Association between blood lead exposure and mental health in pregnant women: Results from the Japan environment and children's study.

OBJECTIVE: Although environmental lead exposure has decreased, several studies have shown that low-level lead exposure can result in adverse psychological symptoms. However, few studies have examined lead neurotoxicity in pregnant women. We investigated the association between lead exposure and psychological symptoms in pregnant women, and between socio-economic status and blood lead levels. METHODS: Blood lead levels were measured in 17,267 pregnant women in the Japan Environment and Children's Study. Odds ratios (ORs) for high blood lead levels were calculated using multinomial logistic regression. Psychological symptoms were assessed using the Kessler Psychological Distress Scale (K6). ORs for depression (K6 ≥ 13 or ≥5) were calculated using logistic regression with adjustment for potential confounders. RESULTS: The geometric mean of whole blood lead levels was 0.58 µg/dl (range 0.14-6.75 µg/dl). Higher blood lead levels were associated with older age (OR 1.79, 9 5% confidence interval [CI] 1.46-2.19), unmarried status (OR 1.75, 95 % CI 1.31-2.33), lower household income (OR 1.76, 95 % CI 1.38-2.24), and lower educational attainment (OR 1.34, 95 % CI 1.20-1.48). The percentage of women with K6 scores ≥13 and ≥5 was 3 % and 28.2 %, respectively. There was no significant association between lead exposure and K6 score (K6 ≥ 13: OR 1.00, 95 % CI 0.76-1.32; K6 ≥ 5: OR 0.98, 95 % CI 0.88-1.09). CONCLUSION: Our results indicate a small but significant association between higher blood lead levels and lower socio-economic status in a population with low blood lead levels, but no association between low-level lead exposure and psychological symptoms.

Neurotoxicity of low-level lead exposure: History, mechanisms of action, and behavioral effects in humans and preclinical models.

Lead is a neurotoxin that produces long-term, perhaps irreversible, effects on health and well-being. This article summarizes clinical and preclinical studies that have employed a variety of research techniques to examine the neurotoxic effects of low levels of lead exposure. A historical perspective is presented, followed by an overview of studies that examined behavioral and cognitive outcomes. In addition, a short summary of potential mechanisms of action is provided with a focus on calcium-dependent processes. The current level of concern, or reference level, set by the CDC is 5 µg/dL of lead in blood and a revision to 3.5 µg/dL has been suggested. However, levels of lead below 3 µg/dL have been shown to produce diminished cognitive function and maladaptive behavior in humans and animal models. Because much of the research has focused on higher concentrations of lead, work on low concentrations is needed to better understand the neurobehavioral effects and mechanisms of action of this neurotoxic metal.

Lead exposure-induced cognitive impairment through RyR-modulating intracellular calcium signaling in aged rats.

Lead is widely distributed in the environment and has become a global public health issue. It is well known that lead exposure induces not only neurodevelopmental toxicity but also neurodegenerative diseases, with learning and memory impairment in the later stage. However, the molecular mechanisms remain elusive. The present study investigated the effects of early life and lifetime lead exposure on cognition and identified the molecular mechanisms involved in aged rats. The results herein demonstrated that the lead concentration in peripheral blood and brain tissues in aged rats was significantly increased in a lead dose-dependent manner. High-dose lead exposure caused cognitive functional impairment in aged rats, concomitant with a longer escape latency and a lower frequency of crossing the platform via Morris water maze testing compared to those in the control and low-dose lead exposure groups. Importantly, neuron functional defects were still observed even in early life lead exposure during the prenatal and weaning periods in aged rats. The neurotoxicity induced by lead exposure was morphologically evidenced by a recessed nuclear membrane, a swollen endoplasmic reticulum, and mitochondria in the neurons. Mechanistically, the exposure of aged rats to lead resulted in increasing free calcium concentration, reactive oxygen species, and apoptosis in the hippocampal neurons. Lead exposure increased RyR3 expression and decreased the levels of p-CaMKIIα/CaMKIIα and p-CREB/CREB in the hippocampus of aged rats. These findings indicated that early life lead exposure-induced cognition disorder was irreversible in aged rats. Lead-induced neurotoxicity might be related to the upregulation of RyR3 expression and high levels of intracellular free calcium with increasing lead concentration in injured neurons.

Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA normative aging study.

BACKGROUND AND AIMS: Lead exposure in children and occupationally exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure-as measured by lead in bone-and performance on the grooved pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS). METHODS: GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (s) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome. RESULTS: The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7)µg/g and 19.2 (14.6)µg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (ß per 15µg/g bone=4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (ß per 20µg/g=3.93, 95% CI: 1.11, 6.76, p=0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (ß per 15µg/g bone=1.27, 95% CI: 0.24, 2.29, p=0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption. CONCLUSIONS: Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.

Association of maternal and child blood lead and hemoglobin levels with maternal perceptions of parenting their young children.

Biological and psychosocial factors affect child development and behavior. Whereas biological underpinnings behind the neurotoxic effects of lead are studied extensively, the effects of psychosocial factors contributing to poor behavioral outcomes in lead-exposed children are not well understood. Parental attributes and practices may moderate or mediate the effects of lead on children's behavioral outcomes. We investigated the hypothesis that maternal and child lead and hemoglobin levels are associated with maternal perceptions of their parenting. Specifically, we hypothesized that children with higher blood lead (BLL) and lower hemoglobin concentrations would be associated with poorer maternal self-assessments of their parenting skills or the mother-child relationship. Children aged 13-55 months and their mothers (n=109) were recruited from among the participants of a previous lead and anemia screening study and from preschools in Montevideo, Uruguay. The mother-child pair attended two study visits: one to collect biological samples and answer demographic and child questionnaires, including statements regarding parenting; and a second to evaluate maternal IQ, depression and stress, and child development. Of the children, 51.6% had blood lead concentrations (BLLs) ≥ 5 µg/dL, 18.0% had anemia, and 8% had both conditions. Among mothers, 48.4% had BLLs ≥ 5 µg/dL, 16.0% had anemia, and 11% had both. BLLs ≥ 5 µg/dL in mother or child were associated with lower maternal perceptions of being skilled at discipline (p<0.05). Maternal anemia was associated with lower likelihood that mothers would let their children explore and play (p<0.05), whereas child anemia was associated with maternal perception of lower emotional support (p<0.01). In addition to shared environmental exposures, parenting and family interactions need to be considered as potentially contributing factors to poorer outcomes in lead-exposed children.

Severe neurotoxicity following ingestion of tetraethyl lead.

Organic lead compounds are potent neurotoxins which can result in death even from small exposures. Traditionally, these compounds are found in fuel stabilizers, anti-knock agents, and leaded gasoline. Cases of acute organic lead intoxication have not been reported for several decades. We report a case of a 13-year-old Iraqi male who unintentionally ingested a fuel stabilizer containing 80-90% tetraethyl lead, managed at our combat support hospital. The patient developed severe neurologic symptoms including agitation, hallucinations, weakness, and tremor. These symptoms were refractory to escalating doses of benzodiazepines and ultimately required endotracheal intubation and a propofol infusion. Adjunctive therapies included chelation, baclofen, and nutrition provided through a gastrostomy tube. The patient slowly recovered and was discharged in a wheelchair 20 days after ingestion, still requiring tube feeding. Follow-up at 62 days post-ingestion revealed near-resolution of symptoms with residual slurred speech and slight limp. This case highlights the profound neurotoxic manifestations of acute organic lead compounds.

Blood lead, serum homocysteine, and neurobehavioral test performance in the third National Health and Nutrition Examination Survey.

Regression analysis was used to estimate and test for relationships between blood lead, serum folate, red blood cell folate, serum vitamin B12, serum homocysteine, and neurobehavioral test performance in adults, 20-59 years old, participating in the third National Health and Nutrition Examination Survey. The three neurobehavioral tests included in the survey were simple reaction time, symbol-digit substitution, and serial digit learning. Serum folate, red blood cell folate, and serum vitamin B12 decreased as the blood lead concentration increased. Serum homocysteine increased as the blood lead concentration increased. Serum homocysteine decreased as the serum folate and serum vitamin B12 concentrations increased. Neurobehavioral test performance was not related to the blood lead, serum folate, or serum vitamin B12 concentrations. In adults 20-39 years old, performance on the serial digit learning test improved as the serum homocysteine concentration increased. In adults 40-59 years old, neurobehavioral test performance was not related to the serum homocysteine concentration. Homocysteine may impair cognitive function by acting at N-methyl-D-aspartate receptors, and improve cognitive function by acting at N-methyl-D-aspartate or gamma-aminobutyric acid receptors.

Impact of cognitive reserve on the relationship of lead exposure and neurobehavioral performance.

BACKGROUND: Cognitive reserve (CR)--a construct studied in many neurologic disorders--refers to the maintenance of cognitive performance in spite of ongoing underlying brain pathology. OBJECTIVE: We hypothesized that a dose-effect relationship would exist between chronic occupational lead exposure and cognitive effects in workers with low CR but not in workers with high CR and identical lead exposure, and that level of CR would not influence the relationship between lead exposure and motor performance. METHODS: We stratified currently employed lead smelter workers by Wide Range Achievement Test-R for reading (WRAT), a recognized measure of CR, into loCR and hiCR groups. From these two groups we matched 56 pairs on working lifetime weighted blood lead (TWA). We performed a factor analysis on 14 neuropsychological outcome variables. Within each CR group regression analyses after adjusting for age, alcohol use, and depression scale score tested for dose-effect relationships between TWA and outcome variables. RESULTS: Both CR groups had comparable age, years employed, alcohol use, and current blood lead levels. Factor analysis provided three factors and five tests used in the regression analyses. Significant dose-effect relationships between TWA and cognitive tests present only in the loCR group included Attention Factor and Digit Symbol. Both CR groups demonstrated significant dose-effect relationships on the Motor Factor. CONCLUSION: This study found that cognitive reserve protects against the effect of chronic lead exposure on select measures of cognitive performance but not on motor performance.

Possibilities of newer ALAD polymorphism influencing human susceptibility to effects of inorganic lead on the neurobehavioral functions.

OBJECTIVE: A cross-sectional study was conducted to study the association between some new ALAD polymorphism and susceptibility to effects of inorganic lead on the neurobehavioral functions. METHOD: We recruited 120 healthy male workers with lead exposure in a factory which manufacture lead stabilizer. The ALAD SNPs studied were HpyCH4, HpyIV RFLP in intron 6, Rsa and Msp RFLP in exon 4, Sau3A in intron 12 and Rsa39488 in exon 5. The World Health Organization Neurobehavioral Core Test Battery (WHO-NCTB) and a few other tests were used. General linear model (GLM) was applied to compare outcome scores between subgroups of each ALAD SNP while controlling for possible confounders. RESULTS: The mean age of the workers was 39.7 years (S.D. 10.7), mean exposure duration of 10.2 years (S.D. 7.9) and mean blood lead of 22.1 microg/dl (S.D. 9.4). Among the 6 SNPs studied, Rsa and Rsa39488 appear to be the main candidate SNPs. Workers with Rsa and Rsa39488 ALAD 2-2 genotypes fare significantly better in the Aiming Pursue Test Correct (AC), Groove Peg Board non-preferred hand (GPNP), Groove Peg Board Mean (GPM), San Ana Preferred Hand (SAP), San Ana Both Hands (SAB) and AC, GPNH, GPM, Digit Symbol (DIS) tests; respectively compared to Rsa and Rsa39488 ALAD 1-1/1-2 genotypes adjusted for age, race, exposure duration and blood lead levels. CONCLUSION: The presence of the homozygote Rsa and Rsa39488 ALAD 2-2 seems to offer some protection against the effect of lead on motor dexterity function. While it may appear that newer ALAD polymorphism other than the commonly reported Msp SNP might influence human susceptibility to effects of inorganic lead on the neurobehavioral functions further study involving a larger cohort of workers with Rsa and Rsa39488 ALAD2 allele would be needed to confirm this inference.

Multivariate modeling of age and retest in longitudinal studies of cognitive abilities.

Longitudinal multivariate mixed models were used to examine the correlates of change between memory and processing speed and the contribution of age and retest to such change correlates. Various age- and occasion-mixed models were fitted to 2 longitudinal data sets of adult individuals (N>1,200). For both data sets, the results indicated that the correlation between the age slopes of memory and processing speed decreased when retest effects were included in the model. If retest effects existed in the data but were not modeled, the correlation between the age slopes was positively biased. The authors suggest that although the changes in memory and processing speed may be correlated over time, age alone does not capture such a covariation.

Differential effects of lead exposure on components of verbal memory.

AIMS: To determine if verbal learning and memory requiring acquisition and retention of information is differentially affected by lead exposure. METHODS: The Rey Auditory Verbal Learning Test (RAVLT), a test of verbal learning and memory, was administered to 256 English speaking lead smelter workers who had a mean (SD) age of 41 (9.4) years and employment duration of 17 (8.1) years. Lead exposure variables, based on up to 25 years of prior blood lead data, included a mean (SD) current blood lead (PbB) of 28 (8.8) microg/dl, working lifetime time weighted average blood lead (TWA) of 39 (12.3) microg/dl, and working lifetime integrated blood lead index (IBL) of 728 (434.4) microg-y/dl. Associations of these chronic and recent lead exposure variables with measures from the RAVLT were modelled through multiple linear regressions after controlling for age and educational achievement. RESULTS: PbB was not associated with any of the RAVLT variables. However, TWA and IBL contributed significantly to the explanation of variance of measures of encoding/storage and retrieval but not to immediate memory span, attention, and learning. Grouping study participants by RAVLT performance according to three recognised clinical memory paradigms showed significantly higher TWA and IBL in the group with "generalised memory impairment" after adjusting for age and educational achievement. We examined recall mechanisms in each group by serial position in the word list and found stronger primacy (recall of words from the beginning of the list) in the "no impairment" and "retrieval difficulties" groups while the "generalised memory impairment" group had better performance on recency (recall of words from the end of the list). CONCLUSIONS: Lead exposure over years and not PbB interfered with the organisation and recall of previously learned verbal material. Chronic lead exposure affects encoding/storage and retrieval of verbal information.

[Late sequelae of tetraethyl lead poisoning]. / Odlegle nastepstwa zatrucia czteroetylkiem olowiu.

In our previous study a tetraethyl lead poisoning due to a rural environmental exposure of four family members was described. A differently intensified OUN dysfunction dominated clinical picture. Cognition status and degree of OUN dysfunction was monitored using generally accepted neurobehavioral test battery. The tests applied were fitted individually to each poisoned family member in accordance to current intensification of symptoms. Basing on the neurobehavioral performance results a consecutive imagine techniques were introduced to full CNS evaluation of intoxicated patients. Results of neuropsychological monitoring in 12 months period were compared to brain CT, SPET 99mTc-ECD used to evaluation of regional brain perfusion disturbances, MRI and MRS and presented in the study.

Cognitive deficits and magnetic resonance spectroscopy in adult monozygotic twins with lead poisoning.

Seventy-one-year-old identical twin brothers with chronic lead poisoning were identified from an occupational medicine clinic roster. Both were retired painters, but one brother (J.G.) primarily removed paint and had a history of higher chronic lead exposure. Patella and tibia bone lead concentrations measured by K-X-ray fluorescence in each brother were 5-10 times those of the general population and about 2.5 times higher in J.G. than in his brother (E.G.). Magnetic resonance spectroscopy (MRS) studies examined N-acetylaspartate:creatine ratios, a marker of neuronal density. Ratios were lower in J.G. than in his brother. Scores on neurocognitive tests that assess working memory/executive function were below expectation in both twins. Short-term memory function was dramatically worse in J.G. than in his brother. These results demonstrate some of the more subtle long-term neurologic effects of chronic lead poisoning in adults. In particular, they suggest the presence of frontal lobe dysfunction in both twins, but more dramatic hippocampal dysfunction in the brother with higher lead exposure. The MRS findings are consistent with the hypothesis that chronic lead exposure caused neuronal loss, which may contribute to the impairment in cognitive function. Although a causal relation cannot be inferred, the brothers were genetically identical, with similar life experiences. Although these results are promising, further study is necessary to determine whether MRS findings correlate both with markers of lead exposure and tests of cognitive function. Nevertheless, the results point to the potential utility of MRS in determining mechanisms of neurotoxicity not only for lead but also for other neurotoxicants as well.

Assessment of neurobehavioral performance as a function of current and cumulative occupational lead exposure.

A cross sectional field study was planned to assess neurotoxic effects caused by low-level occupational lead exposure. Two groups of 66 workers and 86 controls were examined with a battery including a questionnaire on neurotoxic symptoms, the measure of performance at neurobehavioral testing, the detection of visual contrast sensitivity, and the dosage of serum prolactin. Both current and cumulative exposure to lead were defined. The average PbB was 27.50 +/- 28 microg/dl (median 28, range 6-61) in the exposed and 8.11 +/- 4.47 microg/dl (median 7, range 2-21). The test results were controlled for possible confounders including age, schooling, alcohol and coffee intake. Significant differences were observed between exposed and controls regarding neurotoxic symptoms reporting, the exposed reporting more frequently mood changes and abnormal fatigue. The exposed subjects showed a decreased visual contrast sensitivity, and a marked increase of prolactin secretion. No changes emerged regarding neurobehavioral testing. The alterations observed resulted associated to the current lead exposure and not to the cumulative indices. A safe exposure level was calculated on the basis of dose-response relationship with prolactin alteration, yielding a PbB value of 10 microg/dl.