Review A Critical Review of Biomarkers Used for Monitoring Human Exposure to Lead: Advantages, Limitations, and Future Needs Fernando Barbosa Jr.,1 José Eduardo Tanus-Santos,1 Raquel Fernanda Gerlach,2 and Patrick J. Parsons3 1Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; 2Department of Morphology, Estomatology and Physiology, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil; 3Wadsworth Center, New York State Department of Health, Albany, New York, USA Lead concentration in whole blood (BPb) is the primary biomarker used to monitor exposure to this metallic element. The U.S. Centers for Disease Control and Prevention and the World Health Organization deﬁne a BPb of 10 µg/dL (0.48 µmol/L) as the threshold of concern in young children. However, recent studies have reported the possibility of adverse health effects, including intellectual impairment in young children, at BPb levels < 10 µg/dL, suggesting that there is no safe level of expo- sure. It appears impossible to differentiate between low-level chronic Pb exposure and a high-level short Pb exposure based on a single BPb measurement; therefore, serial BPb measurements offer a better estimation of possible health outcomes. The difﬁculty in assessing the exact nature of Pb expo- sure is dependent not so much on problems with current analytical methodologies, but rather on the complex toxicokinetics of Pb within various body compartments (i.e., cycling of Pb between bone, blood, and soft tissues). If we are to differentiate more effectively between Pb stored in the body for years and Pb from recent exposure, information on other biomarkers of exposure may be needed. None of the current biomarkers of internal Pb dose have yet been accepted by the scientiﬁc commu- nity as a reliable substitute for a BPb measurement. This review focuses on the limitations of bio- markers of Pb exposure and the need to improve the accuracy of their measurement. We present here only the traditional analytical protocols in current use, and we attempt to assess the inﬂuence of con- founding variables on BPb levels. Finally, we discuss the interpretation of BPb data with respect to both external and endogenous Pb exposure, past or recent exposure, as well as the signiﬁcance of Pb determinations in human specimens including hair, nails, saliva, bone, blood (plasma, whole blood), urine, feces, and exfoliated teeth. Key words: biomarkers, biomonitoring, blood, bone, feces, hair, lead, plasma, saliva, teeth, toxicokinetics, urine. Environ Health Perspect 113:1669–1674 (2005). doi:10.1289/ehp.7917 available via http://dx.doi.org/ [Online 11 August 2005] Over the last two decades, atmospheric concen- trations of lead have decreased significantly around the globe as more and more nations have chosen to remove tetraethylead from gaso- line (Thomas et al. 1999). However, humans may also be exposed to Pb through contami- nated food, water, and house dust and through industrial activities such as metal recycling and the battery industry. In the United States, for example, although the use of Pb in house paint peaked in 1940 and was banned in 1978, 40% of the nation’s housing stock is estimated to still contain Pb-based paint (Wakeﬁeld 2002). After Pb enters the body, it can travel along several pathways depending on its source and, by extension, its bioavailability. The frac- tion of Pb that is absorbed depends mainly on the physical and chemical form, particularly particle size and the solubility of the speciﬁc compound. Other important factors are spe- ciﬁc to the exposed subject, such as age, sex, nutritional status and, possibly, genetic back- ground [Agency for Toxic Substances and Disease Registry (ATSDR) 1999; National Research Council 1993]. One of the earliest toxicokinetics studies reported that Pb, once absorbed into the blood compartment, has a mean biological half-life of about 40 days in adult males (Rabinowitz et al. 1976). The half- life in children and in pregnant women was reported to be longer, because of bone remod- eling (Gulson et al. 1996; Manton et al. 2000). However, another study was unable to conﬁrm this ﬁnding (Succop et al. 1998). Like many other “bone-seeking” elements, Pb from blood is incorporated into calciﬁed tis- sues such as bone and teeth, where it can remain for years (Rabinowitz 1991; O´Flaherty 1995). According to Rabinowitz (1991), the half-life of Pb in bone (bone-Pb) ranges from 10 to 30 years. However, the use of the term “half-life” to describe the biological clearance of Pb from bone implicitly makes assumptions about the kinetics of the process by which Pb is released. Some researchers prefer to use the term “residence time” to avoid implying more precision than what can be directly determined (Chettle D, personal communication). From calcified tissue stores, Pb is slowly released, depending on bone turnover rates, which in turn are a function of the type of bone, whether compact (slow turnover) or trabecular (rapid turnover) (O´Flaherty 1995). Brito et al. (2002) reported that the release rate of Pb from bone varies with age and intensity of exposure. Brito et al. (2005) also examined estimates of exchange rates among compartments. The transfer of Pb from blood to other compart- ments was much more rapid than the 1-month estimate reported previously (Brito et al. 2005), Environmental Health Perspectives • VOLUME 113 | NUMBER 12 | December 2005 with the overall clearance rate from blood (sum of rates from blood to cortical bone, to trabecu- lar bone and to other tissue), implying a half- life of 10−12 days (Brito et al. 2005). This highlights the difference between the overall clearance viewed from outside, when no allowance can be made for recirculation, and actual transfer rates. Physiologic differences between children and adults account for much of the increased susceptibility of small children to the deleteri- ous effects of Pb: whereas in adults 94% of Pb body burden is stored in bones and teeth, this proportion is only 70% in children (Barry 1981). In addition, the continuous growth of young children implies constant bone remod- eling for skeletal development (O´Flaherty 1995). This contributes to a state in which Pb stored in bone is continually released back into the blood compartment, a process that has been described as “endogenous contamina- tion” (Gulson et al. 1996). This process is par- ticularly significant for pregnant women because pregnancy causes an increase in bone remodeling. The apparently limited success of various Pb hazard control measures in decreas- ing blood Pb (BPb) levels in exposed children and pregnant women may reflect a constant bone resorption process (Rust et al. 1999). Popovic et al. (2005) recently reported very different long-term Pb kinetics between men and women, with premenopausal women appearing to retain Pb more avidly or release Pb more slowly compared to postmenopausal women and to men. Biomonitoring Human Exposure to Lead Biomonitoring for human exposure to Pb reﬂects an individual’s current body burden, which is a function of recent and/or past exposure. Thus, the appropriate selection and measurement of biomarkers of Pb exposure is of critical importance for health care manage- ment purposes, public health decision making, and primary prevention activities. Address correspondence to F. Barbosa Jr., Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo–FMRP- USP, Av. Bandeirantes, 3900, Monte Alegre, CEP 14049-900, Ribeirão Preto, SP, Brazil. Telephone: 5516 6023183. E-mail: fbarbosajr@yahoo.com The authors declare they have no competing ﬁnancial interests. Received 11 January 2005; accepted 10 August 2005. 1669