Vulnerability to Lead.

Absorption Varies with Genotype

Generic factors may modify the toxicokinetics of lead in humans--that is, how lead is absorbed, distributed, metabolized, and excreted. Attention has centered on the enzyme [Delta]-aminolevulinic dehydratase (ALAD), which is coded by a single gene with two alleles, [ALAD.sup.1] and [ALAD.sup.2]. In this month's issue, Brian S. Schwartz of the Johns Hopkins School of Hygiene and Public Health and colleagues present their study on the influence of polymorphisms in the ALAD and vitamin D receptor (VDR) genes on concentrations of lead in blood and the tibia, and the amount of lead chelatable with dimercaptosuccinic acid (DMSA) and excreted in the urine [EHP 108:949-954]. Their results confirm past observations that the ALAD gene modifies lead toxicokinetics and furnish new evidence that the VDR gene does so as well.

Earlier research established that ALAD is a principal lead-binding protein in red blood cells, and recent data suggest that polymorphisms in the VDR gene influence tibia lead concentrations. In particular, the polymorphism denoted as BsmI has three genotypes, designated as bb, Bb, and BB, that appear to be linked with lead concentrations in bone.

In this study, 798 Korean lead workers and 135 controls without occupational lead exposure provided blood samples, and blood lead was assessed with an atomic absorption spectrometer. Tibia lead was evaluated using [sup.109]Cd-induced X-ray fluorescence, and chelatable lead was measured as a 4-hour urinary lead excretion after the study subjects were orally dosed with DMSA. The scientists also completed ALAD and VDR genotyping on the subjects. Whether the workers used tobacco or alcohol was taken into account during statistical analysis.

Adjusted analyses showed that subjects with the VDR B allele had significantly higher blood and tibia lead concentrations and greater excretion of lead after DMSA dosing than did those with the VDR bb genotype. The effect of the VDR B allele on blood lead concentrations turned out to be greater than that of the [ALAD.sup.2] allele. However, the mechanisms by which these genes influence blood lead concentrations probably differ, because [ALAD.sup.2] and VDR B were both associated with higher blood lead concentrations, but only VDR B was associated with higher tibia lead concentrations and greater lead excretion after DMSA dosing.

After binding to the VDR, vitamin D is known to increase intestinal absorption of lead. It is possible that the influence of vitamin D on lead absorption from the gut differs by genotype, and that people with VDR B allele have greater absorption of lead via the intestines and greater uptake and subsequent release of lead from bone. The scientists note, however, that tibia lead measurements by X-ray fluorescence were complicated by the fact that such analyses are standardized to bone mineral content. Thus, higher tibia lead readings could be attributed to higher lead content, lower calcium content, or both.

Subjects with [ALAD.sup.2] allele showed higher blood lead concentrations but no differences in tibia or chelatable lead concentrations compared with subjects lacking this allele. The results reinforce observations that the [ALAD.sup.2] allele increases red blood cell binding of lead, and so probably decreases the relative deposition of lead in critical target organs, possibly protecting against the toxicity of lead by increasing the amount of legal excreted in urine.

All studies to date suggest that the [ALAD.sup.1] allele is more likely to confer health risks from lead exposure. The researchers also found that lead workers homozygous for the [ALAD.sup.1] allele were much less likely to have the VDR bb genotype; the two genes are apparently linked despite the fact that they are located on different chromosomes. Although the VDR gene may play a role in susceptibility to the health effects of lead, there are not enough data to indicate whether its polymorphisms will modify health risks, and if so, which allele brings about such risks. Compared with controls, lead workers seem to have a higher prevalence of [ALAD.sup.2] and VDR B. It may be that the [ALAD.sup.2] and VDR B alleles are protective, and there might be selection by genotype among lead workers--perhaps because workers who become symptomatic upon exposure to lead would choose to leave the occupation--but this speculation requires further study.