Tibia Lead Research Articles

DNA Methylation Biomarkers for Cumulative Lead Exposures and Cognitive Impairment

BackgroundRecent evidence suggests that cumulative low-level lead exposure has adverse effects on cognitive function in the elderly. To date, the few studies that have measured bone lead exposure relied on K-X-ray fluorescence (KXRF), methods that are mostly unavailable in large community-based studies. Here, we employ a methylation-based estimation method for bone and blood lead in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. MethodsTibia, patella, and blood lead levels were estimated using blood DNA methylation (DNAm) biomarkers in 625 participants from the ADNI cohort. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Longitudinal analyses were conducted using linear mixed-effect regression models. Participants had different years of baseline (2010-2014) and follow-up visits (2014-2015). ResultsDNAm derived tibia and patella lead levels were negatively associated with MoCA scores throughout follow-up, while DNAm derived blood lead level was not associated with MoCA scores. On average, we observed lower MoCA scores with increasing DNAm tibia lead (per interquartile range (IQR): β=-0.23; 95%CI: -0.44, -0.03) and DNAm patella lead, albeit the latter was weaker (per IQR: β=-0.19; 95%CI: -0.41, 0.04). When stratifying by gender, women showed a stronger decrease in cognitive function with increasing DNAm tibia lead (per IQR β=-0.34; 95%CI: -0.65, -0.04) than men (per IQR β=-0.15; 95%CI: -0.42, 0.13). The estimated decrease in MoCA scores per DNAm tibia lead IQR increase was stronger among participants with one or two APOE4 alleles (per IQR β=-0.37; 95%CI: -0.74, -0.01) than those with zero alleles (per IQR β=-0.14; 95%CI: -0.38, 0.10). ConclusionThese findings strengthen the evidence that cumulative long-term lead exposures levels are associated with decreased cognitive function in the elderly, especially among women and carriers of one or two APOE4 alleles. These findings based on whole blood methylation data corroborate previous epidemiologic studies that used KXRF for measuring bone lead.

Do we underestimate risk of cardiovascular mortality due to lead exposure?

BackgroundStudies using data from the National Health and Nutrition Examination Survey-III (NHANES-III) have demonstrated significant prospective associations between blood lead levels and increased mortality. Bone lead represents cumulative lead burden and thus is a better biomarker for assessing chronic impacts, but its in vivo assessment requires special K-x-ray fluorescence (KXRF) instrumentation. Our team recently developed an algorithm predicting bone lead levels from a combination of blood lead levels, age and other socioeconomic and behavioral variables. We examined the associations of our algorithm-estimated bone lead levels and mortality in NHANES-III. MethodsWe included 11,628 adults followed up to December 31, 2019. Estimated tibia lead and patella lead levels were calculated using our prediction algorithms. We used survey-weighted Cox proportional hazards models to compute hazard ratios (HRs) and 95 % confidence intervals (CIs). ResultsDuring the median follow-up of 26.8 years, 4900 participants died (mortality rate = 1398 per 100,000 adults/year). Geometric means (95 % CIs) of blood lead, predicted tibia lead, and predicted patella lead were 2.69 μg/dL (2.54, 2.84), 6.73 μg/g (6.22, 7.25), and 16.3 μg/g (15.9, 16.8), respectively. The associations for all-cause mortality were similar between blood lead and bone lead. However, the associations for cardiovascular mortality were much greater with predicted bone lead markers compared to blood lead: for comparing participants at the 90th vs. 10th percentiles of exposure, HR = 3.32 (95 % CI: 1.93–5.73) for tibia lead, 2.42 (1.56–3.76) for patella lead, 1.63 (1.25–2.14) for blood lead. The population attributable fractions for cardiovascular disease mortality if everyone's lead concentrations were declined to the 10th percentiles were 45.8 % (95 % CI: 28.1–59.4) for tibia lead, 33.1 % (18.1–45.8) for patella lead, and 22.8 % (10.4–33.8) for blood lead. ConclusionsThese findings suggest that risk assessment for cardiovascular mortality based on blood lead levels may underestimate the true mortality risk of lead exposure.

Epigenetic Biomarkers of Lead Exposure and Cardiovascular Disease: Prospective Evidence in the Strong Heart Study.

Background Lead is a cardiotoxic metal with a variety of adverse health effects. In the absence of data on bone lead exposure, epigenetic biomarkers can serve as indicators of cumulative lead exposure and body burden. Herein, we leveraged novel epigenetic biomarkers of lead exposure to investigate their association with cardiovascular disease (CVD) incidence and mortality. Methods and Results Blood DNA methylation was measured using the Illumina MethylationEPIC BeadChip among 2231 participants of the Strong Heart Study (SHS) at baseline (1989-1991). Epigenetic biomarkers of lead levels in blood, patella, and tibia were estimated using previously identified cytosine-guanine dinucleotide (CpG) sites. CVD incidence and mortality data were available through 2017. Median concentrations of lead epigenetic biomarkers were 13.8 μg/g, 21.3 μg/g, and 2.9 μg/dL in tibia, patella, and blood, respectively. In adjusted models, the hazard ratio (HR) (95% CI) of CVD mortality per doubling increase in lead epigenetic biomarkers were 1.42 (1.07-1.87) for tibia lead, 1.22 (0.93-1.60) for patella lead, and 1.57 (1.16-2.11) for blood lead. The corresponding HRs for incident CVD were 0.99 (0.83-1.19), 1.07 (0.89-1.29), and 1.06 (0.87-1.30). The association between the tibia lead epigenetic biomarker and CVD mortality was modified by sex (interaction P value: 0.014), with men at increased risk (HR, 1.42 [95% CI, 1.17-1.72]) compared with women (HR, 1.04 [95% CI, 0.89-1.22]). Conclusions Tibia and blood epigenetic biomarkers were associated with increased risk of CVD mortality, potentially reflecting the cardiovascular impact of cumulative and recent lead exposures. These findings support that epigenetic biomarkers of lead exposure may capture some of the disease risk associated with lead exposure.

Predicting cumulative lead (Pb) exposure using the Super Learner algorithm

Chronic lead (Pb) exposure causes long term health effects. While recent exposure can be assessed by measuring blood lead (half-life 30 days), chronic exposures can be assessed by measuring lead in bone (half-life of many years to decades). Bone lead measurements, in turn, have been measured non-invasively in large population-based studies using x-ray fluorescence techniques, but the method remains limited due to technical availability, expense, and the need for licensing radioactive materials used by the instruments. Thus, we developed prediction models for bone lead concentrations using a flexible machine learning approach--Super Learner, which combines the predictions from a set of machine learning algorithms for better prediction performance. The study population included 695 men in the Normative Aging Study, aged 48 years and older, whose bone (patella and tibia) lead concentrations were directly measured using K-shell-X-ray fluorescence. Ten predictors (blood lead, age, education, job type, weight, height, body mass index, waist circumference, cumulative cigarette smoking (pack-year), and smoking status) were selected for patella lead and 11 (the same 10 predictors plus serum phosphorus) for tibia lead using the Boruta algorithm. We implemented Super Learner to predict bone lead concentrations by calculating a weighted combination of predictions from 8 algorithms. In the nested cross-validation, the correlation coefficients between measured and predicted bone lead concentrations were 0.58 for patella lead and 0.52 for tibia lead, which has improved the correlations obtained in previously-published linear regression-based prediction models. We evaluated the applicability of these prediction models to the National Health and Nutrition Examination Survey for the associations between predicted bone lead concentrations and blood pressure, and positive associations were observed. These bone lead prediction models provide reasonable accuracy and can be used to evaluate health effects of cumulative lead exposure in studies where bone lead is not measured.

DNA methylation biomarker for cumulative lead exposure is associated with Parkinson\u2019s disease

Lead, a known neurotoxicant, has previously received attention in Parkinson’s disease (PD) research, but epidemiologic studies have been limited in sample size and findings are equivocal. We generated two methylation-based biomarkers for cumulative tibia and patella bone-measured lead exposure in 1528 PD patients and 1169 controls. PD status was associated with increased levels of the DNAm biomarker for tibia-lead levels. We estimated a meta-OR for PD of 1.89 per unit DNAm tibia-lead increase (95% CI 1.59, 2.24; p = 8.1E−13). The current study supports the notion that chronic and long-term lead exposure tracked via DNAm may contribute to PD pathogenesis.

Prenatal blood lead levels and reduced preadolescent glomerular filtration rate: Modification by body mass index

BackgroundFor the developing kidney, the prenatal period may represent a critical window of vulnerability to environmental insults resulting in permanent nephron loss. Given that the majority of nephron formation is complete in the 3rd trimester, we set out to test whether 1) prenatal lead exposure is associated with decreased preadolescent kidney function and 2) whether preadolescent obesity acts synergistically with early life lead exposure to reduce kidney function. MethodsOur study included 453 mother–child pairs participating in the PROGRESS birth cohort. We assessed prenatal blood lead levels (BLLs) in samples collected in the 2nd and 3rd trimesters and at delivery, as well as tibial and patellar bone lead measures assessed one-month postpartum. Preadolescent estimated glomerular filtration rate (eGFR) was derived from serum levels of creatinine and/or cystatin C measured at age 8–12 years. We applied linear regression to assess the relationship between prenatal bone and BLL with preadolescent eGFR, and adjusted for covariates including age, sex, BMI z-score, indoor tobacco smoke exposure, and socioeconomic status. We also examined sex-specific associations and tested for effect modification by BMI status. ResultsWe observed null associations between prenatal lead exposure and eGFR. However, in interaction analyses we found that among overweight children, there was an inverse association between BLL (assessed at 2nd and 3rd trimester and at delivery) and preadolescent eGFR. For example, among overweight participants, a one ln-unit increase in 2nd trimester BLL was associated with a 10.5 unit decrease in cystatin C-based eGFR (95% CI: −18.1, −2.8; p = 0.008). Regardless of lead exposure, we also observed null relationships between BMI z-score and eGFR overall, as well as among overweight participants. However, among participants with preadolescent obesity, we observed a significant 5.9-unit decrease in eGFR. We observed no evidence of sex-specific effects. ConclusionsOur findings, if confirmed in other studies, suggest a complex interplay between the combined adverse effects of adiposity and perinatal lead exposure as they relate to adolescent kidney function. Future studies will assess kidney function and adiposity trajectories through adolescence to better understand environmental risk factors for kidney function decline.

Do We Underestimate Risk of Mortality due to Lead Exposure?

Background/Aim: Studies using data from the National Health and Nutrition Examination Survey-III (NHANES-III) have demonstrated significant associations between blood lead levels and increased mortality. However, blood lead reflects primarily recent exposure and lead mobilized from internal organs. Bone lead represents cumulative lead burden and thus is a better biomarker for assessing chronic impacts, but its in vivo assessment requires special K-x-ray fluorescence (KXRF) instrumentation. Our team used KXRF measurements of lead in bone and blood lead levels in participants of the Normative Aging Study to develop an algorithm predicting bone lead levels from a combination of blood lead levels and standard biochemical, hematologic, and questionnaire data. We examined the associations of our algorithm-estimated bone lead levels and mortality in NHANES-III.Methods: We included 11,065 adults followed up to December 31, 2015. Estimated tibia and patella bone lead levels were calculated using our prediction algorithm. We used survey-weighted Cox proportional hazards models to compute hazard ratios (HRs) and 95% confidence intervals (CIs).Results: During the median follow-up of 22.4 years (216,565 person-years), 4,103 participants died (mortality rate=1,895 per 100,000 adults/year). Means (95% CIs) of blood lead, tibia lead, and patella lead were 3.47 μg/dL (3.27-2.67), 2.98 μg/g (2.23-3.75), and 3.04 μg/g (1.94-4.14), respectively. After adjustment for potential confounders, the HRs comparing participants at the 90th vs. 10th percentiles of exposure with regards to all-cause mortality were 1.25 (95% CI: 1.05-1.50) for blood lead, 1.91 (1.36-2.68) for tibia lead, 2.00 (1.45-2.77) for patella lead; for CVD mortality, 1.67 (1.20-2.34) for blood lead, 1.89 (0.98-3.67) for tibia lead, 2.24 (1.26-4.00) for patella lead; and for cancer mortality, 1.35 (0.98-1.84) for blood lead, 2.52 (1.30-4.90) for tibia lead, 2.45 (1.29-4.66) for patella lead.Conclusions: These findings suggest that risk assessment based on blood lead levels may underestimate the true mortality risk of lead exposure.

Blood-based DNA methylation biomarkers for cumulative lead exposure: associations with cardiovascular disease incidence and mortality in the Strong Heart Study

Lead is a ubiquitous toxicant associated with increased cardiovascular disease (CVD) risk. Blood and bone (patella and tibia) lead are established biomarkers of cumulative lead exposure, but because specialized technologies are needed for analysis, they are typically not available for clinical and epidemiological applications. We recently developed and validated three polygenic biomarkers that estimate lead exposure in blood, patella, and tibia samples based only on blood DNA methylation (DNAm) data. Whether these methylation-biomarkers predict lead-related CVD risk is unknown. We thus investigated the associations of these DNAm lead biomarkers with CVD incidence and mortality in the Strong Heart Study (SHS), a population-based cohort study of CVD in American Indian adults recruited in 1989-1991. The three DNAm lead biomarkers were computed from Illumina EPIC BeadChip blood DNAm data available at baseline among 2,321 SHS participants aged 45-75 years (~41% male). During a median follow-up of ~20 years, 1,023 participants had incident CVD events and 452 died due to CVD. After adjustment for sociodemographic and cardiovascular risk factors, the three DNAm lead biomarkers were associated with CVD mortality, but not with non-fatal CVD events. The hazard ratios (95% CI) for CVD mortality were 1.15 (1.01 - 1.31), 1.12 (1.01 - 1.25), and 1.20 (1.06 - 1.37) per interquartile increase in DNAm-estimated blood, patella, and tibia lead biomarkers. All biomarkers were also associated with coronary heart disease mortality. In subgroup analyses, the associations of lead biomarkers with CVD mortality were stronger in males and ever smokers. These newly developed DNAm lead biomarkers may aid in identifying individuals at risk for CVD mortality resulted from cumulative lead exposure.

Blood DNA methylation biomarkers of cumulative lead exposure in adults.

Background:Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels—validated measures of cumulative exposure—require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally-invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles—obtainable via Illumina450K or IlluminaEPIC bead-chip assays.Methods:We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity and sensitivity.Findings:Participants were 73 years old on average (standard deviation, SD=6), with moderate lead levels of (mean±SD patella:27±18 μg/g; tibia:21±13 μg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r=0.62 patella, r=0.59 tibia) and had low mean square error (MSE) (MSE=0.68 patella, MSE=0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p>0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74% and 73% for patella and tibia lead levels, respectively, with 70% sensitivity.Interpretation:DNA-methylation-based lead biomarkers are novel tools that can be used to reconstruct decades’ worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

Cocaine addiction severity exacerbates the negative association of lifetime lead exposure with blood pressure levels: Evidence from a pilot study.

Background:High blood pressure (BP) is associated independently with cocaine use and lead exposure. It is not known whether cocaine use and lead exposure act jointly to disrupt cardiovascular health.Objective:To determine whether cocaine use modifies the association between cumulative lead levels and elevated BP.Materials and Methods:We measured cumulative tibia lead levels in 35 adults: 20 with cocaine use disorder (CUD) and 15 non-CUD controls using in vivo K-shell X-ray fluorescence. Generalized estimating equation regression determined associations between log2-transformed lead and BP (systolic, diastolic, and mean arterial pressure) and assessed the modifying association of cocaine use (as addiction severity) on the lead-BP relationship, adjusting for age, sex, smoking, and education. Sensitivity analyses included correction for potential selection bias.Results:Cases and controls differed by sex (%male: 90% vs. 67%), age (50.7 vs. 39.9 years), education (12.8 vs. 14.4 years), and tibia lead (3.50 vs. 2.35 μg/g). Lead was positively associated with systolic (P = 0.01) and diastolic BP (P = 0.01). We observed an interaction between lead and addiction severity on BP (P values for systolic BP: 0.01, diastolic BP: 0.003, and mean arterial BP: <0.0001); the association was stronger among individuals with more severe cocaine addiction: Systolic BP: Est.: 17.89, 95% confidence interval (CI): 9.52; 26.26, diastolic BP Est.: 17.89, 95% CI: 7.33; 13.79, mean arterial BP: Est.: 13.09, 95% CI: 10.34; 15.83.Conclusions:Lead was adversely associated with BP. This association was strongest among individuals with more severe cocaine addiction. The results from this small pilot study suggest that the interaction between lead and cocaine should be considered in studies of substance abuse-related health outcomes.

Blood DNA Methylation Biomarkers of Cumulative Lead Exposure in Adults

Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels—validated measures of cumulative exposure—require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles—obtainable via Illumina 450K or IlluminaEPIC bead-chip assays. We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity. Participants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity. DNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades’ worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

Low-Level Cumulative Lead and Resistant Hypertension: A Prospective Study of Men Participating in the Veterans Affairs Normative Aging Study.

BackgroundBone lead offers a better method over blood lead measurement to discern long‐term lead exposure and accumulation. We examined the risk of resistant hypertension based on bone lead levels in a prospective cohort study of NAS (Normative Aging Study).Methods and ResultsParticipants had clinic data on hypertension (systolic blood pressure, diastolic blood pressure, and antihypertension medication), lead (blood, bone‐patella, bone‐tibia), and demographic and confounding variables. Cases of resistant hypertension were identified by meeting criteria for: (1) inadequate systolic blood pressure (>140 mm Hg) or diastolic blood pressure (>90 mm Hg) while taking 3 medications or (2) requiring >4 medications for blood pressure control. A modified Poisson regression was used for model analysis. Of the 475 participants, 97 cases of resistant hypertension (20.4%) were identified. Among the cases of resistant hypertension, the median tibia and patella lead levels were 20 μg/g and 25 μg/g, respectively, while median tibia and patella lead levels were 20 μg/g and 27.5 μg/g, respectively, in participants without resistant hypertension. Tibia lead demonstrated a significant association with resistant hypertension (relative risk, 1.19; 95% confidence interval, 1.01–1.41 [P=0.04]) per interquartile range increase in tibia lead (13–28.5 μg/g). Patella lead was not associated with resistant hypertension (relative risk, 1.10; 95% confidence interval, 0.92–1.31 [P=0.31]) per interquartile range increase in patella lead (18–40 μg/g). Blood lead levels were not significantly associated with resistant hypertension (relative risk, 1.11; 95% confidence interval, 0.88–1.40 [P=0.38]).ConclusionsTibia lead represents a novel risk factor for resistant hypertension. Our study demonstrates an increased association between tibia lead and resistant hypertension status, with an increased risk of 19% per 1 interquartile range increase in tibia lead.

Dietary patterns, bone lead and incident coronary heart disease among middle-aged to elderly men

BackgroundMost absorbed lead ends up in the bone, where it can be measured as a biomarker of cumulative exposure, elevations of which have been shown to predict a higher risk of coronary heart disease (CHD). Knowledge about the role of dietary patterns is critical to the development of effective interventions for the cardiovascular toxicity of cumulative lead exposure. Methods594 men, free of CHD at baseline, were followed from August 1991 to June 2011 in the Normative Aging Study. Bone lead concentrations were measured by K-shell-X-ray fluorescence. Dietary patterns were identified using principal components analysis. Two dietary patterns were identified: a ‘prudent’ pattern characterized by high intake of fruit, vegetables, legumes, tomatoes, poultry, and seafood; and a ‘Western’ pattern, with high intake of red meat, processed meat, refined grains, high-fat dairy products, high-energy drinks, fries, butter and eggs. Cox proportional hazard models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. Effect modification on the multiplicative scale was examined through cross-product interaction terms. Results137 men developed incident CHD events during 5071 person-years of follow-up. After adjusting for age, body mass index, total energy intake, smoking status, total cholesterol to high-density lipoprotein ratio, education and occupation, an HR of incident CHD was 1.64 (95% CI: 1.27–2.11) with each doubling in patella lead concentration in the low prudent diet group (< median prudent score); and the HR decreased to 1.07 (95% CI: 0.86–1.34) in the high prudent diet (≥ median prudent score) (p-for-interaction = 0.01), suggesting protective effects of prudent diet against lead-related CHD. By contrast, the association between tibia lead and CHD was non-significantly larger in the low Western diet group (HR = 1.43, 95% CI: 1.14–1.80) compared with the high Western diet group (HR = 1.08, 95% CI: 0.86–1.34) (p-for-interaction = 0.06). No significant effect modifications were detected by Western diet in the patella lead-CHD association and by prudent diet in the tibia lead-CHD association. ConclusionsPrudent diet may reduce the risk of development of CHD in relation to patella lead. However, these findings need to be interpreted with caution, given the modest sample size.

Association of Lead Exposure on Cognitive Decline due to Mediation and Interaction with Uric Acid

BACKGROUND: Low-level cumulative lead exposure has been associated with cognitive decline in adults. Previous studies suggest that lead increases levels of the antioxidant uric acid and that uric acid may also predict changes in cognitive function. We explored whether uric acid mediated or interacted with lead in the association between lead exposure and cognitive decline.METHODS: From 1991 to 2002, a subset of the Normative Aging Study cohort of community-dwelling men was assessed for cumulative lead exposure in the tibia and patella bones. The Mini-Mental State Examination (MMSE) was administered as a test of global cognition starting in 1992. We conducted formal mediation analysis using the first bone lead measurement, uric acid concurrent with baseline MMSE, and the difference between the second and baseline MMSE scores, adjusted for age at baseline MMSE, education, serum creatinine, smoking status and pack-years, drinking status, and years between the two MMSE tests.RESULTS: 552 men [mean (standard deviation) age: 67.27 (6.52)] took two MMSE tests that were 3.92 (1.80) years apart and had valid bone lead measurements. The total change in MMSE score for an interquartile range (20 µg/g) increase in patella lead was -0.29 (95% confidence interval: -0.49, -0.08) (p&amp;#61;0.007), due mostly to the direct association with lead [-0.25 (-0.44, -0.06) (p&amp;#61;0.01)] when uric acid was set to the mean value; the component due to interaction only was -0.03 (-0.07, 0.004) (p&amp;#61;0.08), due to mediation and interaction was 0.02 (-0.001, 0.05) (p&amp;#61;0.06), and due to mediation only was -0.03 (-0.07, 0.01) (p&amp;#61;0.20). Results with tibia lead were less robust.CONCLUSIONS: Prior studies have indicated significant effects of patella lead on cognitive decline, but accounting for uric acid may be needed to understand the full association between lead and cognitive decline.

Bone Lead Associations with Blood Lead, Kidney Function, and Blood Pressure among U.S. Lead-Exposed Workers in a Surveillance Program

Background: Measurements of lead in bone represent cumulative exposure which, in many studies, has been more strongly associated with lead effects than blood lead (BL), which represents recent exposure. Aim: Determine whether maximum BL in the past is correlated with current bone lead and compare associations of bone lead with kidney function and blood pressure (BP) among workers. Methods: Adult men in a lead surveillance program living within 200 miles of New York City were enrolled during 2016-2017. Participants had tibia lead measured via K-shell X-ray fluorescence, BP taken, and blood drawn to measure BL and estimated glomerular filtration rate (eGFR). Maximum past BL was obtained from occupational surveillance programs (mean year first BL 1997). eGFR was calculated using serum creatinine and cystatin C. Multivariable linear and logistic regression models were used to determine associations with bone lead. Systolic and diastolic BP models excluded participants taking BP medicine. Results: Among 211 participants, median (interquartile range) bone lead, current BL, and maximum past BL were 13.8 (9.4-19.5) mg of lead per gram of bone mineral, 2.5 (1.5-4.4) mg/dl, and 29.0 (14.0-38.0) mg/dl, respectively. Maximum past BL, but not current blood lead, significantly predicted current bone lead in adjusted analyses (p&amp;lt;0.0001, model R-square&amp;#61;0.27). In adjusted models, bone lead was moderately associated with low eGFR (bone lead odds ratio and 95% CI per 10 mg of bone lead for eGFR&amp;lt;60 &amp;#61; 1.34 [0.97-1.87]; the regression coefficient and p-value for continuous eGFR was also significant [p&amp;#61;0.05], model R-square&amp;#61;0.29). Bone lead in adjusted analyses was associated with increased systolic BP (regression coefficient&amp;#61;0.36, p&amp;#61;0.02, model R-square&amp;#61;0.16). There were no associations between current blood lead and eGFR or BP. Conclusion: Bone lead was significantly correlated with past maximum BL and was associated with modest decreases in eGFR and increases in systolic BP.

Prenatal lead exposure modifies the association of maternal self-esteem with child adaptive ability.

A child's adaptive ability is important for personal career and social development. Maternal self-esteem may help shape a child's behavior. This study aims to investigate whether maternal self-esteem measured when their children were toddlers predicts their children's adaptive skills at school age, and whether prenatal lead exposure modifies such a relationship. We assessed prenatal lead exposure using cord blood lead and maternal bone lead around delivery (tibia and patella lead measured in vivo by K-x-ray-fluorescence) among 192 mother-child pairs investigated in Mexico from 1994 to 2011. Maternal self-esteem was measured using the Coopersmith-Self-esteem-Inventory when children were 2 years old. When children were 7-to-15 years old, we measured children's blood lead levels and administered the 2nd edition of Behavior-Assessment-System-for-Children (BASC-2) parent-rating-scales (PRS) and Self-Reports of Personality (SRP) to evaluate children's adaptive skills. Median (P25, P75) values for maternal patella and tibia lead, cord blood lead and children's current blood lead levels were 12.6 (3.2, 21.7) μg/g, 10.2 (4.1, 16.0) μg/g, 5.5 (3.5, 8.1) μg/dL and 2.7 (2.0, 4.0) μg/dL, respectively. In adjusted models, increased maternal self-esteem was associated with increased adaptive T-scores on the BASC-2 PRS and SRP scales. This relationship was weaker in high prenatal lead-exposure groups (high cord blood lead or patella lead groups, P25P100) compared with low prenatal lead-exposure (low cord blood lead or patella lead groups, P1P25) groups (P-interaction values < 0.10). No significant interactions between maternal tibia lead and self-esteem on children's adaptive T-scores were observed (P-interaction values > 0.10). Toddlers of mothers with high (vs. low) self-esteem have better adaptive abilities when they are of school-age. Prenatal lead exposure may attenuate or eliminate this positive association.

Bone Lead Levels and Risk of Incident Primary Open-Angle Glaucoma: The VA Normative Aging Study.

Background:Oxidative stress may play an important role in the etiology of primary open-angle glaucoma (POAG). The association between risk of POAG and lead exposure, which is an environmental source of oxidative stress, has not been fully investigated yet.Objective:Our objective was to determine the association between bone lead—a biomarker of cumulative lead dose (tibia lead) or an endogenous source of stored lead (patella lead)—and incident POAG.Methods:We examined a prospective cohort of 634 POAG-free men [mean baseline y of age ()] from the Normative Aging Study (NAS) who had tibia and patella K X-ray fluorescence lead measurements between 1 January 1991 and 31 December 1999. They also had standard ocular evaluations by NAS optometrists until 31 December 2014. POAG cases were identified by consistent reports of enlarged or asymmetric cup-to-disc ratio together with visual field defect or existence of disc hemorrhage. We used Cox proportional hazards regressions to estimate hazard ratios (HRs) of incident POAG and adjusted survival curves to examine changes in the risk of POAG during follow-up according to bone lead quartiles.Results:We identified 44 incident cases of POAG by the end of follow-up (incidence per 10,000 person-years; median y). In fully adjusted models, 10-fold increases in patella lead and tibia lead were associated with HRs of 5.06 (95% CI: 1.61, 15.88, ) and 3.07 (95% CI: 0.94, 10.0, ), respectively. The HRs comparing participants in the third and fourth quartiles with the lowest quartile were 3.41 (95% CI: 1.34, 8.66) and 3.24 (95% CI: 1.22, 8.62) for patella lead (), and 3.84 (95% CI: 1.54, 9.55) and 2.61 (95% CI: 0.95, 7.21) for tibia lead ().Conclusions:Our study provides longitudinal evidence that bone lead may be an important risk factor for POAG in the U.S. population. https://doi.org/10.1289/EHP3442

Abstract 134: Does Low-Level Cumulative Lead Play a Role in Resistant-Hypertension?

Purpose: Deposition of lead into bone offers a better method over conventional blood lead measurement to discern long-term lead exposure and its insidious accumulation within the body. Bone lead deposition has been identified as an independent risk factor for hypertension (HTN). Yet, little is known how bone lead as a risk factor for HTN can be translated into clinical utility. We examined the association between bone lead levels and resistant-HTN. Methods: All subjects were males, participating in the Veterans Affairs Normative Aging Study (NAS) with an age variation of 48-93 years old. Participants were included if there was complete data on HTN (systolic blood pressure, diastolic blood pressure, and anti-HTN medication), lead (blood, bone-patella, bone-tibia), as well as demographic and confounding variables. Cases of resistant-HTN were identified by meeting criteria for a) inadequate SBP (≥140 mmHg) or DBP (≥90 mmHg) on 3 medications or b) requiring ≥ 4 medications for blood pressure control. Resistant-HTN was categorized as a dichotomous variable, based upon meeting the noted criteria, while tibia and patella bone lead were treated as continuous variables. The data was analyzed using a binomial logistic regression, accounting for demographic and confounding variables. Results: Of the 871 total study participants, 111 cases of resistant-HTN (12.7%) were identified. Amongst the cases of resistant-HTN, the mean tibia and patella lead levels were 23.1 μg/g and 31.5 μg/g, respectively. Both mean levels were higher than those among the participants without resistant-HTN (21.5 μg/g and 30.9 μg/g, respectively). Tibia lead levels demonstrated a significant association with resistant-HTN (OR=1.27 (95% CI, 1.01-1.59) per one IQR increase in tibia lead (15μg/g), p=0.04) after adjusting for age, BMI, cigarette pack-year burden, income, education, and ethnicity. A weak, non-significant association was observed between patella lead and resistant-HTN (OR = 1.16 (95% CI, 0.92-1.46) per one IQR increase in patella lead (21μg/g), p=0.21). Conclusion: Lead has been long-studied for its effect on blood pressure. Yet, lead has not previously been assessed for the role it plays in clinical outcomes. Difficulty in attaining goal blood pressure may be influenced by environmental exposures. Our study demonstrates an increased association between tibia lead and resistant-HTN status, with an OR of 1.27 per one IQR increase in tibia lead. Tibia lead represents a novel risk factor for resistant-HTN. Future research should consider screening and mitigation strategies for populations with resistant-HTN exposed to long-term low-levels of lead.

The decrease in population bone lead levels in Canada between 1993 and 2010 as assessed by in vivo XRF

Objective and Approach: A study, conducted in Toronto, Canada, between 2009 and 2011, measured the bone lead concentrations of volunteers aged 1–82 years using in vivo x-ray fluorescence (XRF) technology. Main results: Bone lead levels were lower compared to Ontario in vivo XRF studies from the early 1990s. In adults, the slope of tibia lead content versus age was reduced by 36–56%, i.e. bone lead levels for a given age group were approximately half compared to the same age group 17 years prior. Further, bone lead levels of individuals fell over that time period. In 2010, an average person aged 57 years had a bone lead level approximately 1/3 less than their bone lead level age 40 years in 1993. Using this data, the half-lives of lead in the tibia were estimated as 7–26 years. Tibia lead levels were found to be low in children. The reduction in bone tibia content in children was not significant (p = 0.07), but using data from additional north eastern US studies, there is evidence that childhood tibia stores are lower than in the 1990s. Significance: In vivo XRF analysis shows that there has been a reduction in the level of lead in bone in Canada over the last two decades. Public health measures have been very successful in reducing ongoing exposure to lead and in reducing bone lead stores.

A Western Diet Pattern Is Associated with Higher Concentrations of Blood and Bone Lead among Middle-Aged and Elderly Men

Background: Little is known about the effects of overall dietary pattern on lead concentration.Objective: We examined the association of overall dietary patterns, derived from a semiquantitative food frequency questionnaire, with bone and blood lead concentrations.Methods: These longitudinal analyses included mostly non-Hispanic white, middle-aged-to-elderly men from the Veterans Affairs Normative Aging Study. Long-term lead exposures were measured as tibia and patella lead concentrations by using K-shell-X-ray fluorescence. Short-term lead exposures were measured as blood lead concentrations by using graphite furnace atomic absorption spectroscopy. Dietary pattern scores were derived by using factor analysis. Linear mixed-effects models were utilized to predict blood lead concentrations among 983 men, aged 44-92 y at baseline, with a total of 3273 observations (during 1987-2008). We constructed linear regression models to determine the relations between dietary patterns and bone lead concentrations among 649 participants with an age range of 49-93 y.Results: Two major dietary patterns were identified: a prudent dietary pattern, characterized by high intakes of fruit, legumes, vegetables, whole grains, poultry, and seafood; and a Western dietary pattern, characterized by high intakes of processed meat, red meat, refined grains, high-fat dairy products, French fries, butter, and eggs. After adjusting for age, smoking status, body mass index, total energy intake, education, occupation, neighborhood-based education and income level, men in the highest tertile of the Western pattern score (compared with the lowest) had 0.91 μg/dL (95% CI: 0.41, 1.42 μg/dL) higher blood lead, 5.96 μg/g (95% CI: 1.76, 10.16 μg/g) higher patella lead, and 3.83 μg/g (95% CI: 0.97, 6.70 μg/g) higher tibia lead. No significant association was detected with the prudent dietary pattern in the adjusted model.Conclusions: These findings suggest that the Western diet is associated with a greater lead body burden among the middle-aged-to-elderly men. More studies are needed to examine the underlying mechanisms by which dietary patterns are associated with lead concentrations.