Historical Perspective on LeadBiokinetic ModelsMichael RabinowitzMarine Biological Laboratory and Harvard Medical School,Woods Hole, Massachusetts

A historical review of the development of biokinetic model of lead is presented. Biokinetics isinterpreted narrowly to mean only physiologic processes happening within the body. Proceedingchronologically, for each epoch, the measurements of lead in the body are presented along withmathematical models in an attempt to trace the convergence of observations from two disparatefields-occupational medicine and radiologic health-into some unified models. Kehoe's earlybalance studies and the use of radioactive lead tracers are presented. The 1960s saw the jointapplication of radioactive lead techniques and simple compartmental kinetic models used toestablish the exchange rates and residence times of lead in body pools. The applications of stableisotopes to questions of the magnitudes of respired and ingested inputs required thedevelopment of a simple three-pool model. During the 1980s more elaborate models were

developed. One of their key goals was the establishment of the dose-response relationshipbetween exposure to lead and biologic precursors of adverse health effects. Environ HealthPerspect 106(Suppl 6):1461-1465 (1998). http://ehpnetl.niehs.nih.gov/docs/1998/Suppl-6/1461-1465rabinowitz/abstract.html

Key words: lead, stable isotopes, model, compartmental analysis

Consideration of lead biokinetics from ahistorical perspective promises to providesome useful insights. The evolution of ourthinking on this topic reveals which con-cerns or problems are transient, dealt withonce years ago and no longer requiring fur-ther validation, and which issues seem to berecurring, and the forms these recurringtopics take today.

For this presentation the term biokineticsis interpreted rather narrowly to mean onlyphysiologic processes happening within thebody. It is concerned with how lead is dis-tributed within our body rather than themany processes in the environment thatbring the lead to the mouth. These bio-kinetic models are conceptual, numericaldescriptions that could explain observa-tions or predict hypothetical situations. Sothe emphasis in this article is our changing

This paper is based on a presentation at theWorkshop on Model Validation Concepts and TheirApplication to Lead Models held 21-23 October 1996in Chapel Hill, North Carolina. Manuscript received atEHP 16 January 1998; accepted 18 March 1998.

Address correspondence to M. Rabinowitz,Marine Biological Laboratory and Harvard MedicalSchool, 7 MBL Street, Woods Hole, MA 02543.Telephone: (508) 289-7613. Fax: (508) 540-6902.E-mail: mrabinow@mbl.edu

Abbreviations used: 203Pb, radioisotope of lead;204Pb, stable isotope of lead; 210Pb, radioisotope oflead; 212Pb, radioisotope of lead; U.S. EPA, U.S.Environmental Protection Agency.

understanding of how lead is distributedwithin the body, how long it resides there,and how it is excreted. Less stress is placedon means of exposure or uptake of envi-ronmental lead. Proceeding chronolog-ically, for each epoch the measurements oflead in the body will be presented alongwith mathematical models in an attemptto trace the convergence of observationsfrom two disparate fields-occupationalmedicine and radiologic health-intosome unified models.

Early ObservationsThe earliest clinic observations of leadpoisoning noted its peculiar time course.The Devonshire colic, documented by SirGeorge Baker in 1768, serves as an exam-ple (1). It was caused by the use of lead inapple cider presses and vats. Sometimeslead metal was added to the cider to pre-vent spoilage. The abrupt onset of abdomi-nal symptoms was some time after thepatient started to drink the tainted cider,longer than simple food poisoning. Thepalsy came even later. Even in cases of fataloutcome, the symptoms did not appearwith the onset of exposure. The notion wasthat the delay in onset of symptoms wascaused by the accumulation of lead in thebody until it reached sufficient levels.Similar experience with industrial leadpoisoning, for example, noted by Charles

Dickens in 1861 (2), reinforced thisnotion that illness, should it come, wouldnot come immediately, but only aftersufficient time for the lead to accumulate.

Moving forward to the 1930s inCincinnati, Ohio, Kehoe et al. (3) reportedstudies of the absorption and excretion oflead in normal adults and in those withlead poisoning. These included dosinghuman volunteers and measuring theirintakes, outputs, and blood lead levels.Kehoe et al. reported that small, naturalamounts of lead are present in human tis-sues. They used a spectrographic methodbut did not appreciate until later the roleof laboratory contamination of samples.They reported mean blood lead levels ofnonexposed adults prior to 1938 to be 58pg/dl, with 75% being between 20 and 70pg/dl. Later they reduced this value byabout one-half. Kehoe et al. (4) stated thatlead intake and excretion were in near bal-ance, and with increased exposure andabsorption came increased excretion, butthe balance was not neutral. There wassome accumulation of lead; about 8% ofdaily intake in normal adults was retained.

Unfortunately, Kehoe's conclusionswere based on small differences in leadcontent among samples, so small errorsproduced by unappreciated contaminationcaused difficulties in measuring lead levels.This was especially true in the normal,nonpoisoned subjects, for example, incomparing the differences between diet,feces, and urinary output and relating thenet differences to changes in blood leadlevels. Of course, in situations of gross leadintake-more than 1 mg/day-these errorsbecame less important. Furthermore,Kehoe did not seem to appreciate, or didany of his generation of researchers, that,even after he made more adequate blankcorrections in 1938 and later and obtainedwhat he thought were normal values forblood lead of less than 30, the values heconsidered normal were actually those oflead-contaminated urban Americans.Natural lead levels were many times lower.

By 1938 some authors concluded thatlead levels in blood were a more reliableindex of lead absorption than lead excretedin urine according to Traeger and Schmitt(5) in Germany, who relied on colorimetry.Teisinger (6) and Bass (7) using electro-chemical methods, reached the same conclu-sion. Earlier, using emission spectroscopy,Shipley et al. (8) at Johns Hopkins foundthat blood lead concentrations were useful

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for the diagnosis of lead poisoning.Similarly, Willoughby and Wilkins reportedthat blood lead concentrations are morestable than those in urine

Similar studies were carried out in the1950s by Imamura (10), who tried toduplicate Kehoe's approach in a Japanesesetting. Imamura illustrated the presence oflead in the body. He found that lead accu-mulated in the bodies of control cases andthat lead excretion was always less thanlead exposure. Among men who were givenfirst 3 mg and then 6 mg lead daily, cumu-lative lead excretion never accounted forthe total dose, and the balance accumu-lated daily. About 15% of the doseremained in the body. The mean bloodlead among controls was 32 pg/dl, and itreached 80 pg/dl for the lead takers. Atmost only 10 mg of the absorbed leadwould remain in the blood, the other50 mg was thought to be elsewhere in thebody, only to leave slowly over a period ofmany months.

Application ofRadioactive TracersMeanwhile, and separately, during the1940s tremendous advances were beingmade with the use of radioactive isotopes inphysiology and medicine. It was recognizedthat many physiologic and biochemicalprocesses, hitherto quite unmeasurable,could be quantified with tracers (11). Forexample, Shemin and Rittenberg (12) deter-mined the biologic half-life of human redblood cells using a radioactive glycine label.

The mathematical analysis of thesetracer experiments was also being formal-ized. Chemical kinetics were applied tocompartments or pools of physiologicinterest. By measuring the rates of dis-appearance of radioactive tracers, it waspossible to identify pools of distributionof the compound within the body andestimate both the exchange rates amongthe pools and the pools' turnover time.These equations took the form of coupleddifferential equations that had solutionsin the form of sums of terms with expo-nential decay factors. Simple one andtwo-pool models were written so thatexperimental data could be converted torates (13).

Stable isotope tracers as well asradioisotopes were under consideration,using Geiger counters and Nier-type massspectrometers (14). There was little delaybefore radioactive tracer methodology andconcepts of compartmental analysis wereapplied to lead measurements. However,

the application of stable isotopes wouldtake another quarter-century. By 1954 themetabolism of lead in dogs was being stud-ied with 210Pb (20-year half-life)(15). Also,radioactive 203Pb (52-hour half-life) wasused to study tissue uptake of lead in rats(16). Generally these studies examined theuptake of the radioactive lead by differentorgans and how that uptake and releasecould be modified by citrate, which wasused to treat lead poisoning at the time(17). These and other early applications ofradioactive lead are reviewed by Wolf andFischer (18). By 1957 the use and sophisti-cation of these mathematical models hadreached the level of complication necessaryto explain the simplest issues of leadbiokinetics, a three-pool model (19).

The 1960s saw the joint application ofradioactive lead techniques and simplecompartmental kinetic models to establishthe exchange rates and residence times oflead in body pools. Catellino and Aloj(20) determined the elimination constantsof 210Pb from various rat tissues. Theykilled 10 groups of five rats from 1 to 336hr after intravenous administration of a1 00-jg dose of labeled lead acetate. Theyidentified slow and fast pools, with rapidelimination from the blood and slow elim-ination from the bones. They recognizedthat lead was bound reversibly to tissues.

Another early application of radioactivelead was to examine whether human teethcould serve as good indicators of skeletallead stores. This was of interest becauseradioactive lead is an 0-emitter and largeinternal doses were of concern from theviewpoint of radiologic health. Researchersfound that the tooth-to-tooth variability ofthese extracted adult teeth was 25% withinthe same individual, which was viewed astroublesome. Correlations between teethand a postmortem iliac crest specimen weresignificant. The authors concluded thatteeth were as adequate as small bonesamples in estimating skeletal burdens ofa-emitting bone-seeking elements. There-fore, as early as 1963, teeth were recognizedas biomarkers for lead stores (21).A significant mathematical advance

was the recognition that lead and othertrace elements occur in environmentalsamples, including food and water inconcentrations that approach a log-normaldistribution. The daily amounts of intakeand output from the body were thenviewed as randomly distributed. Themathematical distribution for the amountof lead stored in the body as a whole wasfound to be log-normal (22).

Also in the 1960s, Holtzman (23) atthe Argonne National Laboratory consid-ered the dynamics of lead within thebody. 2`0Pb was a potential radiologicconcern on its own, but it also was anindicator of other radon daughter prod-ucts as well. Special attention was given tothe uptake of lead by bone and itsresidence time there because the skeletonwas a key target organ in terms of radio-logic safety. The long half-life of 210Pb(21 years) lends itself to the study of theslow process, which may take decades.Holtzman was among the pioneers whoapplied numeric models of compart-mental analysis to predict lead levels overtime in different parts of the human body.Among his observations was a boneretention half-life estimate of 17 years,which has held up well as more recentaccumulations of estimates have becomeavailable. One recent case report involvesbeing able to measure 210Pb both in theurine and retained, by y-emissions fromthe skull, over a 10-year follow up. It hasyielded long-term half-lives of 16± 1 and18 ± 5 years (24).

Barltrop and Smith's work withradioactive lead demonstrated the uptakeof lead by red blood cells (25). They alsorecognized the firm but reversible natureof lead's binding. During the late 1960sand the 1 970s, a series of experimentswith radioactive lead were carried outincluding those by Hursh (26), whoexamined the time course of 210Pb in dogsand presented a model with four exponen-tial terms. He clearly showed blood andurine elimination dynamics. His otherstudies on men who inhaled 212Pb(10-hrhalf-life) yielded invaluable estimates ofabsorption and clearance, processes thatoccur within a day or two (27). He alsofed men 212Pb to calculate gut absorptionrates (28). Although these were very usefulstudies, because of the short half-life of212Pb, processes longer than a few dayscannot be examined; such processesinclude blood pool turnover, biliaryexcretion and other sources of endogenousfecal excretion, or hair or nail uptake.Chamberlain (29) later summarized theseefforts, using them to estimate the impactof airborne lead.

Stable Isotope TracersAt about this time, from 1970 to 1975, Iemployed stable isotope tracer methods atUniversity of California Los Angeles (30).My teachers George Wetherill and JoelKopple enabled me to address the question

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of how much lead was entering people byrespiration compared to ingestion. In LosAngeles in the early 1970s, this was amatter of concern. We fed the volunteers alow-lead diet supplemented with tracer204Pb, which is nonradioactive. As such,204Pb has distinct advantages over 212Pb,which has such a short half-life that phe-nomena taking more than a few dayscannot be investigated. Similarly, it is moreuseful than 210Pb, which has such a longradioactive half-life (21 years) and adecades-long biologic half-life that to getmeasurable amounts of disintegration, thelifetime exposure to radiation would beunacceptably high.We observed the rapid appearance of

the tracer in the feces and urine and itsgradual accumulation in the blood (31).After some months, the extent of labelingof the blood did not increase but reached anear steady state, reflecting the mixture ofthe blood daily inputs: from the labeleddiet and the unlabeled air but also someamount from the unlabeled skeletal stores.Consequently, a large part of our efforts-and this included modeling-was requiredto estimate this skeletal output andaccount for it as we estimated the relativemagnitudes of the two external inputs, airand food. A simple linear model of threewell-mixed compartments was sufficientfor our purpose.

Skeletal lead output was determined bydiscontinuing the labeled diet and watchingthe very slow, long-term disappearance ofthe tracer in the blood and urine, which istracer that had been stored in the skeletonduring the feeding portion of the study. Wealso had to know the relative amounts oflabeled and unlabeled lead in the skeleton;and although modeling was useful, severaliliac biopsies provided an additional esti-mate of the turnover and pool size of theskeletal pool. So, in the process of trying toestimate the size of the daily respired leadintake, we were forced to estimate theimpact of the skeletal pool and to devise asimple three-pool model (32).We had no doubt that an actual body is

composed of many more pools, since wesaw different tracer uptake rates in differ-ent types of samples: feces, blood, bile,pancreatic secretions, saliva, sweat, facialhair, nails, and bone. Each sample type hada different extent of labeling, so each mustcome from a different pool, since poolsare, by definition, well mixed (33).However, we considered three pools to besufficient for our study. Additional ancil-lary information was gathered about gut

absorption factors, the blood pool volumeof distribution and its turnover, endoge-nous fecal excretion, and the urinaryclearance rates (34).

The gradual rise and slow decline wesaw in tracer lead was remarkably similarto the changes seen in blood lead levelsin the occupationally exposed population,which was also being well documentedin the early 1970s. Both total lead andtracer lead moved with response times ofalmost a month plus a smaller, longerterm component (35).

This similarity encouraged modelers. By1977 data were available for both the rapidpools and the slower pools, as differentradioactive isotopes with very different half-lives had been used. Also, some radioactivelead is the daughter of 214Bi, and bismuthdistributions are different from lead distrib-utions. For this reason Bernard (36) createda more complete model.

This sluggish response of blood tochanges in exposure is caused by the longresidence time of lead in blood, about amonth (37). The longer term accumula-tion of lead in the skeleton is seen as afuture source of blood lead. This release ofstored lead is the rate-limiting factor in itsclearance of lead from the blood. Even ifthe kidneys were functioning with youthfulefficiency, filtering lead from the bloodplasma, the slow release of lead from bonewould still be responsible for blood leadbeing elevated years after the accumulationof exposure was discontinued. This hasbeen noted also in clinical (38) and indus-trial settings (39), as well as with stableisotope tracers.

Recent EffortsDuring the 1980s more elaborate modelsof whole body lead metabolism werepresented. Kneip et al. (40) presented asomewhat more complex model with sixcompartments, based on radioactive leadstudies of infant and juvenile baboons.This approach had the advantage ofallowing for age-specific changes in leadmetabolism, as it was thought to be moreappropriate to children than a model basedon adult men.

One of the key accomplishments of the1980s supported by the U.S. EnvironmentalProtection Agency (U.S. EPA) was the estab-lishment of the dose-response relationshipsbetween time-varying patterns of exposure tolead and biologic precursors of adverse healtheffects (41). To this end Marcus (42)created a series of models for the long-term,bone-related activity, considering the bone as

several compartments, as well as consideringthe blood pool as composed of three quickerpools in blood. These biokinetic models arethe precursors of the biokinetic uptakemodels we are considering today. A six-poolmodel introduced by Bert et al. (43) in1989, does a better job than the Bernardmodel of predicating events with a time scaleof months by virtue of its inclusion of poolsof intermediary half-lives.

The 1980s also saw additional extensionin scope of experimental studies of leadmetabolism. Heard and Chamberlain (44)performed a series of experiments with203Pb (48-hr half-life). After intravenousinjections, gamma counting the y-ray emis-sion from the feet was used to estimateskeletal uptake. Urinary output and bloodsamples allowed calculations of the fate ofdose and clearance rates. Skeletal uptake,whole blood and plasma, and urinary clear-ance rates of lead were calculated and com-pared to other alkaline earth elements,calcium and strontium. In a separate seriesof studies, adults were fed 203Pb in solutionand incorporated into lamb organ meatsand vegetables (45). Coincident ingestion oftea, coffee, beer, calcium, and phosphatewere also measured. Absorption rates variedfrom 3 to 19% and up to 50% while sub-jects were fasting. Other studies sought bet-ter understandings of tracer methodologyand factors modulating oral inputs. Com-pared to the earlier studies with 212Pb, thelonger half-life of 203Pb allowed for theexamination of slower processes. Keller andDoherty (46) studied lead kinetics in devel-oping and adult mice using 210Pb. Theyobserved that a simple, three-compartmentmodel did not adequately account for brainlead levels.

In addition to whole body kinetics, themany details of cellular lead metabolismreceived closer attention. For example,Pounds and Mittlestaedt (47) examinedthe cellular metabolism of lead in isolatedrat hepatocytes. Fowler et al. (48) used203Pb to study lead interactions with thekidney cortex components such as thebrush-border membrane. Rosen (49)examined lead and calcium and the osteo-cyte. Each of these studies is of interest interms of the storage and release of lead,but each one also tells us much about thekinetics of the several specific targets oflead toxicity, such as the kidney andsubcellular sites.

It is too early to write a history ofadvances in lead biokinetics in the 1990s,but some accomplishments and trends arequite apparent. Models are not getting any

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simpler. At the same time that there hasbeen this elaboration with more and morepools, there have also been efforts to recon-cile these mathematical models with epi-demiologic data. In a recent review, Mushak(50) noted that recent advances in the areaof toxicokinetics of lead are explaining therole of past lead exposure in the valuesobtained from longitudinal lead studies andintervention trials, and in elucidating theimpact of approaching menopause onwomen who grew up in the 1940s to 1970swhen environmental lead levels weregenerally much higher than they are today.

Three recent modeling efforts are esp-ecially worth mentioning here. O'Flaherty(51) has published a series of physiologicallybased models. This model has been cali-brated for children, and has the virtue ofcontaining age-dependent terms for bonegrowth and bone mass as well as age-dependent ingestion rates and dietarychanges. This allows testing of blood andbone lead levels to be more labile duringearly childhood, tracking environmentallevels fairly closely. A similar model wasdeveloped for adults (52).

Legett has presented an age-specifickinetic model of lead metabolism (53) thatwas developed within a physiologically basedframework designed to address calciumlikebone-seeking elements. Although originallyconceived to address environmental alkalineearth radionuclides, which would includelead, it is a credible and versatile method forexamining the response of humans tochanges in their lead exposure. A rather com-plete, elaborate, multiple-pool model isoffered with generally linear, first-ordertransport among the pools. The actual para-meters used for each of the 39 pathwayswere derived, as much as possible, fromavailable experimental tracer data from theliterature. These parameters are allowed tochange with age. Nonlinear plasma-red cellrelationships are introduced. The model isgenerally consistent with data from a varietyof experimental and natural conditions.

The most recent example of such amultipool model is a series of integratedenvironmental uptake biokinetic modelsgenerated by the U.S. EPA. An early exam-ple is LEAD, version 0.5, produced by theEnvironmental Criteria (Research TrianglePark, NC 27709) and Assessment Office,designed in 1991 for use on IBM PC-compatible microcomputers running DOSas a stand-alone software program that usesthe concentrations of lead in variousenvironmental media (air, water, soil, etc.)to predict the blood lead distributions in

children of various ages. It consists ofinterconnected pools or body compart-ments. The intended use is to assess the con-sequences of alternative lead exposurescenarios in terms of the percentage of thechildren whose blood lead would exceed anygiven standard. These models, with theirmany pools and transfer rates, can be variedto fit existing blood lead data without regardto the extent of lead in these many interme-diate pools. Only the blood lead fit is usedas an index of goodness of fit, so there areample degrees of freedom.

An additional topic that has receivedincreasing attention is the interactionbetween lead and neurons (54). In thesearch for the impact of lead at each targetorgan, it seems the study of neurons offersthe chance to examine lead's effects at thelowest effect level. There is a fast-growingbody of literature in this area and only onerecent example will serve as an introduc-tion. The developing brains of tadpoleswere exposed to lead in nanomolar con-centrations. Lead reduced the area andbranch tip number of retinal ganglial cellaxon arborization. Their stunting by leadwas reversed by administering dimethyl-L-succinic acid (DMSA) chelator. Clearly,we need to learn more about lead interac-tions with target tissues in terms of thekinetics of thresholds and reversibility orpermanence of lead's toxic effects.

ConclusionBiokinetic models that have been con-structed usefully describe the general charac-teristics of lead toxicity, observations of itsclinical course, and laboratory findings. Theclinical picture of chronic plumbism ismarked by latency of onset of symptomsand by frequent remissions. Responding tochanges in exposure, blood lead levels risefaster than they fall. Another peculiar fea-ture of lead toxicity is the relatively largeamount of lead that can be held innocu-ously in the skeleton, while much smallerquantities of lead are toxic to neurons. Also,biokinetic models provide a conceptualframework for interpreting this variety ofclinical and laboratory findings. Of course,risk assessment of radioactive lead would beimpossible with biokinetic models.

Because opportunities for lead exposurecan come from a variety of sources, expo-sure assessment and risk characterizationrequire the use of biokinetic models. Thisneed extends to children, the occupation-ally exposed, and elderly adults, whetherthey be exposed to lead via soil, dust,water, food, or air. At this workshop we

heard how these models are being used as aguide to help risk assessors and managersto identify populations at risk, to predictthe effectiveness of intervention, to setclean-up standards, and to determine if ahouse or neighborhood requires remedia-tion. A better understanding of the extentto which a particular biokinetic modelshould be used for a certain situation is oneof this workshop's main purposes, but suchquestions are beyond the narrow scope ofthis historical presentation.A major limitation of current models

is the limited data on which they arebased. It is striking how many differentattempts at modeling used human datafrom 1970 to 1975 and how very littlenew data there is, on adults, children, orchimpanzees. A noteworthy study under-way in Australia is watching blood leadisotopic composition change during preg-nancy in women who immigrated withunusual amounts of lead stored in theirbones (55). Another recent study [Smithet al. (56)] compares lead ratios frombone biopsies with those from blood.These studies directly address the issue ofmobilizing bone lead stores. But theseongoing efforts aside, I believe that thefield has developed as far as it can withoutmore new data on lead kinetics. Suchtracer studies on volunteers are safe, andautomated mass spectrometers can nowrun a rack of samples in one day.

Twenty-five years ago, a study reportedlead data for five adult males. For bio-kinetic studies to be more useful, weshould have available much more humandata. Also, we could consider how chela-tors modify these lead pathways and pools.Modeling, particularly including the targetsites, also has something to contribute tothe questions of thresholds or reversibilityor permanence of lead's effects.

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