Mariano E. Cebrián

Chronic Arsenic Poisoning in the North of Mexico

1 We compared the prevalence of signs and symptoms of chronic arsenic poisoning in two rural populations. 2 The arsenic concentration in the drinking water of the exposed population was 0.41 mg/l, and 0.007 mg/l in the control population. 3 The arsenic was present mainly (70%) in its pentavalent form. 4 The objective was to quantitate health effects and risks derived from chronic ingestion of arsenic in contaminated water. 5 In the exposed population, 21.6% of the sample, showed at least one of the cutaneous signs of chronic arsenic poisoning against 2.2% in the control town. 6 Non-specific symptoms were more prevalent in the exposed population and they occurred more frequently in those individuals with skin signs. 7 The relative risk of suffering a particular manifestation of poisoning, ranged from 1.9 to 36 times higher in the exposed population. 8 We estimated the risks above mentioned, which were derived from exposure to minute quantities of arsenic in a known proportion of its oxidation states during a life time period.

Arsenic exposure and cognitive performance in Mexican schoolchildren.

Background Previous studies have suggested an effect of high arsenic concentration on cognitive and neurobehavioral function in humans. Objective Our goal was to identify demographic and nutritional factors that are associated with As exposure and the influence of this exposure on cognitive function in school-age children. Methods We recruited 602 children 6–8 years of age living within 3.5 km of a metallurgic smelter complex in the city of Torreón, Mexico, to participate in a cross-sectional evaluation. Of these, 591 had complete anthropometry, iron, and zinc status by biochemical measurements in serum, blood lead concentration (PbB), and arsenic in urine (UAs), and 557 completed several cognitive performance tests. Results The mean for UAs was 58.1 ± 33.2 μg/L; 52% of the children had UAs concentrations > 50 μg/L, and 50.7% of children had PbB ≥10 μg/dL. UAs concentration was associated with low socioeconomic status. Nutritional status indicators were not related to UAs concentrations. Linear and logistic regressions adjusted for hemoglobin concentration, PbB, and sociodemographic confounders showed a significant inverse association between UAs and Visual–Spatial Abilities with Figure Design, the Peabody Picture Vocabulary Test, the WISC-RM Digit Span subscale, Visual Search, and Letter Sequencing Tests (p < 0.05). Boys excreted significantly more UAs (p < 0.05) and were affected on different cognitive areas than girls. Conclusions Children living in an area contaminated with both As and lead showed that As contamination can affect children’s cognitive development, independent of any effect of lead.

The oxidation states of arsenic in well-water from a chronic arsenicism area of Northern Mexico

Aquifers in the Región Lagunera in northern Mexico are heavily contaminated with arsenic. The range of total arsenic concentrations in 128 water samples analyzed was 0.008 to 0.624 mg litre(-1), and concentrations greater than 0.05 mg litre(-1) were found in 50% of them. Approximately 400 000 people living in rural areas were exposed to high As concentrations. Most of the As was in inorganic form and pentavalent arsenic [As(V)] was the predominant species in 93% of the samples. In 36% of the samples, however, variable percentages (20-50) of trivalent As [As(III)] were found. Organic arsenicals were present in very small amounts. Since As(III) is several times more toxic than As(V), we suggest that periodic studies be performed on the As(III)/As(V) ratio in wells whose total As concentrations are above 0.05 mg litre(-1), in combination with epidemiological studies to evaluate possible differences in health effects produced by different As species.

Cytogenetic effects in human exposure to arsenic

The cytogenetic effects of arsenic exposure were studied among rural populations that live in the same geographical area and have similar socioeconomic status, but different degree of exposure to inorganic arsenic (As) via drinking water. A group of inhabitants of Santa Ana (408.17 micrograms/l of As in drinking water) were considered the exposed individuals and a group of inhabitants of Nazareno (29.88 micrograms/l) were considered as controls. Blood and urine samples were obtained from volunteers. Past and current exposure, health, and nutritional status as well as the presence of arsenic skin lesions were ascertained in study participants through questionnaires and physical examination. The frequencies and types of chromosomal aberrations in first-division metaphases were studied in whole blood lymphocyte cultures while the presence of micronuclei (MN) was studied in exfoliated epithelial cells obtained from the oral mucosa and from urine samples. Total arsenic (TAs) content, and the relative proportions of inorganic arsenic (IAs), and the metabolites monomethylarsonic (MMA) and dimethylarsinic (DMA) acid were determined in urine samples. Exposed individuals showed a significant increase in the frequency of chromatid and isochromatid deletions in lymphocytes and of MN in oral and urinary epithelial cells. Males were more affected than females, and a higher number of micronucleated oral cells were found among those individuals with skin lesions. The type of cytogenetic damage observed gives evidence of arsenic as a clastogenic/aneugenic carcinogen.

Exposure to Phthalates and Breast Cancer Risk in Northern Mexico

Background Phthalates, ubiquitous environmental pollutants that may disturb the endocrine system, are used primarily as plasticizers of polyvinyl chloride and as additives in consumer and personal care products. Objectives In this study, we examined the association between urinary concentrations of nine phthalate metabolites and breast cancer (BC) in Mexican women. Methods We age-matched 233 BC cases to 221 women residing in northern Mexico. Sociodemographic and reproductive characteristics were obtained by direct interviews. Phthalates were determined in urine samples (collected pretreatment from the cases) by isotope dilution/high-performance liquid chromatography coupled to tandem mass spectrometry. Results Phthalate metabolites were detected in at least 82% of women. The geometric mean concentrations of monoethyl phthalate (MEP) were higher in cases than in controls (169.58 vs. 106.78 μg/g creatinine). Controls showed significantly higher concentrations of mono-n-butyl phthalate, mono(2-ethyl-5-oxohexyl) phthalate, and mono(3-carboxypropyl) phthalate (MCPP) than did the cases. After adjusting for risk factors and other phthalates, MEP urinary concentrations were positively associated with BC [odds ratio (OR), highest vs. lowest tertile = 2.20; 95% confidence interval (CI), 1.33–3.63; p for trend < 0.01]. This association became stronger when estimated for premenopausal women (OR, highest vs. lowest tertile = 4.13; 95% CI, 1.60–10.70; p for trend < 0.01). In contrast, we observed significant negative associations for monobenzyl phthalate (MBzP) and MCPP. Conclusions We show for the first time that exposure to diethyl phthalate, the parent compound of MEP, may be associated with increased risk of BC, whereas exposure to the parent phthalates of MBzP and MCPP might be negatively associated. These findings require confirmation.

Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic

Exposure of several human populations to arsenic has been associated with a high incidence of detrimental dermatological and carcinogenic effects. To date, studies examining the immunotoxic effects of arsenic in humans, and specifically in children, are lacking. Therefore, we evaluated several parameters of immunological status in a group of children exposed to arsenic through their drinking water. Peripheral blood mononuclear cells (PBMCs) of 90 children (6 to 10 years old) were collected. Proportions of lymphocyte subpopulations, PBMC mitogenic proliferative response, and urinary arsenic levels were evaluated. Increased urine arsenic levels were associated with a reduced proliferative response to phytohemaglutinin (PHA) stimulation (P=0.005), CD4 subpopulation proportion (P=0.092), CD4/CD8 ratio (P=0.056), and IL‐2 secretion levels (P=0.003). Increased arsenic exposure was also associated with an increase in GM‐CSF secretion by mononucleated cells (P=0.000). We did not observe changes in CD8, B, or NK cell proportions, nor did we observe changes in the secretion of IL‐4, IL‐10, or IFN‐γ by PHA‐activated PBMCs. These data indicate that arsenic exposure could alter the activation processes of T cells, such that an immunosuppression status that favors opportunistic infections and carcinogenesis is produced together with increased GM‐CSF secretion that may be associated with chronic inflammation.

In Utero p,p′-DDE Exposure and Infant Neurodevelopment: A Perinatal Cohort in Mexico

Background Evidence suggests that p,p′-dichlorodiphenyldichloroethene (DDE) affects neurodevelopment in infants, although a critical exposure window has not yet been identified. Objectives Our goal was to assess the prenatal DDE exposure window and its effect on the psychomotor development index (PDI) and mental development index (MDI) during the first year of life. Methods We recruited 244 children whose pregnancies and deliveries were uncomplicated, and whose mothers were monitored throughout the pregnancy. Participating mothers were not occupationally exposed to DDT (dichlorodiphenyltrichloroethane) but were residents of a zone in Mexico with endemic malaria. We measured serum levels of DDE before pregnancy and during each trimester of the pregnancy. We evaluated PDI and MDI of the Bayley Scales for Infant Development (BSID-II), at 1, 3, 6, and 12 months of age. We adjusted for quality of the home environment and maternal intellectual coefficient (IQ). We used generalized mixed-effects models for statistical analysis. Results Third-trimester DDE level (7.8 ± 2.8 ppb) was significantly higher than the level at baseline, first, and second trimesters, but the differences never exceeded 20%. Only DDE levels during the first trimester of pregnancy were associated with a significant reduction in PDI (every doubled increase of DDE level reduced the PDI 0.5 points). DDE was not associated with MDI. Conclusions A critical window of exposure to DDE in utero may be the first trimester of the pregnancy, and psychomotor development is a target of this compound. Residues of DDT metabolites may present a risk of developmental delay for years after termination of DDT use.

Variability in human metabolism of arsenic.

Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary excretion. While there is debate as to the role of methylation in activation/detoxification, variations in arsenic metabolism may affect individual risks of toxicity and carcinogenesis. Using data from three populations, from Mexico, China, and Chile, we have analyzed the distribution in urine of total arsenic and arsenic species (inorganic arsenic (InAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA). Data were analyzed in terms of the concentration of each species and by evaluating MMA:DMA and (MMA+DMA):InAs ratios. In all persons most urinary As was present as DMA. Male:female differences were discernible in both high- and low-exposure groups from all three populations, but the gender differences varied by populations. The data also indicated bimodal distributions in the ratios of DMA to InAs and to MMA. While the gene or genes responsible for arsenic methylation are still unknown, the results of our studies among the ethnic groups in this study are consistent with the presence of functional genetic polymorphisms in arsenic methylation leading to measurable differences in toxicity. This analysis highlights the need for continuing research on the health effects of As in humans using molecular epidemiologic methods.

Biomarkers of oxidative stress and damage in human populations exposed to arsenic.

Arsenic (As) is an ubiquitous element in the environment for which the main route of human exposure is through consumption of drinking water. Reactive oxygen species generation (ROS) associated with As exposure is known to play a fundamental role in the induction of adverse health effects and disease (cancer, diabetes, hypertension, and cardiovascular and neurological diseases). However, the precise mechanisms of oxidative stress and damage from As exposure are not fully understood and moreover the use of non-invasive methods of measuring ROS generation and oxidative damage footprints in humans is no easy task. Although As induces adverse health effects not all exposed individuals develop degenerative chronic diseases or even manifest adverse effects or symptoms, suggesting that genetic susceptibility is an important factor involved in the human response to As exposure. This mini-review summarizes the literature describing the molecular mechanisms affected by As, as well as the most used biomarkers of oxidative stress and damage in human populations. The most reported biomarkers of oxidative DNA damage are the urinary excretion of 8-OHdG and the comet assay in lymphocytes, and more recently DNA repair mechanism markers from the base and nuclear excision repair pathways (BER and NER). Genetic heterogeneity in the oxidative stress pathways involved in As metabolism are important causative factors of disease. Thus further refinement of human exposure assessment is needed to reinforce study design to evaluate exposure-response relationships and study gene-environment interactions. The use of microarray-based gene expression analysis can provide better insights of the underlying mechanisms involved in As-induced diseases and could help to identify target genes that can be modulated to prevent disease.

Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-κB activation and cell proliferation in human breast cancer MCF-7 cells

Epidemiological evidence has associated exposure to arsenic (As) in drinking water with an increased incidence of human cancers in the skin, bladder, liver, kidney and lung. Sodium arsenite mimics the effects of estradiol and induces cell proliferation in the estrogen responsive breast cancer cell line MCF-7. Therefore, our aim was to further explore the ability of sodium arsenite to induce MCF-7 epithelial breast cell proliferation and some of its underlying mechanisms by studying ROS production, c-Myc and HO-1 protein levels, 8-OHdG formation and NF-kappaB activation. Low arsenite concentrations (0.5-5 microM) induced ROS production and ROS-related depolarization of the mitochondrial membrane suggesting that mitochondria played an important role in the oxidative effects of As. ROS-mediated DNA damage as measured by the presence of 8-OHdG DNA-adducts in their nuclei, IkappaB phosphorylation, NF-kappaB activation and increases in c-Myc and HO-1 protein levels were also observed, suggesting that these factors play a relevant role in the arsenite induced MCF-7 cell recruitment into the S-phase of the cell cycle and cell proliferation observed. In conclusion, arsenite activates several pathways involved in MCF-7 cell proliferation suggesting that arsenite exposure may pose a risk for breast cancer in human exposed populations notwithstanding that most studies to date have not yet implicated this metalloid as a cofactor in the etiology of this disease.