Lead in your body: genotype determines what stays, what goes. (Science Selections).

The same lead exposure can cause widely varying symptoms of lead intoxication and levels of organ dysfunction in different people. According to Howard Hu of Harvard University and his colleagues, an underlying cause may be genetic polymorphism in the [delta]-aminolevulinic acid dehydratase (ALAD) gene [EHP 109:827-832].

The team studied ALAD polymorphism and its relation to altered concentrations of bone and blood lead among 726 middle-aged and elderly men who had been exposed to lead nonoccupationally. Given their ages, these men would have faced now-obsolete lead exposures such as inhaling combusted leaded gasoline and ingesting food from lead-soldered cans, as well as still-present exposures such as eating vegetables grown in lead-contaminated soil. The men were participants in the Normative Aging Study, a longitudinal study of aging begun in 1963. Middle-aged to elderly men are at the highest risk for the onset of certain chronic diseases such as hypertension, stroke, heart attack, and dementia, and Hu and colleagues believe that cumulative lead exposure may be a signifant risk factor for these problems.

Bone lead measurements were taken at the thigh and the knee. These sites were chosen because they consist, respectively, of pure cortical and pure trabecular bone. Cortical bone has very slow turnover; lead that is deposited there persists for many decades and thus provides a good reflection of total lead exposure. Conversely, trabecular bone has a relatively rapid turnover and releases a good deal of lead into the blood. Trabecular bone is therefore a good reflection of bone lead stores that can be mobilized into circulation.

The results showed that patella lead was the major predictor of blood lead in this aging nonoccupationally exposed population and that ALAD polymorphism significantly affected this association. For example, when patella lead exceeded 60 [micro]g/g, blood lead concentrations in carriers of the ALAD 2 allele were higher than those in ALAD 1-1 carriers. By contrast, when patella lead concentrations were lower than 40 [micro]g/g, blood lead concentrations were higher in ALAD 1-1 carriers than in ALAD 2 carriers. On the basis of their results, Hu and his colleagues suggest that when blood lead concentrations are relatively low--less than about 8 [micro]g/dL, for instance--ALAD 1-1 carriers will have higher blood lead concentrations than ALAD 2 carriers.

Some earlier studies on ALAD polymorphism and blood lead found that individuals with the ALAD 2 allele had higher blood lead concentrations. Others did not find this relationship. The results of Hu's study suggest a possible reason for this discrepancy: the relationship between the ALAD polymorphism and blood lead may actually depend on how much lead is in bone, a parameter that had not been previously measured in most ALAD polymorphism studies. Hu and colleagues caution, however, that this finding is tentative and needs to be verified in other community-exposed population studies.

ALAD polymorphism, then, might modify the exchange of lead between blood and bone, which in turn could modify a person's risk for lead toxicity. Several previous studies have indeed found that ALAD polymorphism modifies certain symptoms of lead intoxication, such as impaired kidney, reproductive, and neuropsychological function. For instance, one study found the ALAD 2 allele to correlate with impaired kidney function, yet other studies found this same allele to be protective of neuropsychological and male reproductive function. More research is needed for a precise definition of the mechanism of function and of the potential impact of ALAD polymorphism on lead kinetics and toxicity.