Medicine Cumulative to test - Occupational and ...Neurobehavioural test performance has been associated with sex, butthe magnitude ofthe associations differs for the specific test."'0

Occupational and Environmental Medicine 1 995;52:2-12

Cumulative exposure to inorganic lead andneurobehavioural test performance in adults: an

epidemiological review

JohnM Balbus-Kornfeld, Walter Stewart, Karen I Bolla, Brian S Schwartz

AbstractObjectives-To evaluate the current evi-dence that cumulative exposure to inor-ganic lead is associated with decreasedperformance in neurobehavioural tests inadults.Methods-21 unique studies werereviewed from 28 published manuscripts.An algorithm was developed to determinethe usefulness of each study on the basisof exposure assessment, control of con-founding variables, methods of subjectselection, test conditions, and data analy-sis. Highest emphasis was placed on theuse of cumulative measures of exposureor absorption.Results-Only three studies used a mea-sure ofcumulative exposure to or absorp-tion oflead, and two others used durationof exposure as a surrogate for cumulativeexposure. All other studies used a mea-sure that did not adequately estimatecumulative exposure to lead, most oftencurrent blood lead concentration. 20 ofthe studies controlled for age as a con-founding variable, although in severalstudies the possibility for residual con-founding by age remained. 16 studiescontrolled for intellectual ability beforeexposure; all of them used educationallevel for this purpose. Of the five studiesthat used direct or surrogate measures ofcumulative exposure to or absorption oflead, two were thought to be of low use-fulness because of inadequate duration ofexposure. The three remaining studiesfound stronger associations of neurobe-havioural performance with recent expo-sure measures than with those ofcumulative exposure.Conclusion-The current scientific liter-ature provides inadequate evidence toconclude whether or not cumulative ex-posure to or absorption of lead adverselyaffects performance in neurobehaviouraltests in adults. The current evidence isflawed because of inadequate estimationof cumulative exposure to or absorptionof lead and inadequate control for ageand intellectual ability before exposure.

(Occup Environ Med 1995;52:2-12)

Keywords: lead; neurotoxins; neuropsychological tests

Although the detrimental effect of low tomoderate exposure to lead on the central

nervous system (CNS) has been generallyaccepted in children,' such an effect remainscontroversial in adults. Manifestations of leadintoxication of the CNS in adults have beenwell described and consist of ataxia, memoryloss, and at the highest levels coma and death.Low to moderate exposure has been consis-tently associated with symptoms of malaise,fatigue, irritability, lethargy, headache, anddecreased libido.2 Such exposure has alsobeen reported to decrease neurobehaviouraltest scores in the cognitive or motor domainsof psychomotor speed, manual dexterity,memory, and learning ability. These quantita-tive tests are more reproducible than symp-tom scores and are the only currently availablemeasures of the functional integrity of theCNS.An important unresolved issue is whether

cumulative exposure to lead causes chronicdysfunction of the CNS in adults. Althoughseveral methods exist to estimate cumulativeexposure to or absorption of lead, recentblood lead concentrations are inadequate inthis regard.6 Associations found with recentblood lead concentrations may reflect tran-sient and reversible changes because thismeasure reflects primarily exposure receivedin the most recent few months, especially incurrently exposed workers. We report theresults of a rigorous evaluation of the evidencethat cumulative exposure to lead is associatedwith decreased neurobehavioural test perfor-mance in adults.

MethodsMEDline, NIOSHTIC, HSELINE (Britishemphasis-published by the Health and SafetyExecutive) and CISDOC (internationalemphasis-published by the InternationalOccupational Safety and Health InformationCentre of the UN Labour Organisation) data-bases were searched with the keywords lead,neurotoxicity, and neurobehavioural. Also,the references of papers identified from the lit-erature searches were examined to identifyother studies. Peer reviewed studies were con-sidered if they included adults exposed toinorganic lead, performed neuropsychologicaltests, and did not involve mixed exposures toneurotoxins.

Each study was scored for its ability tospecifically examine the association betweencumulative exposure to lead and neurobehav-ioural function. The overall score was basedon an assessment of the following factors: themethod by which neurobehavioural data were

Department ofEnvironmental HealthSciencesJ M Balbus-KomfeldW StewartB S SchwartzDepartment ofEpidemiology, JohnsHopkins School ofHygiene and PublicHealth, Baltimore,Maryland, USAW StewartB S SchwartzDepartment ofNeurology, JohnsHopkins BayviewMedical Center,Baltimore, Maryland,USAK I BollaCorrespondence to:Dr Brian Schwartz, JohnsHopkins University Schoolof Hygiene and PublicHealth, 615 N Wolfe Street,Room 7041, Baltimore,Maryland 21205, USA.Accepted I September 1994

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Cumulative exposure to inorganic lead and neurobehavioural test performance in adults: an epidemiological review

collected; the definition of exposure; prospec-tive v cross sectional design; use of a non-exposed group, and if a non-exposed groupwas used its comparability with the exposedgroup; and the adequacy of methods of con-trol for potential confounding variables. Therationale for selecting and priority given toeach factor, as well as the specific criteriaused, are described.

EXPOSURE ASSESSMENTStudies were evaluated for the extent to whichthey estimated cumulative exposure to orabsorption of lead. Four methods were con-sidered adequate for this purpose. Firstly,cumulative exposure could be calculated asthe product of intensity of exposure (esti-mated from industrial hygiene data) and dura-tion of exposure for each job that involvedexposure to lead. Secondly, cumulative leadabsorption could be directly measured as leadin bone by x ray fluorescence. Although notan estimate of total lead body burden, chelat-able lead (most often estimated as the amountof lead excreted in the urine for six or 24hours after a 1 g intravenous dose of ethylene-diamine tetraacetate (EDTA)) was also con-sidered to be a third relevant surrogate forcumulative absorption because chelatable leadis thought to reflect the total bioavailable leadpool.7 A fourth measure that was thought toprovide an accurate estimate of cumulativeabsorption was the sum of the products ofinterval blood lead concentrations and thetime intervals between samples. Such a mea-sure requires blood lead samples from theentire duration of exposure to be most useful.This is equivalent to the area under the curveof a plot of blood lead concentrations v timefor the period of employment in jobs exposedto lead, which in turn has been shown to cor-relate highly with bone lead as measured by xray fluorescence.7

Studies that used any one of these fourmethods were considered to be the most usefulfor this review. Studies that used duration ofemployment alone as a surrogate for cumula-tive exposure were considered useful, becauseduration of exposure is likely to be an ade-quate estimate of cumulative dose for toxinswith long half lives such as inorganic lead."The use of time weighted averages-for exam-ple, of blood lead, zinc protoporphyrin (ZPP),or intensity of exposure-alone was consid-ered less useful, as two subjects with the sametime weighted average could differ substan-tially in duration and therefore cumulativedose. Studies that used recent biological mea-sures-for example, current blood lead, ZPP,urinary aminolevulinic acid (ALAU)-werealso thought to be of low usefulness. Growingevidence has shown that the current bloodlead concentration, for example, is an inade-quate estimate of the total absorbed dose oflead.7 9 10

Duration of exposure and its variationamong study subjects was also assessed.Although no threshold has been establishedbelow which cumulative effects of lead wouldnot be expected, a population comprising

people with predominantly short term expo-sure (less than three years) would be less likelyto show a cumulative effect of lead than onewith a longer duration of exposure.

CONTROL OF CONFOUNDING VARIABLESIn order of priority, the following factors wereconsidered to be the most important potentialconfounding variables:

AgeNeurobehavioural performance declines withincreasing age. The age at which such declinebecomes obvious as well as the extent of thedecline, however, vary with both sex and thespecific test." 12

Intellectualfunctioning before exposureCapability and performance before exposureare highly predictive of test performance aftera toxic exposure.3 In the absence of dataon intellectual functioning before exposure,verbal intelligence measures-for example,the Wechsler adult intelligence scale revised(WAIS-R) vocabulary score-and years ofeducation are often used to control for differ-ences before exposure. Although the numberof years of education is easy to measure and isnot affected by exposure to neurotoxins, it is amodest predictor of capability before expo-sure. On the other hand, the WAIS-R vocab-ulary subscore may correlate well withperformance on a range of neurobehaviouraltests, but there are few data to support thecontention that it is resistant to the effects ofneurotoxins. Despite these limitations, how-ever, there are no realistic alternatives to thesesurrogate measures, and their use is preferableto not considering the issue. Studies weretherefore evaluated for adequacy of controlfor capability before exposure.

SexNeurobehavioural test performance has beenassociated with sex, but the magnitude of theassociations differs for the specific test."'0Studies were assessed for their control for sexdifferences.

AlcoholAcute alcohol intoxication affects neurobe-havioural test performance. Studies weretherefore evaluated as to whether recent alco-hol ingestion was evaluated. It is less clear,however, that a history of chronic alcoholingestion is a significant confounding vari-able.'4 Control for chronic alcohol ingestionwas assessed, but was not considered to be ofgreat importance.

Other neurotoxinsSolvents, carbon disulphide, heavy metals,and other substances have all been shown toaffect neurobehavioural performance. Studieswere evaluated on adequacy of control forearlier exposure to other neurotoxins in bothexposed and non-exposed subjects.

STUDY DESIGNProspective studies offered several advantages

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Balbus-Kornfeld, Stewart, Bolla, Schwartz

over cross sectional studies: firstly, they couldseparate effects of past exposure from recentexposure; secondly, they enabled comparisonsof groups both in terms of cross sectionalneurobehavioural functioning and changes infunction over time. The comparison of func-tion over time would allow direct assessmentof functioning before exposure if the subjectentered the study at the time of initial employ-ment; alternatively, measurement of change inneurobehavioural function over time, if sub-jects were old, would allow an estimate of therate of decline in neurobehavioural functionassociated with aging.

Subject selection and recruitment methodswere considered most useful when they werepopulation based and minimised self selec-tion. Participation and drop out rates wereevaluated; at least 50% participation wasthought to be essential.

DATA COLLECTIONWe considered four factors that could con-tribute to group differences: (a) if comput-erised tests were not used, blinding ofexaminers to exposure; (b) uniform test con-

Algorithm for determining overall use of study.

ditions; (c) several different examiners; and(d) assessment of reliability between testers ifseveral examiners were used.

ASSESSMENT OF OVERALL USEFULNESSWith the above criteria, each study wasassessed for its overall usefulness to assess thehypothesis that cumulative exposure to low tomoderate levels of lead causes decreasedneurobehavioural test performance in adults(figure). Slightly different criteria were usedfor prospective and cross sectional studies. Astudy was considered of little usefulness if itdid not use a measure of cumulative exposureor absorption as described above. Cross sec-tional studies that did not study comparableexposed and non-exposed populations andprospective studies that experienced higherthan 50% drop out rates were also consideredof little usefulness, even if they used a cumula-tive exposure measurement. To be consideredhighly useful, a study had to meet the abovecriteria and also clearly define selection nWth-ods for exposed and non-exposed subjects,fully assess potential confounding variables,and use test conditions that were standardizedand blinded to exposure. Studies not meetingthese additional criteria were consideredmoderately useful.

ResultsA total of 21 unique studies were identifiedfrom 28 published manuscripts. Eleven man-uscripts were identified from the literaturesearch, and an additional 17 papers wereidentified from references cited in those 11papers. When more than one paper was pub-lished from a single cross sectional study, onlyone paper was selected for entry into thetables, but all papers were used in extractingstudy characteristics. Similarly, preliminarypapers published from prospective studieswere excluded unless they had significantlydifferent conclusions or data analysis com-pared with the final paper-for example,Baker et al, 1984 and 1985.333 The totalnumber of study participants in the 21 studiesranged from nine to 708 (table 1).Most studies (n = 16) used a cross sec-

tional design and a non-exposed comparisongroup (table 2). Most studies controlled forage (n = 20), sex (n = 19), and educationallevel (n = 16) by either matching or adjust-ment. Seven studies had similar group meansfor age and four studies had similar means foreducation without describing the method ofcontrol. In 12 studies the mean or medianduration of exposure was greater than threeyears; in five it was less than three years, andfour studies did not report duration of expo-sure.

Only three studies used a direct measure ofcumulative exposure to or dose of lead; inanother two studies duration of exposure wasused as a measure of exposure in the analysis.The remaining 16 studies did not use a mea-sure of cumulative exposure or dose by ourcriteria.The average blood lead concentration in

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Table ) Published studies of adult neurobehavioural test performance associated with exposure to inorganic lead, 1976 to the present

Reference Design Sample size

Milburn et al" Cross sectional 16 Exposed,15 non-exposed

Repko et al 7 Cross sectional 85 Exposed,55 non-exposed

Grandjean et all' Cross sectional 42 Exposed.22 non-exposed

Haenninen et al! Cross sectional 49 Exposed,24 non-exposed

Valciukas etal'!" Cross sectional 90 Exposed,25, 99 and 93non-exposed

\Valciukas et af2' Cross sectional 90, 28 and 23Exposed,265 non-exposed

Johnson er al ' Cross sectional 209 and 234exposed, 126 and139 non-exposed

Arnvig et a!2' Cross sectional 9 Exposed,0 non-exposed

Hogstedt et al Cross sectional 49 Exposed,27 non-exposed

Campara et al- Cross sectional 40 Exposed,20 non-exposed

Jeyaratnam. et al Cross sectional 49 Exposed,36 non-exposed

Williamson and Teo2n Cross sectional 59 Exposed,59 non-exposed

Ryan et al Cross sectional 288 Exposed,181 non-exposed

Ahmed et a! Cross sectional 45 Exposed,0 non-exposed

Pasternak et al Cross sectional 24 Exposed,29 non-exposed

Stollerv et al! Cross sectional 91 Exposed,0 non-exposed

Mantere et al 2 Prospective 11 Exposed,10 non-exposed

Baker et al Prospective 99 Exposed,61 non-exposed

Baker etal" Prospective 36 Exposed,14 non-exposed

Yokoyama et al Prospective 17 Exposed,1 1 non-exposed

Stollery et al Prospective 70 Exposed,0 non-exposed

Author's conclusiors (excerptsfront abstracts)

"The three performance tests revealed no differences between the exposed and the non-exposed groups."

deficits in visual reaction time ... were adversely affected by low-level absorption. Nodifferences were noted in the strength, eye-hand coordination, or other psychological!socialmeasures."

"Significant differences. concerning long-term memory, verbal and visuospatial abstraction,and psychomotor speed."

"A significant relationship between impaired psychological performance and lead uptakewithin the exposed group. The performances that were most affected by lead depended onvisual intelligence and visual-motor function."

"Secondary lead smelter workers showed significantly poorer performance scores than thenonexposed control groups." Decreased performance on block design, digit symbol,embedded figures, and Santa Ana (both hands).

"A significant association between performance test scores and increased lead absorptionwas found ... It is concluded that workers exposed to lead at levels considered 'safe'might be at risk of developing brain dysfunction with long term exposure."

"Smelter groups, when compared with community groups, showed: lengthened choicereaction time in the order of 10 percent ."

"Intelligence tests indicated normal intellectual potential, but memory, attention,concentration and psychomotor performance were severely impaired."

"The exposed group performed less well in 11 of 14 nonverbal tests, and there weresignificant differences in tests of memory and reaction time."

"The group of workers with the highest PbB levels showed significantly poorer performance... the poorer performance was mainly due to an impairment of general functioning andonly to some extent to a deterioration in specific functions."

"The performance of the lead workers was found to be significantly poorer for digit symbol,Bourdon-Wiersma, trail making test (part A), Santa Ana test, flicker fusion and simplereaction time."

"Most neurobehavioural functions tested showed some impairment in the lead workers.Multiple linear regression analysis showed that performance on the sensory store memorytest alone was significantly related to exposure."

"There is little support for the view that older adults with current blood lead levels in the lowto moderate range are at risk for developing significant CNS dysfunction ."

"Results indicated that most of the subjects studied have a comparably high PbBI. Theyalso showed significantly poorer performance scores than that obtained in a previousstudy with a group of textile workers of the same age and educational levels."

"We demonstrated a significant difference from controls in measures of psychomotor speed,motor strength and verbal memory."

"Workers with high blood lead concentrations showed clear impairment of sensory motorfunctions in the absence of correspondingly strong evidence for impaired processing andmemory functions."

"Although the impairment of the lead workers' performance was rather slight and thedispersion in the psychological changes was wide, it svas evident that some higher nervousfunctions were affected by lead levels above (30 pgAdl)."

"Workers with blood lead concentrations between 40 and 60 usg'dl showed impairedperformance on tests of verbal concept formation, visualtmotor performance, memoryand mood."

"This investigation confirms the importance of compliance with workplace standardsdesigned to lower exposures to ensure that individual blood lead concentrations remainbelow 50 pg/dl."

"Psychological performance was significantly affected by lead absorption in the firstexamination, resulting in a reduction in score on picture completion at the BPb level of40-46 pg/dl."

"The primary psychological profile of lead impairment is one of sensory motor slowingcoupled with difficulties in remembering incidental information."

the most exposed groups varied from 27-8jeg/dl to 68-3 ug/dl, whereas most non-

exposed groups had blood lead concentrationsless than 20 jg/dl (table 3). Several studies(Grandjean et al, Baker et al, Ryan et al) com-

bined workers with very short (< 6 months)and very long (> 20 years) duration of expo-

sure without controlling for the effects ofduration of exposure in the data analysis. 18 28 33

Many studies that did not use computer tests

either did not blind examiners or did not pro-

vide any information on this issue.Most exposed groups were recruited from

battery plants or lead smelters (table 4). Moststudies did not explicitly report selection andrecruitment methods or participation rates

among exposed workers. The source of non-

exposed groups varied; in nine studies, thenon-exposed group was comparable with theexposed group (similar industries, same fac-tory or union), whereas in six, the non-

exposed group was likely to differ fromexposed subjects on such important factors associoeconomic or educational background(community volunteers, male nurses). Twostudies did not provide enough informationon the selection of non-exposed subjects topermit such a judgment. Control of con-founding variables also varied from study tostudy. Although most studies reported no sig-nificant overall differences between groupswith respect to age and ability before expo-sure, few studies controlled for these variablesin regression models. Thus, residual con-founding may still have been present. Fewstudies assessed potential confounding byalcohol consumption or earlier exposure toneurotoxins, although these factors areunlikely to have resulted in significant con-founding. All studies that controlled for abilitybefore exposure used education for this pur-pose.

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Table 2 A summary of study characteristics considered to be useful in evaluating theneurobehavioural effects of inorganic lead in adults

Study factor Category Studies (an (%/.))

Design Cross sectionalProspective

Assessment of exposure Quantitative cumulative exposure*Cumulative absorptionChelatable lead*Semiquantitative cumulative exposuresDuration of exposures + current biomarkerTWA biomarkerilCurrent biomarker only

Non-exposed group YesNo

Source of non-exposed Same plantgroup Different industry

Community volunteersUnknown

Non-exposed matched Age and educationto exposed Age only

Education onlyUnknownAdjustment used

Percentage of studies that Agecontrolled for Education levelconfounding Verbal IQ

SexRecent alcoholOther neurotoxins

Examiner blinded to Yesexposure No

UnknownNot applicable (computer used)

Median duration of >5exposure (y) 3-5

<3Not given

16 (76)5 (24)0 (0)1 (5)1 (5)1 (5)2 (9)6 (29)10 (48)17 (81)4 (19)4 (24)10 (59)2 (12)1 (6)6 (35)1 (6)1 (6)6 (35)3 (18)

20 (95)16 (76)0 (0)19 (90)10 (48)11 (52)6 (29)3 (14)9 (43)3 (14)10 (48)1 (5)5 (24)5 (24)

*Estimated by product of time weighted average air lead concentrations and duration ofexposure.tEstimated by product of time weighted average blood lead concentrations and duration ofexposure.tUrinary lead excretion for 24 hours after 20 mg/kg IV EDTA.SProduct of ordinal ranking of intensity of exposure based on expert opinion and duration ofexposure.¶Current biomarker = blood lead, zinc protoporphyrin, or aminolevulinic acid.IlTime weighted average blood lead, zinc protoporphyrin, or aminolevulinic acid, obtained attime of neurobehavioural test, and averaged over a range of one to nine years before test.

Few studies used a measure of cumulativeexposure or absorption. Three of the fivestudies that used such a measure werethought to be of moderate usefulness(Valciukas et al, Yokoyama et al, and Stollery etat) 20 35356 Although another two studies(Williamson and Teo, Pasternak et al) used ameasure of cumulative exposure or absorp-tion, the duration of exposure among workerswas thought to be too short to adequately sep-arate cumulative from concurrent effects.Specifically, in the study of Williamson andTeo, the median duration of exposure was2-08 years and in the study of Pasternak et althe mean duration of exposure was 2-80 years(77% of the workers were exposed for lessthan three years.)27 30

After ranking the studies on the basis ofoverall usefulness, examination of compar-isons performed and associations foundshowed several notable findings (table 5).Firstly, among the five studies that used ameasure of cumulative exposure to or absorp-tion of lead, neurobehavioural test perfor-mance was more strongly associated withcurrent rather than cumulative measures.Secondly, the most rigorous studies generallyfound fewer significant differences in neu-robehavioural function than less rigorousstudies. Finally, dexterity (17 out of 21 stud-ies) and executive or psychomotor (11 out of21) were the neuropsychological domainsmost frequently associated with any measureof exposure to or absorption of lead.

DiscussionThe scientific literature offers little evidencethat cumulative exposure to low to moderatelevels of inorganic lead affects neurobehav-ioural test performance in adults. Notably, thedata are also insufficient to conclude that suchexposure does not affect the adult CNS. Themain reason for this lack of useful evidence isthat all but five of the published studies failedto use an estimate of cumulative exposure toor absorption of lead. Although the studiesthat used current measures reported associa-tions between exposure to lead and neuro-behavioural function, associations with recentexposure may be transient or reversible andtherefore of limited significance to publichealth. Two of the five studies that usedcumulative measures (Valciukas et al andYokoyama et at) found that neurobehaviouraltest performance was associated with cumula-tive exposure and chelatable lead, respec-tively, in the domains of visuomotor function,dexterity, and formation of visual concepi.2035Stollery et al, on the other hand, did not findany association between duration of exposureand neurobehavioural performance. Thethree studies differed greatly on a variety ofstudy design features, so it is difficult toaccount for this inconsistency in results. Ingeneral, fewer and weaker associations werefound between cumulative measures and testscores than between current measures andtest scores. Unfortunately, even those studiesthat used cumulative measures primarilyreported analyses with current measures.

Three studies estimated exposure as thetime weighted average of blood lead concen-trations obtained during the course ofemployment (Haenninen et al, Hogstedt et al,Ryan et at.)92428 Although such a measureyields an average intensity of absorption, itdoes not account for duration of exposure. Asthe exposed subjects had varying durations ofexposure, average intensity was a poor relativeestimate of cumulative absorption. For exam-ple, younger workers, often employed in themost highly exposed jobs, would have highertime weighted average blood lead concentra-tions but lower cumulative absorption of leadthan older, long term workers whose averageintensity of exposure may have been lower.The lack of association between timeweighted average blood lead and age inHaenninen et al 19 emphasises this point; age isgenerally correlated with cumulative exposureand lead in cortical bone.7 ' Thus, associa-tions such as those found by Haenninen et al, ifcausal, may be due to the effects of relativelyshort term, not cumulative exposure.

Several otherwise well designed studies(Stollery et al and Campara et at) found associ-ations between measures of current bloodlead and decrements in neurobehavioural testperformance.25 31 As current concentrations ofblood lead are more likely to reflect recentexposures, as stated previously, the associa-tions found may be due to an acute ratherthan cumulative effect of lead. In other stud-ies, confounding by capability before expo-sure or age could account for the associations.

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Table 3 Exposure variables used and characteristics ofdata collection considered important in assessment of the use ofstudies that evaluated theneurobehavioural effects of inorganic lead in adults

Mean (SD)Mean (SD) PbB in non-

Range of PbB in exposed or UniformExposure Exposure Duration of PbB exposed group least exposed Blinded test Examiners

Reference variables5 models exposure (y) (pg/dl) (pgldl) group (pgldl) examiners conditions (n)Cross sectional studies:

Milburn PbB Categorical Mean (SD) ? 61 (12) 28 (10) ? ? ?et all' 12-5(95)

Repko et al' PbB, FEP, ALAD, Categorical Mean (range) ? 46-04 (1-7) 17 98 (1 0) ? ? ?PbU (spot), continuous 8-7 (0-25-34)ALAU

Grandjean PbB, PbH, ZPP Categorical! Median (range) 2 12 6-88 2 46-2 16 6 No ? ?et alI continuous (0 0833-25)

Haenninen PbB, Max PbB, Categorical! 2-9 ? 32-3 (10-6) 11-9 (4 6) ? ? ?et all' TWA PbB continuous

Valciukas PbB, ZPP, EXP Categorical/ ? <30->80 50 5 "94% <40 Yes ? ?et all' DUR, mean continuous ug/dl"

relative level ofexposuresintegrated intensityof exposure

Valciukas PbB, ZPP Categorical/ ? <30->80 51-2 (12-0) PbB not Yes ? ?et all' continuous done

Johnson PbB, ZPP, FEP Categorical/ Means for men ? 56 1 (12-9) 22-3 (8-9) ? ? 2 (Reliabilityetal22 ALAU continuous 124, 119 39 3 (16-8) 15-2 (6 3) ch-k not

mentioned)Arnvig et a t" PbB Categorical 7-40 58-82 ?

Hogstedt PbB, ZPP, Categorical >7 27-68 41 4etal 24 TWA-7-PbB (TWA-PbB

given)

No Yes ?

14-5 No Yes 3 (Reliabilitycheck notmen-tioned)

Campara PbB, Max PbB Categorical/ Mean (range) 25-9-60 52-2 20-4 Yeetal"5 continuous 11-5 (5-25)

Jeyaratnam PbB Categorical ? ? 48-7 15 ?et al"2 ("Estimated"

from sampleof Singaporeworkers)

Williamson PbB, EXP, DUR Categorical Mean (range) 24-75-81-54 49-06 PbB not ?and Teo2' 8109-2 (13-25) done

(<500->15000)(h)

Ryan at all' TWA-PbB, PbB Categorical/ Mean (range) ? 40-01 7-2 Yemax, proportion continuous 13 (1-39) (13-17)>60 ,qg/dl, ZPP

Ahmed PbB, ALAD Categorical/ Median (range) 37-5-97 5 68-28 Not given ?et al 2" continuous about 3 (1-33)

Pastemak PbB max, PbB Categorical/ Range 0-47-10 27-5-85 47-46 4 (Except Ccet al median, PbB continuous (77% < 3) for one

mean, ZPP max, worker atZPP median, ZPP 17)mean, EXP DUR,product of EXPDUR and PbBmedian, product ofEXP DUR andZPP median

Stollery PbB, ALAU, ZPP Categorical! Range 4-8-11-7 5-72 50 C(er al' continuous

Prospective studies:Mantere PbB, TWA-PbB Categorical! Range 45-5 13-48 31-5 (8-8)

et al"1 continuous

Baker et al PbB, TWA-l-PbB Categorical! Mean (range) 10-80 32-8continuous 0 99 (0-5)

Baker et al PbB, Max PbB, Categorical ? 8-50 ?TWA-1l25-PbB,quadratic average,threshold TWA

Yokoyama PbB, chelatable Pb, Categorical! Median (range) 30-64 40etral" ALAD continuous 12 (1-16)

Stollery PbB, ZPP, Categorical Means across ? 52etal 6 ALAU, EXP groups

DUR 7 4-10 9

es Yes ?

es Yes Reliabilitychecked

? ?

computer Computer Computer

smputer Computer Computer

Yes

Yes

Yes

12

14

? ?

Yes ?

Yes ? Not given,sametestersfor y 2and 3

Yes 1

Computer Computer Computer

*PbB = current blood lead concentration; FEP = free erythrocyte protoporphyrin; ALAD = amino levulinic acid dehydratase; PbU = urinary lead concentration;ALAU = urinary aminolevulinic acid concentration; PbH = hair lead concentration; ZPP = zinc protoporphyrin concentration; Max = maximum; TWA = timeweighted average-a number afterTWA indicates the number of years averaged; EXP DUR = exposure duration; chelatable Pb = 24 hour urinary excretion of leadafter 20 mg/kg dose of EDTA.t Indicates whether exposure variable was used as a continuous variable or analysed as a categorical variable by separating subjects into groups based on exposurelevels.* Indicates no information reported on this characteristic.§ Defined as the mean of ratings of intensity of exposure from I to 3 for each job held as determined by an industrial hygienist.¶Defined as the sum of the products of the rating of intensity of exposure for each job and the duration of employment in each job.

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Table 4 Sources ofexposed and non-exposed groups, percentage participation, and methods ofcontrolfor confounding variables in twenty-one studiesthat evaluated the neurobehavioural effects of inorganic lead in adults

Selection issues Method ofcontrol ofconfounders

Participation(%o, and Ability Previous

Reference Study group follow up) Control group Age before exposure Alcohol exposures

Cross sectional studies:Milburn Male workers from lead acid ?*

et all' battery plant

Repko et ali Volunteers from one of two ?storage battery plants

Grandjean Workers from five different ?et all' factories; selection method

not statedHaenninen Workers from two storage ?

et all' battery plants or railwaymachine shop; selectionmethod not stated

Valciukas Workers from secondary ?et al IO lead smelter in Los

Angeles

Male workers from Unknownt ? ? ?plastics departmentof same company

Same locations; controls Matched# Matched on ? Unknownwere younger, more educationwomen, more collegegraduates

Controls from food oil Unknown Unknown Unknown Unknownprocessing mill

RestrictedNew employees of one Matched, Matched on ?of the battery plants, restricted educationelectrical workers

Three control groups: Matched, Matched, ?steelworkers from adjusted adjustedsame union in Los on educationAngeles, papermillworkers from Virginia,Wisconsin farmers

Valciukas Cable splicers, cable ? Residents of Michigan Adjusted Adjusted on ? ?et al21 manufacturers from New screened for PCB's; education

York; secondary lead no lead concentrationssmelter workers from measuredLos Angeles; selectionmethod not stated

Johnson Randomly selected men, all 100% Ofwomen Volunteers from nearby Matched ? Restricted ?et al22 women from lead and ? men communities, one of

zinc smelters which hadenvironmental leadexposure

Arnvig et al"l Selected on basis of ? Scores compared to ? ? ? ?presumed high exposure reference data fromfrom battery plant orthopedic and other

groupsHogstedt Recruited from occupational 84% Controls selected from Unknown Restricted Unknown Unknown

et al surveillance laboratory; same laboratory; (pre-exposureworked in secondary lead more shift workers in tests availablesmelters and battery control group and equalfactories (55% v 24%) for 37% of cases

and 44% ofcontrols)

Campara Selected on basis of recent 11% Of a Control group maleet all' and maximal blood lead population of nurses from local Matched

values; worked at storage 350 exposed hospitalbattery plant workers; no

refusalsmentioned

Matched on Restricted Restrictededucation

Jeyaratnam Workers from Singapore ? Controls selected from Unknown Matched on ?et al26 plant that used lead other industrial (statistically education

stabilisers in PVC workers in Singapore, significantproduction; selection selection method difference)method not given not given

Williamson Male workers from either ?and Teon battery factory or

secondary lead smelter;selection method not given

Source of controls not Matchedgiven; 17% of controlgroup women

Matched on Matchededucation acute and

chronic

Ryan et al"2 Randomly selected from 67% Randomly selected from Matched Matched, Matched, Restthree battery plants car and lorry chassis adjusted on restricted

plant; 33% of controls educationscreened out by leadconcentrations

Ahmed Randomly selected from ? Unpublished data on Unknown Unknown ? ?et at29 Alexandria traffic textile workers from

controllers another study used asreference

Pasternak Volunteers from electrical ? ('Most" Recruited from different Unknown Unknown Unknown ?et alt" component factory workers; area of same plant (high

numbers of numbers ofexposed non-workers not respondersknown) to questionnaire

on this)Stollery Recruited from battery and ? No control group Adjusted Adjusted for age High group ?

et alP printing plants left school hadsignificantlyhigherrecent intake

* Indicates information was not reported.t Unknown indicates study reported similar group means, but method of control was not reported.* Despite matching, substantial difference remained between groups.

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Table 4 continuedfrom page 8

Selecion issues Method of control of confounders

Participationt'I, and Ability Previous

Reference Study group follow up) Control group Age before exposure Alcohol exposures

Prospective studies:Mantere Recruited from new 100% Recruited from cable Unknown ? ? Unknown

et al32 employees at battery 27% At I y and electronics plantsplant 18% At 2 y

12% At 4 yBaker et al/) Recruited from foundry 91% Controls recruited from Adjusted Adjusted for Restricted Restricted

43% At 1 y adjacent assembly education38% At 2 y plant

Baker et all' Recruited from foundry See above 66% Of exposed, 78% Adjusted Adjusted for Restricted Restrictedof controls lost from educationIst to 3rd y

Yokoyama Recruited from gun metal ? Steel foundry workers at Unknown Unknown Unknown Noet all' foundry same factory. Although previous

difference not significant, exposurecontrols were younger to lead(median 43 v 49) anddrank less alcohol (155v 200 ml/week)

Stollery Recruited from battery and 77% Of initial Young, high exposure Adjusted Adjusted for ? Unknownet al3l printing plants cohort at eight workers lost age left school

months disproportionately

Age is a strong predictor of neurobehaviouralperformance, but it was controlled in moststudies only by matching means or medians.This may still allow residual confounding ifthe range of ages is wider in the exposed thannon-exposed subjects, as was true in several ofthe studies (Repko et al and Haenninen etal).779 As neurobehavioural test performanceremains fairly stable until advanced age(50-65 depending on the test), the olderworkers from the group with the moreextreme range are likely to exert a stronginfluence on the associations found.

Control for intellectual ability before expo-sure, especially in cross sectional studies, isparticularly difficult. Nearly all studies usededucation, either to match group means ingroup comparisons, or as a covariate in multi-ple linear regression models. Several studiesstill found substantial differences betweengroups in vocabulary scores. This suggeststhat education may be an inadequate controlfor intellectual ability before exposure. Forexample, Baker et al found that exposure tolead had a strong negative association with thevocabulary test score.33 This may either repre-sent a causal association or that less capableworkers are most likely to work in the mosthighly exposed jobs. To the extent that thevocabulary score reflects overall intellectualability before exposure, the difference foundin this measure limits the inferences that canbe made from other associations found.

Study results were not pooled for the pur-poses of a quantitative meta-analysis becauseof differences in exposure and outcome vari-ables among studies. Comparison of datafrom studies that used the same neurobehav-ioural tests showed that test scores had greatervariability between studies than betweenexposed and non-exposed groups within thesame study (data not shown). This variationcould either be due to unassessed differencesin cumulative exposure (the differences inaverage blood lead concentrations were not

significant) or to differences in age, abilitybefore exposure, or test methods among thestudy populations. These possible explana-tions are indistinguishable without accuratecumulative exposure measures.The distinction between effects of cumula-

tive and recent exposure has important publichealth implications. It is possible that subclin-ical neurobehavioural dysfunction associatedwith short term recent exposure may bereversible if exposure ceases and blood leadconcentrations decline. Decreased neurobe-havioural test performance associated withcumulative lead exposure or absorption ismore likely to be irreversible, and hence maycontribute to premature dementia and neuro-logical dysfunction as the subject ages.

Future studies will need to incorporatedesign features that allow more accurate dis-tinction between the acute and chronic effectsof exposure to lead. To detect chronic, irre-versible effects, one approach would be aprospective study of workers over the age of50 with many years of exposure to lead. Such adesign may be compromised by a survivoreffect, in that the workers with symptomaticneurobehavioural effects may have left theworkplace before the age of 50. On the otherhand, this design can assess the change inneurobehavioural function over time, allowthe remaining workers to function as theirown controls, and avoid several other biasesinherent in a cross sectional study of a popula-tion of older workers. Evaluation of workerswith similar current concentrations of bloodlead but different levels of cumulative expo-sure would help to distinguish the relativecontributions of cumulative exposure (bonelead) and current internal dose (blood lead).Measurement of changes in bone lead,bioavailable lead (chelatable lead), and bloodlead over time would help to define whetherremobilisation of stores of bone lead in olderpeople contributes to ongoing neurotoxicity.An alternative study design would be a

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Table S List of neurobehavioural tests that showed signficant differences between groups, or significant association with exposure variables (studies listed inapproximate order of overall usefulness)

Significant Tests that showed signfcantComparisons differences between differences between Association between performance and

Reference Tests done made exposure groups exposure groups * exposure variable

Studies of moderate usefulness:Stollery et all30 5

Valciukas et all' 5

Yokoyama et al "5 5

Studies of low usefulness:Ryan et alI"

Stollery et al 3

Hogstedt et al"4

16

215

15

215

1523

Haenninen et all' 16 27

Pastemak et al 3}

Mantere et a! 2

Repko et a'

Johnson et al22

Baker et al I'

Baker et all'

Campara eta!Is

Valciukas et a2!i

23 23

10 10

Reaction time, category recall

BD, dig sym, emb fig

PC

Grooved pegboardCategory search, reaction timeBenton errors, Claeson-Dahl,

reaction time

None

Fingertap, dig sp F (x 2),vis mem

BD, SA coord, dig sp

RT (RH)

RT

Voc, sim, dig sym, SA,ment conc, vis repro

N/A

Sim, voc, dig sym, PC, symbcopy, cancellation, Rey

N/A

Dig sym, Bourdon Wiersmaspeed, trail A, SA (RH + LH),flick fus, RT

Critical flick fus, RT,memory, hand steadiness

Yes; PbB, ZPP, AIAU, not EXPDUR

Yes; ZPP> integrated exposurevariable

Yes; PbB >chelatable Pb

NoYesNo linear correlation; dose effect

seen when upper quartileseparated

Yes

Not done

Yes

Not done; correlated with ulnarNCV*

No

Yes

Yes (y 2 only)

Yes

Yes; ZPP > PbB

Not done

Only one test (memory) with only1 y PbB

4

2

17

12

17 6

No group comparison made

13 25 7

3 No group comparison made

Jeyaramam et a!26 14 15

Williamson andTeo et al

9

Grandjean et al I' 18 27 15

Milburn et all' 3 11 1

Ahmed et al I' 2 2 2

Arnvig et al2" 16 16 7-15§

Vis gestalts repro, graphic contperf time, finger tap, WAIS-Rexcept dig sp, PC, obj ass,verbal IQ, perf IQ, total IQ

RT to peripheral stimulus

BD, SA

N/A

* BD = block design subtest of Wechsler adult intelligence scale (WAIS); dig sym = digit symbol substitution subtest of WAIS; emb fig = embedded figures; PC =picture completion subtest of WAIS; RT = reaction time; vis mem = visual memory; dig sp = digit span (F indicates forward only); voc = vocabulary subtest ofWAIS; sim = similarities subtest ofWAIS; SA = Santa Ana coordination test (RH/LH denotes hand tested); ment conc = mental concentration subtest ofWAIS; visrepro = visual reproduction subtest of WAIS; trail A/B = Trailmaking A or B; flick fus = flicker fusion test; symb copy = symbol copying; paired association lrn =paired associative learning subtest of Wechsler memory scale; vis gestalts repro = visual gestalts reproduction; obj ass = object assembly subtest of WAIS; perf IQ =

performance IQ.t Abbreviations as for table 3.*NCV = nerve conduction velocity.S Denotes range of number of tests found abnormal per individual in comparison with population standards. Because of variability of individual tests and poorcomparability of non-exposed group, individual tests are not named.

randomised trial of chelation treatment and provides inadequate evidence to concludeits effect on neurobehavioural function. whether or not cumulative absorption of leadRandomisation of workers should effectively adversely affects neurobehavioural test perfor-control for important confounding variables, mance in adults. The current evidence isand the association of neurobehavioural func- flawed because of inadequate estimation oftion with changes in tissue, blood, and chelat- cumulative absorption of lead and inadequateable lead concentrations after chelation would control for age and intellectual ability beforeallow inferences to be made about the exposure. Because of the failure to estimatereversible and irreversible effects of lead. cumulative exposure to or absorption of lead,

In summary, the current scientific literature the published studies do not allow separation

Yes

Not done

Not done

Not done

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Tests that showed significant association *

Reaction time, category recall


PC

Domains of significant difference or association

Dexterity, verbal memory

Visuomotor, visual concept formation, dexterity

Executive/psychomotor

Factors decreasing use

Cumulative measure was duration of exposure, bulk of analysisdirected at more recent exposure and dose measures

Percentage participation not given; alcohol ingestion notcontrolled; data collection not well characterised

Cumulative measure not used for categorical comparison;confounding by age, education not well controlled; selectionmethods not given

N/ACategory search, reaction timeBenton errors, Claeson-Dahl,

reaction time

BD, vis repro, SA

N/A

BD, SA

N/A

N/A

Voc, sim, ment conc; correlated withcurrent PbB, not TWA-12-PbB

Paired association Irn, SA (both)correlated with several averagesand current PbB

Voc, PC, sim, DSST, card sorting


N/A

Memory

DexterityDexterity, executiveMemory, learning, dexterity

Visuomotor, visual learning, dexterity

Dexterity, verbal memory, visual memory

Dexterity, .visuomotor

Dexterity

Dexterity

Verbal intell, visuomotor, verbal conceptformation, attention, visual memory

Verbal learning, dexterity

Verbal intell, executive, memory, visual conceptform, visual learning, attention

Visuomotor, visual conc form, dexterity

Dexterity, executive/psychomotor, attention/concentration

Dexterity, memory visuomotor

Vis gestalts repro, graphic count perf time, Verbal memory and learning, visual memory andfinger tap, WAIS-R except dig sp, PC, learning, dexterity, executive, attention/obj ass, verbal IQ perf IQ, total IQ concentration

N/A Attention/concentration

Executive/psychomotor, dexterity

N/A

N/A

N/A

No cumulative measureNo cumulative measure, percentage participation not givenNo cumulative measure; examiners not blinded, method of

control of confounders not stated

No cumulative measure; percentage participation not given;level of exposure low for PbB; data collection not well-characterised

Short exposure duration; small numbers; half of exposedgroup underwent chelation; cumulative measure calculatedbut not used in regression analysis

73% Dropout after first year; additional 54% dropoutsubsequent to first year; exposure duration short; nocumulative measure per se OTWA-PbB in group with similarexposure duration)

No cumulative measure; percentage participation unknown;neurobehavioural tests limited in scope

No cumulative measure; tests limited to eye-handcoordination and RT; no control for ability before exposure

No cumulative measure; strongest correlation with vocab andsim scores

No cumulative measure; dropout rate 66% exposed, 78%controls; large intergroup differences in vocabulary scores

No cumulative measure. large intergroup differences invocabulary scores; non-exposed group not comparable

No cumulative measure; no PbB data on reference group;reference group not comparable to exposed groups

No cumulative measure; poor control of confounders,selection methods not stated, duration of exposure notstated but mean age of exposed 26-1 y

Poorly matched on sex; controls younger, more educated with0-05 < P < 0-10; PbB concentrations not measured in controlgroup; median duration of employment for exposed group< 3 y

No cumulative measure; no control for confounders; medianexposure 2 y; no description of selection or data collectionmethods

Lead exposed were significantly faster than non-exposed onreaction time test; no cumulative measure; small numbers;8 of 15 non-exposed had history of lead exposure > 5 ybefore study; no control for pre-exposure ability

No cumulative measure; neurobehavioural test results notshown; control group data from different study; poorcontrol of confounders

No cumulative measure; study design similar to case series; nocontrol of confounders; reference group not similar

of the acute and chronic effects of lead.Studies that use direct measures of cumulativeabsorption, such as x ray fluorescence, andthat use prospective designs will be necessaryto adequately resolve this issue.

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Medicine Cumulative to test - Occupational and ...Neurobehavioural test performance has been associated with sex, butthe magnitude ofthe associations differs for the specific test."'0