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PubMed1997

Serum beta-carotene level, arsenic methylation capability, and incidence of skin cancer.

To elucidate the associations of arsenic-induced skin cancer with serum beta-carotene level and arsenic methylation capability, a total of 654 residents of age 30 or older were recruited from three arseniasis-hyperendemic villages in Taiwan and regularly examined for skin lesions during the follow-up period. There were 33 cases affected with newly diagnosed skin cancer during the follow-up, giving an incidence of 14.74 per 1000 person-years. Although most study subjects had stopped consuming high-arsenic artesian well water more than 20 years ago, the risk of skin cancer was found to increase significantly with cumulative arsenic exposure before the cessation of drinking artesian well water in a dose-response relationship. Frozen serum samples collected at the recruitment from newly developed skin cancer cases and matched controls were tested for beta-carotene levels by high-performance liquid chromatography. Frozen urine samples of these subjects were examined by high-performance liquid chromatography to speciate arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMA), and dimethylarsinic acid and then quantitated by hydride generator combined with atomic absorption spectrometry. Skin cancer cases had a significantly lower serum level of beta-carotene than matched healthy controls. Although the primary methylation capability indexed by the ratio of MMA/(AsIII + AsV) was greater in cases than in controls, the secondary methylation capability indexed by the ratio of dimethylarsinic acid/MMA was lower in cases than in controls. An elevated proportion of MMA in total urinary arsenic level was associated with an increased risk of skin cancer. Subjects with a cumulative arsenic exposure of > or = 20.0 mg/liter-year and a proportion of MMA in total urinary arsenic level >26.7% had a multivariate-adjusted odds ratio of developing skin cancer as high as 20.91 (95% confidence interval, 2.63-166.5) compared wih those who had a cumulative arsenic exposure of <20.0 mg/liter-year and a MMA percentage of < or = 26.7%. Whether the association with capability of inorganic methylation is also applied to cancers of internal organs, including lung, liver, and urinary bladder, remains to be elucidated.

Adult↗
PubMed1998

Never on a Saturday (or a Sunday): the case against using weekend urine specimens to assess arsenic exposure.

The Wisconsin Department of Health and Family Services Bureau of Public Health recently investigated two cases of suspected arsenic poisoning. These cases involved four adults whose urinary arsenic levels ranged from 340 to 1485 ug/L (normal 0-30 ug/L). These findings were initially interpreted as evidence of an ongoing exposure to a toxic form of arsenic, however follow-up investigations determined that all of the urine specimens had been collected on a weekend and that each of these individuals had consumed fish within 48-hours of urine collection. Most of the fish was consumed at "Friday night fish fries" which are a popular tradition at many local restaurants. Urine samples collected after these individuals eliminated fish from their diets contained normal arsenic levels. This report suggests the need for laboratories to differentiate non-toxic forms of arsenic that are present in fish and seafood products from other species of this element. Until more specific analytical methods become available, patients should be instructed to omit fish and seafood from their diets for several days prior to collecting urine for arsenic analysis. In addition, elevated urinary arsenic levels should be interpreted cautiously and exposure to toxic forms should be confirmed before a diagnosis of arsenic poisoning is entertained.

Adult↗
PubMed1993

Therapeutic efficacy of new dimercaptosuccinic acid (DMSA) analogues in acute arsenic trioxide poisoning in mice.

The therapeutic efficacy of six newly synthesized analogues of dimercaptosuccinic acid (DMSA) was investigated in acute arsenic trioxide poisoning in mice. Meso-2,3-di(acetylthio)succinic acid (DATSA) and meso-2,3- di(benzoylthio)succinic acid (DBTSA) are analogues of DMSA with protected thiol groups ("prodrugs"), and DMDMS, DEDMS, DnPDMS, and DiPDMS are various di-esters of DMSA with methyl, ethyl, n-propyl, and isopropyl alcohols, respectively. Thirty minutes after s.c. injection of an LD80 of arsenic trioxide (65 mumol/kg) male NMRI mice were treated with a single equimolar dose (0.7 mmol/kg) of DMSA i.p. or one of the analogues i.p. or via gastric tube (i.g.). Control animals received arsenic trioxide and saline 30 min later. The survival rate was recorded for 30 days. All of the animals treated with DMSA i.p. survived and all controls died within 2 days. Administered i.g., DATSA and DBTSA increased the survival rate to 29% and 43%, and injected i.p. to 86%. Treatment with DMDMS i.p. and i.g., and with DEDMS, DnPDMS, and DiPDMS i.g. did not reduce lethality. Given i.p., DnPDMS increased the survival rate to 72%, and DEDMS and DiPDMS to 86%, respectively. To investigate the efficacy of the DMSA analogues in reducing the tissue content of arsenic, male NMRI mice received an s.c. injection of an LD5 of arsenic trioxide containing a tracer dose of 73-As(III) (42.5 mumol/kg body wt). Thirty minutes later, saline (controls) or a single equimolar dose (0.7 mmol/kg) of DMSA i.p., or one of the analogues i.p. or i.g. was administered. The arsenic content of various organs (blood, liver, kidneys, heart, lungs, spleen, small intestine, large intestine, brain, testes, skeletal muscle, and skin) at 30 min, 2 h, 4 h, 6 h, and 8 h after the arsenic injection was measured using a gamma counter.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Repetitive endoscopy and continuous alkaline gastric irrigation in a case of arsenic poisoning.

BACKGROUND: The poor prognosis of patients with persistent gastrointestinal radio-opacities after oral arsenic poisoning supports efficient gastrointestinal decontamination as critical for survival. In a case of massive arsenic ingestion, we performed repetitive gastric endoscopy and a continuous alkaline irrigation of the stomach over several days. CASE REPORT: A 41-year-old woman was admitted 4 hours after intentional ingestion of trivalent arsenic powder 5 g. The admission abdominal X-ray confirmed the presence of multiple gastric opacities. Initial treatment was gastric lavage with normal saline, dimercaprol chelation, and supportive therapy. Since gastric opacities persisted on the abdominal X-ray at 34 hours despite repeated gastric lavage, a gastroscopy was performed showing nonremovable agglomerates. In an attempt to achieve further gastric decontamination, we performed a continuous gastric alkaline irrigation. After 3 days of alkaline irrigation, the abdomen was normal on X-ray but the gastroscopy still showed arsenic concretions. Alkaline irrigation was continued for another 3 days until total disappearance of arsenic agglomerates at the gastroscopy. Admission urinary arsenic was 3663 microg/L. A total of 46.2 mg of inorganic arsenic, or less than 1% the ingested dose, was extracted from the stomach by this technique. The patient was discharged from the intensive care unit 20 days after admission without sequelae.

Adult↗
PubMed2006

Sister chromatid exchange analysis in smelting plant workers exposed to arsenic.

There are many studies documenting the genotoxic effects of environmental exposure to arsenic. Nevertheless, few data are available on the genotoxic risks of occupational arsenic exposure. In the present study, we have evaluated whether or not occupational exposure to arsenic in a copper smelting plant results in a significant increase in the frequency of sister chromatid exchange (SCE). SCE frequencies, proliferation rate index (PRI), and high frequency cells (HFCs) were evaluated in peripheral blood lymphocytes from a group of 105 arsenic-exposed workers from a Chilean smelting plant (exposed group). Similar assays were conducted on a group of 55 workers employed at the same mine but involved in administrative jobs (internal control), and on 48 workers of another mine, with no significant levels of arsenic (external control). Small but significant increases in SCE frequency were observed in the arsenic-exposed workers compared with the external control group (6.28+/-0.09 vs. 5.84+/-0.14 SCE/cell; P<0.01). Also, significantly higher frequencies of HFCs were observed in the exposed group (2.21%+/-0.20%) than in either the external control group (1.20+/-0.23; P=0.002) or the internal control group (1.30+/-0.24; P=0.008). However, there was no relationship between arsenic levels in the urine of the subjects and SCE or HFC frequency. The results of the study indicate that copper smelting results in slightly increased levels of DNA damage. However, our data were not consistent with arsenic exposure being the cause of the increase.

Adult↗
PubMed2006

Cytogenetic damage and genetic variants in the individuals susceptible to arsenic-induced cancer through drinking water.

In West Bengal, India, more than 300,000 arsenic-exposed people are showing symptoms of arsenic toxicity, which include cancers of skin and different internal organs. Since only 15-20% of the exposed population manifest arsenic-induced skin lesions, it is thought that genetic variation might play an important role in arsenic toxicity and carcinogenicity. A total of 422 unrelated arsenic-exposed subjects (244 skin-symptomatic and 178 asymptomatic) were recruited for this study. Cytogenetic damage, as measured by chromosomal aberrations in lymphocytes and micronuclei formation in oral mucosa cells, urothelial cells and binucleated lymphocytes, was studied in unexposed, skin-symptomatic and asymptomatic individuals with similar socioeconomic status. Identification of null mutations in GSTT1 and GSTM1 genes were carried out by PCR amplification. GSTP1 SNPs, implicated in susceptibility to various cancers, were assessed by PCR-RFLP method. Symptomatic individuals had higher level of cytogenetic damage compared to asymptomatic individuals and asymptomatic individuals had significantly higher genotoxicity than unexposed individuals. No difference in allelic variants in GSTT1 and GSTP1 was observed between these 2 groups. Incidence of GSTM1 null gene frequencies was significantly higher in the asymptomatic group. Individuals with GSTM1-positive (at least one allele) had significantly higher risk of arsenic-induced skin lesions (odds ratio, 1.73; 95% confidence interval, 1.24-2.22). These results show a protective role of GSTM1 null in arsenic toxicity. This study also indicates that asymptomatic individuals are sub clinically affected and are also significantly susceptible to arsenic-induced genotoxicity.

Adolescent↗
PubMed2002

Arsenic, drinking water, and health: a position paper of the American Council on Science and Health.

The purpose of this American Council on Science and Health report is to review issues and sources of uncertainty affecting assessment of potential health risks related to drinking water in the United States. Some background is included on how these issues arose, as is a review of the 1999 National Research Council report (with references to an updated version), to formulate a position based on the current science concerning how much of a risk of adverse health effects actually exists from arsenic in drinking water in the United States. ACSH concludes that there is clear evidence that chronic exposure to inorganic arsenic at concentrations of at least several hundred micrograms per liter may cause: (1) cancer of skin, bladder, lung (and possibly several other internal organs, including kidney, liver, and prostate), and (2) noncancer effects, including classic cutaneous manifestations that are distinctive and characteristic of chronic arsenic poisoning (diffuse or spotted hyperpigmentation and palmar-plantar hyperkeratoses). Noncancer effects may be multisystemic, with some evidence of peripheral vascular, cardiovascular, and cerebrovascular disease, diabetes, and adverse reproductive outcomes. Further study is needed to know if beneficial effects of arsenic in animal studies apply to humans. ACSH concludes that there is little, if any, evidence of a detrimental health effect in humans from inorganic arsenic in drinking water at the current maximum contaminant level (MCL) of 50 microg/L or below, either in the United States or elsewhere. As noted in the 1999 NRC report, "No human studies of sufficient statistical power or scope have examined whether consumption of arsenic in drinking water at the current MCL results in an increased incidence of cancer or noncancer effects" (NRC, 1999, p. 7). Based on our review, described in this article, ACSH finds that the limitations of the epidemiological data available and the state-of-the-science on the mode-of-action of arsenic toxicity, including can cer, are inadequate to support the conclusion that there are adverse health effects in the United States from arsenic in drinking water at or below the limit of 50 microg/L.

Arsenic↗
PubMed1998

Effect of glutathione depletion and metallothionein gene expression on arsenic-induced cytotoxicity and c-myc expression in vitro.

Arsenic exposure is clearly linked to human cancer. In rodent cells, arsenic has been reported to induce aberrant gene expression, including activation of the proto-oncogene c-myc. Abnormal or altered expression of such oncogenes can be involved in the acquisition of a malignant phenotype. Although its mechanism of action is unclear, arsenic is known to exert at least some of its toxic effects through interaction with sulfhydryl groups, and the non-protein sulfhydryl glutathione (GSH) appears to play an important role in detoxication of arsenic. Similarly, metallothionein (MT), a metal-binding protein with high sulfhydryl content, often functions in defense against metal-induced or oxidative cellular injury. Therefore, we examined the relationship among GSH, MT gene expression, and arsenic-induced toxicity or c-myc expression in cultured rat myoblast (L6) cells. In initial toxicity studies, arsenic was used in both the trivalent (arsenite) and pentavalent (arsenate) forms. The role of GSH was studied by pretreating cells with L-buthionine sulfoximine (BSO), which induces a marked depletion of GSH. In vitro exposure of L6 cells to BSO (1 to 25 microM) resulted in dose-dependent decreases in GSH. GSH depletion sensitized cells to both arsenite and arsenate. Zinc pretreatment, at levels which highly activated MT expression, had no effect on arsenite-induced cytotoxicity. Arsenite (1 microM) alone modestly increased c-myc expression from 1 to 4 h after treatment (maximum of 2.0-fold over control). After GSH depletion cells responded to arsenite exposure with much larger increases in c-myc transcription (3.2-fold over control). Zinc pretreatment had no reductive effect on arsenite-induced c-myc expression despite markedly activating the MT gene. Thus, it appears that the cellular levels of GSH, but not MT gene expression, play an important role in resistance to arsenic toxicity and aberrant gene activation. Moreover, depletion of GSH enhances arsenic-induced proto-oncogene activation, which might contribute to subsequent transformation.

Animals↗
PubMed1993

Effects of arsenic on DNA synthesis in human lymphocytes.

Effects of arsenic on DNA synthesis in human lymphocytes were biphasic: Either trivalent (arsenic trioxide and sodium arsenite) or pentavalent (sodium arsenate) arsenic compounds at very low concentrations enhanced DNA synthesis in human lymphocytes stimulated by phytohemagglutinin (PHA), whereas higher concentrations inhibited DNA synthesis. There were differences among individual susceptibilities to arsenic-induced DNA synthesis. Either stimulating or inhibiting effects of trivalent arsenic on DNA synthesis in PHA-stimulated lymphocytes were always stronger than those of pentavalent arsenic. Both trivalent and pentavalent arsenic could be rapidly taken up into the human lymphocytes and immediately stimulate or inhibit DNA synthesis. A possible dual effect of arsenic at very low concentrations as both comutagen and inhibitor of mutagenesis is discussed.

Arsenic↗
PubMed1996

Carcinogenic risks of inorganic arsenic in perspective.

Induction of cancer by inorganic arsenic occurs inconsistently between species and between routes of exposure, and it exhibits different dose-response relationships between different target organs. Inhaled or ingested arsenic causes cancer in humans but not in other species. Inhaled arsenic primarily induces lung cancer, whereas ingested arsenic induces cancer at multiple sites, including the skin and various other organs. Cancer potency appears to vary by route of exposure (ingestion or inhalation) and by organ site, and increases markedly at higher exposures in some instances. To understand what might explain these inconsistencies, we reviewed several hypotheses about the mechanism of cancer induction by arsenic. Arsenic disposition does not provide satisfactory explanations. Induction of cell proliferation by arsenic is a mechanism of carcinogenesis that is biologically plausible and compatible with differential effects for species or differential dose rates for organ sites. The presence of other carcinogens, or risk modifiers, at levels that correlate with arsenic in drinking water supplies, may be a factor in all three inconsistencies: interspecies specificity, organ sensitivity to route of administration, and organ sensitivity to dose rate.

Aged↗
PubMed1980

Comparative toxicity of arsenic compounds and their accumulation in invertebrates and fish.

The toxicity of arsenic III, arsenic V, sodium dimethyl arsenate, and disodium methyl arsenate to stoneflies, snails, amphipods, and trout, and the bioaccumulation of these compounds were studied during a 28-day flow-through test. Daphnia magna were exposed for 21 days in static tests to determine life-cycle effects. All animals were exposed to concentrations of approximately 100 and 1000 microgram/L (as arsenic) of each of the compounds. Arsenic III, the most toxic compound, caused a significant reduction in the survival of amphipods at 1000 microgram As/L after seven days. None of the compounds significantly affected the survival of other test species after 28 days or reduced young production in Daphnia after 14 days of exposure. The concentration of accumulated arsenic in stoneflies, snails, and Daphnia was as much as 131, 99, and 219 times greater than the water concentration, whereas amphipods and rainbow trout contained arsenic residues similar to the controls. Residues in stoneflies, snails, and Daphnia exposed to 1000 microgram As/L were higher than those in animals exposed to 100 microgram As/L, but appeared to reach a steady state after 14 days. Total arsenic accumulation was greatest in organisms exposed to inorganic arsenic, particularly at 100 microgram/L.

Animals↗
PubMed1976

Thermal effects on the accumulation of arsenic in green sunfish, Lepomis cyanellus.

The pattern of arsenic concentration in several tissues of Lepomis cyanellus was measured (by neutron activation analysis) as a function of exposure time at 10 degrees, 20 degrees, and 30 degrees C and 0, 30, 60 ppm of arsenic as sodium arsenate. Individual variability of aresenic uptake did not override trends of greater uptake with increasing exposure time, temperature, and arsenic concentration. The mean temperature coefficient of 4.5 for arsenic uptake in livers was higher than O'Hara's (1968) metabolic figures of 1.6 to 3.0 for Lepomis species. The biological half-life of arsenic in liver and gut of live specimens exposed to 30 and 60 ppm of arsenic at 10 degrees C was about one week. Percentage survival decreased and mean arsenic uptake increased slightly as temperature and arsenic concentration increased.

Animals↗
PubMed1993

Effects of arsenic on DNA synthesis in human lymphocytes stimulated by phytohemagglutinin.

Effects of arsenic on DNA synthesis in human lymphocytes were biphasic: either trivalent (arsenic trioxide and sodium arsenite) or pentavalent (sodium arsenate) arsenic compounds at very low concentrations enhanced DNA synthesis in human lymphocytes stimulated by phytohemagglutinin (PHA), whereas higher concentrations inhibited DNA synthesis. There were differences among individual susceptibilities to arsenic-induced DNA synthesis. Either stimulating or inhibiting effects of trivalent arsenic on DNA synthesis in PHA-stimulated lymphocytes were always stronger than those of pentavalent arsenic. It was also shown that both trivalent and pentavalent arsenic could be rapidly taken up into the human lymphocytes, and immediately stimulated or inhibited DNA synthesis. A possible dual effect of arsenic at very low concentrations as both comutagen and inhibitor of mutagenesis is discussed.

Adult↗
PubMed1999

Determination of total arsenic concentrations in nails by inductively coupled plasma mass spectrometry.

The analysis of trace elements in biological samples will extend our understanding of the impact that environmental exposure to these elements has on human health. Measuring arsenic content in nails has proven useful in studies evaluating the chronic body burden of arsenic. In this study, we developed methodology with inductively coupled plasma-mass spectrometry (ICP-MS) for the determination of total arsenic in nails. We assessed the utility of the washing procedures for removing surface contamination. Four types of preanalysis treatments (water bath, sonication, water bath plus sonication, and control) after sample decomposition by nitric acid were compared to evaluate the digestion efficiencies. In addition, we studied the stability of the solution over 1 wk and the effect of acidity on the arsenic signal. Arsenic content in the digested solution was analyzed by using Ar-N2 plasma with Te as the internal standard. The results suggest that washing once with 1% Triton X-100 for 20 min for cleaning nail samples prior to ICP-MS analysis is satisfactory. Repeated measurement analysis of variance revealed that there was no significant difference among the various sample preparation techniques. Moreover, the measurements were reproducible within 1 wk, and acidity seemed to have no substantial influence on the arsenic signal. A limit of detection (on the basis of three times the standard deviation of the blank measurement) of 7 ng As/g toenail was achieved with this system, and arsenic recoveries from reference materials (human hair and nails) were in good agreement (95-106% recovery) with the certified/reference values of the standard reference materials. ICP-MS offers high accuracy and precision, as well as high-throughput capacity in the analysis of total arsenic in nail samples.

Arsenic↗
PubMed2004

Arsenic intoxication-induced reduction of glutathione level and of the activity of related enzymes in rat brain regions: reversal by DL-alpha-lipoic acid.

The purpose of this study was to examine the effects of DL: -alpha-lipoic acid (LA) on arsenic (As) induced alteration of glutathione (GSH) level and of the activity of glutathione-related enzymes-glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH)-in rat brain regions (cortex, hypothalamus, striatum, cerebellum and hippocampus). Male Wistar rats of 150+/-10 g weight were divided into four groups: control and three experimental groups supplemented with arsenic (sodium arsenite) alone (100 ppm mixed in drinking water), lipoic acid alone (70 mg kg(-1) body weight), arsenic plus lipoic acid (100 ppm arsenic in drinking water plus 70 mg lipoic acid kg(-1) body weight). The arsenic content of brain regions was found to increase with the administration of sodium arsenite. Arsenic exposure elicited a significant decline in glutathione content and in the activity of related enzymes, with the greatest decreases seen in the cortex, striatum, and hippocampus, whereas there were no significant differences between control rats and the group treated with lipoic acid alone. Highly elevated content of the thiobarbituric acid-reactive substance malondialdehyde (MDA) in the brain regions of arsenic-exposed rats reflected extensive lipid peroxidation (LPO) processes. Simultaneous lipoic acid treatment was effective in reducing brain regional arsenic levels and lipid peroxidation and in increasing the glutathione content and the activity of its related enzymes. Lipoic acid, by acting as an alternative sulfhydryl nucleophile to glutathione, prevents its oxidation to glutathione disulfide in detoxifying reactions against reactive oxygen species and consequently increases the activity of glutathione-related enzymes.

Animals↗
PubMed1998

Sensitivity of wild cotton rats (Sigmodon hispidus) to the immunotoxic effects of low-level arsenic exposure.

Arsenic is a ubiquitous contaminant of many toxic waste sites around the country and experimental animal trials have indicated that arsenic may be immunotoxic to laboratory rodents. Because wild rodents such as the herbivorous cotton rat (Sigmodon hispidus) reside on many of these toxic waste sites, we explored the sensitivity of their immune systems to oral exposures of environmentally relevant concentrations of inorganic arsenic. We exposed adult male cotton rats (n = 36) to either 0 (controls), 5 (low dose), or 10 (high dose) ppm sodium arsenite in drinking water for 6 weeks. Daily food intake decreased in a dose-dependent manner, ranging from an average of 10.03 +/- 0.45 in the high-dose group to 11.27 +/- 0.42 (SE) g/animal/day in the control group. Mass of testes in the low-dose group increased significantly compared to controls, but there was no difference between the high-dose and control groups. Masses of liver, kidney, adrenals, popliteal lymph nodes, spleen, epididymides, and seminal vesicles and selected hematological parameters were unaffected by arsenic exposure. In vivo cell-mediated immunity, as measured by a phytohemagglutinin-hypersensitivity response to an intradermal challenge, was suppressed 30% in the low-dose group compared to controls; however, responses of those receiving a high dose of arsenic were similar to controls. Arsenic treatment did not have a measurable impact on lymphoproliferative responses of cultured splenocytes to the mitogens Concanavalin A and Pokeweed mitogen, or to the lymphokine interleukin-2. We also observed no impact of low-level arsenic exposure on macrophage phagocytic activity and tumoricidal activity of lymphokine-activated killer cells in vitro. It is possible that malnutrition caused by decreased food intake may eventually lead to atrophy of lymphoid organs and render animals more susceptible to environmental pathogens. However, direct effects of low-level arsenic exposure on immune function of cotton rats was minimal (a moderate depression in the in vivo cell-mediated immunity assay) and may not be clinically relevant with regard to susceptibility to disease in the wild.

Animals↗
PubMed2002

Intra-individual variation in the metabolism of inorganic arsenic.

OBJECTIVE: Inorganic arsenic is metabolized to methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are excreted in the urine. Previous studies have shown a marked inter-individual variation in the metabolism, but the within-person variation is unknown. Therefore, we determined the variation in the relative amount of urinary arsenic metabolites, i.e., inorganic arsenic, MMA and DMA, over time in women living in an Andean village with elevated arsenic levels in drinking water. METHODS: For our investigation of the individual day-to-day variation, daily spot urine samples were collected (at the same time of the day) for 5 consecutive days by 15 women. For our investigation of the within-day variation, seven women collected all the urine voided over a 72-h period, each voided into a separate container. RESULTS: Repeated measures analysis of variance (ANOVA) revealed no significant day-to-day variation, either in the relative distribution of inorganic arsenic metabolites (inorganic arsenic, MMA and DMA), or in the concentration of the metabolites. However, the percentage of DMA was slightly higher (on average 5.0%; P=0.003) and the percentage of inorganic arsenic lower (on average 5.8%; P=0.001) during the morning/day (03:00-15:00) compared with the evening/night (15:00-03:00). No within-day variation in the percentage of MMA was observed. CONCLUSION: The arsenic methylation efficiency of an individual is remarkably stable over time.

Adult↗
PubMed1991

Differential sensitivity of Trypanosoma brucei rhodesiense isolates to in vitro lysis by arsenicals.

Clinical isolates of Trypanosoma brucei rhodesiense, which were resistant to arsenical drugs in murine infections, were examined for resistance in vitro. A rapid lysis assay was developed which was able to predict in vivo sensitivity to melarsoprol (Mel B, Arsobal) and melarsen oxide. The assay was based on the finding that long slender bloodforms of drug-sensitive isolates would lyse in the presence of arsenicals upon incubation in heat-inactivated fetal bovine serum. On the basis of plots of decrease in the absorbance of trypanosome suspensions vs time of incubation with drug, L50 values, reflecting the drug concentration necessary for lysis of 50% of the cells within 30 min. were calculated for five strains. These values ranged from less than 30 microM for arsenical-sensitive strains to greater than 75 microM in proven arsenic refractory isolates. Calcium was essential for lysis, and the presence of the Ca2+ chelator EGTA (10 mM) in serum delayed lysis of sensitive strains. Ca2+ channel antagonists (Verapamil, Diltiazem), however, did not enhance lysis of refractory isolates when used at 20 to 30 microM. Intracellular concentrations of reduced trypanothione, the apparent target of arsenicals, were similar for all isolates, approximately 1.02 +/- 0.28 nmol/10(8) cells, as detected by monobromobimane derivitization and HPLC analysis. Uptake of melarsen oxide was found to be reduced in arsenical refractory strains. Uptake was judged by reduction of free reduced trypanothione as a result of formation of the trypanothione-arsenic complex Mel T. Little change was found in arsenical-resistant strains, but sensitive strains had 50 to 70% reductions in trypanothione levels after incubation with a low (1 microM) level of melarsen oxide.

Animals↗