NHANES III is a survey representative of the civilian, noninstitutionalized U.S. population and was conducted in 1988–1994 (National Center for Health Statistics 1994). The sample was selected through a complex, multistage probability design and included oversampling of non-Hispanic blacks, Mexican Americans, children, and the elderly (National Center for Health Statistics 1994). Sample weights account of differential probability of selection and nonresponse and are poststratified to census population estimates. Individuals participated in an interview conducted at home and also received an extensive physical examination performed at a mobile examination center (MEC), which included blood and urine collection. The total number of participants from the second phase of NHANES III (1991–1994) was 16,530. The NHANES III DNA bank contains specimens from 7,159 participants ≥ 12 years of age who were examined during the second phase of NHANES III (1991–1994) (Chang et al. 2009). The sample weights were derived from the NHANES III phase 2 MEC-examined sample weights, and they were recalculated using previously described methods (Lohr 1999) for the 7,159 participants for whom DNA was available to avoid nonresponse bias for the NHANES III genetic data.

The present study included participants in the NHANES III DNA bank ≥ 17 years of age and self-reported as non-Hispanic white, non-Hispanic black, or Mexican American (n = 6,016). Further details regarding the NHANES III DNA bank have been previously described (Chang et al. 2009).

Table 1 illustrates the characteristics of participants (n = 6,016) from the NHANES III DNA bank weighted to be representative of the U.S. population. The mean age of the population was 44 years (data not shown). Approximately 52% of individuals were female. Non-Hispanic whites accounted for 81.6% of the total population. Approximately 43%, 47%, and 49% of the people reported that they had attended some college, never used alcohol, and never smoked, respectively. The mean (± SE) for systolic BP was 119.0 ± 0.39 mmHg and for diastolic BP was 73.5 ± 0.27 mmHg. Hypertension was observed in 22.7% of the population. For those not currently treated for hypertension, 9.2% and 5.5%, had systolic (≥ 140 mmHg) and diastolic (≥ 90 mmHg) hypertension, respectively. We estimated the mean (± SE) BLL to be 2.98 ± 0.09 μg/dL. Table 1 also summarizes the characteristic of the study participants by race/ethnicity.

Table 2 summarizes the characteristics of the study participants by BLL quartile. Individuals in the highest BLL quartiles tended to be older, male, current smokers, regular drinkers, less educated, and more likely to have hypertension and to have increased serum creatinine, hematocrit, and systolic and diastolic levels of BP.

Table 3 presents the ALAD genotypes and mean BLL by ALAD genotype and by BLL quartile for each of the three major race/ethnic groups in the United States. ALAD2 carriers comprised 13.6% of the total population, 15.6% (370 of 2,017) of non-Hispanic whites, 2.6% (49 of 1,621) of non-Hispanic blacks, and 8.8% (137 of 1,609) of Mexican Americans. Among participants with the ALAD1-1 genotype, we observed a slightly higher BLL for all race/ethnic subgroups compared with the participants with ALAD1‐2 or ALAD2‐2 genotypes. However, this association was significant only in non-Hispanic blacks in the third BLL quartile.

Our results for the association of blood lead with BP and with hypertension in the race/ethnic groups in the U.S. population is consistent with previous NHANES III studies (Den Hond et al. 2002; Nash et al. 2003; Vupputuri et al. 2003). Estimates from the coefficient regressions for blood lead (Table 6) predicted that a 2-fold increase of BLL was correlated with increases of 1.76 mmHg (95% CI, 1.06–2.47) and 0.72 mmHg (95% CI, 0.19–1.26) in systolic BP for non-Hispanic blacks and whites, respectively. Although we did not observe an association with BLL and hypertension in non-Hispanic whites and Mexican Americans, we did find an increased prevalence of hypertension in non-Hispanic blacks in the second, third, and fourth lead quartile compared with those in the lowest BLL quartile. A previous evaluation of lead levels and hypertension in the NHANES III population by Vupputuri et al. (2003) also showed that black and white women with BLL ≥ 5 μg/dL had statistically significantly higher odds ratio for having hypertension compared with those with BLL < 5 μg/dL.

We found that within the highest quartile of lead for the non-Hispanic white population, the prevalence of hypertension was significantly higher among ALAD2 carriers compared with ALAD1 homozygote individuals. In addition, estimates from regression coefficients of the interaction terms shown in Table 6 indicate that, for a doubling of BLL, systolic BP increased by an estimated 2.46 mmHg for ALAD1‐2/2‐2 individuals and 0.72 mmHg for ALAD1 homozygous individuals for the non-Hispanic white population. In contrast, for non-Hispanic black individuals, for a doubling of BLL, systolic BP decreased by an estimated 4.04 mmHg for ALAD1-2/2-2 individuals and increased by 1.76 mmHg for ALAD1 homozygous individuals. This finding may not be reliable for non-Hispanic blacks because there were substantially fewer ALAD2 carriers in this population in our study (n < 50).

Of the two previous studies on ALAD, BLL, and BP, one reported an increase in systolic BP among Korean ALAD2 carriers who were occupationally exposed to lead (Lee et al. 2001), whereas the other reported that ALAD was not associated with systolic BP (Smith et al. 1995).

The mechanisms of lead-induced hypertension are not well characterized. One hypothesis is that lead induces hypertension through direct effects on the kidney (Muntner et al. 2003). Another hypothesis is that the accumulation of lead in the walls of arteries results in arterial stiffness, which induces hypertension. Lead has been reported to both accumulate in the human aorta (Poklis 1975; Schroeder and Tipton 1968) and contribute to the increase in pulse pressure that occurs with aging (Perlstein et al 2007). Elevated aortic stiffness is also known to induce high systolic BP and increase pulse pressure (O’Rourke and Mancia 1999). Finally, it is also possible that lead may alter BP by interference with vascular signaling pathways. Endothelial nitric oxide (NO) regulates vascular function, and the disruption of the NO activity is important in the development of hypertension (Chowdhary and Townend 2001). Lead exposure has been reported to significantly inhibit endothelial NO production (Barbosa et al. 2006), as well as to cause NO inactivation by increasing oxidative stress, thereby decreasing NO availability (Vaziri and Ding 2001; Vaziri et al. 1999).

There was no association between ALAD2 carriers and mean BLL in any of the race/ethnicities. However, in general, ALAD2 carriers had a lower mean BLL than did ALAD1 homozygous subjects, although these differences were not statistically significant. When stratified by BLL quartile, only non-Hispanic white ALAD2 carriers had a marginally higher mean BLL than did ALAD1 homozygous subjects in the fourth BLL quartile. These data are in agreement with the view that ALAD2 allele would significantly affect BLL not at low exposure levels but only at higher levels, when other lead-binding sites have been saturated (Schwartz et al. 1995; Scinicariello et al. 2007). Montenegro et al. (2006) reported that, although ALAD2 carriers had no significantly lower mean BLL than did ALAD1 homozygous individuals, ALAD2 carriers had a significantly higher plasma lead level compared with homozygous ALAD1 subjects. Therefore, it may be possible that non-Hispanic white ALAD2 carriers have higher levels of plasma lead compared with ALAD1 homozygote individuals. Consequently, the higher plasma lead, interacting with other molecular BP regulatory systems, may be responsible for the observed increases in systolic BP in ALAD2 carriers.

The present study has several limitations. The exclusion from our study of persons who reported taking medication for hypertension may have diluted the strength and magnitude of associations in our analysis for systolic and diastolic BP. Second, although we controlled for many of the known factors associated with BP and hypertension, other variables such as serum selenium (Telisman et al. 2001), serum zinc (Schwartz 1991), and blood cadmium (Navas-Acien et al. 2004) might have influenced our findings. Blood cadmium was not measured by NHANES III. However, urinary cadmium, a measured variable in NHANES III, was not a significant variable for hypertension or for systolic or diastolic BP (data not shown). Urinary cadmium reflects cadmium concentration in the renal cortex and is a biomarker of both ongoing and long-term cadmium exposure, whereas blood cadmium is a biomarker of ongoing exposure (Agency for Toxic Substances and Disease Registry 1999). Therefore, it seems unlikely that including blood cadmium in our models would have changed our finding. Our results are based on BLL; because approximately 95% of the total body burden of lead is present in the skeleton, a preferred measure of chronic body burden would be bone lead (Hu et al. 1996). However, the measurement of bone lead in a large sample size, such as NHANES, is not feasible, and blood lead is known to be associated with bone lead (Gwiazda et al. 2005; Todd et al. 2001).

Currently, the CDC designates 10 μg/dL as a BLL of concern and has formulated guidelines for environmental and educational intervention in children at this level (CDC 2002). No corresponding CDC guidance exists for BLL measured in adults. However, in the past few decades the presence of lead in the environment has steadily declined. In the adult U.S. population, mean BLL measured in NHANES surveys conducted in 1976–1980, 1988–1991, and 1999–2002 decreased from 13.1 μg/dL to 3.0 μg/dL and to 01.64 μg/dL, respectively (Muntner et al. 2005; Pirkle et al 1994). This positive and welcome decline has steadily continued with a geometric mean BLL of 1.41 μg/dL in the U.S. adult population ≥ 20 years of age as measured in the NHANES survey conducted in 2005–2006 (Scinicariello F, unpublished data).

We examined the modification by ALAD in the association of BLL and BP and hypertension in the U.S. population. We found that within the highest quartile of lead for the non-Hispanic white population, the prevalence of hypertension was significantly higher among ALAD2 carriers compared with ALAD1 homozygotes. In addition, we found that ALAD2 carriers in non-Hispanic whites may experience a more pronounced effect of lead on systolic BP than do homozygous ALAD1 carriers. These results underscore the importance of reducing environmental sources of lead exposure in the U.S. population, and this should remain a major public health priority based on consistent evidence of increased health risks (Kosnett et al. 2007; Schwartz and Hu 2007). Given the high frequency of ALAD2 carriers (15.6%) in the non-Hispanic white population, and the cross-sectional nature of the present study, prospective studies are needed to confirm and elucidate the role of ALAD polymorphism and these associations.