17 Olympio - Neurotoxicity and Aggresiveness Triggered by Low-level Lead in Children

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266 Rev Panam Salud Publica/Pan Am J Public Health26(3), 2009

Neurotoxicity and aggressiveness triggeredby low-level lead in children: a review

Kelly Polido Kaneshiro Olympio, 1 Claudia Gonçalves, 2

Wanda Maria Risso Günther, 1 and Etelvino José Henriques Bechara 3

Lead-induced neurotoxicity acquired by low-level long-term exposure has special relevance fochildren. A plethora of recent reports has demonstrated a direct link between low-level lead exposure and deficits in the neurobehavioral-cognitive performance manifested from childhoothrough adolescence. In many studies, aggressiveness and delinquency have also been sug

gested as symptoms of lead poisoning. Several environmental, occupational and domestisources of contaminant lead and consequent health risks are largely identified and understood,but the occurrences of lead poisoning remain numerous. There is an urgent need for publichealth policies to prevent lead poisoning so as to reduce individual and societal damages andlosses. In this paper we describe unsuspected sources of contaminant lead, discuss the economic losses and urban violence possibly associated with lead contamination and review themolecular basis of lead-induced neurotoxicity, emphasizing its effects on the social behaviordelinquency and IQ of children and adolescents.

Lead poisoning; neurotoxicity syndromes; oxidative stress; juvenile delinquency.

ABSTRACT

Since ancient times, lead (Pb) has beenknown to be toxic to human health (1).Indeed, lead is now recognized as adevastating neurotoxin. The widespreadcontamination of the environment bylead, the wide range of toxic effects asso-ciated with this metal, and the millionsof people affected worldwide, both inpoor and developed nations, make thisinsidious and ubiquitous neurotoxicant

a public health problem of global magni-tude and concern (2).

The levels of lead considered tolerablefor children have been repeatedly low-ered over the last three decades (3–5). Inthe early 1960s, the toxic threshold wasestablished as venous blood lead levels(BLL) of 60 µg/dL, at which overt physi-cal symptoms were observed (6). In 1970,after the recognition that even lower

blood lead could cause brain damage (7),the threshold was reduced to 40 µg/dL;it was then reduced to 30 µg/dL in 1975,and to 25 µg/dL in 1985. Finally, in 1991,the Centers for Disease Control and Pre-vention (CDC) set the intervention levelat 10 µg/dL. According to Bellinger (8),although this level only intends to serveas a risk guidance and management tool,it has been widely and incorrectly im-

bued with biological significance for theindividual child. Indeed, the intervention

level is often interpreted as a threshold,so that a level lower than 10 µg/dLwould be “safe,” and a higher levelwould be “toxic.” There is not a safe levelof lead exposure because factors such asthe endpoint of interest, the age at expo-sure and at assessment, the duration of

blood lead elevation, and characteristicsof the child’s rearing environment mustalso be considered (8). Recently, studies

by Lanphear et al. (9) and Canfield et al.(10) have shown intellectual impairmentin children with blood lead concentra-tions below 10 mg/dL, and Chiodo et al.(11) have demonstrated child neuro-

behavioral deficits linked to 3 µg/dLconcentrations.

The goal of the present study was todiscuss unexpected sources of contami-nant lead and review the molecular basisof the neurotoxicity induced in children

by low-level lead, emphasizing its effects

Key words

Revisión bibliográfica / Literature review

Olympio KPK, Gonçalves C, Günther WMR, Bechara EJH. Neurotoxicity and aggressiveness triggered by low-level lead in children: a review. Pan Am J Public Health. 2009;26(3):266–75.

Suggested citation

1 Universidade de São Paulo, Faculdade de SaúdePública, Departamento de Saúde Ambiental, SãoPaulo, SP, Brazil. Send correspondence to: KellyPolido Kaneshiro Olympio, Marcondes Salgado 17-71, bl. 13, apto. 24 – Vl, CEP 17013-231, Antártica,Bauru, SP, Brazil. Tel: +55-14-3879.6884; e-mail:[email protected]

2 Centro de Extensão Universitária, São Paulo, SP,Brazil.

3 Universidade de São Paulo, Instituto de Química,Departamento de Bioquímica, São Paulo, SP,Brazil, and Universidade Federal de São Paulo,Departamento de Ciências Exatas e da Terra, SãoPaulo, SP, Brazil.


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on social behavior, criminality and IQ.Finally, we discuss the urgent need forpublic health policies designed to pre-vent lead poisoning.

LEAD TOXICITY:A SHORT HISTORY

According to Needleman (5), child-hood lead poisoning was first recog-nized only one century ago. The authordivides scientific knowledge on lead poi-soning into four periods. First, there waswidespread disbelief concerning reportsof lead-poisoned children in Brisbane(Australia), in 1892 (12). In 1904, it wasestablished that the contamination had been caused by lead-containing paint.Lead paint was later banned for house-hold use in Brisbane (5). Today, paints inthe United States, for example, cannotcontain more than 0.06% of lead in theirformulation (13).

The first report of infantile lead poi-soning in the United States was pre-sented by Blackfan (12) in 1914 (5). Inthis second period in the lead poisoninghistory, lead was associated with onlytwo outcomes: death or complete recov-ery without any sequelae. This miscon-ception was refuted in 1943 with thefirst follow-up of children who had re-covered from acute toxicity. Levinsonand Harris (14) had previously recom-mended that children should perhaps befollowed on a long-term basis to ascer-tain possible neurobehavioral distur- bances. In 1943, lead poisoning sequelaewere well documented by Byers andLord, who followed 20 children withsymptomatic lead poisoning in earlychildhood until school age. They foundthat 19 of these children presented ag-gressive, antisocial, and uncontrollable behavior (15). Thus, in this third pe-riod, it became generally accepted thatlead toxicity caused long-term neurolog-ical impairment, although deficit wasthought to occur only in children withclinical signs of encephalopathy duringthe acute episode. The fourth period began in the 1970s, when studies of chil-dren with no clinical signs of toxicityshowed deficits in IQ scores, attention,and language (16–18).

MAJOR SOURCES OF LEADEXPOSURE

Lead occurs naturally in the lithosphereat concentrations of about 13 mg/kg. Lead

was employed to manufacture tableware,trays and other decorative objects as earlyas 6000 BC. The Romans believed thatlead—the “oldest” metal—was a gift fromSaturn (Khronos), the father of gods. Theyused lead to build aqueducts and to pre-pare lead acetate, a sweetener of wine con-sumed daily by Roman aristocrats. The

name saturnism for lead poisoning wascoined after Saturn.

In addition, lead occurs naturally inthe air, water, soil, biota and in human beings. Human exposure to lead oc-curs through inhalation, ingestion andthrough the skin. Lead may be ingesteddirectly from contaminated water, air,and soil and indirectly by eating contam-inated animal meat, fruit and vegetablesand their derivates. Environmental or oc-cupational exposure may be aggravated by insufficient protective behaviors,habits, and socio-economic factors. Leadis found in food, batteries, solders, plas-tics, household paints and gas, but alsoin glass nursing-bottles, toys, glazedpottery, granite floors, calcium supple-ments, herbal medicines, wild game,facial makeup and cigars. Lead affectsthe brain, kidneys, liver, blood and tes-ticles and impairs learning, attention,IQ, memory, hearing, and sociability. Itcauses hypertension, anemia, nephrop-athies, sterility and encephalopathy, withthe degree of poisoning being dependenton blood levels (Figure 1). Human use of lead increased during the Industrial Rev-olution and in the early 20th century,when there was high demand for leadedgasoline, lead-containing paints, cannedfoods, and car batteries. Importantly, thepopulation of American children with

BLL over 10 µg/dL declined by 80% sincelead was banned from gas, solder incanned food, and house paint (19). TheWorld Health Organization (WHO) rec-ommends constant research on the vari-ous “silent” sources of lead exposure (20).Vigilance is crucial and must be fostered

by raising community awareness. Also,

there must be strict control of productssuspected to contain lead and of importedgoods (21).

According to Goyer (22), the mostcommon source of exposure to lead-contaminated food is lead-soldered cans.Outlawing lead solder in canned food isestimated to have reduced the averagedietary intake of lead in 2-year-old chil-dren from 30 µg/day in 1982 to approxi-mately 2 µg/day in 1991 (22–24). While

banned in the United States, lead soldercontinues to be used in other countries(23, 24). Other less common sources of exposure to dietary lead are ethnic food,dietary supplements, folk medicines andmoonshine. Hair/eyelash/eyebrow dyescan be sources of lead poisoning throughskin (24, 25).

Ingestion of lead does not occur solelythrough dietary sources. Currently, lead-containing paint sold in the United States

between 1884 and 1978 is the majorsource of lead ingestion in young Ameri-can children (23, 24). Although theamount of lead allowable in paint waslowered by federal law in 1971 (13), 80%of U.S. houses were built before 1950—which means that 23 million units stillcontain leaded paint (5). In 2002, it wasreported that 65% of 38 million hous-ing units in the United States had lead-

based paint (26). The replacement of

Rev Panam Salud Publica/Pan Am J Public Health26(3), 2009 267

Olympio et al. • Neurotoxicity and aggressiveness triggered by low-level lead in children Literature review

HypertensionNeuropathy↓ MemoryIrritabilityHeadache↓ Hearing acuityNephropathySterility/Impotence↓ HemoglobinLongevityAnemiaEncephalopathy

µg Pb/dL bloodLearning disabilitiesAttention & IQ deficitsAnti-social behaviorHeadache & seizure↓ Hearing & growthMental retardationAbdominal & joint pain↓ HemoglobinAnemiaNephropathyEncephalopathy

Death

Children Adults

10

50

100

150

FIGURE 1. Effects of lead poisoning on human health a

a Adapted from Gurer and Ercal (49).


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white paints containing highly toxic leadcompounds with very expensive tita-nium oxide-based paints and, hopefullyin the near future, with non-toxic andinexpensive aluminum phosphate orpolyphosphate-based pigments (Biphor ®,Bunge Co.) (27) might help prevent leadpoisoning from paints.

Drinking water can also be contami-nated by lead, either at the source due todeposition from environmental sourcesor in the water distribution system. TheU.S. National Primary Drinking WaterRegulations for Lead and Copper statethat water is unsafe if 10% of a munici-pality’s test sample is determined tohave lead levels greater than 15 ppb (26,28). Several authors have pointed outthat municipal water distribution systeminfrastructures contain components thatmay leach lead, such as lead service linesthat channel water to the homes, leadpipes inside the homes, copper supplypipes that have been joined using leadsolder and lead-containing brass pipesand fixtures that can contain up to 8%lead (29, 30). A recent survey of theWashington, D.C. area by the CDC (31),the D.C. Department of Health and theU.S. Public Health Service estimates that18% of over 30% of the analyzed popula-tion residing in this area had BLL above5 µg/dL, leading to cognitive deficits inchildren (9, 10).

In Brazil, Teixeira (32) has found that11% of pipes used in the water distribu-tion systems of 100 schools in São Paulopresent lead levels above the limit con-sidered safe by the WHO. In 2% of thewater samples, the lead level was foundto be five-fold higher than the highest ac-ceptable value (< 10 µg/L, according tothe WHO), thereby threatening the neu-ropsychiatric health of children.

Several studies have shown that highBLL in preschool children are stronglycorrelated with high lead levels in housedust (33–35). This association has beenattributed to dust intake from the fre-quent hand-to-mouth behavior of youngchildren. Flaking lead-based paint, roaddust, garden soil and airborne lead-bear-ing particles are believed to be thesources of lead in household dust (36).

Leaded gas has caused more exposureto the metal than any other sourceworldwide (37). According to the SãoPaulo State Health Department (19),about 80% of the lead found in urban airsamples before 1982 was derived fromleaded gas. Car battery manufacture is

the main source of secondary lead (38), but other sources cannot be discarded.Thus, it is not surprising that interna-tional bodies such as the World Bank,WHO and the United Nations Commis-sion on Sustainable Development (CSD)agree that countries must give up leadedgas for the sake of public health. In 1994,

the CSD called on governments world-wide to switch from leaded to unleadedpetrol. Nevertheless, up to the year 2000,only 42 countries, including China, NewZealand, the United States, some West-ern and Eastern European countries, andseveral Latin American countries, hadphased out or were phasing out leadfrom gas. India and a dozen or morecountries in Latin America and WesternEurope were committed to making theshift by 2005, while the remaining 150 orso countries in the world had not made adecision (39).

BIOCHEMICAL MECHANISMS OFLEAD TOXICITY

Lead is a heavy metal with no appar-ent biological function. Despite the ex-tensive evidence concerning the toxic ef-fects of lead on human health, themolecular mechanisms underlying thismetal’s poisonous effects on the centralnervous system (CNS) have yet to beclarified (40, 41).

Bioactive lead is a divalent cation that binds strongly to sulfhydryl groups incysteine residues of proteins and en-zymes. Lead toxicity can be largely at-tributed to conformational changes un-dergone by enzymes and structuralproteins upon binding the lead ion, butthis versatile toxic agent has other tar-gets as well. For example, lead interfereswith the endogenous opioid system (42)and efficiently breaks the ribosyl phos-phate group of tRNA (43). Many toxicproperties of lead are putatively due tothe metal’s capacity to mimic and com-pete with calcium and zinc ions in fingerproteins dependent on these metals (44).

Recent studies have also focused on theheme biosynthetic pathway, where manysites of lead interference are encountered.Thus, lead poisoning can be considered achemical or acquired porphyria (45). Thethiol enzymes δ-aminolevulinic acid de-hydratase (ALAD) and ferrochelatase of this pathway are extremely sensitive tolead. Inhibition of these enzymes in-creases, respectively, ALA and protopor-phyrin IX concentrations in urine, blood

and other tissues. ALA has long beenknown to compete with γ -aminobutyricacid (GABA), a neurotransmitter in thecortex, hypothalamus and other tissues of the CNS and the peripheral nervous sys-tem (46).

An increase in ALA in the blood and brain areas could contribute to the trig-

gering of behavior disorders in patientscarrying genetic porphyrias, includingacute intermittent porphyria (AIP) andhereditary tyrosinemia type 1, and alsoin lead poisoned individuals. This hy-pothesis is based on the fact that ALAhas been shown in vitro to exhibit pro-oxidant properties towards biologicalmolecules (proteins, membranes, DNA)and supramolecular structures (mito-chondria, synaptosomes); in vivo, theseproperties have been observed in brain,liver and red muscles of ALA- or lead-treated rats and in the blood of lead ex-posed workers (47–52) (Figure 2). Of ut-most importance was the finding thatALA-driven oxidative injury to GABAreceptors in synaptic membranes, synap-tosomes, and GABA-rich brain slicesleads to a two-fold increase in the disso-ciation constant of the receptor-GABAcomplex (53) and to a significant de-crease in the GABA receptor population(54).

Fundamental questions about the mol-ecular basis of the ALA-induced neuro-logical lesions remain unanswered. It isworth noting that acute porphyric at-tacks of inborn and acquired porphyriapatients correlate with elevation of

blood and urinary ALA and that lead ex-posed subjects with high levels of lead(> 60 µg/dL) and ALA (> 1 µM) in the

blood present neurological manifesta-tions similar to those in AIP (55–57).

LEAD POISONING OF THEINFANT NERVOUS SYSTEM

Studies in several countries have esti-mated that about 4% of their childrenhave high BLL (20). The prevalence may

be even higher in children living ininner-city areas of the United States. Ac-cording to data collected between 1976and 1980, 17% of children presented BLL> 15 µg/dL, 5.2% > 20 µg/dL, and 1.4%> 25 µg/dL (58). Lead poisoning is notconsidered a significant environmentalrisk for children in the rural areas of de-veloping countries. However, in a studywith children living in the rural Philip-pines, 21% (601 of 2 861 children) had


Literature review Olympio et al. • Neurotoxicity and aggressiveness triggered by low-level lead in children


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BLL higher than 10 µg/dL. BLL were in-dependently associated with age, hemo-globin concentration, water source, roof-ing material, household expenditures,and history of breastfeeding. The au-thors evaluated possible environmentalexposures in a sub-sample of childrenwith elevated BLL and found multiplepotential sources, such as fossil fuelcombustion, lead paint (around 38% of homes) and household items (59).

Children are more sensitive to leadthan adults for many reasons. Their ex-posure to lead is favored by the habitof eating non-nutritive substances (picahabit). A child’s intestine absorbs leadmuch faster than that of an adult, andthe developing CNS of infants is morevulnerable to toxic agents than themature CNS, especially in the case of undernourished children. Neural prolif-eration, differentiation and plasticity arestrongly impaired by lead.

In the United States, overall childhoodBLL have declined as a result of federalregulatory measures to reduce popula-tion exposure to environmental lead.Screening data from the late 1960s and

early 1970s indicate that 20 to 45% of thechildren tested had BLL ≥ 40 µg/dL. Be-tween 1976 and 1980, the weighted geo-metric mean of blood lead among 1 to 5-year-old children in the United Stateswas 15 µg/dL (60). Data from the ThirdNational Health and Nutrition Exami-nation Survey (NHANES III), phase 1(1988–1991), showed a decline in the geo-metric mean of lead level to 3.6 µg/dL(60). NHANES III (1991–1994) showed afurther decline in this biomarker to2.7 µg/dL. NHANES III, phase 2 data in-dicated that approximately 4.4% of 1 to5-year-old children (about 890 000 chil-dren) had blood levels ≥ 10 µg/dL (61).Bernard et al. (29) analyzed data fromNHANES III (1988–1994) and found thatthe overall prevalence of blood levels≥ 5 µg/dL was 25.6%, although 76% of these children had BLL < 10 µg/dL.

In Argentina, studies carried out in thecities of Cordoba and Buenos Airesshowed that between 10 and 40% of chil-dren younger than 15 years of age pre-sented BLL > 10 µg/dL (62). In Uruguay(63), in the beginning of 2001, BLL > 25µg/dL were detected in children from a

specific sector of Montevideo where sev-eral metal smelting plants and other in-dustrial activities had been in operationfor the past 50 years. Because of that,the Uruguayan public health ministrycommissioned a second study, whichshowed that 61% of 2 351 studied chil-dren presented BLL > 10 µg/dL.

In Brazil, studies on environmentallead exposure are rare, limiting the un-derstanding about the impact of lead onthe Brazilian public health (64). Silvany-Neto et al. (65) found mean BLL of36.7 ± 20.7 µg/dL in children living closeto a primary lead smelting plant in SantoAmaro, state of Bahia. In 1996, using theZn-protoporphyrin method, the samegroup (66) found lead levels as high as65.5 µg/dL in children in the same area.These levels have remained abnormallyhigh since 1980 due to the contaminationof soil by lead. In 2003, the group foundBLL close to 17 µg/dL, and 5 µg/dLhigher in children with pica habit, inde-pendent of age, visible presence of scumsurrounding the home, employment sta-tus of the father, family history of leadpoisoning, and malnutrition (67).



In vitro single-strandbreaks in plasmid DNA

IRP-1 activation(iron regulatory protein)

Lipid peroxidationin cardiolipin-rich

liposomes (mitochondriamodel) catalyzed by ferritin

Disruption of mitochondrialmembrane potential,matrix Ca2+ release,

and increased state-4respiration

Increased glycolyticmetabolism in chronically

ALA-treated rats

HO radical in vivo detection in ALA-treated

rats

DNA guanine oxidationto 8-HOdG in vitro

and rat liver

GABAergic receptordamage in synaptic

membranes, neuronal cellsand brainElevated levels of

SOD and Gpx inAIP and plumbism

patients

Iron releasefrom ferritin

DOVA-DNAadduct formation

Iron mobilizationto liver and brain of

succinylacetone-treated

rats

HO

HO

HO

O

O

O

OO

NH2

O2 – + H2O2

O2

NH4+

DOVA

ALA

Abbreviations: AIP, acute intermittent porphyria; ALA,δ-aminolevulinic acid; DOVA, 4,5-dioxovaleric acid; GABA,γ -butyric acid; Gpx, glutathione peroxidase; 8-OHdG, 8-hydroxy-2’-deoxyguanosine; IRP, iron regulatory protein; SOD, superoxide dismutase.a Adapted from Bechara et al. (52).

FIGURE 2. Production of reactive oxygen species by the aerobic oxidation of -aminolevulinic acid (ALA), a heme precursor accumulated in leadpoisoning, ALA-driven oxidative damage to biomolecules, and biological consequences observed in ALA-treated rats and lead poisoned individuals a


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In Cubatão (state of São Paulo), one of the most industrialized areas of Brazil,Santos Filho et al. (68) found BLL aver-aging 17.8 µg/dL in the general popula-tion. Paoliello (69) found a median BLLof 11.25 µg/dL in children living in theupper Ribeira do Iguape river valley.Freitas (70) carried out an evaluation of

lead exposure in a contaminated area of the city of Bauru. In that study, a batteryrecycling plant had contaminated theneighboring residential area with leadoxides during the previous 8 years. Envi-ronmental lead contamination was as-sessed by the state authority for environ-mental control CETESB and the plant wasclosed in 2002. Over half of the 311 chil-dren presented BLL between 15 and19 µg/dL, 21% between 20 and 39 µg/dL,and less than 1% (3 children) had BLL of 40 µg/dL or higher. Compared to otherlead contaminated areas in Brazil, theBLL found in the Bauru study were ratherlow (median of 7.3 µg/dL) (71). In Brazil,there are no public policies establishingan official procedure for sampling andanalyzing lead in human tissues, nor toscreen lead in schoolchildren, even in thepresence of psychomotor and learningdisabilities (19).

Lead effects on IQ and socialbehavior

Cognitive function, measured by psy-chometric IQ tests, has been the majorfocus of most studies on lead exposure inchildhood. However, there are reasonsto believe that cognitive dysfunctionmay not be the most important effect of lead (5).

Denno (72) traced the behavioral pat-terns of 987 African-American youthsfrom birth to age 22. She found thatamong the dozens of sociologic and bio-logic correlates of delinquency, lead poi-soning was among the strongest for malesubjects. Lead-induced aggressiveness isnot an entirely new notion. Parents havefrequently reported a dramatic change inthe behavior of children after recoveryfrom an episode of acute lead poisoning,with the child becoming restless, inatten-tive and aggressive (5). In 1943, Byersand Lord reported attention deficits andaggression in a sample of lead-poisonedchildren (15).

Needleman et al. (73) studied 301 pri-mary school students and found thatchildren with elevated bone lead levelsscored higher on the attention-deficit,

aggression, and delinquency clusters of the Child Behavior Checklist after ad-

justment of covariates. Dietrich et al. (74)found that prenatal lead exposure wasassociated with parental reports of delin-quency and aggression, and postnatallead exposure was associated with self-reports of delinquent acts. A case-control

study including 194 arrested and con-victed delinquent youths (aged 12 to 18years) and 146 non-delinquent controlsrevealed an increased risk of delin-quency associated with bone lead con-centrations measured by X-ray fluores-cence (75). The covariate-adjusted oddsratio was 4 (95% CI: 1.4–11.1). In Brazil, across-sectional study was conducted toverify the association between dentalenamel lead levels and anti-social behav-ior. The study included 173 adolescentsaged 14 to 18 years and their parents(n = 93), residents of impoverishedneighborhoods in the city of Bauru (stateof São Paulo), a region with high crimerates. The covariate-adjusted odds ratiosindicated that high dental enamel leadlevels were associated with increasedrisk of externalizing problems and of ex-ceeding the clinical score for somaticcomplaints, social problems, and rule-

breaking behavior. The authors con-cluded that exposure to high lead levelscan indeed trigger antisocial behavior,which claims for public policies to pre-vent lead poisoning in the country (76).

Recently, Chiodo et al. (77) haveshown a relationship between BLL andneurobehavioral outcome in 7-year-oldAfrican American children. Among thestudied variables, social problems, delin-quent behavior and total behavior prob-lem scores were associated with BLL(β = 0.10, β = 0.09 and β = 0.09; P < 0.05).

A number of recent ecological investi-gations have correlated leaded gasolinesales and lead in air particulates withcrime rates, strongly suggesting an as-sociation between lead exposure andcrime. Stretesky and Lynch (78), whencomparing homicide rates in 3 111 coun-ties in the United States with adjustmentfor 15 covariates, reported a four-fold in-crease in homicide rates in counties withthe highest air lead levels compared tocontrols. Nevin (79) correlated sales of leaded gasoline with violent crime ratesand, after adjustment for unemploymentand percent of population in the high-crime age group, found a statisticallysignificant association between lead andcrime. It has been speculated that one of

the reasons for the recent decline incrime rates in the United States might beattributed to the adoption of public poli-cies to ban lead in paints, gas, andcanned food, therefore reducing expo-sure to lead. In 2007, Nevin (80) carriedout single and combined national regres-sions, identifying “best-fit” lags for each

crime analyzed, with the highest signifi-cance ( t-value) for blood lead and per-cent of crime rate variation explained(R2). The results presented a strong asso-ciation between preschool blood leadand subsequent crime rate trends overseveral decades in nine countries. Fur-thermore, regression analyses of the av-erage murder rates for the period be-tween 1985 and 1994 in American citiessuggests that murder could be especiallyassociated with more severe cases of childhood lead poisoning.

Many studies provide evidence of aninverse relationship between lead expo-sure and cognitive ability (81). There is,however, disagreement about the IQ to

blood lead slope (IQ points lost per in-crease of 1 µg/dL in blood lead) and theinfluence of confounding variables (82,83). There is strong evidence that youngchildren face the greatest risk of IQlosses due to lead exposure, especiallyduring the first 3 years of life, when basiccognitive abilities develop (82). This in-formation is very important becausemany painted toys may contain lead,posing risk especially because childrenare likely to introduce them into theirmouths. Cognitive losses due to lead ex-posure during the first 3 years of life ap-pear to be most evident in IQ tests car-ried out some years later, around age 10or older, when IQ scores are more stableand predictive of future outcomes (81,82). There is no consensus, however, onwhether lead exposure is more stronglyassociated with verbal IQ, mathematicalskills or performance IQ. However, de-spite the similarity with a pattern of out-comes typical of brain injury, detailedcomparisons of children’s deficits indi-cate that lead, like most other causes of

brain injury, does not produce exactlythe same set of impairments in all pa-tients (84).

Although data on yearly changes in IQare unavailable, temporal data are avail-able for specific types of social behaviorassociated with lower IQ scores. Herrn-stein and Murray (85), in their controver-sial book The Bell Curve, cite data show-ing that individuals with lower IQ levels


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account for a disproportionate share of violent crime and unwed births.

In 1960, in the United States, the ac-cepted threshold for BLL in children was60 µg/dL. Follow-up studies carried outin American cities showed that 10 to 20%of the children in these cities presentedBLL of up to 40 µg/dL. This finding sup-

ported the notion that some learningdifficulties and behavior disorders (sub-clinical manifestations) could be attrib-uted to lead. Five studies on lead levelsand behavior in children without overtsigns or symptoms of lead poisoningwere carried out in the 1970s. Three of them reported an association betweenlead and IQ (16, 17), and two did notconfirm this connection (86, 87). Thosestudies had limitations of design: thenumber of patients in each study wassmall, and blood lead was used as a bio-marker. Blood lead is reliable as a bio-marker of short-term exposure only,since it has a half-life of 36 days in the blood (88).

Three meta-analyses have confirmedthat exposure to low levels of lead may be associated with IQ deficiency (82, 83,89). In response to these data, in 1991,the CDC reviewed the acceptable levelsfor BLL, reducing the 60 µg/dL bloodthreshold established in 1970 to the pres-ent value of 10 µg/dL. More recent datapoint toward cognitive, attention and be-havior deficits in children with BLL be-tween 3 and 5 µg/dL (9). In 2007, Chiodoet al. (77) presented data showing that athreshold below which BLL is not associ-ated with harmful outcomes does notexist. The authors suggest a reduction of the “acceptable” level, considering therecent scientific evidence. Dudek andMerecz (90) found that the fastest deteri-oration of IQ was observed with BLL be-tween 5 and 10 and 11 to 15 µg/dL, con-sistent with the finding by Schwartz (82)of an increased slope at lower BLL (79).

In recent decades, violent crime andunwed pregnancies have been associatedwith teenagers and young adults livingin poor urban areas. The average BLL inchildren from deprived urban areas hasprobably begun to rise as early as the1940s, due to the addition of tetraethyllead to gasoline combined with use of lead-based pigments in house paints.Therefore, temporal data on leaded gaso-line consumption might serve as a roughindicator for changes in blood lead inpoor urban children from 1940 to 1987. If childhood lead exposure affects IQ, and

IQ affects population rates for crime andunwed pregnancy, then changes in crimeand unwed pregnancy rates from 1960to the late 1990s could reflect changes inIQ associated with temporal trends inleaded gasoline consumption from 1940through the early 1980s (79).

PRIMARY PREVENTION:BENEFITS FOR PUBLIC HEALTH

A cost-benefit analysis carried out bythe United States Public Health Serviceestimated the cost of abatement of oldhouses painted with lead-containingpaints over a 30-year period at US$33.7 billion, in 1991. The estimated benefitfrom avoided health care costs and in-creased income due to raised IQ would be US$61.7 billion. This cost analysismay be conservative, as it does not con-template the prevention of delinquencyand cardiovascular disease, both demon-strated effects of lead exposure, amongother health effects (4).

According to Needleman (5), currentanalyses also demonstrate that preven-tion of primary lead exposure yieldslarge economic benefits. Grosse et al. (91)calculated that the IQ of preschool chil-dren was increased by 2.2 to 4.7 pointsabove what it might have been if leadedgasoline and blood lead had not been re-duced. From this, they calculated the IQ-related increase in income and estimatedthat the economic benefit for each year’s birth cohort was between US$110 andUS$319 billion. Landrigan et al. (92), as-suming no threshold for the lead-IQassociation, estimated the loss of futureearnings for the 1-year cohort of childrenaged 5 in 1997 at US$43.4 billion.

The monetary cost associated with theubiquitous exposure of fetuses and chil-dren to lead in industrialized societieshas also been calculated by Schwartz(93). That author estimated medical costsassociated with the treatment of childrenwith undue lead exposure, the increasein remedial education, and the costs as-sociated with reduced birth-weight andreduced gestational age, among otherfactors. The largest single cost was earn-ings lost as a result of decreased intellec-tual capability (Table 1). According toanother analysis using the comprehen-sive National Longitudinal Survey of Youth database to attribute monetaryvalue to the effect of decreased cognitiveability on earning capacity, the estimatedgain in earnings would be US$7.5 billion

per year for a decrease of 1 µg/dL in BLLin the U.S. population (94). It is obviousthat the effect of lead on IQ represents anenormous cost to society in terms of lostpotential and increased need for medicalcare and special education.

According to Needleman (5), the evi-dence that lead toxicity extends down tothe lowest measurable levels, that phar-macological therapies are ineffective atpreventing sequelae in those with lowlevels, and that reduction of exposureyields huge economic as well as health

benefits provides a strong argument infavor of the systematic abatement of leadfrom the single remaining major sourcein the United States: older homes. Onthe other hand, an association has beenfirmly established between air lead con-centrations and levels of lead in the body(95–99). To determine if data on potentiallead exposure drawn from the Environ-mental Protection Agency’s CumulativeExposure Project (CEP) were correlatedwith BLL at the county level, Streteskyand Lynch (78) collected data from theOhio Department of Health on childrenyounger than 6 years who had BLL above10 µg/dL in 1998. The CDC identified thedata from Ohio as more valid than datafrom most states because a large propor-tion of children across all Ohio countiesare tested for lead poisoning. The au-thors found that across Ohio’s counties,CEP-estimated air lead concentrationswere positively and significantly corre-lated with the percentage of children(among children who were screened)who had elevated BLL (Pearson correla-tion coefficient: 0.44; P < 0.001; n = 88).This relationship persisted (Pearson cor-relation coefficient, 0.48; P < 0.001; n = 88)after adjustment for the percentage of houses built before the 1950s (1990 cen-sus estimate), reinforcing previous find-ings suggesting that lead exposure mayresult from a variety of contaminationsources, including lead-contaminated air.


TABLE 1. Annual benefits of a 1 µg/dL reduc-tion in the mean blood lead concentration ofthe infant population in the United States a

Annual benefits US$ million

Medical costs 189Compensatory education 481Infant mortality 1,140Neonatal care 67Earnings 5,060

Total 6,937

a According to Schwartz (93).



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An important and interesting exampleof primary prevention is that of the cityof Hartford, state of Connecticut, in theUnited States. The Hartford Health De-partment implemented a public healthcampaign to increase the lead poisoningawareness. The actions involved severalnovel elements and partnerships, includ-

ing the use of municipal sanitationtrucks to disseminate lead-poisoningprevention messages throughout thecity. The most important results were asfollows: recall of campaign componentsranged from 21.5 to 62.6%, with newspa-per advertisements and signs on busesand billboards recalled most often and avideo broadcast on public-access televi-sion recalled least often; more than 45%of respondents reported that they tooksteps to prevent lead poisoning becauseof at least one of the campaign items,with newspaper advertisements beingthe most effective component in terms of prompting lead-poisoning prevention behavior. However, the awareness of re-spondents was particularly low concern-ing how medical personnel and proce-dures could or could not detect andprevent lead poisoning in children. Thiscampaign inspired caregivers to take thenecessary steps to prevent lead poison-ing and may help public health profes-sionals in other communities to developnew ideas for similar initiatives (100).

In Brazil, according to the São PauloState Health Department, some measureshave been adopted for protecting thepopulation, despite the lack of an officialprogram for environmental lead expo-sure prevention. Since 1978, tetraethyllead has no longer been added to gaso-line as an anti-detonator. In addition,there are regulations for acceptable leadlevels in food and water (101, 102). Re-garding acceptable levels in humans,until recently only occupational exposurehad been regulated. In 2008, however, alaw was enacted to establish the maxi-mum amount of lead in the manufactureof materials for children in educational

settings, as well as in varnishes and fur-niture (103). It should be noted that be-fore this law some manufacturers fromnon-regulated sectors followed interna-tionally accepted lead parameters. Ac-cording to the Brazilian Association of Paint Manufacturers, there is a trend that

began in the 1990s to replace lead pig-

ments in paints. At present, Brazilian do-mestic paints are free of lead. However,lead is still used as an anti-corrosive,such as red lead in iron gates, refrigera-tors, cars, stoves, bicycles, and manyother goods. In this case, a covering paintmust be applied (19). As mentioned, thenon-toxic and inexpensive Biphor ® whitepigment, based on aluminum phos-phates and polyphosphates, will greatlydecrease paint-related lead poisoning(27). Still in Brazil, studies conducted atthe Adolfo Lutz Institute (104) havefound lead in pencils, pens, coloredpaints, erasers and other school supplies.This study recommended the drawing of regulatory guidelines for the manufac-ture of such products, which are nowregulated by the 2008 law mentioned ear-lier (103).

Canned food manufacturers in Brazilhave also replaced lead-based solders.Regarding the contamination of freshfood by lead, Sakuma (105) found securelead levels for human consumption inBrazil. Glazed ceramic containers can bea source of lead poisoning when leadleaches into stored beverages, especiallyin the case of acidic fruit juices such asthose made from grapes and citrus fruit(106). Lead from glazed ceramics ispromptly dissolved by the tartaric andcitric acids present in these juices, due tothe chelation of the metal by these acids.

Since 1986, an Environmental ImpactReport (EIA/RIMA) has been officiallyrequired for the approval of potentiallypolluting industrial plants, as an obliga-tory document to license these compa-nies (107). The strategies proposed inthis report to minimize the pollution

by the plant must be analyzed and ap-

proved (102). Nevertheless, companiesstarted before 1986 are not mandated tofollow this protocol, unless they havecaused environmental damage (108). Ac-cording to information from the SãoPaulo State Health Department SanitaryVigilance Center (19), several small com-panies and domestic sources of lead con-

tamination do not issue warnings to pre-vent lead exposure.

FINAL REMARKS

Considering that a healthy social tis-sue can be seriously harmed by lead, it isextremely important to establish publicpolicies against lead contamination andguarantee an adult population that issocially well balanced and productive.In a recent paper, provocatively named“Childhood lead poisoning preven-tion—too little, too late,” Lanphear (109)calls attention to the importance of pre-venting lead poisoning for the good of individuals and of society. In this con-text, it is tempting to state that there is ahigh probability that many young delin-quents are actually victims of lead poi-soning and not necessarily genetic or so-cial criminals. We close with a plea forpublic health policies to prevent leadpoisoning in underdeveloped and devel-oping countries, such as those that havelong been adopted in the United States,Europe, and Japan.

Acknowledgements. This work wassupported by grants from Fundação deAmparo à Pesquisa do Estado de SãoPaulo (FAPESP), Conselho Nacional deDesenvolvimento Científico e Tecnológico(CNPq), and Projeto Milênio Redoxoma.KPKO is the recipient of a fellowship fromCoordenação de Aperfeiçoamento dePessoal de Nível Superior (CAPES). Theauthors are indebted to Prof. Abner Lall(Howard University, USA) and to Dr.Brian Bandy (University of Saskatche-wan, Canada) for kindly revising thismanuscript.

1. Major RH. Some landmarks in the historyof lead poisoning. Ann Med Hist. 1931;3:218–27.

2. Satcher DS. The surgeon general on the con-tinuing tragedy of childhood lead poisoning.Public Health Rep. 2000;115(6):579–80.

3. Lin-Fu JS. Health effects of lead, an evolvingconcept. In: Mahaffey KR, editor. Dietary

and environmental lead: human health ef-fects. Amsterdam: Elsevier; 1985. Pp. 58–9.(Topics in Environmental Health vol. 7).

4. Centers for Disease Control and Preven-tion. Preventing lead poisoning in youngchildren: a statement. Atlanta: U.S. Depart-ment of Health and Human Services, PublicHealth Services; 1991.

5. Needleman H. Lead poisoning. Annu RevMed. 2004;55:209–22.

6. Lidsky TI, Schneider JS. Lead neurotoxicityin children: basic mechanisms and clinicalcorrelates. Brain. 2003;126(Pt 1):1–19.

7. Lin-Fu JS. Undue absorption of lead amongchildren: a new look at an old problem. NEngl J Med. 1972;286(13):702–10.

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8. Bellinger DC. Lead. Pediatrics. 2004;113(4Suppl):1016–22.

9. Lanphear BP, Dietrich K, Auinger P, Cox C.Cognitive deficits associated with blood leadconcentrations


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La neurotoxicidad adquirida inducida por la exposición prolongada a bajos niveles deplomo tiene una importancia especial en los niños. Una plétora de publicaciones re-cientes ha demostrado el vínculo directo existente entre la exposición a bajos niveles deplomo y el déficit en el desempeño neuroconductual-cognitivo manifestado desde lainfancia hasta el final de la adolescencia. En numerosos estudios, la agresividad y ladelincuencia juvenil también se han considerado síntomas de la intoxicación porplomo. Se han identificado y explicado ampliamente varias fuentes ambientales, labo-rales y domésticas de contaminación por plomo y los riesgos resultantes para la salud,pero aún son numerosos los casos de intoxicación por plomo. Se necesitan urgentes po-líticas de salud pública para prevenir la intoxicación por plomo de manera de reducirlos daños y las pérdidas, tanto individuales como para la sociedad. En este artículo sedescriben algunas fuentes no sospechadas de contaminación por plomo y se discutenlas pérdidas económicas y la violencia urbana posiblemente asociada con este tipo decontaminación. Además, se hace una revisión de las bases moleculares de la neuroto-xicidad inducida por plomo, con énfasis en sus efectos sobre el comportamiento social,la delincuencia juvenil y el coeficiente intelectual de los niños y los adolescentes.

Intoxicación por plomo; síndrome de neurotoxicidad; estrés oxidativo; delincuencia juvenil.

RESUMEN

Neurotoxicidad y agresividaddesencadenadas por bajosniveles de plomo en niños:

una revisión

Palabras clave

17 Olympio - Neurotoxicity and Aggresiveness Triggered by Low-level Lead in Children

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