A 28-year-old female presented for evaluation of left flank pain and polyuria after having been exposed to cadmium in the jewelry manufacturing industry for approximately 3 years. This patient possessed both elevated 24-hr urinary ss2-microglobulin and elevated blood cadmium levels. Approximately 6 months after initial presentation, the patient resigned from her job due to shortness of breath, chest pain, and anxiety. Exposure to cadmium in the jewelry industry is a significant source of occupational cadmium exposure. Other occupational sources include the manufacture of nickel-cadmium batteries, metal plating, zinc and lead refining, smelting of cadmium and lead, and production of plastics. Cadmium is also an environmental pollutant that accumulates in leafy vegetables and plants, including tobacco. Major toxicities anticipated from cadmium exposure involve the renal, pulmonary, and, to a lesser extent, gastrointestinal systems. These include the development of renal proximal tubular dysfunction, glomerular damage with progressive renal disease, and respiratory symptoms including pneumonitis and emphysema. Low-level cadmium exposure has also been associated with increased urinary calcium excretion and direct bone toxicity, effects that recent research suggests may result in the development of osteoporosis. The body burden of cadmium, over half of which may reside in the kidneys, is most often measured through the use of urinary cadmium levels. Blood cadmium measurements generally reflect current or recent exposure and are especially useful in cases with a short exposure period and only minimal accumulation of cadmium in the kidneys. Both ss2-microglobulin and alpha1-microglobulin serve as organ-specific, early-effect biomarkers of tubular proteinuria and thus play a role in identifying early signs of cadmium-induced renal damage in those with potential exposures. In addition to ensuring workplace compliance with Occupational Safety and Health Administration-mandated monitoring and screening measures, it is prudent for those with cadmium exposure to maintain adequate intake of both iron and calcium, appropriate measures even in the absence of exposure.

Studies have suggested that plasma lead levels may better reflect the toxicologically labile fraction of circulatory Pb that is more freely available for exchange with target tissues than do Pb levels in whole blood. Studies have also reported an apparent severalfold variation in the relative partitioning of Pb between whole blood and plasma (or serum) for a given whole-blood Pb level. This may reflect inherent differences in the plasma Pb/whole blood Pb partitioning among individuals and/or methodologic challenges associated with the collection and analyses of samples that generally contain < 1-2 ng total Pb. Here, we conducted a longitudinal assessment of the relationship between Pb in whole blood and plasma in environmentally exposed reproductive-age women (n = 63) living in Mexico City, Mexico. We collected whole blood and plasma samples using trace metal clean techniques and analyzed them for Pb using high-resolution inductively coupled plasma mass spectrometry. A subset of subjects provided repeated blood samples weekly for 4 consecutive weeks (n = 17 subjects) or every 1-2 months over a 9-month period (n = 14 subjects). Plasma Pb concentration was significantly positively associated with whole-blood Pb in a curvilinear fashion over the range of blood Pb values observed here (2.13-39.7 microg/dL). This relationship was best described by the function Plasma Pb = e (-2.392 + 0.0898 x blood Pb), where SE(coefficient) = 0.0054, SE(constant) = 0.063 (n = 63 subjects, n = 141 observations). Results from the short- and long-term repeated collection subjects indicated that the within- and between-subject variance components were not significantly different between the two subsets of subjects. The between-subjects component accounts for 78% of the variance in plasma Pb levels, while the residual variance (22%) may be attributed to other unmeasured factors. Collectively, this study demonstrates that plasma Pb measurements may be applied to general clinical settings, provided that established trace metal clean techniques are adopted. This study also shows that the relative (%) partitioning of whole-blood Pb in plasma naturally varies by a factor of about 2-4-fold among subjects at a given blood Pb level. Because Pb in the plasma is considered to more closely represent the fraction of Pb in the circulation that is readily exchanged with peripheral target tissues (e.g., brain, kidney, skeleton), the routine assessment of plasma Pb may provide a more meaningful measure of toxicologically available Pb.

Objective

We previously demonstrated that exposure to polyvinyl chloride plastic medical devices containing di(2-ethylhexyl) phthalate (DEHP) was associated with higher urinary concentrations of several DEHP metabolites in 54 premature infants in two neonatal intensive care units than in the general population. For 42 of these infants, we evaluated urinary concentrations of several phenols, including bisphenol A (BPA), in association with the use of the same medical devices.

Measurements

We measured the urinary concentrations of free and total (free plus conjugated) species of BPA, triclosan, benzophenone-3, methyl paraben, and propyl paraben.

Results

The percentage of BPA present as its conjugated species was > 90% in more than three-quarters of the premature infants. Intensity of use of products containing DEHP was strongly associated with BPA total concentrations but not with any other phenol. Adjusting for institution and sex, BPA total concentrations among infants in the group of high use of DEHP-containing products were 8.75 times as high as among infants in the low use group (p < 0.0001). Similarly, after adjusting for sex and DEHP-containing product use category, BPA total concentrations among infants in Institution A were 16.6 times as high as those among infants in Institution B (p < 0.0001).

Conclusion

BPA geometric mean urinary concentration (30.3 μg/L) among premature infants undergoing intensive therapeutic medical interventions was one order of magnitude higher than that among the general population. Conjugated species were the primary urinary metabolites of BPA, suggesting that premature infants have some capacity to metabolize BPA. The differences in exposure to BPA by intensity of use of DEHP-containing medical products highlight the need for further studies to determine the specific source(s) of exposure to BPA.

Background

Fetal lead exposure is associated with adverse pregnancy outcomes and developmental and cognitive deficits; however, the mechanism(s) by which lead-induced toxicity occurs remains unknown. Epigenetic fetal programming via DNA methylation may provide a pathway by which environmental lead exposure can influence disease susceptibility.

Objective

This study was designed to determine whether prenatal lead exposure is associated with alterations in genomic methylation of leukocyte DNA levels from umbilical cord samples.

Methods

We measured genomic DNA methylation, as assessed by Alu and LINE-1 (long interspersed nuclear element-1) methylation via pyrosequencing, on 103 umbilical cord blood samples from the biorepository of the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) study group. Prenatal lead exposure had been assessed by measuring maternal bone lead levels at the mid-tibial shaft and the patella using a spot-source Cd K-shell X-ray fluorescence instrument.

Results

We found an inverse dose–response relationship in which quartiles of patella lead correlated with cord LINE-1 methylation (p for trend = 0.01) and and tibia lead correlated with Alu methylation (p for trend = 0.05). In mixed effects regression models, maternal tibia lead was negatively associated with umbilical cord genomic DNA methylation of Alu (β= −0.027; p = 0.01). We found no associations between cord blood lead and cord genomic DNA methylation.

Conclusions

Prenatal lead exposure is inversely associated with genomic DNA methylation in cord blood. These data suggest that the epigenome of the developing fetus can be influenced by maternal cumulative lead burden, which may influence long-term epigenetic programming and disease susceptibility throughout the life course.

Background

Rates of preterm birth have been rising over the past several decades. Factors contributing to this trend remain largely unclear, and exposure to environmental contaminants may play a role.

Objective

We investigated the relationship between phthalate exposure and preterm birth.

Methods

Within a large Mexican birth cohort study, we compared third-trimester urinary phthalate metabolite concentrations in 30 women who delivered preterm (< 37 weeks of gestation) with those of 30 controls (≥ 37 weeks of gestation).

Results

Concentrations of most of the metabolites were similar to those reported among U.S. females, although in the present study mono-n-butyl phthalate (MBP) concentrations were higher and monobenzyl phthalate (MBzP) concentrations lower. In a crude comparison before correcting for urinary dilution, geometric mean urinary concentrations were higher for the phthalate metabolites MBP, MBzP, mono(3-carboxylpropyl) phthalate, and four metabolites of di(2-ethyl-hexyl) phthalate among women who subsequently delivered preterm. These differences remained, but were somewhat lessened, after correction by specific gravity or creatinine. In multivariate logistic regression analysis adjusted for potential confounders, elevated odds of having phthalate metabolite concentrations above the median level were found.

Conclusions

We found that phthalate exposure is prevalent among this group of pregnant women in Mexico and that some phthalates may be associated with preterm birth.

Background

Lead exposure has long been associated with deficits in IQ among children. However, few studies have assessed the impact of lead on specific domains of behavior and cognition.

Objective

We evaluated the associations between lead and different domains of neurobehavior and their relative sensitivity to lead.

Methods

We determined blood lead levels using a LeadCare instrument in 756 children 3–7 years of age attending pre- and elementary schools in Chennai, India. Anxiety, social problems, inattention, hyperactivity, and attention deficit hyperactivity disorder (ADHD), as well as executive function were assessed in children by their schoolteachers using Conners’ Teacher Rating Scales-39, Conners’ ADHD/Diagnostic and Statistical Manual for Mental Disorders, 4th Edition Scales (CADS), and the Behavior Rating Inventory of Executive Function questionnaires, with higher scores denoting worse behavior. Analyses were carried out using multivariate generalized estimating equations with comparisons of outcome Z-scores to assess the relative strengths of the associations between log-blood lead and the different domains of behavior.

Results

Mean blood lead level was 11.4 ± 5.3 μg/dL. Blood lead was associated with higher anxiety (β = 0.27, p = 0.01), social problems (β = 0.20, p = 0.02), and higher scores in the ADHD index (β = 0.17; p = 0.05). The effect estimate was highest for global executive function (β = 0.42; p< 0.001).

Conclusions

Higher blood lead levels in this population of young children is associated with increased risk of neurobehavioral deficits and ADHD, with executive function and attention being particularly vulnerable domains to the effects of lead.

Background

Individuals previously exposed to lead remain at risk because of endogenous release of lead stored in their skeletal compartments. However, it is not known if long-term cumulative lead exposure is a risk factor for tooth loss.

Objectives

We examined the association of bone lead concentrations with loss of natural teeth.

Methods

We examined 333 men enrolled in the Veterans Affairs Normative Aging Study. We used a validated K-shell X-ray fluorescence (KXRF) method to measure lead concentrations in the tibial midshaft and patella. A dentist recorded the number of teeth remaining, and tooth loss was categorized as 0, 1–8 or ≥ 9 missing teeth. We used proportional odds models to estimate the association of bone lead biomarkers with tooth loss, adjusting for age, smoking, diabetes, and other putative confounders.

Results

Participants with ≥ 9 missing teeth had significantly higher bone lead concentrations than those who had not experienced tooth loss. In multivariable-adjusted analyses, men in the highest tertile of tibia lead (> 23 μg/g) and patella lead (> 36 μg/g) had approximately three times the odds of having experienced an elevated degree of tooth loss (≥ 9 vs. 0–8 missing teeth or ≥ 1 vs. 0 missing teeth) as those in the lowest tertile [prevalence odds ratio (OR) = 3.03; 95% confidence interval (CI), 1.60–5.76 and OR = 2.41; 95% CI, 1.30–4.49, respectively]. Associations between bone lead biomarkers and tooth loss were similar in magnitude to the increased odds observed in participants who were current smokers.

Conclusion

Long-term cumulative lead exposure is associated with increased odds of tooth loss.

Background

Low-level exposure to lead and to chronic stress may independently influence cognition. However, the modifying potential of psychosocial stress on the neurotoxicity of lead and their combined relationship to aging-associated decline have not been fully examined.

Objectives

We examined the cross-sectional interaction between stress and lead exposure on Mini-Mental State Examination (MMSE) scores among 811 participants in the Normative Aging Study, a cohort of older U.S. men.

Methods

We used two self-reported measures of stress appraisal—a self-report of stress related to their most severe problem and the Perceived Stress Scale (PSS). Indices of lead exposure were blood lead and bone (tibia and patella) lead.

Results

Participants with higher self-reported stress had lower MMSE scores, which were adjusted for age, education, computer experience, English as a first language, smoking, and alcohol intake. In multivariable-adjusted tests for interaction, those with higher PSS scores had a 0.57-point lower (95% confidence interval, −0.90 to 0.24) MMSE score for a 2-fold increase in blood lead than did those with lower PSS scores. In addition, the combination of high PSS scores and high blood lead categories on one or both was associated with a 0.05–0.08 reduction on the MMSE for each year of age compared with those with low PSS score and blood lead level (p < 0.05).

Conclusions

Psychological stress had an independent inverse association with cognition and also modified the relationship between lead exposure and cognitive performance among older men. Furthermore, high stress and lead together modified the association between age and cognition.

Background

DNA methylation is an epigenetic mark that regulates gene expression. Changes in DNA methylation within white blood cells may result from cumulative exposure to environmental metals such as lead. Bone lead, a marker of cumulative exposure, may therefore better predict DNA methylation than does blood lead.

Objective

In this study we compared associations between lead biomarkers and DNA methylation.

Methods

We measured global methylation in participants of the Normative Aging Study (all men) who had archived DNA samples. We measured patella and tibia lead levels by K-X-Ray fluorescence and blood lead by atomic absorption spectrophotometry. DNA samples from blood were used to determine global methylation averages within CpG islands of long interspersed nuclear elements-1 (LINE-1) and Alu retrotransposons. A mixed-effects model using repeated measures of Alu or LINE-1 as the dependent variable and blood/bone lead (tibia or patella in separate models) as the primary exposure marker was fit to the data.

Results

Overall mean global methylation (± SD) was 26.3 ± 1.0 as measured by Alu and 76.8 ± 1.9 as measured by LINE-1. In the mixed-effects model, patella lead levels were inversely associated with LINE-1 (β = −0.25; p < 0.01) but not Alu (β = −0.03; p = 0.4). Tibia lead and blood lead did not predict global methylation for either Alu or LINE-1.

Conclusion

Patella lead levels predicted reduced global DNA methylation within LINE-1 elements. The association between lead exposure and LINE-1 DNA methylation may have implications for the mechanisms of action of lead on health outcomes, and also suggests that changes in DNA methylation may represent a biomarker of past lead exposure.

Background

Anemia and lead exposure remain significant public health issues in many parts of the world, often occurring together. Animal studies suggest that the dopamine D2 receptor (DRD2) mediates the effects of both lead and iron on cognition and behavior.

Objective

We tested the hypothesis that the DRD2 Taq IA polymorphism modifies the effects of lead and hemoglobin on intelligence quotient (IQ) among children.

Methods

Blood lead and hemoglobin were assessed in 717 children 3–7 years of age attending 12 schools in Chennai, India. IQ was determined using the Binet-Kamat scales of intelligence. Genotyping for the DRD2 polymorphism was carried out using a MassARRAY iPLEX platform. Stratified analyses and interaction models, using generalized estimating equations (GEEs), were used to explore interactions between lead and hemoglobin, and DRD2 Taq IA categories [homozygous variant (A1) vs. presence of wild-type allele (A2)].

Results

After we controlled for potential confounders, a one-unit increase in log blood lead was associated with a decrease of 9 IQ points [95% confidence interval (CI), −18.08 to −0.16] in the homozygous-variant children (n = 73) compared with a decrease of 4 IQ points (95% CI, −7.21 to −0.69) among those with the wild-type allele (n = 644). Higher hemoglobin levels were associated with higher IQ in the children who carried the wild-type allele DRD2, but in children homozygous for the variant allele, an increase of 1 g/dL hemoglobin was associated with a decrease in 1.82 points of IQ (95% CI, −5.28 to 1.64; interaction term p-value = 0.02).

Conclusion

The results of this study suggest that the DRD2 Taq IA polymorphism disrupts the protective effect of hemoglobin on cognition and may increase the susceptibility to the deficits in IQ due to lead exposure.

Background

Lead exposure and psychological stress have been independently associated with hypertension in various populations, and animal studies suggest that when they co-occur, their effects may be exacerbated.

Objectives

We examined whether psychological stress modifies the impact of cumulative lead exposure (measured as bone lead levels) on hypertension and blood pressure in Boston-area community–exposed men participating in the Normative Aging Study.

Methods

We evaluated the modifying effect of stress on lead exposure on baseline hypertension status (513 participants) and on blood pressure in those without hypertension (237 participants), cross-sectionally. In baseline nonhypertensives, we examined the same risk factors in relation to prospective risk of developing hypertension.

Results

Cross-sectional analysis revealed a positive interaction between stress and tibia lead on systolic blood pressure, after adjusting for age, body mass index, family history of high blood pressure, education, smoking, alcohol consumption, physical activity, and nutritional factors. In prospective multivariate analyses, high stress also modified the effect of tibia lead and patella lead on the risk of developing hypertension. Those reporting high stress had 2.66 [95% confidence interval (CI), 1.43–4.95] times the risk of developing hypertension per standard deviation increase in tibia lead and had 2.64 (95% CI, 1.42–4.92) times the risk per standard deviation increase in patella lead.

Conclusion

To our knowledge, these are the first analyses to look at interactive effects of stress and lead on hypertension in humans. These results suggest that the effect of lead on hypertension is most pronounced among highly stressed individuals, independent of demographic and behavioral risk factors.

Background

Cumulative lead exposure is associated with a widened pulse pressure (PP; the difference between systolic and diastolic blood pressure), a marker of arterial stiffness and a predictor of cardiovascular disease. Polymorphisms in the hemochromatosis gene (HFE) have been shown to modify the impact of cumulative lead exposure on measures of adult cognition and cardiac function.

Objectives

We examined whether the HFE mutations modify the impact of lead on PP in community-dwelling older men.

Methods

We examined 619 participants with a total of 1,148 observations of PP from a substudy of bone lead levels (a measure of cumulative exposure, measured by in vivo K-shell X-ray fluorescence) and health in the Normative Aging Study between 1991 and 2001. Linear mixed-effects regression models with random intercepts were constructed.

Results

Of the 619 subjects, 138 and 72 carried the HFE H63D and C282Y variants, respectively. After adjusting for age; education; alcohol intake; smoking; daily intakes of calcium, sodium, and potassium; total calories; family history of hypertension; diabetes; height; heart rate; high-density lipoprotein (HDL); total cholesterol:HDL ratio; and waist circumference, baseline bone lead levels were associated with steeper increases in PP in men with at least one H63D allele (p-interaction = 0.03 for tibia and 0.02 for patella) compared with men with only the wild types or C282Y variant.

Conclusions

The HFE H63D polymorphism, but not the C282Y mutation, appears to enhance susceptibility to the deleterious impact of cumulative lead on PP, possibly via prooxidative or pro-inflammatory mechanisms.

Background

Research using reconstructed exposure histories has suggested an association between heavy metal exposures, including lead, and Parkinson’s disease (PD), but the only study that used bone lead, a biomarker of cumulative lead exposure, found a nonsignificant increase in risk of PD with increasing bone lead.

Objectives

We sought to assess the association between bone lead and PD.

Methods

Bone lead concentrations were measured using Cd excited K-shell X-ray fluorescence from 330 PD patients (216 men, 114 women) and 308 controls (172 men, 136 women) recruited from four clinics for movement disorders and general-community cohorts. Adjusted odds ratios (ORs) for PD were calculated using logistic regression.

Results

The average age of cases and controls at bone lead measurement was 67 (SD = 10) and 69 (SD = 9) years of age, respectively. In primary analyses of cases and controls recruited from the same groups, compared with the lowest quartile of tibia lead, the OR for PD in the highest quartile was 3.21 [95% confidence interval (CI), 1.17–8.83]. Results were similar but slightly weaker in analyses restricted to cases and controls recruited from the movement disorders clinics only (fourth-quartile OR = 2.57; 95% CI, 1.11–5.93) or when we included controls recruited from sites that did not also contribute cases (fourth-quartile OR = 1.91; 95% CI, 1.01–3.60). We found no association with patella bone lead.

Conclusions

These findings, using an objective biological marker of cumulative lead exposure among typical PD patients seen in our movement disorders clinics, strengthen the evidence that cumulative exposure to lead increases the risk of PD.

Background

Identifying windows of vulnerability to environmental toxicants is an important area in children’s health research.

Objective

We compared and contrasted statistical approaches that may help identify windows of vulnerability by formally testing differences in exposure effects across time of exposure, incorporating continuous time metrics for timing of exposure, and efficiently incorporating incomplete cases.

Methods

We considered four methods: 1) window-specific and simultaneously adjusted regression; 2) multiple informant models; 3) using features of individual exposure patterns to predict outcomes; and 4) models of population exposure patterns depending on the outcome. We illustrate them using a study of prenatal vulnerability to lead in relation to Bayley’s Mental Development Index at 24 months of age (MDI24).

Results

The estimated change in MDI24 score with a 1-log_e-unit increase in blood lead during the first trimester was −2.74 [95% confidence interval (CI), −5.78 to 0.29] based on a window-specific regression. The corresponding change in MDI24 was −4.13 (95% CI, −7.54 to −0.72) based on a multiple informant model; estimated effects were similar across trimesters (p = 0.23). Results from method 3 suggested that blood lead levels in early pregnancy were significantly associated with reduced MDI24, but decreasing blood leads over the course of pregnancy were not. Method 4 results indicated that blood lead levels before 17 weeks of gestation were lower among children with MDI24 scores in the 90th versus the 10th percentile (p = 0.08).

Conclusions

Method 2 is preferred over method 1 because it enables formal testing of differences in effects across a priori–defined windows (e.g., trimesters of pregnancy). Methods 3 and 4 are preferred over method 2 when there is large variability in the timing of exposure assessments among participants. Methods 3 and 4 yielded smaller p-values for tests of the hypothesis that not only level but also timing of lead exposure are relevant predictors of MDI24; systematic power comparisons are warranted.

Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts.

Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP.

Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders.

Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals.

Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure.

Background

Climate change and associated increases in climate variability will likely further exacerbate global health disparities. More research is needed, particularly in developing countries, to accurately predict the anticipated impacts and inform effective interventions.

Objectives

Building on the information presented at the 2009 Joint Indo–U.S. Workshop on Climate Change and Health in Goa, India, we reviewed relevant literature and data, addressed gaps in knowledge, and identified priorities and strategies for future research in India.

Discussion

The scope of the problem in India is enormous, based on the potential for climate change and variability to exacerbate endemic malaria, dengue, yellow fever, cholera, and chikungunya, as well as chronic diseases, particularly among the millions of people who already experience poor sanitation, pollution, malnutrition, and a shortage of drinking water. Ongoing efforts to study these risks were discussed but remain scant. A universal theme of the recommendations developed was the importance of improving the surveillance, monitoring, and integration of meteorological, environmental, geospatial, and health data while working in parallel to implement adaptation strategies.

Conclusions

It will be critical for India to invest in improvements in information infrastructure that are innovative and that promote interdisciplinary collaborations while embarking on adaptation strategies. This will require unprecedented levels of collaboration across diverse institutions in India and abroad. The data can be used in research on the likely impacts of climate change on health that reflect India’s diverse climates and populations. Local human and technical capacities for risk communication and promoting adaptive behavior must also be enhanced.

Background: Cumulative prenatal lead exposure, as measured by maternal bone lead burden, has been associated with smaller weight of offspring at birth and 1 month of age, but no study has examined whether this effect persists into early childhood.

Objective: We investigated the association of perinatal maternal bone lead, a biomarker of cumulative prenatal lead exposure, with children’s attained weight over time from birth to 5 years of age.

Methods: Children were weighed at birth and at several intervals up until 60 months. Maternal tibia and patella lead were measured at 1 month postpartum using in vivo K-shell X-ray fluorescence. We used varying coefficient models with random effects to assess the association of maternal bone lead with weight trajectories of 522 boys and 477 girls born between 1994 and 2005 in Mexico City.

Results: After controlling for breast-feeding duration, maternal anthropometry, and sociodemographic characteristics, a 1-SD increase in maternal patella lead (micrograms per gram) was associated with a 130.9-g decrease in weight [95% confidence interval (CI), –227.4 to –34.4 g] among females and a 13.0-g nonsignificant increase in weight among males (95% CI, –73.7 to 99.9 g) at 5 years of age. These associations were similar after controlling for concurrent blood lead levels between birth and 5 years.

Conclusions: Maternal bone lead was associated with lower weight over time among female but not male children up to 5 years of age. Given that the association was evident for patellar but not tibial lead levels, and was limited to females, results need to be confirmed in other studies.

Background: No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points.

Objective: We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities.

Methods: We assessed blood lead, bone lead—a biomarker of cumulative lead exposure—measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders.

Results: Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42–14.45) increase in heart rate–corrected QT (QTc) interval and a 5.94-ms increase in heart rate–corrected QRS (95% CI, 1.66–10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22–5.25) and JT prolongation (heart rate–corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93–6.91). Results were weaker for patella lead. No associations were identified with blood lead.

Conclusions: This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics.

Background: Most toxicologic studies focus on a single agent, although this does not reflect real-world scenarios in which humans are exposed to multiple chemicals.

Objectives: We prospectively studied manganese–lead interactions in early childhood to examine whether manganese–lead coexposure is associated with neurodevelopmental deficiencies that are more severe than expected based on effects of exposure to each metal alone.

Methods: Four hundred fifty-five children were enrolled at birth in an longitudinal cohort study in Mexico City, provided blood samples, and were followed until 36 months of age. We measured lead and manganese at 12 and 24 months and assessed neurodevelopment at 6-month intervals from 12 to 36 months of age using Bayley Scales of Infant Development–II.

Results: Mean (± SD) blood concentrations at 12 and 24 months were, respectively, 24.7 ± 5.9 μg/L and 21.5 ± 7.4 μg/L for manganese and 5.1 ± 2.6 μg/dL and 5.0 ± 2.9 μg/dL for lead. Mixed-effects models, including Bayley scores at five time points, showed a significant interaction over time: highest manganese quintile × continuous lead; mental development score, β = –1.27 [95% confidence interval (CI): –2.18, –0.37]; psychomotor development score, β = –0.92 (95% CI: –1.76, –0.09). Slopes for the estimated 12-month lead effect on 18-month mental development and 24- through 36-month psychomotor development scores were steeper for children with high manganese than for children with midrange manganese levels.

Conclusions: We observed evidence of synergism between lead and manganese, whereby lead toxicity was increased among children with high manganese coexposure. Findings highlight the importance of understanding health effects of mixed exposures, particularly during potentially sensitive developmental stages such as early childhood.

Background

Pulse pressure increases with age in industrialized societies as a manifestation of arterial stiffening. Lead accumulates in the vasculature and is associated with vascular oxidative stress, which can promote functional and structural vascular disease.

Objectives

We tested the hypothesis that cumulative community-level lead exposure, measured with K-X-ray fluorescence, is associated with pulse pressure in a cohort of adult men.

Methods and results

In a cross-sectional analysis of 593 men not treated with antihypertensive medication, tibia lead was positively associated with pulse pressure (p < 0.001). Adjusting for age, race, diabetes, family history of hypertension, education, waist circumference, alcohol intake, smoking history, height, heart rate, fasting glucose, and total cholesterol-to-HDL ratio, increasing quintiles of tibia lead remained associated with increased pulse pressure (p_trend = 0.02). Men with tibia lead above the median (19.0 μg/g) had, on average, a 4.2-mmHg (95% confidence interval, 1.9–6.5) higher pulse pressure than men with tibia lead level below the median. In contrast, blood lead level was not associated with pulse pressure.

Conclusions

These data indicate that lead exposure may contribute to the observed increase in pulse pressure that occurs with aging in industrialized societies. Lead accumulation may contribute to arterial aging, perhaps providing mechanistic insight into the observed association of low-level lead exposure with cardiovascular mortality.