A POLYMORPHISM IN THE DELTA-AMINOLEVULINIC-ACID DEHYDRATASE GENE MAY MODIFY THE PHARMACOKINETICS AND TOXICITY OF LEAD

Associations between the presence of a consitutional variant of delta-aminolevulinic acid dehydratase (ALAD-2) and lead concentrations in blood and bone, as well as between this allele and indices of kidney function,, were investigated among 691 members of a construction trade union. The average blood lead level in this group was 7.78 mu g/dl. No significant difference was observed in blood lead concentration in ALAD-2 carriers compared to those homozygous for the more common ALAD-1 allele (7.78 (+/- 3.62 mu g Pb/dl vs. 7.73 (+/- 3.48 mu g Pb/dl, respectively; P = 0.73). Bone lead was measured in a subset of 122 of the study subjects. Patella minus tibia lead concentrations for each individual averaged 3.35 +/- 11.99 mu g Pb/g bone mineral in ALAD-1 homozygotes and 8.62 +/- 9.47 mu g Pb/g bone mineral in ALAD-2 carriers (p = 0.06). Comparisons of blood urea nitrogen (BUN) and uric acid by geno-type indicated elevated levels among ALAD-2 individuals (p = 0.03 and 0.07, respectively). In logistic regression models accounting for other variables potentially associated with BUN and uric acid levels, BUN was significantly associated with blood lead levels (p = 0.01). Associations of BUN and uric acid levels with ALAD-2 were of borderline statistical significance in these models (p = 0.06 and 0.07). Taken together, these results suggest that the ALAD-2 genotype may influence the pharmacokinetic distribution and chronic renal toxicity of lead, perhaps due to differential binding of lead to the variant protein.