Search PubMed⌕ Search

Biomedical subjects

T W Clarkson

Publications and source records attributed to T W Clarkson.

At least 37 records · Page 2Linked 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

Biological monitoring of iodine, a water disinfectant for long-term space missions.

In order to establish guidelines for exposure of astronauts to iodine, used as a water disinfectant in space, we studied the usefulness of hair, saliva, and urine for biological monitoring in humans and in the human hair/nude mouse model. The monitoring of iodine in patients that received 150 mCi of Na131I (carrier-free) showed similar patterns of elimination for blood, saliva, and urine. The mean correlation coefficient (r) between iodine elimination for blood/saliva was 0.99, for blood/urine, 0.95, and for saliva/urine, 0.97. The absolute value of iodine concentrations in urine revealed marked variability, which was corrected by adjusting for creatinine levels. The autoradiographic studies of human hair demonstrated that iodine is rapidly incorporated into external layers of the hair root and can be removed easily during washing. These data were confirmed after iodine exposure using the human hair/nude mouse model. Hair does not provide satisfactory information about exposure due to unstable incorporation of iodine. The most useful medium for biological monitoring of astronauts exposed to high doses of iodine in drinking water is urine, when adjusted for creatinine, and saliva, if quantitative evaluation of flow rate is provided.

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↗
PubMed1995

The Seychelles study of fetal methylmercury exposure and child development: introduction.

Studies of outbreaks of methylmercury poisoning in Japan and Iraq from consumption of methylmercury (MeHg)-contaminated fish or bread proved that brain was the target organ, the toxic effects were dose-related, and the fetal brain was especially susceptible. Previous population studies suggested that a 5% risk of minimal fetal effect may be associated with a maternal hair mercury concentration during pregnancy of 10-20 ppm (mu g/g), a level that can be readily achieved by frequent consumers of fish. However, these studies had limitations, and as a result no definite conclusion concerning the lowest effect level could be reached and the question of a possible hazard to public health remained unanswered. There was a clear need for a more definitive study that would be prospective, involve a large enough cohort for risk analysis and adhere to accepted epidemiological principles. An appropriate site for such a study is the Republic of Seychelles, a location that afforded successful collaboration between the Seychelles Ministry of Health and faculty of the University of Rochester. A pilot study of 804 infant-mother pairs was followed by a main study of 779 mother-infant pairs. In the pilot study children were examined once between 5 and 109 weeks of age; in the main study they are being evaluated longitudinally starting at 6 1/2 months of age. This paper introduces both the pilot and main studies, describes their design, and summarizes the findings through 6 1/2 months of age. When the Seychelles study is completed, the analyses will provide a database for those nations that choose to regulate their citizens' fish consumption and/or provide dietary education.

Child↗
PubMed1995

The Seychelles child development study on neurodevelopmental outcomes in children following in utero exposure to methylmercury from a maternal fish diet: background and demographics.

Studies in Japan showed that fetal exposure to methylmercury during pregnancy can lead to severe neurodevelopmental changes in the infant while the mother suffers no or minimal effects. Fish contains methylmercury and there is concern that adverse neurodevelopmental effects may occur secondary to low-dose methylmercury exposure in utero from maternal fish consumption. The Seychelles Child Development Study has been examining the relationship between prenatal exposure to methylmercury during pregnancy in a population with high fish consumption and the neurodevelopmental outcome. Over 80% of Seychellois women eat fish daily, and the median fish meals per week during pregnancy is 12. Following a pilot study of 804 mother-infant pairs, a longitudinal main study of another 779 mother-infant pairs was initiated. The main study design includes collection of educational and socioeconomic information about the family and periodic standardized neurodevelopmental tests at specific ages from 6 1/2 months to 66 months of age. In this paper, we describe the background to the studies and give demographic characteristics of both the pilot and main study cohorts.

Age Distribution↗
PubMed1995

A pilot neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet.

It is not known if fetal neurodevelopmental damage occurs in humans at the low-level methylmercury exposure achieved by eating fish. To address this question, a cohort of 804 children in the Republic of Seychelles was identified who had fetal methylmercury exposure from a maternal diet high in oceanic fish. Mercury was determined by measuring the maternal total hair mercury during pregnancy, a standard index of methylmercury exposure. The median fetal mercury exposure was 6.6 ppm. Children were evaluated once between 5 to 109 weeks of age. Testing included the revised Denver Developmental Screening Test (DDST-R) and a neurological examination. The association between maternal hair mercury levels and developmental outcome was evaluated by multiple logistic regression analysis. Covariates for the child included gender, birth weight, one and five-minute Apgar score, age at testing, and medical problems, and, for the mother, age, tobacco and alcohol consumption during pregnancy, and medical problems. An association between fetal mercury exposure and development was found when DDST-R scores of questionable and abnormal were combined, a procedure used by previous investigators. These results should be viewed with caution since the association disappeared when DDST-R scores of questionable were treated in the standard manner as passes.

Animals↗
PubMed1995

Main neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: outcome at six months.

Methylmercury (MeHg) is a human neurotoxin to which the developing fetal brain is especially sensitive. The lowest dose of MeHg that impairs neurodevelopment in the human fetus is not known. The Seychelles Child Development Study (SCDS) is testing the hypothesis that fetal MeHg exposure from a maternal diet high in oceanic fish is related to child neurodevelopmental outcomes. Fish is the major protein source in the Republic of Seychelles, where a cohort of 779 mother-infant pairs was enrolled in a prospective longitudinal study. Maternal total hair mercury values during pregnancy were determined by cold vapor atomic absorption and ranged from 0.5 ppm to 26.7 ppm with a median of 5.9 ppm. When the children were 6 1/2 months of age, an examiner blinded to the maternal mercury value performed a neurological examination, the Fagan test of visual recognition memory, and the Denver Developmental Screening Test-Revised (DDST-R). On the DDST-R 2% scored other than normal while 3.4% had an overall neurological score other than normal. The Fagan test of visual recognition memory showed a median score of 60.5%, and the Rose attention measure from that test showed a median score of 37.9. The association between fetal mercury exposure and neurodevelopmental endpoints was examined by multiple regression analyses. After adjusting for covariates, no association between the maternal hair mercury level during pregnancy and an adverse neurodevelopmental outcome of the child was identified at 6 1/2 months of age.

Adult↗
PubMed1995

An analysis of autopsy brain tissue from infants prenatally exposed to methymercury.

Brains from 32 neonatal autopsies from the Seychelles were examined histologically and analyzed for mercury levels. Six brain regions were sampled: frontal and occipital cortex, temporal cortex with hippocampus, basal ganglia with thalamus, cerebellum, and pons with medulla. Tissue blocks for histology and mercury analysis were taken from opposing faces to provide for correlation of findings. Similar studies were performed on 12 reference neonatal brains from Rochester, New York. No clear-cut developmental abnormality was found, but some brains exhibited low-grade, non-specific destructive changes. Total mercury levels, most of it in the organic form, were elevated in many of the Seychelles specimens. No correlation was demonstrated between mercury levels and degree or type of histologic change. There was considerable variability in total mercury for each anatomic region among the 32 Seychelles cases, as well as from one region to another in individual brains. All values of total mercury were under 300 ppb. Statistical analysis of mean mercury levels for each region demonstrated higher values in deep subcortical nuclei, brain stem, and cerebellum, phylogenetically older parts of the brain. When total mercury concentration of each region was paired with all other areas in the same brain and the paired values plotted for the entire group of brains, high correlations were obtained for all brain pairs, suggesting a strong concentration-dependent relationship between mercury intake and brain content. Analysis of mercury levels in separately dissected blocks of grey and white matter from 12 specimens revealed no significant differences between grey and white. In comparison with other human developmental studies and with experimental developmental studies in animals, where toxicity has been demonstrated with total mercury brain levels above 1,000 ppb, this study found no evidence of toxicity within a range of mercury levels below 300 ppb. Submicroscopic changes, subcellular alterations, subtle disturbances in the unfolding of brain architectonics -- none of these are excluded with methods used in this report. Further studies of threshold effects of MeHg on fetal brain are essential. That approximately half of the mercury resides in glial elements in white matter reinforces the need to focus attention upon glia as well as neurons during development.

Brain↗
PubMed1995

Monitoring methylmercury during pregnancy: maternal hair predicts fetal brain exposure.

Autopsy brains were obtained from infants dying from a variety of causes within a few days of birth in a population exposed to methylmercury in fish. Infant and maternal blood and hair samples were also obtained. The concentration of total mercury in 6 major brain regions were highly correlated with maternal hair levels. This correlation was confirmed by a sequence of comparisons of maternal hair to maternal blood to infant blood and finally to infant brain. The results lend support to the use of maternal hair in assessing fetal exposure to methylmercury in fish-eating populations.

Brain↗
PubMed1995

Summary of the Seychelles child development study on the relationship of fetal methylmercury exposure to neurodevelopment.

The Seychelles Child Development Study is examining the association between fetal methylmercury exposure from a maternal diet high in fish and subsequent child development. The study is double blind and uses maternal hair mercury as the index of fetal exposure. An initial cross-sectional pilot study of 804 infants aged 1 to 25 months suggested that mercury may affect development. A follow up of 217 pilot children at 66 months of age also suggested that neurodevelopmental effects might be present, but the result was dependent on outcomes in a small number of children. On the basis of initial results in the pilot study a prospective, longitudinal main study with more covariates and expanded endpoints was begun on a new cohort of 779 children. No association with neurodevelopment was seen at 6 1/2, 19, or 29 months of age, but there was an inverse relationship at 29 months in boys only between mercury level and activity as judged by the examiner. Adverse neurodevelopmental effects from fetal mercury exposure in the pilot study are highly dependent on how the data are analyzed and no definite effects have been detected through 29 months of age in the main study. In a related study, 32 brains were obtained at autopsy from Seychellois infants. These were examined histologically and analyzed for mercury. No clear histological abnormalities were found. Mercury levels ranged from a background of about 50 ppb up to 300 ppb, and correlated well between brain regions. For 27 brains maternal hair from delivery was available and hair mercury correlated well with brain mercury.

Child Development↗
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↗
PubMed1993

Reduced methylmercury accumulation in a methylmercury-resistant rat pheochromocytoma PC12 cell line.

Rat pheochromocytoma PC12 cell sublines with increasing resistance to methylmercury (MeHg) were isolated by exposure to MeHg in two sequential steps. The strongest resistance (PC12/TM) among the clones obtained by the first cloning was characterized. PC12/TM cells exhibited about an 8- to 10-fold increase in resistance compared with parent PC12 cells on the bases of the concentration required for 50% inhibition of growth and colony-forming activity. PC12/TM cells accumulated smaller amounts of MeHg (one-half to one-fifth) than parent PC12 cells. This reduced MeHg accumulation in PC12/TM cells resulted from the slow uptake and rapid efflux. A close correlation between reduced MeHg accumulation and MeHg resistance was found among seven sublines of PC12 cells with different sensitivity to MeHg. The reduced retention of MeHg in PC12 sublines was also well correlated with the sensitivity to MeHg. Phenol-3,6-dibromophthalein disulfonate inhibited MeHg efflux from PC12/TM cells and increased its accumulation. These results suggest that efflux of MeHg from PC12/TM cells is associated with glutathione.

Animals↗
PubMed1993

Mercury: major issues in environmental health.

In the past, methylmercury compounds were manufactured as fungicides or appeared as unwanted byproducts of the chemical industry, but today the methylation of inorganic mercury in aquatic sediments and soils is the predominant if not the sole source of methylmercury. This form of mercury is bioaccumulated to a high degree in aquatic food chains to attain its highest concentrations in edible tissues in long-lived predatory fish living in both fresh and ocean waters. It is well absorbed from the diet and distributes within a few days to all tissues in the body. It crosses without hindrance the blood-brain and placental barriers to reach its principal target tissue, the brain. It is eliminated chiefly in the feces after conversion to inorganic mercury. The biological half-time of methylmercury in human tissues is about 50 days, but there is wide individual variation. Adult poisoning is characterized by focal damage to discrete anatomical areas of the brain such as the visual cortex and granule layer of the cerebellum. A latent period of weeks or months may ensue before the appearance of signs and symptoms of poisoning. The latter manifest themselves as paresthesia, ataxia, constriction of the visual fields, and hearing loss. The prenatal period is the most sensitive stage of the life cycle to methylmercury. Prenatally poisoned infants exhibit a range of effects from severe cerebral palsy to subtle developmental delays. Methylmercury is believed to inhibit those processes in the brain specially involved in development and growth such as neuronal cell division and migration.

Dose-Response Relationship, Drug↗
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↗