Linda H. Nie

Longitudinal changes in bone lead levels: the VA Normative Aging Study.

Objective:Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population. Methods:Lead was measured every 3 to 5 years by k-x-ray fluorescence and mixed-effect models with random effects were used to evaluate change over time. Results:A total of 554 participants provided up to four bone lead measurements. Final models predicted a −1.4% annual decline (95% CI: −2.2 to −0.7) for tibia lead and piecewise linear model for patella with an initial decline of 5.1% per year (95% CI: −6.2 to −3.9) during the first 4.6 years but no significant change thereafter (–0.4% [95% CI: −2.4 to 1.7]). Conclusions:These results suggest that bone lead half-life may be longer than previously reported.

Manganese Accumulation in Bone Following Chronic Exposure in Rats: Steady-State Concentration and Half-life in Bone

Literature data indicate that bone is a major storage organ for manganese (Mn), accounting for 43% of total body Mn. However, the kinetic nature of Mn in bone, especially the half-life (t(1/2)), remained unknown. This study was designed to understand the time-dependence of Mn distribution in rat bone after chronic oral exposure. Adult male rats received 50 mg Mn/kg (as MnCl2) by oral gavage, 5 days per week, for up to 10 weeks. Animals were sacrificed every 2 weeks during Mn administration for the uptake study, and on day 1, week 2, 4, 8, or 12 after the cessation at 6-week Mn exposure for the t(1/2) study. Mn concentrations in bone (MnBn) were determined by AAS analysis. By the end of 6-weeks treatment, MnBn appeared to reach the steady state (T(ss)) level, about 2-3.2 fold higher than MnBn at day 0. Kinetic calculation revealed t(1/2)s of Mn in femur, tibia, and humerus bone of 77 (r=0.978), 263 (r=0.988), and 429 (r=0.994) days, respectively; the average t(1/2) in rat skeleton was about 143 days, equivalent to 8.5 years in human bone. Moreover, MnBn were correlated with Mn levels in striatum, hippocampus, and CSF. These data support MnBn to be a useful biomarker of Mn exposure.

Prospective cohort study of lead exposure and electrocardiographic conduction disturbances in the Department of Veterans Affairs Normative Aging Study.

Background: No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points. Objective: We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities. Methods: We assessed blood lead, bone lead—a biomarker of cumulative lead exposure—measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders. Results: Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42–14.45) increase in heart rate–corrected QT (QTc) interval and a 5.94-ms increase in heart rate–corrected QRS (95% CI, 1.66–10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22–5.25) and JT prolongation (heart rate–corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93–6.91). Results were weaker for patella lead. No associations were identified with blood lead. Conclusions: This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics.

XRF-measured bone lead (Pb) as a biomarker for Pb exposure and toxicity among children diagnosed with Pb poisoning

Abstract Childhood lead (Pb) poisoning remains a global issue, especially in industrial areas. In this study, 115 children with average age 5.7 years were recruited as either patient diagnosed with Pb poisoning or controls at Xinhua Hospital in China. The subjects’ bone Pb was measured with a K-shell X-ray fluorescence (KXRF) and a portable X-ray fluorescence (XRF) system. A significant correlation between KXRF bone Pb and blood Pb and portable XRF and KXRF measurements were observed. The half-life of blood-lead was calculated to be 9.96 ± 3.92 d. Our results indicate that bone is a useful biomarker for Pb in children.

Embryonic ionizing radiation exposure results in expression alterations of genes associated with cardiovascular and neurological development, function, and disease and modified cardiovascular function in zebrafish

The relationship between ionizing radiation (IR) and carcinogenesis is long established, but recently the association between IR and other diseases is starting to be recognized. Currently, there is limited information on the genetic mechanisms governing the role of IR in non-cancer related adverse health effects and in regards to an early developmental exposure. In this study, zebrafish embryos were exposed to a range of IR doses (0, 1, 2, 5, 10 Gy) at 26 h post fertilization (hpf). No significant increase in mortality or hatching rate was observed, but a significant decrease in total larval length, head length, and eye diameter was observed in the 10 Gy dose. Transcriptomic analysis was conducted at 120 hpf to compare gene expression profiles between the control and highest IR dose at which no significant differences were observed in morphological measurements (5 Gy). 253 genes with well-established function or orthology to human genes were significantly altered. Gene ontology and molecular network analysis revealed enrichment of genes associated with cardiovascular and neurological development, function, and disease. Expression of a subset of genetic targets with an emphasis on those associated with the cardiovascular system was assessed using Quantitative PCR (qPCR) to confirm altered expression at 5 Gy and then to investigate alterations at lower doses (1 and 2 Gy). Strong correlation between microarray and qPCR expression values was observed, but zebrafish exposed to 1 or 2 Gy resulted in a significant expression alteration in only one of these genes (LIN7B). Moreover, heart rate was analyzed through 120 hpf following IR dosing at 26 hpf. A significant decrease in heart rate was observed at 10 Gy, while a significant increase in heart rate was observed at 1, 2, and 5 Gy. Overall these findings indicate IR exposure at doses below those that induce gross morphological changes alters heart rate and expression of genes associated with cardiovascular and neurological functions.

Childhood and Adult Socioeconomic Position, Cumulative Lead Levels, and Pessimism in Later Life: The VA Normative Aging Study

Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age.

A compact DD neutron generator–based NAA system to quantify manganese (Mn) in bone in vivo

A deuterium-deuterium (DD) neutron generator-based neutron activation analysis (NAA) system has been developed to quantify metals, including manganese (Mn), in bone in vivo. A DD neutron generator with a flux of up to 3*10(9) neutrons s(-1) was set up in our lab for this purpose. Optimized settings, including moderator, reflector, and shielding material and thickness, were selected based on Monte Carlo (MC) simulations conducted in our previous work. Hand phantoms doped with different Mn concentrations were irradiated using the optimized DD neutron generator irradiation system. The Mn characteristic γ-rays were collected by an HPGe detector system with 100% relative efficiency. The calibration line of the Mn/calcium (Ca) count ratio versus bone Mn concentration was obtained (R(2) = 0.99) using the hand phantoms. The detection limit (DL) was calculated to be about 1.05 μg g(-1) dry bone (ppm) with an equivalent dose of 85.4 mSv to the hand. The DL can be reduced to 0.74 ppm by using two 100% HPGe detectors. The whole body effective dose delivered to the irradiated subject was calculated to be about 17 μSv. Given the average normal bone Mn concentration of 1 ppm in the general population, this system is promising for in vivo bone Mn quantification in humans.

Cumulative Lead Exposure and Age at Menopause in the Nurses' Health Study Cohort

Background: Early menopause has been associated with many adverse health outcomes, including increased risk of cardiovascular disease morbidity and mortality. Lead has been found to be adversely associated with female reproductive function, but whether exposures experienced by the general population are associated with altered age at menopause has not been explored. Objective: Our goal was to assess the association between cumulative lead exposure and age at natural menopause. Methods: Self-reported menopausal status and bone lead concentration measured with K-shell X-ray fluorescence—a biomarker of cumulative lead exposure—were obtained from 434 women participants in the Nurses’ Health Study. Results: The mean (± SD) age at natural menopause was 50.8 ± 3.6 years. Higher tibia lead level was associated with younger age at menopause. In adjusted analyses, the average age of menopause for women in the highest tertile of tibia lead was 1.21 years younger (95% CI: –2.08, –0.35) than for women in the lowest tertile (p-trend = 0.006). Although the number of cases was small (n = 23), the odds ratio for early menopause (< 45 years of age) was 5.30 (95% CI: 1.42, 19.78) for women in the highest tertile of tibia lead compared with those in the lowest tertile (p-trend = 0.006). There was no association between patella or blood lead and age at menopause. Conclusions: Our results support an association between low-level cumulative lead exposure and an earlier age at menopause. These data suggest that low-level lead exposure may contribute to menopause-related health outcomes in older women through effects on age at menopause. Citation: Eum KD, Weisskopf MG, Nie LH, Hu H, Korrick SA. 2014. Cumulative lead exposure and age at menopause in the Nurses’ Health Study Cohort. Environ Health Perspect 122:229–234; http://dx.doi.org/10.1289/ehp.1206399

Feasibility of a portable X-ray fluorescence device for bone lead measurements of condor bones

Lead based ammunition is a primary source of lead exposure, especially for scavenging wildlife. Lead poisoning remains the leading cause of diagnosed death for the critically endangered California condors, which are annually monitored via blood tests for lead exposure. The results of these tests are helpful in determining recent exposure in condors and in defining the potential for exposure to other species including humans. Since condors are victim to acute and chronic lead exposure, being able to measure both would lend valuable information on the rates of exposure and accumulation through time. A commercial portable X-ray fluorescence (XRF) device has been optimized to measure bone lead in vivo in humans, but this device could also be valuable for field measurements of bone lead in avian species. In this study, we performed measurements of bone Pb in excised, bare condor bones using inductively coupled plasma mass spectrometry (ICP-MS), a cadmium 109 (Cd-109) K-shell X-ray fluorescence (KXRF) system, and a portable XRF system. Both KXRF and portable XRF bone Pb measurement techniques demonstrated good correlations with ICP-MS results (r=0.93 and r=0.92 respectively), even with increasing skin thickness (r=0.86 between ICP-MS and portable XRF at 1.54mm of soft tissue). In conclusion, our results suggest that a portable XRF could be a useful option for measurement of bone Pb in avian species in the field.

Customized compact neutron activation analysis system to quantify manganese (Mn) in bone in vivo

OBJECTIVE In the US alone, millions of workers, including over 300 000 welders, are at high risk of occupational manganese (Mn) exposure. Those who have been chronically exposed to excessive amount of Mn can develop severe neurological disorders similar, but not identical, to the idiopathic Parkinsons disease. One challenge of identifing the health effects of Mn exposure is to find a reliable biomarker for exposure assessment, especially for long-term cumulative exposure. APPROACH Mns long biological half-life as well as its relatively high concentration in bone makes bone Mn (BnMn) a potentially valuable biomarker for Mn exposure. Our group has been working on the development of a deuterium-deuterium (D-D)-based neutron generator to quantify Mn in bone in vivo. Main results and significance: In this paper, we report the latest advancements in our system. With a customized hand irradiation assembly, a fully characterized high purity germanium (HPGe) detector system, and an acceptable hand dose of 36 mSv, a detection limit of 0.64 µg Mn/g bone (ppm) has been achieved.