Tibia Bone Lead Research Articles

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.

Could Lifetime Lead Exposure Play a Role in Limbic-predominant Age-related TDP-43 Encephalopathy (LATE)?

Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease in which the clinical presentation mimics that of Alzheimer's disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are today. Thus, each successive birth cohort entering old age has had less cumulative lifeime exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in conjunction with brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE.

Effect of Dietary Sodium and Potassium Intake on the Mobilization of Bone Lead among Middle-Aged and Older Men: The Veterans Affairs Normative Aging Study

Bone is a major storage site as well as an endogenous source of lead in the human body. Dietary sodium and potassium intake may play a role in the mobilization of lead from bone to the circulation. We examined whether association between bone lead and urinary lead, a marker of mobilized lead in plasma, was modified by dietary intake of sodium and potassium among 318 men, aged 48–93 years, in the Veterans Affairs (VA) Normative Aging Study. Dietary sodium and potassium were assessed by flame photometry using 24-h urine samples, and a sodium-to-potassium ratio was calculated from the resulting measures. Patella and tibia bone lead concentrations were measured by K-shell-x-ray fluorescence. Urinary lead was measured by inductively coupled plasma mass spectroscopy in 24-h urine samples. Linear regression models were used to regress creatinine clearance-corrected urinary lead on bone lead, testing multiplicative interactions with tertiles of sodium, potassium, and sodium-to-potassium ratio, separately. After adjustment for age, body mass index, smoking, vitamin C intake, calcium, and total energy intake, participants in the highest tertile of sodium-to-potassium ratio showed 28.1% (95% CI: 12.5%, 45.9%) greater urinary lead per doubling increase in patella lead, whereas those in the second and lowest tertiles had 13.8% (95% CI: −1.7%, 31.7%) and 5.5% (95% CI: −8.0%, 21.0%) greater urinary lead, respectively (p-for-interaction = 0.04). No statistically significant effect modification by either sodium or potassium intake alone was observed. These findings suggest that relatively high intake of sodium relative to potassium may play an important role in the mobilization of lead from bone into the circulation.

Lead Exposures and Psychological Symptoms

OPS 40: Metals: neurological effects, Room 412, Floor 4, August 28, 2019, 10:30 AM - 12:00 PM Background: Lead exposures have been associated with worse psychological symptoms in adults. Uric acid (UA) has potent antioxidant properties that could modify effects of exposures like lead. We evaluated whether UA modified the association between lead exposures and psychological symptoms. Methods: Biomarker measures of lead in bone (cumulative exposure) and blood (recent exposure) and psychological assessments were available for 793 men in the Normative Aging Study in 1991-2002. Self-reported psychological symptoms were evaluated with the Brief Symptom Inventory (BSI). We assessed global indices of distress and dimensions previously associated with lead exposures: global severity index (GSI), positive symptom total (PST), positive symptom distress index, anxiety, phobic anxiety, depression, somatization, and hostility, with responses greater than one standard deviation above the mean considered as high symptoms. Up to three BSI assessments were considered in repeated measures generalized estimating equations with lead biomarkers, UA, and their interaction, adjusted for age, education, smoking status, cumulative smoking, white collar job, marital status, alcohol intake, and serum creatinine, all assessed at baseline. Results: Participants were 68.0 (SD: 7.0) years old, and proportion of high symptoms ranged from 7.3% (phobic anxiety) to 14.9% (PST), at the baseline BSI assessment. Interactions between patella lead and UA were significant for all global indices and dimensions except hostility. Odds ratio for high GSI for an interquartile (20 µg/g) increase in patella bone lead was 1.36 (1.01-1.84) at the 25th percentile of UA and 1.00 (0.73-1.36) at the 75th percentile of UA. Interactions between tibia bone lead or blood lead and UA were not significant. Conclusions: UA modified the adverse association between patella bone lead and psychological symptoms such that the association was less pronounced at higher levels of UA. These results suggest that strategies involving antioxidants could potentially mitigate the detrimental effects of past lead exposures on psychological symptoms.

Effect of Dietary Sodium and Potassium Intake on the Mobilization of Bone Lead among Middle-aged and Older Men

Bone is a major storage site as well as an endogenous source of lead in the human body. Dietary sodium and potassium intake may play a role in the mobilization of lead from bone to the circulation. We examined whether association between bone lead and urinary lead, a marker of mobilized lead in plasma, was modified by dietary intake of sodium and potassium among 318 men, aged 48-93 years, in the Veterans Affairs (VA) Normative Aging Study. Dietary sodium and potassium were assessed by flame photometry using 24-h urine samples, and a sodium-to-potassium ratio was calculated from the resulting measures. Patella and tibia bone lead concentrations were measured by K-shell-x-ray fluorescence. Urinary lead was measured by inductively coupled plasma mass spectroscopy in 24-h urine samples. Linear regression models were used to regress creatinine clearance-corrected urinary lead on bone lead, testing multiplicative interactions with tertiles of sodium, potassium, and sodium-to-potassium ratio, separately. After adjustment for age, body mass index, smoking, vitamin C intake, calcium, and total energy intake, participants in the highest tertile of sodium-to-potassium ratio showed 28.1% (95% CI: 12.5%, 45.9%) greater urinary lead per doubling increase in patella lead, whereas those in the second and lowest tertiles had 13.8% (95% CI: -1.7%, 31.7%) and 5.5% (95% CI: -8.0%, 21.0%) greater urinary lead, respectively (p-for-interaction = 0.04). No statistically significant effect modification by either sodium or potassium intake alone was observed. These findings suggest that relatively high intake of sodium relative to potassium may play an important role in the mobilization of lead from bone into the circulation.

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.

APOE ε4 allele modifies the association of lead exposure with age-related cognitive decline in older individuals

BackgroundContinuing chronic and sporadic high-level of lead exposure in some regions in the U.S. has directed public attention to the effects of lead on human health. Long-term lead exposure has been associated with faster cognitive decline in older individuals; however, genetic susceptibility to lead-related cognitive decline during aging has been poorly studied. MethodsWe determined the interaction of APOE-epsilon variants and environmental lead exposure in relation to age-related cognitive decline. We measured tibia bone lead by K-shell-x-ray fluorescence, APOE-epsilon variants by multiplex PCR and global cognitive z-scores in 489 men from the VA-Normative Aging Study. To determine global cognitive z-scores we incorporated multiple cognitive assessments, including word list memory task, digit span backwards, verbal fluency test, sum of drawings, and pattern comparison task, which were assessed at multiple visits. We used linear mixed-effect models with random intercepts for individual and for cognitive test. ResultsAn interquartile range (IQR:14.23μg/g) increase in tibia lead concentration was associated with a 0.06 (95% confidence interval [95%CI]: −0.11 to −0.01) lower global cognition z-score. In the presence of both ε4 alleles, one IQR increase in tibia lead was associated with 0.57 (95%CI: −0.97 to −0.16; p-value for interaction: 0.03) lower total cognition z-score. A borderline association was observed in presence of one ε4 allele (Estimate-effect per 1-IQR increase: −0.11, 95%CI: −0.22, 0.01) as well as lack of association in individuals without APOE ε4 allele. ConclusionsOur findings suggest that individuals carrying both ε4 alleles are more susceptible to lead impact on global cognitive decline during aging.

Altered miRNA expression in the cervix during pregnancy associated with lead and mercury exposure.

Toxic metals including lead and mercury are associated with adverse pregnancy outcomes. This study aimed to assess the association between miRNA expression in the cervix during pregnancy with lead and mercury levels. We obtained cervical swabs from pregnant women (n = 60) and quantified cervical miRNA expression. Women's blood lead, bone lead and toenail mercury levels were analyzed. We performed linear regression to examine the association between metal levels and expression of 74 miRNAs adjusting for covariates. Seventeen miRNAs were negatively associated with toenail mercury levels, and tibial bone lead levels were associated with decreased expression of miR-575 and miR-4286. The findings highlight miRNAs in the human cervix as novel responders to maternal chemical exposure during pregnancy.

Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: The Normative Aging Study

IntroductionOlfactory dysfunction has been identified as an early warning sign for Alzheimer's disease, Parkinson's disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone. MethodsOlfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE). ResultsThe average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD=5.7) years. Mean tibia lead was 16.3 (SD=12.0)μg/g bone, mean patella lead was 22.4 (SD=14.4)μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD=7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15μg/g tibia lead: β=−1.57; 95% CI: −2.93, −0.22; p=0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE β=2.26; 95% CI: 0.09, 4.43; p=0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15μg/g tibia lead: β=−1.25; 95% CI: −2.64, 0.14; p=0.08) while the HFE term dropped 15% (β=1.91; 95% CI: −0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene–lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n=149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15μg/g tibia lead β=−1.39; 95% CI: −3.00, 0.22; p=0.09). ConclusionCumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene status may also affect olfactory function.

Lead exposure and tremor among older men: the VA normative aging study.

Background: Tremor is one of the most common neurological signs, yet its etiology is poorly understood. Case–control studies suggest an association between blood lead and essential tremor, and that this association is modified by polymorphisms in the δ-aminolevulinic acid dehydrogenase (ALAD) gene.Objective: We aimed to examine the relationship between lead and tremor, including modification by ALAD, in a prospective cohort study, using both blood lead and bone lead—a biomarker of cumulative lead exposure.Methods: We measured tibia (n = 670) and patella (n = 672) bone lead and blood lead (n = 807) among older men (age range, 50–98 years) in the VA Normative Aging Study cohort. A tremor score was created based on an approach using hand-drawing samples. ALAD genotype was dichotomized as ALAD-2 carriers or not. We used linear regression adjusted for age, education, smoking, and alcohol intake to estimate the associations between lead biomarkers and tremor score.Results: In unadjusted analyses, there was a marginal association between quintiles of all lead biomarkers and tremor scores (p-values < 0.13), which did not persist in adjusted models. Age was the strongest predictor of tremor. Among those younger than the median age (68.9 years), tremor increased significantly with blood lead (p = 0.03), but this pattern was not apparent for bone lead. We did not see modification by ALAD or an association between bone lead and change in tremor score over time.Conclusion: Our results do not strongly support an association between lead exposure and tremor, and suggest no association with cumulative lead biomarkers, although there is some suggestion that blood lead may be associated with tremor among the younger men in our cohort.Citation: Ji JS, Power MC, Sparrow D, Spiro A III, Hu H, Louis ED, Weisskopf MG. 2015. Lead exposure and tremor among older men: the VA Normative Aging Study. Environ Health Perspect 123:445–450; http://dx.doi.org/10.1289/ehp.1408535

Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study.

BackgroundAlthough the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness.MethodsWe examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements.ResultsAdjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1.ConclusionsThis study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-069X-14-5) contains supplementary material, which is available to authorized users.

Prenatal Lead Exposure and Blood Pressure in Children: Possible Effect Modification by Socioeconomic Status

Prenatal Lead Exposure and Blood Pressure in Children: Possible Effect Modification by Socioeconomic StatusAbstract Number:2309 Roman Pabayo*, Howard Hu, Aimin Zhang, Brisa Sanchez, Adrienne Ettinger, Karen Peterson, Sung Kyun Park, David Cantonwine, Lourdes Schnaas, Robin O. Wright, Hector Lamadrid-Figueroa, Martha Maria Tellez-Rojo Roman Pabayo* Harvard School of Public Health, United States, E-mail Address: [email protected] Search for more papers by this author , Howard Hu Dalla Lana School of Public Health, University of Toronto, Canada, E-mail Address: [email protected] Search for more papers by this author , Aimin Zhang University of Michigan, School of Public Health, Department of Environmental Health Sciences, United States, E-mail Address: [email protected] Search for more papers by this author , Brisa Sanchez University of Michigan, School of Public Health, Department of Biostatistics, United States, E-mail Address: [email protected] Search for more papers by this author , Adrienne Ettinger Yale School of Public Health, Department of Epidemiology, United States, E-mail Address: [email protected] Search for more papers by this author , Karen Peterson University of Michigan, School of Public Health, Department of Environmental Health Sciences, United States, E-mail Address: [email protected] Search for more papers by this author , Sung Kyun Park University of Michigan, School of Public Health, Department of Environmental Health Sciences, United States, E-mail Address: [email protected] Search for more papers by this author , David Cantonwine University of Michigan, School of Public Health, Department of Environmental Health Sciences, United States, E-mail Address: [email protected] Search for more papers by this author , Lourdes Schnaas Division of Public Health, National Institute of Perinatology, Mexico City, Distrito Federal, Mexico Search for more papers by this author , Robin O. Wright Mount Sinai Hospital Search for more papers by this author , Hector Lamadrid-Figueroa Division of Statistics, Center for Evaluation Research and Surveys, National Institute of Public Health Search for more papers by this author , and Martha Maria Tellez-Rojo Division of Statistics, Center for Evaluation Research and Surveys, National Institute of Public Health, E-mail Address: [email protected] Search for more papers by this author AbstractBackground: Cumulative environmental lead exposure to the fetus is a predisposing risk factor for higher blood pressure (BP) during childhood. We investigated whether Socioeconomic Status (SES) moderated the relationship between prenatal lead exposure and blood pressure in 7 to 15 year-old boys and girls.Methods: We evaluated 457 mother-child pairs, originally recruited for an environmental birth cohort study between 1994 and 2003 in Mexico City that comprise the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT), and at a follow-up visit in 2008-2010. Prenatal lead exposure was assessed by measurement of maternal tibia and patella bone and umbilical cord lead. A SES score was calculated using a wealth index, education of the mother, education of the father, and mother’s marital status. The median score was used as a threshold for low vs. high SES. Models for SBP and DBP were simultaneously fitted using generalized estimating equations. Analyses were stratified by sex and by the median of the SES score, marital status of the mother and by education.Results: After adjusting for socio-demographic and nutritional covariates, umbilical cord lead was significantly associated with SBP among boys from low SES backgrounds only. Among low SES boys, an interquartile range increase in umbilical cord lead was associated with 4.14-mm Hg [95% confidence interval (CI)=1.76, 6.52] increases in SBP. Tibia bone lead was associated with SBP among boys whose mothers do not have a post- secondary education (ß=2.07, 95% CI=0.13,4.00) only. Among girls whose mothers were single, an interquartile increase in tibia lead exposure was associated with a 1.86 mmHg (95% CI=0.08, 3.64) and 2.02-mmHg (95% CI: 0.37,3.68) increases in SBP and DBP, respectively.Conclusions: Lead exposure is associated with increased BP among children from low SES backgrounds. SES may be a proxy for another factor that may cause a biological vulnerability to lead that has an impact on BP.

Lead exposure and rate of change in cognitive function in older women

BackgroundHigher long-term cumulative lead exposure predicts faster cognitive decline in older men, but evidence of an association in women is lacking. ObjectiveTo determine if there is an association between lead exposure and cognitive decline in women. MethodsThis study considers a sample of 584 women from the Nurses' Health Study who live in or near Boston, Massachusetts. We quantified lead exposure using biomarkers of lead exposure assessed in 1993–2004 and evaluated cognitive decline by repeated performance on a telephone battery of cognitive tests primarily assessing learning, memory, executive function, and attention completed in 1995–2008. All cognitive test scores were z-transformed for use in analyses. We used linear mixed models with random effects to quantify the association between each lead biomarker and change in cognition overall and on each individual test. ResultsConsideration of individual tests showed greater cognitive decline with increased tibia lead concentrations, a measure of long-term cumulative exposure, for story memory and category fluency. The estimated excess annual decline in overall cognitive test z-score per SD increase in tibia bone lead concentration was suggestive, although the confidence intervals included the null (0.024 standard units, 95% confidence interval: −0.053, 0.004 – an additional decline in function equivalent to being 0.33 years older). We found little support for associations between cognitive decline and patella or blood lead, which provide integrated measures of exposure over shorter timeframes. ConclusionsLong-term cumulative lead exposure may be weakly associated with faster cognitive decline in community-dwelling women, at least in some cognitive domains.

Tibial Bone Lead, but Not Serum Polychlorinated Biphenyl, Concentrations Are Associated With Neurocognitive Deficits in Former Capacitor Workers

To determine the relationships between tibial bone lead and serum polychlorinated biphenyl (PCB) concentrations and neurocognitive function. The study population consisted of men and women former capacitor workers had been employed by the General Electric Corporation between 1946 and 1977. Regression analyses evaluated the association between neurocognitive function and lipid-adjusted serum PCB and tibia lead concentrations. Tibia lead, but not serum PCBs, was significantly correlated with deficits in neurocognitive function. Women showed more associations between tibia lead and neurocognitive function than men, especially regarding executive function. These results demonstrate that low levels of tibia lead, but not serum PCBs, are associated with neurocognitive deficits and that postmenopausal women show a greater number of deficits in executive function than men.

Cumulative exposure to lead and cognition in persons with Parkinson's disease

Dementia is an important consequence of Parkinson's disease (PD), with few known modifiable risk factors. Cumulative exposure to lead, at levels experienced in the community, may exacerbate PD-related neural dysfunction, resulting in impaired cognition. Among 101 persons with PD ("cases") and, separately, 50 persons without PD ("controls"), we evaluated cumulative lead exposure, gauged by tibia and patella bone lead concentrations, in relation to cognitive function, assessed using a telephone battery developed and validated in a separate sample of PD patients. We also assessed the interaction between lead and case-control status. After multivariable adjustment, higher tibia bone lead concentration among PD cases was associated with worse performance on all of the individual telephone tests. In particular, tibia lead levels corresponded to significantly worse performance on a telephone analog of the Mini-Mental State Examination and tests of working memory and attention. Moreover, higher tibia bone lead concentration was associated with significantly worse global composite score encompassing all the cognitive tests (P = 0.04). The magnitude of association per standard deviation increment in tibia bone lead level was equivalent to the difference in global scores among controls in our study, who were approximately 7 years apart in age. The tibia lead-cognition association was notably stronger within cases than within controls (P(difference) = 0.06). Patella bone lead concentration was not consistently associated with performance on the tests. These data provide evidence suggesting that cumulative exposure to lead may result in worsened cognition among persons with PD.

RELATION OF CHRONIC ENVIRONMENTAL LEAD EXPOSURE TO DEPRESSION AND ANXIETY SYMPTOMS IN OLDER WOMEN

Background and Aims: Environmental lead exposure has been associated with adverse cardiovascular and cognitive outcomes, which are themselves correlated with psychological symptoms. Yet few studies have examined links between lead exposure and psychological symptoms. We explored the association between bone lead—a biomarker of cumulative lead exposure—and depression and anxiety symptoms among older women. Methods: We measured patella and tibia bone lead by K-X-Ray-Fluorescence, and obtained repeated measures of depression and anxiety symptoms using the Mental Health Index 5-item subscale (MHI-5) and Crown-Crisp Index phobic anxiety scale (CCI) in 615 women in the Nurses Health Study. We analyzed MHI scores as a continuous variable using linear regression and estimated the odds of a CCI score ≥4 using generalized estimating equations, in both cases accounting for correlation between repeated outcomes (MHI: 3; CCI: 2) and adjusting for potential confounders. Results: The average age of participants was 61 (sd=6) years at the time of bone lead measurement. While tibia lead was associated with moderately worse MHI-5 and CCI scores among all women, results were much stronger among women who, at bone lead measurement, were premenopausal or had been consistently on hormone replacement therapy (HRT) since menopause. In these analyses, women in the highest tibia lead tertile scored 8.16 points worse (95% CI: -11.60, -4.72; p-trend&lt;0.0001) on the MHI-5 than women in the lowest tertile, and had increased odds of high phobic anxiety (CCI ≥4; OR=2.41; 95% CI: 1.06-5.50; p-trend=0.04). We found no relation of patella lead to depression and anxiety symptoms. Conclusions: Our results support an association of cumulative environmental lead exposure with increased risk of depression and anxiety symptoms among older women. Weaker results when including women not consistently on HRT after menopause may be an artifact of increased error in estimating cumulative exposure with bone lead among these women.

LEAD EXPOSURE ALTERS NEURAL MECHANISMS OF LEARNING: A PILOT STUDY OF FEAR-POTENTIATED STARTLE IN ELDERLY MEN

Background and Aims: Physiologically-based indicators of neurological function could provide mechanistic insight into toxicant actions on the brain, and perhaps prove a more objective and sensitive measure of such effects than other methods. We explored the effects of lead exposure on classical conditioning of the acoustic startle reflex (ASR)—a simple form of learning in the brain—in a population of elderly men. Methods: Fifty-one men from the Normative Aging Study (NAS) with patella and tibia bone lead measurements made with K-XRay-Fluorescence participated in a fear-conditioning protocol. One of two visual conditioned stimuli (CS) on a computer was paired with a mild finger shock. Eye-blink responses (electromyogram) to a loud noise burst were recorded with surface electrodes. Conditioning was indexed as the difference in z-scored eye-blink responses to noise bursts delivered in the presence of the paired and non-paired CS after the pairing process—when no shocks were delivered. Results: The mean age of the men was 76 years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.4μg/g bone (sd=12.2; range=5-63). In unadjusted analyses among 37 men with valid eyeblink responses at the end of the protocol, conditioning was 0.56sd less (95% CI:-1.02, -0.11; p=0.02) per 20 μg/g patella lead (the interquartile range of the parent NAS population). Tibia results were similar. Adjusting for age weakened associations only slightly, but there was no association between age itself and conditioning. Baseline startle amplitude was associated with age (β=-26.577μV per year; 95% CI:-47.67, -5.48; p=0.0137), but not with conditioning. Conclusions: In elderly men patella bone lead concentrations, a marker of cumulative lead exposure, predicted learning in a fear-conditioning startle paradigm. While the data are taken from a relatively small sample, this initial exploration offers the possibility that the ASR may provide a new paradigm to explore the effects of neurotoxicant exposure.

Effect of Increased Blood and Tibia Lead on the Change of Bone Mineral Density in Retired Male Lead Workers

PP-31-162 Background/Aims: To investigate the effect of increased blood and tibia lead on the change of bone mineral density in retired male lead workers. Methods: One hundred nine retired male lead workers who worked in 4 different lead industries and 51 nonoccupationally lead exposed male subjects were recruited from March 2004 to October 2004. Bone mineral density (BMD) was measured by broadband ultrasound attenuation (BUA) at left calcaneous bone area with broadband ultrasound attenuation method of QUS-2 (Metra Biosystems Inc, USA). Tibia bone lead was measured for skeletal bone lead with K-xray fluorescence (K-XRF) and blood lead was analyzed with flameless atomic spectrophotometer. Hemoglobin, hematocrit, serum calcium and iron were also analyzed. In addition, information for smoking and drinking status and basic personal data such as age and lead exposure were also collected using questionnaire inquiry. Results: Blood lead was correlated with tibia lead (r = 0.711) and these 2 variables were negatively correlated with BUA in bivariate analysis. BUA and tibia lead showed significant main effects on the change of blood lead after adjusting covariates. The effect modification by the level of BMD (low: lower than the median of BUA and high: higher than the median of BUA) was observed between the association of tibia lead and blood lead after adjustment of covariates. The subjects who had higher BMD seemed to have lower blood lead by the increase of tibia lead than those of lower BMD. In the multiple regression analysis of blood lead and tibia lead on BUA after adjustment of covariates, only blood lead showed statistically significant effect on BUA. Conclusion: This study confirmed that BMD and blood lead were significantly associated. To verify the causal association of BMD on blood lead and vice versa, further longitudinal studies are needed.

Cumulative Bone Lead Exposure, Length of Gestation, and Risk of Prematurity

ISEE-0783 Objectives: Premature birth constitutes a significant public health issue worldwide and findings on the role of environmental toxicants, including lead exposure, in the complex etiology of this adverse birth outcome are inconsistent. It has been shown that lead can persist in bone for many years after exposure, serving as an endogenous source of exposure for the developing fetus. We assessed the effect of cumulative bone lead exposure on gestational age and risk of premature delivery. Methods: Tibia and patella bone lead measurements were obtained 1 month post-partum by K-X-ray fluorescence from 1393 pregnant women recruited in Mexico City from three different birth cohorts between 1994–2001. Data were analyzed using linear and logistic regression adjusting for maternal age, maternal education, history of adverse birth outcome, maternal cigarette smoking during pregnancy, infant gender, birth cohort, and number of prior pregnancies, in order to examine the associations of tibia and patella bone lead exposure, gestational age (days) and risk of premature delivery (< 37 weeks gestation). Results: Of the 1393 eligible participants, there were 93 (6.7%) preterm deliveries. An increase of 10 μg/g in either tibia or patella bone lead did not result in a significant association with gestational age, after controlling for covariates of interest, decline in gestational age of −0.14 days (95%CI −0.50, 0.70), and −0.12 days (95%CI −0.60, 0.40), respectively. In adjusted logistic regression models, highest quartile of tibia and patella bone lead resulted in a 1.19 (95%CI 0.51, 2.75) and 1.23 (95%CI 0.62, 2.46) increased odds of delivering prematurely when compared to the lowest quartile of tibia and patella bone lead, respectively. Conclusion: Results and limitations of our study will be discussed more in depth, but initial findings indicate that cumulative tibia and patella bone lead levels do not significantly impact length of gestation or risk of premature delivery.

Association of cumulative lead and neurocognitive function in an occupational cohort.

Lead is a neurotoxicant that accumulates in bone with a half life of 25-30 years. To evaluate the association of lead biomarkers and cognitive function, a cohort of exposed and nonexposed workers who had been previously assessed in 1982 was retested approximately 22 years later. For the current assessment, both blood lead and tibia bone lead levels were determined. In addition, cognitive function was tested with the Pittsburgh Occupational Exposures Test battery, which had previously been administered in 1982. In exposed workers, bone lead level predicted lower current cognitive performance and cognitive decline over 22 years. In those lead-exposed workers older than age 55, higher levels of bone lead predicted poorer cognitive scores, suggesting vulnerability for older workers with higher past lead exposure. Finally, there was no association with bone lead level and recency of exposure, suggesting that cumulative body burden is most likely responsible for the progressive cognitive decrement evidenced with vulnerability because of aging.