Barbosa et al. blood; however, the correlations were not par- ticularly robust. In contrast, correlations with isotopic ratios were excellent. According to Tsaih et al. (1999), cortical bone contributes a mean of 0.43 µg Pb per day excreted in urine, whereas trabecular bone contributes as much as 1.6 µg Pb per day. Cavalleri et al. (1983) observed different Pb kinetics between exposed and nonexposed subjects after the administra- tion of CaNa2EDTA. In unexposed subjects BPb levels remained stable even after 5 hr of CaNa2EDTA administration. However, plasma-Pb levels in the unexposed group decreased by as much as one half, while urine-Pb increased by a factor of 10. In the Pb- exposed group the same amount of chelation therapy resulted in plasma-Pb levels increasing by a factor of 2, while BPb levels decreased by a factor of 2, with a higher urine-Pb excretion. Thus, it seems that in nonexposed subjects a major contribution for urine-Pb is derived from the Pb fraction in soft tissues that is in equilib- rium with that in plasma compartment. We could speculate that the larger the amount of erythrocyte-bound Pb, the weaker the binding forces, and that a signiﬁcant fraction of Pb is released from red blood cell membranes into plasma and is then filtered by the kidney. Because the amount of Pb excreted is very high, the kidneys are unable to remove it rapidly from the blood stream; this may account for the temporal elevation of plasma-Pb levels. The availability of reliable urine quality- control materials and reference materials certi- fied for Pb content and participation in external quality assessment schemes for urine-Pb are important factors in assuring the accuracy of analytical results. However, the tendency for urate salts to precipitate out of urine during transit and storage can be a com- plicating factor in the analysis. Moreover, because only a few studies have examined asso- ciations between urine-Pb and other biomark- ers, the use of urine-Pb measurements is essentially limited to long-term occupational monitoring programs, monitoring patients during chelation-therapy, and, until very recently, to clinical evaluation of potential can- didates for chelation therapy. Measurement of fecal-Pb content over sev- eral days is one possible approach to estimating the overall magnitude of childhood Pb intake. According to Gwiazda et al. (2005), fecal-Pb content should give an integrated measure of Pb exposure/intake from all sources, dietary and environmental, inside and outside the home (by isotopic composition). However, a limitation to the use of fecal-Pb is that the col- lection of complete fecal samples over multiple days may not be feasible. As stated by Gwiazda et al. (2005), fecal-Pb reflects unabsorbed, ingested Pb plus Pb that is eliminated via endogenous fecal (biliary) routes; interindivid- ual variations in these physiologic processes 1672 may show up as variation that is wrongly attributable to environmental Pb exposure. Nail Lead Like hair, nails have many superﬁcial advan- tages as a biomarker for Pb exposure, especially because specimen collection is noninvasive and simple and because nail specimens are very sta- ble after collection, not requiring special stor- age conditions. Nail-Pb is considered to reﬂect long-term exposure because this compartment remains isolated from other metabolic activities in the body (Takagi et al. 1988). Because toe- nails are less affected by exogenous environ- mental contamination than fingernails, they have been preferred for Pb exposure studies. Toenails have a slower growth rate than ﬁnger- nails (up to 50% slower, especially in winter) and thus may provide a longer integration of Pb exposure. Lead concentration in nails depends on the subject’s age (Nowak and Chmielnicka 2000), but it seems not to depend on the sub- ject’s sex (Rodushkin and Axelsson 2000). Gulson (1996a) reported high variability in Pb levels measured in the same ﬁngernails and toenails of various subjects, even after rig- orous washing procedures; such lack of repro- ducibility suggests that nail specimens offer only limited scope in assessing exposure to Pb. Bone Lead Because bone accounts for > 94% of the adult body burden of Pb (70% in children) (O´Flaherty 1995), many researchers accept that a cumulative measure of Pb dose may be the most important determinant of some forms of toxicity (cumulative measure means an exposure that is integrated over many years, rather than based on a single BPb measure- ment) (Landrigan and Todd 1994; Hu et al. 1998). In support of this hypothesis, recent studies have shown that bone-Pb but not BPb is signiﬁcantly related to declines in hematocrit and hemoglobin among moderately Pb- exposed construction workers and to decreased birth weight and increased odds of clinically relevant hypertension (Gonzalez-Cossio et al. 1997; Hu et al. 1996). According to Hu et al. (1998), other adverse health outcomes likely to be associated with bone-Pb levels include impairment of cognitive performance and growth in children and kidney failure, gout, elevated blood pressure, reproductive toxicity, and adverse cardiovascular events in adults. As pointed by Hu et al. (1998), two major paradigms relate to skeletal Pb: bone-Pb as an indicator of cumulative Pb exposure (bone-Pb as a repository), and bone-Pb as a source of body burden that can mobilized into the circu- lation (bone-Pb as a source). Hernandez-Avila et al. (1998) reported a strong association between bone-Pb levels and serum-Pb levels of adults exposed to Pb. That study indicated the potential role of the skeleton as an important source of endogenous, labile Pb that may not be adequately discerned through measurement of BPb levels. The same authors argued that skeletal sources of Pb accumulated from past exposures should be considered along with cur- rent sources when exposure pathways are being evaluated. In an attempt to characterize the source of Pb exposure, Gulson et al. (1995) measured the 206Pb/204Pb isotopic ratios in immigrant Australian subjects, Australian-born subjects, and environmental samples. The immigrant population exhibited Pb isotopic ratios from 17.7 to 18.5, distinct from the ratio in Australian-born subjects (~ 17.0). This dif- ference allowed a distinction to be drawn between current exposure acquired from Australian sources and older bone-stored Pb that was not acquired from Australian sources. Differing bone types have differing bone-Pb mobilization characteristics. For exam- ple, the tibia principally consists of cortical bone, whereas the patella is largely trabecular bone. Pb in trabecular bone is more biologi- cally active than Pb in cortical bone, and tra- becular bone has a shorter turnover time. The endogenous contribution of Pb from bone stores is an important health consideration. The O´Flaherty kinetic model can be used to indicate the quantity of Pb delivered from bone as a function of bone turnover and Pb exchange (O´Flaherty 1995). A recent revision of this model (Fleming et al. 1999) suggests that a smeltery worker with a tibia Pb concentration of 100 µg/g can expect a continuous endoge- nous contribution to BPb of 16 µg/dL. A preg- nant woman with a tibia Pb concentration of 50 µg/g can end up with a contribution of 8 µg/dL BPb; this ﬁgure does not consider the increased rate of bone turnover associated with pregnancy. Individuals not exposed to Pb in the workplace typically display tibia Pb levels up to about 20 µg/g (Roy et al. 1997). Over the last decade bone-Pb measure- ments based on noninvasive in vivo X-ray ﬂuo- rescence (XRF) methods have become increasingly accepted. The technique uses ﬂuo- rescing photons to remove an inner-shell elec- tron from a Pb atom, leaving it in an excited state. The result is emission of X-ray photons that are characteristic of Pb. Measurements are performed by using one of four kinds of XRF: two involve fluorescence of the K-shell elec- trons of Pb (K-XRF), and the other two involve fluorescence of the L-shell electrons (L-XRF) (Todd et al. 2002a). Several groups, mainly in North America, have reported the development of in vivo measurement systems; the majority have adopted the K-XRF approach based on excitation with a 109Cd iso- tope and backscatter geometry because of its advantages: it provides a robust measurement with a better detection limit and a lower effec- tive (radiation) dose (as compared to L-XRF) VOLUME 113 | NUMBER 12 | December 2005 • Environmental Health Perspectives