Antonio Aro

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.

K X-ray fluorescence measurements of bone lead concentration: the analysis of low-level data

K line x-ray fluorescence (KXRF) measurements of bone lead have emerged as a promising new biological marker of internal lead dose in epidemiological studies. Some disagreements exist, however, over the analysis of data at low levels of bone lead concentration. In this study, we performed 30 serial measurements on each of three phantoms containing spiked amounts of lead. Chemical analysis of these phantoms using an inductively coupled plasma mass spectrometer (ICPMS) indicated that the lead concentrations were 0.30, 5.77, and 11.57 micrograms g-1. Analysis of the data was performed using several definitions of a minimum detectable limit (MDL) to recode data below the MDL, and using all of the continuous point estimates of lead concentration in the phantom (including negative estimates). The results demonstrate that the use of MDLs to recode low-level observations reduces the efficiency of the analysis and the ability to distinguish between the phantoms. Retaining all point estimates of KXRF-measured bone lead concentration provides less bias and greater efficiency in comparing the mean or median levels of bone lead of different populations.

Effect of Maternal Bone Lead on Length and Head Circumference of Newborns and 1-Month-Old Infants

Abstract The authors evaluated the effects that maternal bone lead stores have in anthropometry at birth in 223 mother-infant pairs. The participants were recruited between April and November 1994. Anthropometric data were collected within the first 12 hr following delivery. Maternal information was obtained 1 mo after delivery occurred. Bone lead burden was determined with in-vivo K-x-ray fluorescence of the tibia (cortical bone) and the patella (trabecular bone). The authors transformed anthropometric measurements to an ordinal 5-category scale, and the association of measurements with other factors was evaluated with ordinal logistic-regression models. Mean bone lead levels were 9.8 μg/gm bone mineral and 14.4 μg/gm bone mineral for the tibia and patella, respectively. Birth length of newborns decreased as tibia lead levels increased. Compared with women in the lower quintiles of the distribution of tibia lead, those in the upper quintile had a 79% increase in risk of having a lower birth length newborn (odds ratio = 1.79; 95% confidence interval = 1.10, 3.22). The authors adjusted by birth weight, and the effect was attenuated—but nonetheless significant. Patella lead was positively and significantly related to the risk of a low head circumference score; this score remained unaffected by inclusion of birth weight. The authors estimated the increased risk to be 1.02 per μg lead/gm bone mineral (95% confidence interval = 1.01, 1.04 per μg lead/gm bone mineral). Odds ratios did not vary substantially after the authors adjusted for birth weight and other important determinants of head circumference.

Electrocardiographic conduction disturbances in association with low-level lead exposure (the Normative Aging Study)

Recent research indicates that cumulative exposure to lead may be more toxic than previously thought. This study was undertaken to examine the relation of low-level lead exposure to electrocardiographic (ECG) conduction disturbances among 775 men who participated in the Normative Aging Study (average age 68 years; range 48 to 93). We used K-x-ray fluorescence to measure lead levels in the tibia and patella, and graphite furnace atomic absorption spectroscopy to measure blood lead levels. The mean (SD) values for blood lead, tibia lead, and patella lead were 5.8 (3.4) microg/dl, 22.2 (13.4) microg/g, and 30.8 (19.2) microg/g, respectively. Bone lead levels were found to be positively associated with heart rate-corrected QT and QRS intervals, especially in younger men. Specifically, in men <65 years of age, a 10 microg/g increase in tibia lead was associated with an increase in the QT interval of 5.03 ms (95% confidence interval [CI], 0.83 to 9.22) and with an increase in the QRS interval of 4.83 ms (95% CI, 1.83 to 7.83) in multivariate regression models. In addition, an elevated bone lead level was found to be positively associated with an increased risk of intraventricular block in men <65 years of age and with an increased risk of atrioventricular (AV) block in men > or = 65 years of age. After adjustment for age and for serum high-density lipoprotein (HDL) level, a 10 microg/g increase in tibia lead was associated with an odds ratio (OR) of 2.23 (95% CI, 1.28 to 3.90) for intraventricular block in men <65 years of age and with an OR of 1.22 (95% CI, 1.02 to 1.47) for AV block in men > or = 65 years of age. Blood lead level was not associated with any of the ECG outcomes examined. The results suggest that cumulative exposure to lead, even at low levels, may depress cardiac conduction.

Dietary calcium supplements to lower blood lead levels in lactating women: a randomized placebo-controlled trial.

Background. Pregnancy and breastfeeding mobilize lead stored in bone, which may be a hazard for the fetus and infant. We tested the hypothesis that in lactating women a dietary calcium supplement will lower blood lead levels. Methods. Between 1994 and 1995 we conducted a randomized trial among women in Mexico City. Lactating women (N = 617; mean age = 24 years; mean blood lead level = 8.5 ug/dL) were randomly assigned to receive either calcium carbonate (1200 mg of elemental calcium daily) or placebo in a double-blind trial. Blood samples were obtained at baseline, and 3 and 6 months after the trial began. Blood lead was determined by graphite furnace atomic absorption spectroscopy. Bone lead was measured at baseline with a 109cd K x-ray fluorescence instrument. The primary endpoint was change in maternal blood lead level, which was analyzed in relation to supplement use and other covariates by multivariate generalized linear models for longitudinal observations. Results. An intention-to-treat analysis showed that women randomized to the calcium supplements experienced a small decline in blood lead levels (overall reduction of 0.29 ug/dL; 95% confidence interval = −0.85 to 0.26). The effect was more apparent among women who were compliant with supplement use and had high bone lead levels (patella bone lead ≥5 &mgr;g/gm bone). Among this subgroup, supplement use was associated with an estimated reduction in mean blood lead of 1.16 ug/dL (95% confidence interval = −2.08 to −0.23), an overall reduction of 16.4%. Conclusions. Among lactating women with relatively high lead burden, calcium supplementation was associated with a modest reduction in blood lead levels.

Relationship of blood and bone lead to menopause and bone mineral density among middle-age women in Mexico City.

To describe the relationship of blood lead levels to menopause and bone lead levels, we conducted a cross-sectional study on 232 pre- or perimenopausal (PreM) and postmenopausal (PosM) women who participated in an osteoporosis-screening program in Mexico City during the first quarter of 1995. Information regarding reproductive characteristics and known risk factors for blood lead was obtained using a standard questionnaire by direct interview. The mean age of the population was 54.7 years (SD = 9.8), with a mean blood lead level of 9.2 microg/dL (SD = 4.7/dL) and a range from 2.1 to 32.1 microg/dL. After adjusting for age and bone lead levels, the mean blood lead level was 1.98 microg/dL higher in PosM women than in PreM women (p = 0.024). The increase in mean blood lead levels peaked during the second year of amenorrhea with a level (10.35 microg/dL) that was 3.51 microg/dL higher than that of PreM women. Other important predictors of blood lead levels were use of lead-glazed ceramics, schooling, trabecular bone lead, body mass index, time of living in Mexico City, and use of hormone replacement therapy. Bone density was not associated with blood lead levels. These results support the hypothesis that release of bone lead stores increases during menopause and constitutes an internal source of exposure possibly associated with health effects in women in menopause transition.

Validation of K x-ray fluorescence bone lead measurements by inductively coupled plasma mass spectrometry in cadaver legs.

K x-ray fluorescence (KXRF) systems are being used in a growing number of epidemiologic studies to measure bone lead levels as a biological marker of accumulated lead exposure. Although validation of the KXRF technique in lead-doped phantoms and bare bone specimens has been repeatedly demonstrated, few studies have compared KXRF to chemical measurements of actual intact cadaver limbs (with skin and soft tissues). In this study, lead levels in eight amputated human legs were measured by KXRF; after dissection, levels in the bare bones were again measured by KXRF and then by inductively coupled plasma mass spectrometry (ICP-MS). We observed close agreement between the KXRF and ICP-MS measurements with correlation coefficients for both the tibia and patella greater than 0.9. In this study we provide further support for the validity of KXRF measurements, particularly with respect to the patella.

Delta‐aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini‐Mental Status Examination in older men: the Normative Aging Study

Objective: To determine whether a polymorphism the in δ-aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults. Methods: The authors studied men participating in the Department of Veterans Affairs’ Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K-shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini-Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD-2, versus men without the allele. Results: Sixteen per cent of men carried the ALAD-2 allele. Median tibia and patella lead levels (first-third quartile) were 19 (13–28) and 27 (18–39) μg/g. Blood lead levels were consistent with non-occupational exposure: only 6% of men had levels ⩾10 μg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD-2 carriers, among whom a 3 μg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI −0.54 to 0.01), compared with a 0.04 point lower score (95% CI −0.16 to 0.07) among non-carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (pinteraction = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD-2 status. Conclusions: Although not statistically significant, these findings suggest that ALAD genotype may modify blood lead’s adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.

Determinants of bone and blood lead concentrations in the early postpartum period

OBJECTIVE This study investigated determinants of bone and blood lead concentrations in 430 lactating Mexican women during the early postpartum period and the contribution of bone lead to blood lead. METHODS Maternal venous lead was measured at delivery and postpartum, and bone lead concentrations, measured with in vivo K-xray fluorescence, were measured post partum. Data on environmental exposure, demographic characteristics, and maternal factors related to exposure to lead were collected by questionnaire. Linear regression was used to examine the relations between bone and blood lead, demographics, and environmental exposure variables. RESULTS Mean (SD) blood, tibial, and patellar lead concentrations were 9.5 (4.5) μg/dl, 10.2 (10.1) μg Pb/g bone mineral, and 15.2 (15.1) μg Pb/g bone mineral respectively. These values are considerably higher than values for women in the United States. Older age, the cumulative use of lead glazed pottery, and higher proportion of life spent in Mexico City were powerful predictors of higher bone lead concentrations. Use of lead glazed ceramics to cook food in the past week and increased patellar lead concentrations were significant predictors of increased blood lead. Patellar lead concentrations explained one third of the variance accounted for by the final blood lead model. Women in the 90th percentile for patella lead had an untransformed predicted mean blood lead concentration 3.6 μg/dl higher than those in the 10th percentile. CONCLUSIONS This study identified the use of lead glazed ceramics as a major source of cumulative exposure to lead, as reflected by bone lead concentrations, as well as current exposure, reflected by blood lead, in Mexico. A higher proportion of life spent in Mexico City, a proxy for exposure to leaded gasoline emissions, was identified as the other major source of cumulative lead exposure. The influence of bone lead on blood lead coupled with the long half life of lead in bone has implications for other populations and suggests that bone stores may pose a threat to women of reproductive age long after exposure has declined.

Season Modifies the Relationship between Bone and Blood Lead Levels: The Normative Aging Study

Abstract Bone serves as a repository for 75% and 90–95% of lead in children and adults, respectively. Bone lead mobilization heightens during times of increased bone turnover, such as pregnancy, lactation, hyperthyroidism, and the rapid growth of childhood. Blood lead levels show seasonal periodicity. Children demonstrate peak blood lead levels in midsummer and a secondary peak in late winter. Pregnant women demonstrate the highest mean blood lead levels in winter (January-March) and the lowest in summer (July-September). This fluctuation in blood lead levels may be related to seasonal patterns of environmental exposures, but it may also be partially related to the increased mobilization of bone lead stores during the winter months. We performed bone lead measurements using a K-x-ray fluorescent instrument to determine micrograms of lead per gram of bone mineral (parts per million) in middle-aged and elderly men who participated in the Normative Aging Study. We obtained measurements of blood and bone lead during the high sun exposure months of May-August (summer; n = 290); the intermediate sun exposure months of March, April, September, and October (spring/fall; n = 283); and the low sun exposure months of November-February (winter; n = 191). Mean blood lead concentrations were 5.8 μg/dl, 6.1 μg/dl, and 6.6 μg/dl for the summer, spring/fall, and winter, respectively. Mean patella (trabecular bone) lead concentrations were 34.3 μg/gm, 29.7 μ/gm, and 29.0 μg/gm for the summer, spring/fall, and winter time periods, respectively. In multivariate regression models, adjusted for age, smoking, alcohol ingestion, and dietary intake of iron and vitamin C, the authors found a strong interaction between season and bone lead level—with bone lead levels exerting an almost 2-fold greater influence on blood levels during the winter months than the summer months. The authors concluded that elevated blood lead levels in winter may be related to increased mobilization of endogenous bone lead stores, potentially from decreased exposure to sunlight, lower levels of activated vitamin D, and enhanced bone resorption.