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Enuironmental Health Perspectives Vol. 91, pp 63-70, 1991 Lecad in Bone: Implications for Toxicology durin Pregnancy and Lactation by E. K. Shcbergeld* Advances in understanding the distribution and retention of lead in mineralized tissues are im- portant for two reasons: first, bone lead may be a more accurate dosimeter of integrated absorption associated with chronic exposures, and second, bone lead may be a source of internal exposure to the host'organism. Little attention has been paid to this second aspect, the remobilization of lead from bone. Mobilization of lead from bone is likely to occur during periods of altered mineral metabolism; since calciotropic factors determine the uptake and storage of lead in this compartment, changes in calcium-related regulatory factors are likely to affect lead compartmentation. Calcium metabolism changes drastically in humans during pregnancy and lactation; although relatively little is known of lead kinetics during these critic per o t e y that bone lead is mobilized and transferred to the more bioavailable compartment of the maternal circulation, with potential toxic effects on the fetus and the mother. Introdurction The title of this conference, "Lead in Bone, Implica- tions for Dbsimetry and Toxicology;" examines two op- portunities presented by the ability to measure lead in bone. The first opportunity is the improvement in evaluatinEg lead dose, particularly chronic, integrated dose, or the inflwc of lead into bone. The second oppor- tunity is the ability to study lead in bone as a source of internal lead exposure, or the efflux of lead from bone. Understanding the effects of lead on reproduc- tion will. 1'* advanced by using bone lead measure- ments for both influx and efflux of lead into this com- partment. The efieets of lead on fetal growth, intrauterine de- velopment, and postnatal status have long been of con- cern in oxupational and environmental medicine. More recently, several large epidemiological studies have repOrted deficits in early infant development ob- served in children born to mothers whose blood lead levels during pregnanc,r were only slightly elevated as compare+i ;o a control group (1- - ecause t ese expos- ures', as measure y oo ea , fall within the range found in much of.the population of the United States, the findin~p have implications for defining perinatal lead toxicity as an epidemic (4). Further definition of dose response and understanding of critical time peri- ods durini; pre- and postnatal development for the neurotoxic effects of lead are critical for designing ap- propriate ,9creening and intervention. The data cur- 'Enviromnental Defense Fund, 1616 ^ Street, Washington, DC 20036 and :Program in Toxicology, University of Maryland, Baltimore, IVhD. rently available do not clearly separate the effects of prenatal exposure from those of postnatal exposure, particularly in terms of relative persistence. The two large-scale prospective studies on lead ex- posure in the U.S. (1,2) and the prospective study un- derway in Yugoslavia (5), may provide data that will help to define these i s. At present, the results from the Cincinnati stud (2) have been interpreted to sup- port a hypothesis that prenatal lead e sure results in more persistent de Icl in vior t an oes earl + pos na exposure, w e the n study res ts appear to support the opposite hypothesis. A complication in interpreting these studies lies in major uncertainties concerning lead toxicokinetics during pregnancy. The most commonly used marker for lead exposure is the measurement of lead in blood, which is a useful indicator of relatively recent or steady-state lead exposure given that the half-life of lead in this compartment is only 35 days (6). The inter- pretation of these studies is based on the assumption that blood lead levels usually measured once, at deliv- ery, accurately reflect exposure of the mother and the fetus over pregnancy. However, blood levels change over pregnancy, and lead is rapidly transferred across the placenta to the fetus (7). To evaluate fully the significance of fetal lead expos- ure, it is critical to know the determinants of fetal lead dose. Total fetal dose reflects not only the transfer of lead derived from mother to fetus associated with the mother's exposures during her pregnancy but also the transfer of lead stored in the mother accumulated over her prior history of lead exposure. In addition, the mobilization of lead from bone dur- ing pregnancy and lactation may have toxic effects Z025546268

E. K. SILBERGELD -ipon the mother. Lead toxicity must reflect the phar- nacodynamic: interactions of lead with its intracellu- lar sites of tcxic action; the more frequently and in- tensively atoms of lead pass by these receptors, the more likely cell and organ level toxicity will be pro- duced. From the perspective of the receptor, a recycled atom of lead is the same as a newly absorbed atom. Mobilization of bone lead into the circulation increases the amount of lead in the proximately bioavailable compartment of the plasma. This paper will discuss evidence for the hypothesis that mobilization of maternal lead stores occurs dur- ing pregnancy and that this mobilization is an impor- tant factor in overall fetal exposure and potential toxic effects to both mother and fetus. Although the focus of this paper is on maternal-fetal lead toxicokinetics and toxicity, it is not meant to imply that these are the only effects of sig,nificance related to lead and perinatal de- velopment. '.M:ale-mediated exposures and effects of lead on male reproduction are not considered in this paper, but m.ay. well be of importance in assessing the overall significance of relatively low-level lead eapos- ures on reproduction and child development. The paper will review available data on lead kinetics during pregnancy and lactation from both clinical and experimental studies,and the few case studies of effects observed in .m.others and children. It will also review what is known of mineral metabolism during preg- nancy since the factors regulating mineral metabolism hat respond t~a the physiological and hormonal chang- es during these periods also affect lead storage and bioavailability. Lead Tox,icok6netics during Pregnancy and Lactation Human Dalm Our information on the toxicokinetics of lead during pregnancy is indirect. As noted by Miller (8), kinetic studies in pregnancy must account for complex interre- lationships involving three compartments: the mother, the fetus, and the placenta. For studies involving post- natal exposurid via lactation, the child and the addi- tional compartment of breastmilk must be included. In clinical studies, these three compartments are not readily available at the same time for sampling and analysis. Unfortunately, in most experimental studies, these compartments have not been studied in an inte- grated manner. For lead, within humans, both mother and fetus, there are several compartments of kinetic importance: blood, soft tissue, and'bone (9). As discussed by Rabin- owitz (6), each of these;compartments may have several binding and storage sites with internal fluxes that reg- ulate overall .intercompartmental fluxes and eventual- ly maternal-fel:al lead kinetics. Two types of studies of maternal blood lead levels iave been conducted during pregnancy: cross-sectional and longitudinal. The'cross-sectional studies of women at different stages of pregnancy show a tendency for de- creased blood lead from the first to second trimester and relatively little chaiig ere r owever, cr D99--97-= =3~hL.fL~~.iF a y be confounded by age, which is a significant factor in determining blood lead levels and which may influence mineral metabo- lism (see below). The longitudinal studies, following cohorts over pregnancy, have not shown clear trends (12,13). Studies of blood lead at delivery, based upon sampling fetal blood from the umbilical cord, indicate that lead is readily transferred across the placenta. The correlations between maternal blood lead levels and those in cord blood are almost 1,0 (5). Lead absorption and reten ion e has been extensively studied by Barltrop (12). He found signifi- cant incr-eases in lead content (but not concentration) in fetal bone and organs over station. A more recent stu'3y concIn33' a ea i not accumulate in hu- man fetuses during the first trimester (14), which is not inconsistent with what is known of mineral metabol- ism over pregnancy (see below). Two case studies provide evidence that there can be significant mobilization of lead from bone during preg- nancy. One case study suggests that the mobilization of lead during pregnancy can result in relatively high- dose exposure with overt toxicological consequences for the infant (15). Over the course of pregnancy, one woman's blood lead levels increased dramatically to 74 gg/dL, with clinical signs of intoxication and her baby's blood lead level was 55 jug/dL. There was no evidence of increased exposure to external lead sources over this period of time. The authors determined thatshe ha had excessive ea exposure as a young child, over 30 years prior to this pregnancy. In another case study, Manton measured his wife's blood lead and speciated it by stable isotopic ratia He reported changes in stable isotopic ratios that indi- cated contributions to blood lead over pregnancy from a pool that did not correspond to the external source of lead at the time of measurement (16). We have investigated changes in bone lead stores somewhat more directly by using the NHANES II dataset U7). In a group of postmenopausal women, we found significant increases in blood lead concentra- tions as compared to premenopausal women, after con- trolling for age, calcium intake, and other variables potentially related to both external lead exposure and mineral metabolism (Table 1). Of relevance to this topic, we also found that in postmenopausal women who had ever been pregnant, the extent of st- menopausal increase in blood ea-ad - tly0 N 1 ss an menopausal wonen ~ ' g EfT . ese data sugges urnng prior pregnan- N cies (and possible lactation), there was some mobiliza- ~ tion of bone lead such that less was subsequently avail- ~ able for mobilization during demineralization after 'Pb menopause. Alternatively, nulliparous women may be ~ more at risk for postmenopausal bone demineraliza- ~ tion, although epidemiological studies of postmeno- pausal osteoporosis have not clearly shown this (18). C.0 M

1\+II:+f ca. LEAD IN BONE: PREGNANCY AND LACTATION 65 'lyble 1. Var@ables entered in univartate _ and nnitivariate analysea. Leui-related variablea A,gm (in yearn) Ag: squared Pwx" Lncomeb Deigree of urbaniution` Loead used in gasoline (10• g/day) Number of cigaretten per day Alcohol drinker (greater than one drink/week) Vaiii,blea related to osteoporoeiu IHa tary calcium (mg/day) ftylpertenaive medication Body mau indez+ Subacapular skinfold (cm) Dietary phoaphoru.(g/day) hietary protein (g/day) 'Irixp .kinfold (cm) A',esaeational exercise° Hypathesis variables hienopau9e status 5e®rs aince tnenopaune Ptvgnancy history Faim • 1 - blac9c otherwise 0. b 1- leea than t50U0/year; 2- f5000-15,000/year; 3 - i15,000/ynat ` 1 - cities over 3,000,000 to 6- rural under 2500. d Weight/Rieight'. • 1- little cr none; 2® moderate; 3 - heavy. 15 12 9 9 3 rr T u.m oL_- All Uaan t+-u0 TT_-T' ' pre,wti ki-mm 6satwro kwuu I W is T 12.97 Paataaeu Pro h-471 FtcuxE 1. BloA lead concentrationa in black and white women, aged 40 to 00 years (n - numbers in sample used for analymii). Premeno, r:remenopauaai women; poatmeno, postmenopauaal women; pcotmeno null para, postmenopauaal women with no prior pregnancies; pcatmeno para, postmenopaueal women with at least onie pregnancy. Data from NHANES 11 survey; see Sil- bergeld et iJ. (17) for detaile of analyses. Lead is also secreted in breastmilk in a range from 0.24 to 35 mcg/dL. External exposures influence reas mi :c{- ea eve s, as expected, such that urban populations i eneral have higher levels than rural populatioias (19. Lead is found in concentrations higher than those found in plasma at the same time (20). Breastmilk lead concentrations may increase over lactation, although no comprehensive studies have been done. Women older than 30 ears had si ificant- ly higher eve s o reas ml ea than women ween an ~years o age (11). This may reflect t e generaZ lncre`~ase in sto~Trec an3circulating levels of lead as a function of age or altered mineral metabolism dur- ing lactation in older women. Experimental Data Only a few studies of experimental animals exposed to lead have examined lead kinetics over pregnancy. These studies are further limited in interpretation be- cause of incomplete design and because rodents may not be adequate models for the physiology ofpregnancy in humans. These studies have confirmed that lead is rapidly transferred from mother to fetus, particularly during the late stages of gestation. Moreover, after midgestation in the rodent, the flux of lead from ma- ternal to fetal circulation favors the placental and fetal compartments (21).'Ibtal fetal lead content of the fetus increased with time but concentration tends to de- crease (as noted by Baritrop in hu**+Ana (12)] because of the relatively greater rate of fetal growth during this period. Two experimental studies have examined the poten- tial for redistribution of lead from the mother to the fetus and infant during pregnancy and lactation. Buchet et al. (22) found that in rats exposed to lead for 150 days, whose exposure was then discontinued for 50 days prior to mating, there was a substantial mobiliza- tion of lead from mother to fetus. This transfer was more pronounced in the di° continuous exposure group than in groups in which lead exposure was continued up to or through gestation, which the authors inter- preted to reflect differences in bone resorption rather than lead dosage. Keller and Doherty (23) examined lead kinetics with4~ radiotracer lead (=10Pb) in female rats over gestation and lactation. They found that the major period of bone lead mobilization occurred durin lactation rather ~ than gestation. is lnvo ved both the lead admi ~Cnis re actating mothers and the mobilization of lead stored in maternal bone from prior esposure. This lat- ter source of lead transfer from maternal bone aral- leled the measured decrease in one t over the same pen owever, not all this lead was ~ transferred to the sucking infant via milk; maternal excretion of lead was also ' ased durin actatton. ecause o the re ative lack of clinical data an un- ~ ~ availability of information from primate models of lead ~,y ~ toxicokinetics during these periods, interpretation of these results must be guarded. It is appropriate to con- ,~ clude that there is evidence that lead metabolism changes during pregnancy and lactation and that the transfer of lead to the fetus and neonate is likely to be ~ enhanced. O

66 E. K. SILBERGELD EARLY MEGHANCY PPX:COLAhCY -a, Pn, \ V f 3Lmo vtx,txME ~ ~ 1+nesiwca••aosorpron trorAL cucK*A +88TaorEN N\ \ j C\i- snslfon ~ I cAa.aroraa+ IMNeY4-J FIGURE 2. Calcium metabolism in early pregnancy. A major physio- logical (hnnge influencing calcium metabolism is the increaae in maternal blood volume during this period; as a consequence, in order tc aaaintain'circula~'ving levels of calcium, total calcium in the blocd compartment is increased primarily through increas- ing intestinal calcium absorption and reducing renal calcium ex- cretion. It is also possible that the decreased production of estro- gen in pregnancy affects bone cell status through estrogen reoep• tors in a manner similar to that observed in poatmenopaueal oateoporaoia, that it, to increase bone resorption. The major hor- monal Wi;nala governing these changes are parathyroid hor- mone and 1,25-dihydroxyvitamin D, both of which are increased in the cxtoulation. LATE PREGNANCY ,__~ 4 r-eW ca- nq*-ant I I 1.25-(OH)=VfTAMIN D --=~ ~ Ca" I~o~on BONE E-- PTH i- 4+ostImal Wood (Cs'l I - PROLA=N FtcuRE 3. Calcium metabolism in late pregnancy (third trimester). During this period, fetal oeaification becomes a driving factor in altering maternal calcium metabolism. Calcium is supplied to the fetus, and maternal calcium metaboli.m is regulated by vita- min D, parathyroid hormone, and prolactin. LACTATION I Mineral Metabolism during Ca- I in m& Pregnancy and Lactation Pregnancy and lactationPlace significant demands + on the availability of calcium from the diet and from 1^~~ ~[oa") physiological stores in mineralized tissue (24,25). As '~- tkfts*W oa" absoMt~w shown in lFi gures 2 and 3, during pregnancy, two major F ~' changes affect calcium physiology: first, blood volume ~E pM ,_ significantly increases, which requires incre~ a-' sir- '~~ ~:~T~~N D culating c:aflcium to maintain normal [Ca2-], and sec- FtGURe 4. Calcium metabolism during lactation. During this peri- ond, the fet us exerts a demand for c8lcium or oss' ica- od, the stress on maternal calcium metabolism is qualitatively tion anTg_r .-1is second requirement for calcium greatest, and the extent of bone demineralization is potentially is greatest during'the third trimester when the fetus the largeat. Prolactin, parathyroid hormone, and vitamin D all obtains aku_t _2_0__g_o__f _the total intraLtPr;n__ P?~.~ire- regulate changes in calcium metabolism during lactation. ment of 30~ o calf ciu (25,26). During lactation, an ad- ditionaI a~.nereyn er demand is placed upon ma- Calcium requirements for pregnant and lactating ternal source o ca cium for the secretion of this women are much greater than those for adult men. % essential mineral,in breast milk (Fig. 4). These de- During the last trimester, the fetus retains about 250 mands of the developing organis an mother have mg of calcium per day, generating a maternal daily in- only two possible sources of supply: increased dietary take requirement of about 1100 m/da . Durin Ia sources through a change in diet and enhanced reten-(~t ion, about 400 and 1600 mg/day is secrete in breast- tion of exogenously derived calcium, or a draw upon ~ recommen e ke of calcium in b one through the modification of bone turn- calcium is even grea r, a out mg y(25). At over to favor resorption. During pregnancy, however, this ime, o ca cium a sorption increases an cal- along with i;ncreased calcium absorption (about twice cium is drawn frorn bone stores. normal levels), calcium excretion is also increase 24•) -) However, there is still some controversy over calcium

LEAD IN BONE: PREGNANCY AND LACTATION requirements during pregnancy. It has been assumed that adequate dietary intake of calcium will prevent demineralieation of maternal bong'~However, the clinical data are s'1-'iII incomp ete, in t at many studies were not controlled for calcium intake or measurement of calciurn balance. Physiologically, maternal metabo- lism adapts during pregnancy to exploit both external and interruil sources of calcium. Dietary calcium is conserved by increasing gut absorp1don of calcium and decreasingrena excre ion. ormona c anges are t e major factors controlling these adaptations. There is a stead and significant increase in circulating levels of 1roxyvi . in D during pregnancy m umans (,2 anTcirc a mg eve s o para e may~1Z increase ac in is ano er major hormonal mechanism for modifying calcium metabolism during prei;nancy ' and lactation, increasing calcium absorption and placental transfer of calcium (29,30). However, in many pregnant and lactating women, bone may be an additional source of calcium as evidenced by changes in bone formation rate, loss of bone mineral, and frank iDsteo orosis in some caso4 (31,32). Some studies havi® ound as muc as 1% oss o ne mineral in lactating women whose iets were only somewhat rats wit ca im Ttif icien a ut mg ay a a eMt cium an va min in e, between 15 and 40% cf bone mineral can be lost during lactation (34) _" More detailed studies have demonstrated the com- plexity of bone physiology during pregnancy (Figs. 2 and 3). Purclie et al. (35) reported increased rates of re- sorption in early pregnancy, followed by increased rates of formation in late pregnancy, a finding paral- leled by experimental studies in rats (34). This bipha- sic change in bone mineral status, which may result in part from changes in circulating estrogen levels could reflect a sto,rage mechanism to provide calcium for the 67 of lead in bone and its later availability for mobiliza- tion, as suggested by Rabinowitz (6). Maternal Age. In addition to determining body lead burden and concentrations in bone, maternal age may influence mineral metabolism. Adolescent mothers with inadequate calcium meta lism have relatively high bone loss during lactatio (3 . Given the preva- lence of dietry ec"icincies in is population and the increasing rate of pregnancy among adolescents, par- ticularly in groups at high risk for environmental lead exposure (37), the coincidence of these two highly cor- related factors, age and nutrition, may be very impor- tant for lead exposure. In another age-related observa- tion, older women appear to secrete higher levels of lead in breastmilk than do younger women, but this may reflect general trends in lead exposure and body lead burden. Gestational Age. Gestational age clearly influences mineral metabolism in both mother and fetus. The fetus produces 1,25-dihydroxyvitamin D and hence regulates its own active calcium uptake across the pla- centa (26,38). The most active phase of calcium trans- fer to the fetus occurs in the last trimester of preg- nancy, a period that coincides with the critical phases of neurodevelopment in which synaptogenesis and ar- borization of the cortex and cerebellum occur (39). This coincidence is unfortunate because of the effects of lead to inhibit synaptic formation (40) and to block neuro- transmitter-directed cytoarchiural development of the brain (41). MaternaT 1Vutritionat Statu& As noted above, ma- ternal nutrition is a major determinant of maternal mineral metabolism during pregnancy and lactation. Calcium- and vitamin D-deficient diets during these periods result in substantial bone demineralization (33). Maternal nutritional status will also affect the ab- tion and retention of lead; although it is not clear greater denlands of lactation (Fig. 4). There is also that supplementing the diet with calcium can reduce some sugge9tion that different parts of bone are differ- lea a sorp ion or ec ead kinetics, deficiencies entially mobilized'during different phases of bone re- clearly enhance the absorption of le (42). sorption, which may be of importance in estimating Parity. Little is known of the influence o umber of relative availability of lead stored in specific regions or pregnancies upon maternal mineral metabolism. In types of bor e (36). ~ Important Factors in Bone Lead Mobiloz,a~~ion epidemiological studies, parity number is confounded by age and weight, variables that also affect mineral ? physiology (43). We found that parity influenced the magnitude oT"postmenopausal increases in blood lead levels (17), as discussed above, but we could not ex- It seems r~dasonable to conclude that bone lead is a amine the impact of number of pregnancies due to potential source of lead for the fetus and neonate and small sample size available for analysis of this vari- that the kinetics of lead in bone follow those of calcium able. Parity is a complex variable in studies of post- in bone du~~i,ng the periods of pregnancy and lactation. menopausal osteoporosis, and number of pregnancies If this is the case, it is important to determine those fac- as well as age at pregnancy are important, although in- tors modulating the movement of lead from bone in hu- completely understood, factors (18). man pregnancy. Some of these factors are discussed Race For demographic and socioeconomic reasons below. primarily, race is a determinant of lead exposure in Lead Exposure. Integrated, cumulative lead expo- American populations (37). Nutritional status also sure is obviously important in determining fetal and varies with race in the U.S., and calcium-deficient diets neonatal exposure from both stored lead and concur- are more common among poor, disadvantaged minor- rent externa 1 exposures (7). Also, the dose rate of lead ity women than among other groups. Race is also a var- exposure may influence the location and concentration iable in mineral metabolism, with black women ex-

68 E. K. SILBERGELD iriencing much lower incidence of postmenopausal ,steoporosis than white women (18). We found a signif i- cant difference between whit_dgnd'61ack women in the relative ina°ease in blood lead levels following meno- pause, consistent with a decreased loss of bone mineral in black wn men. Among Asian and Turkish women, osteomalacia has been diagnosed during and after pregnancy olFsufficient severity to increase the risks of fractures dwring pregnancy and rickets in their infants (44). This anndition may be due to inadequate intake of vitamin D in_these populations and hence to socio- economic and cultural factors rather than genetics. Summary and Research Needs This conf:erence has focused on bone lead primarily as an improved dosimeter for determining cumulative lead exposure in specific groups at risk, primarily chil- dren and workers. However, given the lability of bone mineral stores, there are additional toxicological con- cerns aboixt the potential for release of lead from bone stores duriing normal physiological conditions that increase bone mineral loss. Of major importance for public health is the potential mobilization of lead from bone during pregnancy and lactation, with potential toxic conseq[uences for both the mother and the neonate. Most attention has been paid to the potential expo- -tre of the fiatus; however, the remobilization of lead iring pregnancy and lactation may have toxic conse- quences for the mother as we , as lead is returned to the bioavailable compartment (plasma) and may be re- distributed #a such target organs as brain, heart, and kidney. The available data are sparse. Some experimental data conf`ir.m that both dietary and stored lead are transferred to the fetus avidly and that maternal bone stores of leacfl•may be mobilized, particularly durin lactation.lli humans, there is at least' one case o ma- terna7intoxic:ation during pregnancy due to mobiliza- tion of signif icant bone lead stores (15). Indirect evi- dence fdr su ch mobilization was also found in a large population-based survey of the U.S. population, in which postnie.nopau~al women were found to have sig- nificant increases in blood lead, but this increase was diminished by prior pregnancy (17). to prevent untoward mobilization of lead from bone. Fourth, methods for determining the overall toxico- kinetics of lead during pregnancy, particularly the flux of lead from bone to the fetus, must be developed. • There is a consensus as to the research needed in order to develop feasible implementation of bone lead measurements for better estimation of lead dose-the influx term (36). For the purpose of estimating poten- tial exposure to bone lead-the efflux term-somewhat different research strategies may be important. For dosimetry, a stable compartment that reflects accumu- lation of lead over time is important; for mobilization, it is important to be able to measure lead in unstable compartments of mineral tissue and to be able to esti- mate rates of bone formation/absorption at the same time. The field of lead toxicology may be transformed by the availability of new technology for measuring lead stores in bone, the major pool for lead in the body. Bone lead may prove to be a vast improvement in dosimetry and, as such, advance our understanding of the dose- response relationships of lead at low dose and the long- term consequences of low level lead exposure. That there are children with very high bone lead stores sug- gests that they may be persons at considerable risk of lead toxicity whose risk is not adequately assessed by measurements of blood lead levels or chelatable lead in urine In ce in populations at risk for bone demineraliza- tion for reasons of normal physiological change, aging, or disease, it may be important to determine bone lead stores as a determinant of potential risk of toxicity from mobilized lead during these periods. However, it is clear that much needs to be known about mineral metabolism and bone physiology during such periods as pregnancy and lactation in order to evaluate the po- tential risk of lead stored in bone for such persons. In addition, the possibility that lead may affect the endocrinological signals regulating mineral metabo- lism and bone cell function requires further investiga- tion, as suggested by Pounds (46). It may be that bone cells containing lead respond differently to the hor- monal signals accompanying pregnancy, lactation, and menopause, which appear to be the determinants of altered bone status. We have suggested that lead may enhance processes of demineralization by inhibit- If bone lead. §Ipres are a potential source of lead for ing activation of vitamin D, decreasing calcium ab- the fetus, there are several important implications for ,gorption, and interfering with hormonal signals, such the medical management of lead exposure and inter- as prolactin (17). Finally, these studies may at last vention as well as needed areas for research. First, the possible contribution of prior lead exposure, resulting in increased bone lead, must be evaluated in epidemi- ological studlies associating lead dose with outcome in infants and young children. Second, the prior history of lead exposure may be important to determine in evaluating individuals and populations at risk. Third, 'zterminants of bone status during pregnancy may be portant not only for preventing osteomalacia, hypo- calcinemia, h;Terphosphatemia, and other mineral- related problems of pregnancy and the fetus, but also focus attention upon bone as a target for lead toxicity. It has been remarkable that this compartment, in which the overwhelming majority of lead is stored, has long been considered as an inert depot into which lead is transferred and in which no biological response to this very toxic element was thought to occur. Advances in mineralized tissue physiology, not least the finding that most hormones that regulate bone cell status are shared by, among other organs, the brain (47), should serve to direct research toward understanding the en- docrinological effects of lead and the cellular conse-

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