Identification of metabolites from salts of pyridine-2-thiol-1-oxide following intravenous and dermal adminstration to swine.
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Administration, Topical↗
Biomedical subjects
R A Howd
Publications and source records attributed to R A Howd.
Metabolic disposition of cytembena in rats and dogs.
1. The metabolic disposition of cytembena (sodium cis-3-p-methoxybenzoyl-3-bromoacrylate)labelled at both carbonyl carbon atoms was studied in rats and dogs. 2. Rats excreted over 70% and dogs excreted over 50% of the radioactive dose in 24 h. Most of the radioactivity was found in urine. Kidney retained the highest level of radioactivity after 24 h. Renal cortex was responsible for the observed high retention. Both species exhibited similar tissue distribution and urinary metabolic patterns. 3. Cytembena was metabolized by demethylation catalysed by microsomes and by debromination and double bond saturation catalysed by the 100,000 g supernatant fraction in the presence of glutathione and NADPH. Tentative structures of the metabolites identified by mass spectrometry and the probable metabolic pathway of cytembena are presented,
Acrylates↗
Mechanisms by which quipazine, a putative serotonin receptor agonist, alters brain 5-hydroxyindole metabolism.
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Animals↗
L-tryptophan and rat fetal brain serotonin.
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Age Factors↗
The effects of drugs on accumulation and release of catecholamines in rat brain slices.
Pretreatment of rats with reserpine decreased the uptake and release of labelled NE and DA in rat slices. MAO inhibition with nialamide partially antagonized the effects of reserpine, but nialamide itself decreased the release of labelled DA. Treatment of brain slices in vitro with phenoxybenzamine or desmethylimipramine inhibited uptake of catecholamines, and affected spontaneous and electrically-stimulated release in a manner consistent with the existence of an alpha-receptor-mediated feedback regulation of release at both NE and DA nerve terminals. The effect of phenoxybenzamine on stimulated release was observed to be dependent on stimulation rate.
Animals↗
Development of California Public Health Goals (PHGs) for chemicals in drinking water.
As part of a program for evaluation of environmental contaminants in drinking water, risk assessments are being conducted to develop Public Health Goals (PHGs) for chemicals in drinking water, based solely on public health considerations. California's Safe Drinking Water Act of 1996 mandated the development of PHGs for over 80 chemicals by 31 December 1999. The law allowed these levels to be set higher or lower than federal maximum contaminant levels (MCLs), including a level of zero if data are insufficient to determine a specific level. The estimated safe levels and toxicological rationale for the first 26 of these chemicals are described here. The chemicals include alachlor, antimony, benzo[a]pyrene, chlordane, copper, cyanide, dalapon, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 2,4-D, diethylhexylphthalate, dinoseb, endothall, ethylbenzene, fluoride, glyphosate, lead, nitrate, nitrite, oxamyl, pentachlorophenol, picloram, trichlorofluoromethane, trichlorotrifluoroethane, uranium and xylene(s). These risk assessments are to be considered by the State of California in revising and developing state MCLs for chemicals in drinking water (which must not exceed federal MCLs). The estimates are also notable for incorporation or consideration of newer guidelines and principles for risk assessment extrapolations.
Algorithms↗
Community exposure to a paraquat drift.
A mixture of paraquat and water was applied, by helicopter, to agricultural fields near a residential community and near an associated commercial complex. Drift from the application passed directly over the community, which resulted in resident complaints to the local county agricultural department. A community survey was undertaken to determine what health consequences, if any, resulted from the drift. A comparison of 2-wk self-reported symptom rates between the exposed community and three historical control communities indicated that 10 symptoms were elevated significantly at p < .05: cough, diarrhea, eye irritation, headache, nausea, rhinitis, throat irritation, trouble breathing, unusual tiredness, and wheezing. An internal comparison, which predicted symptom rates by an index of paraquat exposure (smelling an unusual odor in the prior 2-wk period), indicated fever (relative risk [RR] = 11.97) and nausea (RR = 3.75) to have elevated relative risks. Odor perception also predicted the report of a greater than the average number of symptoms. Based upon these findings, it was concluded that these residents probably did experience an increase in health symptoms from the drift. It is recommended that paraquat not be sprayed near residential communities.
California↗
Irritative and systemic symptoms following exposure to Microban disinfectant through a school ventilation system.
Microban, a pesticide not registered in California, was sprayed into an operating heating/ventilation/air conditioning (HVAC) unit at an elementary school in San Francisco, California. This incident occurred on Monday, September 28, 1992, while 396 students and 67 staff members were in the school. The Microban formulation used contains ortho-phenylphenol (0.21%), a quaternary ammonium complex (di-isobutylphenoxy-ethoxy-ethyldimethylbenzyl-ammonium chloride, 0.69%), and bromine (0.04%). This study of the health effects of Microban mist exposure on the school staff was conducted as a result of legal and toxicological concerns. California registration for this formulation had been denied because of inadequate data and because there were concerns about inhalation toxicity in test animals. Predicted health effects from short-duration exposure to Microban are primarily skin and mucous membrane irritation. A self-administered health symptom questionnaire that covered the work week following the evacuation was used to determine a pattern of higher symptom risks for those who were at work on Monday and who reported that they felt they were exposed to a chemical. Symptoms, which were generally consistent with exposure to an irritating chemical, were elevated on Monday and Tuesday; the symptoms normalized by the end of the work week. No additional health effects were detected following application of chlorpyrifos to cracks and crevices for ant control 2 d following the Microban incident. Strict supervision and coordination of pesticide use in public schools are recommended to prevent adverse health effects and emotional trauma in students and staff.
Adult↗
Toluene-induced ototoxicity by subcutaneous administration.
Inhalation exposure of rats to toluene causes irreversible hearing loss (e.g., Pryor et al.). To determine whether noise emanating from the inhalation system was a major contributing factor and whether exposure by a noninhalation route would cause a similar effect, weanling, male Fischer-344 rats were injected SC twice daily in a quiet environment with PEG-300 (control) or with 1.5 or 1.7 g/kg of toluene for 7 days. After being trained to perform a multisensory conditioned avoidance response (CAR) task, tone intensity-response functions were generated at 4, 8, 12, and 20 kHz, and behavioral auditory response thresholds were estimated. Toluene caused a dose-related hearing loss at frequencies of 8 kHz and above, with no effect on performance of the CAR in response to light, nonaversive footshock, or the 4-kHz tone. The similarity of this effect to that observed following inhalation exposure indicates that noise is not a major factor in the toluene-induced hearing loss, although possible interactions between noise and toluene remain to be investigated. These results also demonstrate that direct penetration of the toluene vapors through the external ear structure, as might occur during inhalation exposure, is not a necessary condition for inducing the hearing loss.
Air Pollutants↗
A comparison of the rates of development of functional hexane neuropathy in weanling and young adult rats.
Chronic inhalation exposure of adult rats to hexane causes neural toxicities to develop over a period of several weeks. Because the developing organism is in many cases more vulnerable to toxic insult than the adult, and children make up a substantial proportion of the population of solvent abusers, we compared the effects of exposing weanling and young adult rats to 1000 ppm of hexane for 24 hrs/day, 6 days/week, for 11 weeks. Within two weeks of exposure, significance decreases in body weight and grip strength were observed in rats of both ages. However, the subsequent effects of the treatment on these indices of toxicity were greater in the young adults than in the rats first exposed as weanlings. The older rats also exhibited earlier and more severe signs of hindlimb flaccid paralysis. In contrast, the effects of hexane on tail nerve conduction time and on the brainstem auditory-evoked response were about the same in rats of both ages, with latencies increasing compared to controls over the exposure period. The relative resistance of the weanling rats to hexane neuropathy may be due to shorter, smaller-diameter axons, or to a greater rate of growth and repair in their peripheral nerves compared to those of adults.
Action Potentials↗
Transient cognitive deficits and high-frequency hearing loss in weanling rats exposed to toluene.
In a previous experiment we found that weanling rats subchronically exposed to toluene by inhalation were deficient in learning a multisensory conditioned avoidance response (CAR) task and a tone-intensity discrimination task when trained several hours after each daily 14-hour exposure ended. The present experiment was done to determine whether this deficit represented a residual pharmacologic effect or more persisting nervous system damage. Independent groups of rats were trained on the CAR task either during the last week of a 5-week exposure to 1400 or to 1200 pm toluene (14 hr/day, 7 days/week) or during the first or third weeks after the exposures ended. None of the three groups of toluene-exposed rats were able to acquire the auditory CAR, whereas it had been 4 kHz in the previous experiment. Subsequent tests, in which the frequency and intensity of the tone were varied, revealed that hearing in these rats was unimpaired at 4 kHz, slightly impaired at 8 kHz, and markedly impaired at 12 kHz and above. Thus, although toluene has been shown to be relatively innocuous as a toxicant, this new finding suggests that this solvent should be examined further in terms of its potential hazard, especially with regard to its frequent abuse.
Animals↗
Neurobehavioral effects of subchronic exposure of weanling rats to toluene or hexane.
Using several behavioral and neurophysiologic tests, we examined the effects of subchronic inhalation exposure of rats to toluene and compared them with the effects of the known neurotoxicant hexane. The rats were exposed to toluene (900 and 1400 ppm) or hexane (2000 ppm) 14 hr/day, 7 days/week for 14 weeks. Both solvents inhibited weight gain. Hexane caused a neurotoxic syndrome characterized by reductions of grip strength (especially hindlimb), motor activity, and startle responses, and increased latencies of several evoked potential components. Initial acquisition of a conditioned avoidance response (CAR) was also impaired, but subsequent performance was intact. Toluene did not cause the peripheral motor symptoms associated with exposure to hexane. However, a component of the brainstem auditory-evoked response was depressed and CAR acquisition was impaired along with the acquisition of a tone-intensity discrimination task when tested within hours after the daily exposure ended.
Action Potentials↗
Toluene-induced hearing loss in rats evidenced by the brainstem auditory-evoked response.
Behavioral results showing that toluene causes hearing loss in rats precipitated an electrophysiologic study of the auditory thresholds of these rats using the brainstem auditory-evoked response (BAER). Twenty-three-day-old male Fischer-344 rats had been exposed to 1400 or 1200 ppm toluene 14 hrs/day, for 4 or 5 weeks while a control group was exposed only to air. The rats were tested 2.5 mo after termination of the exposures. BAERs, recorded with 25-gauge needle electrodes placed over the nose and posterior skull, were evoked by 100-microseconds-duration clicks and 1-msec-duration tone pips at eight intensities. Thresholds for the appearance of BAERs in the toluene-exposed rats were elevated by 13 to 27 dB, and latency-intensity functions were consistent with the occurrence of sensorineural hearing loss. The amplitudes of the third and fifth components of the BAER were attenuated at high stimulus intensities in the toluene-exposed rats. These behavioral and electrophysiologic results are apparently the first to indicate the ototoxicity of toluene in experimental animals.
Animals↗
Importance of schedule of exposure to hexane in causing neurotoxicity.
Male Fischer rats exposed continuously (24 hr per day) to 1,000 ppm hexane five days per week for 11 weeks developed clear and long-lasting neurotoxic signs, as reflected by a marked decrease in hind-limb grip strength and severe impairment of performance of a multisensory conditioned avoidance response (CAR); transient decreases in undifferentiated motor activity and fore-limb grip strength were also seen. Other rats were only slightly affected by repeated, brief (10 min) exposures to high concentrations (24,000 or 48,000 ppm) of hexane 6 or 12 times per day, five days per week for 18 weeks; when the frequency of exposure to 48,000 ppm hexane was increased to 24 times per day (10 min on and 5 min off), five days per week, for 4 additional weeks, more severe signs of neurobehavioral toxicity appeared.
Animals↗
Effects of hexane on the brainstem auditory response and caudal nerve action potential.
In a study on the neurotoxicity of abused inhalants, male Fischer rats were exposed by inhalation to several concentrations of hexane, administered continuously or intermittently. The fifth component of the brainstem auditory-evoked response (BAER) increased in latency and decreased in amplitude in rats exposed to 1,000 ppm of hexane 24 hours per day, 5 days per week, for 11 weeks. The first component of the BAER was only slightly affected, indicating that the increased latency of the fifth component reflected a brainstem dysfunction. Latency returned to normal within 5 weeks after termination of exposures, but amplitude did not. Latency of the compound action potential of the ventral caudal nerve of the tail of these rats was also increased, and this effect was still present 22 weeks after termination of the exposure. Other rats were not as severely affected by repeated, brief (10 minutes) exposures to 24,000 or 48,000 ppm hexane 6 or 12 times per day; only the amplitude of the fifth BAER component was affected by the 48,000-ppm exposure.
Animals↗
Relation between schedules of exposure to hexane and plasma levels of 2,5-hexanedione.
Male Fischer rats were exposed repeatedly to high concentrations of hexane for 10 minutes in a pattern resembling human solvent abuse or to low concentrations of hexane continuously for 8 or 24 hours daily. Concentrations of hexane in blood and brain were linearly related to the concentrations of hexane in the chamber after a 10-minute exposure, and declined thereafter, with half lives of about 2 1/2 and 4 minutes in blood and brain, respectively. Despite the rapid elimination of hexane, neurotoxic levels of 2,5-hexanedione (2,5-HD) were formed from repeated 10-minutes exposures to a high concentration of hexane when the interexposure interval was 20 minutes. Neurotoxic levels of 2,5-HD also resulted from continuous exposure to much lower concentrations of hexane. Both exposure schedules caused an increase in 2,5-HD concentrations in blood after repeated daily treatments, suggesting induction of liver microsomal enzymes synthesizing 2,5-HD from hexane. The minimal sustained plasma 2,5-HD concentration that will result in neurotoxicity appears to be less than 50 micrograms/ml in the rat.
Animals↗