115n1 focus rpp · 2017. 3. 7. · extending the dose–effect relation to con-siderably lower...

Environews Focus

A 30 VOLUME 115 | NUMBER 1 | January 2007 • Environmental Health Perspectives

Environmental Health Perspectives • VOLUME 115 | NUMBER 1 | January 2007 A 31

Focus | The Weight of LeadG

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Lead toxicity is not a problem of

the past, nor is it the exclusive

domain of children. In fact, lead con-

tinues today to pose a serious threat to

the health of many U.S. adults.

It’s true that in the United States,

environmental lead levels are much

lower than before the toxic metal was

removed from gasoline, food cans, and

other products in the 1970s and early

1980s. The National Health and

Nutrition Examination Surveys have

shown that average adult blood lead

levels have declined from about

15 µg/dL in the 1970s to today’s

1–2 µg/dL. But there are still pockets

of high exposures, such as among

workers in certain industries.

Despite reductions in exposure fol-

lowing OSHA’s 1978 publication of

lead standards for general industry,

more than 80% of elevated lead levels

in adults come from workplace expo-

sures. Industries most affected include

lead mining, refining, and smelting;

construction work involving paint

removal, demolition, and mainte-

nance of outdoor metal structures

such as bridges and water towers; auto

repair; and battery manufacturing and

recycling.

When workplaces adhere to the

OSHA standard, occupational expo-

sures are usually reduced below levels

that cause symptomatic lead poisoning.

But as far back as 1990, studies have

Effects AddUp In Adults

THE OFWeight

Lead

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Focus | The Weight of Lead

suggested that significant health effects hap-pen at levels below those allowed by OSHA.“Historically people had huge lead expo-sures, so the OSHA standard, when it wasoriginally established, was protective. Butright now nobody thinks that that’s a protec-tive standard,” says Rosemary Sokas, directorof the Division of Environmental andOccupational Health Sciences at theUniversity of Illinois at Chicago School ofPublic Health.

Now scientists say the evidence is over-whelming that action needs to be taken tofurther reduce lead exposures in both theworkplace and the general environment.“What’s driving concern over the need toreduce permissible levels of exposure in theworkplace are . . . more subtle or chronicproblems such as hypertension, and contri-butions to cognitive dysfunction,” saysMichael Kosnett, an associate clinical profes-sor of clinical pharmacology and toxicologyat the University of Colorado HealthSciences Center.

With the lower levels of lead found inthe general population in the United States,much of the worry is aboutlead’s health effects over thelong haul. The most recentevidence from epidemiologi-cal and toxicological studiessuggests that low levels ofexposure can, over time,damage the heart, kidneys,and brain. Some of thesehealth effects, such as a1-mm rise in blood pressureor a slight cognitive decline,seem small when expressed asthe average impact to theentire population. In oneindividual, they may noteven be noticed. But theoverall impact on publichealth nevertheless worriesscientists.

Better Tools to MeasureSmaller EffectsTests to measure lead expo-sure itself and its healtheffects have become moresophisticated. The blood leadlevel, long the gold standardfor assessing risk, reflects theamount of lead circulating inthe body at the time of thetest but may not offer a reli-able indication of an individ-ual’s past or cumulativeexposure. For example, simi-lar blood lead concentrationsin two individuals (or popu-lations) do not necessarily

translate to similar exposure histories. Onereason is that the body stores lead in thebone, and it’s released from the bone intothe blood at differing rates, depending onage, gender, and other factors. For instance,lead will mobilize from bone more quicklyin people with conditions in which the bodyis resorbing bone, such as pregnancy orosteoporosis.

Stores of lead in bone are a more reliablemarker of cumulative lead exposure. In thelate 1980s a noninvasive way of measuringbone lead emerged, using X-ray fluorescencetechnology. Scientists began applying thetechnique in epidemiological studies in the1990s. But since the technology is availableat only a handful of institutions in theUnited States, it isn’t currently feasible forroutine medical management.

Measurement of lead’s health effects haveimproved as well. Studies of cognitive func-tion, for example, now have the benefit ofmore sensitive markers, including tests ofmemory, visuospatial function, and the abil-ity to communicate or understand commu-nication. In addition, studies with larger

sample sizes and those that look at commu-nity-based populations, not just occupation-ally exposed workers, have sharpened thepicture of the effects. “Industry studies ofworkers suffer from a number of method-ological limitations, such as the inability tofollow workers who leave the industry,” saysHoward Hu, chairman of the Department ofEnvironmental Health Sciences at theUniversity of Michigan School of PublicHealth.

Much of the evidence in humans comesfrom epidemiological studies, which showassociations between lead and health effects,although alone they don’t definitively provecausation. But animal studies support manyof these findings and suggest mechanisms forsome of these health effects.

Putting Pressure on the HeartAccording to Stephen Rothenberg, a seniorresearcher at Centro de Investigación y deEstudios Avanzados-Mérida in Yucatán,Mexico, the cardiovascular system is the mostthoroughly studied system in adults in termsof lead’s effects. A large number of these stud-

ies have investigated theeffects of lead on blood pres-sure. Increases in both bloodlead and bone lead appear tobe associated with bloodpressure increases.

Many epidemiologicalstudies in humans suggestthat rising blood lead corre-lates with rising bloodpressure. Overall, most epi-demiological studies of thegeneral population haveshown a 1-mm increase insystolic pressure for everydoubling of blood lead, andthis increase has been seen ata range of concentrations,from 1 to 40 µg/dL. “Whenapplied to large numbers ofpeople,” Rothenberg says,“those increments shift theblood pressure curve to theright, to higher values,meaning that anywhere fromtens or hundreds of thou-sands more people . . . totens to hundreds of millionsmore are going to have bloodpressures that are higher thanmost physicians currentlythink is safe.”

In the last 15 years ,about a dozen studies havealso tied bone lead to bloodpressure increases. For exam-ple, in a longitudinal studypublished in the 15 January


Pressure point. Increases in both bone lead and blood lead appear to beassociated with possibly dangerous increases in blood pressure.


2001 American Journal of Epidemiology,Yawen Cheng of Harvard Medical Schooland colleagues found that in men who beganthe study without hypertension, baselinebone lead level predicted development of thecondition six years later.

Rothenberg points outthat although blood leadprimarily reflects recentexposures, it can also in partreflect the leaching of bonelead stores back into thebloodstream. “The combi-nation of these two results—significant blood lead effectson blood pressure, and sig-nificant bone lead effectson blood pressure—makesresearchers feel that pastexposures, especially whencurrent exposure is low, maybe the dominant factor indetermining lead effects onblood pressure,” he says.

Lead is also associated withincreased mortality from dis-eases of the heart. In a studypublished 26 September 2006in Circulation, Andy Menke ofTulane University and col-leagues found an increasedrisk of death from all causesas well as from cardiovasculardisease and stroke in associa-tion with blood lead concen-trations as low as 2 µg/dL.The study analyzed data frommore than 13,000 partici-pants in the Third NationalHealth and Nutrition Exam-ination Survey Mortality Study.

An editorial accompany-ing the Circulation articlepoints out some of its limi-tations, including the factthat participants’ mortalitycould have resulted in partfrom higher lead exposuresthat occurred prior to thestudy period. But the editorial also statesthat the report “breaks new ground byextending the dose–effect relation to con-siderably lower blood lead concentrationsthan reported in previous studies.”

Study coauthor Paul Muntner, an asso-ciate professor of epidemiology at TulaneUniversity, says these associations stayed“remarkably consistent” across subgroups,including smokers, diabetics, males, andfemales. The consistent results suggest theassociations aren’t likely due to chance orother artifacts, he says.

So, how does lead actually cause cardio-vascular effects? Animal studies show that

lead can promote the growth of vascularsmooth cells, which play a role in the forma-tion of atherosclerotic plaques. Lead’s pro-motion of oxidative stress is thought to playa role in its cardiovascular effects (as it is inother lead-linked health effects). Oxidative

stress happens when chemically reactive oxy-gen and nitrogen damage cells in a processsimilar to how oxygen rusts metal.

Damage from lead-induced oxidativestress has been demonstrated in studies ofrats as well as in studies of human cells inculture, says N.D. Vaziri, chief of theDivision of Nephrology and Hypertensionat the University of California, Irvine,Medical Center. In Vaziri’s studies of humanendothelial cells, for instance, developmentof oxidative stress has been seen immediate-ly after lead exposure.

But in animals it takes 10 to 12 weeks forlead exposure to result in hypertension, and

in humans it likely takes years to decades,Vaziri says. One possible reason is that thebody launches a variety of defense mecha-nisms that prevent or minimize rapid rise inblood pressure and gross tissue damage.However, over time, these defense mecha-

nisms gradually fail, bloodpressure begins to rise, anddetectable tissue damageappears.

Vaziri demonstrated thisprogression in cell culturestudies published in the May2000 issue of the AmericanJournal of Hypertension.Immediately after lead expo-sure, the levels of a free radi-cal called superoxide rose,“but then the cells are able todefend themselves,” Vazirisays. “A day later, the super-oxide went down, but anenzyme that is made to cap-ture the free radicals andtemporarily prevent themfrom causing damage—theenzyme called superoxidedismutase—went up. So wehad a reduction in superox-ide at an interim period. Butthe defending enzyme con-verts superoxide to hydrogenperoxide, which is less toxicthan the original free radicalbut still toxic, and capable ofcausing injury and dysfunc-tion upon prolonged expo-sure.” Thus, Vaziri explains,the organism mounts adefense that is able to, at leastfor the time being, preventthe expression of disease andinjury as such. Ultimately,however, lead exhausts thesystem.

Filtering the Evidenceon Kidney FunctionEpidemiological studies of

the general population suggest that kidneyfunction may be altered at the lowest levelsof blood lead studied to date in relation torenal effects. In a review published in theDecember (2) 2006 issue of KidneyInternational, E.B. Ekong and colleagues atThe Johns Hopkins University wrote thatlead contributed to kidney damage at con-centrations below 5 µg/dL. “Many differentstudies—in Europe, Asia, and the UnitedStates—have shown that higher blood leadlevels are associated with lower creatinineclearance, indicating worse kidney func-tion,” says Virginia Weaver, an associate pro-fessor of environmental health sciences atBr

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Renal reality. Studies show that higher blood lead concentrations are linked todecreases in kidney function.

Johns Hopkins and one of the authors of thereview.

Some of these studies have been longitu-dinal, which helps address a chicken-and-egg question: is kidney damage associatedwith higher blood lead levels because leadcauses the damage, or because damaged kid-neys can’t excrete lead? “If you look at thelongitudinal data, initial lead level predictssubsequent decline in renal function,”Weaver says.

In addition, lead’s effects on the kidneysare thought to play a major role in itseffect on blood pressure. This is becausethe kidneys help regulate blood volumeand vascular tone, which are the principaldeterminants of blood pressure. “The kid-ney is the pathway through which we get ridof the excess salt and fluids. Consequently,impairment of the kidney’s ability to effi-ciently excrete salt and fluids can result inthe rise in blood volume and, hence, bloodpressure,” Vaziri says. “Also, the kidney pro-duces hormones that regulate the tone ofblood vessels. Thus, alterations of kidneyfunction or structure can cause the bloodvessels to constrict throughout the body,thereby raising blood pressure.”

Small But Measurable CognitiveDeclinesSome studies of lead workers have shownassociations between blood lead concentra-tions of 20 to 40 µg/dL and subclinical cog-nitive decline, in-cluding changes inmemory or mentalprocessing speed thatare measurable butdon’t put an indi-vidual outside thenormal range offunction. “Effects oflead at these levelsmay be such that inany one person theywouldn’t be able tonotice a difference,”says Kosnett. But aswith cardiovasculareffects, when aver-aged across thewhole population,there’s a measurableeffect.

Declines in cog-nitive function aremore likely to beassociated with lower-level environmentalexposures over time, rather than recent acuteexposures. “Some of the literature suggeststhat lead may contribute to or accelerate anage-related decline in cognitive function,”

Kosnett says. “That may be a consequence ofcumulative lead exposure.”

One subgroup especially vulnerable tothe effects of low-level lead exposure are preg-nant women, whose exposure may affecttheir offspring’s cognitive function. In theMay 2006 issue of EHP, Lourdes Schnaas ofthe Mexican National Institute of Peri-natology and colleagues published one of thefew studies of this relationship to pinpointprenatal lead exposure as a greater risk to off-spring IQ than childhood exposure. Previousstudies had shown the strongest effects withpostnatal exposure. In the EHP study,though, prenatal exposure had a more signif-icant effect than postnatal exposure, and thestrongest effects were seen at the lowest levelsof exposure, says Rothenberg, a coauthor onthe study. The pregnant women’s blood leadconcentrations ranged from 1 to 33 µg/dL,with a mean level of 8 µg/dL.

In other neurotoxic effects, animal stud-ies have suggested that lead exposure increas-es the risk of brain cancer. Some associationstudies in humans also have suggested a link.For instance, a 1 September 2006 report inthe International Journal of Cancer by Edwinvan Wijngaarden, an assistant professor ofcommunity and preventive medicine at theUniversity of Rochester, showed that workersin jobs with high lead exposure were morelikely than unexposed subjects to die frombrain cancer. The study’s value lies in its largesample size; it analyzed the lead–brain cancer

death association among more than 300,000subjects in the National LongitudinalMortality Study, a prospective census-basedstudy of the U.S. population. But the study

did not measure actual lead exposure;instead, Wijngaarden used participants’ self-reported occupations and the job exposurematrix developed by the National CancerInstitute (NCI) to estimate lead exposure.“This data set and the occupational jobexposure matrix that NCI has come up withcertainly gave me a lot more statistical powerthan any of the studies [regarding lead expo-sure and brain cancer] that have been pub-lished so far,” Wijngaarden says.

Wijngaarden is now recruiting partici-pants for a pilot study in which he will meas-ure bone lead in patients with brain tumors.“The main goal is to get a system ready for alarger study and to get preliminary data,” hesays. No studies to date have measured bonelead in cancer patients.

Despite these findings, however, studiesof brain cancer and lead have been inconsis-tent—some studies have found elevated ratesof brain cancer associated with lead exposure,and some have not. For cancer in general,most studies show a positive associationbetween low levels of lead exposure and can-cer, but with relatively few cancer deaths, saysKyle Steenland, a professor of environmentaland occupational health at Emory University.

Is There Any Safe Level of Lead? Current research hasn’t been able to deter-mine a threshold for many of lead’s effects.That is, scientists haven’t yet found a con-centration of lead below which no effect

occurs. Some scien-tists say that deter-mining a thresholdwould require long-term prospectivestudies of adultswith blood lead lev-els commonly foundin the current popu-lation. “We need tobe able to character-ize the dose–responsecurve at very low lev-els of exposure ifthese data are goingto be used to intel-ligently plan regula-tion,” Rothenbergsays.

Scientists dis-agree on just how lowmeasurements needto go. “Is it going todo us much good toreduce the standardfor intervention for

kids or pregnant women from ten to five[µg/dL], or do we really have to get down toone or below in order to prevent measurabledamage?” says Rothenberg. Further, policy


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Cognition and cancer. Lead exposure is known to cause declines in brain function, but the link tobrain cancers is less clear.


makers will want to know ifthere is a level of blood leadbelow which the resultingimprovement in publichealth no longer outweighsthe cost of further exposurereduction. “We won’t knowwhere that turnover point inthe cost–benefit function isuntil we include studies thatreliably measure blood leadin many subjects belowpoint-one micrograms perdeciliter,” he says.

Rothenberg suggests thatscientists should take ad-vantage of advanced tech-nologies such as inductivelycoupled plasma–mass spec-trometry to measure ultralowlevels of blood lead—below1 µg/dL. That technologyisn’t widely available, and it’sat least five times moreexpensive than current meth-ods used to measure bloodlead.

Hu agrees that to betterdefine risk, prospective stud-ies are needed of adults withlow to modest lead exposure(in the blood lead range of1 to 10 µg/dL). But hebelieves that studying levelsbelow 1 µg/dL would be“overkill.”

Weaver cautions thatthough population studiesclearly show health effects atblood lead levels below5 µg/dL, it’s hard to rule outthe possibility that thosehealth effects were caused bypast higher exposures. “We don’t know if thisis a cohort effect and how much of thesehealth effects will further decrease as leadexposure continues to decline,” she says.

At least one longitudinal study supportsthe idea that health effects seen at low bloodlead levels aren’t artifacts of higher pastexposures. The Normative Aging Study,conducted among more than 2,000 men inBoston, showed lasting renal effects in agroup that was known to have maintainedblood lead levels below 10 µg/dL since1979. “They found some of the strongestassociations in that group,” Weaver says.Still, the group could have had higher expo-sures before 1979.

“That’s always the trick with a cumulativetoxicant,” Weaver says. “The blood levels yousee today could have been much higher in thepast. You don’t have any way of telling unlessyou do bone lead measurements in everyone.”

Medical ManagementPhysicians can get some idea of cumulativeexposure by measuring blood lead regularly.“For any employer or employee who is fac-ing a job in which there’s lead exposure, tak-ing regular blood leads, keeping thoserecords, and periodically calculating a cumu-lative exposure index is inexpensive and reli-able,” Hu says.

What’s a reasonable blood lead level insomeone who’s exposed to lead on the job?Hu says that at levels at or below 20 µg/dL,a worker is assuming some increased riskbut an amount that may be acceptable. “Ifyou have a blood lead of twenty for a work-ing lifetime—let’s say forty-five years—youwill get a cumulative blood lead indexthat we calculated would be equivalent to abone lead of a certain level,” Hu says.“That bone lead level in our epidemiologystudies still corresponds to a certain

excessive risk of developinghypertension and declinedcognition. But it’s not great-ly above what the generalpopulation sees.”

Kosnett recommendsthat at occupational expo-sures as low as 10 µg/dL,physicians should increasemonitoring and reduce leadexposures. He recommendsremoving people from alllead exposure when bloodlead levels are at 20 µg/dLand remain there when a sec-ond measurement is takenfour weeks later, or if a singlecheck registers a level ofmore than 30 µg/dL.

By contrast, OSHA’s cur-rent lead standard doesn’trequire full removal fromexposure until blood leadconcentrations exceed anaverage of 50 µg/dL overthree successive tests or twoback-to-back measurementsof 60 µg/dL. Scientists havebeen calling for reductions inthese cutoffs as far back as1991. But OSHA has longbeen reluctant to revise stan-dards proactively, says Sokas,who once served as chiefmedical officer at OSHA.

“The lead standard isvery strong in terms of wagereplacement if blood lead isabove a certain cut line,”says Kenneth Rosenman,chief of the Division ofOccupational and Environ-mental Medicine at Michi-

gan State University. And the standarddoes include a provision that, even atblood lead levels below the mandatorycutoffs, physicians can recommend med-ical removal when workers have a specificmedical condition, with these workersentitled to the same job and salary protec-tion as those whose blood lead levels riseabove the 50/60 µg/dL cutoff.

Still, although that provision protectsagainst overt lead poisoning, it does noth-ing to promote preventative removal atlower levels—such as 20 µg/dL—thatmay pose long-term health risks. By thesame token, there’s nothing in the lawthat prohibits a pregnant woman fromworking with lead until her blood levelreaches 60 µg/dL. Indeed, a 1991 SupremeCourt decision in the case of AutomobileWorkers v. Johnson Controls held that pre-cluding such women from exposureG

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Blood and bone. Measurements of lead in the body are taken from blood andbone, but each has limitations. More accurate methods are needed, particularly tomeasure effects of low-level exposures.

would be unlawfully discriminatory. “So onthe books now, it’s still acceptable for a preg-nant woman to be highly exposed to lead tothe same degree as men, even though the evi-dence is overwhelming that fetuses areexquisitely vulnerable to lead,” Hu says.

In the past, OSHA has touted its empha-sis on voluntary medical surveillance pro-grams and other measures to reduce exposure.Industry tends to favor voluntary exposurereduction as well. “The science has developedsince the last time the OSHA standard wasvisited, and we’re aware of that,” says DavidWeinberg, counsel for the Battery CouncilInternational. “I’m not sure it’s necessary thatOSHA reopen the lead standard. The batteryindustry and the secondary smelter industryhave worked pretty hard on these issues, andhave worked with and expect to continue towork with OSHA and others in voluntaryprograms to make sure that the progress that’sbeen made continues.”

Protection for the Most VulnerableOther subgroups that are very susceptible tolead exposure are emerging, and scientistssay these groups pose another reason thatregulations should be strengthened. Peo-ple with certain genetic susceptibilitiesmight constitute one such group. “It’s been

recognized for a long time that there can beconsiderable interindividual variability inpeople’s susceptibility to the development ofsymptomatic lead poisoning,” Kosnett says.

Even at a blood lead level as high as60 µg/dL, for instance, some people willshow symptoms and others won’t. Now, sci-entists are finding that the same is true of theemergence of health effects at very low levelsof lead exposure, and recent research sug-gests that genetic variations may play a role.“Further research is needed to explore andunderstand this aspect of gene–environmentinteraction,” Kosnett says.

People who already have medical condi-tions are also at increased risk. In theNovember 2006 issue of EHP, Hu and col-leagues showed that lead exposure was asso-ciated with increased heart rate variability(an indicator of poor cardiovascular health),especially in people with metabolic syn-drome, a cluster of conditions includingobesity, high blood sugar, and high bloodpressure. People with any or all of these con-ditions are also known to be at increased riskfor kidney damage and so may be more sus-ceptible to lead’s effects. “With the obesityepidemic in so many countries, diabetes andhypertension are increasing, so we do havemore groups at risk,” Weaver says.

Such studies point to another reasonwhy lead exposure is very much a problemof the present. “As a nation, the work forceis aging, and we’re expecting ourselves andour workers to keep working when they’reolder,” Hu says. “But that means that a lotof them will have medical conditions, andwe have to anticipate their vulnerability toenvironmental risk factors like lead.”

Muntner says that more work is neededto find effective and safe interventions forlowering lead exposure at the populationlevel for people whose blood lead concen-trations are already below 10 µg/dL. Hepoints out that although blood lead levelshave decreased substantially in the last30 years, they are still much higher thanthey were in preindustrial times, beforehumans began spreading lead into the air,water, and soil.

“So we need to not be complacent andsay, ‘We’ve lowered lead,’ but rather we needto think about it in terms of how can wereduce lead more, such that we eliminatethis environmental toxicant,” Muntner says.“There’s really no biological function oflead, and there’s really no reason why weshould be exposed to it.”

Angela Spivey



115n1 focus rpp · 2017. 3. 7. · extending the dose–effect relation to con-siderably lower...

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