Cumulative Lead Research Articles

Telomere length in peripheral leukocytes is a sensitive marker for assessing genetic damage among workers exposed to isopropanol, lead and noise: the case of an electronics manufacturer

BackgroundWorkers in electronics manufacturers may be exposed to various occupational hazards such as isopropanol, lead, and noise. Telomeres are special segments of cap-like DNA protein complex at end of liner chromosomes in eukaryotic cells. Telomere length is a potential marker of genetic damage. The aim of this study is to evaluate the effect of occupational hazards on the relative telomere length (rTL) of peripheral blood cells of workers in an electronics manufacturer, and to explore whether relative telomere length could be a biomarker for assessing genetic damage in the electronics manufacturing industry.MethodsWe investigated a large-scale electronics manufacturer in the Pearl River Delta Region. We ultimately collected 699 qualified workers (248 with isopropanol exposure, 182 with lead exposure, 157 with noise exposure, and 112 controls). During physical examination of the workers, we gave them questionnaires to understand their health statuses and living habits. We also collected peripheral blood samples from these workers to test exposure levels and rTL in the leucocytes.ResultsThe concentrations of air isopropanol in all monitored workshops was 25.3 mg/m3 and air lead smoke was 0.020 mg/m3. The maximum equivalent continuous A sound level noise exposure position was 82.2dB (A). All were lower than those in the Occupational Exposure Limits in Workplaces in China. Urinary acetone in the isopropanol exposed group was 1.04 (0, 1.50) mg/L, and cumulative urinary acetone was 1.48 (0, 5.09) mg-years/L. Blood lead levels (BLLs) were 28.57 (22.77, 37.06) µg/dL, and cumulative blood lead levels (CBLLs) were 92.75 (55.47, 165.13) µg-years/dL. rTL was different between occupational exposed workers and controls: rTL was 0.140 units (95 % CI: 0.022, 0.259) shorter in lead exposed workers and 0.467 units (95 % CI: 0.276–0.658) shorter in noise exposed workers compared to the controls. There is no statistical difference in rTL between isopropanol exposure workers and the controls. In order to elucidate the relationship between rTL and occupational hazards exposure, we divided the isopropanol exposure workers into three groups (0, ~1.43 mg/L, and >1.43 mg/L). None of the rTL difference was statistically significant among exposed workers at different uroacetone levels (P>0.05).The groups with ≥100 µg/dL blood lead had shorter rTL than the group with blood lead below 100 µg/dL (F=4.422, P=0.013). We incorporated age, gender, birthplace, race, education level, smoking, and alcohol consumption into the linear regression equation. Only blood lead concentration (X) was entered into the regression equation, yielding a multivariate linear regression equation of Y=0.397-0.124X (F=8.091, P=0.005). Workers with different hearing loss also had statistically significant differences in rTL (F=5.731, P=0.004). rTL was a protective factor for the occurrence of noise-induced hearing loss (NIHL). The longer the rTL, the lower the risk of NIHL [OR=0.64 (0.42, 0.98)].ConclusionsrTL was shorter in lead exposed workers and noise exposed workers, and it was a protective factor for the occurrence of the noise-induced hearing loss. Thus, rTL of peripheral blood may be a sensitive marker of genetic damage among workers in environments with lead and noise exposure.

Early-life exposure to lead and antisocial behaviors during childhood and adolescence

BACKGROUND AND AIM: An association between lead (Pb) exposure and antisocial behaviors has been documented over the last decades, but the findings have been inconsistent. We aimed to estimate the association between prenatal, early-childhood, and preadolescent/adolescent (periadolescent) Pb exposure, and aggression and conduct problems in periadolescents of Mexico City. METHODS: We studied participants from the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohorts. We used 1) maternal patella Pb at puerperium as a proxy for prenatal Pb exposure, 2) cumulative blood lead index (a summary of repeated blood Pb (BPb) measurements) between birth and 60 months of age as a measure of early-childhood Pb exposure, and 3) a single BPb measurement concurrent with behavioral evaluation as a measure of periadolescent Pb exposure. The parent-reported scales of aggression and conduct problems of the Behavioral Assessment System for Children-2nd version (BASC-2) were evaluated during periadolescence (at a mean age of 10.38 years). We estimated the association between Pb exposure at each stage and having obtained an elevated T-score (≥60) in each scale, while adjusting for household socioeconomic status, maternal education and age at delivery, child sex, and Pb exposure at previous stages. RESULTS:743, 704, and 595 participants were included in the models for prenatal, early-childhood, and periadolescent Pb exposure, respectively. On average, mothers had 10.6 years of education, and were 26.3 years old at delivery. 49% of children were female. A one-unit increase in Pb exposure during the prenatal period (1 µg/g of maternal patella Pb), but not during childhood or periadolescence, was associated with increased odds of aggression (Odds Ratio (OR)=1.021; 95% Confidence Interval (CI): 1, 1.041) and conduct problems (OR=1.019; 95% CI: 1.002, 1.037) CONCLUSIONS:Exposure to Pb during the prenatal stage, but not during childhood or adolescence, was associated with aggression and conduct problems during periadolescence in this longitudinal cohort study. KEYWORDS: Heavy metals, Neurodevelopmental outcomes, Children's environmental health

Cumulative Lead Exposure Resulting from Coal Power Plants in India

BACKGROUND AND AIM: Coal pollution can lead to a myriad of toxic exposures and toxicity resulting from coal power generation has not been well-defined. As part of this study, we sought to identify cumulative lead exposure measured as bone lead in communities living near coal power plants. METHODS: We chose three communities at 1 km (n=50), 9 km (n=50), and 38 km (n=50) from coal power plants near Chennai, India and measured their bone lead using a portable x-ray fluorescence device. RESULTS:The bone lead identified in all participants was significantly higher than that found in typical occupationally exposed populations in the United States. We identified a dependency on location with the community living within 1 km of coal power plants experiencing higher cumulative lead exposure than the community farthest from the coal power plants. Lead exposure decreased at a rate of 0.92 ug/g/km. From our models, a 40-year-old adult at 1 km from a coal power plant would have an average bone lead level of 22.3 ug/g, whereas a 40-year-old at 10 km would have an average bone lead level of 14.3 ug/g. Further, we identified a population of over 704,185 that would be living in communities within 1 km of a coal power plant, equivalent to our highest exposure group. CONCLUSIONS:Our study was the first to identify a relationship between cumulative lead exposure and coal pollution, demonstrating a dramatic increase in lead exposure for communities near coal power plants. The community within 1 km of the coal power plants experienced bone lead on average 1.5 times higher than our control group. The control group had higher cumulative lead exposure than typical occupational exposures in the United States. These exposures would lead to drastic consequences throughout the body including cardiovascular and neurologic health impacts while ultimately increasing mortality from all causes. KEYWORDS: Coal, lead, cumulative, xrf, India, bone lead

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.

Association between cumulative childhood blood lead exposure and hepatic steatosis in young Mexican adults

BackgroundExposure to environmental toxicants may play a role in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD). Cumulative exposure to lead (Pb) has chronic and permanent effects on liver function. Pediatric populations are vulnerable to the toxic effects of Pb, even at low exposure levels. The purpose of the study was to estimate the association between cumulative Pb exposure during childhood and hepatic steatosis biomarkers in young Mexican adults. MethodsA subsample of 93 participants from the ELEMENT cohort were included in this study. Childhood blood samples were collected annually from ages 1–4 years and were used to calculate the Cumulative Childhood Blood Lead Levels (CCBLL). Hepatic steatosis during adulthood was defined as an excessive accumulation of hepatic triglycerides (>5%) determined using Magnetic Resonance Imaging (MRI). Liver enzymes were also measured at this time, and elevated liver enzyme levels were defined as ALT (≥30 IU/L), AST (≥30 IU/L), and GGT (≥40 IU/L). Adjusted linear regression models were fit to examine the association between CCBLL (quartiles) and the hepatic steatosis in young adulthood. ResultsIn adulthood, the mean age was 21.4 years, 55% were male. The overall prevalence of hepatic steatosis by MRI was 19%. Elevate levels of the enzymes ALT, AST, and GGT were present in 25%, 15%, and 17% of the sample, respectively. We found a positive association between the highest quartile of CCBLL with the steatosis biomarkers of hepatic triglycerides (Q4 vs. Q1: β = 6.07, 95% CI: 1.91–10.21), elevated ALT (Q4 vs. Q1: β = 14.5, 95% CI: 1.39–27.61) and elevated AST (Q4 vs. Q1: β = 7.23, 95% CI: 0.64–13.82). No significant associations were found with GGT. ConclusionsChronic Pb exposure during early childhood is associated with a higher levels of hepatic steatosis biomarkers and hepatocellular injury in young adulthood. More actions should be taken to eliminate sources of Pb during the first years of life.

Associations of blood lead levels with multiple genotoxic biomarkers among workers in China: A population-based study.

Carcinogenic effects from low doses of lead (Pb) exposure to populations have been suspected but not concluded. Therefore, a large-scale cross-sectional study was conducted by us to investigate genotoxic effects from Pb exposure during 2016-2018 in North China. Blood lead levels (BLLs) and cumulative blood lead levels (CBLLs) were measured. Multiple relevant biomarkers were used to assess genotoxicity of Pb: mitochondrial DNA copy number (mtDNAcn, n=871), Comet Tail Intensity (n=872), γ-H2AX (n=345), relative telomere length (rTL, n=757), micronuclei (MN, n=934) and phosphatidylinositol glycan class A mutation (PIG-A, n=362). The BLL data show right-skewed distribution, with increase of the median (P25, P75) from 17.4 (8.9, 26.4) μg/dl in 2016 to 18.5 (10.5, 27.2) μg/dl in 2017, and to 20.8 (11.3, 31.0) μg/dl in 2018. Multivariate regression analyses show that mtDNAcn was non-linearly associated with BLLs or CBLLs, i.e. decreased at low levels but increased at the higher levels. Comet and Micronuclei data show positive dose-response relationships with BLLs as well as CBLLs. γ-H2AX data show an overall increased trend with BLLs while rTL data show a shortening trend. No associations were found for PIG-A mutation with Pb exposure. Our findings indicate that current low dose exposure to Pb can still cause health hazards to occupational populations, and the mechanism may be via the induction of DNA & chromosome damage rather than via the mutagenesis pathway.

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.

A Prospective Study of Cumulative Lead Exposure Following Pregnancy and Bone Composition among Women of the Early Life Exposure to Environmental Toxicants (ELEMENT) Mexico City Cohort

Background: Recent epidemiologic and basic science research indicates lead may negatively impact long term bone composition. To our knowledge, there are no longitudinal studies in women of the association between lead in bone (PbB) and bone composition: mineral density (BMD) and organic matrix (OM). Furthermore, this association could be modified by obesity, previously linked to increased BMD.Methods: We measured PbB in patella (trabecular-T) and tibia (cortical-C), by K x-ray fluorescence (KXRF) at one year postpartum among 101 women participating in ELEMENT between 1994-2004. In 2017 we performed iDXA scans to analyze body composition and determine z-scores of BMD of the lumbar spine (T) and femur (C) and Speed of Sound-MiniOmni scans to obtain OM z-scores of radius (T) and tibia (C) bone. Obesity was defined as a BMI of >=30. We examined the association between PbB exposure (patella and tibia in separate models) and z-scores for the 4 bone z-scores (BMD and SOS) simultaneously using multivariate models adjusted for BMI, parity and menopause status, and subsequently stratified by obesity. Results: Patella PbB had a mean (SD) of 13.36 (11.30) µg lead/g bone mineral and tibia PbB of 10.97 (8.47) µg lead/g bone mineral. Mean (SD) BMD Z-scores were lumbar spine -0.17 (1.14), femur 0.77 (0.95); and for OM: radius -0.38 (1.47), tibia 0.34 (1.28). Overall, tibia PbB was negatively associated with all bone z-scores except lumbar spine, however there was no statistical significance. There was a strong negative association between BMI and z-scores for OM and lumbar spine BMD, but positive for femur BMD. In stratified models tibia PbB was negatively associated with tibia BMD (-0.05 (95% CI:-0.09, -0.01) in non-obese women (n=57), but not in obese women.Conclusions: PbB may have a long-term negative impact on lower BMD in cortical bone, with obesity masking the association.

Echocardiographic findings in patients with cardiac implantable electronic devices-analysis of factors predisposing to lead-associated changes.

The constant interaction between intracardiac leads and the heart and veins results in excessive accumulation of fibrous connective tissue around the leads. The extent of this pathological phenomenon, which is visible on transesophageal echocardiography (TEE), and predisposing factors are not well defined. We examined 936 transesophageal echocardiograms prior to transvenous lead extraction (TLE) performed at a high-volume centre between 2015 and 2019. The most important echocardiographic findings were fibrous binding sites between leads and cardiovascular structures, lead-to-lead adhesions, excessive lead loops, lead-dependent tricuspid dysfunction (LDTD), asymptomatic masses on endocardial leads (AMEL) and vegetations. Fibrotic reaction within the walls of the heart and veins correlated with the presence of lead loops (OR=1.771; p<.01) and lead dwell time (OR=1.111; p<.001). Women were more likely to have excessive lead loops (OR=1.639; p<.01), and the occurrence of loops increase with the number of implanted leads (OR=2.557; p<.001). Heart failure (OR=4.016; p<.001), lead looping (OR=2.603; p<.01) and longer cumulative lead dwell time (OR=1.017; p<.05) increased the likelihood of LDTD. A variety of AMEL were identified in this study, most commonly in patients with older leads (OR=1.043; p<.001). Lead dwell time is the main factor predisposing to the occurrence of most lead-associated phenomena visualized by TEE in patients with cardiac implantable electronic devices (CIED). Excessive looping of the lead is an important cause of fibrous binding sites and LDTD. AMEL are frequently detected in CIED patients, and their various forms concurrent with vegetations could represent an evolutionary stage of lead-associated masses.

The association of blood lead levels and renal effects may be modified by genetic combinations of Metallothionein 1A 2A polymorphisms

Metallothionein (MT) is a protein with function of heavy metal detoxification. However, studies about how single nucleotide polymorphisms (SNPs) of MT genes influence lead nephropathy are relatively scarce. Therefore, our aim is to investigate the association between blood lead levels and renal biomarkers and to study whether this association is influenced by the combination of MT1A and MT2A SNPs. Blood lead, urinary uric acid (UA), and urinary N-acetyl-beta-d-glucosaminidase (NAG) levels were analyzed from 485 participants. Genotyping were performed on MT1A SNPs (rs11640851 and rs8052394) and MT2A SNPs (rs10636 and rs28366003). The combined MT1A 2A SNPs were divided into 16 groups. Among renal biomarkers, urinary UA was negatively significant associated with the time-weighted index of cumulative blood lead (TWICL), while urinary NAG was positively significant with TWICL. Furthermore, the association between urinary UA and TWICL was significantly modified by group 6 of combined SNPs (MT1A 2 A SNPs combination were AAAGGGAA, ACAGGGAA, and ACGGGGAA). In conclusion, the negative association of urinary UA and TWICL is modified by group 6, which means participants of group 6 are more susceptible to lead nephrotoxicity.

Long-term longevity and clinical outcomes of Linox S/SD implantable cardioverter-defibrillator leads: a single-center experience.

Since the introduction of the Biotronik Linox S/SD leads in 2006, there have been multiple reports of premature lead failure. The purpose of this study was to investigate the longevity of the Linox S/SD leads and to identify the possible predictors of lead failure in a single tertiary implant center. We retrospectively reviewed patients who underwent implantation of Linox S/SD leads or Sorin Vigila 1CR/2CR leads (the same Linox S/SD leads marketed by Sorin) at our center. The cumulative lead survival was estimated using the Kaplan-Meier curve, and variables associated with lead failure were assessed by Cox proportional hazard model. A total of 187 patients (154 (82%) male) underwent Linox S/SD or Vigila 1CR/2CR implantation between 2007 and 2013. During follow-up with a median time of 75months, nine lead failures were identified (4.8%). The mean and median times from lead implantation to lead failure were 70.7 ± 21months and 64 (45-111) months, respectively. The cumulative survival probability for the Linox S/SD at 5years was 97.1% and at 12years was 90.3%. Non-physiological high-rate sensing was the most common type of lead failure in patients. In two-thirds of these patients, this led to inappropriate shock. We did not find any significant relationships between patients' clinical and procedural characteristics and lead failure. At our center, the 5-year lead survival of the Linox S/SD has been better than reports from other centers. The majority of lead failures presented as non-physiological high-rate sensing with subsequent inappropriate therapy.

PIG-A gene mutation as a genotoxicity biomarker in human population studies: An investigation in lead-exposed workers.

The rodent Pig-a gene mutation assay has demonstrated remarkable sensitivity in identifying in vivo mutagens, while much less is known about the value of the human PIG-A assay for risk assessment. To obtain more evidence of its potential as a predictive biomarker for carcinogen exposure, we investigated PIG-A mutant frequencies (MFs), along with performing the Comet assay and micronucleus (MN) test, in 267 workers occupationally exposed to lead. Multivariate Poisson regression showed that total red blood cell PIG-A MFs were significantly higher in lead-exposed workers (10.90 ± 10.7 × 10-6 ) than in a general population that we studied previously (5.25 ± 3.6 × 10-6 ) (p < .0001). In contrast, there was no increase in lymphocyte MN frequency or in DNA damage as measured by percentage comet tail intensity in whole blood cells. Current year worker blood lead levels (BLL), an exposure biomarker, were elevated (232.6 ± 104.6 μg/L, median: 225.4 μg/L); a cumulative blood lead index (CBLI) also was calculated based on a combination of current and historical worker BLL data. Chi-square testing indicated that PIG-A MFs were significantly related to CBLI (p = .0249), but independent of current year BLL (p = .4276). However, % comet tail intensity and MN frequencies were better associated with current year BLL than CBLI. This study indicates that the PIG-A assay could serve as biomarker to detect the genotoxic effects of lead exposure and demonstrates that a battery of genotoxicity biomarkers having mechanistic complementarity may be useful for comprehensively monitoring human carcinogenic risk.

Effects of Vitamin D Receptor, Metallothionein 1A, and 2A Gene Polymorphisms on Toxicity of the Peripheral Nervous System in Chronically Lead-Exposed Workers.

Chronic exposure to lead is neurotoxic to the human peripheral sensory system. Variant vitamin D receptor (VDR) genes and polymorphisms of metallothioneins (MTs) are associated with different outcomes following lead toxicity. However, no evidence of a relationship between lead neurotoxicity and polymorphisms has previously been presented. In this study, we investigated the relationship between the polymorphisms of VDR, MT1A, and MT2A genes and lead toxicity following chronic occupational lead exposure. We measured vibration perception thresholds (VPT) and current perception thresholds (CPT) in 181 workers annually for five years. The outcome variables were correlated to the subject’s index of long-term lead exposure. Polymorphisms of VDR, MT1A, and MT2A were defined. The potential confounders, including age, sex, height, smoking, alcohol consumption, and working life span, were also collected and analyzed using linear regression. The regression coefficients of some gene polymorphisms were at least 20 times larger than regression coefficients of time-weighted index of cumulative blood lead (TWICL) measures. All regression coefficients of TWICL increased slightly. MT1A rs11640851 (AA/CC) was associated with a statistically significant difference in all neurological outcomes except hand and foot VPT. MT1A rs8052394 was associated with statistically significant differences in hand and foot CPT 2000 Hz. In MT2A rs10636, those with the C allele showed a greater effect on hand CPT than those with the G allele. Among the VDR gene polymorphisms, the Apa rs7975232 (CC/AA) single nucleotide polymorphism was associated with the greatest difference in hand CPT. MT2A rs28366003 appeared to have a neural protective effect, whereas Apa (rs7975232) of VDR and MT2A rs10636 increased the neurotoxicity as measured by CPT in the hands. MT1A rs8052394 had a protective effect on large myelinated nerves. MT1A rs11640851 was associated with susceptibility to neurotoxicity.

The Medtronic Sprint Fidelis® lead history revisited-Extended follow-up of passive leads.

Due to high failure rates, Medtronic withdrew the Sprint Fidelis lead (SFL) from the market. Passive fixation lead models exhibited better survival than active models, but most studies have limited follow-up. Aim of this study was to give insights into passive lead survival with a follow-up of 10 years. In two large Swiss centers, patients with passive SFLs were identified and data from routine implantable cardioverter defibrillator (ICD) follow-ups were collected. Patients were censored at time of death, last device interrogation (if lost to follow-up), time of lead revision (in non-SFL-related problems), or at database closure (31th December 2017). We defined lead failure as any of the following: lead fracture with inappropriate discharge; sudden increase in low-voltage impedance to>1500 or high-voltage impedance to>100Ω;>300 nonphysiological short VV-intervals. We identified 145 patients. Age at implant was 60±12 years with a median follow-up of 10.2 (interquartile range [IQR]: 5.0-11.2) years. Thirty-five percent of patients died after 5.4±2.7 years. A total of 19 leads (13%) failed after 6.7±3.2 years (range: 1.2-12.0). Overt malfunction with shocks existed in four patients (3%). Cumulative lead survival was 93.1% at 6, 88.2% at 8, 83.8% at 10, and 77.6% at 11 years, respectively, with 35% of implanted leads under monitoring at 10 years. Lead survival fits best a Weibull distribution with accelerating failure rates (k=1.95, 95% CI 1.32-2.87, P<0.001). During very long-term follow-up, failure rate of the passive SFL shows an increase resulting in an impaired lead survival of 84% at 10 years.

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.

Cumulative Childhood Lead Levels in Relation to Sleep During Adolescence.

Lead exposure has been linked to adverse cognitive outcomes among children, and sleep disturbances could potentially mediate these relationships. As a first step, whether childhood lead levels are linked to sleep disturbances must be ascertained. Prior studies of lead and sleep are scarce and rely on parent-reported sleep data. The study population included 395 participants from the Early Life Exposure in Mexico to Environmental Toxicants project, a group of sequentially enrolled birth cohorts from Mexico City. Blood lead levels measured from ages 1 to 4 years were used to calculate a cumulative measure of early childhood lead levels. Average sleep duration, sleep fragmentation, and movement index were assessed once between the ages of 9 and 18 years with wrist actigraphs worn for a continuous 7-day interval. Linear regression models were fit with average sleep duration, fragmentation, or movement as the outcome and cumulative lead levels divided into quartiles as the exposure, adjusted for age, sex, and maternal education. Mean (standard deviation) age at follow-up was 13.8 (1.9) years, and 48% of participants were boys. Median (interquartile range) cumulative childhood lead level was 13.7 (10.8, 18.0) μg/dL. Patients in the highest quartile of the cumulative childhood lead group had on average 23 minutes less sleep than those in the first quartile in adolescence (95% confidence interval [7, 39]; P, trend = .02). Higher cumulative lead level was associated with higher sleep fragmentation in younger adolescents (younger than 14 years) only (P, interaction = .02). Shorter sleep duration may represent an as-yet unrecognized adverse consequence of lead exposure in youth.

Association between blood lead level and subsequent Alzheimer's disease mortality.

Background:Previous studies suggest that cumulative lead exposure is associated with cognitive decline, but its relation with Alzheimer’s disease (AD) remains unclear. Therefore, this study investigated the longitudinal association between blood lead level (BLL) and AD mortality.Methods:This study included 8,080 elders (60 years or older) with BLL data from the 1999 to 2008 US National Health and Nutrition Examination Survey. Mortality was determined from linked 1999–2014 National Death Index data. A causal diagram presented causal assumptions and identified a sufficient set of confounders: age, sex, poverty, race/ethnicity, and smoking. Cox proportional hazard models were used to determine the association between BLL and subsequent AD mortality. Impacts of competing risks and design effect were also assessed. Adjusted hazard rate ratio (HRR) and 95% confidence interval (CI) were reported.Results:Follow-up ranged from <1 to 152 months (median, 74). Eighty-one participants died from AD over 632,075 total person-months at risk. An increase in BLL was associated with an increase in AD mortality after adjusting for identified confounders. We estimated that those with BLL of 1.5 and 5 μg/dl had 1.2 (95% CI = 0.70, 2.1) and 1.4 (95% CI = 0.54, 3.8) times the rate of AD mortality compared to those with BLL of 0.3 μg/dl, respectively, after accounting for competing risks. Adjusted HRRs were 1.5 (95% CI = 0.81, 2.9) and 2.1 (95% CI = 0.70, 6.3), respectively, after considering design effect.Conclusions:This longitudinal study demonstrated a positive, albeit not statistically significant, association between BLL and AD mortality after adjustment for competing risks or design effect.

Case-control investigation of occupational lead exposure and kidney cancer

ObjectivesLead is a suspected carcinogen that has been inconsistently associated with kidney cancer. To clarify this relationship, we conducted an analysis of occupational lead exposure within a population-based study of...

Neurocognitive function in relation to blood lead among young men prior to chronic occupational exposure.

Objectives Higher than contemporary exposure levels and advanced age of study participants have limited the interpretation of previous studies relating neurocognitive function to lead exposure. We reassessed this association in young American men prior to chronic occupational exposure at lead recycling plants, using baseline measurements of the Study for Promotion of Health in Recycling Lead (NCT02243904). Methods We administered the Stroop test (ST) and the digit-symbol test (DST) to 339 men (mean age, 28.6 years; participation rate 82.7%). Whole blood lead (BL) was determined by inductively coupled plasma mass spectrometry and related ST and DST test results using multivariable-adjusted regression. Results Average values were 4.26 μg/dL for BL, 1624 ms and 1474 ms for mean reaction time in incongruent and congruent ST trials, and 109 sec for mean total latency in DST. The number of participants with fully correct answers amounted to 281 (82.9%) and 334 (98.5%) in incongruent and congruent ST trials, respectively, and to 198 (58.4%) in the DST. In multivariable-adjusted analyses, there was no association between cognitive performance and BL except for a weak but opposite association in DST; for a 10-fold BL increment, mean total latency was 5.4% (95% confidence interval, -0.4‒11.5%; P=0.066) higher, whereas the error score was 42% (-10‒69%; P=0.096) lower. To exclude an effect of the cumulative lead dose, sensitivity analyses restricted to workers <40, 35 and 30 years were confirmatory. Conclusions At the exposure levels in our current study, we failed to demonstrate a consistent inverse association of BL with neurocognitive performance in young American men.