Juan Alguacil

Association of arsenic, cadmium and manganese exposure with neurodevelopment and behavioural disorders in children: A systematic review and meta-analysis

The aim of this study was to analyse the scientific evidence published to date on the potential effects on neurodevelopment and behavioural disorders in children exposed to arsenic, cadmium and manganese and to quantify the magnitude of the effect on neurodevelopment by pooling the results of the different studies. We conducted a systematic review of original articles from January 2000 until March 2012, that evaluate the effects on neurodevelopment and behavioural disorders due to pre or post natal exposure to arsenic, cadmium and manganese in children up to 16 years of age. We also conducted a meta-analysis assessing the effects of exposure to arsenic and manganese on neurodevelopment. Forty-one articles that evaluated the effects of metallic elements on neurodevelopment and behavioural disorders met the inclusion criteria: 18 examined arsenic, 6 cadmium and 17 manganese. Most studies evaluating exposure to arsenic (13 of 18) and manganese (14 of 17) reported a significant negative effect on neurodevelopment and behavioural disorders. Only two studies that evaluated exposure to cadmium found an association with neurodevelopmental or behavioural disorders. The results of our meta-analysis suggest that a 50% increase of arsenic levels in urine would be associated with a 0.4 decrease in the intelligence quotient (IQ) of children aged 5-15 years. Moreover a 50% increase of manganese levels in hair would be associated with a decrease of 0.7 points in the IQ of children aged 6-13 years. There is evidence that relates arsenic and manganese exposure with neurodevelopmental problems in children, but there is little information on cadmium exposure. Few studies have evaluated behavioural disorders due to exposure to these compounds, and manganese is the only one for which there is more evidence of the existence of association with attention deficit disorder with hyperactivity.

Smokeless and other noncigarette tobacco use and pancreatic cancer: a case-control study based on direct interviews.

Cigarette smoking is an important and well-established cause of pancreatic cancer. In contrast, little is known about the effects of smoking cigars, pipes, and use of smokeless tobacco on pancreatic cancer risk. The objective of the present study was to examine the association between noncigarette tobacco use (i.e., cigars, pipes, smokeless tobacco) and pancreatic cancer risk among nonsmokers of cigarettes. A population-based case-control study of pancreatic cancer was conducted during 1986–1989 among residents of Atlanta, Georgia, Detroit, Michigan,, and 10 counties in New Jersey. Direct interviews were successfully completed with 526 newly diagnosed pancreatic cancer patients and 2153 controls ages 30–79 years. This analysis was restricted to lifelong nonsmokers of cigarettes and based on interviews with 154 cases newly diagnosed with carcinoma of the exocrine pancreas and 844 population controls who reported no history of cigarette smoking. We observed a consistent pattern of increased risk associated with cigar smoking, although these elevations were not statistically significant. Participants who smoked cigars regularly (i.e., at least one cigar/week for ≥6 months) experienced a 70% increased risk [95% confidence interval (CI): 0.9–3.3], and those who never used other form of tobacco had a 90% increased risk (95% CI: 0.8–4.3). Risk was elevated among those who smoked more than one cigar/day [odds ratio (OR) = 1.8; 95% CI: 0.8–4.2) and among those who smoked cigars > 20 years (OR = 1.9; 95% CI: 0.9–3.9). Trends in risk with increasing amount and duration smoked were consistent but not statistically significant (P = 0.17 and P = 0.16, respectively). Subjects who used smokeless tobacco regularly had a 40% increased risk of pancreatic cancer (95% CI: 0.5–3.6) compared with nonusers of tobacco. We observed a marginally significant increasing risk with increased use of smokeless tobacco (P = 0.04); participants who used >2.5 oz of smokeless tobacco a week had an OR of 3.5 (95% CI: 1.1–11). Long-term use of smokeless tobacco (i.e., >20 years) was also associated with a nonsignificant increased risk (OR = 1.5; 95% CI: 0.6–4.0). In contrast, pipe smokers experienced no increased risk (OR = 0.6; 95% CI: 0.1–2.8). Our results suggest that heavy use of smokeless tobacco, and to a lesser extent, cigar smoking may increase the risk of pancreatic cancer among nonsmokers of cigarettes.

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

INTRODUCTION We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. METHODS Between 2008-2013, 10,106 subjects aged 20-85 were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,112 cases with a new diagnosis of prostate cancer, 1,738 of breast cancer, 2,140 of colorectal cancer, 459 of gastro-oesophageal cancer, 559 cases with chronic lymphocytic leukaemia and 4,098 population controls frequency matched to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. DISCUSSION This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain.

Coffee drinking: The rationale for treating it as a potential effect modifier of carcinogenic exposures

Clinical and epidemiological studies on cancer etiology seldom treat coffee drinking as a potential effect modifier. Yet caffeine exerts significant effects upon a large variety of physiologic, cellular and molecular systems. Caffeine, ‘the worlds most popular drug’, is also a fundamental research tool, widely used in clinical studies on drug metabolism, and in experimental studies on cell cycle checkpoints, DNA repair, and apoptosis, among many other. Caffeine can profoundly alter cell cycle checkpoint function and several mechanisms of DNA repair, as well as carcinogen metabolism. The impact of caffeine on cell cycle checkpoint function occurs in spite of it being nonmutagenic in traditional mutagenesis assays. A complex body of biologic evidence suggests that caffeine-containing beverages can both enhance and antagonise potentially carcinogenic exposures. However, most pathways leading to the ultimate effects in human beings remain unknown. It is unclear whether any of the hundreds of compounds contained in coffee and tea exert a direct and significant carcinogenic effect per se in any human tissue at usual conditions of use. Reasons exist to consider that coffee may sometimes be an indirect, positive confounder. The study of interactions between caffeine-containing beverages and environmental agents in well defined groups of healthy and diseased people could yield new insights into checkpoint signal transduction and other mechanisms of carcinogenesis. Information on the use of caffeine-containing beverages should more often be integrated in studies on the role of gene–environment interactions in the pathogenesis of cancer.

Occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons and other agents and K-ras activation in human exocrine pancreatic cancer

ras genes are known critical DNA targets for chemical carcinogens. Exocrine pancreatic cancer (EPC) is the human tumor with the highest prevalence of K‐ras mutations at diagnosis. We analyzed the relationship between past occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons (PAHs) and other agents and mutations in codon 12 of the K‐ras gene in 107 incident cases of EPC. Information on occupational and life‐style factors was obtained from personal interviews conducted during hospital stay. Occupational exposures were examined using industrial hygienists (IH) assessment and the Finnish job‐exposure matrix (Finjem). Specific occupational exposures among K‐ras mutated EPC cases (n = 83) were compared to those of K‐ras wild‐type EPC cases (n = 24) (case‐case analysis). Multivariate‐adjusted odds ratios (OR) and their corresponding 95% confidence limits were estimated by unconditional logistic regression. Cases with K‐ras mutations were significantly more likely than wild‐type cases to have been exposed to dyes and organic pigments (OR 4.8; p<0.05). There was some indication of weaker associations between K‐ras mutations and occupational exposure to lead, PAHs, benzo[a]pyrene, gasoline, nickel, inhalatory exposure to chromium and sedentary work. The association with chromium compounds was stronger for G to T transversions, a finding compatible with experimental studies on mutation spectra for chromium. Results lend moderate support to the hypothesis of indirect relationships between occupational exposure to dyes and organic pigments and the activation of the K‐ras gene in the etiopathogenesis of human exocrine pancreatic cancer.

The MOBI-Kids study protocol: challenges in assessing childhood and adolescent exposure to electromagnetic fields from wireless telecommunication technologies and possible association with brain tumor risk

The rapid increase in mobile phone use in young people has generated concern about possible health effects of exposure to radiofrequency (RF) and extremely low frequency (ELF) electromagnetic fields (EMF). MOBI-Kids, a multinational case–control study, investigates the potential effects of childhood and adolescent exposure to EMF from mobile communications technologies on brain tumor risk in 14 countries. The study, which aims to include approximately 1,000 brain tumor cases aged 10–24 years and two individually matched controls for each case, follows a common protocol and builds upon the methodological experience of the INTERPHONE study. The design and conduct of a study on EMF exposure and brain tumor risk in young people in a large number of countries is complex and poses methodological challenges. This manuscript discusses the design of MOBI-Kids and describes the challenges and approaches chosen to address them, including: (1) the choice of controls operated for suspected appendicitis, to reduce potential selection bias related to low response rates among population controls; (2) investigating a young study population spanning a relatively wide age range; (3) conducting a large, multinational epidemiological study, while adhering to increasingly stricter ethics requirements; (4) investigating a rare and potentially fatal disease; and (5) assessing exposure to EMF from communication technologies. Our experience in thus far developing and implementing the study protocol indicates that MOBI-Kids is feasible and will generate results that will contribute to the understanding of potential brain tumor risks associated with use of mobile phones and other wireless communications technologies among young people.

Cadmium exposure and neuropsychological development in school children in southwestern Spain

This study assessed the association between cadmium exposure and neuropsychological development in children from a region with high industrial and mining activities in southwestern Spain. We conducted a cross-sectional study with 261 children aged 6-9 years between January and March 2012. Cadmium exposure was measured in urine and hair of children, and neuropsychological development was assessed with the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) and with three computerized tests from the Behavioral Assessment and Research System (BARS): Reaction Time Test (RTT), Continuous Performance Test (CPT) and Selective Attention Test (SAT). Multivariate linear regression models, adjusted for potential confounders, were used to estimate the association between neuropsychological development and cadmium exposure measured in urine and hair samples. Geometric means of urine and hair cadmium levels were 0.75 μg/g creatinine and 0.01 μg/g, respectively. We observed that doubling of levels of cadmium in urine was associated with a reduction of two points (95% CI: -3.8 to -0.4) in the Full-Scale intelligence quotient (IQ) in boys. By domains, association was statistically significant for Verbal Comprehension (β=-2.0; p=0.04) and close to the significance level for Perceptual Reasoning (β=-1.8; p=0.06). Among girls, only Verbal Comprehension showed suggestive associations with cadmium exposure (β=-1.7; p=0.06). Cadmium exposure is associated with cognitive delays in boys in our region. Our results provide additional evidence of the neurotoxic effect of low-level postnatal cadmium exposure among children, and support the hypothesis of differences between sexes in the neurotoxic effect of metals on children.

Short-term effects of particulate matter constituents on daily hospitalizations and mortality in five South-European cities: results from the MED-PARTICLES project.

BACKGROUND Few recent studies examined acute effects on health of individual chemical species in the particulate matter (PM) mixture, and most of them have been conducted in North America. Studies in Southern Europe are scarce. The aim of this study is to examine the relationship between particulate matter constituents and daily hospital admissions and mortality in five cities in Southern Europe. METHODS The study included five cities in Southern Europe, three cities in Spain: Barcelona (2003-2010), Madrid (2007-2008) and Huelva (2003-2010); and two cities in Italy: Rome (2005-2007) and Bologna (2011-2013). A case-crossover design was used to link cardiovascular and respiratory hospital admissions and total, cardiovascular and respiratory mortality with a pre-defined list of 16 PM10 and PM2.5 constituents. Lags 0 to 2 were examined. City-specific results were combined by random-effects meta-analysis. RESULTS Most of the elements studied, namely EC, SO4(2-), SiO2, Ca, Fe, Zn, Cu, Ti, Mn, V and Ni, showed increased percent changes in cardiovascular and/or respiratory hospitalizations, mainly at lags 0 and 1. The percent increase by one interquartile range (IQR) change ranged from 0.69% to 3.29%. After adjustment for total PM levels, only associations for Mn, Zn and Ni remained significant. For mortality, although positive associations were identified (Fe and Ti for total mortality; EC and Mg for cardiovascular mortality; and NO3(-) for respiratory mortality) the patterns were less clear. CONCLUSIONS The associations found in this study reflect that several PM constituents, originating from different sources, may drive previously reported results between PM and hospital admissions in the Mediterranean area.

Occupational exposures and risk of stomach cancer by histological type

Objective To explore the relationship between stomach cancer (SC), by histological type, and occupations and occupational exposures. Methods The authors conducted a hospital-based case–control study in south-east Spain. Subjects were 399 incident histological confirmed SC cases (241 intestinal and 109 diffuse adenocarcinomas) and 455 controls frequency matched by sex, age and province of residence. Occupation was coded according to the Spanish National Classification of Occupations 1994. Occupational exposures were assessed by the FINJEM Job Exposure Matrix. ORs were estimated by unconditional logistic regression adjusting for matching variables and education, smoking, alcohol and diet. Results In men, statistically significant increased risk of the diffuse subtype was found for ‘cooks’ (OR 8.02), ‘wood-processing-plant operators’ (OR 8.13) and ‘food and related products machine operators’ (OR 5.40); for the intestinal subtype, a borderline association was found for ‘miners and quarry workers’ (OR men 4.22, 95% CI 0.80 to 22.14). Significant increased risk was observed between the diffuse subtype of SC and the highest level of exposure to ‘pesticides’ (ORH both sexes 10.39, 95% CI 2.51 to 43.02, ptrend=0.02) and between the intestinal subtype and asbestos (ORH men 3.71, 95% CI 1.40 to 9.83, ptrend=0.07). Restricted analyses of exposures of 15 years and longer showed significant associations between the diffuse subtype and the exposure to ‘wood dust’ (OR men 3.05). Conclusions This study supports the relationship previously suggested between SC and occupational exposure to dusty and high temperature environments. Several occupations may also increase the risk of diffuse SC but not the intestinal subtype.

Occupational exposures and risk of oesophageal cancer by histological type: a case–control study in eastern Spain

Objective: To explore the relationship between occupations and specific occupational exposures and oesophageal cancer (OC) by histological type. Methods: A multicentre hospital-based case–control study was conducted in two Mediterranean provinces of Spain. Occupational, sociodemographic and lifestyle information was collected from 185 newly diagnosed male oesophageal cancer patients (147 squamous cell, 38 adenocarcinoma) and 285 frequency matched controls. Occupation was coded according to the Spanish National Classification of Occupations 1994. Occupational exposure to a selection of carcinogenic substances was assessed by the FINJEM job exposure matrix. Odds ratios were calculated by unconditional logistic regression adjusting for age, education, alcohol intake and cigarette smoking. Results: For the squamous cell variety, statistically significant associations were found for waiters and bartenders (OR 8.18, 95% CI 1.98 to 33.75) and miners, shotfirers, stone cutters and carvers (OR 10.78, 95% CI 1.24 to 93.7) in relation to other occupations. For the adenocarcinoma variety, statistically significant associations were observed for carpenters and joiners (OR 9.69), animal producers and related workers (OR 5.61) and building and related electricians (OR 8.26), although these observations were based on a low number of cases. Regarding specific exposures, the study found a statistically significant increased risk of squamous cell carcinoma for ionising radiation, and of adenocarcinoma for high exposure to volatile sulphur compounds (OR 3.12) and lead (OR 5.30). For all histological types of OC combined, a three-fold increase in risk was found with a significant trend for asbestos exposure (OR 3.46, 95% CI 0.99 to 12.10). Conclusions: The data suggest that some occupational exposures may specifically increase the risk of oesophageal squamous cell carcinoma or adenocarcinoma, while other exposures such as asbestos may increase the overall risk of OC.