Neurotoxicity and Biomarkers of Lead Exposure: a Review

Kang-sheng Liu, Jia-hu Hao, Yu Zeng, Fan-chun Dai, and Ping-qing Gu

1State Key Laboratory of Reproductive Medicine, Department of Clinical Laboratory, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210029, China

2Department of Maternity and Child Health Care, School of Public Health, Anhui Medical University, Hefei 230032, China

3Child Health Care Department, 4Obstetrical Department, Nanjing Maternity and Child Health Care Hospital Affiliated to Nanjing Medical University, Nanjing 210004, China

5Department of Epidemiological and Health Statistics, School of Public Health of Nanjing Medical University, Nanjing 210029, China

IN some countries, there are many complex sources of lead exposure (mining activities, pollution from leaded gasoline remaining in the atmosphere and industrial emissions, cosmetics, etc.).1Routes of exposure to lead include contaminated air, water, soil, food, and consumer products. Occupational exposure is a common cause of lead poisoning in adults. According to estimates made by the National Institute of Occupational Safety and Health (NIOSH), more than 3 million workers in the United States are potentially exposed to lead in the workplace. One of the largest threats to children is lead paint that exists in many homes, especially older ones； thus children in older housing with chipping paint are at greater risk. Prevention of lead exposure can range from individual efforts (e.g. removing lead-containing items such as piping or blinds from the home) to nationwide policies (e.g. laws that ban lead in products or reduce allowable levels in water or soil).

A remarkable explosion in the literature about the health effects of lead has occurred since the dissemination of US Occupational Safety and Health Administration lead standards in 1993 stating that workers can attain blood lead levels up to 40 μg/dL for their working lifetime.2,3Since then, many longitudinal studies have provided evidence that cumulative lead dose causes cognitive dysfunction or decline.4The neurotoxic effects of lead in workers can be induced at blood lead (BPb) levels below 18 μg/dL, somewhat higher than the critical level of lead neurotoxicity in children (5 μg/dL).5Adverse health effects caused by lead exposure include intellectual and behavioral deficits in children, including hyperactivity； deficits in fine motor function, hand-eye coordination, and reaction time； and lowered performance on intelligence tests. Recent evidence has revealed other important health effects of lead exposure, such as hypertension and other cardiovascular outcomes,6renal disease.7Chronic lead exposure in adults can also lead to decreased fertility, cataracts, nerve disorders, muscle and joint pain, and memory or concentration problems. Extreme lead exposure can cause a variety of neurologic disorders, such as lack of muscular coordination, convulsions, and coma. As lead affects several enzymatic processes responsible for heme synthesis, the he- matologic system is also a highly sensitive target for lead toxicity.

BIOMARKERS AND BIOLOGICAL MONITORING OF LEAD EXPOSURE

Biological monitoring has been defined as the measure- ment and assessment of agents or their metabolites either in tissues, secreta, excreta, expired air or any combination of these to evaluate exposure and health risks compared with an appropriate reference.8-10The term biological marker is a general term used for a system that specifically measures an interaction between a biological system and a chemical, physical, or biological environmental agent. Biological monito- ring techniques are useful for risk assessment of toxic agents in the field of environmental health. Biomarkers are generally classified into three groups: biomarkers of exposure, effect, and susceptibility. A variety of biomarkers are available to monitor human exposure to lead. Appropriate selection and measurement of lead biomarkers of exposure are critically important for health care management purposes, public health decision making, and primary prevention synthesis. Although different biologic tissues and fluids (breast milk lead, blood, urine, bone, tooth, hair, and nail) have been used to test for lead exposure, no biomarker of bioavailable lead has been generally accepted.

The main body compartments that store lead are the blood, soft tissues, and bone； the half-life of lead in these tissues is measured in weeks for blood, months for soft tissues, and years for bone.11Lead in the bones, teeth, hair, and nails is bound tightly and not available to other tissues, and is generally thought not harmful.12In adults, 94% of absorbed lead is deposited in the bones and teeth, but children only store 70% in this manner, a fact which may partially account for the more serious health effects on children.13The estimated half-life of lead in bone is 20 to 30 years, and bone can introduce lead into the bloodstream long after the initial exposure is gone.14The half-life of lead in the blood in men is about 40 days, but it may be longer in children and pregnant women, whose bones are undergoing remodeling, which allows the lead to be continuously re- introduced into the bloodstream.13Also, if lead exposure takes place over years, clearance is much slower, partly due to the re-release of lead from bone.15Many other tissues store lead, but those with the highest concen- trations (other than blood, bone, and teeth) are the brain, spleen, kidneys, liver, and lungs.16

In a study of the environmental, dietary, demographic, and activity variables associated with biomarkers of lead exposure, BPb was found to be associated with: 1, housedust concentrations of lead； 2, the duration of time spent working in a closed workshop； 3, low-income people often live in old housing with lead paint and the year in which the subject moved into the residence.17An important weakness of BPb is its poor response to changes in exposure at high levels.18Other currently available biomarkers of internal lead dose have not yet been accepted by the scientific community as a reliable substitute for BPb measurement.19Nevertheless, in certain cases bone or teeth (for past exposures), feces (for current gastrointestinal exposure), or urine (for organic lead) are sometimes more useful than blood. As the plasma fraction is rapidly exchangeable in the blood, the toxic effects of lead are assumed to be primarily associated with plasma lead (PPb). Although PPb should be more germane than BPb to lead exposure and distribution, little is known about the association between PPb and clinical outcome. The determina- tion of PPb is problematic because erythrocyte hemolysis can shift the metal into the plasma and artificially increase PPb levels. Many researchers accept that a cumulative lead exposure integrated over many years, in bone for example, rather than a single BPb measurement of lead dose may be the most important determinant of some forms of toxicity. Bone Pb (BnPb) accounts for ＞ 94% of the adult body burden of lead (70% in children).20-22Hernandez-Avila and colleagues23reported a strong association between BnPb levels and serum lead levels of adults exposed to lead. The findings of this study indicated the potential role of the skeleton as an important source of endogenous labile lead that may not be adequately discerned through the measure- ment of BPb levels. The most informative recent epidemio- logic studies of the impact of lead on health are those that could derive estimates of both recent (BPb) and cumulative (BnPb) exposure for each participant. In a recent review of studies measuring both BPb and BnPb at exposure levels encountered after environmental exposure, the associa- tions between the biomarkers of cumulative dose (mainly in tibia) and cognitive function in adults were stronger and more consistent than were the associations with BPb levels.7Patella (kneecap) lead, representing a pool that may capture aspects of both current bioavailable and cumulative lead dose thus offering advantages over tibia or BPb, was used by Wright et al24to determine whether lead-exposure biomarkers are associated with declines in cognitive test scores in older persons. The researchers found that among subjects in the lowest quartile of patella lead levels, Mini-Mental Status Exam (MMSE) scores decreased by 0.03 points per year (CI=-0.07 to 0.005), whereas in the highest quartile, the MMSE score decreased by 0.13 points per year (CI=-0.19 to -0.07). Similar interactions were found between BPb levels and age. Increased levels of BnPb and BPb were found inversely associated with cognitive performance among older men, suggesting that lead exposure might accelerate age-associated cognitive decline.

In comparison to bone, teeth accumulate lead over the long term. The intrinsic importance of teeth as historical records of lead exposure has been recognized, tested and discussed for several decades. From the seminal papers of Rabinowitz to the more recent works of studies by Robbins et al,25,26research has revealed the value of dental enamel and dentine as biological indicators of exposure. Central of many of these studies has been the aim to develop a blood lead biomarker as an alternative to blood lead measurements (BPb). The latter are still the most reliable indicator of recent lead exposure, both for screening and for bio-monitoring purposes. As succinctly stated by Barbosa et al,27it appears impossible to differentiate between low-level chronic Pb exposure and a high-level short Pb exposure based on a single BPb measure- ment. By contrast, deciduous teeth are easy to collect (i.e. require non-invasive procedures), chemically stable and in theory provide a continuous record from in utero to several years after birth. Unfortunately, previous work has not had the desired degree of control over the temporal relation- ship between blood sampling and that part of the tooth corresponding to the exact time of sampling. This failure has been exacerbated by the different analytical tools employed, as a result of which, published tooth data have proven hard to interpret.28Recent studies have sought to resolve this problem using the neonatal line as a fixed point in time.29Whilst advancing our understanding, there remain issues to address concerning the processes governing the incorporation of lead into dental tissues and the stability of lead once incorporated.

The collection of urine lead (UPb) is favored for long-term biomonitoring, especially for occupational exposures. UPb originates from PPb that is filtered at the glomerular level and excreted through the kidneys. According to certain authors30UPb levels adjusted for glomerular filtration rate can serve as a proxy for PPb. Fukui et al31concluded that the correlation of UPb with BPb among workers occupationally exposed to lead was close enough to suggest that UPb can be a good alter- native to BPb on a group basis, but not close enough to allow UPb to predict BPb on an individual basis.

Although lead excreted in hair has been suggested for the assessment of lead exposure,32an extensive debate ensues about hair lead (HPb) as a biomarker (discussed in [27]). Hair is a biological specimen that is easily and non-invasively collected with minimal cost and is easily stored and transported to the laboratory for analysis. Such advantages should make hair an attractive biomonitoring substrate, at least superficially. Similar to hair, nails have many superficial advantages as a lead exposure biomarker, especially as specimen collection is noninvasive and simple and specimens are very stable after collection, not requiring special storage conditions. Nail lead (NPb) is considered to reflect long-term exposure because this compartment remains isolated from other metabolic activities in the body.33Because toenails are less affected than fingernails by exogenous environmental contamination, toenails have been preferred for lead-exposure studies. The lead concentration in nails depends on the age of the subject,34but apparently not on the subject's gender.35Saliva is a convenient source and therefore a potential substitute for blood as a biomarker for lead exposure.36Nevertheless, saliva has not been generally accepted as a reliable biomarker of lead exposure because of conflicting and unreliable saliva lead (SPb) measurements. Early research suggested an association between SPb levels and BPb and PPb levels.37,38Subsequently, data from a study by Thaweboon et al39compared BPb and SPb in an area highly contaminated from lead mining, Thailand. The geometric mean for the BPb content was 24.03 μg/dL (range 11.80-46.60 μg/dL) whereas the SPb content was 5.69 μg/dL (range 1.82-25.28 μg/dL), suggesting that saliva is not suitable material for biological monitoring with respect to lead exposure. Similarly, Barbosa and coworkers40evaluated the use of parotid SPb levels as a surrogate of BPb or PPb levels to diagnose lead exposure. Age or gender did not affect SPb levels or the SPb:PPb ratio. Only a weak correlation was found between Log SPb and Log BPb (r=0.277, P<0.008), and between Log SPb and Log PPb (r=0.280, P=0.006), suggesting that SPb cannot be used as a biomarker to diagnose lead exposure or as a surrogate of PPb levels, at least for low to moderately lead-exposed populations. A later study by this group29did show a clear relation between SPb and environmental contamination by lead. The authors suggested that further studies on SPb should be undertaken to investigate the usefulness of saliva as a biomarker of lead exposure, particularly in children.

Some study has shown that human milk could be a feasible biological matrix for use as a biomarker for lead exposure, with the goal of evaluating the risk to children's health using a noninvasive biological procedure. The WHO has reported that 2-5 μg/L of Pb may exist in the breast milk 3 months postpartum under normal conditions based on its research conducted in 1989 in five countries (Sweden, Hungary, Zaire, The Philippines, Guatemala and Nigeria).41Pb levels in breast milk vary widely around the world (0.5-126.6 μg/L).42-53The difference in the breast milk levels may depend on various factors such as the time of sampling (morning or night), the time of lactation (colostrum/transient/mature milk or fore-milk/ hind-milk), the method of sampling (pump or manual), mater- nal factors (parity and maternal Pb burden), as well as environ- mental factors (place of residence and exposure level/duration). However, such variations also reflect several other factors (methods of analysis and contamination of the samples) that might interfere in the final results.54-57Some studies conducted in Turkey have reported that the breast milk Pb levels range from 2.3 to 21.7 μg/L.58-61Recently, in a study reported from Iran, the mean and SD of lead concentration in human milk was 10.39 and 4.72 μg/L, respectively.62The results of some studies show that smoking habits increased lead concentration in milk significantly.63The differences found between different countries might also be due to different assays employed.

EFFECTS OF LEAD ON BRAIN FUNCTION AND DEVELOPMENT

Lead, a known toxic element, is a public health problem due to its adverse effects, mainly those affecting the central nervous system (CNS) in the most vulnerable populations, such as pregnant and lactating women and children. In the absence of a safe exposure limit of children to lead and because of its ability to accumulate in the body for a long time, a great interest in the evaluation of the adverse effects of this metal in low concentrations has emerged.64-67New research provides additional evidence of the effects of early lead exposure persisting into late childhood, manifested by poor cognitive outcomes and school achievement. As the main target for lead toxicity is the CNS, the brain is the organ most studied in lead toxicity.

Lead exposure damages cells in the hippocampus, a part of the brain involved in memory. Hippocampi in the lead- exposed rats show structural damage such as irregular nuclei and denaturation of myelin (DNS) compared to controls (top).68Lead interferes with the release of neurotransmitters, chemi- cals used by neurons to send signals to other cells.69It inter- feres with the release of glutamate, a neurotransmitter impor- tant in many functions including learning, by blocking N-methyl-D-aspartic acid (NMDA) receptors. The targeting of NMDA receptors is thought to be one of the main causes for lead's toxicity to neurons.70A report found that in addition to inhibiting the NMDA receptor, lead exposure decreased the amount of the gene for the receptor in part of the brain.71In addition, lead has been found in animal studies to cause programmed cell death in brain cells.70

A child's BPb measurement is estimated to account for 2% to 4% of variance in neurodevelopment measures (approximately 4% to 8% of the explained variance).72,73Agency for Toxic Substances and Disease Registry (ATSDR) cautions, however, that when studying the effects of lead on child development, the influence of multiple factors like treatment by parents or other adult caregivers should be taken into account. A child's family and personal psychosocial experiences are strongly associated with performance on neurodevelopment measures and account for a greater proportion of the explained variance in these measures than BPb levels. Many studies have examined the effects of lead on children's development outcomes covering varying ages at which BPb was measured and varying ages over which BPb levels were averaged. Statistically significant associations have been identified between average BPb levels over a specific period (for example, 0-5 years) and various adverse health outcomes； other studies have reported statistically significant associations with a single lead measurement at a specific age (for example, prenatal, 24 months, 6.5 years) or with a peak measurement. In contrast to adults, central nervous system effects are more prominent than peripheral effects in the developing ner- vous system.74The developmental effects of lead occur during a critical time window (age ＜ 2 years of age).

Although the toxic effects of high levels of lead have been well documented for centuries, of great concern is the relative recent discovery that low levels of BPb (＜10 μg/dL) are associated with adverse effects in the developing orga- nism. In 1991, Centers for Disease Control and Prevention (CDC) in the US declared that a BPb level of 10 μg/dL should prompt public health actions,75while concurrently recognizing that although useful as a risk management tool, 10 μg/dL BPb should not be interpreted as a threshold for toxicity. Indeed, no threshold has yet been identified. Subse- quently, low-level exposure to lead during early childhood was shown to be inversely associated with neuropsy- chological development through the first 7 years of life.57In 2007, the CDC76summarized the findings of a review of clinical interpretation and management of blood lead levels (BLLs) ＜10 μg/dL conducted by CDC's Advisory Committee on Childhood Lead Poisoning Prevention and concluded that research conducted since 1991 has strengthened the evidence that children's physical and mental development can be affected at BLLs ＜10 μg/dL.

IN UTERO LEAD EXPOSURE

Lead is readily transferred to the fetus through the placenta.77In the absence of placental barrier efficacy, the fetus would be exposed to lead in a concentration very close to that of the mother. Fetus vulnerability can occur even if the mother's exposure had ceased many years earlier.78,79Lead interferes with signal transmission at the synapse and with cellular adhesion molecules, causing disruption in cell migration during critical times in the nervous system development.80Other adverse effects related to prenatal lead exposure have also been reported, such as reproductive effects, conduct disorder in children, cardiovascular functioning, and genomic methylation of DNA.81-84Prenatal lead exposure not only can affect various organ systems of the mother, but also would provide a plumbeous environment for the fetus and newborns and may affect the fetus in a number of detrimental ways because it can cross the placenta freely.85,86Elevated BPb levels during pregnancy are associated with an increased risk of preterm births, spontaneous abortion, and other anomalies.87-89Therefore, it is particularly important to reduce lead exposure of pregnant women for aristogenesis. Lead exposure is the inherent accompaniment of economy development and is inevitable for human being. The BLLs and susceptibility to lead toxicity of pregnant women can be influenced by many factors such as environ- mental exposure, life styles, diet habits, and nutritional status. Moreover, the increase in lead level in breast milk with increasing maternal BPb levels represents an additional risk to the newborn infant.90

Prenatal lead exposure, assessed using umbilial cord blood lead (UCPb) as a biomarker, has long been known to impair the cognitive development of the infant. Strong evidence on the early developmental effects of exposure to lead was first provided by Bellinger and colleagues.91Scores from the Bayley Scales of Infant Development (BSID) revealed that high cord blood levels were associated with lower covariance-adjusted scores on the Mental Development Index (MDI) but not on the Psychomotor Development Index (PDI). The level of BPb at 6 months of age was not associated with scores on either MDI or PDI, consistent with the hypothesis that low levels of lead are delivered transplacentally and are toxic to infants. In a later study covering 6 and 12 months of age,92the lead concentration of capillary blood measured at both ages showed that MDI scores, adjusted for confounding, were inversely related to infants' UCPb level. As the scores were not significantly related to postnatal BPb levels at either age, the prenatal exposure to lead level was deemed to be associated with less favorable development through the first year of life.

In a prospective longitudinal cohort study of 249 children from birth to two years of age. Bellinger et al93assessed the relation between prenatal and postnatal exposure to low levels of lead and early cognitive development. The development of children with UCPb was assessed semiannually, beginning at the age of 6 months, with the MDI (mean±SD, 100±16). Infants in the high-prenatal-exposure group scored lower than those in the other two groups at all ages, and as before, the scores were not related to the infants' postnatal BPb levels.

A nonlinear relation between the first trimester of pregnancy BPb and the MDI at age 24 months was reported.94The results of the analyses showed that both maternal PPb and whole BPb levels during the first trimester (but not in the second or third trimester) were significant predictors (P＜0.05) of poorer postnatal MDI scores. Additionally, the effect of first-trimester maternal PPb was substantially greater than the effects of second- and third- trimester PPb. On the other hand, another study excluding the first trimester showed that the intelligence quotient (IQ) of 6-10 year old children decreased significantly (P＜0.0029, 95% CI=-6.45 to -1.36) with increasing natural-log third trimester BPb, but not with BPb at other times during pregnancy or postnatal BPb measurements.95

Although a causal association between lead exposure and impaired cognitive functioning was most likely in early studies, the potential for residual confounding, particularly by social factors, made the strength and shape (linear or nonlinear) of this association across. A direct link exists between low-level lead exposure during early development and deficits in neurobehavioral-cognitive performance evident late in childhood through adolescence.96Strong evidence for an association between low BPb levels and intellectual impairment in children, especially for those having maximal measured BPb levels of ＜10 μg/dL, emerged from a pooled analysis of 1333 children followed from birth or infancy until 5-10 years of age.97Of these, 18% had a maximal BPb concentration of ＜10 μg/dL and 8% had a maximal blood lead concentration of ＜7.5 μg/dL. After adjustment for covariates, an inverse relation was found between BPb concentration and the full-scale IQ score. A log linear model revealed a 6.9 IQ point decrement (95% CI=4.2-9.4) associated with an increase in concurrent BPb levels from 2.4 to 30 μg/dL. The respective estimated IQ point decrements associated with an increase in BPb from 2.4 to 10 μg/dL, 10 to 20 μg/dL, and 20 to 30 μg/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). For a given increase in BPb, the lead-associated intellectual decrement for children with a maximal BPb level ＜7.5 μg/dL was significantly greater than that observed for those with a maximal blood lead level ≥7.5 μg/dL (P=0.015). Téllez-Rojo et al98also studied the longitudinal associations between low concentrations of BPb and neurobehavioral development in environmentally exposed children in Mexico City in 294 children having a BPb ＜10 μg/dL at both 12 and 24 months of age, with a gestation ≥37 weeks and a birth weight ＞2000 g. The MDI and PDI of the BSID II translated into Spanish were used for the evaluation. Also included in the multivariate models were maternal age and IQ and children's gender and birth weight. The finding of inverse associations between 24-month BPb level and concurrent MDI and PDI scores on the BSID II indicated that children's neurodevelopment is inversely related to their BPb levels in the range of ＜10 μg/dL, providing further evidence that 10 μg/dL should not be viewed as a biological threshold for lead neurotoxicity.

An association was found between prenatal and childhood BPb concentrations and criminal arrests in early adulthood. Between 1979 and 1984, Wright et al99recruited pregnant women living in poor areas of Cincinnati, which had a high concentration of older, lead contaminated housing, into the Cincinnati Lead Study. The researchers measured the women's BPb concentrations during pregnancy, as an indication of the prenatal lead exposure of the offspring, and the child's BPb levels regularly until the children were six and half years old. The authors then obtained information from the local criminal justice records on how many times each of the 250 offspring had been arrested between becoming 18 years old and the end of October 2005. Increased BPb levels before birth and during early childhood were associated with higher rates of arrest for any reason and for violent crimes. For example, for every 5 μg/dL increase in BPb levels at six years of age the risk of being arrested for a violent crime as a young adult increased by almost 50% (RR=1.48) (see Hwang70).

NEUROTOXICITY OF LEAD IN ADULTS

A early study by Stokes and colleagues100evaluated young adults (mean age 24.3 years) 20 years after lead exposure as children. The exposed group grew up around a lead smelter which was operated without emission-reducing devices. The average BLL for children in this area was 50 μg/dL in 1974 and 39.6 μg/dL in 1975. The BPb level (49.3 μg/dL) was known for only 25% of the exposed group. At the time of evaluation both groups had low BLLs. The exposed group performed significantly worse on each test of cognitive functioning as well as on tests of fine motor functioning and postural stability. The neuropsychological functioning of a group of adults 50 years after hospitalization for lead poisoning at the age of 4 years or younger was evaluated in a study by White and colleagues.101Each individual in the exposed group had a history of lead exposure. When tested, the lead-exposed group had poorer performance on tasks of abstract reasoning, cognitive flexibility, verbal memory, verbal fluency, and fine motor speed. In the late 1970s, Tonge et al102found microscopically a significant correlation between cerebellar calcification and raised BnPb lead levels in 10% to 15% of autopsies. A decade later Reyes and colleagues103described CT findings of cerebral and cerebellar calcification in three adults with known lead exposure for ≥30 years and elevated SPb levels at admission (54-72 μg/dL； normal range, 0-30 μg/dL). Punctiform, curvilinear, speck-like, and diffuse calcification patterns were found in the subcortical area, basal ganglia, vermis, and cerebellum. All three patients showed nonspecific neurologic symptoms of dementia, loss of visual acuity, and peripheral neuropathy. Schroter and colleagues104reported a case of a 59-year old potter in Germany who presented lead neuropathy after 37 years of occupational exposure. The patient had a 25-year history of normochromic normocytic anemia with moderate basophilic stippling. The patient also reported history of 3 short psychotic episodes. Cranial CT showed extensive, bilateral, symmetrical calcification in the cerebellar hemispheres and minor calcification in the subcortical area of the cerebral hemispheres and basal ganglia. T2-weighted MRI showed high signal intensity in the periven- tricular white matter, basal ganglia, insula, posterior thalamus, and pons. Most research on lead exposure has focused on deficits in memory and learning. A large body of evidence shows, however, that lead also influences other behaviors such as mood (depression), anxiety, and violence/aggression. Observations of the relations between early lead-exposure and neuropsychological abnormalities have been carried out through- out the course of life. Chronic lead exposure has been linked to the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease (reviewed by Brubaker et al105). Alzheimer's disease is characterized by the formation between neurons of waxy plaques consisting predominantly of β-amyloid protein, and lead increases the expression of the amyloid precursor protein. Schizophrenia is also a candidate due to its features that closely resemble the behavior deficits linked to lead exposure.106Opler et al107conducted a study of prenatal lead exposure and schizophrenia using the biomarker of exposure δ-aminolevulinic acid in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959-1966) based in Oakland, California. The authors found a possible association between prenatal Pb exposure and the development of schizophrenia in later life. Although several limitations constrained generalizability in a second study in 2008 by the same group, the results provided further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders.

Recent studies showed that lead poisoning can cause nerve damage to the sense organs and nerves controlling the body, leading to neurodegenerative diseases like Alzheimer's and Parkinson's disease,108hearing and vision impairment, schizophrenia, and impaired cognitive function. Which cognitive domains are affected has only begun to be explored in detail. Weisskopf et al109found that low-level cumulative exposure to lead in nonoccupational settings can adversely affect cognitive function, particularly in the visuospatial/ visuomotor domain. Bleecker et al110administered the Rey Auditory Verbal Learning Test (RAVLT), a test of verbal learning and memory, to 256 English speaking lead smelter workers (mean age of 41±9.4 years and employment duration of 17±8.1 years). The findings of study are consis- tent with other investigations that have found that early expo- sure to lead is associated with long-term and apparently irre- versible effects on behavioral, cognitive, and neuroradiological endpoints in adults.108Lead exposure variables, based on up to 25 years of prior BPb data, included a mean current BPb of 28±8.8 μg/dL, working lifetime time weighted average blood lead (TWA) of 39±12.3 μg/dL, and a working lifetime integrated blood lead index (IBL) of 728 (434.4) μg-y/dL. The results indicated that BPb was not associated with any of the RAVLT variables, but TWA and IBL contributed significantly to the explanation of variance of measures of encoding/storage and retrieval but not immediate memory span, attention, and learning. Thus, lead exposure over years but not current BPb interfered with the organization and recall of previously learned verbal material. Associations between PbB and/or BnPb and poorer performance in neurobehavioral tests have been reported in older populations having a current mean BPb ＜10 μg/dL .

CONCLUSIONS

Lead pervades almost every organ and system in the human body, but the main target for lead toxicity is the CNS, both in adults and in children. Blood is the most common tissue used as a biomarker of lead exposure although many other tissues and body fluids including breast milk lead, bone, hair, nail, saliva, tooth, urine, and umbilical cord blood have been considered. Lead is more toxic in young and unborn children than in older children and adults. In children, they are at high risk for lead poisoning because their smaller bodies are in a continuous state of growth and development. Lead poisoning has been associated with brain damage, mental retardation, behavioral problems, developmental delays, violence, and death at high levels of exposure. The metal has also been related to the damage of sense organs and nerves controlling the body, impaired cognitive function, as well as hearing and vision impairment in adults.

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