Genetic Make-up May Decrease or Increase Risk of Lead Poisoning

Scientists at the Johns Hopkins School of Public Health have found evidence suggesting that genetic factors may significantly influence how susceptible a person is to lead exposure -- that is, a person's genetic make-up may in part determine how lead is handled by the body, and how it collects in the blood and the bone. The study appears in the October 2000 issue of Environmental Health Perspectives.

An increasing body of evidence suggests that tiny differences in the DNA sequence among individuals can modify the uptake, distribution, and elimination of lead by the body. The present study looks at two normal variants (or alleles) in each of two genes: the ALAD gene, which is responsible for production of the enzyme delta-aminolevulinic acid dehydratase, and the VDR gene, responsible for the vitamin D receptor. The researchers not only confirmed past observations that ALAD's two alleles (ALAD1 and ALAD2) affect the absorption and excretion of lead quite differently, but in addition they have shown for the first time an even more marked difference in the actions of the two variants of VDR (VDR b and VDR B).

The study was performed in the Republic of Korea and participants included 798 lead workers as well as 135 persons without occupational lead exposure. Participants' blood and bone lead levels were measured, and lead workers were given a chelator, dimercaptosuccinic acid (DMSA), so the scientists could determine how readily lead could be removed from the body. Genetic tests determined what combinations of the two gene's variants made up the two genes within each subject.

Information about the participants' demographics, medical and occupational history, blood pressure, and neurologic and strength tests was also obtained, to permit the investigators to find out if such variables as age, sex, hemoglobin, weight, height, job duration, or tobacco and alcohol consumption might be affecting lead levels.

The analyses revealed that subjects with either one or two VDR B alleles had significantly higher blood, bone, and chelatable lead levels than those with two VDR b alleles, and that the ALAD2 allele was also associated with higher blood lead levels. Surprisingly, however, compared to controls, lead workers overall had a higher prevalence of the VDR B and ALAD2 variants, suggesting that these two alleles may somehow permit people to tolerate higher levels of the metal without falling ill.

First author Brian S. Schwartz, MD, MS, associate professor, Environmental Health Sciences, the Johns Hopkins School of Public Health, said, "Lead workers show a prevalence of ALAD2 and VDR B, which causes us to speculate that these two alleles are protective. That is, those lead workers with less protective genetic make-ups would tend to develop acute symptoms of lead poisoning and quit working." The authors think that the protective alleles, for example, may bind lead in parts of the body that do not result in toxicity, or may enhance the excretion of lead, eliminating it from the body.

Support for this study was provided by the National Institute of Environmental Health Sciences.