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T W Clarkson

Publications and source records attributed to T W Clarkson.

At least 19 recordsLinked to original sources
PubMed1995

Environmental contaminants in the food chain.

Both terrestrial and aquatic food chains are capable of accumulating certain environmental contaminants to toxic concentrations. This article focuses on the aquatic food chain because we have less control over contaminant entry into this chain than we have for the terrestrial chain. In general, at least three special properties are required for a contaminant to bioaccumulate in an aquatic food chain: 1) a high octanol-water partition coefficient, 2) chemical and metabolic stability in water and in organisms in the food chain, and 3) a low toxicity to organisms in the chain so that the chain is not broken by loss of an intermediate species. Few of the thousands of chemicals produced by human industry meet these requirements. In terms of organic chemicals, the best known examples of bioaccumulation in aquatic food chains are the polychlorinated biphenyls (PCBs), dioxins, and organochlorine pesticides such as dichlorodiphenyltrichloroethane (DDT). Few examples exist of bioaccumulation of metal compounds. Methylmercury is arguably the most dramatic and best documented example of high bioaccumulation.

Animals↗
PubMed1995

Methylmercury-thiol uptake into cultured brain capillary endothelial cells on amino acid system L.

Recent in vivo studies suggest that the neurotoxin methylmercury (MeHg) is transported into brain as an L-cysteine complex by amino acid transport system L. To test this hypothesis, the mechanism of MeHg uptake into cultured calf brain capillary endothelial cells, an in vitro model of the blood-brain barrier, was examined. Uptake of Me203Hg-L-cysteine followed Michaelis-Menten kinetics, with a Km of 234 +/- 58 microM (mean +/- S.E.) and a Vmax of 57 +/- 25 pmol.micrograms DNA-1.15 sec-1. Uptake of 10 microM MeHg-L-cysteine was stereoselective and Na+ independent and it was inhibited by the system L substrates L-leucine, 2-amino-2-norbornanecarboxylic acid and L-methionine (5 mM), consistent with transport of MeHg-L-cysteine by the L amino acid carrier. L-Glutamate and methylaminoisobutyric acid, which are transported by the acidic and A amino acid carriers, respectively, had no effect. Moreover, uptake of 3H-L-leucine (5 microM) was inhibited by 1 mM MeHg-L-cysteine is transported into brain capillary endothelial cells by the L carrier. Uptake of other MeHg-thiols was also measured. MeHg-D, L-homocysteine uptake was 82 +/- 11% of MeHg-L-cysteine uptake, whereas uptakes of MeHg complexes of L-penicillamine, dimercaptosuccinic acid, N-acetyl-L-cysteine and glutathione were 57 +/- 16%, 19 +/- 7%, 10 +/- 4% and 8 +/- 5% of MeHg-L-cysteine uptake, respectively. These results illustrate the potential to minimize transport of MeHg across brain capillary endothelium by the careful choice of thiol complexing agent.

Amino Acids↗
PubMed1994

Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family.

For 3 months in 1969 a family in the United States that included a pregnant mother consumed pork containing methylmercury. Children, aged 20, 13, and 8 years and a neonate, developed severe neurological signs. Twenty-two years later, the 2 oldest had cortical blindness or constricted visual fields, diminished hand proprioception, choreoathetosis, and attentional deficits. Magnetic resonance images showed tissue loss in the calcarine and parietal cortices and cerebellar folia. The youngest had quadriplegia, blindness, and severe mental retardation until their deaths. The brain of the 8-year-old who died at age 30 showed cortical atrophy, neuronal loss, and gliosis, most pronounced in the paracentral and parietooccipital regions. The total mercury level in formalin-fixed, left occipital cortex was 1,974 ng/gm as measured by atomic absorption. Regional brain mercury levels correlated with extent of brain damage. A control patient had 38.5 ng of mercury/gm in the occipital cortex. Systemic organs in the patient and a control subject had comparable mercury levels. In mercury-intoxicated rats, we found that only 5 to 10% of total brain mercury was lost by formalin fixation. Brain inorganic mercury in the patient ranged from 82 to 100%. Since inorganic mercury crosses the blood-brain barrier poorly, biotransformation of methyl to inorganic mercury may have occurred after methylmercury crossed the blood-brain barrier, accounting for its persistence in brain and causing part of the brain damage.

Adolescent↗
PubMed1994

Establishment and characterization of methylmercury-resistant PC12 cell line.

Methylmercury (MeHg)-resistant sublines of rat pheochromocytoma (PC12) cells were isolated by repeated exposure to stepwise increased concentrations of MeHg. One of the sublines (PC12/TM) showed an 8- to 10-fold increase in resistance to MeHg compared with parent PC12 cells on the basis of the concentration required for 50% inhibition (IC50) of growth. PC12/TM cells accumulated smaller amounts of MeHg than parent PC12 cells. This reduction in MeHg accumulation in PC12/TM cells resulted from slow uptake and rapid efflux. The intracellular glutathione (GSH) level in PC12/TM cells was four times higher than that of PC12 cells. Pretreatment of PC12/TM cells with buthionine sulfoximine, which decreased the GSH level to that of the parent PC12 cells, increased the sensitivity of PC12/TM cells to MeHg. A close correlation between the MeHg accumulation and MeHg sensitivity was found among seven sublines of PC12 cells and parent PC12 cell line. The GSH level in PC12 sublines was also correlated with their sensitivity to MeHg.

Animals↗
PubMed1992

Methylmercury transport across the blood-brain barrier by an amino acid carrier.

The mechanism by which methylmercury (MeHg) crosses the blood-brain barrier was examined in the rat. Previous studies demonstrated that intravenous injection of L-cysteine with MeHg accelerates MeHg uptake into brain. Since the complex of MeHg with L-cysteine is structurally similar to L-methionine, a substrate for the L (leucine-preferring) amino acid transport system, this carrier may be involved in MeHg uptake. To examine this hypothesis, the rapid carotid infusion technique was used in the anesthetized rat. The concentration dependence of 203Hg uptake into brain after injection of Me203Hg-L-cysteine complex was nonlinear, exhibiting characteristics of saturable transport (apparent Michaelis constant 0.39 mM, vmax 33 nmol.min-1.g-1). A slower, nonsaturable uptake was seen after MeHg-L-cysteine uptake was inhibited by methionine and the amino acid analogue 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), an L system substrate, but not by alpha-methylaminoisobutyric acid, an alanine-preferring system substrate. Furthermore, L-[14C]methionine transport was inhibited by MeHg-L-cysteine but not by MeHgCl. There was a significant amount of uptake of 203Hg when injected as Me203Hg-glutathione, and this was inhibited by L-methionine and BCH but not D-methionine. S-ethylglutathione also inhibited 203Hg uptake after administration as Me203Hg-glutathione but had no effect on Me203Hg-L-cysteine uptake. These results suggest that MeHg may enter the brain as a cysteine complex via the L system and that plasma MeHg-glutathione serves as a source of MeHg-cysteine.

Amino Acid Transport Systems↗
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↗