The National Institute of Environmental Health Sciences (NIEHS) is collaborating with JSTOR to digitize, preserve and 

extend access to Environmental Health Perspectives.

http://www.jstor.org

Blood Lead Levels and Death from All Causes, Cardiovascular Disease, and Cancer: Results from 

the NHANES III Mortality Study 

Author(s): Susan E. Schober, Lisa B. Mirel, Barry I. Graubard, Debra J. Brody and Katherine M. 

Flegal 

Source: Environmental Health Perspectives, Vol. 114, No. 10 (Oct., 2006), pp. 1538-1541

Published by: The National Institute of Environmental Health Sciences (NIEHS)

Stable URL: http://www.jstor.org/stable/3838177

Accessed: 28-09-2015 14:38 UTC

Your use of the JSTOR archive indicates your acceptance of the Terms & Conditions of Use, available at http://www.jstor.org/page/

info/about/policies/terms.jsp

JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content 

in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. 

For more information about JSTOR, please contact support@jstor.org.

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:38:05 UTC

All use subject to JSTOR Terms and Conditions
Research 

Blood Lead Levels and Death from All Causes, Cardiovascular Disease, and 

Cancer: Results from the NHANES Ill Mortality Study 

Susan E. Schober,1 Lisa B. Mirel,2 * Barry L Graubard,3 Debra J. Brody,' and Katherine M. Flegal1 

1Division of Health and Nutrition Examination Statistics, National Center for Health Statistics, Centers for Disease Control and 

Prevention, Hyattsville, Maryland, USA; 2Harris Corporation, Falls Church, Virginia, USA; 3Division of Cancer Epidemiology and 

Genetics, National Cancer Institute, Rockville, Maryland, USA 

BACKGROUND: Analyses of mortality data for participants examined in 1976-1980 in the second 

National Health and Nutrition Examination Survey (NHANES II) suggested an increased risk of 

mortality at blood lead levels > 20 pgIdL. Blood lead levels have decreased markedly since the late 

1970s. In NHANES III, conducted during 1988-1994, few adults had levels > 20 ,ug/dL. 

OBJECTIvE: Our objective in this study was to determine the risk of mortality in relation to lower 

blood lead levels observed for adult participants of NHANES III. 

METHODS: We analyzed mortality information for 9,757 participants who had a blood lead measurement and who were 2 40 years of age at the baseline examination. Using blood lead levels categorized as < 5, 5 to < 10, and 2 10 pg/dL, we determined the relative risk of mortality from all causes, 

cancer, and cardiovascular disease through Cox proportional hazard regression analysis. 

RESULTS: Using blood lead levels < 5 pg/dL as the referent, we determined that the relative risk of 

mortality from all causes was 1.24 [95% confidence interval (CI), 1.05-1.48] for those with blood 

levels of 5-9 pg/dL and 1.59 (95% CI, 1.28-1.98) for those with blood levels 2 10 ,g/dL (p for 

trend < 0.001). The magnitude of risk was similar for deaths due to cardiovascular disease and 

cancer, and tests for trend were statistically significant (p < 0.01) for both causes of death. 

CONCLUSION: In a nationally representative sample of the U.S. population, blood lead levels as low 

as 5-9 pg/dL were associated with an increased risk of death from all causes, cardiovascular disease, 

and cancer. 

KEY WORDS: cancer, cardiovascular disease, lead, mortality, National Health and Nutrition 

Examination Survey (NHANES), United States. Environ Health Perspect 114:1538-1541 (2006). 

doi:10. 1289/ehp.9123 available via http.//dx.doi.orgl [Online 6 July 2006] 

Toxic effects of exposure to high levels of lead 

among adults in occupational settings and 

from poisonings include neurologic and renal 

impairment as well as effects on other organ 

systems [Agency for Toxic Substances and 

Disease Registry (ATSDR) 1999]. Environmental exposure to lead-exposure much 

lower than that found in occupational settings-is associated with long-term adverse 

effects, particularly on blood pressure (Cheng 

et al. 2001; Glenn et al. 2003; Hertz-Picciotto 

and Croft 1992; Hu et al. 1996; Moller and 

Kristensen 1992; Nash et al. 2003), renal 

function (Kim et al. 1996; Muntner et al. 

2003; Payton et al. 1994; Staessen et al. 1992; 

Tsaih et al. 2004), and cognition (Payton 

et al. 1998; Weisskopf et al. 2004; Wright 

et al. 2003). Recent reports suggest that even 

blood lead levels that are currently typical in 

the U.S. population are associated with renal 

dysfunction (Muntner et al. 2005) and 

peripheral arterial disease (Muntner et al. 

2005; Navas-Acien et al. 2004). Lead and lead 

compounds are reasonably anticipated to be 

human carcinogens based on evidence from 

occupational mortality and animal studies 

[National Toxicology Program (NTP) 2005]. 

Lead exposure declined dramatically 

beginning in the late 1970s largely because of 

mandated removal of lead from gasoline, from 

paint, and to a lesser extent, from solder used 

in cans (Annest et al. 1983; Pirkle et al. 1994). 

Blood lead measurements from the National 

Health and Nutrition Examination Surveys 

(NHANES) have provided documentation of 

lead exposure in the U.S. population beginning 

with data from NHANES II conducted during 

1976-1980. Among person 1-74 years of age, 

the geometric mean of blood lead level dropped 

from 12.8 pg/dL in 1976-1980 to 2.8 ,ug/dL 

in 1988-1991 (Annest et al. 1983), and to 

2.3 pg/dL in 1991-1994 [Centers for Disease 

Control and Prevention (CDC) 1997]. 

Analyses of mortality follow-up data for 

participants of NHANES II suggested an 

increased risk of mortality at blood lead levels 

> 20 pg/dL Uemal et al. 2002; Lustberg and 

Silbergeld 2002). Mortality follow-up through 

the year 2000 is now available for NHANES 

III participants. The purpose of our study was 

to examine the risk of mortality from all 

causes, cardiovascular disease, and cancer in 

relation to blood lead levels observed for adult 

participants of NHANES III. 

Methods 

NHANES III was fielded in two phases, the 

first from 1988 through October 1991 and 

the second from November 1991 through 

1994. The survey consisted of a household 

interview and a standardized physical examination in a mobile examination center. The 

NHANES III sample was selected through a 

complex, multistage probability design. The 

survey has been described in detail elsewhere 

(CDC 1994). 

During the physical examination, blood 

was obtained by venipuncture for all survey 

participants ? 1 year of age. Blood lead concentrations were measured by graphite furnace 

atomic absorption spectrophotometry and 

expressed in micrograms per deciliter. Details 

regarding laboratory methods and quality control procedures have been described previously 

(Pirklet al. 1994). 

NHANES III participants ?17 years of 

age were eligible for passive mortality followup, which has been completed for deaths 

occurring through December 2000. Mortality 

information isbased on the results of a probabilistic match between NHANES III and the 

National Death Index records [National 

Center for Health Statistics (NCHS) 2006]. 

This analysis was limited to persons 

? 40 years of age at the time of the examination. Of the 10,202 persons ? 40 years of age, 

9,762 (95.7%) had a blood lead measurement at baseline. Five persons were excluded 

because of insufficient information to allow 

for follow-up, resulting in a sample of 

9,757 persons. The median length of followup was 8.55 years, during which there were 

2,515 deaths (25.8% of participants). The 

International Classification of Diseases, Tenth 

Revision (ICD-10; NCHS 2006) was used to 

identify deaths due to malignant neoplasm 

(ICD-10 codes COO-C97) and major cardiovascular disease (ICD-10 codes 100-178). 

Persons who were not matched to a death 

record were considered alive through the 

Address correspondence to S. Schober, NHANES 

Program, NCHS, CDC, 3311 Toledo Rd., Room 

4210, Hyattsville, MD 20782 USA. Telephone: 

(301) 458-4484. Fax: (301) 458-4028. E-mail: 

SSchober@cdc.gov 

*Current address: Government Accountability 

Office, Washington, DC. 

This research was supported in part by the 

Intramural Research Program of the Department of 

Health and Human Services, National Institutes of 

Health, National Cancer Institute. 

The findings and conclusions in this article are 

those of the authors and do not necessarily represent 

the views of the Centers for Disease Control and 

Prevention or the Government Accountability Office. 

At the time this research was conducted, L.B.M. 

was an employee of Harris Corporation working 

under contract for the CDC/NCHS. The other 

authors declare they have no competing financial 

interests. 

Received 24 February 2006; accepted 5 July 2006. 

1538 VOLUME 1141 NUMBER 10 1 October 2006 * Environmental Health Perspectives 

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:38:05 UTC

All use subject to JSTOR Terms and Conditions
Blood lead levels and mortality risk, NHANES IIl 

follow-up period and administratively censored 31 December 2000. 

Blood lead levels were categorized as < 5, 

5 to < 10, and ? 10 pg/dL. The sample size 

for persons with blood lead levels ? 20 ,ug/dL 

was too small to provide reliable estimates of 

mortality risk for this group. Because of the 

skewed distribution of blood lead concentrations, log-transformed values were used for 

additional analyses using lead levels as a continuous variable. 

A participant's age was defined as his or 

her age in years at the baseline examination. 

Race/ethnicity was categorized as nonHispanic white, non-Hispanic black, Mexican 

American, and other. Education level was categorized as < 12 years or ? 12 years of education. Total family income was defined as 

< $20,000/year or 2 $20,000/year. Region, as 

defined by the U.S. Census Bureau (2006), 

was recorded as Northeast, Midwest, West, or 

South. Urban status of residence was defined 

by population size and place of residence, and 

categorized into two groups: central or fringe 

counties of metropolitan areas with population size of ? 1 million versus all other areas. 

History of cigarette smoking was categorized 

as never, former, or current. Alcohol consumption was used as a continuous variable 

and defined by summing the number of 

drinks of beer, wine, or liquor consumed per 

week. More than 21 drinks was truncated and 

counted as 21. 

We used Cox proportional hazard regression analysis, using age as the time scale to 

examine the relative hazard (or relative risk) of 

mortality from all causes, cancer, and cardiovascular disease using categories of blood lead 

concentrations adescribed above (Korn et al. 

1997). As recommended by Korn et al. 

(1997), we stratified the baseline hazard by 

birth cohort; we used 6-year intervals. This 

controls for potential cohort differences in 

cumulative exposure to lead before the late 

1 970s, when current exposure to lead began to 

decline dramatically (Annest et al. 1983; 

Pirkle et al. 1994). Blood lead levels largely 

reflect current exposure (Rabinowitz et al. 

1976) and are an imperfect measure of a person's lifetime exposure to lead. Because current lead exposure and blood lead levels 

continued to decline over the 6-year period of 

blood collection in NHANES (CDC 1997; 

Pirkle et al. 1994), we also stratified the baseline hazard by survey phase. For cause-specific 

analyses, follow-up for those who died from 

other causes was censored at the age of death. 

Initial models assessed univariate associations of covariates and mortality. Next, we 

constructed multivariate proportional hazard 

models to examine the association of lead 

exposure and mortality after adjusting for 

potential confounders. All two-way interactions with blood lead category were assessed. 

We assessed the proportional hazard assumption by examining the consistency of the relative hazards of mortality across three age 

groups. We defined three age categories, 

40-74, 75-84, and ? 85 years, so that there 

were an approximately equal number of deaths 

from all causes in each category. Study subjects 

can be induded in more than one age group as 

their ages change during the follow-up period. 

Because the cancer mortality and blood lead 

relationship was different for men and women 

in a previous study of the NHANES II cohort, 

we also stratified multivariate models separately 

for males and females. 

We analyzed the dose-response relationship of blood lead and mortality in two ways. 

First, the multivariate-adjusted relative risks 

across the three blood lead categories were 

tested for trend. A linear term consisting of 

the median values for each lead group was 

placed in the proportional hazards model 

instead of the dummy variables for each 

group, and this linear term was analyzed 

using a Wald test. Second, the dose-response 

relationship between lead and mortality from 

all causes was evaluated using log-transformed 

blood lead concentration as a continuous variable with a five-knot cubic regression spline in 

the multivariate proportional hazards model 

(Durrleman and Simon 1989). We used a 

Wald test to evaluate the dose-response 

relationship. 

Statistical analyses were conducted using 

the SAS System for Windows (release 9.1; 

SAS Institute Inc., Cary, NC) and SUDAAN 

(release 9.0; Research Triangle Institute, 

Research Triangle Park, NC). All analyses 

included sample weights that accounted for 

the unequal probabilities of selection and 

nonresponse. All variance calculations incorporated the sample weights and accounted for 

the complex sample design using Taylor series 

linearization. All significance tests were twosided using p < 0.05 as the level of statistical 

significance. 

Results 

Table 1 summarizes characteristics of the 

NHANES III cohort by blood lead categories. 

Person-years offollow up were approximately 

53,000, 20,000, and 4,500 by blood lead categories < 5, 5-9, and ? 10 1ig/dL, respectively. 

Remaining estimates are weighted by the sample weights. Blood lead levels increased with 

age. Blood lead concentrations were disproportionately higher for men, non-Hispanic 

blacks, those with low income, those with 

educational attainment of < 12 years, current 

smokers, and residents of the Northeast, and 

persons who participated in the first phase of 

the survey. Alcohol intake was positively associated with blood lead concentrations. No differences in blood lead concentrations by urban 

status of residences were noted. 

The number of deaths and multivariateadjusted relative risks of mortality due to all 

causes, cardiovascular disease, and cancer by 

blood lead category are presented in Table 2. 

The multivariate results exclude 71 persons 

with missing information on education level, 

for a final sample size of 9,686. After this 

exclusion, there were a total of 2,485 deaths 

from all causes, 1,189 from cardiovascular 

disease, and 543 from cancer. For each category of deaths, statistical testing did not support the null hypothesis that proportional 

Table 1. Characteristics of the study cohort by blood lead level. 

Blood lead level (pg/dL) 

Characteristic < 5 5-9 > 10 

Sample size 6,608 2,532 617 

Person-years 53,398 19,939 4,509 

Median blood lead level (pg/dL) 2.6 6.3 11.8 

Mean age at baseline (years) 57.0 60.6 62.0 

Male (%) 39.1 65.2 74.2 

Race/ethnicity (%) 

Non-Hispanic white 82.7 78.1 65.7 

Non-Hispanic black 7.4 12.3 22.6 

Mexican-American 3.4 3.5 4.3 

Other 6.5 6.1 7.5 

Total family income < $20,000 (%) 29.8 41.2 52.3 

Education level < 12 years (%) 26.2 39.0 50.8 

Smoking status at baseline (%) 

Never 48.1 26.1 19.3 

Former 33.8 39.0 36.5 

Current 18.1 34.9 44.2 

Mean alcohol intake (drinks/week) 2.0 4.6 5.5 

Census region (%) 

Northeast 17.4 29.1 36.2 

Midwest 25.1 25.2 17.8 

South 36.3 27.8 31.7 

West 21.2 18.0 14.3 

Urban status (%) 45.6 52.1 51.3 

Phase 1 of survey (%) 44.4 58.2 65.3 

Environmental Health Perspectives * VOLUME 114 1 NUMBER 10 1 October 2006 1 539 

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:38:05 UTC

All use subject to JSTOR Terms and Conditions
Schober et at. 

hazards were constant by age, although the 

lead-mortality relationships were generally 

consistent across age strata. For completeness, 

age-stratified results are shown in addition to 

results for all ages combined. The following 

covariates were included in all multivariate 

models: sex, race/ethnicity, education level, 

and smoking status. Census region and urban 

status of residence were not predictive, and 

alcohol intake was weakly predictive of mortality in our analysis. Including these three 

covariates in the analysis did not alter the 

blood lead and mortality relationships; therefore, we excluded these three covariates from 

the final multivariate models. Socioeconomic 

status, as indicated by either annual family 

income (categorized as < $20,000 and 

? $20,000) or education level was an important confounder in the multivariate analyses. 

We chose to use education level rather than 

income in our final models because there was 

less missing information for this variable. In 

general, interaction terms between lead and 

covariates were not statistically significant. We 

found a p-value of 0.02 for the interaction 

terms lead x education in the cardiovascular 

disease model and lead x race/ethnicity in the 

cancer mortality model; however, the interactive effects were not large and did not alter 

the direction of the lead-mortality relationships. Therefore, we did not include these 

terms in our final models. 

In general, we found an increased risk of 

mortality from all causes with increasing blood 

lead levels (Table 2), where the reference category was blood lead levels < 5 ,ug/dL. For all 

ages combined, the relative risks of mortality 

were 1.24 [95% confidence interval (CI), 

1.05-1.48) for those with blood levels of 

5-9 pg/dL and 1.59 (95% CI, 1.28-1.98) for 

those with blood levels of ? 10 pg/dL (test for 

trend, p < 0.001). For mortality due to cardiovascular disease, there was also a pattern of 

increasing risk with increasing blood lead. For 

all ages combined, the estimated relative risk of 

mortality from cardiovascular disease was 1.20 

(95% CI, 0.93-1.55) for those with blood lead 

levels of 5-9 ,ug/dL and 1.55 (95% CI, 

1.16-2.07) for those with blood lead levels of 

? 10 1g/dL (test for trend, p < 0.01). For all 

ages combined, the estimated relative risk of 

mortality from cancer was 1.44 (95% CI, 

1.12-1.86) for those with blood lead levels of 

5-9 ,ug/dL and 1.69 (95% CI, 1.14-2.52) for 

those with blood lead levels of ? 10 pg/dL (test 

for trend, p < 0.01). 

We further explored the dose-response 

relationship between blood lead concentrations 

and mortality from all causes by modeling the 

proportional hazards using log-transformed 

blood lead levels on a continuous scale with a 

five-knot cubic regression spline. The spline 

analysis results displayed as relative hazards 

using a referent blood lead level of 1.5 ,ug/dL 

(12.5th percentile) and 95% CIs are shown 

graphically in Figure 1. This result is adjusted 

for all covariates included in the final model 

shown in Table 2. The lower bound of the 

95% CI of the relative hazard exceeds unity at 

a blood lead concentration of approximately 

5.5 ,ug/dL. The relative hazard remains < 2 for 

blood lead levels < 10 ,ug/dL. 

Discussion 

In this analysis of mortality among a large 

cohort of adults representative of the U.S. 

population, we found an increased risk of 

death from all causes, cardiovascular disease, 

and cancer associated with elevated blood lead 

levels. Overall, the increase in risk was small; 

however, the increase was observed for blood 

lead levels as low as 5-9 1g/dL. Our finding 

of dose-response relationships between mortality risk and increasing blood lead levels for 

all three classes of death strengthens the conclusion that blood lead levels are associated 

with an increased risk of mortality. 

Previous research has examined mortality 

risk and blood lead levels in the general population of the United States using mortality 

follow-up data for participants 30-74 years 

of age from NHANES II, a study with baseline data collected during 1976-1980 and 

follow-up through 1992 (emal et al. 2002; 

Lustberg and Silbergeld 2002). Lustberg and 

Silbergeld (2002) analyzed data for persons of 

all races and concluded that risk of mortality 

from all causes, circulatory disease, and cancer 

was elevated for persons with blood lead levels 

of 20-29 ,ug/dL compared with those with 

levels < 10 pg/dL. Multivariate-adjusted 

results did not show an increased risk for those 

with blood lead levels of 10-19 pg/dL. In an 

analysis limited to white participants, Jemal 

et al. (2002) found no dose-response relationship between quartiles of blood lead and risk 

of death from cancer, but they did find evidence of a threshold effect for women, with 

risk becoming significantly elevated at a blood 

lead concentration of approximately 24 pg/dL. 

The results of our study showing increased 

mortality at levels as low as 5-9 pg/dL are consistent with other research that suggests health 

effects associated with low levels of lead exposure. Recent cross-sectional analyses of the current, ongoing NHANES, with data from 

1999-2002, suggest an increased risk of peripheral arterial disease, hypertension, and renal dysfunction in a population with blood lead levels 

of approximately 2pg/dL on average (Muntner 

et al. 2005; Navas-Acien et al. 2004). Other 

analyses of population-based studies support 

these results. For example, in the Normative 

Aging Study, blood lead levels < 10 pg/dL were 

associated with renal function and cognitive 

impairment (Kim et al. 1996; Payton et al. 

1994, 1998; Weisskopf et al. 2004; Wright 

et al. 2003). Cross-sectional analyses of the 

NHANES III cohort have shown that blood 

lead levels are related to increased blood pressure (Nash et al. 2003) and decreased renal 

function (Muntner et al. 2003). 

Exposure misclassification is a potentially 

important limitation of our analysis. We classified exposure based on blood lead levels 

2.0 

1.8 

1 .6 

*E1.4\ 

co 

co 1.2 

CD 1.2 i0 77777 

0000tS0 0t0 

~0.8 

0.6 

0.4 

0.2 

0.0I 

1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 

Blood lead (gg/dL) 

Figure 1. Relative risk of all cause mortality for different blood lead levels compared with referent 

level of 1.5 pg/dL (12.5th percentile). The solid line 

shows the fitted five-knot spline relationship; the 

dashed lines are the point-wise upper and lower 

95% Cls. 

Table 2. Multivariate adjusteda relative risks for all-cause, cancer, and cardiovascular disease mortality 

by blood lead level and age category. 

Cause of death/ No. of Relative risk (95% Cl) by age category (years) 

blood lead level deaths 40-74 75-84 > 85 All 

All causes 

< 5 pg/dL 1,402 1 1 1 1 

5-9 pg/dL 828 1.30 (1.03-1.65) 1.38 (1.04-1.83) 0.98 (0.85-1.14) 1.24 (1.05-1.48) 

? 10 pg/dL 255 1.73 (1.28-2.35)b 1.39 (0.93-2.08)c 1.67 (1.11-2.53) 1.59 (1.28-1.98)b 

Cardiovascular disease 

< 5 pg/dL 684 1 1 1 1 

5-9 pg/dL 394 1.11(0.79-1.56) 1.41(0.87-2.28) 1.07 (0.87-1.31) 1.20 (0.93-1.55) 

2 10 pg/dL 111 1.47 (0.93-2.33) 1.71 (0.94-3.09)c 1.45(0.85-2.48) 1.55(1.16-2.07)d 

Cancer 

< 5 pg/dL 282 1 1 1 1 

5-9 pg/dL 194 1.44 (0.91-2.28) 1.46 (1.03-2.07) 1.44 (0.92-2.26) 1.44 (1.12-1.86) 

? 10 pg/dL 67 2.27 (1.38_3.74)d 0.80 (0.38-1.69) 2.2 (1.13-4.29)d 1.69 (1.14-2.52)d 

Cl, confidence interval. 

8Adjusted for sex, race/ethnicity, education, and smoking status. bp-Value for trend test < 0.001. cp-Value for trend test 

< 0.05. dp-Value for trend test < 0.01. 

1540 VOLUME 1141 NUMBER 10 1 October 2006 * Environmental Health Perspectives 

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:38:05 UTC

All use subject to JSTOR Terms and Conditions
Blood lead levels and mortality risk, NHANES Ill 

measured at only one point in time. Most 

(75-95%) lead in the body is found in bone 

(Saltzman et al. 1990), where the half-life is 

5-19 years (Rabinowitz 1991). Therefore, 

measures of bone lead indicate cumulative, 

long-term exposure and are the best measure to 

study chronic effects. The half-life of lead in 

blood is approximately 1 month (Rabinowitz 

et al. 1976); thus blood levels are related to 

current exposure. Lead is released from bone 

through resorption, such as occurs with aging, 

and this contributes to levels found in blood 

(Hu et al. 1998; Smith et al. 1996). Older persons in the NHANES III cohort were more 

likely to have higher cumulative lead exposure, 

and their blood lead levels may be disproportionately influenced by release of lead from 

bone stores compared with younger persons. 

That our results show an increased risk of 

mortality at lower blood lead levels than the 

mortality studies of the NHANES II cohort 

may be related to exposure classification being 

based on a single blood lead measurement. 

Blood lead levels of NHANES III participants 

were close to 80% lower than in the NHANES 

II cohort, and few adults had blood lead levels 

> 20 pg/dL (CDC 1997; Pirkle et al. 1994). 

This reflects reductions in the current exposure 

of the study participants because of the elimination of lead from gasoline and other environmental sources. We speculate that the 

difference in cumulative lead exposure among 

adults across the two surveys is relatively 

smaller than the difference in current exposure. 

For example, it is likely that within the same 

birth cohort, most persons who had blood lead 

levels > 20 ng/dL in 1976-1980 would have 

levels < 10 pg/dL in 1988-1994. The particularly dramatic decrease in blood levels that 

occurred during the NHANES II (Annest 

et al. 1983) makes the evaluation of a doseresponse relationship of blood lead level and 

mortality even more problematic and may 

explain why the previous analyses of NHANES 

II Uemal et al. 2002; Lustberg and Silbergeld 

2002) did not find as strong a dose effect as in 

our present analyses of NHANES III, which 

had more stable blood lead levels. 

It is not possible to differentiate an acute 

effect of lead in blood from a chronic effect in 

studies that only use blood lead levels to indicate exposure (Hu et al. 1998). With advances 

in measuring bone lead through X-ray fluorescence, several studies have evaluated the association of health effects with both bone and 

blood lead measures. Both cross-sectional and 

longitudinal analyses of the Normative Aging 

Study suggest that cumulative exposure, as well 

as current exposure, to lead is associated with 

declines in renal function (Kim et al. 1996; 

Payton et al. 1994) and cognition (Payton 

et al. 1998; Weisskopf et al. 2004; Wright 

et al. 2003). Results from the Normative Aging 

Study suggest that cumulative but not current 

exposure is associated with an increased risk of 

hypertension (Tsaih et al. 2004); however, in a 

longitudinal study of a cohort who had previous occupational exposure, Glenn et al. (2003) 

concluded that the effect of lead on blood pressure is consistent with both acute and chronic 

modes of action. 

From the present study we conclude that 

mortality is associated with lead exposure as 

indicated by a single blood lead measurement 

typical for the U.S. adult population during 

1988-1994. Extrapolating from this to mortality risk related to cumulative lead exposure 

or blood lead measurements from different 

calendar periods can only be speculative. The 

blood lead and mortality relationship that we 

observed may be due to lead being a surrogate 

for some other factor that is associated with 

an increase in mortality. For example, socioeconomic status may not be sufficiently controlled for by measures of education level or 

family income. However, we adjusted for 

well-know confounders without observing a 

substantial reduction in the blood lead 

relationship. Also, the observed relationships 

for each category of mortality were fairly consistent across age and groups. 

The major strengths of our study, that the 

NHANES cohort is representative of the U.S. 

population and that the sample size is large 

enough to evaluate small differences in risk, 

are notable. Our analysis adds to the body of 

evidence demonstrating adverse health consequences related to blood lead levels that fall 

below current levels of concern. Further 

research is needed to assess cumulativexposure and adverse health consequences, including mortality, for persons who were not 

exposed to high levels of lead in the environment that were typical before lead was 

removed from gasoline in the late 1970s. 

REFERENCES 

Annest JL, Pirkle JL, Makuc D, Neese JW, Bayse DD, 

Kovar MG. 1983. Chronological trend in blood lead levels 

between 1976 and 1980. N EngI J Med 308:1373-1377. 

ATSDR. 1999. Toxicological Profile for Lead. Atlanta, GA:Agency 

for Toxic Substances and Disease Registry. 

CDC (Centers for Disease Control and Prevention). 1994. Plan 

and Operation of the Third National Health and Nutrition 

Examination Survey, 1988-94. Vital Health Stat 1(32). 

Available: http://www.cdc.gov/nchs/data/series/sr-O1/ 

srOl_032.pdf [accessed 21 August 20061. 

CDC (Centers for Disease Control and Prevention). 1997. Update: 

blood lead levels-United States, 1991-1994. MMWR Morb 

Mortal Wkly Rep 46:141-146. 

Cheng Y, Schwartz J, Sparrow D, Aro A, Weiss ST, Hu H. 2001. 

Bone lead and blood lead levels in relation to baseline 

blood pressure and the prospective development of hypertension. The Normative Aging Study. Am J Epidemiol 

153:164-171. 

Durrleman S, Simon R. 1989. Flexible regression models with 

cubic splines. Stat Med 8:551-561. 

Glenn BS, Stewart WF, Links JM, Todd AC, Schwartz BS. 2003. 

The longitudinal association of lead with blood pressure. 

Epidemiology 14:30-36. 

Hertz-Picciotto I,Croft J. 1992. Review of the relation between 

blood lead and blood pressure. Epidemiol Rev 15:352-373. 

Hu H, Aro A, Payton M, Korrick S, Sparrow D, Weiss ST, et al. 

1996. The relationship of bone and blood lead to hypertension. The Normative Aging Study. JAMA 275:1171-1179. 

Hu H, Rabinowitz M, Smith D. 1998. Bone lead as a biological 

marker in epidemiologic studies of chronic toxicity: conceptual paradigms. Environ Health Perspect 106:1-8. 

Jemal A, Graubard BI, Devesa SS, Flegal KM. 2002. The association of blood lead level and cancer mortality among whites 

in the United States. Environ Health Perspect 110:325-329. 

Kim R, Rotinsky A, Sparrow D, Weiss S, Wager C, Hu H. 1996. A 

longitudinal study of low-level lead exposure and impairment of renal function. The Normative Aging Study. JAMA 

275:1177-1181. 

Korn EL, Graubard BI, Midthune D. 1997. Time-to-event analysis 

of longitudinal follow-up of a survey: choice of the timescale. Am J Epidemiol 145:72-80. 

Lustberg M, Silbergeld E. 2002. Blood lead levels and mortality. 

Arch Intern Med 162:2443-2449. 

Moller L, Kristensen TS. 1992. Blood lead as a cardiovascular 

risk factor. Am J Epidemiol 136:1091-1100. 

Muntner P, He J, Vupputuri S, Coresh J, Batuman V. 2003. Blood 

lead and chronic kidney disease in the general United States 

population: resuits from NHANES Ill. Kidney Int 63:1044-1050. 

Muntner P, Menke A, DeSalvo KB, Rabito FA, Batuman V. 2005. 

Continued decline in blood lead levels among adults in the 

United States: the National Health and Nutrition 

Examination Surveys. Arch Intern Med 165:2155-2161. 

Nash D, Magder L, Lustberg M, Sherwin RW, Rubin RJ, 

Kaufmann RB, et al. 2003. Blood lead, blood pressure, and 

hypertension in perimenopausal and postmenopausal 

women. JAMA 289:1523-1532. 

Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, 

Silbergeld E, Guallar E. 2004. Lead, cadmium, smoking, and 

increased risk of peripheral arterial disease. Circulation 

109:3196-3201. 

NCHS (National Center for Health Statistics). 2006. NHANES Ill 

Linked Mortality File. Available: http://www.cdc.gov/nchs/ 

r&d/nchs_datalinkage/nhanes-data-linkage-activities.htm 

[accessed 30 January 20061. 

NTP. Report on Carcinogens, Eleventh Edition. 2005. Research 

Triangle Park, NC:National Toxicology Program. Available: 

http://ntp.niehs.nih.gov/ntpfroc/toc1l.html [accessed 

20 October 20051. 

Payton M, Hu H, Sparrow D, Weiss ST. 1994. Low-level lead 

exposure and renal function in the Normative Aging Study. 

Am J Epidemiol 140:821-829. 

Payton M, Riggs, KM, Spiro A, Weiss ST, Hu H. 1998. Relations 

of bone and blood lead to cognitive function: the VA 

Normative Aging Study. Neurotoxicol Teratol 20:19-27. 

Pirkle JL, Brody DJ, Gunter EW, Kramer RA, Paschal DC, 

Flegal KM, et al. 1994. The decline in blood lead levels in 

the United States. The National Health and Nutrition 

Examination Surveys (NHANES). JAMA 272:284-291. 

Rabinowitz MB. 1991. Toxicokinetics of bone lead. Environ 

Health Perspect 91:33-37. 

Rabinowitz MB, Wetherill GW, Kopple JD. 1976. Kinetic analysis of lead metabolism in healthy humans. J Clin Invest 

58:260-270. 

Saltzman BE, Gross SB, Yeager OW, Meiners BG, Gartside PS. 

1990. Total body burdens and tissue concentrations of lead, 

cadmium, copper, zinc, and ash in 55 human cadavers. 

Environ Res 52:126-145 

Smith DR, Osterloh JD, Flegal AR. 1996. Use of endogenous, 

stable lead isotopes to determine release of lead from the 

skeleton. Environ Health Perspect 104:60-66. 

Staessen JA, Lauwerys RR, Buchet J-P, Bulpitt CJ, Rondia D, 

Vanrenterghem Y, et al. 1992. Impairment of renal function 

with increasing blood lead concentrations in the general 

population. N Engl J Med 327:151-156. 

Tsaih S-W, Korrick S, Schwartz J, Amarasiriwardena C, Aro A, 

Sparrow D, et al. 2004. Lead, diabetes, hypertension, and 

renal function: The Normative Aging Study. Environ Health 

Perspect 112:1178-1182. 

U.S. Census Bureau 2006. Census Bureau Regions and Divisions 

with State FIPS Codes. Available: http://www.census.gov/ 

geo/www/reg.div.txt [accessed 21 August 2006]. 

Weisskopf MG, Wright RO, Schwartz J, Spiro A Ill, Sparrow D, 

Aro A, et al. 2004. Cumulative lead exposure and prospective change in cognition among elderly men: the VA 

Normative Aging Study. Am J Epidemiol 160:1184-1193. 

Wright RO, Tsaih SW, Schwartz J, Spiro A Ill, McDonald K, 

Weiss ST, et al. 2003. Lead exposure biomarkers and minimental status exam scores in older men. Epidemiology 

14:713-7 18. 

Environmental Health Perspectives - VOLUME 1141 NUMBER 10 I October 2006 1 541 

This content downloaded from 130.111.46.54 on Mon, 28 Sep 2015 14:38:05 UTC

All use subject to JSTOR Terms and Conditions