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T W Clarkson

Publications and source records attributed to T W Clarkson.

At least 55 records · Page 3Linked to original sources
PubMed1992

Principles of risk assessment.

This review discusses the basic principles of risk assessment as used in general toxicology and in monitoring side-effects of therapeutic treatments. It also outlines how these principles may apply to assessment of biological reactions to dental restorative materials. Mercury exposure from amalgam fillings is used as an example. The calculations performed are intended only as illustrations, and many other factors must be taken into account. Thus, the calculations are not intended as the last word in risk assessment of amalgam fillings.

Body Burden↗
PubMed1991

Biliary-hepatic recycling of a xenobiotic: gallbladder absorption of methyl mercury.

The role of the gallbladder in the disposition of methyl mercury was investigated in guinea pig, hamster, and macaque monkey. 203Hg-labeled methyl mercury or inorganic mercury (5 microM) and [14C]inulin were instilled into the in situ guinea pig or hamster gallbladder. After 2 h, only 27.6 +/- 7.0% of the methyl mercury remained in guinea pig gallbladder fluid as compared with 85.0 +/- 3.2% of the inorganic mercury and 90.7 +/- 4.5% of the [14C]-inulin. In the hamster, 42.5 +/- 4.5% of methyl mercury and 95% +/- 0.9% of inorganic mercury remained after 2 h. When the sulfhydryl-containing compounds L-cysteine, glutathione, and bovine serum albumin (20 microM) were added to the test solution, cysteine increased and albumin decreased absorption of methyl mercury. Ligation of guinea pig cystic artery decreased gallbladder fluid absorption from 72.7 +/- 8.6 to 26.5 +/- 9.8% over 2 h but did not alter methyl mercury absorption. Bile was also sampled from gallbladders of four monkeys exposed chronically to CH3HgCl and from three control monkeys. For one of the exposed and one of the control monkeys, bile was also collected from the common hepatic duct. In both methyl mercury-exposed and control monkeys, the concentration of methyl mercury in gallbladder bile was lower than in hepatic bile. In contrast, the concentration of inorganic mercury in gallbladder bile was four to seven times that of hepatic bile, suggesting that methyl mercury but not inorganic mercury was being reabsorbed. To assess the functional significance of methyl mercury reabsorption by the gallbladder, guinea pig cystic ducts were ligated, the animals were given CH3 203HgCl (10 mumol/kg iv), and body burden of 203Hg was measured over 16 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1991

Mercury and monomethylmercury: present and future concerns.

Global atmospheric changes carry the potential to disrupt the normal cycling of mercury and its compounds. Acid rain may increase methylmercury levels in freshwater fish. Global warming and increased ultraviolet radiation may affect the global budget of methylmercury, including its formation and degradation in both biotic and abiotic environments. In this article we review current knowledge on mercury and monomethylmercury with regard to their environmental fate and the potential for human health effects. Recent findings indicate that atmospheric Hg deposition readily accounts for the total mass of Hg in fish, water, and sediment of Little Rock Lake, a representative temperate seepage lake in north-central Wisconsin. It is strikingly evident that modest increases in atmospheric Hg loading could lead directly to elevated levels in the fish stock. It is doubtful, given the experimental limitations in many recent studies, that the temporal pattern for Hg emissions, for background atmospheric Hg concentrations, and for changes in Hg depositional fluxes has been identified. Thus, the present and future questions of whether the environmental impact is of local, regional, or hemispheric significance remain. Contemporary investigations must address these important questions. Human exposure to methylmercury in the United States is probably increasing due to increased consumption of fish and fish products. A recent epidemiological investigation indicates high susceptibility to brain damage during prenatal exposures to Hg. An important objective for future investigation is to establish the lowest effect level for human exposure to methylmercury.

Air Pollutants↗
PubMed1990

Uptake of mercury by the hair of methylmercury-treated newborn mice.

Human hair has unique advantages in monitoring environmental exposures to methylmercury. Using newborn Balb/c mice as a model system, the incorporation of methylmercury into the hair was studied and compared with methylmercury distributions in other tissues. Newborn mice were given intraperitoneal injections of 203Hg-labeled methylmercury at designated times according to hair growth stages of the mouse. Animals were sacrificed 2 days after dosing. Distribution of mercury in pelt and other tissues was measured. The level of mercury in pelt was found to correlate with hair growth. The amount of mercury in pelt peaked when hair growth was most rapid and the total amount of mercury in pelt was significantly higher than that in other tissues, constituting 40% of the whole body burden. However, when the hair ceased growing, the amount of mercury in pelt dramatically dropped to 4% of whole body burden and mercury concentrations in other tissues except brain were elevated. Autoradiographic studies with tritium-labeled methylmercury demonstrated that methylmercury concentrated in hair follicles in the skin. Within hair follicles and hairs, methylmercury accumulated in regions that are rich in high-sulfur proteins. The uptake of inorganic mercury (administered as HgCl2) by pelt was also compared with that of methylmercury. The amount of inorganic mercury found in pelt was less than one-half that of methylmercury in animals with growing hair. Cessation of hair growth did not decrease the inorganic mercury level in pelt to the same extent as in the case of methylmercury.

Animals↗
PubMed1990

Extracorporeal regional complexing haemodialysis treatment of acute inorganic mercury intoxication.

A 70-year-old white female presented approximately 24 h after ingesting three 475 mg tablets (1.425 g) of mercuric chloride in a suicide attempt. Acute renal failure necessitated the initiation of haemodialysis approximately 4 d after the ingestion. Treatment with BAL (2,3-dimercaptopropanol) resulted in only small increases in mercury output into dialysate. A new procedure involving the extracorporeal infusion of the chelating agent dimercaptosuccinic acid (DMSA) into the arterial blood line during haemodialysis was initiated. This procedure of Extracorporeal Regional Complexing Haemodialysis (ERCH) had been effective in increasing methylmercury removal in patients poisoned by contaminated grain. The first DMSA-ERCH procedure was performed 6 d after poisoning. There was a dramatic increase in mercury output into the dialysate. During three treatment sessions of 80 min each, 1189 micrograms of mercury were removed from the patient. The dialysed mercury represented the only mercury output since the patient was anuric and not producing faeces. DMSA-ERCH appears to be much more effective than BAL and haemodialysis in the treatment of acute inorganic mercury poisoning. The long interval between poisoning and initiation of treatment probably contributed to the patients ultimate demise, 28 d after poisoning. Efficacy of the DMSA-ERCH procedure for inorganic mercury poisoning is likely to be improved as the interval between exposure and treatment is reduced.

Aged↗
PubMed1989

The effects of dose of elemental mercury and first-pass circulation time on exhalation and organ distribution of inorganic mercury in rats.

The lung plays a major role in the removal of dissolved elemental mercury (Hg0) from the bloodstream. During the first passage through the lung after an intravenous dose of Hg0 dissolved in aqueous buffer, from 10 to 17% was exhaled depending on the dose (0.11 or 1.1 micrograms Hg/rat) and the injection site (jugular versus tail vein). Furthermore, evidence is presented that subsequent exhalation over the next 50 s, before the rats were killed and the mercury determined in the lung at that time, was largely Hg0-extracted during the first pass. The total mercury extracted during the 60 s period was in the range of 40-49% of the dose. The oxidation of Hg0 to Hg2+ in red cells is important in limiting the availability of Hg0 to certain tissues. Thus, after a short residence time in blood (0.6 s after jugular vein injection), 12.9-17% is exhaled in the first pass as compared to 10.4-12.2% with a longer residence time (1.8 s after tail vein injection). Furthermore, there was a general tendency, even at 60 s after dosing, for certain tissues - lung, brain, and heart - to have higher values after dosing from the jugular vein. It was estimated that the half-time for oxidation was 3.3 s. Our results confirm previous observations that the form of inorganic mercury greatly influences the short-term deposition in certain tissues. Thus as compared to Hg2+, administration of Hg0 increases lung levels 5-10-fold; brain, 4-fold; and heart, 3-fold. Blood levels are lower after Hg0, particularly after the higher dose. Such findings are consistent with a model wherein Hg0 is in part oxidized by red blood cells, the remainder rapidly diffusing in tissues where it is also oxidized to Hg2+.

Animals↗
PubMed1989

Vasocystostomy: a model for studying male reproductive toxicity in the rat.

A nonsacrificial rat model has been developed which permits the easy collection and measurement of spermatozoa. The ductus deferens is anastomosed to the bladder (Vasocystostomy) and urinary sperm is collected daily. The correlation between testicular histology and sperm counts indicates that this model is reliable. Using this model we demonstrate inhibition of sperm production by fluoroacetate.

Anastomosis, Surgical↗
PubMed1989

Dose-response analysis of infants prenatally exposed to methyl mercury: an application of a single compartment model to single-strand hair analysis.

A new method of estimating fetal exposure is used in a dose-response analysis of data from the 1971 outbreak of methyl mercury poisoning in rural Iraq. An X-ray fluorescence instrument for the measurement of single strands of human hair was employed to obtain longitudinal profiles recapitulating fetal exposure. Logit and hockey-stick models as well as nonparametric smoothing are used to describe data on delayed development and central nervous system abnormality.

Bread↗
PubMed1989

Methyl mercury uptake across bovine brain capillary endothelial cells in vitro: the role of amino acids.

Previous studies in the rat in vivo have demonstrated that co-injection of methyl mercury (MeHg) with L-cysteine into the common carotid artery enhances brain Hg levels following a single capillary pass through the CNS vasculature. In order to elucidate the relationship between MeHg transport and the neutral amino acid transport carrier system, regulatory aspects of MeHg transport across the bovine blood-brain barrier were investigated in isolated brain microvessel preparations. Following 1 hour co-incubations of 203Hg-MeHgCl with 0.1 mM L-cysteine at 37 degrees, 203Hg uptake by suspended microvessels was significantly increased (P less than 0.05) compared with controls. This enhanced capillary uptake of 203Hg was abolished by co-incubations of microvessels with 0.1 mM L-cysteine-L-methionine, or 0.1 mM L-cysteine plus AT-125 (alpha S, 5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazolacetic acid), an irreversible inhibitor of gamma-glutamyl-transpeptidase. One hr co-incubations of bovine capillaries with 203Hg-MeHgCl and 0.1 mM D-cysteine at 37 degrees or 0.1 mM L-cysteine at 0 degrees did not increase rat of 203Hg uptake compare with controls. These results indicate that L-cysteine enhances the rate of capillary MeHg uptake. The accumulation of 203Hg in the bovine microvessels appears to be a carrier-mediated process. It is inhibited by L-methionine, a competitive substrate for neutral amino acid transport, and by AT-125. Capillary uptake of 203Hg is stereospecific to the L-enantiomorph of cysteine, suggesting selective uptake of MeHg across the blold-brain barrier. The data emphasize the relationship between the L-enantiomorph neutral amino acid carrier system and MeHg transport across the capillaries.

Amino Acids↗
PubMed1988

Uptake of methylmercury in the rat brain: effects of amino acids.

Aspects of the regulation of methylmercury (MeHg) transport across the blood-brain barrier (BBB) were investigated in the in vivo Long-Evans female rat. Fifteen s after intracarotid injection, brain 203Hg concentration was significantly increased in animals injected with 0.05 mM [203Hg]MeHgCl plus 0.1 mM L-cysteine compared with controls (P less than 0.05). This L-cysteine-enhanced 203Hg brain uptake was abolished by coinjections of [203Hg]MeHgCl with 0.1 mM L-cysteine-L-methionine, or 0.1 mM L-cysteine plus AT-125 (alpha S, 5S-alpha-amino-3-chloro-4,5-dihydro-5-isoxazolacetic acid), an irreversible inhibitor of gamma-glutamyl transpeptidase. Coinjections of rats with [203Hg]MeHgCl and 0.1 mM D-cysteine did not result in an increase in the rate of 203Hg uptake compared with controls. Furthermore, [203Hg]MeHg uptake at 15 s after intracarotid injections in the rat was stereospecific to the neutral amino acid carrier, as 203Hg uptake across the BBB was not inhibited by coinjections of [203Hg]MeHgCl with aspartic acid, an acidic amino acid. These results indicate the presence in brain capillaries of a transport system capable of selectively mediating MeHg uptake across the brain capillary endothelial cell membrane.

Amino Acids↗
PubMed1988

Distribution of mercury 203 in pregnant rats and their fetuses following systemic infusions with thiol-containing amino acids and glutathione during late gestation.

To investigate the effect of amino acids and the tripeptide glutathione (GSH) on tissue uptake of methylmercury (MeHg) in the developing rat fetus in utero, pregnant rats were continuously infused into the external jugular vein with 0.1 mM L-cysteine, 0.1 mM L-leucine, 0.1 mM GSH or saline commencing on day 17 of gestation. This was followed at 24, 48, and 72 hours by external jugular infusion of 50 microM [203Hg]-MeHgCl administered in 1 ml over 1 hour. Pups were surgically removed from the uterus on gestational day 21. Whole body, brain, kidney, liver, and placental 203Hg radioactivity was measured by means of gamma-spectrometry. Brain 203Hg concentration in pups exposed in utero to L-cysteine was significantly higher compared with pups exposed to saline (P less than 0.05). Brain 203Hg concentration in pups exposed in utero to L-leucine and GSH was significantly depressed compared with pups exposed to saline (P less than 0.05). Kidney 203Hg concentration was not significantly changed in all treatment groups compared with controls. Liver 203Hg concentration was significantly depressed in L-leucine- and GSH-treated pups compared with controls (P less than 0.05). Placental 203Hg concentration was not affected by any treatment compared with controls. These effects occurred despite no difference in total 203Hg body burden among pups, irrespective of the treatment. In addition, infusion with L-cysteine resulted in a significant increase in 203Hg brain concentration in dams compared with controls, and 203Hg brain concentration in L-leucine- and GSH-treated dams was significantly depressed compared with controls. Thus 203Hg distribution in both adult and developing animals is altered by chronic amino acid or GSH infusions and suggests that MeHg uptake may be mediated through the formation of a cysteine-MeHg complex which is transported across the blood-brain barrier by the neutral amino acid carrier transport system.

Animals↗
PubMed1988

Mercury vapor uptake and hydrogen peroxide detoxification in human and mouse red blood cells.

The uptake of Hg vapor (Hg0) by suspensions of human and BALB-c mouse erythrocytes was studied in a closed exposure system. The formation of catalase-compound-I and thereby the oxidation of Hg0 was initiated by microinfusion of hydrogen peroxide. The degradation of H2O2 by the glutathione (GSH)/GSH peroxidase system was reduced by t-butyl-hydroperoxide (t-BOOH) or by 1-chloro-2,4-dinitrobenzene (CDNB). In human red blood cells, CDNB and t-BOOH increased the rate of Hg vapor oxidation at the low and intermediate H2O2 supplementation rates. In mouse erythrocytes, Hg uptake was increased by CDNB over the entire H2O2 infusion range. In human cells, t-BOOH (0.1 mM) produced a remarkably high Hg uptake even without added H2O2. This Hg uptake in absence of exogenous H2O2 was inhibited by aminotriazole as was the activity of catalase. Hence, the Hg uptake was likely to have been induced by endogenous hydrogen peroxide. These findings support the view that the intact GSH/GSH peroxidase system can diminish the efficiency of compound-I-induced Hg vapor oxidation in erythrocytes.

Animals↗
PubMed1988

In vitro oxidation of mercury by the blood.

A method is described for studying the in vitro oxidation of mercury vapour by red blood cells at short times and with diminishing mercury vapour concentrations. It is found that for 40% red blood cell suspensions and 37 degrees at concentrations greater than about 6 ng mercury vapour/ml, the oxidation rate is zero order, and that at lower concentrations the rate changes to first order. The effect of temperature and of added hydrogen peroxide are studied. Results are considered in terms of the generally accepted belief that the catalase-compound I system is the main path of oxidation. If the results obtained in vitro in these experiments apply in vivo to man, it follows that inhaled mercury is carried in the blood to the brain and other organs primarily as dissolved vapour rather than as inorganic mercury ions.

Erythrocytes↗
PubMed1988

Estimation of mercury burdens in rats by chelation with dimercaptopropane sulfonate.

The chelation of mercury by 2,3-dimercaptopropane-1-sulfonate (DMPS) and its usefulness in the estimation of mercury burdens was investigated by exposing male, Sprague-Dawley rats to 203HgCl2 (0.1-2 mg of Hg per kg i.p.) or 203Hg vapor (0.5-2.0 mg of Hg per m3). DMPS (0.2-2.0 mmol/kg) was injected i.p. at times ranging from 1 to 38 days after exposure to the mercurial. Urine and feces were collected for 24 hr before and after DMPS treatment. Whole body mercury levels, tissue levels and excretion of mercury were measured by radioactivity counting. After DMPS treatment there was a significant decrease of whole body mercury levels and an increase in urinary excretion. The increase in urinary excretion was directly proportional to the whole body burden of mercury at the time of dosing with DMPS in animals dosed with HgCl2 and exposed to mercury vapor. Furthermore, the increase in urinary excretion induced by DMPS was almost equal to the amount of mercury lost from the kidneys.

Animals↗
PubMed1987

Biological monitoring of metals with special references to the early stages of the life cycle.

In summary, the biological monitoring of toxic metals in the early stages of the life cycle has not yet received the attention it deserves. Most metals have simply not been studied at all. Some successful applications with mercury, lead, and cadmium have been reviewed here. But even for these widely studied metals, there is a great need to study physiological models for metal disposition in developing animals.

Animals↗
PubMed1987

Fetal methylmercury poisoning. Relationship between concentration in single strands of maternal hair and child effects.

Pregnant women consumed bread that was prepared from methylmercury-treated wheat. Single strands of maternal head hair were analyzed by x-ray fluorescence spectrometry. The index of fetal exposure was the maximum hair mercury concentration during gestation. Effects were measured by the frequency of psychomotor retardation, seizures, and neurological signs in the children. A dose-response relationship was demonstrated for fetal effects of methylmercury. Analysis of single hair strands provides a better index of acute or subacute fetal exposure than analysis of bundles of hair; the duration and degree of exposure are more accurately defined. A sex difference in response is discussed.

Developmental Disabilities↗
PubMed1987

Mercury 203 distribution in pregnant and nonpregnant rats following systemic infusions with thiol-containing amino acids.

Near-term pregnant (gestational day 17) and nonpregnant Long-Evans female rats were continuously infused into the external jugular vein with 0.1 mmole/hour L-cysteine, 0.1 mmole/hour L-leucine, or saline. At 24, 48, and 72 hours, 50 mumole/hour [203Hg]-MeHgCl was administered over 1 hour. Total 203Hg body burden, brain, kidney, liver, and blood 203Hg concentrations were determined at 96 hours by gamma scintillation spectrometry. Despite significantly greater 203Hg whole body retention in the pregnant animals 203Hg concentrations in blood, brain, kidney, and liver were higher in nonpregnant rats. In addition, brain 203Hg concentrations in both pregnant and virgin rats were significantly higher in L-cysteine-treated rats compared with controls. These results suggest that the fetus may act as a "sink" for MeHg, thus decreasing 203Hg concentrations in maternal blood, brain, kidney, and liver. Furthermore, the data indicate that brain uptake of methylmercury in both pregnant and nonpregnant rats is enhanced by chronic L-cysteine infusion, lending support to the hypothesis that methylmercury in the rat may be translocated across the blood-brain barrier by the neutral amino acid carrier transport system.

Animals↗