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Biomedical subjects

L L Hall

Publications and source records attributed to L L Hall.

At least 55 records · Page 3Linked to original sources

Transection or electrical stimulation of the hypoglossal nerve increases glial fibrillary acidic protein immunoreactivity in the hypoglossal nucleus.

Glial fibrillary acidic protein (GFAP) immunoreactivity within rat hypoglossal (XIIth) nuclei was examined 1-50 days following either unilateral nerve transection or modest electrical stimulation using indirect immunofluorescence and PAP immunohistochemistry. Both nerve transection and stimulation provoked an increase in the immunodetected GFAP within the XIIth nucleus.

Animals↗

In vivo and in vitro dermal penetration of 2,4,5,2',4',5'-hexachlorobiphenyl in young and adult rats.

Penetration of 2,4,5,2',4',5'-[14C]hexachlorobiphenyl (HCB) through skin of young (33 days) and adult (82 days) female Fischer 344 rats was determined in vivo and by two in vitro methods. In vivo dermal penetration at 120 hr was 45% in young and 43% in adults. At 72 hr in vivo dermal penetration was 35% in young and 26% in adults compared to 1.5% for young and 1.0% for adult as measured with a continuous flow in vitro system and 2.9% for young and 1.9% for adults as measured with a static in vitro system. Most of the dermally absorbed HCB remained in the body as only 4.9 and 2.6% of that absorbed was excreted by young and adult rats, respectively, at the end of 120 hr. Significant differences in dermal penetration and kinetics of HCB between young and adult female rats were observed. The elimination of HCB-derived material was approximately six times higher in feces than in urine. A physiological pharmacokinetic model was fitted to the organ and tissue radioactivity distribution data. Parameters in the model determined from dermal dosing of female Fischer 344 rats were in reasonable agreement with those reported in the literature for adult male Sprague-Dawley rats (iv dose). The rat constant for dermal penetration was 0.83 x 10(-4) min-1 for adults and 0.96 x 10(-4)min-1 for young. The delay or lag time parameter for dermal penetration was 4.4 hr in adults and 1.1 hr in young.

Administration, Cutaneous↗

A morphometric analysis of the somata and organelles of regenerating hypoglossal motoneurons from the rat.

A detailed morphometric evaluation of the somata and organelles of regenerating hypoglossal motoneurons from the rat was conducted. The volume of the hypoglossal nucleus and various parameters used to appraise neuronal size were estimated from 50 microns sections. The subcellular composition of randomly selected neurons was quantified from 1 micron and ultrathin sections. The volume of neuronal nuclei, nucleoli, mitochondria and lysosomes as well as the surface area of intracellular membranes were determined. Seven to 30 days following axotomy the volume of the hypoglossal nucleus was significantly diminished, undoubtedly reflecting dendritic retraction (P less than 0.05). Concomitantly, all estimates of neuronal size indicated significant neuronal enlargement (P less than 0.05). Ultrastructural alterations were most prominent 7 days following nerve transection: nucleolar volume was significantly increased, rough endoplasmic reticulum surface area was reduced, and non-Golgi smooth membrane surface area increased (P less than 0.05). In general, other organelles resisted the influence of axotomy and all ultrastructural parameters returned to control levels 21 to 30 days following the nerve transection. Functional recovery was detected in all animals 21 and 30 days following axotomy. The measured responses of axotomized hypoglossal motoneurons are similar to those reported for retinal ganglion cells of the goldfish (Whitnall & Grafstein, 1982, 1983), suggesting common metabolic events among these distinct neuronal populations following axonal transection.

Animals↗

Distribution and retention of organic and inorganic mercury in methyl mercury-treated neonatal rats.

Seven-day-old Long Evans rats received one mumol of 203Hg-labeled methyl mercury/kg sc and whole body retention and tissue distribution of organic and inorganic mercury were examined for 32 days postdosing. Neonates cleared mercury slowly until 10 days postdosing when the clearance rate abruptly increased. During the interval when whole body clearance of mercury was extremely slow, methyl mercury was metabolized to inorganic mercury. Peak concentration of mercury in kidney occurred at 2 days postdosing. At 32 days postdosing, 8% of mercury in kidney was in an organic from. Liver mercury concentration peaked at 2 days postdosing and organic mercury accounted for 38% at 32 days postdosing. Brain concentrations of mercury peaked at 2 days postdosing. At 10 days postdosing, organic mercury accounted for 86% of the brain mercury burden, and, at 32 days postdosing, for 60%. The percentage of mercury body burden in pelt rose from 30 to 70% between 1 and 10 days postdosing. At 32 days postdosing pelt contained 85% of the body burden of mercury. At all time points, about 95% of mercury in pelt was in an organic form. Compartmental analysis of these data permitted development of a model to describe the distribution and excretion of organic and inorganic mercury in methyl mercury-treated neonatal rats.

Animals↗

Sexual differences in the excretion of organic and inorganic mercury by methyl mercury-treated rats.

Adult male and female Long Evans rats received 1 mumole of methyl (203Hg) mercuric chloride per kilogram sc. Whole-body retention of mercury and excretion of organic and inorganic mercury in urine and feces were monitored for 98 days after dosing. Females cleared mercury from the body more rapidly than did males. The major route of mercury excretion was feces. By 98 days after dosing, cumulative mercury excretion in feces accounted for about 51% of the dose in males and about 54% of the dose in females. For both sexes, about 33% of the dose was excreted in feces as inorganic mercury. Cumulative excretion of organic mercury in feces accounted for about 18 and 21% of the dose in males and females, respectively. Urinary excretion of mercury was quantitatively a smaller route for mercury clearance but important sexual differences in loss by this route were found. Over the 98-day experimental period, males excreted in urine about 3.2% of the dose and females excreted 7.5%. Cumulative organic Hg excretion in urine accounted for 1.8% of the dose in males and 5.3% of the dose in females. These sexual differences in urinary and fecal excretion of organic and inorganic mercury following methyl mercury treatment were consistent with previous reports of sexual differences in mercury distribution and retention in methyl mercury-treated rats, particularly sexual differences in organic mercury uptake and retention in the kidney. Relationships between body burdens of organic or inorganic Hg and output of these forms of Hg in urine and feces were also found to be influenced by the interval after MeHg treatment and by sex. Relationship between concentration of Hg in liver and feces and in kidney and urine differed for organic and inorganic Hg and depended upon sexual status and interval after MeHg treatment. These findings emphasize that sexual differences in distribution, retention, and metabolism of methyl mercury are factors to be considered in estimations of hazards associated with exposure to this agent.

Animals↗

Comparison of the penetration of 14 pesticides through the skin of young and adult rats.

In vivo percutaneous absorption of 14 pesticides was studied in young (33-d-old) and adult (82-d-old) female Fischer 344 rats, at three different dose levels. Carbon-14-labeled pesticides in acetone were applied to previously clipped middorsal skin. The treatment area was 2-3% of the body surface area. Penetration of the pesticides during a 72-h period ranged from approximately 1%-90%, depending on compound, dose, and age of animal. No clear age-related pattern of dermal absorption among compounds was found. Only chlordecone, folpet, and permethrin did not show significant age-dependent differences in skin penetration. Atrazine, carbaryl, chlorpyrifos, and hexachloro-biphenyl had greater absorption in the young, while carbofuran, captan, dinoseb, DSMA, MSMA nicotine, and parathion displayed greater absorption in the adult. The majority of the compounds showed dose-dependent penetration. The dose-response curves for penetration were not parallel for 8 of the 14 compounds studied.

Age Factors↗

Dermal penetration of carbofuran in young and adult Fischer 344 rats.

Dermal penetration of carbofuran was determined in young (33 d) and adult (82 d) female Fischer 344 rats employing in vivo and in vitro methods. In vivo dermal penetration at 120 h was 43% for young and 18% for adult rats. The half-time for carbofuran skin penetration (in vivo) was 128 h for the young and 400 h for the adults. The young to adult ratio of dermal penetration was greater than 1 at all time points (average 2.9) and had a maximum of 4.2 at 24 h. Cumulative urinary excretion approached about 95% of the absorbed dose in both the young and adult animals at 120 h. Whole-body retention was slightly higher in adults. Kidney showed the highest tissue-to-blood concentration ratio (4.6 in adult, 2.3 in young). The ratio for the carcass was 2.8 in the adult and 2.4 in the young. The urine/blood concentration ratio was high, 435 in the adult and 573 in the young. The feces/blood ratio was 44 in the adult and 65 in the young. Skin absorption by the in vitro continuous-flow system was 41% for the young and 11% for the adult at 72 h, compared to 36% and 13% by the in vivo method. The static in vitro method gave consistently lower skin penetration values of 12% for the young and 8.8% for the adult. Differences in the kinetics of retention and excretion were observed between the young and adult animals.

Administration, Topical↗

Toxicity of mercuric chloride to the developing rat kidney. III. Distribution and elimination of mercury during postnatal maturation.

Mercuric chloride is a potent nephrotoxicant in the adult rat, but has little effect on newborns. Nephrotoxicity increases with postnatal maturation. This study assesses the changes in tissue distribution and excretion of Hg during postnatal development. Sprague-Dawley rats were injected sc with 5 mg/kg 203HgCl2 on postnatal Day 1, 8, 15, 22, or 29. Hg concentration was measured in the whole body, renal cortex, medulla and papilla, liver, and subcellular fractions of liver and kidney. Binding to cytosolic metallothionein was assessed. Whole-body elimination of Hg was slow at the three younger age groups, as only 20% of the initial load was eliminated by 5 days after injection. Excretion was much more rapid in the two older groups, which eliminated about half of the initial load within 5 days. Concentration of Hg was highest in renal cortex (the principal site of Hg toxicity), and there was an age-related increase in cortical Hg concentration. This may explain the increased toxicity of Hg with age. There was an age-related decrease in hepatic Hg concentration. The high levels of metallothionein present in perinatal rat liver may protect the renal cortex from receiving a toxic dose of Hg; however, the increased concentration of hepatic Hg in newborns is insufficient to account for all of the cortical decrease. It is probable that Hg was distributed to other tissues. In liver and kidney cells of neonates, Hg concentration was highest in the cytosol, decreasing in an age-related manner. This was accompanied by an age-related increase of Hg in the nuclear/mitochondrial fraction. Hg in the cytosol was largely bound to metallothionein, although there were substantial amounts associated with very low-molecular-weight molecules and high-molecular-weight proteins. There are significant maturational changes in the organ, cellular and subcellular distribution of Hg in the rat during the first 4 weeks after birth. These probably explain the increasing sensitivity with maturity to Hg nephrotoxicity.

Aging↗

Sexual differences in the distribution and retention of organic and inorganic mercury in methyl mercury-treated rats.

At 56 days of age, male and female Long-Evans rats received 1 mumole of 203Hg-labeled methyl mercuric chloride per kilogram sc and total, organic, and inorganic mercury contents and concentrations in tissues were determined for up to 98 days postdosing. Whole body clearance of mercury was faster in females than in males, and females attained higher peak percentages of the methyl mercury dose in kidney and brain than did males. Females had significantly higher mean percentages of the mercury dose present in the kidney and brain as organic or total mercury and in brain as inorganic mercury than did males. Males had significantly higher mean percentages of the dose present as organic or total mercury in pelt and whole body than did females. When expressed on a concentration basis, the only significant sexual difference was in the higher average concentration of organic mercury in the kidneys of females. When expressed on a tissue content basis, significant male-female differences in the kinetics (sex X time interactions) of organic mercury retention were found in kidney, brain, skeletal muscle, pelt, and whole body. Significant sex X time interactions in the concentrations of organic mercury were found in kidney, skeletal muscle, and whole body. Kinetics of retention and concentration of inorganic Hg in the pelt differed significantly for males and females. Discordance in degree of statistical significance of differences in mercury contents and concentrations reflected in part differences in relative body composition of males and females. Integrated exposures of tissues of males and females to organic or inorganic mercury were determined by fitting multiexponential retention functions to retention data. Differences in integrated exposure were estimated by the female-to-male ratio of areas under retention curves. Reconstruction of whole body organic and inorganic mercury burdens from constituent tissues indicated that integrated exposures of males and females to inorganic mercury were equal but females had a lower integrated exposure to organic mercury. Integrated exposure of liver to either form of mercury was about equal in males and females. However, the integrated exposure of the brain of females to inorganic mercury was 2.19 times that of males suggesting a sexual difference in accumulation or retention of inorganic mercury in the nervous system. These sexual differences in distribution and retention of organic and inorganic mercury after methyl mercury exposure may underlie reported sexual differences in sensitivity to the toxic effects of methyl mercury.

Animals↗

Reproductive physiology of the clouded leopard: I. Electroejaculates contain high proportions of pleiomorphic spermatozoa throughout the year.

Ejaculates were analyzed from clouded leopards (Neofelis nebulosa) subjected to a regimented anesthesia/electroejaculation protocol. Group I males (n = 4), maintained individually in an environment with natural fluctuations in photoperiod, were electroejaculated on the same day at monthly intervals (January-December). Group II clouded leopards (n = 8), maintained in random zoo populations throughout the U.S., were evaluated on a single occasion. Phase contrast and electron microscopy indicated a high proportion of structurally abnormal spermatozoa in seminal fluid (Group I range, 14.8-78.9%; Group II range, 32.3-93.0%), the predominant deformity being a tightly coiled flagellum. Semen quality, including spermatozoal concentration and the incidence of abnormal sperm forms, varied (p less than 0.05) among males. Evaluating the numbers of motile spermatozoa/ejaculate (MS/E) among individual males from Group I on a monthly basis suggested a seasonal influence; gradually increasing MS/E values with peaks in June and July were observed in three of four animals. A simultaneous analysis of international breeding records for captive female clouded leopards demonstrated that 46.2% of parturitions occurred in March and April, indicating that most estrual periods occurred from late December through February. These data suggest that a physiological asymmetry may exist in peak reproductive performance between the male and female clouded leopard, perhaps as a result of differing adaptations to the captive environment. Motile spermatozoa can be recovered throughout the year using electroejaculation and, when used over time, a standardized procedure can determine a hierarchy of seminal quality among males of unknown reproductive potential. The relatively high proportions of structurally abnormal spermatozoa in the ejaculates of the clouded leopard may be related to a low degree of genetic variation within the species and/or hyperadrenal activity in captive populations.

Aging↗

Dermal absorption of pesticides calculated by deconvolution.

Using published human data on skin-to-urine and blood-to-urine transfer of 12 pesticides and herbicides, the skin-to-blood transfer rates for each compound were estimated by two numerical deconvolution techniques. Regular constrained deconvolution produced an estimated upper limit on cumulative dermal absorption of the radiolabel, while minimized deconvolution produced an upper bound on cumulative dermal absorption of parent compound. Dermal absorption rate was largest within 8 h of dosing for all pesticides examined. Only carbaryl showed a lag (3.5 h) in penetration. This may indicate a prolonged transit time through skin or a chemical transformation in skin has occurred. After onset, absorption occurred rapidly with 45% of the 120 h cumulative absorption occurring in 8 h. For parathion and dieldrin, over 50% of the 120 h total absorption occurred in the first 4 h. The deconvolution technique described here permits the calculation of the temporal aspect of dermal absorption for linear systems.

Humans↗

Dermal absorption and disposition of 1,3-diphenylguanidine in rats.

Dermal absorption, distribution, and metabolism of 1,3-diphenylguanidine (CAS 102-06-7) (DPG), widely used as an accelerator in processing rubber and in food packaging, was studied in adult female Sprague-Dawley rats. DPG shows 10% penetration through clipped back skin of the rats in 5 d. The first-order dermal absorption rate constant as determined by least square method was 0.021 +/- 0.002 d-1 (T1/2 = 33.6 d). Approximately 13% of the absorbed dose remained in the body in 5 d. Retention in skin, muscle, liver, intestine and fat contributed most to the body burden of DPG-derived radioactivity in 5 d. All tissues showed tissue to blood ratios greater than 1, with liver and intestine ratios of 26 at 5 d. Approximately 61% of the absorbed dose was eliminated into urine and 27% into feces in 5 d showing rapid clearance of absorbed DPG from the body. High-pressure liquid chromatography (HPLC) analysis of urine revealed two major peaks [parent compound and metabolite(s)]. Within 72 h, approximately 50% of the DPG-derived radioactivity excreted in the urine was parent compound. After 72 h, the DPG-derived radioactivity in the urine was present in the form of a single metabolite, and no parent compound was detected. No parent compound was detected in feces. Two metabolites, neither of which occurred in urine, were detected in feces. The HPLC analysis of the radioactivity at the application site showed only parent compound. Even though DPG shows slow dermal penetration, this route of exposure needs to be considered in the risk assessments because of the suspected chronic toxicity of DPG.

Animals↗

Ion-pair high-performance liquid chromatographic separation of a multicomponent anticholinergic drug formulation.

N,N'-Trimethylene-bis-(pyridinium-4-aldoxime)dibromide, 4-pyridine aldoxime, atropine sulfate, benactyzine hydrochloride, methyl paraben and propyl paraben are separated by ion-pair high-performance liquid chromatography. The method is specific for detecting and quantifying each compound in a complex mixture without solvent extraction or pretreatment. Levels as low as 1 ng on column are quantifiable by the procedure. All components are eluted within 9 min subsequent to the initial injection. Because of the simplicity of the method, the procedure is suitable for routinely monitoring the stability of the various compounds in the formulation during storage.

Atropine↗

Disposition of 14C and/or 74As-cacodylic acid in rats after intravenous, intratracheal, or peroral administration.

The distribution, excretion, and possible metabolism of (14)C- and/or (74)As-cacodylic acid, an organoarsenical herbicide, was studied in rats following a single intravenous injection, intratracheal instillation or oral gavage. Male Sherman rats were dosed at levels ranging from 200 mg/kg to 120 mug/kg. The extent and rate of lung absorption was greater than gastrointestinal absorption. Concentrations in the liver and whole blood were higher after peroral dosing than intravenous administration. Levels observed in plasma and other tissues were similar after all three routes following the absorptive phase. The percent dose found in the whole blood, red blood cells, and plasma was similar for all doses given by these routes. Less than 0.1(1/2) of the administered dose was recovered as (14)CO(2) by any route at 24 hr after administration. Twenty-four hours after intravenous, intratracheal, and peroral administration, 71, 60, and 25%, respectively, was excreted in the urine. After intravenous administration of 200 mg/kg, sufficient (14)C-cacodylic acid was recovered in bile to account for the small amount excreted in the feces. Cacodylic acid is probably not metabolized to inorganic arsenic since the disposition of (14)C and (74)As-cacodylic acid were identical.Kinetic analyses of the plasma curve for (14)C-cacodylic acid (high dose) yielded three half-times; 0.014, 0.214 and 3.42 hr with an apparent volume of distribution of 15.3 ml. Highest initial concentrations were found in the whole blood, muscle, kidney, liver and lung. Levels in all tissues decreased rapidly, but remained high in whole blood. The red blood cells were found to be the major site of body burden of cacodylic acid.

Absorption↗

Dermal irritancy of metal compounds. Studies with palladium, platinum, lead, and manganese compounds.

Dermal irritancy of 14 materials, including several compounds of palladium, platinum and lead, and methylcyclopentadienyl manganese tricarbonyl, plus deionized water (negative control) and glacial acetic acid (positive control), was tested on male albino rabbits weighing 2 to 3 kg. Procedures and evaluation criteria were adopted from those in use by the National Institute for Occupational Safety and Health. Five materials were evaluated as unsafe for intact or abraded skin contact as judged by severity of responses: glacial acetic acid (C3H5PDCl)2, (NH4)2PdCl4, (NH4)2PdCl6, and PtCl4; one as safe for intact, but not for abraded, skin: K2PdCl6; and two as safe for intact skin but not for abraded skin unless protected: K2PdCl4 and PdCl2. The remainder were evaluated as safe for intact or abraded skin contact (irritancy grade less than 1 on a scale of 4): H2O, Pd(NH3)2Cl2, PdO, PtO2, PtCl2, PbCl2, PbO, MMT.

Acetates↗