BONE LEAD AS A BIOLOGICAL MARKER IN EPIDEMIOLOGIC STUDIES OF CHRONIC TOXICITY - CONCEPTUAL PARADIGMS

The skeleton contains the majority of the body's lead burden in both c hildren and adults. The half-life of lead in bone is in the range of y ears to decades, depending on bone type, metabolic state, and subject age, among other things. Measurement of skeletal lead has bent fired g reatly from the recent development of X-ray fluorescence (XRF) instrum ents that can make rapid, safe, accurate, and relatively precise measu rements of lead in bone. Two types of XRF technologies exist, LXRF and KXRF; this paper focuses on KXRF, which has been the most widely vali dated and used. KXRF is proving to be a powerful analytical methodolog y for evaluating bone lead levels as a measure of time-integrated (i.e ., cumulative) lead dose hi epidemiologic studies of the effects of ch ronic lead exposure. However, insufficient attention has been given to conceptualizing the paradigms by which bone lead levels reflect lead exposure and by which the skeleton serves as an endogenous source of l ead. Consideration of these paradigms, which rely on bone lead kinetic s, is necessary for the proper development of a priori hypotheses invo lving bone lead accumulation and release, the selection of bone sires for measurement by KXRF, and the design of epidemiologic studies invol ving bone lead dynamics. We discuss and present supporting evidence fo r a conceptual model that distinguishes two major paradigms of skeleta l lead, including 1) bone lead as an indicator of cumulative lead expo sure (bone lead as repository), and 2) bone lead as a source of body l ead burden that is mobilizable into the circulation (bone lead as sour ce). These two roles are not mutually exclusive. Instead, they are com ponents of the processes controlling lead accumulation into and releas e from bone over time, Developing successful strategies for distinguis hing these two processes in epidemiologic studies will require separat e measurements of lead in cortical and trabecular bone and additional measurement of specific markers of bone mineral turnover and resorptio n. It may also involve developing accurate methods for evaluating lead in labile compartments of the circulation, such as plasma, as a poten tially useful and responsive measure of bone lead release, of the part itioning of circulatory lead, and of the toxicological significance of lead released from bone to other target organs.