Prenatal lead levels, plasma amyloid ß levels, and gene expression in young adulthood.

BACKGROUND: Animal studies suggest that early-life lead exposure influences gene expression and production of proteins associated with Alzheimer's disease (AD). OBJECTIVES: We attempted to assess the relationship between early-life lead exposure and potential biomarkers for AD among young men and women. We also attempted to assess whether early-life lead exposure was associated with changes in expression of AD-related genes. METHODS: We used sandwich enzyme-linked immunosorbent assays (ELISA) to measure plasma concentrations of amyloid ß proteins Aß40 and Aß42 among 55 adults who had participated as newborns and young children in a prospective cohort study of the effects of lead exposure on development. We used RNA microarray techniques to analyze gene expression. RESULTS: Mean plasma Aß42 concentrations were lower among 13 participants with high umbilical cord blood lead concentrations (≥ 10 µg/dL) than in 42 participants with lower cord blood lead concentrations (p = 0.08). Among 10 participants with high prenatal lead exposure, we found evidence of an inverse relationship between umbilical cord lead concentration and expression of ADAM metallopeptidase domain 9 (ADAM9), reticulon 4 (RTN4), and low-density lipoprotein receptor-related protein associated protein 1 (LRPAP1) genes, whose products are believed to affect Aß production and deposition. Gene network analysis suggested enrichment in gene sets involved in nerve growth and general cell development. CONCLUSIONS: Data from our exploratory study suggest that prenatal lead exposure may influence Aß-related biological pathways that have been implicated in AD onset. Gene network analysis identified further candidates to study the mechanisms of developmental lead neurotoxicity.

Low-level environmental lead exposure in childhood and adult intellectual function: a follow-up study.

BACKGROUND: Early life lead exposure might be a risk factor for neurocognitive impairment in adulthood. OBJECTIVES: We sought to assess the relationship between early life environmental lead exposure and intellectual function in adulthood. We also attempted to identify which time period blood-lead concentrations are most predictive of adult outcome. METHODS: We recruited adults in the Boston area who had participated as newborns and young children in a prospective cohort study that examined the relationship between lead exposure and childhood intellectual function. IQ was measured using the Wechsler Abbreviated Scale of Intelligence (WASI). The association between lead concentrations and IQ scores was examined using linear regression. RESULTS: Forty-three adults participated in neuropsychological testing. Childhood blood-lead concentration (mean of the blood-lead concentrations at ages 4 and 10 years) had the strongest relationship with Full-Scale IQ (ß = -1.89 ± 0.70, p = 0.01). Full-scale IQ was also significantly related to blood-lead concentration at age 6 months (ß = -1.66 ± 0.75, p = 0.03), 4 years (ß = -0.90 ± 0.41, p = 0.03) and 10 years (ß = -1.95 ± 0.80, p = 0.02). Adjusting for maternal IQ altered the significance of the regression coefficient. CONCLUSIONS: Our study suggests that lead exposure in childhood predicts intellectual functioning in young adulthood. Our results also suggest that school-age lead exposure may represent a period of increased susceptibility. Given the small sample size, however, the potentially confounding effects of maternal IQ cannot be excluded and should be evaluated in a larger study.

Past occupational exposure to lead: association between current blood lead and bone lead.

Mobilization of lead from bone is known to increase with age. The authors performed the current study to determine whether there was an association between current blood lead and bone lead in workers with no current exposure but with significant past workplace exposure. The authors assessed 58 men, aged 40 to 76 years, who had earlier exposure to lead and determined both current blood lead levels and bone lead levels. At the time of the current assessment, the average blood lead level was 10.9 microg/dL and tibia bone lead concentrations ranged from -12.5 to 223.3. The authors divided workers into 3 groups by age (40-49, 50-59, and 60-76). Correlations between blood lead and bone lead were highest in the 2 oldest age groups (.49 and .75, respectively). Hierarchical regression analysis was significant for an interaction between bone lead and age in predicting blood lead (the combination of age and bone lead significantly predicted an increase in current blood lead levels). The results support the hypothesis that lead stored in bone is a significant source of blood lead later in life. Older workers with past occupational exposure may face a particular risk for recirculation of lead in blood with advancing age.

Low-level environmental lead exposure and children's intellectual function: an international pooled analysis.

Lead is a confirmed neurotoxin, but questions remain about lead-associated intellectual deficits at blood lead levels < 10 microg/dL and whether lower exposures are, for a given change in exposure, associated with greater deficits. The objective of this study was to examine the association of intelligence test scores and blood lead concentration, especially for children who had maximal measured blood lead levels < 10 microg/dL. We examined data collected from 1,333 children who participated in seven international population-based longitudinal cohort studies, followed from birth or infancy until 5-10 years of age. The full-scale IQ score was the primary outcome measure. The geometric mean blood lead concentration of the children peaked at 17.8 microg/dL and declined to 9.4 microg/dL by 5-7 years of age; 244 (18%) children had a maximal blood lead concentration < 10 microg/dL, and 103 (8%) had a maximal blood lead concentration < 7.5 microg/dL. After adjustment for covariates, we found an inverse relationship between blood lead concentration and IQ score. Using a log-linear model, we found a 6.9 IQ point decrement [95% confidence interval (CI), 4.2-9.4] associated with an increase in concurrent blood lead levels from 2.4 to 30 microg/dL. The estimated IQ point decrements associated with an increase in blood lead from 2.4 to 10 microg/dL, 10 to 20 microg/dL, and 20 to 30 microg/dL were 3.9 (95% CI, 2.4-5.3), 1.9 (95% CI, 1.2-2.6), and 1.1 (95% CI, 0.7-1.5), respectively. For a given increase in blood lead, the lead-associated intellectual decrement for children with a maximal blood lead level < 7.5 microg/dL was significantly greater than that observed for those with a maximal blood lead level > or = 7.5 microg/dL (p = 0.015). We conclude that environmental lead exposure in children who have maximal blood lead levels < 7.5 microg/dL is associated with intellectual deficits.

Values, errors, and precautions.

In the environmental health literature, errors in interpreting studies or data are not infrequent. Many are of the Type II variety. Common solecisms of this type are: treating the criterion of p < 0.05 as a sacrament; demanding complete confounder control; arguing for the existence of phantom confounders; arguing that the effect size is trivial; building nonveridical models; arguing for no effect from inadequate sample size; demanding causal proof; arguing that causality is reversed; conducting a ballot of published studies. These are examined in this paper.

Implications of the Precautionary Principle in research and policy-making.

The Precautionary Principle (PP) has recently been formally introduced into national and international law. The key element is the justification for acting in the face of uncertainty. The PP is thereby a tool for avoiding possible future harm associated with suspected, but not conclusive, environmental risks. Under the PP, the burden of proof is shifted from demonstrating the presence of risk to demonstrating the absence of risk and it is the responsibility of the producer of a technology to demonstrate its safety rather than the responsibility of public authorities to show harm. Past experiences show the costly consequences of disregarding early warnings about environmental hazards. Today, the need for applying the PP is even greater. New research is needed to expand current insight into disease causation, to elucidate the full scope of potential adverse implications resulting from environmental pollutants, and to identify opportunities for prevention. Research approaches should be developed and strengthened to counteract innate ideological biases and to support our confidence in applying the PP for decision-making in the public policy arena.

Bone lead levels in adjudicated delinquents. A case control study.

BACKGROUND: Lead exposure shares many risk factors with delinquent behavior, and bone lead levels are related to self-reports of delinquent acts. No data exist as to whether lead exposure is higher in arrested delinquents. The goal of this study is to evaluate the association between lead exposure, as reflected in bone lead levels, and adjudicated delinquency. METHODS: This is a case-control study of 194 youths aged 12-18, arrested and adjudicated as delinquent by the Juvenile Court of Allegheny County, PA and 146 nondelinquent controls from high schools in the city of Pittsburgh. Bone lead was measured by K-line X-ray fluorescence (XRF) spectroscopy of tibia. Logistic regression was used to model the association between delinquent status and bone lead concentration. Covariates entered into the model were race, parent education and occupation, presence of two parental figures in the home, number of children in the home and neighborhood crime rate. Separate regression analyses were also conducted after stratification on race. RESULTS: Cases had significantly higher mean concentrations of lead in their bones than controls (11.0+/-32.7 vs. 1.5+/-32.1 ppm). This was true for both Whites and African Americans. The unadjusted odds ratio for a lead level > or =25 vs. <25 ppm was 1.9 (95% CL: 1.1-3.2). After adjustment for covariates and interactions and removal of noninfluential covariates, adjudicated delinquents were four times more likely to have bone lead concentrations >25 ppm than controls (OR=4.0, 95% CL: 1.4-11.1). CONCLUSION: Elevated body lead burdens, measured by bone lead concentrations, are associated with elevated risk for adjudicated delinquency.