thereafter; dosed with vehicle from birth to 300 days of age and lead thereafter. Blood lead concentrations averaged 3-6 micrograms/dl when monkeys were not being dosed with lead, 32-36 micrograms/dl when being dosed with lead and having access to infant formula, and 19-26 micrograms/dl when being dosed with lead after weaning from infant formula. When monkeys were 6-7 years old, they were tested on a spatial delayed alternation task. The task required the monkey to alternate responses between two push buttons. The initial delay was 0.10 sec and was increased in steps to 15 sec by the end of the experiment. All three treated groups were impaired to approximately an equal degree. Deficits were observed in the initial training procedure, and at the longer delay values. These results suggest that there is not an early critical period for lead-induced impairment on this task and that exposure only during infancy results in impairment comparable to ongoing exposure beginning at birth. These results are in contrast to previous findings on a series of nonspatial discrimination reversal tasks, in which the group exposed early in life only was unimpaired, while the group exposed beginning after infancy was less impaired that the group exposed continuously from birth.

Age Factors↗

PubMed1990

Determination of potential migrants from commercial amber polyethylene terephthalate bottle wall.

Potential migrants were isolated from commercial polyethylene terephthalate (PET) bottles using Soxhlet extraction. The concentrated extract was then subjected to GC/MS analysis. A total of 19 migrants has been identified. The majority of compounds appeared to be intermediate reaction products or residual monomers of their dehydration and transesterification products. Several processing aids such as fatty acids and commonly used plasticizers were also identified. The amount of seven compounds present in the major portion of exhaustive extract of the PET bottle wall ranged from 800 micrograms/g polymer to as low as 0.6 microgram/g.

Drug Packaging↗

PubMed1989

Effects of chronic developmental lead exposure on monkey neuroanatomy: visual system.

The effects of lead on specific areas of the visual system were examined in two groups of monkeys (Macaca fascicularis). The first group (N = 3) received 2000 micrograms Pb/kg/day from infancy onward, while the second group (N = 4) received 25 micrograms Pb/kg/day from birth onward. Monkeys were killed at approximately 6 years of age. Areas of the visual system, including optic nerve, lateral geniculate nucleus, and primary area V1 and one visual projection area V2, were examined by a combination of light and electron microscopy and Golgi impregnation. No effect of lead on optic nerve was identified, nor were there consistent differences in the lateral geniculate nucleus. Within areas V1 and V2, the neuronal volume density was significantly reduced in the high dose compared to the low dose group. Moreover, analysis of the dendritic arborization by Golgi analysis revealed a relative decrease in the number of arborizations among pyramidal neurons in both areas V1 and V2. These data suggest that lead exposure beginning during the early postnatal period may result in changes in cytoarchitecture in visual areas V1 and V2.

Animals↗

PubMed1988

Adverse pregnancy outcome in the monkey (Macaca fascicularis) after chronic caffeine exposure.

Caffeine and the related methylxanthine theophylline are consumed regularly by pregnant women. In a study originally designed to assess the neurotoxic potential of caffeine in the infant, 40 female monkeys (Macaca fascicularis) were divided into three groups and administered caffeine in their drinking water at concentrations equivalent to 0, 10 to 15 or 25 to 35 mg/kg/day of caffeine 7 days a week. After a period of adaptation to caffeine these monkeys were mated with untreated males. Reproductive failure in the form of stillbirths and miscarriages was observed in the treated groups. Subsequently, 12 control monkeys and 1 low-dose monkey were added to the study and most of the original monkeys rebred. The second round of pregnancies confirmed that the treated monkeys had an increased rate of stillbirths and miscarriages. The precise cause of death of the stillborn infants could not be determined. Maternal weight gain and infant birth weights decreased in a dose-related manner. These results indicate that in utero exposure to methylxanthines (caffeine and/or its major metabolite theophylline) adversely affects pregnancy outcome in the monkey.

Abortion, Veterinary↗

PubMed1987

Low-level lifetime lead exposure produces behavioral toxicity (spatial discrimination reversal) in adult monkeys.

Cynomolgus monkeys (Macaca fascicularis) were dosed from birth with 0, 50, or 100 micrograms/kg/day of lead. This regimen resulted in blood lead concentrations of 3, 15, or 25 micrograms/dl, respectively, before withdrawal of infant formula at 200 days of age. Blood lead concentration declined thereafter over the next 100 to 150 days to steady-state concentrations of 3, 11, or 13 micrograms/dl. At 9 to 10 years of age, these monkeys were tested on a series of spatial discrimination reversal problems. The monkey was required to respond on the right-most of two push buttons in order to receive a fruit-juice reward. When the task was learned, the left-most button became correct for a total of 15 such reversals on each of three tasks. The stimuli for the first task included no irrelevant cues, the second task included irrelevant form cues, and the third task included irrelevant form and color cues. Treated monkeys were impaired relative to controls in the presence but not in the absence of irrelevant cues. Moreover, the lower dose group was impaired only during the first task after the introduction of irrelevant stimuli, but not after irrelevant stimuli were familiar. These findings represent behavioral impairment in adult monkeys as a result of lifetime lead exposure resulting in blood lead concentrations that are typical for humans in industrialized environments.

Animals↗

PubMed1987

Sensory testing in non-human primates.

Sensory testing in non-human primates can be used to detect subtle sensory toxicity of chemicals. Examples are given covering the determination of spatial contrast sensitivity in monkeys exposed to methyl mercury as an example of visual psychophysics, and the assessment of vibration sensitivity in monkeys exposed to acrylamide, as an example of somatosensory psychophysics.

Acrylamides↗