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Biomedical subjects

J L Mattsson

Publications and source records attributed to J L Mattsson.

At least 37 records · Page 2Linked to original sources

Lack of neuropathologic consequences of repeated dermal exposure to 2,4-dichlorophenoxyacetic acid in rats.

A 24% aqueous solution of the dimethylamine salt of 2,4-dichlorophenoxyacetic acid (2,4-D amine) was applied to the legs of male Fischer 344 rats 2 hr/day, 5 days/week, for 2 weeks. Because this concentration caused severe skin lesions, a second group of rats was treated similarly with a 12% solution of 2,4-D amine for 3 weeks. The 12% solution caused only mild skin changes. The plasma 2,4-D content, at the end of exposure, was nearly five times greater in the rats exposed to the 24% solution than to the 12% solution (323 vs 66.5 micrograms/ml). The severe skin changes probably facilitated absorption in the rats treated with the 24% solution. Rats treated with either concentration weighed less than controls. Although histologically normal, kidneys of treated rats weighed more than controls. The increased kidney weights were attributed to physiological adaptation due to active excretion of absorbed 2,4-D. Light microscopic examination of tissues, other than skin, revealed no differences between treated and control animals. There were no nervous system pathologic changes although the rats were exposed to sufficient amounts of 2,4-D amine to cause severe skin lesions, decreased body weights, and increased kidney weights.

2,4-Dichlorophenoxyacetic Acid↗

Neurotoxicity of methyl chloride in continuously versus intermittently exposed female C57BL/6 mice.

This study evaluated the relationship between methyl chloride (MeCl) exposure duration and neurotoxicity. Female C57BL/6 mice were exposed to MeCl for 11 days, either continuously (22 hr/day) to 15, 50, 100, 150, or 200 ppm, or intermittently (5.5 hr/day) to 150, 400, 800, 1600, or 2400 ppm. This strain and sex of mouse was chosen because it is sensitive to MeCl neurotoxicity and was a good candidate to allow the evaluation of morphological effects and the quantitation of functional effects. A simple quantitative relationship between neurotoxicity and continuous vs intermittent exposure was not observed. Although the no-observable-effect levels for continuous and intermittent MeCl exposures were very nearly proportionate to exposure concentration multiplied by duration, the dose-response curve was much steeper for continuously exposed mice. Cerebellar granular cell layer degeneration was observed in mice exposed continuously to 100 ppm MeCl and in mice exposed intermittently to 400 ppm. This histopathologic effect was observed at lower concentrations than a decrement in rotating rod running performance. No effects were observed in mice exposed to 50 ppm continuously or to 150 ppm intermittently. Continuous exposure to MeCl produced the cerebellar lesion with less effect on other tissues than did intermittent exposure. In mice exposed to 2400 ppm intermittently, there were renal and hematopoietic effects in addition to relatively slight cerebellar granular cell layer degeneration. These 2400-ppm exposed mice developed hemoglobinuria, apparently as a result of intravascular hemolysis. Although the effect of exposure duration on MeCl toxicity was complex, this study indicated that careful judgment is necessary when extrapolating intermittent exposure data to a continuous exposure situation.

Animals↗

Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat.

Hexachloroethane (HCE) was fed to Fischer 344 rats at approximate doses of 0, 1, 15 or 62 mg/kg/day for 16 weeks. Selected tissues were assayed at termination for HCE content. Histopathological examination identified the kidney as the primary target organ with male rats more sensitive than female rats. The kidney concentration of HCE increased proportionately with dose in the males, but there were disproportionately small increases with dose in females. A group of male rats was given 62 mg/kg/day for 8 weeks to estimate tissue clearance. Clearance of HCE from fat, liver, kidney and blood occurred in an apparent first-order manner with a half-life of approximately 2.5 days. The apparent first-order elimination suggests that HCE metabolism and excretion were not saturated in rats given up to 62 mg/kg/day and suggests that, in the range of doses given, toxicity should be proportional to exposure concentration. The no-observable-effect level (NOEL) for toxicity was 1 mg/kg/day for male and female rats.

Administration, Oral↗

H-reflex waveform and latency variability in rats.

The right tibial nerve of each of 11 anesthetized male Fischer 344 rats was electrically stimulated at the ankle, and H-reflexes were recorded simultaneously from four locations in the hind foot. Needle electrodes were used for stimulating and recording. The mean (+/- SD) latency to the dominant peak of the H reflex was 10.21 +/- 0.75 msec. Individual rats had a 10% difference in latency from the "fastest" to the "slowest" locations in the foot, although any of the four locations could produce the fastest (shortest latency) response. The H reflexes varied from simple, single peak waveforms to complex multiple peak waveforms. The dominant peak polarity was unpredictably either positive or negative. These variations in complexity and latency occurred among rats and among the four locations within an individual rat. The dominant peak was identified in complex waveforms by adjusting the stimulating intensity and by recording from more than one location in the foot. The smallest coefficient of variation (5.57%) resulted from selecting data from the fastest electrode locations.

Action Potentials↗

Prevention of radiation emesis in dogs by combinations of drugs.

Male mixed-breed dogs were used to evaluate the effectiveness of cimetidine (Cim), promethazine (Pro), and thiethylperazine (Thi), singly and in combination, to raise the threshold for radiation-induced emesis. Cim was chosen as an H2 antihistamine, Pro as an H1 antihistamine, and Thi as a phenothiazine derivative dopamine blocker. Doses were: 167 mg/m2 i.v. for Cim; 13.9 mg/m2 i.m. for Pro; and 5.6 mg/m2 i.m. for Thi. These doses were calculated on a mg/m2 basis to approximate doses for an average human (1.8 m2) of 300 mg Cim, 25 mg Pro, and 10 mg Thi. Exposure was to 60Co at 60 rad (midline) per min. The dogs were fed 0.4 kg canned dog food 1 hour before exposure, and injected with the appropriate drugs 30 minutes prior to exposure. Emesis onset times, number of episodes, and time to last episode were recorded. The radiation dose (midline tissue rad) to cause a 50% incidence of emesis (ED50) was calculated using an up-and-down procedure. The ED50 (95% confidence limits) were: 258 (212-315) for controls; 240 (151-380) for Cim; 313 (256-384) for Pro; 405 (319-514) for Thi; 334 (284-394) for Cim + Pro; 446 (365-546) for Cim + Thi; 347 (306-399) for Pro + Thi; and 478 (428-539) for Cim + Pro + Thi.

Animals↗

Effects of benactyzine on an equilibrium and multiple response task in rhesus monkeys.

Five Macaca mulatta were tested for performance changes following exposure to benactyzine HCl (intramuscular) at four doses ranging from 0.054 mg/kg to 1.7 mg/kg. Subjects simultaneously operated a primate equilibrium platform and responded to a multiple alternative reaction task. Performance on both the continuous and discrete tasks were progressively degraded as benactyzine dose increased. At the higher doses it appeared that they concentrated their efforts on one of the tasks while neglecting the other. Thus, performance on one task might be normal and at the same time performance on another task would be degraded.

Animals↗

Early effects of methylmercury on the visual evoked response of the dog.

A disturbing characteristic of methylmercury (MeHg) intoxication is the preclinical "silent" stage. This stage is followed by the sometimes rapid onset of clinical signs such as peripheral sensory loss, motor difficulties, and visual and auditory impairment. The objective of this study was to search for "preclinical" changes in the electrophysiological activity of the central nervous system of dogs exposed to methylmercury chloride. Because of the prominence of the visual system in the MeHg literature, the visual evoked response (VER) was selected for evaluation. A dose rate of 500 microgram/kg/day po was expected to cause clinically apparent toxicosis in about 2 mon. After 1 week of exposure, a subtle distortion of the VER occurred. In a parallel group of dogs, blood mercury was 0.74 microgram/ml at this time, and brain mercury content was 1.28 microgram/g at the occipital cortex. Although the dogs continued to receive MeHg, VERs remained remarkably stable for the next 5 to 8 weeks, and then rapidly degraded during the nest few days as the dogs exhibited visual and motor disabilities. In many species, when brain Hg is about 15 microgram/g, clinical and histopathologic changes are usually present, and may even be detected at 8 microgram/g. Distortion of the VER at 1.28 microgram/g Hg at the visual cortex demonstrates that CNS changes exist during the "silent" stage of toxicosis, and at a brain Hg content suggesting physiologic dysfunction of neurons rather than neuronal death.

Animals↗

Acute and chronic propylene glycol dinitrate exposure in the monkey.

Rhesus monkeys (Macaca mulatta) were exposed to propylene glycol 1,2-dinitrate (PGDN) vapors on either an acute (4-h) or chronic (125-d) schedule. During acute exposures, PGDN concentrations ranged from a low of 2 ppm (parts per million) to a high of 33 ppm. Free operant avoidance behavior and visual evoked responses were monitored and free operant avoidance was not affected at any dose level. The late positive (100-150 ms) wave of the visual evoked response increased 20% at 2 ppm and decreased 25% at concentrations up to 33 ppm. Although these changes were statistically different from control values, they were within the limits caused by distracting events (+/-40%), and might possibly have been caused by the irritating or distracting properties of the vapor. Other monkeys were exposed to successively increasing concentrations of PGDN vapors at 0.3-4.2 ppm. 23 h/d, for 125 d. Daily performance testing included alternating sessions of discrete-trial cued avoidance and free operant avoidance. Non of the PGDN concentrations had a discernible effect on either type of avoidance performance.

Animals↗

Radiation and G tolerance in rats.

Male hooded rats were exposed to 2100 rad 60Co radiation and 18 h later were exposed to +Gz acceleration until heart rate was reduced to 50% of baseline rate. G tolerance was 9.2% less in irradiated rats than in controls. Although small, this difference was significant at p less than 0.05. A similar group of rats was anesthetized 18 h postirradiation and carotid mean arterial pressures were measured. Mean arterial pressure was 122.1 torr for controls and 114.5 for irradiated. This difference was not significant.

Acceleration↗

Control of radiation-induced emesis with promethazine, cimetidine, thiethylperazine, or naloxone.

Promethazine (2 mg/kg), cimetidine (4 mg/kg), thiethylperazine (0.86 mg/kg), and naloxone (0.08 mg/kg) were each evaluated for their ability to increase the threshold of radiation-induced emesis in the dog. Each dog was fed a can of dog food (ca 0.4 kg) and then injected IM with the appropriate drug 1 hour before being irradiated by a 60Co teletherapy unit. The total radiation dose given an individual dog was determined by an up-and-down exposure schedule. Dogs were then observed continuously for 10 hours while the number, time of onset, and duration of each emetic episode were monitored. The dose of radiation causing emesis in 50% (ED50 +/- SEM) of control dogs was 170 +/- 38.5 rad. The ED50 +/- SEM was increased to 402 +/- 18.6 rad by promethazine, to 331 +/- 27.3 rad by cimetidine, and to 320 +/- 38.5 rad by thiethylperazine. This increased tolerance was significant at P less than 0.05 for each drug. The ED50 for naloxone was 262.5 +/- 92.9 rad, which was not a statistically significant increase in threshold.

Animals↗

Maturation of the visual evoked response in newborn miniature pigs.

As a prelude to neurobehavioral toxicologic studies in neonatal minipigs, normal maturational changes in the visual evoked response (VER) were determined in 6 Hormel-bred minipigs. The VER were highly variable for the 1st several days of life, but were reasonably stable by the 2nd weeks. All adult waveform components were present at birth, and maturational changes primarily affected waveform latency and consistency. Only one waveform (Pi) was sufficiently distinct and consistent for statistical evaluation. At birth the latency to Pi was about 102 ms. The latency of Pi rapidly decreased to about 56 ms during the next 25 days, and subsequent changes were minimal. Comparison with other species indicates many cross-species relationships of specific VER components, with the minipig VER having many maturational and topographic similarities to the human VER.

Animals↗

Classical conditioning of hippocampal theta patterns in the rat.

Electrical stimulation (88 HZ) of the lateral hypothalamus elicited a sustained theta response at hippocampal recording sites of rats immobilized with succinylcholine. By pairing this unconditioned stimulus with a 10-sec presentation of a light, conditioned theta responses were demonstrated in as few as 40 trials. Spectral analysis of hippocampal bioelectric patterns during acquisition, extinction, and reconditioning indicated that the earliest change as a result of conditioning is a loss of power in EEG frequency below 8 HZ, followed by the development of a peak at 8 HZ with further conditioning. Extinction was associated with an increase in power in the frequencies below 8 HZ. When the conditioned rats were tested in the absence of the neuromuscular blocking agent, the conditioned stimulus elicited a theta response that was associated with slow motor activity on 70% of the trials.

Animals↗

Effect of electromagnetic pulse on avoidance behavior and electroencephalogram of a rhesus monkey.

A 12-kg male rhesus monkey was exposed to electromagnetic pulse (EMP) at 266 kv/m, 5 pulses/s, for 1 h (18,700 pulses). The effects of EMP on Sidman avoidance behavior and on post-exposure electroencephalogram were evaluated, and no significant changes were detected. An analysis of an EMP showed that it contained various frequency components extending from 0 Hz to 10(9) Hz. However, the pulse configuration was such that its power was mainly confined to the longer wave-lengths (less than 30 MHz). The lack of biologic effect was attributed to the fact that the wavelengths were long relative to the size of the monkey, and little energy deposition was likely to occur. In addition, the electric field was evenly distributed across all lower frequencies so that only a very small electric field component existed at any specific low frequency.

Animals↗

A chest harness and pole-leash for routine transfer of rhesus monkeys from home cage to behavioral test apparatus and back.

A chest harness and pole-leash method to transfer rhesus monkeys (Macaca mulatta) weighing up to 16 kg from home cage to primate restraint chair was designed. The harness was made of leather straps that crossed the chest in an X-fashion, and created a V-neck. The V-neck eliminated the strangulation hazard of neck collars, and minimized interference between the harness and neck hole of restraint chairs. Two pole-leashes attached to 2 points on the harness gave the handler considerable control over the posture of the monkey, making it easier to teach the monkey to walk with a leash and to climb into its restraint chair or test apparatus. During transfer the rigid pole prevented escape and protected the handler from attack. Quick release mechanisms on the pole-leash allowed prompt, complete separation from the animal when it re-entered its home cage.

Animals↗