Blood Levels of Environmental Heavy Metals are Associated with Poorer Iron Status in Ugandan Children: A Cross-Sectional Study.

BACKGROUND: Iron deficiency (ID) and environmental exposure to metals frequently co-occur among Ugandan children, but little is known about their associations, although iron and other divalent metals share the same intestinal absorption transporter, divalent metal transporter 1 (DMT1). OBJECTIVES: We examined associations between iron status and blood concentrations of lead, manganese (Mn), cobalt (Co), and cadmium, both singly and as a mixture. METHODS: We used data on sociodemographic status, iron biomarkers, and blood concentrations of heavy metals collected from a cross-sectional survey of 100 children aged 6-59 mo in Kampala, Uganda. We compared blood concentrations of metals in ID with iron-sufficient children. We examined associations between a metal mixture and iron biomarkers using multiple linear regression and weighted quintile sum regression. RESULTS: The median (interquartile range) blood Mn (µg/L) was higher in ID children defined by soluble transferrin receptor (sTfR) and ferritin (ID compared with iron-sufficient children): (sTfR [21.3 {15.1, 28.8}, 11.2 {8.6, 18.5}], ferritin [19.5 {15.0, 27.2}, 11.2 {8.8, 19.6}]; P < 0.001 for both). Similarly, the median (interquartile range) blood Co (µg/L) was higher in ID children by ferritin ([0.5 {0.4, 0.9}, 0.4 {0.3, 0.5}], P = 0.05). Based on the multiple linear regression results, higher blood Co and Mn were associated with poorer iron status (defined by all 4 iron indicators for Co and by sTfR for Mn). The weighted quintile sum regression result showed that higher blood concentrations of a metal mixture were associated with poorer iron status represented by sTfR, ferritin, and hepcidin, mainly driven by Co and Mn. CONCLUSIONS: Our study findings suggest that poorer iron status is associated with overall heavy metal burden, predominantly Co and Mn, among Ugandan children. Further prospective studies should confirm our primary findings and investigate the combined effects of coexposures to neurotoxicants on the neurodevelopment of young children.

Environmental exposure to metal mixtures and linear growth in healthy Ugandan children.

BACKGROUND: Stunting is an indicator of poor linear growth in children and is an important public health problem in many countries. Both nutritional deficits and toxic exposures can contribute to lower height-for-age Z-score (HAZ) and stunting (HAZ < -2). OBJECTIVES: In a community-based cross-sectional sample of 97 healthy children ages 6-59 months in Kampala, Uganda, we examined whether exposure to Pb, As, Cd, Se, or Zn were associated with HAZ individually or as a mixture. METHODS: Blood samples were analyzed for a mixture of metals, which represent both toxins and essential nutrients. The association between HAZ and metal exposure was tested using multivariable linear regression and Weighted Quantile Sum (WQS) regression, which uses mixtures of correlated exposures as a predictor. RESULTS: There were 22 stunted children in the sample, mean HAZ was -0.74 (SD = 1.84). Linear regression showed that Pb (ß = -0.80, p = 0.021) and Se (ß = 1.92, p = 0.005) were significantly associated with HAZ. The WQS models separated toxic elements with a presumed negative effect on HAZ (Pb, As, Cd) from essential nutrients with presumed positive effect on HAZ (Se and Zn). The toxic mixture was significantly associated with lower HAZ (ß = -0.47, p = 0.03), with 62% of the effect from Pb. The nutrient WQS index did not reach statistical significance (ß = -0.47, p = 0.16). DISCUSSION: Higher blood lead and lower blood selenium level were both associated with lower HAZ. The significant associations by linear regression were reinforced by the WQS models, although not all associations reached statistical significance. These findings suggest that healthy children in this neighborhood of Kampala, Uganda, who have a high burden of toxic exposures, may experience detrimental health effects associated with these exposures in an environment where exposure sources are not well characterized.

Association of Prenatal and Perinatal Exposures to Particulate Matter With Changes in Hemoglobin A1c Levels in Children Aged 4 to 6 Years.

Importance: Environmental risk factors for childhood type 2 diabetes, an increasing global problem, are understudied. Air pollution exposure has been reported to be a risk factor for this condition. Objective: To examine the association between prenatal and perinatal exposures to fine particulate matter with a diameter less than 2.5 µm (PM2.5) and changes in hemoglobin A1c (HbA1c), a measure of glycated hemoglobin and marker of glucose dysregulation, in children aged 4 to 7 years. Design, Setting, and Participants: The Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) study, a birth cohort study conducted in Mexico City, Mexico, recruited pregnant women from July 3, 2007, to February 21, 2011, through public health maternity clinics. The present analysis includes 365 mother-child pairs followed up until the child was approximately 7 years of age. This study included data from only study visits at approximately 4 to 5 years (visit 1) and 6 to 7 years (visit 2) post partum because HbA1c levels were not measured in earlier visits. The data were analyzed from March 11, 2018, to May 3, 2019. Exposures: Daily PM2.5 exposure estimates at participants' home addresses from 4 weeks prior to mothers' date of last menstrual period (LMP), a marker of the beginning of pregnancy, to 12 weeks after the due date. Exposure was estimated from satellite measurements and calibrated against ground PM2.5 measurements, land use, and meteorological variables. Main Outcomes and Measures: Outcomes included HbA1c levels at 4 to 5 years and 6 to 7 years of age, and the change in the level from the former age group to the latter. Results: The sample included 365 children, of whom 184 (50.4%) were girls. The mean (range) age of the children was 4.8 (4.0-6.4) years at visit 1, and 6.7 (6.0-9.7) years at visit 2. At the time of delivery, the mean (range) age of the mothers was 27.7 (18.3-44.4) years, with a mean (range) prepregnancy body mass index of 26.4 (18.5-43.5). The mean (SD) prenatal PM2.5 exposure (22.4 µg/m3 [2.7 µg/m3]) was associated with an annual increase in HbA1c levels of 0.25% (95% CI, 0.004%-0.50%) from age 4 to 5 years to 6 to 7 years compared with exposure at 12 µg/m3, the national regulatory standard in Mexico. Sex-specific effect estimates were statistically significant for girls (ß = 0.21%; 95% CI, 0.10% to 0.32%) but not for boys (ß = 0.31%; 95% CI, -0.09% to 0.72%). The statistically significant windows of exposure were from week 28 to 50.6 after the mother's LMP for the overall cohort and from week 11 to the end of the study period for girls. Lower HbA1c levels were observed at age 4 to 5 years in girls (ß = -0.72%; 95% CI, -1.31% to -0.13%, exposure window from week 16 to 37.3) and boys (ß = -0.98%; 95% CI, -1.70% to -0.26%, exposure window from the beginning of the study period to week 32.7), but no significant association was found in the overall cohort (ß = -0.13%; 95% CI, -1.27% to 1.01%). There was no significant association between PM2.5 exposure and HbA1c level at age 6 to 7 years in any group. Conclusions and Relevance: The findings of this study suggest that prenatal and perinatal exposures to PM2.5 are associated with changes in HbA1c, which are indicative of glucose dysregulation, in early childhood. Further research is needed because this finding may represent a risk factor for childhood or adolescent diabetes.

Toxic Metals and Chronic Kidney Disease: a Systematic Review of Recent Literature.

PURPOSE OF REVIEW: Arsenic (As), cadmium (Cd), and lead (Pb) are ubiquitous toxicants with evidence of adverse kidney impacts at high exposure levels. There is less evidence whether environmental exposure to As, Cd, or Pb plays a role in development of chronic kidney disease (CKD). We conducted a systematic review to summarize the recent epidemiologic literature examining the relationship between As, Cd, or Pb with CKD. RECENT FINDINGS: We included peer-reviewed studies published in English between January 2013 and April 2018 for As and Cd, and all dates prior to April 2018 for Pb. We imposed temporality requirements for both the definition of CKD (as per NKF-KDOQI guidelines) and environmental exposures prior to disease diagnosis. Our assessment included cohort, case-control or cross-sectional study designs that satisfied 5 inclusion criteria. We included a total of eight articles of which three, two, and four studies examined the effects of As, Cd, or Pb, respectively. Studies of As exposure consistently reported positive association with CKD incidence; studies of Pb exposure were mixed. We found little evidence of association between Cd exposure and CKD. Additional well-designed prospective cohort studies are needed and we present recommendations for future studies.

Piloting a Developmental Screening Tool Adapted for East African Children.

There is a need for developmental screening that is easily administered in resource-poor settings. We hypothesized that known risk factors would predict failed developmental screening on an adapted screening tool in East African children living in poverty. The sample included 100 healthy Ugandan children aged 6⁻59 months. We adapted a parent-reported developmental screener based on the Child Development Review chart. The primary outcome was failure to meet age-appropriate milestones for any developmental domain. Venous blood was analyzed for lead, and caregivers completed a demographics questionnaire. We used multivariate logistic regression models to determine if elevated blood lead and stunting predicted failure on the screener, controlling for maternal education level, age in months past the lower bound of the child's developmental age group, and absence of home electricity. In the sample, 14% (n = 14) of children failed one or more milestones on the screener. Lead levels or stunting did not predict failing the screener after controlling for covariates. Though this tool was feasibly administered, it did not demonstrate preliminary construct validity and is not yet recommended for screening in high-risk populations. Future research should include a larger sample size and cognitive interviews to ensure it is contextually relevant.

Assessment of blood levels of heavy metals including lead and manganese in healthy children living in the Katanga settlement of Kampala, Uganda.

BACKGROUND: Exposure to environmental heavy metals is common among African children. Although many of these metals are known neurotoxicants, to date, monitoring of this exposure is limited, even in countries such as Uganda that are undergoing rapid industrialization. An assessment of the burden and potential causes of metal exposure is a critical first step in gauging the public health burden of metal exposure and in guiding its elimination. METHODS: In May 2016, we enrolled 100 children between the ages of 6 and 59 months living in the Katanga urban settlement of Kampala, Uganda. We measured whole blood concentrations of antimony, arsenic, barium, cadmium, cesium, chromium, cobalt, copper, lead, manganese, nickel, selenium, and zinc. Applying reference cutoffs, we identified metals whose prevalence of elevated blood concentrations was > 10%. We also administered an environmental questionnaire to each child's caregiver to assess potential exposures, including source of drinking water, cooking location and fuel, materials used for roof, walls, and floor, and proximity to potential pollution sources such as main roads, garbage landfills, and fuel stations. We compared log-transformed blood metal concentrations by exposure category, using t-test for dichotomous comparisons and ANOVA for comparisons of three categories, using Tukeys test to adjust for multiple comparisons. RESULTS: The prevalence of high blood levels was elevated for six of the metals: antimony (99%), copper (12%), cadmium (17%), cobalt (19.2%), lead (97%), and manganese (36.4%). Higher blood manganese was significantly associated with having cement walls (p = 0.04) or floors (p = 0.04). Cadmium was greater among children who attended school (< 0.01), and cobalt was higher among children who lived near a garbage landfill (p = 0.01). CONCLUSIONS: Heavy metal exposure is prevalent in the Katanga settlement and may limit neurodevelopment of children living there. Future studies are needed to definitively identify the sources of exposure and to correct potential nutritional deficiencies that may worsen metal absorption.

State-of-the-science review of the occupational health hazards of crystalline silica in abrasive blasting operations and related requirements for respiratory protection.

Excessive exposures to airborne crystalline silica have been known for over 100 years to pose a serious health hazard. Work practices and regulatory standards advanced as the knowledge of the hazards of crystalline silica evolved. This article presents a comprehensive historical examination of the literature on exposure, health effects, and personal protective equipment related to silica and abrasive blasting operations over the last century. In the early 1900s, increased death rates and prevalence of pulmonary disease were observed in industries that involved dusty operations. Studies of these occupational cohorts served as the basis for the first occupational exposure limits in the 1930s. Early exposure studies in foundries revealed that abrasive blasting operations were particularly hazardous and provided the basis for many of the engineering control and respiratory protection requirements that are still in place today. Studies involving abrasive blasters over the years revealed that engineering controls were often not completely effective at reducing airborne silica concentrations to a safe level; consequently, respiratory protection has always been an important component of protecting workers. During the last 15-20 yr, quantitative exposure-response modeling, experimental animal studies, and in vitro methods were used to better understand the relationship between exposure to silica and disease in the workplace. In light of Occupational Safety and Health Administration efforts to reexamine the protectiveness of the current permissible exposure limit (PEL) for crystalline silica and its focus on protecting workers who are known to still be exposed to silica in the workplace (including abrasive blasters), this state-of-the-science review of one of the most hazardous operations involving crystalline silica should provide useful background to employers, researchers, and regulators interested in the historical evolution of the recognized occupational health hazards of crystalline silica and abrasive blasting operations and the related requirements for respiratory protection.

Deoxygenated phosphorothioate inositol phosphate analogs: synthesis, phosphatase stability, and binding affinity.

Inositol phosphates, such as 1D-myo-Inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)], are cellular second messengers with potential roles in cancer prevention and therapy. It typically is difficult to attribute specific pharmacological activity to a single inositol phosphate because they are rapidly metabolized by phosphatases and kinases. In this study, we have designed stable analogs of myo-inositol 4,5-bisphosphate [Ins(4,5)P(2)] and Ins(1,4,5)P(3) that retain the cyclohexane scaffold, but lack hydroxyl groups that might be phosphorylated and have phosphate groups replaced with phosphatase-resistant phosphorothioates. An Ins(1,4,5)P(3) analog, 1D-2,3-dideoxy-myo-inositol 1,4,5-trisphosphorothioate, was synthesized from (-)-quebrachitol, and an Ins(4,5)P(2) analog, 1D-1,2,3-trideoxy-myo-inositol 4,5-bisphosphorothioate, was prepared from cyclohexenol. The Ins(1,4,5)P(3) analog was recognized by Ins(1,4,5)P(3) receptor with a binding constant (K(d)) of 810 nM, compared with 54 nM for the native ligand Ins(1,4,5)P(3), and was resistant to dephosphorylation by alkaline phosphatase under conditions in which Ins(1,4,5)P(3) is extensively hydrolyzed. Analogs developed in this study are potential chemical probes for understanding mechanisms of inositol phosphate actions that may be elucidated by eliciting specific and prolonged activation of the Ins(1,4,5)P(3) receptor.

Kinetics and mechanism of the sensitized photodegradation of lignin model compounds.

The kinetics of the sensitized photodegradation of a variety of well-defined lignin model compounds was studied to determine the mechanisms responsible for lignin's photochemically-mediated oxidation. Monomeric and dimeric models representing lignin's phenolic end groups and nonphenolic dimers representing its inner core were studied. It was determined that the rate constants for the reaction of the deprotonated phenolic models with singlet oxygen (1O2) range from 0.96 to 7.2 x 10(7) M(-1) s(-1). The models were substituted with zero, one, or two electron-donating methoxy groups on both aryl rings and, while the rate constants showed little dependence on the substitution of the nonphenolic ring, the rate constants increased dramatically with increasing methoxy substitution of the phenol. Reaction between these deprotonated models and 1O2 is thus proposed to occur at the phenolate ring. Under neutral conditions, it was observed that the phenolic models react with excited state sensitizer, with this reaction also occuring at the phenol ring. The sum of the rate constants for quenching of and reaction with excited state sensitizer by lignin model compound ranges from 5.4 to 75 x 10(7) M(-1) s(-1). This study corrects previous reports that attribute the sensitized degradation of neutral lignin model compounds to reaction with 1O2. A nonphenolic aromatic ketone inner-core model was observed to undergo direct photolysis, and its reduced analog was not degraded by direct photolysis or reaction with 1O2 or excited state sensitizer. The oxidized inner-core model was also shown to be able to act as a sensitizer for the degradation of a phenolic lignin model compound.