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.

Blood lead levels and associated sociodemographic factors among preschool children in the South Eastern region of China.

Children are especially vulnerable to lead toxicity, and exposure to lead has been linked to poor school performance and delinquency in children and adolescents. Even low-level lead exposure [blood lead level (BLL) <10 µg/dL] can cause intellectual deficit. In China, BLLs in children decreased slightly after the phasing out of lead in gasoline, but few studies have examined the sociodemographic factors associated with BLL above 10 µg/dL. In this study, we sought to examine the hypothesis that sociodemographic factors predict BLLs. We measured BLLs of 1344 preschool children (3-5 years old) from the China Jintan Child Cohort Study. Children's sociodemographic and health statuses, as well as parental sociodemographic data, were collected using questionnaires. Regression models were used to explore the association between sociodemographic factors and log-transformed BLLs as well as the relationship between sociodemographic factors and the risk of BLL ≥10 µg/dL. We found the median BLL to be 6.2 µg/dL (range: 1.8-32.0 µg/dL); 8% of children had BLLs ≥10 µg/dL. Boys had a higher median BLL (6.4 µg/dL) than girls and were more likely to have BLL ≥10 µg/dL [odds ratio = 1.77, 95% confidence interval 1.14, 2.74]. BLLs increased as children aged, with a median BLL of 6.6 µg/dL among 5-year-old children. Children with siblings had a higher average BLL and greater prevalence of a BLL ≥10 µg/dL than those without siblings. Living in a crowded neighbourhood was also associated with increased BLLs. Mother's lower education, father's occupation (as professional worker) and parental smoking at home were associated with increased BLLs. This study shows that children in this area still have relatively high BLLs even after the phasing out of leaded gasoline. Both children's and parental factors and community condition are associated with increased BLLs. Future efforts are needed to identify other sources of exposure and develop targeted prevention strategies.

Community-based participatory research (CBPR) approach to study children's health in China: experiences and reflections.

BACKGROUND: Community-based participatory research principles have been successfully applied to public health research in U.S. settings. While there is a long history of collaboration between government and communities in China, to date, community-based participatory research has not been used in children's environmental health studies. METHOD: This article describes how community-based participatory research principles were applied by an international research group to the China Jintan Child Cohort Study, a longitudinal study of malnutrition and lead exposure on cognitive and neurobehavioral development. Challenges emerged and lessons learned from implementing the study were discussed and recommendations were presented. CONCLUSION: We conclude that the community-based participatory research model can be applied in conducting and promoting environmental health research in China and researchers should be prepared for special challenges and cultural constraints in the implementation of the research in regards to human subject regulations, information dissemination, and culture.

Regular breakfast and blood lead levels among preschool children.

BACKGROUND: Previous studies have shown that fasting increases lead absorption in the gastrointestinal tract of adults. Regular meals/snacks are recommended as a nutritional intervention for lead poisoning in children, but epidemiological evidence of links between fasting and blood lead levels (B-Pb) is rare. The purpose of this study was to examine the association between eating a regular breakfast and B-Pb among children using data from the China Jintan Child Cohort Study. METHODS: Parents completed a questionnaire regarding children's breakfast-eating habit (regular or not), demographics, and food frequency. Whole blood samples were collected from 1,344 children for the measurements of B-Pb and micronutrients (iron, copper, zinc, calcium, and magnesium). B-Pb and other measures were compared between children with and without regular breakfast. Linear regression modeling was used to evaluate the association between regular breakfast and log-transformed B-Pb. The association between regular breakfast and risk of lead poisoning (B-Pb≥10 µg/dL) was examined using logistic regression modeling. RESULTS: Median B-Pb among children who ate breakfast regularly and those who did not eat breakfast regularly were 6.1 µg/dL and 7.2 µg/dL, respectively. Eating breakfast was also associated with greater zinc blood levels. Adjusting for other relevant factors, the linear regression model revealed that eating breakfast regularly was significantly associated with lower B-Pb (beta = -0.10 units of log-transformed B-Pb compared with children who did not eat breakfast regularly, p = 0.02). CONCLUSION: The present study provides some initial human data supporting the notion that eating a regular breakfast might reduce B-Pb in young children. To our knowledge, this is the first human study exploring the association between breakfast frequency and B-Pb in young children.

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.

Low level lead exposure: history and discovery.

The history of lead toxicity spans 2 millennnia. With increasingly sensitive methods, deficits due to lead exposure have been demonstrated at lower and lower doses. Persuasive evidence suggests that no threshold for lead toxicity exists.

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.

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.

Pesticide testing in humans: ethics and public policy.

Pesticide manufacturers have tested pesticides increasingly in human volunteers over the past decade. The apparent goal of these human studies is to establish threshold levels for symptoms, termed "no observed effect levels." Data from these studies have been submitted to the U.S. Environmental Protection Agency (EPA) for consideration in standard setting. There are no required ethical guidelines for studies of pesticides toxicity conducted in humans, no governmental oversight is exercised, and no procedures have been put in place for the protection of human subjects. To examine ethical and policy issues involved in the testing of pesticides in humans and the use of human data in standard setting, in February 2002 the Center for Children's Health and the Environment of the Mount Sinai School of Medicine convened an expert workshop for ethicists, physicians, toxicologists, and policy analysts. After a peer consensus process, participants developed a number of ethical and public policy recommendations regarding the testing of pesticides in humans. Participants also strongly encouraged active biomonitoring of every pesticide currently in use to track human exposure, particularly in vulnerable populations, and to assess adverse effects on health.

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.