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Selenium deficiency has been shown to affect the neurological development in animals, but human research in this area is scarce. We aimed to assess the impact of selenium status during pregnancy on child development at 1.5 years of age.This prospective cohort study was nested into a food and micronutrient supplementation trial (MINIMat) conducted in rural Bangladesh. Using inductively coupled plasma mass spectrometry, we measured selenium concentrations in erythrocyte fraction of blood collected from 750 mothers at gestational week 30, and calculated μg per g hemoglobin. A revised version of Bayley Scales of Infant Development was used to assess children's mental and psychomotor development. A Bangladeshi version of MacArthur's Communicative Development Inventory was used to assess language comprehension and expression. Linear regression analyses adjusted for multiple covariates were used to assess the associations.Maternal erythrocyte selenium concentrations varied considerably, from 0.19 to 0.87 μg/g hemoglobin (median 0.46 μg/g hemoglobin), and were associated with developmental measures. An increase in erythrocyte selenium by 0.50 μg/g hemoglobin was associated with an increase in children's language comprehension by 3.7 points (0.5 standard deviations; 95% confidence interval: 0.40, 7.1; p = 0.028). The same increase in erythrocyte selenium corresponded to an increase in the girls' psychomotor development by 12 points (0.9 standard deviation; 95% confidence interval: 4.3, 19; p = 0.002), but much less in boys.Low prenatal selenium status seems to be disadvantageous for children's psychomotor and language development. Further studies are needed to elucidate the underlying mechanisms of these effects.

Mastermind-like 1 (MAML1) is a transcriptional coregulator of diverse/multiple activators, such as Notch, p53, myocyte enhancer factor 2C, NF-κB, beta-catenin, papillomavirus E6 proteins, early growth response 1 and runt-related transcription factor 2. Thus, MAML1 functions in various signaling pathways, most of them connected to cell proliferation, which suggests that MAML1 might play a potential role as a cell proliferation marker. In this study we show that MAML1 expression in the kidney correlates in silico with established cell proliferation markers including PCNA, CDC2 and XRCC5 (Ku80). Over-expression of MAML1 increased proliferation of human embryonic kidney (HEK) 293 cells, while MAML1 downregulation by siRNA decreased cell proliferation. Exposure of HEK293 cells to inorganic arsenic (arsenite) showed reduced levels of MAML1, in combination with a decreased proliferation rate. Our findings provide evidence that arsenic can inhibit proliferation of embryonic kidney cells, possibly through reduction of MAML1 gene expression.

Hg2+ (0.1 microM-0.5 microM) modified the Ca2+ signals elicited by either KCl or the glutamate-receptor agonist, N-methyl-D-aspartate (NMDA), in cerebellar granule cells (CGCs). Hg2+ enhanced the intracellular Ca2+ transient elicited by high K+ and prevented a complete recovery of the resting intracellular Ca2+ concentration ([Ca2+]i) after either KCl or NMDA stimulation. Higher Hg2+ concentrations (up to 1 microM) increased [Ca2+]i directly. Following the short-term exposure to Hg2+, CGCs underwent apoptosis, which was identified by the cleavage of DNA into large (700-50 kbp) and oligonucleosomal DNA fragments, and by the appearance of typical apoptotic nuclei. Combined treatment with 0.1-0.3 microM Hg2+ and a sublethal NMDA concentration (50 microM) potentiated DNA fragmentation and apoptotic cell death. When the exposure to Hg2+ was carried out in Ca2+-free media or in the presence of Ca2+ channel blockers (L-type or NMDA-R antagonists), the effects on signalling and apoptosis were prevented. Our results suggest that very low Hg2+ concentrations can trigger apoptosis in CGCs by facilitating Ca2+ entry through membrane channels.

Indium arsenide and gallium arsenide are important new materials in the semiconductor industry due to their superior electronic properties in comparison with the older silicon-based materials. Animal experiments have shown that exposure to these compounds induces marked alterations in gene expression and immune response. Toxicity to the immune system has frequently been related to T and B cell apoptosis. In the present study we show that the semiconductor elements indium (In) and arsenic (As) are able to induce apoptosis in rat thymocytes in vitro. The results show that exposure to InCl 3 (1, 10, or 100 μM) or Na AsO 2 (0.01, 0.1, or 1 μM) induced DNA laddering after 6 h of incubation without compromising cell viability. These results were corroborated by flow cytometry analysis of propidium iodide-loaded cells, showing a typical high hypodiploid DNA peak in apoptotic thymocytes. Higher doses of In (1 mM) or As (10–100 μM) induced cell death by necrosis. These data indicate that In and As can induce apoptosis and necrosis in T lymphocytes in a dose-dependent manner, which may be of relevance for their immunotoxicity.

The concentrations of copper (Cu), zinc (Zn) and selenium (Se) in the brain and kidneys of second trimester fetuses (abortion cases) and infants (deceased before three months of age) were determined. Concentrations of Cu in brain, 0.31-1.6 mg/kg wet weight, increased with age, and were, on the average, three times higher in the brains of infants than of fetuses. In kidneys, Cu concentrations ranged between 0.34 and 2.9 mg/kg, and increased with age after birth. Concentrations of Zn in the brain decreased significantly with age in the fetuses, from about 7 mg/kg at post-conceptional week 12 to less than 5 mg/kg at week 20, but increased again postnatally. In kidneys, Zn concentrations (12-37 mg/kg) increased in parallel with the increase in tissue density. Concentrations of Se in brain, 0.072-0.14 mg/kg, decreased with age in the fetuses, but increased with age postnatally. Kidney Se concentrations (0.16-0.55 mg/kg) did not change significantly with age during the fetal period, but increased about 2.5 times during the postnatal period. There was a significant association between the concentrations (on molar basis) of Zn and Cu in kidneys, but not in brain. There was no correlation between the concentrations of Cu, Zn or Se and those of mercury, cadmium and lead, previously determined in the same samples, with the exception of mercury and Se in kidneys.

In this prospective cohort study, based on 1,505 mother-infant pairs in rural Bangladesh, we evaluated the associations between early-life exposure to arsenic, cadmium, and lead, assessed via concentrations in maternal and child urine, and children's weights and heights up to age 5 years, during the period 2001-2009. Concurrent and prenatal exposures were evaluated using linear regression analysis, while longitudinal exposure was assessed using mixed-effects linear regression. An inverse association was found between children's weight and height, age-adjusted z scores, and growth velocity at age 5 years and concurrent exposure to cadmium and arsenic. In the longitudinal analysis, multivariable-adjusted attributable differences in children's weight at age 5 years were -0.33 kg (95% confidence interval (CI): -0.60, -0.06) for high (≥95th percentile) arsenic exposure and -0.57 kg (95% CI: -0.88, -0.26) for high cadmium exposure, in comparison with children with the lowest exposure (≤5th percentile). Multivariable-adjusted attributable differences in height were -0.50 cm (95% CI: -1.20, 0.21) for high arsenic exposure and -1.6 cm (95% CI: -2.4, -0.77) for high cadmium exposure. The associations were apparent primarily among girls. The negative effects on children's growth at age 5 years attributable to arsenic and cadmium were of similar magnitude to the difference between girls and boys in terms of weight (-0.67 kg, 95% CI: -0.82, -0.53) and height (-1.3 cm, 95% CI: -1.7, -0.89).

For conducting an adequate human cancer risk assessment of inorganic arsenic (As) in the low-dose region, it is important to establish its mode of action. In this context, the nature of genotoxic effects induced by this agent is of considerable interest. However, the results from such investigations in human have been conflicting. In an attempt to resolve this issue, the clastogenic and aneugenic potential of As was investigated in women and children from native population exposed to high levels (around 0.2 mg/l) of natural As via drinking water in San Antonio de los Corbes in the Andean region of Salta, Northwestern Argentina. The water did not contain elevated levels of heavy metals, such as lead or cadmium, nor was the investigated population exposed to significant industrial pollution or to pesticides. An ethnically similar control group from Rosario de Lerma, Salta, where only extremely low concentration of arsenic in drinking water could be detected, was used as a control. To evaluate the genotoxic effects in peripheral blood lymphocytes, micronuclei (MN) in binucleated cells, sister-chromatid exchanges (SCEs) and the fluorescence in situ hybridization technique (FISH) in combination with chromosome specific DNA libraries were employed. The data obtained clearly indicate a highly significant increase in the frequency of MN and of trisomy in lymphocytes from exposed children and women in comparison with controls, but no notable effects were found on the frequencies of SCEs, specific translocations, or on cell cycle progression. As supported by FISH analysis, at least a proportion of MN appears to originate from whole chromosome loss. An additional finding was the unusually low background levels of MN in unexposed individuals from this ethnic group as compared to other populations, e.g., Caucasians.

A physiologically based pharmacokinetic model (PB-PK) for inorganic arsenic exposure in humans has been developed. This model is an extension of a PB-PK model for hamsters and rabbits, with adjustments for body weight, metabolic rates, and absorption rates. It describes the absorption, distribution, metabolism, and excretion of arsenate, arsenite (As(III)), methyl arsonate, and dimethyl arsinate, the four major metabolites of inorganic arsenic. The routes of intake considered are inhalation of arsenic dust and fumes and oral intake of arsenic via drinking water and food. The PB-PK model for the oral exposure route is validated using data on urinary excretion after repeated oral exposure to As(III) as well as after exposure to inorganic As via drinking water. Absorption by inhalation is validated using data on urinary excretion after occupational exposure to arsenic trioxide dust and fumes. In both cases, the model gives satisfactory results for urinary excretion of the four As metabolites. The PB-PK model is also used in the description of the effects on the kinetics of exposure via different routes and for the simulation of various realistic exposure scenarios.

The concentrations of mercury (Hg), cadmium (Cd) and lead (Pb) in brain (cerebrum) and kidney during fetal (second trimester terminations or abortions, n = 20) and postnatal (infants deceased before three months of age, n = 15) development have been studied. Information on possible sources of exposure was obtained from the mothers of the fetuses, but not from those of the infants. The median concentration of Hg in the brain was 4 micrograms/ kg wet weight in both fetuses and infants (total rangeor = 2-23 micrograms/kg). The concentrations of Hg in the kidneys were significantly higher than in brain, median of Hg 6 micrograms/kg (rangeor = 5-34 micrograms/kg) in fetuses and 10 micrograms/kg (or = 7-37) in infants. There was a tendency of increasing concentration of Hg in the fetal kidney, but not in the brain, with increasing number of amalgam fillings in the mothers. The concentration of Cd in the brain was less than 1 microgram/kg in most cases, both in fetuses and infants. The concentration of Cd in the kidneys was significantly higher, with a median of about 2 micrograms/kg (1-8 micrograms/kg) in both groups. There was no detectable association between tissue Cd concentrations and the smoking habits of the mothers. The concentration of Pb in brain was below 10 micrograms/kg in most cases. In the kidneys, the concentrations of Pb were significantly higher, with a median of 12 micrograms/kg in the fetuses (rangeor = 6-20 micrograms/kg) and 15 micrograms/kg (or = 9-36 micrograms/kg) in the infants. In general, the concentrations of Cd and Pb were lower than in previously reported studies.

Background: Arsenic in drinking water causes severe health effects. Indigenous people in the South American Andes have likely lived with arsenic-contaminated drinking water for thousands of years. Inhabitants of San Antonio de los Cobres (SAC) in the Argentinean highlands generally carry an AS3MT (the major arsenic-metabolizing gene) haplotype associated with reduced health risks due to rapid arsenic excretion and lower urinary fraction of the monomethylated metabolite. Objectives: We hypothesized an adaptation to high-arsenic living conditions via a possible positive selection for protective AS3MT variants and compared AS3MT haplotype frequencies among different indigenous groups. Methods: Indigenous groups we evaluated were a) inhabitants of SAC and villages near Salta in northern Argentina (n = 346), b) three Native American populations from the Human Genome Diversity Project (HGDP; n = 25), and c) five Peruvian populations (n = 97). The last two groups have presumably lower historical exposure to arsenic. Results: We found a significantly higher frequency of the protective AS3MT haplotype in the SAC population (68.7%) compared with the HGDP (14.3%, p < 0.001, Fisher exact test) and Peruvian (50.5%, p < 0.001) populations. Genome-wide microsatellite (n = 671) analysis showed no detectable level of population structure between SAC and Peruvian populations (measure of population differentiation FST = 0.006) and low levels of structure between SAC and HGDP populations (FST < 0.055 for all pairs of populations compared). Conclusions: Because population stratification seems unlikely to explain the differences in AS3MT haplotype frequencies, our data raise the possibility that, during a few thousand years, natural selection for tolerance to the environmental stressor arsenic may have increased the frequency of protective variants of AS3MT. Further studies are needed to investigate this hypothesis.

BACKGROUND: Elevated exposure to the essential element manganese (Mn) can be toxic. Manganese concentrations in ground water vary considerably, and reported associations between Mn and early-life mortality and impaired development have raised concern. We assessed the effects of drinking water Mn exposure during pregnancy upon fetal and infant survival. METHODS: In this population-based cohort study, we identified the outcomes of pregnancies registered between February 2002 and April 2003 in Matlab, Bangladesh. Using inductively coupled plasma mass spectrometry, we measured the concentrations of Mn and other elements in the pregnant women's drinking water. RESULTS: A total of 1,875 women were included in the analysis of spontaneous abortions (n=158) and 1,887 women in the perinatal mortality analysis (n=70). Water Mn ranged from 3.0-6,550 µg/L (median=217 µg/L). The adjusted odds ratio (OR) for spontaneous abortion was 0.65 (95% CI 0.43-0.99) in the highest water Mn tertile (median=1,292 µg/L) as compared to the lowest tertile (median=56 µg/L). The corresponding OR for perinatal mortality was 0.69 (95% CI 0.28-1.71), which increased to 0.78 (95% CI 0.29-2.08) after adjustment for BMI and place of delivery (home/health facility; n=1,648). CONCLUSIONS: Elevated water Mn concentrations during pregnancy appear protective for the fetus, particularly in undernourished women. This effect may be due to the element's role in antioxidant defense.

BACKGROUND: Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation. OBJECTIVES: We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia. METHODS: Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC. RESULTS: Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27-0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure. CONCLUSIONS: The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned.

The metabolism of inorganic arsenic (As) in native women in four Andean villages in north-western Argentina with elevated levels of As in the drinking water (2.5, 14, 31, and 200 micrograms/1, respectively) has been investigated. Collected foods contained 9-427 micrograms As/kg wet weight, with the highest concentrations in soup. Total As concentrations in blood were markedly elevated (median 7.6 micrograms/1) only in the village with the highest concentration in the drinking water. Group median concentrations of metabolites of inorganic As (inorganic As, methylarsonic acid (MMA) and dimethylarsinic acid (DMA)) in the urine varied between 14 and 256 micrograms/1. Urinary concentrations of total As were only slightly higher (18-258 micrograms/1), indicating that inorganic As was the main form of As ingested. In contrast to all other populations studied so far, arsenic was excreted in the urine mainly as inorganic As and DMA. There was very little MMA in the urine (overall median 2.2%, range 0.0-11%), which should be compared to 10-20% of the urinary arsenic in all other populations studied. This may indicate the existence of genetic polymorphism in the control of the methyltransferase activity involved in the methylation of As. Furthermore, the percentage of DMA in the urine was significantly higher in the village with 200 micrograms As/1 in the water, indicating an induction of the formation of DMA. Such an effect has not been observed in other studies on human subjects with elevated exposure to arsenic.

The distribution of accumulated inorganic mercury deposits in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl-mercury (MeHg) and mercuric chloride (inorganic mercury-IHg) has been determined by autometallography. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, and 18 months or 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered inorganic mercury (as HgCl2; 200 micrograms Hg/kg body wt/day) for 3 months by constant rate intravenous infusion via an indwelling catheter. Staining of IHg deposits in the MeHg-exposed groups increased for all cell types with increased length of exposure. The astrocytes and microglia in the MeHg exposure groups contained the largest deposits of IHg. Neurons in the 6-month MeHg exposure group were either not labeled or contained very fine deposits of IHg. The frequency of labeled neurons increased somewhat in the 12-month and clearance exposure groups. Virtually all neurons in the 18-month exposure group contained labeled deposits of IHg; however, these total deposits were considerably smaller than those present within the astrocytes and microglia. The majority of endothelial cells and pericytes did not contain notable mercury deposits, although scattered individual cells were heavily labeled. Labeled oligodendrocytes were relatively rare in all MeHg-exposed groups. Gitter cells, primarily located in a perivascular position, were common in the 12-month, 18-month, and clearance groups and many of these were found to be heavily labeled. The staining of mercury deposits in the IHg-exposed animals was low compared to the MeHg-exposed groups. The astrocytes and microglia were the primary cell types labeled. It is concluded that the astrocytes, and possibly microglia, are the primary location of the demethylation of MeHg into IHg within the cortex of the calcarine sulcus.

Syrian Golden hamster dams were administered 203Hg-labelled methyl mercury (MeHg; 1.6 mumol/kg) 1 day after parturition and milk was collected twice during the 1st week. The excretion of 203Hg in milk and the uptake, retention and tissue distribution of 203Hg in the pups was studied using gamma counting. The fraction of inorganic Hg in milk and in the kidneys of the pups was determined following separation of inorganic Hg and MeHg by ion exchange chromatography. The concentration of 203Hg in milk on the 1st day after MeHg administration was 0.12 nmol/g. 203Hg was mainly (80-90%) excreted as MeHg during the first 6 days of lactation. The whole body and tissue concentration of 203Hg in the pups increased for 10-15 days and decreased thereafter. The content of 203Hg in the pelt and the fraction of inorganic Hg in the kidney increased throughout the study period (4 weeks). The excretion of MeHg in milk corresponded to at least 5% of the dose administered to the dam. Our study demonstrates that breast milk may be a significant source of MeHg exposure during the critical neonatal period.

Three groups of female monkeys (Macaca fascicularis) were exposed to methylmercury (MeHg, p.o. 50 micrograms Hg/kg body wt per day) for 6, 12, or 18 months. One group was exposed to MeHg for 12 months and kept unexposed for 6 months before sacrifice. Another group of three monkeys was exposed to HgCl2 i.v. for 3 months. Total and inorganic mercury concentrations in occipital pole and thalamus were determined by cold vapor atomic absorption spectroscopy. Selenium concentrations were analyzed by hydride generation atomic absorption spectroscopy. The results indicated an association between concentrations of inorganic mercury and selenium in both occipital pole and thalamus in the MeHg-exposed animals. A linear regression model using concentrations of inorganic mercury (nmol/g wet wt) as independent variable, and selenium concentrations (nmol/g wet wt) as the dependent variable showed significant correlations between the variables in both occipital pole and thalamus (r = 0.85 and r = 0.91, P0.0001). The intercept of the regression line was slightly lower (about 2 nmol Se/g wet wt) than the selenium concentrations found in control monkeys (about 3 nmol Se/g wet wt). There was a tendency to a "hockey stick"-shaped relationship between concentrations of selenium and inorganic mercury in the thalamus of monkeys with ongoing exposure to MeHg. An important role for selenium in the retention of mercury in brain is indicated.

Background Chronic exposure to toxic metals such as arsenic and cadmium has been implicated in the development of kidney and cardiovascular diseases but few studies have directly measured exposure during inutero and early child development. Methods We investigated the impact of exposure to arsenic (mainly in drinking water) and cadmium (mainly in rice) during pregnancy on blood pressure and kidney function at 4.5 years of age in rural Bangladesh. The effect of arsenic exposure in infancy was also assessed. Results Within a cohort of 1887 children recruited into the MINIMat study, exposure to arsenic (maternal urinary arsenic, U-As), but not cadmium, during in utero development was associated with a minimal increase in blood pressure at 4.5 years. Each 1 mg/l increase in pregnancy U-As was associated with 3.69 mmHg (95% CI: 0.74, 6.63; P: 0.01) increase in child systolic and a 2.91 mmHg (95% CI: 0.41, 5.42; P: 0.02) increase in child diastolic blood pressure. Similarly, a 1 mg/l increase in child U-As at 18 months of age was associated with a 8.25 mmHg (95% CI: 1.37, 15.1; P: 0.02) increase in systolic blood pressure at 4.5 years. There was also a marginal inverse association between infancy U-As and glomerular filtration rate at 4.5 years (−33.4 ml/min/1.72 m2; 95% CI: −70.2, 3.34; P: 0.08). No association was observed between early arsenic or cadmium exposure and kidney volume at 4.5 years assessed by ultrasound. Conclusions These modest effect sizes provide some evidence that arsenic exposure in early life has long-term consequences for blood pressure and maybe kidney function.

Occupational studies show a high risk of lung cancer related to arsenic exposure by inhalation; however, only a few studies, and with conflicting results, previously examined a potential link between arsenic exposure at work and skin cancer. The aim of this study is to assess airborne arsenic exposures at the workplace and to quantify associations with nonmelanoma skin cancer (NMSC). The study sample consists of 618 incident cases of NMSC and 527 hospital-based controls aged 30-79 years from Hungary, Romania and Slovakia. Exposures were evaluated by local experts using occupational histories. Information on host factors and other exposures was collected and used to adjust the associations of interest using multivariable logistic regression. The lifetime prevalence of exposure to work-related arsenic is 23.9% for cases and 15.5% for controls. No significant association between arsenic exposure in the workplace and NMSC was detected, although an increased adjusted odd ratio was observed for participants with higher cumulative lifetime workplace exposure to arsenic in dust and fumes compared to referents [odds ratios (OR) = 1.94, 95% confidence interval (CI) = 0.76-4.95]. There is evidence for modification of the workplace arsenic-NMSC association by work-related sunlight exposure in women, with a markedly increased adjusted OR in the presence of workplace sunlight exposure (OR = 10.22, 95% CI = 2.48-42.07). Workplace coexposure to arsenic and sunlight may thus pose an increased risk of NMSC.

Prenatal arsenic exposure is associated with increased infant morbidity and reduced thymus size, indicating arsenic-related developmental immunotoxicity. We aimed to evaluate effects of prenatal arsenic exposure on thymic function at birth and related mechanisms of action. In a Bangladeshi cohort, arsenic was measured in urine (U-As, gestational week (GW) 8 and 30) and blood (B-As, GW14) in 130 women. Child thymic index was measured by sonography at birth and thymic function by signal-joint T-cell receptor-rearrangement excision circles (sjTRECs) in cord blood mononuclear cells (CBMC). In a subsample (n = 44), sjTRECs content in isolated CD4(+) and CD8(+) T cells, expression of oxidative-stress defense and apoptosis-related genes in CBMC, arsenic concentrations (urine, placenta, and cord blood), and oxidative stress markers in placenta and cord blood were measured. In multivariable-adjusted regression, ln U-As (GW8) was inversely associated with ln sjTRECs in CBMC (B = -0.25; 95% confidence interval [CI] -0.48 to -0.01). Using multivariable-adjusted spline regression, ln U-As (GW30) and ln B-As (GW14) were inversely associated with ln sjTRECs in CBMC (B = -0.53; 95% CI -0.93 to -0.13 and B = -1.27; 95% CI -1.89 to -0.66, respectively) below spline knots at U-As 150 µg/l and B-As 6 µg/kg. Similar inverse associations were observed in separated CD4(+) and CD8(+) T cells. Arsenic was positively associated with 8-hydroxy-2'-deoxyguanosine in cord blood (B = 0.097; 95% CI 0.05 to 0.13), which was inversely associated with sjTRECs in CD4(+) and CD8(+) T cells. In conclusion, prenatal arsenic exposure was associated with reduced thymic function, possibly via induction of oxidative stress and apoptosis, suggesting subsequent immunosuppression in childhood.

Background: Inorganic arsenic (iAs) is a potent carcinogen, but there is a lack of information about cancer risk for concentrations < 100 μg/L in drinking water. Objectives: We aimed to quantify skin cancer relative risks in relation to iAs exposure < 100 μg/L and the modifying effects of iAs metabolism. Methods: The Arsenic Health Risk Assessment and Molecular Epidemiology (ASHRAM) study, a case–control study, was conducted in areas of Hungary, Romania, and Slovakia with reported presence of iAs in groundwater. Consecutively diagnosed cases of basal cell carcinoma (BCC) of the skin were histologically confirmed; controls were general surgery, orthopedic, and trauma patients who were frequency matched to cases by age, sex, and area of residence. Exposure indices were constructed based on information on iAs intake over the lifetime of participants. iAs metabolism status was classified based on urinary concentrations of methylarsonic acid (MA) and dimethylarsinic acid (DMA). Associations were estimated by multivariable logistic regression. Results: A total of 529 cases with BCC and 540 controls were recruited for the study. BCC was positively associated with three indices of iAs exposure: peak daily iAs dose rate, cumulative iAs dose, and lifetime average water iAs concentration. The adjusted odds ratio per 10-μg/L increase in average lifetime water iAs concentration was 1.18 (95% confidence interval: 1.08, 1.28). The estimated effect of iAs on cancer was stronger in participants with urinary markers indicating incomplete metabolism of iAs: higher percentage of MA in urine or a lower percentage of DMA. Conclusion: We found a positive association between BCC and exposure to iAs through drinking water with concentrations < 100 μg/L.

In low-income countries, the use of some organochlorine pesticides is still common in order to increase food production. Monitoring the chemical exposure is an important step in risk-reducing strategies. This is the first study to report concentrations of organochlorines in breast milk of women from Bangladesh where farming is the main income source. Organochlorines such as p,p′-DDT, o,p′-DDT, p,p′-DDE, p,p′-DDD (i.e., ∑DDT), HCB, α-, β- and γ-HCH, trans-chlordane, cis-chlordane, oxy-chlordane, trans-nonachlor, cis-nonachlor, mirex and polychlorinated biphenyls (CB 28, 52, 99, 101, 105, 114, 118, 123, 128, 138, 141, 149, 153, 156, 157, 163, 167, 170, 180, 183, 187, 189, 194) were analyzed in breast milk collected in 2002 from 72 first-time mothers (median age 20 years) living in the rural area Matlab, Bangladesh. While the concentrations of PCBs and many of the pesticides were low, the concentrations of p,p′-DDT and its metabolite p,p′-DDE were high (median 349 and 1645 ng g−1 lipid, respectively) in comparison to other countries. The median value of ∑DDT was 2123 ng g−1 lipid. The estimated daily exposure to p,p′-DDT, p,p′-DDE and ∑DDTs was 10, 30 and 42 μg kg−1 body weight, respectively, in 3 months old infants. The p,p′-DDE/p,p′-DDT ratio ranged from 1 to 23, where 58% of the mothers had a ratio below 5 indicating recent or ongoing DDT exposure. This study reports infant exposure and maternal body burden of organochlorines through breast milk. Although the findings give no reason to limit breast-feeding, it is essential to identify the main exposure sources and find means to decrease the exposure.

The number of neurons, astrocytes, reactive glia, oligodendrocytes, endothelia, and pericytes in the cortex of the calcarine sulcus of adult female Macaca fascicularis following long-term subclinical exposure to methyl mercury (MeHg) and mercuric chloride (inorganic mercury; IHg) has been estimated by use of the optical volume fractionator stereology technique. Four groups of monkeys were exposed to MeHg (50 micrograms Hg/kg body wt/day) by mouth for 6, 12, 18, and 12 months followed by 6 months without exposure (clearance group). A fifth group of monkeys was administered IHg (as HgCl2; 200 micrograms Hg/kg body wt/day) by constant rate intravenous infusion via an indwelling catheter for 3 months. Reactive glia showed a significant increase in number for every treatment group, increasing 72% in the 6-month, 152% in the 12-month, and 120% in the 18-month MeHg exposed groups, and the number of reactive glia in the clearance group remained elevated (89%). The IHg exposed group showed a 165% increase in the number of reactive glia. The IHg exposed group and the clearance group had low levels of MeHg present within the tissue; however, the level of IHg was elevated in both groups. These results suggest that the IHg may be responsible for the increase in reactive glia. All other cell types, including the neurons, showed no significant change in number at the prescribed exposure level and durations. The identities of the reactive glial cells and the implications for the long-term function and survivability of the neurons due to changes in the glial population following subclinical long-term exposure to mercury are discussed.

Humans are exposed via air, water and food to a number of different arsenic compounds, the physical, chemical, and toxicological properties of which may vary considerably. In people eating much fish and shellfish the intake of organic arsenic compounds, mainly arsenobetaine, may exceed 1000 μg As per day, while the average daily intake of inorganic arsenic is in the order of 10–20 μg in most countries. Arsenobetaine, and most other arsenic compounds in food of marine origin, e.g. arsenocholine, trimethylarsine oxide and methylarsenic acids, are rapidly excreted in the urine and there seem to be only minor differences in metabolism between animal species. Trivalent inorganic arsenic (AsIII) is the main form of arsenic interacting with tissue constituents, due to its strong affinity for sulfhydryl groups. However, a substantial part of the absorbed AsIII is methylated in the body to less reactive metabolities, methylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are rapidly excreted in the urine. All the different steps in the arsenic biotransformation in mammals have not yet been elucidated, but it seems likely that the methylation takes place mainly in the liver by transfer of methyl groups from S-adenosylmethionine to arsenic in its trivalent oxidation state. A substantial part of absorbed arsenate (AsV) is reduced to AsIII before being methylated in the liver. There are marked species differences in the methylation of inorganic arsenic. In most animal species DMA is the main metabolite. Compared with human subjects, very little MMA is produced. The marmoset monkey is the only species which has been shown unable to methylate inorganic arsenic. In contrast to other species, the rat shows a marked binding of DMA to the hemoglobin, which results in a low rate of urinary excretion of arsenic.

Previous animal experiments suggested that the Magos cold vapor atomic absorption spectroscopic (CVAAS) method might overestimate the concentrations of inorganic mercury (I-Hg) in the presence of methylmercury (MeHg). In the present study it is shown that this error is due to a fast degradation of MeHg during the formation of the analytical signal. For brain samples, about 5% of the total amount of MeHg in the reaction vessel is degraded to I-Hg. Speciation of Hg in aqueous solution of MeHg chloride, after purification with ionexchange chromatography using the Magos method, showed that about 9% was I-Hg. Analysis by NMR of MeHg chloride and MeHg hydroxide showed that less than 1% was in the form of I-Hg. The absolute magnitude of the error in the CVAAS method is dependent on the amounts of SnCl2 and MeHg in the reaction vessel; however, the ratio of I-Hg to total (T-Hg) is shown to be independent of the amount of MeHg (25.5–255 ng as Hg) in the reaction vessel. A procedure for corrections is proposed, based on the results from these studies and empirical data from speciation analyses of brain tissue from MeHg-exposed rats and rabbits.

A method for measuring personal nitrogen dioxide (NO2) exposure, using passive samplers, was tested among schoolchildren. Activity patterns and NO2 exposure levels were studied in relation to urban and rural living. Stationary air monitoring data indicated that the urban children were supposed to be exposed to NO2 levels that were among the highest in Sweden. It was shown that NO2 levels measured at the stationary air monitoring station were not representative for the children's exposure. The children spent 90% of their time indoors; only a small percentage of their time was spent in transit. The median daily NO2 exposure level in the urban area (13 micrograms NO2/m3, 7 ppb) was significantly higher (p.001) than in the rural area (7 micrograms NO2/m3, 4 ppb). The most important source of exposure was the indoor ice-skating arenas, where levels up to 8,000 micrograms NO2/m3 (4 240 ppb) were measured during 1-h periods.

BACKGROUND: Exposure to arsenic through drinking water has been associated with impaired cognitive function in school-aged children in a few cross-sectional studies; however, there is little information on critical windows of exposure. METHODS: We conducted a population-based longitudinal study in rural Bangladesh. We assessed the association of arsenic exposure, based on urinary arsenic (U-As; twice during pregnancy and twice in childhood), with the development of about 1700 children at 5 years of age using Wechsler Pre-school and Primary Scale of Intelligence [intelligence quotient (IQ)]. RESULTS: Median maternal U-As in pregnancy was 80 µg/l (10-90 percentiles: 25-400 µg/l). Children's urine contained 35 (12-155) µg/l and 51 (20-238) µg/l at 1.5 and 5 years, respectively. Using multivariable-adjusted regression analyses, controlling for all potential confounders and loss to follow-up, we found that verbal IQ (VIQ) and full scale IQ (FSIQ) were negatively associated with (log) U-As in girls. The associations were consistent, but somewhat stronger with concurrent arsenic exposure [VIQ: B = -2.4, 95% confidence interval (CI) = -3.8 to -1.1; FSIQ: B = -1.4, 95% CI = -2.7 to -0.1, n = 817), compared with that at 1.5 years (VIQ: B = -0.85, 95% CI = -2.1 to 0.4; FSIQ: B = -0.74, 95% CI = -1.9 to 0.4, n = 902), late gestation (VIQ: B = -1.52, 95% CI = -2.6 to -0.4; FSIQ: B = -1.35, 95% CI = -2.4 to -0.3, n = 874) and early gestation (VIQ: B = -1.23, 95% CI = -2.4 to -0.06; FSIQ: B = -0.92, 95% CI = -2.0 to -0.2, n = 833). In boys, U-As showed consistently low and non-significant associations with all IQ measures. An effect size calculation indicated that 100 µg/l U-As was associated with a decrement of 1-3 points in both VIQ and FSIQ in girls. CONCLUSION: We found adverse effects of arsenic exposure on IQ in girls, but not boys, at 5 years of age. Language: en

Cadmium and high vitamin A intake are both proposed risk factors for low bone mineral density (BMD), but potential interactions have not been studied. Within the Women's Health in the Lund Area, a population-based study in southern Sweden, we measured retinol in serum among 606 women aged 54-64 y. Data on BMD were measured by DXA at the distal forearm. Parathyroid hormone (PTH), bone alkaline phosphatase (bALP), and osteocalcin in serum and deoxypyridinoline (DPD) and cadmium in urine were available. Associations were evaluated using multivariable-adjusted linear regression analysis. Serum retinol concentrations (median, 1.9; range, 0.97-4.3 μmol/L) were inversely associated with the bone formation markers bALP and osteocalcin (P ≤ 0.04) and with PTH (P = 0.07) and tended to be positively associated with BMD (P = 0.08) but not with the bone resorption marker DPD, indicating different effects on bone compared to urinary cadmium (median, 0.66; range, 0.12-3.6 nmol/mmol creatinine). Women with serum retinol less than the median and cadmium greater than the median had lower BMD than those with retinol greater than the median and cadmium less than the median (P = 0.016 among all women and P = 0.010 among never-smokers). Our findings suggest that adequate vitamin A status may counteract the adverse association between cadmium and BMD.

Background and aim: The toxic metal cadmium (Cd), commonly occurring in various foods, is embryotoxic and teratogenic in a variety of animal species, indicating that the prenatal period is a critic...

Temporal and seasonal variability of As concentrations in groundwater were evaluated in As-affected areas of Matlab, southeastern Bangladesh. Groundwater samples from 61 randomly selected tubewells were analyzed for As concentrations over a period of three years and four months (from July 2002 to November 2005) and monitored seasonally (three times a year). The mean As concentrations in the sampled tubewells decreased from 153 to 123 μg/L during July 2002 to November 2005. Such changes were pronounced in tubewells with As concentration50 μg/L than those with As concentrations50 μg/L. Similarly, individual wells revealed temporal variability, for example some wells indicated a decreasing trend, while some other wells indicated stable As concentration during the monitoring period. The mean As concentrations were significantly higher in Matlab North compared with Matlab South. The spatial variations in the mean As concentrations may be due to the differences in local geological conditions and groundwater flow patterns. The variations in mean As concentrations were also observed in shallow (40 m) and deep (40 m) wells. However, to adequately evaluate temporal and seasonal variability of As concentration, it is imperative to monitor As concentrations in tubewells over a longer period of time. Such long-term monitoring will provide important information for the assessment of human health risk and the sustainability of safe drinking water supplies.

Osteoporosis and its main health outcome, fragility fractures, are large and escalating public health problems. Cadmium, a widespread food contaminant, is a proposed risk factor; still the association between estimated dietary cadmium exposure and bone mineral density (BMD) has never been assessed. Within a sub-cohort of the Swedish Mammography Cohort, we assessed dietary cadmium exposure based on a food frequency questionnaire (1997) and urinary cadmium (2004-2008) in relation to total-body BMD and risk of osteoporosis and fractures (1997-2009) among 2676 women (aged 56-69 years). In multivariable-adjusted linear regression, dietary cadmium was inversely associated with BMD at the total body and lumbar spine. After further adjustment for dietary factors important for bone health and cadmium bioavailability--calcium, magnesium, iron and fiber, the associations became more pronounced. A 32% increased risk of osteoporosis (95% CI: 2-71%) and 31% increased risk for any first incident fracture (95% CI: 2-69%) were observed comparing high dietary cadmium exposure (≥13 μg/day, median) with lower exposures (

Resistance against anticancer drugs remains a serious obstacle in cancer treatment. Here we used novel strategies to target microsomal glutathione transferase 1 (MGST1) and glutathione transferase pi (GSTP) that are often overexpressed in tumors and confer resistance against a number of cytostatic drugs, including cisplatin and doxorubicin (DOX). By synthetically combining cisplatin with a GST inhibitor, ethacrynic acid, to form ethacraplatin, it was previously shown that cytosolic GST inhibition was improved and that cells became more sensitive to cisplatin. Here we show that ethacraplatin is easily taken up by the cells and can reverse cisplatin resistance in MGST1 overexpressing MCF7 cells. A second and novel strategy to overcome GST mediated resistance involves using GST releasable cytostatic drugs. Here we synthesized two derivatives of DOX, 2,4-dinitrobenzenesulfonyl doxorubicin (DNS-DOX) and 4-mononitrobenzenesulfonyl doxorubicin (MNS-DOX) and showed that they are substrates for MGST1 and GSTP (releasing DOX). MGST1 overexpressing cells are resistant to DOX. The resistance is partially reversed by DNS-DOX. Interestingly, the less reactive MNS-DOX was more cytotoxic to cells overexpressing MGST1 than control cells. It would appear that, by controlling the reactivity of the prodrug, and thereby the DOX release rate, selective toxicity to MGST1 overexpressing cells can be achieved. In the case of V79 cells, DOX resistance proportional to GSTP expression levels was noted. In this case, not only was drug resistance eliminated by DNS-DOX but a striking GSTP-dependent increase in toxicity was observed in the clonogenic assay. In summary, MGST1 and GSTP resistance to cytostatic drugs can be overcome and cytotoxicity can be enhanced in GST overexpressing cells.

The effects of different levels of inorganic mercury (Hg2+) on depolarization- or agonist-stimulated Ca2+ signals were studied in PC12 cells. Exposure to 50-300 nM Hg2+ did not alter the resting cytosolic free Ca2+ concentration ([Ca2+]i), but enhanced the Ca2+ response to KCL-induced depolarization. Patch-clamp experiments revealed that these Hg2+ concentrations increased the voltage-dependent Ca2+ current through L-type channels. Also, Hg2+ treatment amplified the intracellular [Ca2+]i transients elicited by extracellular ATP. In contrast, the Ca2+ increase stimulated by bradykinin was unaffected. At slightly higher concentrations (1 to 2 microM), Hg2+ caused a sustained rise of the resting [Ca2+]i. This increase did not occur in Ca(2+)-free medium and was prevented by pretreatment with NiCl2 or with the L-type Ca2+ channel blockers, verapamil and nifedipine. Hg2+ did not mobilize Ca2+ from intracellular stores sensitive to thapsigargin, 2,5-di-(tert-butyl)-benzohydroquinone, or caffeine. At 2 microM, Hg2+ inhibited the [Ca2+]i transients elicited by bradykinin, ATP, or KCl-induced depolarization. The loss of the intracellular Ca2+ response to bradykinin was independent from the Ca2+ overload elicit by Hg2+; instead, it was associated with inhibition of polyphosphoinositide generation. Exposure to the lower Hg2+ concentrations (0.3-0.5 microM) greatly potentiated NGF-induced PC12 cell differentiation. Conversely, treatment with 2 microM Hg2+ caused cell death. Our results show that inorganic mercury has selective and different effects on Ca2+ signaling in PC12 cells depending on the concentration, within a narrow range.

Arsenic contamination of tubewell water is a major public-health problem in Bangladesh. In the recent years, the use of shallow and deep tubewell water for irrigation and the use of excess amount of cheap fertilizers and pesticides containing cadmium pose a serious threat of contamination of arsenic and cadmium in food. In an exploratory study, arsenic and cadmium were measured in foods from Matlab, a rural area in Bangladesh, that is extensively affected by arsenic and the economy is agriculture-based. Raw and cooked food samples were collected from village homes (households, n=13) and analyzed to quantify concentrations of arsenic and cadmium using atomic absorption spectrophotometry. Washing rice with water before cooking reduced the concentration of arsenic in raw rice by 13–15%. Rice, when cooked with excess water discarded, showed a significant decrease in arsenic concentration compared to that cooked without discarding the water (p

Background Arsenic exposure in pregnancy is associated with adverse pregnancy outcome and infant mortality. Knowledge of the spatial characteristics of the outcomes and their possible link to arsenic exposure are important for planning effective mitigation activities. The aim of this study was to identify spatial and spatiotemporal clustering of fetal loss and infant death, and spatial relationships between high and low clusters of fetal loss and infant death rates and high and low clusters of arsenic concentrations in tube-well water used for drinking. Methods Pregnant women from Matlab, Bangladesh, who used tube-well water for drinking while pregnant between 1991 and 2000, were included in this study. In total 29,134 pregnancies were identified. A spatial scan test was used to identify unique non-random spatial and spatiotemporal clusters of fetal loss and infant death using a retrospective spatial and spatiotemporal permutation and Poisson probability models. Results Two significant clusters of fetal loss and infant death were identified and these clusters remained stable after adjustment for covariates. One cluster of higher rates of fetal loss and infant death was in the vicinity of the Meghna River, and the other cluster of lower rates was in the center of Matlab. The average concentration of arsenic in the water differed between these clusters (319 μg/L for the high cluster and 174 μg/L for the low cluster). The spatial patterns of arsenic concentrations in tube-well water were found to be linked with the adverse pregnancy outcome clusters. In the spatiotemporal analysis, only one high fetal loss and infant death cluster was identified in the same high cluster area obtained from purely spatial analysis. However, the cluster was no longer significant after adjustment for the covariates. Conclusion The finding of this study suggests that given the geographical variation in tube-well water contamination, higher fetal loss and infant deaths were observed in the areas of higher arsenic concentrations in groundwater. This illustrates a possible link between arsenic contamination in tube-well water and adverse pregnancy outcome. Thus, these areas should be considered a priority in arsenic mitigation programs.

Background: Millions of people worldwide are drinking water with elevated arsenic concentrations. Epidemiologic studies, mainly cross-sectional in design, have suggested that arsenic in drinking water may affect pregnancy outcome and infant health. We assessed the association of arsenic exposure with adverse pregnancy outcomes and infant mortality in a prospective cohort study of pregnant women. Methods: A population-based, prospective cohort study of 2924 pregnant women was carried out during 2002-2004 in Matlab, Bangladesh. Spontaneous abortion was evaluated in relation to urinary arsenic concentrations at gestational week 8. Stillbirth and infant mortality were evaluated in relation to the average of urinary arsenic concentrations measured at gestational weeks 8 and 30. Results: The odds ratio of spontaneous abortion was 1.4 ( 95% confidence interval [CI] = 0.96-2.2) among women with urine arsenic concentrations in the fifth quintile "(249-1253 mu g/L; median = 382 mu g/L), compared with women in the first quintile "(

This study assessed concentrations in and intake of toxic and essential elements from formulas and foods intended for infants during their first 6 months of life. Concentrations of the essential elements Ca, Fe, Zn, Mn and Mo were significantly higher in most formulas than in breast milk. Daily intake of Mn from formula varies from ten up to several hundred times the intake of the breast fed infant, levels that may be associated with adverse health effects. One portion of infant food provided significantly more Fe, Mn, Mo, As, Cd, Pb and U than one feeding of breast milk, but less Ca, Cu and Se. Rice-based products in particular contained elevated As concentrations. Drinking water used to mix powdered formula may add significantly to the concentrations in the ready-made products. Evaluation of potentially adverse effects of the elevated element concentrations in infant formulas and foods are warranted.

Exposure to inorganic arsenic during pregnancy may negatively influence the offspring, though efficient metabolism of arsenic to dimethylarsinic acid (DMA) likely reduces the health risks. This study aimed to evaluate methylation of arsenic over the entire pregnancy and the influence of nutritional status. We studied longitudinally the arsenic metabolite pattern in the urine of 324 pregnant women exposed to arsenic via drinking water and food in rural Bangladesh. Metabolism of arsenic to DMA increased markedly over the course of pregnancy, with the greatest improvement occurring in the first trimester, along with a marked decrease in the most risk-associated monomethylated metabolite. This improvement in methylation was not associated with nutritional status, including vitamin B(12) and folate. Efficient methylation to DMA was associated with improved urinary excretion of arsenic, relative to blood arsenic concentrations, indicating that micronutrient-independent up-regulation of arsenic metabolism already in early pregnancy may provide protection for the fetus.

Elevated concentrations of arsenic in drinking water are common worldwide, however, little is known about the presence of other potentially toxic elements. We analyzed 31 different elements in drinking water collected in San Antonio de los Cobres and five surrounding Andean villages in Argentina, and in urine of the inhabitants, using ICP-MS. Besides confirmation of elevated arsenic concentrations in the drinking water (up to 210 microg/L), we found remarkably high concentrations of lithium (highest 1000 microg/L), cesium (320 microg/L), rubidium (47 microg/L), and boron (5950 microg/L). Similarly elevated concentrations of arsenic, lithium, cesium, and boron were found in urine of the studied women (N=198): village median values ranged from 26 to 266 microg/L of arsenic, 340 to 4550 microg/L of lithium, 34 to 531 microg/L of cesium, and 2980 to 16,560 microg/L of boron. There is an apparent risk of toxic effects of long-term exposure to several of the elements, and studies on associations with adverse human health effects are warranted, particularly considering the combined, life-long exposure. Because of the observed wide range of concentrations, all water sources used for drinking water should be screened for a large number of elements; obviously, this applies to all drinking water sources globally.

Background Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. Objectives We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. Methods Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 μg/L] and in rural Bangladesh (n = 361; U-As, 100 μg/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. Results Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p ≤ 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. Conclusions Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide.

Arsenic concentrations in well water often vary even within limited geographic areas. This makes it difficult to obtain valid estimates of the actual exposure, as people may take their drinking water from different wells. We evaluated a spatial model for estimation of the influence of multiple neighbourhood water sources on the actual exposure, as assessed by concentrations in urine in a population in rural Bangladesh. In total 1307 individuals (one per bari, group of families) were randomly selected. Arsenic concentrations of urine and water were analysed. Simple average and inverse distance weighted average of arsenic concentrations in the five nearest water sources were calculated for each individual. Spatial autocorrelation was evaluated using Moran's I statistics, and spatial regression models were employed to account for spatial autocorrelation. The average distance from a household to the nearest tube-well was 32 metres (Inter-Quartile Range 1-49 metres). Water arsenic concentrations of the reported main water sources were significantly correlated with concentrations in urine (R(2) = 0.41, rho0.0001, R(2) for women = 0.45 and for men = 0.36). General model fit improved only slightly after spatial adjustment for neighbouring water sources (pseudo-R(2) = 0.53, spatial lag model), compared to covariate adjusted regression coefficient (R(2) = 0.46). Arsenic concentration in urine was higher than arsenic in main water source with an intercept of 57 microg L(-1), indicating exposure from food. A suitable way of estimating an individual's past exposure to arsenic in this rural setting, where influence of neighbouring water sources was minimal, was to consider the reported main source of drinking water.

The initial sign of cadmium (Cd)-induced renal effects is tubular damage, followed by glomerular damage. For the prevention of Cd-induced renal effects, it is essential to establish the reference exposure below which the risk of adverse health effects is low. In earlier Japanese studies, the estimated reference exposure of creatinine (cre)-adjusted urinary cadmium for renal tubular effect ranged from 1.6 to 4.0 microg/g cre in men and 2.3 to 4.6 microg/g cre in women. The benchmark dose (BMD) is defined as the exposure that corresponds to a certain response change from the background. The lower 95% confidence limit of the BMD (BMDL) can be used in risk assessment as a replacement for the no observed adverse effect level. This is a review of all relevant BMDL of Cd exposure for renal effects estimated so far. Based on studies in Japan, the best estimate is considered to be 1.5-3.2 microg/g cre for urinary Cd, 0.09-0.13 mg/kg for rice Cd concentration, and 0.9-1.4 g Cd for lifetime Cd intake. These BMDLs for renal effects were generally lower than the reference exposure expected from earlier studies, indicating the importance of further discussion regarding comprehensive measures to decrease the Cd exposure in the general population.

Skin exposure to nickel, cobalt, and chromium may cause sensitization and allergic contact dermatitis and it is known that many alloys and platings may release significant amounts of the metals upon contact with skin. Occupational exposure to these sensitizing metals has been studied in different settings with regards to airborne dust and different biological end points, but little is known about deposition on skin from airborne dust and direct contact with materials containing the metals. In this study, skin deposition was studied in 24 workers in an industry for development and manufacturing of gas turbines and space propulsion components. The workers were employed in three departments, representing different exposure scenarios: tools sharpening of hard metal items, production of space propulsion structures, and thermal application of different metal-containing powders. A novel acid wipe sampling technique was used to sample metals from specific skin surfaces on the hands and the forehead of the workers. Total amounts of nickel, cobalt, and chromium were measured by inductively coupled plasma mass spectrometry. The result showed that nickel, cobalt, and chromium could be detected on all skin surfaces sampled. The highest level of nickel was 15 microg cm(-2) h(-1), the highest for cobalt was 4.5 microg cm(-2) h(-1), and for chromium 0.6 microg cm(-2) h(-1). The three departments had different exposures regarding the metals. The highest levels of nickel on the skin of the workers were found in the thermal applications department, cobalt in the tools sharpening department, and chromium in the space propulsion components department. In conclusion, the workers' exposure to the metals was more likely to come from direct skin contact with items, rather than from airborne dust, based on the fact that the levels of metals were much higher on the fingers than on the back side of the hands and the forehead. The skin exposure levels of nickel and cobalt detected are judged capable to induce sensitization and elicit allergic contact dermatitis.

We applied a hybrid approach to estimate the benchmark dose (BMD) and the lower 95% confidence limit (BMDL) for cadmium-induced bone effects in a population with low environmental exposure. Morning urine samples were collected by 794 Swedish women, aged 53-64 years, participating in a population-based study We measured urinary cadmium (U-Cd), a marker of long-term exposure, and bone mineral density, expressed as its T-score (reference 20-year old women) of the non-dominant wrist. BMD and BMDL, adjusted for relevant covariates. corresponding to an additional risk (BMR) of 5% or 10% were calculated, with the background risk at zero exposure set at 1% or 5%. With a BMR of 5% and a background risk of having low bone mineral density (at U-Cd=0) of 1% or 5% (corresponding to T-score cut-offs -2.75 and -2 09, respectively), the BMD of U-Cd ranged 1 8-3.7 mu g/g creatinine, and the BMDL ranged 1.0-2 1 mu g/g creatinine For a 5% BMR of osteoporosis (T-score < -2 5), the BMD was 29 mu g/g creatinine and the BMDL 1 6 mu g/g creatinine. The lowest obtained BMD of U-Cd for wrist bone mineral density was only slightly higher than the lowest reference concentration previously reported for cadmium-related kidney effects Our results provide additional scientific support for the low tolerably weekly intake (TWI) of cadmium set by the European Food Safety Authority in 2009. (C) 2010 Elsevier Ireland Ltd. All rights reserved (Less)

BACKGROUND: Arsenic (As) causes oxidative stress through generation of reactive oxygen species. 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a sensitive marker of oxidative DNA damage, has been associated with As exposure in some studies, but not in others, possibly due to population-specific genetic factors. OBJECTIVES: To evaluate the association between As and 8-oxodG in urine in a population with a low urinary monomethylated As (%MMA) and high dimethylated As (%DMA), as well as the genetic impact on (a) 8-oxodG concentrations and (b) the association between As and 8-oxodG. MATERIALS AND METHODS: Women (N=108) in the Argentinean Andes were interviewed and urine was analyzed for arsenic metabolites (ICPMS) and 8-oxodG (LC-MS/MS). Twenty-seven polymorphisms in genes related to oxidative stress and one in As(+III)methyltransferase (AS3MT) were studied. RESULTS: Median concentration of 8-oxodG was 4.7nmol/L (adjusted for specific weight; range 1.6-13, corresponding to 1.7mug/g creatinine, range 0.57-4.8) and of total urinary As metabolites (U-As) 290mug/L (range 94-720; 380mug/g creatinine, range 140-1100). Concentrations of 8-oxodG were positively associated with %MMA (strongest association, p=0.013), and weakly associated with U-As (positively) and %DMA (negatively). These associations were strengthened when taking ethnicity into account, possibly reflecting genetic differences in As metabolism and genes regulating oxidative stress and DNA maintenance. A genetic influence on 8-oxodG concentrations was seen for polymorphisms in apurinic/apyrimidinic endonuclease 1 (APEX1), DNA-methyltransferases 1 and 3b (DNMT1, DNMT3B), thioredoxin reductase 1 (TXNRD1) and 2 (TXNRD2) and glutaredoxin (GLRX). CONCLUSION: Despite high As exposure, the concentrations of 8-oxodG in this population were low compared with other As-exposed populations studied. The strongest association was found for %MMA, stressing that some inconsistencies between As and 8-oxodG partly depend on population variations in As metabolism. We found evidence of genetic impact on 8-oxodG concentrations. (Less)

The relationship between urinary levels of cotinine (U-cotinine) and arsenic (U-As), blood levels of cadmium (B-Cd), blood levels of lead (B-Pb), lung function, and questionnaire data on smoking habits were studied in 107 parents and their 46 children (7-10 y of age). There was a statistically significant relationship between the reported amount of tobacco smoked and U-cotinine levels. Nonsmokers who were married to persons who smoked had three times higher U-cotinine levels than nonsmokers whose spouses did not smoke. There was a significant association between the number of parents who smoked in the family and the U-cotinine levels of children. If only one parent smoked, maternal smoking was of greater importance than paternal smoking. There was also an association between U-cotinine and B-Cd. A study of lung function in the children revealed that vital capacity and functional residual capacity (corrected for sex, age, and height) increased as the number of parents who smoked increased. Therefore, the present study showed that (1) U-cotinine was a useful index of active smoking and environmental tobacco smoke exposure in adults and children, (2) U-cotinine was associated with the blood concentration of cadmium, and (3) environmental tobacco smoke exposure was associated with changes in lung function of children.

Arsenic is a potent human carcinogen and toxicant. Elevated concentration of arsenic in drinking water is a major public-health problem worldwide. We evaluated risks of adult mortality (due to cancer and cardiovascular and infectious diseases) in relation to arsenic exposure through drinking water.A cohort analysis was applied to survival data prospectively collected during 1991-2000 in a health and demographic surveillance system in Matlab, Bangladesh, where tubewells were installed beginning in the early 1970s. A total of 115,903 persons aged 15 or more years on 1 January 1991 were available for analysis. In this period, 9015 people died and 22,488 were lost to follow-up. Arsenic exposure data were derived from a survey in 2002-2003 of past and current water use and arsenic concentrations in all tubewells. We estimated risk of excess mortality in relation to arsenic exposure, using proportional hazards models.Even at low levels (10-49 mug/L) of arsenic in drinking water, we observed increased risk of death due to all nonaccidental causes (hazard ratio = 1.16 [95% confidence interval = 1.06-1.26]). Increased risks at exposure of 50-149 microg/L were observed for death due to cancers (1.44 [1.06-1.95]), cardiovascular disease (1.16 [0.96-1.40]), and infectious diseases (1.30 [1.13-1.49]). We observed clear dose-response relationships for each of these causes.Arsenic exposure through drinking water has generated excess adult mortality after 20-30 years of exposure.