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Howard Hu,^1,2 Ming-Tsang Wu,¹ Yawen Cheng,² David Sparrow,³ Scott Weiss,² and Karl Kelsey^1,2,4

¹Occupational Health Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA; ²Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; ³The Normative Aging Study, Department of Veterans Affairs, Boston, Massachusetts, USA; ⁴Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts, USA

Abstract

Recent research has indicated that a polymorphic variant of -aminolevulinic acid dehydratase (ALAD) may influence an individual's level of lead in bone and blood and, as a result, may also influence an individual's susceptibility to lead toxicity. In this study, we investigated whether this ALAD polymorphism is associated with altered levels of lead in bone and blood among 726 middle-aged and elderly men who had community (nonoccupational) exposures to lead. We measured levels of blood and bone lead by graphite furnace atomic absorption spectroscopy and a K X-ray fluorescence (KXRF) instrument, respectively. We determined the ALAD MspI polymorphism in exon 4 by a polymerase chain reaction restriction fragment length polymorphism (RFLP) . Of the 726 subjects, 7 (1%) and 111 (15%) were, respectively, homozygous and heterozygous for the variant allele. The mean (SD) of blood lead (micrograms per deciliter) , cortical bone (tibia) lead (micrograms per gram) , and trabecular bone (patella) lead (micrograms per gram) were 6.2 (4.1) , 22.1 (13.5) , and 31.9 (19.5) in subjects who did not have the variant allele (ALAD 1-1) , and 5.7 (4.2) , 21.2 (10.9) , and 30.4 (17.2) in the combined subjects who were either heterozygous or homozygous for the variant allele (ALAD 1-2 and ALAD 2-2) . In multivariate linear regression models that controlled for age, education, smoking, alcohol ingestion, and vitamin D intake, the ALAD 1-1 genotype was associated with cortical bone lead levels that were 2.55 µg/g [95% confidence interval (CI) 0.05-5.05] higher than those of the variant allele carriers. We found no significant differences by genotype with respect to lead levels in trabecular bone or blood. In stratified analyses and a multivariate regression model that tested for interaction, the relationship of trabecular bone lead to blood lead appeared to be significantly modified by ALAD genotype, with variant allele carriers having higher blood lead levels, but only when trabecular bone lead levels exceeded 60 µg/g. These results suggest that the variant ALAD-2 allele modifies lead kinetics possibly by decreasing lead uptake into cortical bone and increasing the mobilization of lead from trabecular bone. Key words: blood, bone, -aminolevulinic acid dehydratase, lead. Environ Health Perspect 109:827-832 (2001) . [Online 13 August 2001]

http://ehpnet1.niehs.nih.gov/docs/2001/109p827-832hu/ abstract.html

Address correspondence to H. Hu, Channing Laboratory, 181 Longwood Ave., Boston, MA 02115 USA. Telephone: (617) 525-2736. Fax: (617) 525-0362. E-mail: howard.hu@channing.harvard.edu

We gratefully acknowledge the research assistance of S. Harcourt, R. Heldman, G. Barbella, S. Oliveira, T. Luu, G. Fleischaker, M. Barr, L. Hennessey, and S. Datta. D. Burger and F. Milder provided technical assistance in the initial phase of our KXRF measurements. J. McCoy provided editorial assistance. Finally, we are indebted, as always, to the continued enthusiastic cooperation of the participants in the Normative Aging Study.

Support for this research was provided by NIEHS grants ES 05257-06A1 and P42-ES05947 Project 4, NIEHS Occupational and Environmental Health Center grant 2 P30 ES00002. The Normative Aging Study is supported by the cooperative studies program/ERIC, U.S. Department of Veterans Affairs, and is a component of the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) . Subjects were evaluated in the outpatient Clinical Research Center of the Brigham and Women's Hospital with support from NIH grant NCRR GCRC M01RR02635. The KXRF instrument used in this work was developed by ABIOMED, Inc., of Danvers, Massachusetts, with support from NIH grant SBIR 2R44 ES03918-02.

Received 17 July 2000 ; accepted 26 February 2001.