Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study.

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.

Factors influencing intestinal cadmium uptake in pregnant Bangladeshi women--a prospective cohort study.

Experimental studies indicate that zinc (Zn) and calcium (Ca) status, in addition to iron (Fe) status, affect gastrointestinal absorption of cadmium (Cd), an environmental pollutant that is toxic to kidneys, bone and endocrine systems. The aim of this study was to evaluate how various nutritional factors influence the uptake of Cd in women, particularly during pregnancy. The study was carried out in a rural area of Bangladesh, where malnutrition is prevalent and exposure to Cd via food appears elevated. The uptake of Cd was evaluated by associations between erythrocyte Cd concentrations (Ery-Cd), a marker of ongoing Cd exposure, and concentrations of nutritional markers. Blood samples, collected in early pregnancy and 6 months postpartum, were analyzed by inductively coupled plasma mass spectrometry (ICPMS). Ery-Cd varied considerably (range: 0.31-5.4microg/kg) with a median of 1.1microg/kg (approximately 0.5microg/L in whole blood) in early pregnancy. Ery-Cd was associated with erythrocyte manganese (Ery-Mn; positively), plasma ferritin (p-Ft; negatively), and erythrocyte Ca (Ery-Ca; negatively) in decreasing order, indicating common transporters for Cd, Fe and Mn. There was no evidence of Cd uptake via Zn transporters, but the association between Ery-Cd and p-Ft seemed to be dependent on adequate Zn status. On average, Ery-Cd increased significantly by 0.2microg/kg from early pregnancy to 6 months postpartum, apparently due to up-regulated divalent metal transporter 1 (DMT1). In conclusion, intestinal uptake of Cd appears to be influenced either directly or indirectly by several micronutrients, in particular Fe, Mn and Zn. The negative association with Ca may suggest that Cd inhibits the transport of Ca to blood.

Exposure to inorganic arsenic metabolites during early human development.

Because of the lack of data on the exposure to and toxic effects of inorganic arsenic during early human development, the transfer of arsenic to the fetus and suckling infant was studied in a native Andean population, living in the village San Antonio de los Cobres in the North west of Argentina, where the drinking water contains about 200 micrograms/liter. The concentration of arsenic in cord blood (median, 9 micrograms/liter) was almost as high as in maternal blood (median, 11 micrograms/liter), and there was a significant correlation between the two. Thus, at least in late gestation, arsenic is easily transferred to the fetus. The median concentration of arsenic in the placenta was 34 micrograms/kg, compared with 7 micrograms/kg previously reported for nonexposed women. Interestingly, essentially all arsenic in the blood plasma of both the newborns and their mothers was in the form of dimethylarsinic acid (DMA), the end product of inorganic arsenic metabolism. Similarly, about 90% of the arsenic in the urine of both the newborns and mothers in late gestation was present as DMA, compared with about 70% in nonpregnant women (p < 0.001). This may indicate that methylation of arsenic is increased during pregnancy and that DMA is the major form of arsenic transferred to the fetus. The increased methylation in late gestation was associated with lower arsenic concentrations in blood and higher concentrations in urine, compared with a few months postpartum. The arsenic concentrations in the urine of the infants decreased from about 80 micrograms/liter during the first 2 days of life to less than 30 micrograms/liter at 4.4 months (p = 0.025). This could be explained by the low concentrations of arsenic in the breast milk, about 3 micrograms/kg.

Metabolism of inorganic arsenic in children with chronic high arsenic exposure in northern Argentina.

This study concerns the metabolism of inorganic arsenic (As) in children in three villages in northern Argentina: San Antonio de los Cobres and Taco Pozo, each with about 200 microg As/l in the drinking water, and Rosario de Lerma, with 0.65 microg As/l. Findings show that the concentrations of As in the blood and urine of the children in the two As-rich villages were on average 9 and 380 microg/l, respectively, the highest ever recorded for children. The concentrations were about 10 and 30 times higher for blood and urine, respectively, than in Rosario de Lerma. Total As in urine was only slightly higher than the sum of metabolites of inorganic As (U-Asmet), i.e., inorganic As, methylarsonic acid (MMA), and dimethylarsinic acid (DMA); this shows that inorganic As was the main form of As ingested. In contrast to previous studies on urinary metabolites of inorganic As in various population groups, the children and women in the present study excreted very little MMA. Thus, there seems to be a polymorphism for the enzymes (methyltransferases) involved in the methylation of As. Interestingly, the children had a significantly higher percentage of inorganic As in urine than the women, about 50% versus 32%. Also, the percentage of inorganic As in the children is considerably higher than in previous studies on children (about 13% in the two studies available) and adults (about 15-25%) in other population groups. This may indicate that children are more sensitive to As-induced toxicity than adults, as the methylated metabolites bind less to tissue constituents than inorganic As. In the children, the percentage inorganic arsenic in urine decreased, and the percentage of DMA increased with increasing U-Asmet, indicating an induction of As methylation with increasing exposure.

Low-level arsenic excretion in breast milk of native Andean women exposed to high levels of arsenic in the drinking water.

OBJECTIVE: To investigate the excretion of arsenic in breast milk of lactating native Andean women living in a village in northwestern Argentina with high concentrations of arsenic in the drinking water (about 200 micrograms/l) and to assess the exposure of children to arsenic during the very first period of life. METHODS: The study included ten lactating women and two nursing babies. Hydride-generation atomic absorption spectrometry (HG-AAS) was used to determine the concentration of arsenic in samples of human milk, drinking water, blood, and urine. RESULTS: The concentrations of arsenic detected in maternal blood (total arsenic) and urine (metabolites of inorganic arsenic) were high, averaging 10 and 320 micrograms/l, respectively. In subjects without known exposure to arsenic the average concentrations found in blood and urine are 1-2 and about 10 micrograms/l, respectively. The metabolites of inorganic arsenic constituted more than 80% of the total arsenic in the urine, which shows that inorganic arsenic was the main form of arsenic ingested. The average concentration of arsenic detected in human milk was 2.3 micrograms/kg fresh weight (range 0.83-7.6 micrograms/kg). Although data on background levels of arsenic in human breast milk are scarce, the present concentrations seem to be slightly elevated. However, considering the high levels of arsenic exposure in the mothers, the total arsenic concentrations measured in human milk were low. In concordance with the low concentrations of arsenic found in the milk, the concentrations of arsenic metabolites measured in the urine of two of the nursing babies were low: 17 and 47 micrograms/l, respectively. CONCLUSIONS: The low concentrations of arsenic detected in the breast milk and urine of the two nursing babies in relation to the high level of maternal exposure to arsenic indicate that inorganic arsenic is not excreted in breast milk to any significant extent. This is a very important reason for long breast-feeding periods.

Validation with biological markers for food intake of a dietary assessment method used by Swedish women with three different dietary preferences.

OBJECTIVES: To validate a dietary assessment method, a 4-day food record together with a duplicate portion technique, with biological markers for food intake. DESIGN: Four days of duplicate portions were collected in parallel with food recording. A 24-h urine sample and the faeces corresponding to the food intake (using a coloured marker) were collected. Completeness of urine and faeces collections was assessed using para-aminobenzoic acid (PABA) in urine and cadmium in faeces, respectively. Biomarkers of food intake (energy, protein, fibre, sodium, potassium, calcium) were measured in urine and faeces. SETTING: Swedish west coast. SUBJECTS: Non-smoking Swedish women, 20-50 years of age, consuming a mixed diet (n = 34), a mixed diet rich in shellfish (n = 17) or a vegetarian/high-fibre diet (n = 23). RESULTS: The average ratio (food intake according to the dietary assessment methods/ biological marker) for protein, sodium, potassium and calcium was 0.86. This indicates an underestimation of the food intake by approximately 15%. The ratio of stated fibre intake to biological marker was 1.20 for the mixed diet and the vegetarian diet group, indicating an overestimation by approximately 20%. CONCLUSIONS: The underestimation of the intake of protein, sodium, potassium and calcium by all three groups and the overestimation of the fibre intake by two groups indicate that underreporting is selective to certain nutrients and foods and to various groups of people. The two dependent dietary assessment methods were equally good in measuring protein intake, which indicates that the women recorded what they actually duplicated.

Bioavailability of cadmium from shellfish and mixed diet in women.

Dietary intake and uptake of cadmium (Cd) were studied in nonsmoking women, 20-50 years of age, consuming a mixed diet low in shellfish (N = 34) or with shellfish once a week or more (N = 17). Duplicate diets were collected during 4 consecutive days for the determination of Cd content. The women kept detailed dietary records, and the intake of energy and various nutrients was calculated. The shellfish diets (median 22.3 micrograms Cd/day) contained twice as much Cd as the mixed diets (median 10.5 micrograms Cd/day; p < 0.0001). Cadmium in feces corresponded to 100 and 99% of that in duplicates of shellfish diets and mixed diets, respectively, indicating a low average absorption of the dietary Cd. In spite of the differences in the daily intake of Cd, there was no statistically significant difference in the concentrations of Cd in blood (B-Cd, shellfish group 0.25 micrograms/liter, mixed diet group 0.23 micrograms/liter) or urine (U-Cd, 0.10 micrograms Cd/liter in both groups). This indicates a lower absorption of Cd in the shellfish group than in the mixed diet group or a difference in the kinetics. A higher gastrointestinal absorption of Cd in the mixed diet group could partly be explained by lower body iron stores as measured by the concentrations of serum ferritin (S-fer, median 18 micrograms/liter, compared to 31 micrograms/liter in the shellfish group). In the mixed diet group, S-fer was negatively correlated with B-Cd and the main determining for B-Cd besides U-Cd in the multiple regression analysis, indicating an increased absorption of Cd at low body iron stores. When women with S-fer exceeding 20 micrograms/liter were compared, the higher dietary intake of Cd in the shellfish group compared to the mixed diet group (24 versus 10 micrograms/day) resulted in higher B-Cd (0.26 versus 0.16 micrograms/liter), although not in proportion to the difference in Cd intake. Thus, there seems to be differences in the bioavailability and/or kinetics of dietary Cd related to the type of diet. This is, to our knowledge, the first study where the influence of various types of diets and nutritional factors on the intake and uptake of cadmium in human subjects has been studied.

A unique metabolism of inorganic arsenic in native Andean women.

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.

Lack of methylation of inorganic arsenic in the chimpanzee.

Most mammals methylate inorganic arsenic (As) to methylarsonic acid (MMA) and dimethylarsinic acid, which are rapidly excreted in the urine. Previous studies have shown that, in contrast to humans, all experimental animals excrete very little MMA. With the aim of finding an appropriate animal model for studies on inorganic As metabolism and toxicity, we have investigated the metabolism of As in two male chimpanzees after a single iv dose of [73As]arsenate (5.8 micrograms As/kg body wt). The initial clearance from plasma was rapid with an apparent half-time of about 1 hr. Urine was found to constitute the major excretory pathway with very little excretion in the feces. About 60% of the administered 73As dose was excreted in the urine within 96 hr in a biphasic manner. The second phase of slow urinary excretion was characterized by first-order kinetics with a half-time of about 7 days. Upon ion-exchange chromatography of ultrafiltrated plasma and urine, only inorganic As could be detected, a finding confirmed by thin-layer chromatography. Thus, the results indicate that the chimpanzee, as previously shown for the marmoset monkey, but unlike all other mammals studied so far, including humans, is unable to methylate and detoxify inorganic As.

Intestinal absorption of dietary cadmium in women depends on body iron stores and fiber intake.

Measurements of intake and uptake of cadmium in relation to diet composition were carried out in 57 nonsmoking women, 20-50 years of age. A vegetarian/high-fiber diet and a mixed-diet group were constructed based on results from a food frequency questionnaire. Duplicate diets and the corresponding feces were collected during 4 consecutive days in parallel with dietary recording of type and amount of food ingested for determination of the dietary intake of cadmium and various nutrients. Blood and 24-hr urine samples were collected for determination of cadmium, hemoglobin, ferritin, and zinc. There were no differences in the intake of nutrients between the mixed-diet and the high-fiber diet groups, except for a significantly higher intake of fiber (p < 0.001) and cadmium (p < 0.002) in the high-fiber group. Fecal cadmium corresponded to 98% in the mixed-diet group and 100% in the high-fiber diet group. No differences in blood cadmium (BCd) or urinary cadmium (UCd) between groups could be detected. There was a tendency toward higher BCd and UCd concentrations with increasing fiber intake; however, the concentrations were not statistically significant at the 5% level, indicating an inhibitory effect of fiber on the gastrointestinal absorption of cadmium. Sixty-seven percent of the women had serum ferritin < 30 micrograms/l, indicating reduced body iron stores, which were highly associated with higher BCd (irrespective of fiber intake). BCd was mainly correlated with UCd, serum ferritin, age, anf fibre intake. UCd and serum ferritin explained almost 60% of the variation in BCd.(ABSTRACT TRUNCATED AT 250 WORDS)