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Biomedical subjects

M W Gill

Publications and source records attributed to M W Gill.

At least 19 recordsLinked to original sources
PubMed1999

Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m-toluamide (DEET).

Chronic toxicity and/or oncogenicity studies were conducted in rats, mice, and dogs with the insect repellent DEET. DEET was mixed in the diet and administered to CD rats for two years at concentrations that corresponded to dosage levels of 10, 30 or 100 mg/kg/day for males and 30, 100, or 400 mg/kg/day for females; to CD-1 mice for 18 months at dosage levels of 250, 500, or 1000 mg/kg/day; and to dogs for one year, via gelatin capsules, at dosage levels of 30, 100, or 400 mg/kg/day. In the rodent studies, each group consisted of 60 animals of each sex, and two concurrent independent control groups, each containing 60 animals/sex were included in each study. Each group in the dog study consisted of four male and four female dogs and one control group was included in the study. Treatment-related effects were observed at the highest dose level in all three studies. For rats, the effects included decreases in body weight and food consumption and an increase in serum cholesterol in females only. In mice, the effects observed were decreases in body weight and food consumption in both sexes. The effects observed in dogs included increased incidences of emesis and ptyalism, and levels of transient reduction in hemoglobin and hematocrit, increased alkaline phosphatase (males only), decreased cholesterol, and increased potassium. One male dog in the high-dose group also exhibited ataxia, tremors, abnormal head movements, and/or convulsions on several occasions during the study. The highest no-observed-effect levels (NO-ELs) for rats, mice and dogs were determined to be 100, 500, and 100 mg/kg/day, respectively. No specific target organ toxicity or oncogenicity was observed in any of the studies.

Animals↗
PubMed1999

The effect of repeated methyl iso-butyl ketone vapor exposure on schedule-controlled operant behavior in rats.

Methyl iso-butyl ketone (MiBK), a commercial solvent, was selected by the US Environmental Protection Agency (US EPA) for testing under the Multi-Substance Rule for the Testing of Neurotoxicity (US EPA, 1993) using schedule-controlled operant behavior (SCOB) to determine if subchronic exposure to MiBK vapor had the potential to alter behavior as an indicator of neurotoxicity. Food-restricted and ad libitum-fed Sprague-Dawley male rats were exposed to 0, 250, 750, or 1500 ppm MiBK for 6 h/day, 5 d/wk for 13 weeks. SCOB testing of food-restricted animals, using a multiple fixed ratio (FR)/fixed interval (FI) schedule (FR20:FI120), was conducted prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. SCOB testing was also evaluated for two weeks following the cessation of exposures. Ad libitum-fed animals were included to assess systemic effects using routine indicators such as changes in body weight, food consumption, and organ weight. No significant differences were seen in fixed-ratio run rate, FR pause duration, fixed-interval response rate, and index of curvature values at any concentration. Animals exposed to 750 and 1500 ppm MiBK exhibited clinical signs associated with transient reduced activity levels, but only during exposure. No signs of reduced activity were observed immediately after exposure for either group. No other treatment-related abnormalities were observed during exposure. Food-restricted animals did not demonstrate any increased or decreased sensitivity to the CNS depressive effects of MiBK relative to the ad libitum-fed animals. No treatment-related body weight differences were observed within either the food-restricted groups or the ad libitum-fed groups, although body weights of the former were clearly depressed compared with those of the latter. Relative and absolute liver, and relative kidney weights were significantly greater for the 750 and 1500 ppm ad libitum-fed animals. No differences in kidney weight were observed for food-restricted animals, but absolute and/or relative liver weights were significantly higher for all the treated food-restricted groups. The results of this study indicate that repetitive exposures to high concentrations of MiBK vapors do not result in adverse effects on operant behavior in the rat.

Administration, Inhalation↗
PubMed1998

Evaluation of subchronic neurotoxicity of n-butyl acetate vapor.

n-Butyl acetate, a common industrial solvent, was selected by the US EPA as a chemical of concern for neurotoxicity as part of the Multisubstance Rule for the Testing of Neurotoxicity. The neurotoxic potential of n-butyl acetate was investigated in Sprague-Dawley rats using a functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior (SCOB) as indicators of neurotoxicity. Animals were exposed to concentrations of 0, 500, 1500, or 3000 ppm of n-butyl acetate for 6 hours per day for 65 exposures over 14 weeks. Functional observational battery and motor activity values for ad libitum-fed male and female rats were measured during Weeks -1, 4, 8, and 13. SCOB testing of food-restricted animals, using a multiple fixed ratio/fixed interval schedule, was conducted daily prior to each exposure to maintain the operant behavior; the data from Weeks -1, 4, 8, and 13 were evaluated for evidence of neurotoxicity. Transient signs of sedation and hypoactivity were observed only during exposure to the 1500 and 3000 ppm concentrations. The only signs of systemic toxicity were reduced body weights for the 3000 ppm ad libitum-fed groups and occasionally for the female 1500 ppm ad libitum-fed group. No evidence of neurotoxicity was seen during the functional observational battery examinations. Motor activity for the 3000 ppm male group was significantly (p < or = 0.05) higher than for the control group only during Week 4. No significant differences were observed among groups for Weeks 8 and 13. No significant differences in motor activity values were observed for female rats. No significant differences were seen in operant behavior at any test vapor concentration. Microscopic evaluations of sections from the brain, spinal cord (cervical and lumbar regions), dorsal and ventral spinal roots, dorsal root ganglia, sciatic nerve, and tibial nerve of animals in the control and 3000 ppm groups did not indicate any treatment-related effects. In conclusion, there was no evidence of cumulative neurotoxicity based on the functional observational battery, motor activity, neurohistopathology, and schedule-controlled operant behavior endpoints. The data presented here are relevant to the neurotoxicity risk assessment of n-butanol due to the rapid hydrolysis of n-butyl acetate in vivo.

Acetates↗
PubMed1997

Assessment of the in vivo mutagenic potential of methyl tertiary-butyl ether.

Methyl tertiary-butyl ether (MTBE) is one of the highest production volume chemicals in the USA. Previous results from in vitro genetic toxicity studies suggested that it was not mutagenic. However, chronic exposure at high levels resulted in liver tumors in female mice and kidney tumors in male rats. The current program assessed in vivo genotoxicity and also explored the possibility that a mutagenic mechanism was involved in the carcinogenic process. The specific tests used included the Drosophila sex-linked-recessive-lethal test, the rat bone marrow cytogenetics test, the mouse bone marrow micronucleus test and the in vivo-in vitro hepatocyte unscheduled DNA synthesis test in the mouse. All tests produced negative results, indicating that the potential for in vivo mutagenic activity was low. These data also suggest that the tumorigenic activity was probably the result of a non-genotoxic process.

Air Pollutants↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗
PubMed1994

Developmental neurotoxicity evaluation of orally administered isopropanol in rats.

Isopropanol was administered by gavage to timed-mated rats from Gestation Day (GD) 6 through Postnatal Day (PND) 21. Doses administered were 0, 200, 700, or 1200 mg/kg/day in a volume of 5 ml/kg. The dams were allowed to deliver and body weights and food consumption were recorded during gestation and lactation. Pups were counted, examined, sexed, and weighed on PND 0, 4, 7, 13, 17, 21, 36, 49, and 68. Litters were culled to eight pups (4:4 or 5:3 sex ratio) on PND 4 and litters without acceptable numbers of male and female pups were eliminated from the study. Pups were weaned on PND 22, and two pups from each litter and their dams were killed. Six of these pups from each dose group were perfused in situ for histopathological examination of the central and peripheral nervous system. Brains of the remaining pups were divided into four regions and weighed. Maternal liver and kidney weights were recorded. Weaned pups were assessed for day of testes descent or vaginal opening and for motor activity on PNDs 13, 17, 21, 47, and 58; auditory startle on PNDs 22 and 60; and active avoidance on PNDs 60-64. These pups were euthanized and examined on PND 68. One high-dose dam died on PND 15, but there were no other clinical observations or effects on maternal weight, food consumption, or gestation length. Pup survival, weight, sex ratio, and sexual maturation were unaffected. There were no biologically significant findings in the behavioral tests, no changes in organ weights, and no pathological findings that could be attributed to isopropanol exposure. In conclusion, there was no evidence of developmental neurotoxicity associated with isopropanol exposure as high as 1200 mg/kg/day.

1-Propanol↗
PubMed1994

Isopropanol 13-week vapor inhalation study in rats and mice with neurotoxicity evaluation in rats.

This study was conducted to evaluate the possible subchronic toxicity as well as neurobehavioral effects of isopropanol, a widely used industrial and commercial solvent. Five groups, each containing 10 Fischer 344 rats/sex and 10 CD-1 mice/sex, were exposed for 6 hr/day, 5 days/week, for 13 weeks to isopropanol vapor at concentrations of 0 (control), 100, 500, 1500, or 5000 ppm. An additional 15 rats/sex were assigned to the 0, 500, 1500, and 5000 ppm groups for assessment of neurobehavioral function. No exposure-related mortalities occurred during the study. The narcotic effects of isopropanol were noted only during exposures at 1500 and 5000 ppm. These signs, noted during exposures, were typically absent following exposures. The only clinical signs observed following exposures included swollen periocular tissue, perinasal encrustation, and ataxia for rats of the 5000 ppm group. Neurobehavioral evaluations indicated no changes in any of the parameters of the functional observational battery; however, increased motor activity for female rats in the 5000 ppm group was noted at Weeks 9 and 13. Decreases in body weight and body weight gain were observed for rats of the 5000 ppm group at the end of the first week of exposure. During the remaining weeks, increases in body weight and/or body weight gain were observed for rats of the 1500 and 5000 ppm groups. No exposure-related effects on body weight were noted for male mice; however, increased body weight and body weight gain were observed for female mice of the 5000 ppm group.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Propanol↗
PubMed1988

Prostatectomy: patients' perception and long-term follow-up.

We have reviewed 500 consecutive prostatectomies with a follow-up period of between 5 and 8 years; 184 surviving patients were sent a questionnaire and patients with residual urinary symptoms were interviewed, examined and a flow rate was performed. The operative mortality rate was 0.5%. Patients who presented with retention of urine had a high mortality rate in the first 3 years after the operation. Thirty-six per cent of surviving patients with chronic retention and 24% of those who underwent elective prostatectomy had residual urinary symptoms at the time of the study. Of patients who were sexually active pre-operatively, 34% felt that the operation was responsible for a deterioration in their sex lives. The incidence of retrograde ejaculation was 93%. It was concluded that prostatectomy is a safe operation with good patient acceptability. Patients with symptoms of prostatism require careful evaluation before prostatectomy and sexually active patients should be warned of the risks of impotence and decreased satisfaction due to retrograde ejaculation.

Age Factors↗
PubMed1987

Effect of chronic primidone treatment on folate-dependent one-carbon metabolism in the rat.

Rats were treated chronically with primidone (100 mg/kg/12 hr, p.o.) for up to 8 weeks. The effects of this treatment on one-carbon metabolism were determined in brain and liver. Serine hydroxymethyltransferase activity increased in both brain (44%) and liver (50%). Methylenetetrahydrofolate reductase activity increased in liver (26%) with a significant correlation to the length of treatment, but in brain it was unchanged. Methyltetrahydrofolate:homocysteine methyltransferase activity increased in brain (43%) with a significant correlation to length of treatment, but in liver no effect was observed. Methionine adenosyltransferase activity in brain was significantly lower than control at only one point after 8 weeks of chronic treatment. S-Adenosylmethionine concentration in liver increased gradually (23%) during treatment. S-Adenosylhomocysteine concentrations decreased in brain (33%) and increased in liver (23%) with chronic primidone treatment. These data support the hypothesis that chronic primidone treatment leads to folate depletion through interference with folate metabolism.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed1985

The effect of diazepam on brain levels of S-adenosyl-L-methionine and S-adenosyl-L-homocysteine: possible correlation with protection from methionine sulfoximine seizures.

Administration of the long latency convulsant, L-methionine-d,1-sulfoximine (MSO) results in an increase in brain methylation flux. We determined the effects of the anticonvulsant, diazepam (DZ) on MSO seizures and on brain levels of S-adenosyl-L-methionine (AdoMet) and S-adenosyl-L-homocysteine (AdoHcy) to indicate possible alterations in the brain methylation pathway. We report a dose related inhibition of MSO seizures by DZ. In addition, DZ significantly increased brain levels of AdoMet and AdoHcy and reversed the MSO-induced decreases in AdoMet and AdoHcy. DZ also blocked the MSO induced increase in the methylation index (AdoMet/AdoHcy). The data indicates an inhibition of MSO induced increases in brain methylation by DZ. Possible mechanisms for the effect of DZ on the cerebral methylation pathway are discussed.

Animals↗
PubMed1983

Effect of mixing conditions on irritant potency of zinc oxide and sulfur dioxide.

Measurement of mechanics of respiration in guinea pigs was used to assess the irritant potency of zinc oxide and sulfur dioxide mixed under different conditions of temperature and humidity. Concentrations were 1-2 mg/m3 zinc oxide and 1 ppm sulfur dioxide. Dry conditions of mixing (Chamber RH 30%) either at 24 degrees C in the exposure chamber or at 480 degrees C in a dry furnace gave a biological response which could be completely accounted for by responses to zinc oxide and/or sulfur dioxide alone. Chemical examination of the aerosols did not indicate the formation of particulate sulfur species. Zinc oxide and sulfur dioxide mixed dry at 480 degrees C and fed into the exposure chamber at 80% RH reacted to produce an irritant aerosol as evidenced by a rapid increase to levels 29% above control; reversal was rapid when exposure ended. Chemical studies indicated the presence of sulfite on these aerosols. Addition of water vapor to the furnace during mixing at 480 degrees C produced a different irritant aerosol. The resistance rose slowly to 19% above control values and remained elevated during the post-exposure hour. Chemical studies indicated the presence of sulfate, sulfite, and adsorbed sulfur trioxide on these aerosols.

Aerosols↗
PubMed1982

Respiratory response of guinea pigs to zinc oxide fume.

Guinea pigs were exposed for 1 hr to submicrometer zinc oxide fume at a concentration of approximately 1 mg/m3. Measurement of pulmonary mechanics was used to assess the response. The exposure produced a slight decrease in compliance which was statistically significant. The compliance showed a further decrease 1 hr post-exposure. In a second group of animals observed for two hours after exposure a progressive decrease in compliance was observed between the first and second post-exposure hours. No changes were observed in resistance, tidal volume, frequency, or minute volume.

Aerosols↗
PubMed1982

Failure of postural manoeuvres to prevent lumbar puncture headache.

Diagnostic lumbar puncture was performed on 76 neurological inpatients. They were randomly allocated to one of four bed rest positions for four hours following the procedure (supine and horizontal, prone and horizontal, supine with head-down tilt and prone with head-down tilt) after which they were allowed to get up. There was no substantial or significant difference in the incidence of headache between the four groups. Expectation of headache did not appear to be an important factor in its development.

Adolescent↗
PubMedDate not supplied

Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat.

The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.

Analysis of Variance↗
PubMedDate not supplied

Subchronic inhalation neurotoxicity study of amyl acetate in rats.

An inhalation toxicity study was conducted with rats to examine the potential for amyl acetate vapor to produce alterations in nervous system structure and function following repeated exposure. The study was performed as part of a USEPA Toxic Substances Control Act (TSCA) Section 4e Enforceable Consent Agreement for amyl acetate. Rats (CD) were exposed to amyl acetate vapor at concentrations of 0, 300, 600 or 1200 ppm, 6 h per day, 4 or 5 days per week, for at least 65 exposures. Treatment groups consisted of 15 rats per gender for the control and 1200 ppm groups and 10 rats per gender for the 300 and 600 ppm groups. Evaluations included clinical observations before, during and after each exposure, weekly detailed clinical examinations, weekly body weight and food consumption measurements and monthly functional observational battery and motor activity measurements conducted on non-exposure days. Neuropathology examination of the central and peripheral nervous system was performed at the end of the study. Exposure to amyl acetate did not result in overt clinical signs of toxicity or changes in body weight or food consumption. Transient, subtle decreases in general activity level during the 6-h exposure period were noted for animals in the 600 and 1200 ppm groups during the first 2 weeks of the study. Functional observational battery evaluations, automated motor activity measurements and neuroanatomy were unaffected by exposure. The no observed-effect level for subchronic neurotoxicity for this study was at least 1200 ppm, which is greater than an order of magnitude above the occupational threshold limit value (8-h, time-weighted average) for amyl acetate (100 ppm).

Administration, Inhalation↗