Tibia Lead Research Articles

Associations of Uric Acid with Polymorphisms in the δ-Aminolevulinic Acid Dehydratase, Vitamin D Receptor, and Nitric Oxide Synthase Genes in Korean Lead Workers

Recent research suggests that uric acid may be nephrotoxic at lower levels than previously recognized and that it may be one mechanism for lead-related nephrotoxicity. Therefore, in understanding mechanisms for lead-related nephrotoxicity, it would be of value to determine whether genetic polymorphisms that are associated with renal outcomes in lead workers and/or modify associations between lead dose and renal function are also associated with uric acid and/or modify associations between lead dose and uric acid. We analyzed data on three such genetic polymorphisms: δ-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR). Mean (± SD) tibia, blood, and dimercaptosuccinic acid–chelatable lead levels were 37.2 ± 40.4 μg/g bone mineral, 32.0± 15.0 g/dL, and 0.77± 0.86 μg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOS Asp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age ≥ median of 40.6 years), ALAD genotype modified associations between lead dose and uric acid levels. Higher lead dose was significantly associated with higher uric acid in workers with the ALAD1-1 genotype; associations were in the opposite direction in participants with the variant ALAD1-2 genotype. In contrast, higher tibia lead was associated with higher uric acid in those with the variant VDR B allele; however, modification was dependent on participants with the bb genotype and high tibia lead levels. We conclude that genetic polymorphisms may modify uric acid mediation of lead-related adverse renal effects.

Assessment of Lead Exposure Risk in Locksmiths

Exposure to lead has been well recognized in a number of work environments, but little is known about lead exposure associated with machining brass keys containing lead. The brass that is widely used for key manufacturing usually contains 1.5% - 2.5 % of lead. Six (6) licensed locksmiths and 6 case-matched controls successfully completed the pilot study to assess the prevalence of increased body lead burden of professional locksmiths. We measured both Blood Lead (atomic absorption spectrometry), bone-lead (KXRF) and had each subject complete a health and lead exposure risk questionnaire. One locksmith had not cut keys during the past two years, therefore this subject and case-matched control was excluded from the blood lead analysis only. The average blood-lead concentration (+/-SEM) for the 5 paired subjects was 3.1 (+/- 0.4) microg/dL and 2.2 (+/- 0.3) microg/dL for controls. Bone measurements, including all 6 paired subjects, showed tibia lead concentration (+/-SEM) for locksmiths and controls was 27.8 (+/- 2.3) microg/g and 13.7 (+/- 3.3) microg/g, respectively; average calcaneus lead concentration for locksmiths and controls was 31.9 (+/- 3.7) microg/g and 22.6 (+/- 4.1) microg/g, respectively: The t-test shows a significantly higher tibia lead (p<0.05) and blood lead (p<0.05) for locksmiths than for their matched controls, but no significant difference for calcaneus lead (p>0.10). Given that the mean tibia bone lead concentration was 13.1 microg/g higher in locksmiths than in their matched controls, this average difference in the two groups would translate to an OR of increased hypertension in locksmiths of between 1.1 and 2.3, based on the published literature. Even with the very small number of subjects participating in this pilot study, we were able to demonstrate that locksmiths had significantly higher current exposure to lead (blood lead concentration) and significantly higher past exposure to lead (tibia lead concentration) than their age, sex and ethnically matched controls. Additional research is needed to fully identify the prevalence and associated risk factors for occupational exposure of lead in this previously understudied profession.

Health Risks Associated With Polychlorinated Biphenyls—Reply

served. Although we did not assess data on family history of cataract, we believe it unlikely that any association between family history of cataract and tibia lead levels would be strong enough to result in significant confounding. We performed additional analyses of the association between tibia lead levels and cataract adjusting for BMI and years of formal education (as a proxy for socioeconomic status), in addition to age, diabetes, smoking status, blood lead levels, and vitamin intake. The results were similar to those we presented in our article. For example, the odds ratio (95% confidence interval) for the highest vs lowest quintile of tibia lead levels was 3.03 (1.36 to 6.76), with a P value for trend of .02 across quintiles of tibia lead levels. In light of previously reported data from the Normative Aging Study showing significantly higher tibia lead levels among men with lower levels of education, these results are consistent with the possibility that lead accumulation may account for some of the increase in risk of cataract attributed to lower SES in other studies.

Headliners: Lead Exposure and Vision

Vol. 113, No. 3 EnvironewsOpen AccessHeadliners: Lead Exposure and Vision Jerry Phelps Jerry Phelps Search for more papers by this author Published:1 March 2005https://doi.org/10.1289/ehp.113-a163AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Lead Accumulation May Lead to CataractsSchaumberg DA, Mendes F, Balaram M, Dana MR, Sparrow D, Hu H. 2004. Accumulated lead exposure and risk of age-related cataract in men. JAMA 292:2750–2754.Although lead toxicity in humans had been recognized for centuries, lead was widely used in industrial products and practices in the twentieth century, resulting in broad exposures and distribution of its effects. Worldwide, lead was a common component of many consumer products including gasoline, paint, craft supplies, and plumbing materials. Some of these routes of exposure still exist in countries outside the United States, making lead a lingering concern around the world.Researchers have identified a number of adverse health effects of lead including neurotoxic effects and learning disorders in children. Other studies have shown that the intrusion of lead into the lens of the eye may cause protein conformational changes that decrease lens transparency. Now NIEHS grantee Howard Hu and colleagues at Harvard University have uncovered what could be another adverse health effect with global implications: cataracts.Cataracts are the leading cause of blindness. About 13 million people over the age of 40 in the United States alone have cataracts, and the costs of cataract surgery reach almost $4 billion annually.The Harvard researchers measured tibial and patellar bone lead levels by k X-ray fluorescence in a subset of participants in the Normative Aging Study, a Boston-based longitudinal study of aging in men. For 600 men aged 60 years and older, the researchers then reviewed eye examination data (collected routinely every 3–5 years) for the period after bone lead measurements were taken. Blood lead levels were also measured. Results were adjusted for pack-years of cigarette smoking, diabetes, blood lead, and intake of vitamin C, vitamin E, and carotenoids.The researchers found that participants with high tibial lead were more than 2.5 times as likely to develop cataracts as men with low tibial lead (bone lead is a measure of long-term lead exposure). Blood lead levels, which are more indicative of short-term lead exposure, were not significantly associated with increased risk of cataract development.This study suggests that accumulated lead exposure, common in the United States and other parts of the industrialized world, may be an important but as yet unrecognized risk factor for development of cataracts. Furthermore, reducing lead exposure could help decrease the global human suffering and financial burden caused by cataracts, and preserve the vision of many people as they age.FiguresReferencesRelatedDetails Vol. 113, No. 3 March 2005Metrics About Article Metrics Publication History Originally published1 March 2005Published in print1 March 2005 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Associations of Patella Lead and Other Lead Biomarkers With Renal Function in Lead Workers

We sought to compare associations of patella lead, which may represent a unique cumulative and bioavailable lead pool, with other lead measures in models of renal function. Renal function measures included blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, and urinary N-acetyl-beta-D-glucosaminidase (NAG) and retinol-binding protein. In 652 lead workers, mean (SD) blood, patella, and tibia lead were 30.9 (16.7) microg/dL, 75.1 (101.1) and 33.6 (43.4) microg Pb/g bone mineral, respectively, and were correlated (Spearman's r = 0.51-0.74). Patella lead was associated (P < 0.05) with NAG in all lead workers. In models of effect modification by age, higher patella lead also was associated with higher serum creatinine in older participants. Similar associations were observed for blood and tibia lead. Associations between patella lead and adverse renal outcomes were not unique; this may be due, in part, to high correlations among the lead biomarkers in this study.

Occupational Lead Exposure and Longitudinal Decline in Neurobehavioral Test Scores

No previous longitudinal studies have compared and contrasted associations of blood lead and tibia lead with declines in cognitive function over the course of time in a large sample of subjects with current and past occupational exposure to inorganic lead. From 1997 through 2001, we conducted a longitudinal study of 803 current and former lead workers in South Korea to evaluate effects on the central and peripheral nervous systems. Three study visits occurred during a mean follow-up duration of 2.20 years. Neurobehavioral test scores, peripheral nervous system function, and blood lead were measured at each of the 3 study visits, whereas tibia lead was measured by x-ray fluorescence at the first and second visits. We limited our analysis to the 576 lead workers who completed testing at all 3 visits. We performed regression analyses using generalized estimating equations. There were consistent associations of blood lead with test scores at baseline and of tibia lead with declines in test scores over the next year, mainly in executive abilities, manual dexterity, and peripheral vibration threshold. The results support the inference that occupational lead exposure can cause declines in cognitive function over the course of time. Lead likely has an acute effect on neurobehavioral test scores as a function of recent dose and a longer-term (possibly progressive) effect on cognitive decline as a function of cumulative dose.

In vivo K-shell X-ray fluorescence bone lead measurements in young adults

The (109)Cd K-shell X-ray fluorescence (XRF) technique was used to measure in vivo tibia lead concentrations of 34 young adults living in the state of Vermont (USA) and the province of New Brunswick (Canada). The subjects ranged in age from 18 to 35 years, and had no known history of elevated lead exposure. Measurement parameters were varied, using the same XRF system for both populations. Tibia lead concentrations were low for both groups, with mean values of 0.7 microg lead g(-1) bone mineral (Vermont) and 0.5 microg g(-1)(New Brunswick). No individual measurement exceeded 7 microg g(-1). Mean uncertainty values obtained for the Vermont and New Brunswick subjects were 4.1 microg g(-1) and 2.6 microg g(-1), respectively. Improved measurement uncertainty in the New Brunswick group was attributed to the use of a reduced source-to-skin distance (approximately 5 mm) and a longer measurement time (3600 seconds) using a weaker radioisotope source (< or =0.42 GBq). Measurement uncertainty tended to increase with body mass index. For a given body mass index, female subjects returned a measurement uncertainty approximately 1 microg g(-1) greater than males.

Cumulative Lead Exposure and Prospective Change in Cognition among Elderly Men: The VA Normative Aging Study

Lead exposure has been found to affect cognitive function in several different populations. Whether chronic low-level environmental exposure to lead results in cognitive decline among adults has not been examined. The authors assessed the relation between biomarkers of lead exposure and change in Mini-Mental State Examination (MMSE) scores in the Normative Aging Study, a cohort of elderly US men. Bone lead was measured with K-shell x-ray fluorescence. A total of 466 men aged 67.4 (standard deviation, 6.6) years took the MMSE on two occasions that were an average of 3.5 (standard deviation, 1.1) years apart during the period 1993-2001 and had bone lead concentrations measured during the period 1991-2002. A one-interquartile range (20 microg/g of bone mineral) higher patella bone lead concentration was associated with a change in MMSE score of -0.24 (95% confidence interval: -0.44, -0.05) after adjustment for age, education, smoking, alcohol intake, and time between MMSE tests. This effect is approximately equivalent to that of aging 5 years in relation to the baseline MMSE score in study data. The association with tibia lead was weaker and that with blood lead was absent. The data suggest that higher patella bone lead levels, a marker of mobilizable accumulated lead burden, are associated with a steeper decline over time in performance on the MMSE test among nonoccupationally exposed elderly men.

Associations among Lead Dose Biomarkers, Uric Acid, and Renal Function in Korean Lead Workers

Recent research suggests that both uric acid and lead may be nephrotoxic at lower levels than previously recognized. We analyzed data from 803 current and former lead workers to determine whether lead biomarkers were associated with uric acid and whether previously reported associations between lead dose and renal outcomes were altered after adjustment for uric acid. Outcomes included uric acid, blood urea nitrogen, serum creatinine, measured and calculated creatinine clearances, and urinary N-acetyl-β-d-glucosaminidase (NAG) and retinol-binding protein. Mean (± SD) uric acid, tibia lead, and blood lead levels were 4.8 ± 1.2 mg/dL, 37.2 ± 40.4 μg/g bone mineral, and 32.0 ± 15.0 μg/dL, respectively. None of the lead measures (tibia, blood, and dimercaptosuccinic-acid–chelatable lead) was associated with uric acid, after adjustment for age, sex, body mass index, and alcohol use. However, when we examined effect modification by age on these relations, both blood and tibia lead were significantly associated (β= 0.0111, p < 0.01 and β= 0.0036, p = 0.04, respectively) in participants in the oldest age tertile. These associations decreased after adjustment for blood pressure and renal function, although blood lead remained significantly associated with uric acid (β= 0.0156, p = 0.01) when the population was restricted to the oldest tertile of workers with serum creatinine greater than the median (0.86 mg/dL). Next, in models of renal function in all workers, uric acid was significantly (p < 0.05) associated with all renal outcomes except NAG. Finally, in the oldest tertile of workers, associations between lead dose and NAG were unchanged, but fewer associations between the lead biomarkers and the clinical renal outcomes remained significant (p ≤0.05) after adjustment for uric acid. In conclusion, our data suggest that older workers comprise a susceptible population for increased uric acid due to lead. Uric acid may be one, but not the only, mechanism for lead-related nephrotoxicity.

Blood Lead Is a Predictor of Homocysteine Levels in a Population-Based Study of Older Adults

Lead and homocysteine are both associated with cardiovascular disease and cognitive dysfunction. We evaluated the relations among blood lead, tibia lead, and homocysteine levels by cross-sectional analysis of data among subjects in the Baltimore Memory Study, a longitudinal study of 1,140 randomly selected residents in Baltimore, Maryland, who were 50–70 years of age. Tibia lead was measured by 109Cd K-shell X-ray fluorescence. The subject population had a mean ± SD age of 59.3 ± 5.9 years and was 66.0% female, 53.9% white, and 41.4% black or African American. Mean ± SD blood lead, tibia lead, and homocysteine levels were 3.5 ± 2.4 μg/dL, 18.9 ± 12.5 μg/g, and 10.0 ± 4.1 μmol/L, respectively. In unadjusted analysis, blood lead and homocysteine were moderately correlated (Pearson’s r = 0.27, p < 0.01). After adjustment for age, sex, race/ethnicity, educational level, tobacco and alcohol consumption, and body mass index using multiple linear regression, results revealed that homocysteine levels increased 0.35 μmol/L per 1.0 μg/dL increase in blood lead (p < 0.01). The relations of blood lead with homocysteine levels did not differ in subgroups distinguished by age, sex, or race/ethnicity. Tibia lead was modestly correlated with blood lead (Pearson’s r = 0.12, p < 0.01) but was not associated with homocysteine levels. To our knowledge, these are the first data to reveal an association between blood lead and homocysteine. These results suggest that homocysteine could be a mechanism that underlies the effects of lead on the cardiovascular and central nervous systems, possibly offering new targets for intervention to prevent the long-term consequences of lead exposure.

Prospective Study of Blood and Tibia Lead in Women Undergoing Surgical Menopause

Despite the dramatic decline in environmental lead exposure in the United States during the past couple of decades, concern has been expressed regarding mobilization during menopause of existing lead stored in bone. To investigate whether bone lead concentrations decrease and blood lead levels increase, we conducted a prospective study of 91 women who were scheduled to undergo a bilateral oophorectomy for a benign condition at Mount Sinai Hospital in New York City during October 1994 through April 1999. We excluded women who were younger than 30 years of age or who were postmenopausal at the time of the surgery. We observed a small but significant increase in median blood lead levels between the baseline visit and the 6-month visit (0.4 μg/dL, p < 0.0001), particularly for women who were not on estrogen replacement therapy (0.7 μg/dL, p = 0.008). No significant change was observed in blood lead values between 6 and 18 months postsurgery, nor was there evidence of significant changes in tibia lead concentrations during the follow-up period. These findings do not point to substantial mobilization of lead from cortical bone during menopause.

Measuring Lead Effects: Blood and Bone Together Are Better

Many studies have reported impaired renal function and kidney disease at high levels of lead exposure, as estimated mainly through concentrations of serum creatinine (SCr) and rates of creatinine clearance from the body. However, lower-level lead exposure has not been correlated with renal effects as conclusively, perhaps because blood lead reflects relatively recent exposure, and therefore is not an adequate measure of total body burden. This month, Shirng-Wern Tsaih of the Harvard School of Public Health and her colleagues report that blood lead levels alone may not be enough to determine whether kidney effects are occurring at low exposure; lead levels in bone also need to be determined [EHP 112:1178–1182]. The Tsaih study is among the first to assess the relationship between low-level bone and blood lead levels and measures of kidney function in a general population sample. In contrast with blood lead, bone lead makes up more than 95% of the adult body burden. The lead in more compacted cortical bones, such as the tibia, is less available for mobilization, because this type of bone is less prone to turnover than spongier trabecular bones, such as the patella. Yet, as people age, bone loss often does take place, so lead that has long been held in bone is released to soft tissue and can find its way to the kidneys. Thus, bone lead may be a better marker for studying the chronic toxicity of accumulated exposure and lead burden. The Tsaih study examined data from a cohort of middle-aged and elderly Boston men with no known heavy exposure to lead. Participants were from the Normative Aging Study, a federal study of aging begun in 1961. A blood sample for lead analysis had been collected every 3–5 years since July 1988; bone lead measurements began in August 1991, when a subset of participants were recruited for a substudy in which bone lead was measured by K X-ray fluorescence. Tsaih and colleagues examined data for 448 men who had a baseline bone lead measurement between 1991 and 1995, and follow-up measurements of SCr 4–8 years later. They examined blood and bone lead concentrations and their correlation with kidney function, taking into account the known nephrotoxic effects of diabetes mellitus and hypertension, which had been diagnosed in 5.8% and 25.7% of the men, respectively, at the time of baseline measurement. Bone lead was measured in the tibia and patella. Tibia lead was observed to be associated with increases in SCr levels in follow-up participants with diabetes. The findings suggest that long-term low-level lead accumulation, estimated by tibia lead, is associated with an increased risk of reduced renal function. This is especially true for diabetics and hypertensives, who already are at risk for kidney impairment because of their disease. In addition, blood lead and tibia lead appeared to be associated with elevated SCr levels and chronic kidney disease among hypertensives. There was no statistical evidence of patella lead being associated with change in renal function, suggesting that chronic absorption of lead is a risk factor for impaired renal function. The study, however, has some limitations. Although SCr is widely used in medicine to measure overall renal function, it provides only a rough estimate of the kidney’s filtration capacity. For instance, increases in SCr definitively show impairment only when kidney function has been reduced by about 50%. Thus, the researchers had great difficulty in detecting more modest effects of lead. In addition, the alternative hypothesis that elevated blood or bone lead levels actually result from impaired kidney function cannot be ruled out. It has not yet been determined whether lead affects blood pressure indirectly through changes in kidney function, or via more direct effects on the circulatory system or neurological blood pressure control. The researchers also know of no studies to date that analyze the potential for diabetes to modify the relationship between lead exposure and renal function. Given that many adults have a history of environmental or occupational lead exposure and the incidence of both type 2 diabetes and hypertension, studies of such interactions, if confirmed, could be of significant public health value.

THE RELATIONSHIP BETWEEN CHRONIC ENVIRONMENTAL LEAD EXPOSURE AND AUDITORY NERVE FUNCTION: THE NORMATIVE AGING STUDY

ISEE-358 Objectives: This study evaluated the cross-sectional relationship between biological markers of chronic environmental lead exposure and hearing impairment amongst a community-based sample of elderly men. It was also designed to evaluate this relation in view of other covariates that may affect auditory function such as age, smoking and occupation. Methods: The participants of this study were derived from the Normative Aging Study, a longitudinal study of aging established by the Veterans Administration since 1963. We measured bone lead concentration using a K-X-ray fluorescence technique as a quantitative index of chronic lead exposure and blood lead using graphite furnace atomic absorption spectroscopy as an index of short-term lead exposure. A pure-tone audiometer was used to measure air and bone conduction hearing in decibel units at frequencies of 250, 500, 1000, 2000, 4000 and 8000 Hz. Results: In this study, 734 subjects were examined who had a mean age of 67.2 (SD 7.2) years, and mean (SD) values for blood, tibia and patella bone lead of 6.04 (3.9) mg/dL, 21.6 (13.4) mg/g, and 31.1 (19.4) mg/g respectively. We considered a subject to have hearing impairment if both ears had hearing thresholds greater than 20 Db at frequencies of 500, 2000 and 4000 Hz. Age was significantly higher in the hearing impaired group at the all frequencies studied (p>0.001). Blood, tibia and patella bone lead were significantly higher in the hearing impaired group at the higher frequencies 2 and 4 KHz for both air and bone conduction (p>0.01). Using multivariate logistic regression blood and patella lead, but not tibia lead, increased the odds of air and bone conduction hearing impairment at 2 KHz after adjustment for age, cumulative smoking and occupation (p<0.01 and p>0.05 respectively). At 4 KHz, both tibia and patella lead levels increase odds of air conduction hearing impairment (p>0.01). At 500 Hz, neither of these covariates seems to increase the odds of hearing impairment. Conclusion: We conclude that environmental lead exposure increases the odds of both air and bone conduction hearing impairment at high frequencies (2 KHz and 4 KHz) more than at lower frequency (500 Hz). Both blood and bone lead levels are good predictors of hearing impairment at higher frequencies.

BONE LEAD LEVELS IN RELATION TO BASELINE PULSE PRESSURE: THE NORMATIVE AGING STUDY

ISEE-368 Background: The lead-exposed rat demonstrates increased vascular reactive oxygen species (ROS), and blood lead level has been positively correlated with increased plasma markers of oxidative stress in humans. ROS contribute to vascular pathophysiology, one manifestation of which is an increase in the pulse pressure [the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP)]. We hypothesized that lead exposure might predict pulse pressure in humans. Methods: In a substudy of the Normative Aging Study, a longitudinal cohort of male veterans, we measured participants' bone lead level using K-shell x-ray fluorescence and blood pressure using standard mercury sphygmomanometry. Subjects were included if they had satisfactory bone lead and blood pressure determinations and were excluded if they were taking antihypertensives. A total of 598 men, aged 48-93, met these criteria. Using simple and multiple linear regression, we computed the difference in pulse pressure associated with progressively higher levels of bone lead. We could not assume a linear association between bone lead and pulse pressure, therefore we examined bone lead in quintiles. Results: The mean levels of tibia lead among the first through the fifth quintiles were 7.4, 14.1, 18.9, 24.9, and 40.8 micrograms per gram, respectively. Pulse pressure ranged from 21 to 95 mm Hg with a mean of 53 mm Hg. In unadjusted analyses, tibia lead levels were positively associated with SBP and negatively associated with DBP. Higher tibia lead level was associated with progressively higher pulse pressure after adjusting for age, age squared, family history of hypertension, fasting plasma glucose, and alcohol intake. Compared with the pulse pressure of men in the lowest quintile of tibia lead, the mean differences in pulse pressure in the second through the fifth quintiles, respectively, were -2.7, -0.08, 2.56, 3.25, p value for trend 0.006. Conclusion: We found that bone lead level independently predicted pulse pressure. This is consistent with lead exposure contributing to ROS mediated vascular pathophysiology. This finding may shed light on previous work in which the positive association of lead with SBP and the negative association of lead with DBP were interpreted as inconsistent.

ASSOCIATIONS AMONG URIC ACID, LEAD BIOMARKERS AND RENAL FUNCTION IN KOREAN LEAD WORKERS

ISEE-343 Introduction: We previously reported that tibia and blood lead were predictors of adverse renal function in lead workers. Recent evidence suggests that uric acid (UA) is nephrotoxic. Since lead is also reported to increase serum UA (urate), we evaluated whether these lead biomarkers were predictors of UA and whether relations between these biomarkers and renal function outcomes were altered after adjustment by UA. Methods: UA was obtained in 803 lead workers. Renal function was assessed with blood urea nitrogen (BUN), serum creatinine, measured creatinine clearance, calculated creatinine clearance, and urinary N-acetyl-b-D-glucosaminidase (NAG) and retinol-binding protein (RBP). Lead measures included tibia and blood lead. Results: Mean (SD) UA, tibia and blood lead were 4.8 (1.2) mg/dl, 37.2 (40.4) mg/g bone mineral and 32.0 (15.0) mg/dl, respectively. After adjustment for age, gender, body mass index, systolic blood pressure and alcohol use, neither lead biomarker was associated with UA. However, when effect modification by age on these relations was examined, blood lead was a significant predictor of UA among workers in the oldest age tertile (age < 46.0 years; b=0.0105; 95th CI=0.0025-0.019). Analysis was next directed towards hypothesis generation regarding causal relations among lead, UA, and renal function. First, when serum creatinine was added to this model, the association was reduced (b=0.0071; 95th CI=-0.001-0.015). Next, effect modification by serum creatinine on relations between UA and the lead biomarkers was evaluated among the 266 oldest lead workers; blood lead was a predictor of UA only in workers with serum creatinine above the median (b=0.0150; 95th CI=0.004-0.026). Finally, the six renal function measures were modeled as outcomes. Previously published analyses in this population showed tibia and blood lead to be predictors of worse renal function primarily among workers in the oldest age tertile. When UA was added to these age interaction models, it was a significant predictor of all renal function measures except NAG. Betas for the lead biomarkers in NAG and RBP models were unchanged. However, betas for the lead measures in models with the four other renal outcomes decreased by as much as 20%. Discussion: These data suggest that older workers, particularly those with worse renal function, comprise a susceptible population for increased UA due to lead. Our data may also indicate that UA is one mechanism for lead-related nephrotoxicity.

LOW-LEVEL LEAD EXPOSURE, DIABETES, AND HEART RATE VARIABILITY: THE VA NORMATIVE AGING STUDY

ISEE-355 Abstract: Decreased heart rate variability (HRV), a marker of poor cardiac autonomic function, has been associated with sudden cardiac death and heart failure. Several observational studies have shown a significantly decreased vagal tone in workers occupationally exposed to lead, compared with non-exposed controls. However, no study has been conducted to evaluate the effects of non-occupational lead exposure on HRV in the general population. A number of studies have shown that diabetes is associated with reduced HRV, and thus diabetics may represent a more vulnerable subpopulation. The purpose of this study was to examine the relationship between alterations in HRV, low-level lead exposure, and diabetes in a large group of community residents. We examined the association of low-level lead exposure with HRV measures among 385 male participants (mean age 73) from the Normative Aging Study. We used K-x-ray fluorescence to measure bone lead levels, and graphite furnace atomic absorption spectroscopy to measure blood lead levels. HRV variables included the standard deviation of normal-to-normal (NN) intervals, the square root of the mean of the squared differences between adjacent NN intervals, power in high (HF, 0.15 to 0.40 Hz) and low frequency (LF, 0.04 to 0.15 Hz), and LF/HF ratio, reflecting sympathovagal balance. Log 10 transformed HRV measures were used as response variables. Diabetes mellitus was defined as fasting blood glucose levels greater than 126 mg/dL and/or physician-diagnosed diabetes (n=77, 20%). After controlling for potential confounders (age, diastolic blood pressure, fasting blood glucose, cigarette smoking, serum cholesterol, and use of angiotensin converting enzyme inhibitor), no lead biomarker was associated with HRVs in the entire cohort. However, stratified analyses showed that an interquartile increase in patella lead (20 micro gram/gram) was associated with a 22.8% increase (95% confidence interval (CI), −4.5% to 78.9%) of the LF/HF ratio in diabetics, and a 7.4% decrease (95% CI, +18.3% to 4.8%) in non-diabetics. The difference in effect between diabetics and non-diabetics was significant (p=0.04 for interaction term). The associations with tibia lead were similar to those with patella lead, but less significant. Blood lead levels were not associated with any of the HRV measures examined. The results suggest that diabetics may be a population that is particularly susceptible to cardiovascular damage by low-level lead exposure, mainly explained by an altered balance of the parasympathetic and sympathetic nerve activities.

RELATION OF DIETARY NUTRIENT INTAKE TO LEAD IN BLOOD, BONE AND BREAST MILK AMONG LACTATING WOMEN AT ONE-MONTH POSTPARTUM

ISEE-479 Abstract: There is evidence to suggest that several nutritional factors may interact with lead absorption, deposition, and redistribution particularly during times of stress to the host such as pregnancy and lactation. We studied relationships between dietary nutrient intake and levels of lead in blood, bone, and breast milk at one-month postpartum among 613 lactating women in Mexico City. Maternal height and weight were measured, blood and breast milk samples were analyzed, and maternal bone lead was estimated by K-X-ray fluorescence. Maternal dietary intake was assessed using a self-administered semi-quantitative, food frequency questionnaire designed to estimate usual dietary intake that had been translated into Spanish and validated for use in the Mexican adult population. Mean levels of lead were: blood 9.3 mcg/dL (SD=4.7, range 1.8-60.1); breast milk 1.4 mcg/L (SD=1.1, range 0.2-8.0); patella 14.9 mcg/g (SD=15.5, range <1-85.9); tibia 10.0 mcg/g (SD=10.1, range <1-76.5). Women reported receiving less than the U.S. recommended daily allowance (U.S. RDA) for pregnant and lactating women for several key nutrients: 52% for calcium, 100% for iron, 54% for zinc, 53% for vitamin D, 95% for vitamin E, and 43% for folate. Fifty-six percent of women reported eating less than 2500 kilocalories per day. After adjustment for maternal age, parity, breastfeeding status (exclusive or partial), total months of breastfeeding in previous pregnancies, maternal hemoglobin, and current use of lead-glazed ceramics, increasing levels of vitamin C were associated with lower levels of breast milk lead. Lower tibia bone lead levels were associated with increasing levels of calcium, iron, phosphorus, magnesium and zinc, while higher levels of tibia lead were associated with increasing levels of dietary fat. Lower levels of patella lead were associated with higher intakes of calcium, vitamin D, and phosphorus. Since over 95% of lead is stored in bone, nutritional status may be an important strategy in preventing accumulation of lead. Our results indicate that these potentially-modifiable nutritional factors may be important determinants of the long-term storage and mobilization of lead in pregnant and nursing women.

Lead, diabetes, hypertension, and renal function: the normative aging study.

In this prospective study, we examined changes in renal function during 6 years of follow-up in relation to baseline lead levels, diabetes, and hypertension among 448 middle-age and elderly men, a subsample of the Normative Aging Study. Lead levels were generally low at baseline, with mean blood lead, patella lead, and tibia lead values of 6.5 μg/dL, 32.4 μg/g, and 21.5 μg/g, respectively. Six percent and 26% of subjects had diabetes and hypertension at baseline, respectively. In multivariate-adjusted regression analyses, longitudinal increases in serum creatinine (SCr) were associated with higher baseline lead levels but these associations were not statistically significant. However, we observed significant interactions of blood lead and tibia lead with diabetes in predicting annual change in SCr. For example, increasing the tibia lead level from the midpoints of the lowest to the highest quartiles (9–34 μg/g) was associated with an increase in the rate of rise in SCr that was 17.6-fold greater in diabetics than in nondiabetics (1.08 mg/dL/10 years vs. 0.062 mg/dL/10 years; p < 0.01). We also observed significant interactions of blood lead and tibia lead with diabetes in relation to baseline SCr levels (tibia lead only) and follow-up SCr levels. A significant interaction of tibia lead with hypertensive status in predicting annual change in SCr was also observed. We conclude that longitudinal decline of renal function among middle-age and elderly individuals appears to depend on both long-term lead stores and circulating lead, with an effect that is most pronounced among diabetics and hypertensives, subjects who likely represent particularly susceptible groups.

Levels of lead in breast milk and their relation to maternal blood and bone lead levels at one month postpartum.

Despite the many well-recognized benefits of breast-feeding for both mothers and infants, detectable levels of lead in breast milk have been documented in population studies of women with no current environmental or occupational exposures. Mobilization of maternal bone lead stores has been suggested as a potential endogenous source of lead in breast milk. We measured lead in breast milk to quantify the relation between maternal blood and bone lead levels and breast-feeding status (exclusive vs. partial) among 310 lactating women in Mexico City, Mexico, at 1 month postpartum. Umbilical cord and maternal blood samples were collected at delivery. Maternal breast milk, blood, and bone lead levels were obtained at 1 month postpartum. Levels of lead in breast milk ranged from 0.21 to 8.02 microg/L (ppb), with a geometric mean (GM) of 1.1 microg/L; blood lead ranged from 1.8 to 29.9 microg/dL (GM = 8.4 microg/dL); bone lead ranged from < 1 to 67.2 microg/g bone mineral (patella) and from < 1 to 76.6 microg/g bone mineral (tibia) at 1 month postpartum. Breast milk lead was significantly correlated with umbilical cord lead [Spearman correlation coefficient (rS) = 0.36, p < 0.0001] and maternal blood lead (rS= 0.38, p < 0.0001) at delivery and with maternal blood lead (rS = 0.42, p < 0.0001) and patella lead (rS= 0.15, p < 0.01) at 1 month postpartum. Mother's age, years living in Mexico City, and use of lead-glazed ceramics, all predictive of cumulative lead exposure, were not significant predictors of breast milk lead levels. Adjusting for parity, daily dietary calcium intake (milligrams), infant weight change (grams), and breast-feeding status (exclusive or partial lactation), the estimated effect of an interquartile range (IQR) increase in blood lead (5.0 microg/dL) was associated with a 33% increase in breast milk lead [95% confidence interval (CI), 24 to 43%], whereas an IQR increase in patella lead (20 microg/g) was associated with a 14% increase in breast milk lead (95% CI, 5 to 25%). An IQR increase in tibia lead (12.0 microg/g) was associated with a 5% increase in breast milk lead (95% CI, -3% to 14%). Our results indicate that even among a population of women with relatively high lifetime exposure to lead, levels of lead in breast milk are low, influenced both by current lead exposure and by redistribution of bone lead accumulated from past environmental exposures.

In vivo tibial lead measurement to assess the health hazard of Venezuelan workers

Gamma-ray induced X-ray emission (GIXE) technique for elemental lead in-vivo tibial measurement using a large volume hyper pure germanium detector is presented with the most convenient source-sample-detector geometry. The system operates advantageously when several parameters are considered for a lower dead time operation. The detection limit (DL) is better that 3.5 μg/g of Ca. Results of in-vivo average tibial lead concentration for some of the monitored groups are: control 7 μg of lead per g of Ca; gasoline filling attendants 6 μg/g of Ca; custom office workers near the DL; industrial workers range from DL up to 84±3 μg/g of Ca, suggesting that lead accumulation in the bone does not represent a major health risk