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CHAPTER 6 POTENTIALLY AT-RISK 

POPULATIONS 

1 The NAAQS are intended to provide an adequate margin of safety for both the population 

2 as a whole and those groups with unique factors that make them potentially at increased 

3 risk for health effects in response to ambient air pollutants (Preface to this ISA). 

4 Interindividual variation in human responses to air pollution exposure suggests that some 

5 populations are at increased risk for detrimental effects of ambient exposure to an air 

6 pollutant. To facilitate the identification of populations at greater risk for Pb-related 

7 health effects, studies have evaluated various factors that may contribute to susceptibility 

8 and/or vulnerability to Pb. The definitions of susceptibility and vulnerability vary across 

9 studies, but in most instances “susceptibility” refers to biological or intrinsic factors 

10 (e.g., age, sex) while “vulnerability” refers to nonbiological or extrinsic factors 

11 (e.g., socioeconomic status [SES]) (U.S. EPA, 2010a, 2009). Additionally, in some cases, 

12 the terms “at-risk” and “sensitive” populations have been used to encompass these 

13 concepts more generally. In this ISA, “at-risk” groups are defined as those with 

14 characteristics that increase the risk of Pb-related health effects in a population. These 

15 characteristics include various factors, such as genetic background, race and ethnicity, 

16 sex, age, diet, pre-existing disease, SES, and characteristics that may modify exposure or 

17 the response to Pb.

18 To examine whether Pb differentially affects certain populations, epidemiologic studies 

19 conduct stratified analyses to identify the presence or absence of effect measure 

20 modification. A thorough evaluation of potential effect measure modifiers may help 

21 identify populations that are at greater risk for Pb-related health effects. Toxicological 

22 studies, using animal disease models, also provide support and biological plausibility for 

23 factors that may lead to increased risk for Pb-related health effects. These epidemiologic 

24 and toxicological studies provide the scientific basis for an overall weight of the evidence 

25 evaluation for the increased risk of specific populations to Pb-related health effects. 

26 The first section of this chapter summarizes physiological factors that possibly influence 

27 Pb levels in the body. The second section of this chapter summarizes information on 

28 factors potentially related to differential Pb exposure. The studies presented in this 

29 section supplement the material provided in Chapters 3 and 4 by examining how factors 

30 such as age, sex, race and ethnicity, SES, proximity to Pb sources, and residential factors 

31 may affect Pb exposure. The third section of this chapter discusses the epidemiologic and 

32 toxicological studies evaluated in Chapter 5 that provide information on potential factors 

33 related to increased risk of Pb-induced health effects. Highlighted studies include only 

34 those where the population was stratified into subgroups (e.g., males versus females or 
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1 smokers versus nonsmokers) for comparative analysis. In the case of many biomarker 

2 studies and the epidemiologic studies considered, this approach allowed for a comparison 

3 between populations exposed to similar Pb concentrations and within the same study 

4 design. Numerous studies that focused on only one potentially at-risk population were 

5 described in previous chapters (Chapter 5) but are not discussed in detail in this chapter 

6 because they lacked stratified analysis with adequate comparison groups. For example, 

7 pregnancy is a lifestage with potentially increased risk for mothers and fetuses, but 

8 because there are no comparison groups for stratified analyses, these studies were 

9 presented in Chapter 5 but are not included here. Included toxicological studies may have 

10 categorized the study populations by age, sex, diet/nutrition status, genetics, etc. or are 

11 those that examined animal models of disease.

12 Additionally, it is understood that some of the stratified variables/factors discussed in this 

13 third section may not be effect measure modifiers but instead may be mediators of Pb14 related health effects. Mediators are factors that fall on the causal pathway between Pb 

15 and health outcomes, whereas effect measure modifiers are factors that result in changes 

16 in the measured associations between Pb and health effects. Because mediators are 

17 caused by Pb exposure and are also intermediates in the disease pathway that is studied, 

18 mediators are not correctly termed “at-risk” factors. Some of the factors discussed in this 

19 third section could be mediators and/or modifiers. These are noted in Table 6-4.

6.1 Physiological Factors that Influence the Internal Distribution 

of Lead

20 Blood and bone Pb measures are influenced to varying degrees by biokinetic processes 

21 (absorption, distribution, metabolism, etc.), which are discussed in detail in 0. These 

22 processes can be affected by multiple factors, such as age, genetics, diet, and co-exposure 

23 with other metals and non-metals. 

24 Age influences the biokinetic response to Pb within the body. Infants may be an at-risk 

25 population because Pb easily crosses the placental barrier and accumulates in fetal tissue 

26 during gestation (Pillai et al., 2009; Wang et al., 2009e; Uzbekov et al., 2007). This 

27 transfer of Pb from mother to fetus is partly due to the remobilization of the mother’s 

28 bone stores (O'Flaherty, 1998; Franklin et al., 1997). This also results in increased 

29 maternal blood Pb levels (Lamadrid-Figueroa et al., 2006; Gulson et al., 2004a; Hertz30 Picciotto et al., 2000; Gulson et al., 1997; Lagerkvist et al., 1996; Schuhmacher et al., 

31 1996; Rothenberg et al., 1994a). Bone growth rate is high during childhood. The majority 

32 of a child’s Pb body burden is not permanently incorporated in the bone, but some Pb 

33 does remain in the bone until older age (McNeill et al., 2000; O'Flaherty, 1995; Leggett, 
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1 1993). Older adults are more likely to have age-related degeneration of bones and organ 

2 systems and a possible redistribution of Pb stored in the bones into the blood stream

3 (Popovic et al., 2005; Garrido Latorre et al., 2003; Gulson et al., 2002).

4 Various genes can also affect Pb biomarker concentrations. Genetic variants of the 

5 vitamin D receptor (VDR) in humans have been associated with varied bone and plasma 

6 Pb levels (Rezende et al., 2008; Theppeang et al., 2004; Schwartz et al., 2000a). Multiple 

7 studies have also examined the association between the aminolevulinate dehydratase 

8 (ALAD) polymorphism and blood Pb levels and found that the ALAD-2 polymorphism 

9 may be biologically related to varying Pb levels, although some studies report no 

10 difference for ALAD alleles (Miyaki et al., 2009; Shaik and Jamil, 2009; Sobin et al., 

11 2009; Chen et al., 2008c; Rabstein et al., 2008; Scinicariello et al., 2007; Zhao et al., 

12 2007; Montenegro et al., 2006; Wananukul et al., 2006).

13 It is well established that diets sufficient in minerals such as calcium, iron, and zinc offer 

14 some protection from Pb exposure by preventing or competing with Pb for absorption in 

15 the GI tract. A study in China reported that children who regularly consumed breakfast 

16 had lower blood Pb levels than those children that did not eat breakfast (Liu et al., 

17 2011b). Diets designed to limit or reduce caloric intake and induce weight loss have been 

18 associated with increased blood Pb levels in adult animals (Han et al., 1999). A 

19 toxicological study reported negative effects of Pb on osmotic fragility, TBARS 

20 production, catalase activity, and other oxidative parameters, but most of these effects 

21 were reduced to the levels observed in the control group when the rats were given 

22 supplementation of zinc and vitamins (Massó-González and Antonio-García, 2009).

23 Toxicological studies by Jamieson et al. (2008; 2006) also reported that a zinc-deficient 

24 diet increases bone and renal Pb content and impairs skeletal growth and mineralization. 

25 A zinc-supplemented diet attenuated bone and renal Pb content. Toxicological studies 

26 have shown that dietary deficiency of calcium induces increased Pb absorption and 

27 retention (Fullmer, 1992; Mykkanen and Wasserman, 1981; Six and Goyer, 1970).

28 Increased calcium intake reduces accumulation of Pb in bone and mobilization of Pb 

29 during pregnancy and lactation (Bogden et al., 1995). Additionally, studies have reported 

30 that iron deficiencies may result in higher Pb absorption or altered biokinetics (Schell et 

31 al., 2004; Marcus and Schwartz, 1987; Mahaffey and Annest, 1986).

32 Finally, co-exposures with other metals and non-metals have also been studied to assess 

33 how they affected the uptake and absorption of Pb. Recent toxicological studies 

34 examined the addition of arsenic (As) to Pb and cadmium (Cd) mixtures, and reported 

35 increased bioavailability of Pb (Wang and Fowler, 2008). A toxicological study by 

36 Sawan et al. (2010) reported co-exposure with fluoride increased Pb deposition in 

37 calcified tissues. 
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1 In summary, age, genetics, diet, and other exposures affect the biokinetics of Pb, which in 

2 turn affects the internal distribution of Pb. These factors were discussed in greater detail 

3 in 0 where more information on overall biokinetics and physiological factors affecting Pb 

4 distribution was provided. 

6.2 Population Characteristics Potentially Related to Differential 

Lead Exposure

5 Elevated or differential Pb exposure and related biomarker levels (such as blood Pb), 

6 have been shown to be statistically related to several population characteristics, including 

7 age, sex, race and ethnicity, SES, proximity to Pb sources, and residential factors (U.S. 

8 EPA, 2006b). In most cases, exposure, absorption, and biokinetics of Pb are all 

9 influenced to varying degrees by such characteristics. Additionally, the relative 

10 importance of population characteristics on exposure, absorption, and biokinetics varies 

11 on an individual basis and is difficult to quantify. This section presents recent studies 

12 demonstrating a relationship between each population characteristic and exposure status. 

13 The studies presented in this section build upon the current body of literature suggesting 

14 that population characteristics differentially influence Pb exposure; the new literature 

15 does not alter our previous understanding of the differential influence of population 

16 characteristics on Pb exposure. Differential response to given Pb exposures is discussed 

17 in Section 6.3.

6.2.1 Age

6.2.1.1 Early Childhood

18 Typically, children have increased exposure to Pb compared with adults because 

19 children’s behaviors and activities include increased hand-to-mouth contact, crawling, 

20 and poor hand-washing that typically result in increased ingestion compared with adults

21 (U.S. EPA, 2006b). Children can also be susceptible to Pb exposure because outdoor play 

22 can lead to hand-to-mouth contact with contaminated soil. For example, Zahran et al.

23 (2010) observed that a 1% reduction in soil Pb concentration led to a 1.55 μg/dL 

24 reduction in median blood Pb levels (p <0.05) among New Orleans children. 

25 Age of the children may influence blood Pb levels through a combination of behavioral 

26 and biokinetic factors. The 2007-2008 NHANES data are presented in Table 6-1 by age 

27 and sex. Among children, highest blood Pb levels occurred in the 1-5 year age group 
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1 (children under age 1 were not included), and within this subgroup (not shown on the 

2 table), 1 year old children had the highest blood Pb levels (99th percentile: 16.9 μg/dL). It 

3 is possible that high blood Pb levels among these young children may also be related to in 

4 utero exposures resulting from maternal Pb remobilization from bone stores from historic 

5 exposures (Miranda et al., 2010) or from contemporaneous Pb exposures if the mothers 

6 were located near sources. Jones et al. (2009a) analyzed the NHANES datasets for the 

7 years 1999-2004 to study trends in blood Pb among two different age groups of children 

8 over time (see Table 6-2). They observed greater percentages of children aged 1-2 years 

9 having blood Pb levels of 2.5 to <5 μg/dL, 5 to <7.5 μg/dL, and ≥ 10 μg/dL, compared 

10 with 3-5 year-old children, but no age difference was noted for the 7.5 to <10 μg/dL 

11 bracket. These distribution differences may be attributable to differences in exposure, 

12 age-dependent variability in biokinetics or diet (e.g., milk versus solid diets). Yapici et al.

13 (2006) studied the relationship between blood Pb level and age among a cohort of 

14 children younger than 73 months living in proximity to a Turkish coal mine. They 

15 observed a low but statistically significant negative correlation between blood Pb and age 

16 (r = -0.38, p <0.001). 

Table 6-1 Blood Pb levels by age and sex, 2007-2008 NHANES

Age Sex N Avg. Std. Dev. 5% 25% 50% 75% 95% 99%

1-5 yr Total 811 2.03 2.01 0.69 1.08 1.54 2.34 4.50 10.60

Male 440 2.01 2.14 0.71 1.10 1.50 2.40 4.21 8.56

Female 371 2.05 1.85 0.66 1.02 1.60 2.28 4.65 10.70

6-11 yr Total 1,002 1.27 0.87 0.49 0.75 1.06 1.50 2.84 4.80

Male 500 1.29 0.92 0.48 0.74 1.08 1.50 2.90 4.76

Female 502 1.25 0.83 0.50 0.78 1.03 1.49 2.80 4.80

12-19 yr Total 1,089 0.99 0.73 0.40 0.59 0.81 1.13 2.11 4.00

Male 586 1.13 0.82 0.44 0.69 0.94 1.30 2.41 4.11

Female 503 0.83 0.57 0.37 0.52 0.69 0.91 1.70 3.36

20-64 yr Total 4,278 1.76 1.57 0.53 0.91 1.40 2.10 4.20 7.42

Male 2,079 2.13 1.93 0.68 1.12 1.65 2.49 5.22 9.07

Female 2,199 1.41 1.01 0.47 0.78 1.13 1.73 3.13 5.10

65+ yr Total 1,086 2.31 1.64 0.80 1.30 1.90 2.70 5.22 8.54

Male 542 2.63 1.66 0.99 1.52 2.19 3.20 5.86 9.03

Female 544 1.98 1.56 0.75 1.17 1.62 2.40 4.14 6.95
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Age Sex N Avg. Std. Dev. 5% 25% 50% 75% 95% 99%

Overall Total 8,266 1.70 1.53 0.51 0.86 1.30 2.04 4.10 7.20

Male 4,147 1.94 1.77 0.58 0.99 1.5 2.3 4.72 8.69

Female 4,119 1.45 1.19 0.46 0.76 1.14 1.78 3.35 5.77

Source: (NCHS, 2010).

Table 6-2 Percentage of children within six categories/brackets of blood Pb 

levels, 1999-2004 NHANES

Pb Units: 

μg/dL 

(95% CI)

n Geometric 

mean <1 μg/dL, % 1 to <2.5 μg/dL, %

2.5 to <5 

μg/dL, %

5 to <7.5 

μg/dL, %

7.5 to <10 

μg/dL, %

≥ 10 

μg/dL, %

Overall 2,532 1.9 (1.8-2.0) 14.0 (11.6-16.6) 55.0 (52.1-57.9) 23.6 (21.1-26.1) 4.5 (3.3-5.9) 1.5 (1.0-2.1) 1.4 (1.0-2.0)

Sex

Female 1,211 1.9 (1.7-2.0) 14.1 (10.8-17.7) 54.5 (51.1-57.8) 23.9 (20.3-27.8) 4.5 (3.3-5.8) 1.4 (0.8-2.3) 1.7 (0.9-2.6)

Male 1,321 1.9 (1.7-2.0) 14.0 (11.4-16.7) 55.5 (51.4-59.5) 23.2 20.3-26.3) 4.6 (3.0-6.5) 1.5 (0.9-2.3) 1.3 (0.7-2.6)

Age

1-2 yr 1,231 2.1 (2.0-2.2) 10.6 (7.7-13.9) 51.0 (46.7-55.3) 27.9 (24.9-31.0) 6.7 (5.0-8.6) 1.4 (0.8-2.2) 2.4 (1.4-3.5)

3-5 yr 1,301 1.7 (1.6-1.9) 16.2 (12.9-19.9) 57.6 (53.8-61.4) 20.7 (17.9-23.7) 3.1 (1.9-4.6) 1.5 (0.8-2.3) 0.9 (0.4-1.5)

Race/Ethnicityc

Non-Hispanic 

Black

755 2.8 (2.5-3.0) 4.0 (2.5-5.7) 42.5 (37.8-47.2) 36.2 (33.1-39.3) 9.4 (6.9-12.2) 4.6 (3.0-6.5) 3.4 (1.8-5.5)

Mexican 

American

812 1.9 (1.7-2.0) 10.9 (8.6-13.4) 61.0 (56.9-65.1) 22.1 (18.0-26.5) 3.4 (2.2-5.0) 1.3 (0.6-2.2) 1.2 (0.4-2.6)

Non-Hispanic 

White

731 1.7 (1.6-1.8) 17.6 (14.0-21.5) 57.1 (52.4-61.7) 19.7 (16.1-23.5) 3.6 (1.9-5.8) 0.8 (0.3-1.6) 1.2 (0.6-2.0)

Poverty-Income Ratio (PIR)c

≤ 1.3 1,302 2.4 (2.2-2.5) 6.7 (4.6-9.2) 49.3 (44.9-53.7) 32.5 (28.6-36.4) 6.9 (2.2-8.8) 2.8 (1.7-4.1) 1.8 (1.1-2.7)

>1.3 1,070 1.5 (1.4-1.6) 19.9 (16.3-23.8) 60.4 (56.9-63.8) 16.0 (12.9-19.3) 2.3 (1.2-3.7) 0.6 (0.1-1.4) 0.8 (0.3-1.6)

Source: Reprinted with permission of the American Acedemy of Pediatrics; Jones et al. (2009a)

1 Fetal and child Pb biomarkers have been demonstrated to relate to maternal Pb 

2 biomarkers; several older studies in the literature were presented in the 2006 Pb AQCD

3 (U.S. EPA, 2006b). Kordas et al. (2010) observed that maternal hair Pb concentration 

4 was a statistically significant predictor of child hair Pb concentration (β = 0.37 ± 0.07, 

5 p < 0.01). Miranda et al. (2010) observed that pregnant women (ages 30-34 years and 35-

6 39 years) had statistically significant higher odds of having greater blood Pb levels than 

7 younger pregnant women in the (25- to 29-year-olds) reference age category. These 

8 results could be related to a historical component to Pb exposure among mothers. These 

9 findings were also consistent with observations that Pb storage in bones increased with 

10 age before subsequent release with bone loss occurring during pregnancy, as described in 

11 Section 4.2 and summarized in Section 6.1. Elevated blood Pb levels among mothers 
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1 present a potential exposure route to their children in utero or through breast milk. 

2 Additionally, maternal pica presents a potential Pb source to a developing fetus

3 (Hamilton et al., 2001).

6.2.1.2 Adulthood

4 Blood Pb levels tend to be higher in older adults compared with the general adult 

5 population (U.S. EPA, 2006b). Table 6-1 presents 2007-2008 NHANES data broken 

6 down by age group and shows that blood Pb levels were highest in the 65+years age 

7 group in comparison with adults aged 20-64 years. In a study of blood Pb and saliva Pb in 

8 a mostly female population in Detroit, Nriagu et al. (2006) found that age was a 

9 statistically significant positive predictor of blood Pb (p < 0.001). Average blood Pb 

10 levels among 14- to 24-year-old subjects was 2.60 ± 0.16 μg/dL compared with 4.29 ± 

11 0.56 μg/dL among subjects aged 55 years or older. Higher average and median levels 

12 among older adults could potentially be due to a shared experience of higher historical Pb 

13 exposures stored in bone in conjunction with remobilization of stored Pb during bone loss 

14 (Section 4.2).

15 Theppeang et al. (2008b) studied Pb concentrations in the blood, tibia, and patella of 

16 subjects age 50-70 as part of the Baltimore Memory Study. They found a statistically 

17 significant relationship between age and tibia Pb (β = 0.37, p <0.01 in a model including 

18 age, race/ethnicity, Yale energy index, and 2 diet variables; β = 0.57, p <0.01 in a model 

19 including age, sex, and an interaction term for sex and age, which was also statistically 

20 significant at p = 0.03). Theppeang et al. (2008b) also noted that patella Pb 

21 concentrations increased with age, although the data quality for patella Pb was not as 

22 high, so the authors did not present the data or significance levels. A statistically 

23 significant relationship was not observed between the log-transform of blood Pb and age 

24 (β = 0.007, p = 0.11), although the age range of subjects may not have been sufficient to 

25 discern a difference in blood Pb level.

6.2.2 Sex

26 Several studies have suggested that sex influences levels of Pb biomarkers because 

27 differences in behavior between sexes may cause a differential increase in exposure. The 

28 2007-2008 NHANES showed that overall, males have significantly higher blood Pb 

29 levels (average: 1.94 μg/dL) than females (average: 1.45 μg/dL) (p < 0.0001). Among 

30 adults aged 20-64 years, average blood Pb levels were 51% higher for males compared 

31 with females (p < 0.0001). Among adults 65 years or older, average blood Pb levels were 
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1 33% higher for males compared with females (p < 0.0001). In their study of Pb burden 

2 among Baltimore adults aged 50-70 years, Theppeang et al. (2008b) observed that 

3 average blood Pb levels were statistically significantly higher (p <0.01) among men 

4 (4.4 μg/dL) than women (3.1 μg/dL). For average tibia Pb levels, Theppeang et al.

5 (2008b) noted no difference (p = 0.12) between men (18.0 μg/g) and women (19.4 μg/g). 

6 Among U.S. children, the 2007-2008 NHANES data showed that blood Pb levels were 

7 higher among girls than boys for the 1- to 5-years age group (Table 6-1). Blood Pb levels 

8 became slightly higher among boys for the 6- to 11-years age group, and levels were 

9 substantially higher among adolescent males than females in the 12- to 19-years age 

10 group. At the same time, blood Pb levels among both adolescent males and females were 

11 lower than blood Pb levels for the other age groups. The 2007-2008 NHANES data 

12 suggest that sex-based differences in blood Pb levels are not substantial until 

13 adolescence.

6.2.3 Race and Ethnicity

14 Higher blood Pb and bone Pb levels among African Americans has been well 

15 documented (U.S. EPA, 2006b). Recent studies are consistent with those previous 

16 findings. For instance, Levin et al. (2008) and Jones et al. (2009a) both analyzed 

17 NHANES survey data to examine trends in childhood blood Pb levels. Data from the 

18 Jones et al. (2009a) study, using NHANES data (NCHS, 2010) from 1988-1991 and 

19 1999-2004 are shown in Figure 6-1. The authors found that differences among children 

20 from different racial/ethnic groups with regard to the percentage with blood Pb levels ≥ 

21 2.5 μg/dL over the period 1999-2004 have decreased since the period of 1988-1991 . The 

22 non-Hispanic black group still had higher percentages with blood Pb levels ≥ 2.5 μg/dL 

23 compared with non-Hispanic whites and Mexican Americans, with large observable 

24 differences for blood Pb levels between 2.5 and <10 μg/dL. It is notable that the 

25 distributions of blood Pb levels among Mexican American and non-Hispanic white 

26 children were nearly identical in the 1999-2004 dataset. Theppeang et al. (2008b) also 

27 explored the effect of race and ethnicity on several Pb biomarkers in a study of older 

28 adults living in Baltimore, MD. They observed a statistically significant difference 

29 between African American (AA) and Caucasian (C) subjects with respect to tibia Pb 

30 (AA: 21.8 μg/g, C: 16.7 μg/g, p <0.01) but not patella Pb (AA: 7.1 μg/g, C: 7.1 μg/g, p = 

31 0.46) or blood Pb levels (AA: 3.6 μg/dL, C: 3.6 μg/dL, p = 0.69). Greater tibia (but lower 

32 patella) Pb levels may indicate greater historical exposure among African Americans 

33 compared to Caucasians in the Baltimore population studied by Theppeang et al. (2008b).
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Data used with permission of the American Academy of Pediatrics, Jones et al. (2009a)

Note: from the NHANES survey, 1988-1991 (top) and 1999-2004 (bottom).

Figure 6-1 Percent distribution of blood Pb levels by race/ethnicity among 

U.S. children (1-5 years).

1 Differences in exposure among ethnic and racial groups have also been noted. In a study 

2 of three parishes in the greater metropolitan New Orleans area, Campanella and Mielke

3 (2008) found that, where soil Pb levels were less than 20 mg/kg, the population was 36% 

4 black, 55% white, 3.0% Asian, and 6.0% Hispanic, based on the 2000 Census, with the 

5 percentage based on the total number living in Census blocks with the same soil Pb 

6 levels. In contrast, they found that for Census blocks in which soil Pb levels were 

7 between 1,000 and 5,000 mg/kg, the population was 62% black, 34% white, 1% Asian, 

0

10

20

30

40

50

60

70

< 1 1 - < 2.5 2.5 - < 5 5 - < 7.5 7.5 - <10 ≥ 10

Percent of Children

1988-1991

0

10

20

30

40

50

60

70

< 1 1 - < 2.5 2.5 - < 5 5 - < 7.5 7.5 - <10 ≥ 10

Percent of Children

Blood Pb Level (ug/dL)

Non-Hispanic black Mexican American Non-Hispanic white

1999 - 2004
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1 and 4% Hispanic (Figure 6-2). As described in Section 6.2.4, the differences observed by 

2 Campanella and Mielke (2008) may also be attributable to SES factors, or SES may be a 

3 confounding factor in the relationship between Pb soil levels and race/ethnicity of nearby 

4 residents.

Source: Data used with permission of Springer Science; Campanella and Mielke (2008).

Note: By Census 2000 race/ethnicity demographic groups.

Figure 6-2 Soil Pb concentration exposure among the population of three 

parishes within greater metropolitan New Orleans.

6.2.4 Socioeconomic Status (SES)

5 Socioeconomic factors have sometimes been associated with Pb exposure biomarkers, 

6 although these relationships have not always been consistent (U.S. EPA, 2006b). Nriagu 

7 et al. (2006) performed a multiple regression analysis of blood Pb and saliva Pb levels on 

8 various socioeconomic, demographic, and exposure variables among an adult population 

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

50,000

Population

Soil Pb Concentration (mg/kg)

Black

White

Asian

Hispanic
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1 in Detroit, Michigan. Blood and saliva Pb were both used as indicators of Pb in unbound 

2 plasma that is available to organs. Nriagu et al. (2006) found that education (p <0.001), 

3 income (p <0.001), and employment status (p = 0.04) were all statistically significant 

4 predictors of blood Pb levels, with blood Pb decreasing with some scatter as education 

5 and income level increased. Statistically significant relationships were also reported by 

6 Nriagu et al. (2006) for saliva Pb level with respect to education (p <0.001), income (p 

7 <0.001), and employment (p = 0.06). However, the highest educational attainment and 

8 income categories had higher saliva Pb levels compared with other groups; Nriagu et al.

9 (2006) attributed these inconsistencies to small sample sizes among the high educational 

10 attainment and income categories.

11 On a national level, the gap between income levels with respect to blood Pb has been 

12 decreasing. For example, Levin et al. (2008) cited 1991-1994 NHANES data [analyzed in 

13 Pirkle et al. (1994)] that the percentage of children aged 1-5 years with blood Pb levels ≥ 

14 10 μg/dL was 4.5% for the lowest income group compared with 0.7% for the highest 

15 income group. Levin et al. (2008) also analyzed data from the 1999-2002 NHANES and 

16 found no statistically significant difference between the percent of children with blood Pb 

17 levels above 10 μg/dL for Medicaid-enrolled children (1.7%) compared with 

18 non-enrolled children (1.3%). However, Medicaid-enrolled children did have higher 

19 median blood Pb levels (2.6 μg/dL) compared to children not enrolled in Medicaid (1.7 

20 μg/dL). When adding data for 2003-2004 to the analysis (i.e., for 1999-2004), the gap 

21 between Medicaid enrolled and non-enrolled children widened for blood Pb levels ≥ 10 

22 μg/dL (1.9% versus 1.1%), but the difference was still not statistically significant (p > 

23 0.05). Median blood Pb levels with respect to Medicaid status did not change when 

24 adding the 2003-2004 data (Levin et al., 2008). Likewise, Jones et al. (2009a) analyzed 

25 blood Pb levels with respect to poverty-income ratio (PIR), which is the ratio of family 

26 income to the poverty threshold appropriate for a given family size. They found 

27 statistically significant differences in median blood Pb for PIR ≤ 1.3 compared with PIR 

28 >1.3. The percentage of 1- to 5-year-old children having blood Pb ≥ 10 μg/dL was higher 

29 for PIR ≤ 1.3 (1.8 versus 0.8); however, this difference was not statistically significant. 

30 Additionally, Campanella and Mielke (2008) observed a linear increase in soil Pb content 

31 outside a home with respect to decreasing average household income, with soil Pb 

32 between 2.5 and 20 mg/kg associated with a Census block-averaged median household 

33 income of $40,000 per year, while soil Pb between 5,000 and 20,000 mg/kg was 

34 associated with a Census block-averaged median household income of $24,000 per year. 
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6.2.5 Proximity to Lead Sources

1 Airborne and soil Pb concentrations are higher in some industrialized and urbanized 

2 areas, as described in Sections 3.2, 3.3, 3.5 and 4.1, as a result of historical and 

3 contemporaneous Pb sources. The highest air Pb concentrations measured using the Pb4 TSP monitoring network have been measured at monitors located near sources emitting 

5 Pb. Elevated soil Pb concentrations have also been measured in urbanized areas 

6 compared with less urbanized or rural locations (Mielke et al., 2010a; Laidlaw and 

7 Filippelli, 2008; Weiss et al., 2006). Several studies describe mechanisms by which larger 

8 particles present in soil can become resuspended to the air by perturbation from traffic9 and wind-generated turbulence (Harris and Davidson, 2008; Lough et al., 2005; Zereini et 

10 al., 2005; Nicholson, 1988; Gillette et al., 1974). However, there are no recent monitoring 

11 studies of this process, and the current routine monitoring network is not designed for the 

12 assessment of the specific contribution of resuspension to ambient air concentrations. Air 

13 Pb concentrations exhibit high spatial variability even at low concentrations (~0.01 

μg/m3 14 ) (Martuzevicius et al., 2004). Proximity to an industrial source likely contributes to 

15 higher Pb exposures, as described in the 2006 Pb AQCD (U.S. EPA, 2006b) for several 

16 studies of Superfund and other industrial sites. This is consistent with the observation of 

17 higher air concentrations at source oriented Pb monitoring sites compared with 

18 non-source oriented sites in the 2007-2009 data presented in Section 3.5. 

19 Jones et al. (2010) found that neonates born near a Pb-contaminated hazardous waste site 

20 had significantly higher umbilical cord blood Pb levels (median: 2.2 μg/dL [95% CI: 1.5, 

21 3.3 μg/dL]) compared with a reference group of neonates not living near a potentially 

22 contaminated site (median: 1.1 μg/dL [95% CI: 0.8, 1.3 μg/dL]), suggesting that Pb23 contaminated hazardous waste sites contribute to neonatal Pb levels. The population 

24 studied in Jones et al. (2010) was 88% African American; 75% had a high school degree 

25 or equivalent, while 20% had a college degree and 5% attended but did not graduate from 

26 high school. However, the Jones et al. (2010) study did not analyze covariation between 

27 exposure and maternal characteristics, so it cannot be determined if differences in 

28 characteristics among the maternal groups (which did and did not report nearby 

29 hazardous waste sites) confounded these results.

30 Studies have suggested that soil Pb exposure is related to land use type and historical 

31 exposures of the soil, as described in Section 3.6.1. For instance, Wu et al., (2010)

32 observed that bioavailable Pb concentrations in Los Angeles soils were significantly 

33 associated with traffic-related variables and parcel age (i.e., length of time since the 

34 parcel was first developed), with parcel age being a highly significant predictor of 

35 bioavailable soil Pb in most models (p < 0.0001). Zahran et al. (2011) observed that soil 

36 Pb levels dropped following Hurricanes Katrina and Rita, from 329 mg/kg to 203 mg/kg 
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1 when comparing samples from 2000 with those from 2006. The reduction in soil Pb was 

2 thought to occur because sediments with lower Pb concentrations were distributed by the 

3 storms and coated existing soils having higher Pb concentrations. At the same time, blood 

4 Pb levels obtained from children ages 0-6 years at the same time periods declined by 

5 1.55 μg/dL for each 1% reduction in soil Pb (p ≤ 0.05). Following this observation, that 

6 lower Pb concentration material can be used to contain older soils with higher 

7 concentrations of Pb, Mielke et al. (2011b) initiated an experiment where a playground 

8 was covered with geotextile material topped with 15 cm of river alluvium. Median soil 

9 Pb concentrations decreased from 558 mg/kg to 4.1 mg/kg after the mitigation.

6.2.6 Residential Factors

10 A recent study of the association between blood Pb and housing factors by Dixon et al.

11 (2009), which drew inference from the NHANES national survey for 1999-2004, is 

12 consistent with previous studies presented in the 2006 Pb AQCD that drew associations 

13 between blood Pb and house dust (U.S. EPA, 2006b; Lanphear et al., 1998; Laxen et al., 

14 1987). Dixon et al. (2009) used NHANES data from 1999-2004 to perform a linear 

15 regression of blood Pb among children 12-60 months old on several factors including 

16 year of construction, floor surface condition, floor dust Pb level, windowsill dust Pb 

17 level, and renovation in homes built before 1978. They found that blood Pb (log 

18 transformed) was significantly associated with homes built after 1950 (p = 0.014), 

19 windowsill Pb level (p = 0.002), dust Pb level (p < 0.001), and renovation in pre-1978

20 homes (p = 0.045). Detailed results of this regression are shown in Table 6-3. As part of 

21 the same study, Gaitens et al. (2009) performed a regression analysis of floor dust Pb 

22 (PbD) and windowsill dusts Pb on several factors. Floor dust Pb (log transformed) was 

23 significantly associated with the following housing-related factors: floor surface 

24 condition (p < 0.001), windowsill dust Pb (log transformed) (p < 0.001), year of 

25 construction (p < 0.001), and renovation in a pre-1950 home (p < 0.001). Windowsill 

26 dust Pb (log transformed) was significantly associated with the following housing-related 

27 factors: year of construction (p < 0.001), window surface condition (0.001), and 

28 deteriorated indoor paint (p = 0.028). 
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Table 6-3 Regression of log-transformed blood Pb level of children 12-60 

months old on various factors related to housing condition, from 

1999-2004 NHANES dataset

Variables Overall p-value Levels Estimate (SE) p-Value

Intercept 0.172 –0.517 (0.373) 0.172

Age (in years) < 0.001 Age 2.620 (0.628) < 0.001 

Age2 –1.353 (0.354) < 0.001

Age3 0.273 (0.083) 0.002

Age4 –0.019 (0.007) 0.008

Year of construction 0.014 Intercept for missing –0.121 (0.052) 0.024

1990–present –0.198 (0.058) 0.001 

1978–1989 –0.196 (0.060) 0.002 

1960–1977 –0.174 (0.056) 0.003

1950–1959 –0.207 (0.065) 0.003

1940–1949 –0.012 (0.072) 0.870 

Before 1940 0.000 —

PIR < 0.001 Intercept for missing 0.053 (0.065) 0.420

Slope –0.053 (0.012) < 0.001

Race/ethnicity < 0.001 Non-Hispanic white 0.000 —

Non-Hispanic black 0.247 (0.035) < 0.001

Hispanic –0.035 (0.030) 0.251

Other 0.128 (0.070) 0.073

Country of birth 0.002 Missing –0.077 (0.219) 0.728

U.S.b 0.000 —

Mexico 0.353 (0.097) < 0.001

Elsewhere 0.154 (0.121) 0.209

Floor surface/condition × log floor PbD < 0.001 Intercept for missing 0.178 (0.094) 0.065

Not smooth and cleanable 0.386 (0.089) < 0.001

Smooth and cleanable or carpeted 0.205 (0.032) < 0.001

Floor surface/condition × (log floor PbD)2 Not smooth and cleanable 0.023 (0.015) 0.124

Smooth and cleanable or carpeted 0.027 (0.008) 0.001

Floor surface/condition × (log floor PbD)3 Uncarpeted not smooth and cleanable –0.020 (0.014) 0.159

Smooth and cleanable or carpeted –0.009 (0.004) 0.012

Log windowsill PbD 0.002 Intercept for missing 0.053 (0.040) 0.186

Slope 0.041 (0.011) < 0.001

Home-apartment type < 0.001 Intercept for missing –0.064 (0.097) 0.511

Mobile home or trailer 0.127 (0.067) 0.066

One family house detached –0.025 (0.046) 0.596

One family house attached 0.000 —

Apartment (1–9 units) 0.069 (0.060) 0.256

Apartment (≥ 10 units) –0.133 (0.056) 0.022

Anyone smoke inside the home 0.015 Missing 0.138 (0.140) 0.331

Yes 0.100 (0.040) 0.015 

No 0.000 —

Log cotinine concentration (ng/dL) in blood 0.004 Intercept for missing –0.150 (0.063) 0.023

Slope 0.039 (0.012) 0.002

Window cabinet or wall renovation in a 

pre-1978 home

0.045 Missing –0.008 (0.061) 0.896

Yes 0.097 (0.047) 0.045

No 0.000 —

n = 2,155; R2 = 40%.

Source: (Dixon et al., 2009)

1 Renovation activities on older homes have been shown to produce excess Pb dust 

2 concentrations. Gaitens et al. (2009) performed a regression analysis on dust Pb 

3 concentrations from 1994-2004 NHANES on demographic and housing variables and 

4 found that renovation of windows, cabinets, or walls in a pre-1950 home was 
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1 significantly associated with floor dust Pb concentration (p < 0.001). Paint scraping 

2 within the last twelve months was nearly significantly associated with windowsill dust Pb 

3 concentration (p = 0.053). Dixon et al. (2009) performed a regression analysis on log4 transformed blood Pb levels from NHANES (1999-2004) on several demographic and 

5 housing variables and found that renovation of windows, cabinets, or walls in pre-1978

6 homes was significantly associated with blood Pb concentration (p = 0.045). Mielke et al.

7 (2001) tested dust produced roughly six months after a home (having paint containing 

8 ~130,000 mg Pb/kg) was power sanded. Dust concentrations in various locations around 

9 the house ranged from 390-27,600 mg/kg after the first sampling. Following several 

10 rounds of cleaning, Pb concentrations dropped. Eight months later, most interior Pb 

11 concentrations were < 3 mg/kg, but five sites ranged from 17-1,340 mg/kg. Two children 

12 had blood Pb tested as part of this study. A 33 month-old child exhibited no change in 

13 blood Pb before or after renovation (blood Pb = 4 μg/dL), while a twelve-month old child 

14 had an increase from 4 μg/dL to 12 μg/dL. Note that blood was acquired in different 

15 manners from the children because the younger child had smaller veins; the older child 

16 had a venous sample while the younger child had a finger-stick. It is unclear if either of 

17 these methods is more prone to contamination than the other. In an occupational study of 

18 men performing home renovations in the U.K., window renovation and wood-stripping 

19 workers specializing in renovation of old houses had significantly higher median blood 

20 Pb levels compared with all workers in similar occupations (wood strippers: 37 μg/dL; 

21 window renovators: 32 μg/dL; all workers: 13.7 μg/dL; p < 0.001) (Mason et al., 2005).

6.3 Factors Potentially Related to Increased Risk of Lead Induced 

Health Effects

22 This section evaluates factors examined in recent studies as effect measure modifiers that 

23 potentially increase the risk of various Pb-related health effects. Table 6-4 provides an 

24 overview of the factors examined and populations identified as “at-risk” of Pb-related 

25 health effects based on the recent evidence integrated across disciplines. Each 

26 characteristic is described in greater detail in the following subsections.
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Table 6-4 Summary of evidence for factors that potentially increase the risk of 

lead-related health effects

Factor Evaluated Potentially Related to Increased Risk

Age (Section 6.3.1) Children

Sex (Section 6.3.2) Males,a Femalesa

Genetics (Section 6.3.3) ALADa, VDRa*, DRD4a*, GSTM1a, TNF-αa, eNOSa, APOEa, HFEa

Pre-existing Disease (Section 6.3.4) Autisma, Atopya,b, Hypertensionb

Smoking (Section 6.3.5) Smokersa

Race/Ethnicity (Section 6.3.6) Non-Hispanic Blacksa, Hispanicsa

Socioeconomic Status (SES) (Section 6.3.7) Low SESa

Nutrition (Section 6.3.10) Iron deficiencya

Stress (Section 6.3.11) High stressa

Cognitive Reserve (Section 6.3.12) Low cognitive reservea,b

Other Metals (Section 6.3.13) High/co-exposure to Cda, Asa, Mna

a

Evidence for this factor was limited.

b

Possible mediator

6.3.1 Age

1 Below is information from epidemiologic and toxicological studies regarding studies of 

2 increased risk for Pb-related health effects among children and older adults. Other age 

3 groups, such as adolescents, have not been evaluated here, if they were not part of 

4 stratified studies of lifestage.

6.3.1.1 Children

5 According to the 2000 Census, 28.6% of individuals living in the U.S. were under the age 

6 of 20, with 6.8% aged 0-4 years, 7.3% aged 5-9 years, 7.3% aged 10-14 years, and 7.2% 

7 aged 15-19 years (SSDAN CensusScope, 2010a). It is recognized that Pb can cross the 

8 placenta and affect the developing nervous system of the fetus (Sections 4.2.2.4 and 

9 5.3.9) and there is strong evidence of increased risk to the neurocognitive effects of Pb 

10 exposure during several lifestages throughout gestation, childhood, and into adolescence 

11 (for more detail, Section 5.3.2.1). However, most recent studies among children do not 

12 have adequate comparison groups between children of various age groups or between 

13 children and adults, and were therefore only presented in Chapter 5. 
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1 A study including multiple U.S. locations examined associations of blood Pb levels with 

2 various immune parameters among individuals living near Pb industrial sites and 

3 matched controls (Sarasua et al., 2000). For several of these endpoints, the association in 

4 the youngest group (ages 6-35 months) and the oldest group (ages 16-75 years) were in 

5 opposite directions. For example, among children ages 6-35 months, the associations 

6 between blood Pb levels and Immunoglobulin A (IgA), Immunoglobulin M (IgM), and 

7 B-cell abundance were positive, whereas the associations among 16-75 year olds were 

8 negative. The opposite associations were also present for T cell abundance. Ig antibodies, 

9 which are produced by activated B cells, are important mediators of the humoral immune 

10 response to antigens. T cells are important mediators of cell-mediated immune responses 

11 that involve activation of other immune cells and cytokines. These findings by Sarasua et 

12 al. (2000) indicate that very young children may be at increased risk for Pb-associated 

13 activation of humoral immune responses and perturbations in cell-to-cell interactions that 

14 underlie allergic, asthma, and inflammatory responses (for more information, see 

15 Sections 5.6.2.1 and 5.6.3). 

16 A study among Lebanese children examined the association between blood Pb levels and 

17 transferrin saturation (TS) less than 12% and iron-deficiency anemia (IDA) (Muwakkit et 

18 al., 2008). A positive association was detected for blood Pb levels ≥ 10 μg/dL and both 

19 TS less than 12% and IDA among children aged 11-23 months old; however, null 

20 associations were observed among children 24-35 months old. Calculations were not 

21 performed for children aged 36-75 months because there were no children in the highest 

22 Pb group (≥ 10 μg/dL) with either TS <12% or IDA. The authors noted that it is difficult 

23 to know whether the Pb levels were “a cause or a result of” IDA levels since previous 

24 studies linked iron deficiency with Pb toxicity.

25 Overall evidence indicates early childhood as a lifestage of increased risk for Pb-related 

26 health effects. Both recent epidemiologic studies summarized above reported associations 

27 among the youngest age groups, although different age cut-points were used with one 

28 study including only infants 35 months of age and younger. Toxicological studies provide 

29 support for increased health effects of Pb among younger age groups. Toxicological 

30 studies have reported that younger animals, whose nervous systems are developing 

31 (i.e., laying down and pruning neuronal circuits) and whose junctional barrier systems in 

32 the brain (i.e., the blood brain barrier) and GI system (i.e., gut closure) are immature, are 

33 more at risk from the effects Pb exposure (Fullmer et al., 1985).
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6.3.1.2 Older Adults

1 The number of Americans over the age of 65 will be increasing in upcoming years 

2 (estimated to increase from 12.4% of the U.S. population to 19.7% between 2000 to 

3 2030, which is approximately 35 million and 71.5 million individuals, respectively)

4 (SSDAN CensusScope, 2010a; U.S. Census Bureau, 2010). As of the 2000 Census, 7.2% 

5 of the U.S. population were ages 60-69, 5.8% were 70-79, and 3.3% were age 80 and 

6 older (SSDAN CensusScope, 2010a).

7 A study using the NHANES III cohort examined blood Pb levels and mortality among 

8 individuals less than 60 years old and individuals 60 years and older (Menke et al., 2006).

9 Positive hazard ratios were observed in both age groups but the hazard ratios were greater 

10 in those less than 60 years old. The interactions terms were not statistically significant. A 

11 similar study using the NHANES III cohort examined the relationship between blood Pb 

12 levels and mortality from all-cause, cardiovascular disease, and cancer broken down into 

13 more specific age groups (Schober et al., 2006). Point estimates were elevated for the 

14 association comparing blood Pb levels ≥ 10 μg/dL to blood Pb levels <5 μg/dL and all15 cause mortality for all age groups (40-74, 75-84, and 85+ year olds), although the 

16 association for 75-84 year olds did not reach statistical significance. The association was 

17 also present when comparing blood Pb levels of 5-9 μg/dL to blood Pb levels <5 μg/dL 

18 among 40-74 year olds and 75-84 year olds, but not among those 85 years and older. 

19 None of the associations between blood Pb and cardiovascular disease-related mortality 

20 reached statistical significance but the point estimates for cardiovascular disease-related 

21 mortality comparing blood Pb levels ≥ 10 μg/dL to blood Pb levels <5 μg/dL were 

22 elevated among all age groups. Finally, the association between blood Pb levels 

23 ≥ 10 μg/dL and cancer mortality was positive among those 40-74 years old and 85 years 

24 and older but the association was null for those 75-84 years old. Among 75-84 year olds 

25 the association was positive comparing blood Pb levels of 5-9 μg/dL to <5 μg/dL. The 

26 other age groups had similar point estimates but the associations were not statistically 

27 significant. 

28 A study using the Normative Aging Study cohort reported an interaction between Pb and 

29 age (Wright et al., 2003b). The inverse association between age and cognitive function 

30 was greater among those with high blood or patella Pb levels. Effect estimates were in the 

31 same direction for tibia Pb but the interaction was not statistically significant.

32 Finally, a study of current and former Pb workers reported that an interaction term of Pb 

33 and age (dichotomous cutpoint at 67th percentile but exact age not given) examined in 

34 models of Pb (measured from blood and patella) and blood pressure was not statistically 

35 significant (Weaver et al., 2008). Thus, no modification by age was observed in this study 

36 of Pb and blood pressure.
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1 Toxicological studies have demonstrated Pb-related health effects among older 

2 populations. The kidneys of older animals appear to be more at-risk for Pb-related health 

3 effects from the same dose of Pb (i.e., continuous 50 mg/L Pb-acetate drinking water) 

4 than younger animals (Berrahal et al., 2011). Increased risk related to older age is also 

5 observed for effects on the brain. Recent studies have demonstrated the importance of Pb 

6 exposure during early development in promoting the emergence of Alzheimer’s like 

7 pathologies in aged animals. Development of pathologies of old age in brains of aged 

8 animals that were exposed to Pb earlier in life has been documented in multiple species 

9 (mice and monkeys, for more details see Section 5.3.6). These pathologies include the 

10 development of neurofibrillary tangles and increased amyloid precursor protein and its 

11 product beta-amyloid (Basha et al., 2005; Zawia and Basha, 2005). Some of these 

12 findings were seen in animals that no longer had elevated blood Pb levels. 

13 In summary, results for age-related modification of the association between Pb and 

14 mortality had mixed results. Limited evidence was available for the associations between 

15 Pb and cognitive function or other health effects among older adults. Toxicological 

16 studies have shown increases in Pb-related health effects by age that may be relevant in 

17 humans. Future studies will be instrumental in understanding older age as a factor that 

18 potentially affects the risk of Pb-related outcomes.

6.3.2 Sex

19 The distribution of males and females in the U.S. is similar. In 2000, 49.1% of the U.S. 

20 population was male and 50.9% was female. The distribution of sex varied by age with a 

21 greater prevalence of females ≥ 65 years old compared to males (SSDAN CensusScope, 

22 2010a). The 2006 Pb AQCD reported that boys are often found to have higher blood Pb 

23 levels than girls, but findings were "less clear" regarding differences in Pb-related health 

24 effects between males and females (U.S. EPA, 2006b).

25 Multiple epidemiologic studies have examined Pb-related effects on cognition stratified 

26 by sex. In previous studies using the Cincinnati Lead Study cohort, Dietrich et al. (1987b)

27 and Ris et al. (2004) observed interactions between blood Pb (prenatal and postnatal) and 

28 sex ; associations of prenatal and postnatal blood Pb and subsequent decrements in 

29 memory, attention, and visuoconstruction were observed only among male adolescents. 

30 More recently, Wright et al. (2008) examined early life blood Pb levels and criminal 

31 arrests in adulthood. The attributable risks were greater among males than females. 

32 Additionally, the association between childhood blood Pb levels and adult gray matter 

33 volume loss was greater among males than females (Cecil et al., 2008). In an expanded 

34 analysis of the developmental trajectory of childhood blood Pb levels on adult gray 
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1 matter, researchers found that associations between yearly mean blood Pb levels and 

2 volume of gray matter loss were more pronounced in the frontal lobes of males than 

3 females (Brubaker et al., 2010). Multiple studies were also conducted in Port Pirie, 

4 Australia that examined blood Pb levels at various ages throughout childhood and 

5 adolescence (Tong et al., 2000; Baghurst et al., 1992; McMichael et al., 1992). These 

6 studies observed Pb effects on cognition deficits were stronger in girls throughout 

7 childhood and into early adolescence. A study in Poland also investigated the association 

8 between umbilical cord blood Pb levels and cognitive deficits and reported a positive 

9 association for boys at 36 months but not for girls (Jedrychowski et al., 2009a). No 

10 association was detected for boys or girls at 24 months.

11 An epidemiologic study examined the association between concurrent blood Pb levels 

12 and kidney function among 12-20 year olds using the NHANES III study cohort

13 (Fadrowski et al., 2010). The results were stratified by sex and no effect measure 

14 modification was apparent.

15 Similarly, a study of current and former Pb workers examined an interaction term 

16 between sex and Pb for the study of blood Pb and blood pressure (Weaver et al., 2008).

17 No modification by sex was present. 

18 Epidemiologic studies have also been performed to assess differences between males and 

19 females for Pb-related effects on various biomarkers. A study comprised mostly of 

20 females reported positive associations between blood Pb and total immunoglobulin E 

21 (IgE) for women not taking hormone replacement therapy or oral contraceptives (Pizent 

22 et al., 2008). No association was reported in males, but other associations, such as 

23 bronchial reactivity and reactive skin prick tests were observed in the opposite of the 

24 expected direction, which questions the validity of the results among the male study 

25 participants. Analysis of an NHANES dataset detected no association between blood Pb 

26 levels and inflammatory markers (Songdej et al., 2010). Although there was no clear 

27 pattern, a few of the associations were positive between blood Pb and C-reactive protein 

28 for males but not females. A study of children living at varying distances from a Pb 

29 smelter in Mexico reported that blood Pb was associated with increased release of 

30 superoxide anion from macrophages, which was greater among males than females

31 (Pineda-Zavaleta et al., 2004).

32 Epidemiologic investigations of cancer have also examined the associations by sex. A 

33 study of the association between occupational exposure to Pb and brain tumors reported 

34 no sex-specific associations for gliomas, but a positive association for cumulative Pb 

35 exposure and meningiomas for males but not females (Rajaraman et al., 2006). An 

36 ecologic analysis of Pb pollution levels and cancer incidence among children reported 
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1 weak correlations overall and the weak correlations were more apparent among males, 

2 whereas no correlation was observed among females (Absalon and Slesak, 2010).

3 A study of all-cause and cardiovascular mortality using the NHANES III cohort reported 

4 no modification of the association between blood Pb and all-cause or cardiovascular 

5 mortality by sex (Menke et al., 2006). This did not differ among women when classified 

6 as pre- or post-menopausal. 

7 Toxicological studies have also reported sex differences in Pb-related effects to various 

8 organ systems. Donald et al. (1986) reported a different time course of enhanced social 

9 investigatory behavior between male and female mice exposed to Pb. In a subsequent 

10 publication, Donald et al. (1987) showed that non-social behavior in mice decreased in 

11 females and increased in males exposed to Pb. Males also had a shorter latency to 

12 aggression with Pb treatment versus controls. Pb affected mood disorders differently for 

13 males and females. Behavioral testing in rats showed males experienced emotional 

14 changes and females depression-like changes with Pb exposure (de Souza Lisboa et al., 

15 2005). In another study, gestational exposure to Pb impaired memory retrieval in male 

16 rats at all 3 doses of Pb exposure; memory retrieval was only impaired in low-dose 

17 female rats (Yang et al., 2003). Sex-specific differences in mice were also observed for 

18 gross motor skills; at the lowest Pb dose, balance and coordination were most affected 

19 among males (Leasure et al., 2008).

20 Pb and stress are co-occurring factors that act in a sex-divergent manner to affect 

21 behavior, neurochemistry, and corticosterone levels. Pb and stress act synergistically to 

22 affect fixed interval operant behavior and corticosterone in female rat offspring. Virgolini 

23 et al. (2008a) found that effects on the offspring’s central nervous system by 

24 developmental Pb exposure (maternal exposure and transferred to the offspring through 

25 lactation) were enhanced by combined maternal and offspring stress and females were 

26 most at risk. Behavioral related outcomes after gestational and lactational Pb exposure 

27 (with and without stress) exhibited sex-differences in exposed offspring (Virgolini et al., 

28 2008b). Pb-induced changes in brain neurochemistry, with or without concomitant stress 

29 exposure, are complex with differences varying by brain region, neurotransmitter type, 

30 and sex of the animal.

31 The brain is known to have a sexually dimorphic area in the hypothalamus, termed the 

32 sexually dimorphic nucleus (SDN). Lesions in this area affect sex-specific phenotypes 

33 including behavior. Across species the SDN has a greater cell number and larger size in 

34 males versus females. This sexually dichotomous area is especially vulnerable to 

35 perturbation during fetal life and the early postnatal period. This may be one area of the 

36 brain that could explain some of the sexually dichotomous effects that are seen with Pb 

37 exposure. One study supporting this line of thought showed that high-dose in utero Pb 
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1 exposure (pup blood Pb level 64 μg/dL at birth) induced reductions in SDN volume in 

2 35% of Pb-exposed male rats (McGivern et al., 1991). Interestingly, another chemical 

3 that is known to cause a hypothalamic lesion in this area, monosodium glutamate, is 

4 associated with adult onset obesity (Olney, 1969); adult onset obesity is seen in the Pb 

5 literature.

6 Obesity in adult offspring exposed to low-dose Pb in utero was reported for male but not 

7 female mice (Leasure et al., 2008). Obesity was also found in male rat offspring exposed 

8 in utero to high doses of Pb that persisted to 5 weeks of age/end of the study, but among 

9 female rats, body weight remained elevated over controls only to 3 weeks of age (Yang et 

10 al., 2003). Additionally, low-dose Pb exposure induced retinal decrements in exposed 

11 male mice offspring (Leasure et al., 2008).

12 A toxicological study of Pb and antioxidant enzymes in heart and kidney tissue reported 

13 that male and female rats had differing enzymatic responses, although the amount of Pb 

14 in the heart tissue or the disposition of Pb also varied between males and females

15 (Sobekova et al., 2009; Alghazal et al., 2008a). The authors reported these results could 

16 be due to greater deposition of Pb in female rats or greater clearance of Pb by males

17 (Sobekova et al., 2009).

18 Multiple associations between Pb and various health endpoints have been examined for 

19 effect measure modification by sex. Although not observed in all endpoints, some studies 

20 reported differences between the associations for males and females, especially in 

21 neurological studies. However, studies on cognition from the Cincinnati Lead Study 

22 cohort and a study in Poland reported males to be an at-risk population, whereas studies 

23 from Australia pointed to females as an at-risk population. A difference in sex is 

24 supported by toxicological studies. Further research is needed to confirm the presence or 

25 absence of sex-specific associations between Pb and various health outcomes and in 

26 which sex the associations are greater.

6.3.3 Genetics

27 The 2006 Pb AQCD stated that, "genetic polymorphisms in certain genes have been 

28 implicated as influencing the absorption, retention, and toxicokinetics of Pb in humans"

29 (U.S. EPA, 2006b). The majority of discussion there focused on the aminolevulinate 

30 dehydratase (ALAD) and vitamin D receptor (VDR) polymorphisms. These two genes, as 

31 well as additional genes examined in recent studies, are discussed below.
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6.3.3.1 Aminolevulinate Dehydratase 

1 The aminolevulinate dehydratase (ALAD) gene encodes for an enzyme that catalyzes the 

2 second step in the production of heme and is also the principal Pb-binding protein (U.S. 

3 EPA, 2006b). Studies have examined whether ALAD variants altered associations 

4 between Pb and various health effects.

5 Associations between Pb and brain tumors observed in an epidemiologic study varied by 

6 ALAD genotype status (Rajaraman et al., 2006). Positive associations between Pb 

7 exposure (determined via interview about occupational exposures) and meningioma were 

8 reported among ALAD2 individuals, but this association was not found among 

9 individuals who had the ALAD1 allele. No associations were observed between Pb and 

10 glioma regardless of ALAD genotype. 

11 Studies investigating the association between Pb levels and cognitive function have also 

12 examined modification by ALAD polymorphisms. The evidence is provided by an 

13 NHANES analysis (Krieg et al., 2009) as well as multiple analyses from the NAS cohort 

14 examining different tests of cognitive function (Rajan et al., 2008; Weuve et al., 2006). In 

15 the study using a cohort from NHANES III, for several indices of cognitive function, 

16 associations with concurrent blood Pb levels were more pronounced in groups with CC 

17 and CG ALAD genotypes (i.e., ALAD2 carriers) (Krieg et al., 2009). In the NAS cohort 

18 of men, Weuve et al. (2006) found that concurrent blood Pb level but not bone Pb level 

19 was associated with a larger decrease in a test of general cognitive function among 

20 ALAD2 carriers. Another NAS study examined functioning of specific cognitive 

21 domains (e.g., vocabulary, memory, visuospatial skills) and found variable evidence for 

22 effect modification by ALAD genotype across tests (Rajan et al., 2008). For example, 

23 among ALAD2 carriers, concurrent blood Pb level was associated with a more 

24 pronounced decrease in vocabulary score but less pronounced decrease in a memory 

25 index and no difference in the associations with other cognitive tests. For tibia and patella 

26 Pb levels, ALAD genotype was found to modify associations with different tests, for 

27 example, executive function and perceptual speed. It is not clear why the direction of 

28 effect modification would vary among different cognitive domains. The limited number 

29 of populations examined, and the different cognitive tests performed in each study, make 

30 it difficult to conclusively summarize findings for effect modification by ALAD variants. 

31 However, in the limited available body of evidence, blood and bone Pb levels were 

32 generally associated with lower cognitive function in ALAD2 carriers.

33 A study of current and former workers exposed to Pb examined the association between 

34 blood Pb and blood pressure and reported no modification by ALAD genotype (Weaver 

35 et al., 2008). However, another study of blood Pb and blood pressure reported 
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1 interactions between blood Pb and ALAD, but this varied by race/ethnicity (non-Hispanic 

2 white, non-Hispanic black, and Mexican American) (Scinicariello et al., 2010).

3 Individuals with ALAD2 variants had greater associations between Pb and kidney 

4 effects; among those with the variant, higher Pb was associated with higher glomerular 

5 filtration measures (Weaver et al., 2006; Weaver et al., 2005b; Weaver et al., 2003b). A 

6 study of workers at a battery plant storage facility in China reported workers with the 

7 ALAD2 allele demonstrated greater associations between blood Pb levels and renal 

8 injury (Gao et al., 2010a). Another study of renal function among Pb workers in Asia also 

9 reported greater associations between blood Pb concentrations and renal function by 

10 ALAD, especially at high blood Pb levels (Chia et al., 2006).

6.3.3.2 Vitamin D Receptor 

11 The vitamin D receptor (VDR) is a regulator of calcium absorption and metabolism. A 

12 recent study of the NHANES III population examined the association between blood Pb 

13 levels and various neurocognitive tests with assessment of effect measure modification 

14 by SNPs and haplotypes of VDR (Krieg et al., 2010). The results were varied, even 

15 among specific SNPs and haplotypes, with some variants being associated with greater 

16 modification of the relationship between Pb and one type of neurocognitive test 

17 compared to the modification of the relationship between Pb and other neurocognitive 

18 tests. In an epidemiologic study of blood Pb levels and blood pressure among a group of 

19 current and former Pb-exposed workers, no modification was reported by VDR (Weaver 

20 et al., 2008).

6.3.3.3 Methylenetetrahydrofolate reductase 

21 Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 

22 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which in turn, is involved in 

23 homocysteine remethylation to the amino acid methionine. A study in Mexico of the 

24 association between Pb and Bayley's Mental Development Index (MDI) score at 24 

25 months reported no effect measure modification by MTHFR 677T allele (Pilsner et al., 

26 2010). Another study in Mexico examined the association between maternal Pb and birth 

27 weight (Kordas et al., 2009). No modification of the Pb-birth weight association by 

28 MTHFR was observed.
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6.3.3.4 Apolipoprotein E 

1 Apolipoprotein E (APOE) is a transport protein for cholesterol and lipoproteins. The gene 

2 appears to regulate synapse formation (connections between neurons), which may be 

3 particularly critical in early childhood. A genetic variant, called the APOE4 allele is a 

4 haplotype between two exonic SNPs and is perhaps the most widely studied genetic 

5 variant with respect to increasing risk of neurologic disease. A study of occupationally6 exposed adults observed tibia Pb levels to be associated with greater cognitive 

7 decrements in some, but not all, neurobehavioral tests (such as digit symbol, pegboard 

8 assembly, and complex reaction time) among adults with at least one APOE-ε4 allele

9 (Stewart et al., 2002). Conversely, in a study of children in Mexico, children without the 

10 APOE-ε4 allele had a greater inverse association between umbilical cord blood Pb and 

11 Bayley’s MDI than children with this allele, although the interaction term was not 

12 statistically significant (Wright et al., 2003a).

6.3.3.5 Hemochromatosis 

13 The hemochromatosis (HFE) gene encodes a protein believed to be involved in iron 

14 absorption. A difference was observed between the association of tibia Pb levels and 

15 cognitive function for men with and without HFE allele variants (Wang et al., 2007a). No 

16 association between tibia Pb and cognitive function was present for men with HFE 

17 wildtype, but a decline in function was associated with tibia Pb levels among men with 

18 any HFE allele variant. A study of bone Pb levels and HFE reported no difference in 

19 effect estimates for bone Pb and pulse pressure between different HFE variants and HFE 

20 wild-type (Zhang et al., 2010a). An interaction was observed between an HFE variant in 

21 mothers and maternal tibia Pb in a study of maternal Pb and birth weight (Cantonwine et 

22 al., 2010b). The inverse association between maternal tibia Pb levels and birth weight 

23 was stronger for those infants whose mothers had the HFE variant. The interaction was 

24 not present between the HFE variants and maternal blood Pb or cord blood Pb 

25 concentrations. 

6.3.3.6 Other Genetic Polymorphisms

26 Some other genetic polymorphisms were also examined as to whether they modify Pb27 related health effects, but only limited data were available for these polymorphisms. 

28 These include dopamine receptor D4 (DRD4), dopamine receptor D2 (DRD2), dopamine 

29 transporter (DAT1), glutathione S-transferase Mu 1 (GSTM1), tumor necrosis factor30 alpha (TNF-α), endothelial nitric oxide synthase (eNOS), and various SNPS. 
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1 A prospective birth cohort reported that increasing blood Pb levels were associated with 

2 poorer rule learning and reversal, spatial span, and planning in their study population

3 (Froehlich et al., 2007). These inverse associations were exacerbated among those 

4 lacking DRD4-7. A study of prenatal and postnatal Pb levels in Mexico City reported no 

5 modification of the associations between Pb levels and neurocognitive development by 

6 DRD2 or DAT1 (Kordas et al., 2011).

7 A study of university students in South Korea reported blood Pb levels to be associated 

8 with biomarkers of inflammation among individuals with GSTM1 null genotype and not 

9 among individuals with GSTM1 present (Kim et al., 2007). This study of blood Pb levels 

10 and inflammation also examined individuals with TNF-α GG, GA, or AA alleles. An 

11 association was present for those with TNF-α GG but not for those with TNF-α GA or 

12 AA.

13 A study of blood Pb and plasma NOX reported no overall association but did report an 

14 inverse correlation among subjects with the eNOS TC+CC genotype (Barbosa et al., 

15 2006a). No correlation was observed for subjects with the eNOS TT genotype; however 

16 the number of subjects in this group was small, especially for those with high blood Pb 

17 levels. 

18 One study examined how the association between occupational Pb exposure and brain 

19 tumors varied among multiple single nucleotide polymorphisms (SNPs) (Bhatti et al., 

20 2009). No effect measure modification of the association between Pb and glioma was 

21 observed for any of the SNPs. GPX1 (the gene encoding for glutathione peroxidase 1) 

22 modified the association for glioblastoma multiforme and meningioma. The association 

23 between Pb and glioblastoma multiforme was also modified by a RAC2 (the gene 

24 encoding for Rac2) variant, and the association between Pb and meningioma was also 

25 modified by XDH (the gene encoding for xanthine dehydrogenase) variant. 

26 Overall, studies of ALAD observed increased Pb-related health effects associated with 

27 certain gene variants. Other genes, such as VDR, APOE, HFE, DRD4, GSTM1, TNF-α, 

28 and eNOS, may also affect the risk of Pb-related health effects but conclusions are 

29 limited due to the small number of studies. 

6.3.4 Pre-existing Diseases/Conditions

30 Studies have also been performed to examine whether certain morbidities increase an 

31 individual’s risk of Pb-related effects on health. Recent studies have explored 

32 relationships for autism, atopy, diabetes, and hypertension.
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6.3.4.1 Autism

1 Rates of individuals with autism have increased in recent years. A study reported a 

2 prevalence rate in 2006 of 9.0 per 1,000 individuals (95% CI: 8.6, 9.3) determined from a 

3 monitoring network (Autism and Developmental Disabilities Monitoring Network) with 

4 11 sites across the U.S. (CDC, 2009).

5 A cross-sectional study of children with and without autism examined the association 

6 between blood Pb levels and various immune function and inflammation genes (Tian et 

7 al., 2011). Blood Pb levels of children with and without autism were associated with 

8 expression of the genes under study; however, the associations observed were in opposite 

9 directions (for children with autism, increased blood Pb levels were associated with 

10 increased expression, whereas for children without autism, increased blood Pb levels 

11 were associated with decreased expression).

6.3.4.2 Atopy

12 Atopy, a type of allergic hypersensitivity, was evaluated as a factor affecting risk in a 

13 study of Pb and IgE (Annesi-Maesano et al., 2003). The study examined hair Pb levels in 

14 infants and IgE and reported a positive correlation overall. However, in stratified 

15 analyses, this association remained only among infants of mothers without atopy. Among 

16 mothers with atopy, the correlation was positive, although smaller, and was not 

17 statistically significant.

6.3.4.3 Diabetes

18 Approximately 8% of U.S. adults have diabetes (Pleis et al., 2009). A few studies have 

19 been conducted to investigate the possibility of diabetes as a modifying factor for Pb and 

20 various health outcomes. 

21 Differences in the association between bone and blood Pb levels and renal function for 

22 individuals with and without diabetes at baseline was examined using the Normative 

23 Aging Study cohort (Tsaih et al., 2004). Tibia and blood Pb levels were positively 

24 associated with measures of poor renal function among individuals with diabetes but not 

25 among individuals without diabetes. However, this association was no longer statistically 

26 significant after the exclusion of individuals who were hypertensive or who used diuretic 

27 medications. Another study with this cohort reported no associations between bone Pb 

28 and heart rate variability, which did not differ among those with and without diabetes

29 (Park et al., 2006).
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1 The NHANES III data were used to evaluate whether the association between blood Pb 

2 and both all-cause and cardiovascular mortality varied among individuals with and 

3 without diabetes (Menke et al., 2006). The 95% CIs among those with diabetes were 

4 large and no difference was apparent among those with and without diabetes.

5 Overall, recent epidemiologic studies found that associations between Pb concentrations 

6 and health outcomes did not differ for individuals with and without diabetes. However, 

7 results from the 2006 Pb AQCD found that individuals with diabetes are at "increased 

8 risk of Pb-associated declines in renal function" (U.S. EPA, 2006b). Future research 

9 examining associations between Pb and renal function, as well as other health outcomes, 

10 among individuals with and without diabetes will inform further on the potential for 

11 increased risk among individuals with diabetes.

6.3.4.4 Hypertension

12 Hypertension affects approximately 24% of adults in the U.S. and the prevalence of 

13 hypertension increases with age (61% of individuals ≥ 75 years old have hypertension)

14 (Pleis et al., 2009).

15 The Normative Aging Study mentioned above evaluating modification of the association 

16 between Pb levels and renal function by diabetes also examined modification by 

17 hypertensive status (Tsaih et al., 2004). The association between tibia Pb and renal 

18 function, measured by change in serum creatinine, was present among individuals with 

19 hypertension but not among individuals that were normotensive. Models of the follow-up 

20 serum creatinine levels demonstrated an association with blood Pb for individuals with 

21 hypertension but not individuals without hypertension (this association was not present 

22 when using tibia or patella Pb). Another study using this population examined 

23 modification of the association between bone Pb and heart rate variability, measured by 

24 low frequency power, high frequency power, and their ratio (Park et al., 2006). Although 

25 a statistically significant association between bone Pb and heart rate variability was not 

26 observed among individuals with or without hypertension, the estimates were different, 

27 with greater odds for individuals with hypertension (bone Pb levels were positively 

28 related to low frequency power and the ratio of low frequency to high frequency power 

29 and were inversely related to high frequency power).

30 A study using the NHANES III cohort reported a positive association between blood Pb 

31 levels and both all-cause and cardiovascular mortality for individuals with and without 

32 hypertension but the associations did not differ based on hypertensive status (Menke et 

33 al., 2006).
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1 The 2006 Pb AQCD reported that individuals with hypertension had increased risk of Pb2 related effects on renal function (U.S. EPA, 2006b). This is supported by recent 

3 epidemiologic studies. As described above, studies of Pb-related effects on renal function 

4 and heart rate variability have observed some differences among individuals with 

5 hypertension, but the difference between adults with and without hypertension was not 

6 observed for Pb-related mortality.

6.3.5 Smoking

7 The rate of smoking among adults 18 years and older in the U.S. is approximately 20% 

8 and about 21% of individuals identify as former smokers (Pleis et al., 2009). Studies of 

9 Pb and various health effects have examined smoking as an effect measure modifier. 

10 A study of blood Pb levels and all-cause and cardiovascular mortality reported no 

11 modification of this association by smoking status, measured as current, former, or never 

12 smokers (Menke et al., 2006). The Normative Aging Study also examined the association 

13 between blood and bone Pb levels and renal function and also reported no interaction 

14 with smoking status (Tsaih et al., 2004).

15 A study of Pb-exposed workers and controls reported similar levels of absolute neutrophil 

16 counts (ANC) across Pb exposure categories among non-smokers (Di Lorenzo et al., 

17 2006). However, among current smokers, higher Pb exposure was associated with higher 

18 ANC. Additionally, a positive relationship was observed between higher blood Pb levels 

19 and TNF-α and granulocyte colony-stimulating factor (G-CSF) among both smokers and 

20 nonsmokers, but this association was greater among smokers (Di Lorenzo et al., 2007). A 

21 recent study of fertile and infertile men examined blood and seminal plasma Pb levels for 

22 smokers and non-smokers (Kiziler et al., 2007). The blood and seminal plasma Pb levels 

23 were higher for smokers of both fertile and infertile groups. Additionally, the Pb levels 

24 were lowest among non-smoking fertile men and highest among smoking infertile men. 

25 Prenatal smoking exposure was examined in a study of children’s concurrent blood Pb 

26 levels and prevalence of attention-deficit/hyperactivity disorder (ADHD) among children 

27 aged 8-15 years. An interaction was observed between children’s current blood Pb levels 

28 and prenatal tobacco smoke exposure; those children with high Pb levels and prenatal 

29 tobacco smoke exposure had the highest odds of ADHD (Froehlich et al., 2009).

30 Overall, the studies have mixed findings on whether smoking modifies the relationship 

31 between Pb levels and health effects. Future studies of Pb-related health effects and 

32 current, former, and prenatal smoking exposures among various health endpoints will aid 

33 in determining changes in risk by this factor.
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6.3.6 Race/Ethnicity

1 Based on the 2000 Census, 69.1% of the U.S. population is comprised of non-Hispanic 

2 whites. Approximately 12.1% of people reported their race/ethnicity as non-Hispanic 

3 black and 12.6% reported being Hispanic (SSDAN CensusScope, 2010b). Studies of 

4 multiple Pb-related health outcomes examined effect measure modification by 

5 race/ethnicity.

6 A study of adults from the NHANES III cohort examined the association between blood 

7 Pb levels and all-cause and cardiovascular mortality (Menke et al., 2006). Stratified 

8 analyses were conducted for non-Hispanic whites, non-Hispanic blacks, and Mexican 

9 Americans and no interaction for race/ethnicity was reported. Other studies have also 

10 used NHANES cohorts to study blood Pb levels and hypertension (Scinicariello et al., 

11 2010; Muntner et al., 2005). While no association was observed between blood Pb and 

12 hypertension for non-Hispanic whites or Hispanics, a positive association was reported 

13 for non-Hispanic blacks in a study using the NHANES III cohort (Scinicariello et al., 

14 2010). In another study, although none of the associations between blood Pb levels and 

15 hypertension were statistically significant, increased odds were observed among 

16 non-Hispanic blacks and Mexican Americans but not for non-Hispanic whites (Muntner 

17 et al., 2005).

18 A study of girls aged 8-18 years from the NHANES III cohort reported an inverse 

19 association between blood Pb levels and pubertal development among blacks and 

20 Mexican Americans (Selevan et al., 2003). For non-Hispanic whites, the associations 

21 were in the same direction but did not reach statistical significance. Of note, less than 3% 

22 of non-Hispanic whites had blood Pb levels over 5 μg/dL, whereas 11.6% and 12.8% of 

23 blacks and Mexican Americans, respectively, had blood Pb levels greater than 5 μg/dL.

24 A study linking educational testing data for 4th grade students in North Carolina reported 

25 declines in reading and mathematics scores with increasing levels of blood Pb (Miranda 

26 et al., 2007b). Although not quantitatively reported, a figure in the study depicted the 

27 association stratified by race, and the slopes appeared to be similar for white and black 

28 children.

29 Blood Pb and asthma incidence was examined for white and black children living in 

30 Michigan (Joseph et al., 2005). When utilizing separate referent groups for the two races, 

31 the only association is an increase among whites (although not statistically significant), 

32 but when restricting to the highest blood Pb levels, the association was no longer 

33 apparent. Whites with low blood Pb levels were used as the referent group for both races 

34 in additional analysis. Although the estimates were elevated for black children compared 
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1 to white children (including at the lowest blood Pb levels), the confidence intervals for 

2 the associations overlapped indicating a lack of a difference by race. 

3 The results of these recent epidemiologic studies suggest that there may be race/ethnicity4 related increased risk for some outcomes, although the overall understanding of potential 

5 effect measure modification by race/ethnicity is limited by the small number of studies. 

6 Additionally, these results may be confounded by other factors, such as socioeconomic 

7 status. 

6.3.7 Socioeconomic Status 

8 Based on the 2000 Census data, 12.4% of Americans live in poverty (poverty threshold 

9 for family of 4 was $17,463) (SSDAN CensusScope, 2010c). Ris et al. (2004) examined 

10 modification of the associations between early-life Pb levels and Learning/IQ among 

11 adolescents in the Cincinnati Lead Study. In models examining the association between 

12 Pb and Learning/IQ, the prenatal and 78-month blood Pb levels were associated with 

13 larger decrements in Learning/IQ in the lower two quintiles of socioeconomic status 

14 (SES) (measured based on family SES levels).

6.3.8 Body Mass Index 

15 In the U.S. self-reported rates of obesity were 26.7% in 2009, up from 19.8% in 2000

16 (Sherry et al., 2010). The NHANES III cohort was utilized in a study of blood Pb levels 

17 and all-cause and cardiovascular mortality, which included assessment of the associations 

18 by obesity (Menke et al., 2006). Positive associations were observed among individuals 

within both categories of body mass index (BMI; normal [<25 kg/m2 19 ] and 

overweight/obese [≥ 25 kg/m2 20 ], determined using measured values of height and weight) 

21 but there was no difference in the association between the two categories. Using the 

22 Normative Aging Study data, an investigation of bone Pb levels and heart rate variability 

23 was performed and reported slight changes in the association based on the presence of 

24 metabolic syndrome; however, none of the changes resulted in associations that were 

25 statistically significant (Park et al., 2006). Overall, no modification by BMI or obesity 

26 was observed among recent epidemiologic studies. 
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6.3.9 Alcohol Consumption

1 There are a limited number of studies examining alcohol as a factor affecting Pb-related 

2 risk. A study using the Normative Aging Study cohort investigated whether the 

3 association between blood and bone Pb levels and renal function would be modified by 

4 an individual’s alcohol consumption (Tsaih et al., 2004). No interaction with alcohol 

5 consumption was observed. However, a toxicological study reported that ethanol 

6 potentiated the effect of Pb exposure by decreasing renal total protein sulfhydryls 

7 (endogenous antioxidants) in rats. Pb and ethanol also decreased other endogenous renal 

8 antioxidants (glutathione and non-protein sulfhydryls) (Jurczuk et al., 2006).

6.3.10 Nutritional Factors

9 Different components of diet may affect the association between Pb concentrations and 

10 health outcomes. Recent epidemiologic and toxicological studies of specific mineral 

11 intakes/dietary components are detailed below.

6.3.10.1 Calcium

12 Using the Normative Aging Study cohort, researchers examined the association between 

13 Pb levels and hypertension, modified by calcium intake (Elmarsafawy et al., 2006). The 

14 associations between Pb levels (measured and modeled separately for blood, patella, and 

15 tibia) and hypertension did not differ based on dichotomized calcium intake 

16 (800 mg/day). 

6.3.10.2 Iron

17 The 2006 Pb AQCD included studies that indicated individuals with iron-deficiency and 

18 malnourishment had greater inverse associations between Pb and cognition (U.S. EPA, 

19 2006b). A recent epidemiologic study of pubertal development among girls observed 

20 inverse associations between blood Pb and inhibin B, but this association was modified 

21 by iron deficiency; girls with iron deficiency had a stronger inverse association between 

22 Pb and inhibin B than those who were iron sufficient (Gollenberg et al., 2010).

23 Toxicological studies also reported that iron-deficient diets exacerbate or potentiate the 

24 effect of Pb. A study of pregnant rats given an iron-deficient diet and exposed to Pb 

25 through drinking water over GD6-GD14, had decreased litter size, more pups with 

26 reduced fetal weight and reduced crown-rump length, increased litter resorption, and a 
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1 higher damblood Pb level in the highest exposure groups (Singh et al., 1993; Saxena et 

2 al., 1991). Thus, in this model, iron deficiency makes rat dams more at risk for Pb3 dependent embryo and fetotoxicity (Singh et al., 1993).

6.3.10.3 Folate

4 A study by Kordas et al. (2009) examined Pb levels and birth size among term births in 

5 Mexico City. The authors reported no interaction between maternal tibia Pb and folate 

6 levels.

6.3.10.4 Protein

7 No recent epidemiologic studies have evaluated protein intake as a factor affecting Pb8 related health effects. However, a toxicological study demonstrated that differences in 

9 maternal protein intake levels could affect the extent of Pb-induced immunotoxicity 

10 among offspring (Chen et al., 2004).

6.3.11 Stress

11 A study of bone (tibia and patella) Pb levels and hypertension reported modification of 

12 the association by perceived stress levels (Peters et al., 2007). Among individuals with 

13 greater perceived stress levels, stronger associations between blood Pb levels and 

14 hypertension were present. Among the same study population, higher perceived stress 

15 was also reported to affect the association between blood Pb levels and cognitive 

16 function; the higher stress group showed a greater inverse association between Pb and 

17 cognitive function than those in the low stress group (Peters et al., 2008). In another 

18 study, the inverse association between tibia Pb levels and some measures of cognitive 

19 function were similarly strengthened by neighborhood psychosocial hazards (Glass et al., 

20 2009).

21 Toxicological studies have demonstrated that early life exposure to Pb and maternal 

22 stress can result in toxicity related to multiple systems (Rossi-George et al., 2009; Cory23 Slechta et al., 2008; Virgolini et al., 2008a; Virgolini et al., 2008b), including 

24 dysfunctional corticosterone responses (Rossi-George et al., 2009; Virgolini et al., 

25 2008b). Additionally, toxicological studies have demonstrated that stressors to the 

26 immune system can also affect associations with Pb exposure. Chickens with low Pb 

27 exposure in ovo, with additional viral stressors, had increased immune cell mobilization 
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1 and trafficking dysfunction (Lee et al., 2002). Similarly, mice with neonatal Pb exposure, 

2 and an additional immune challenge, had a sickness behavior phenotype, likely driven by 

3 IL-6 production (Dyatlov and Lawrence, 2002).

4 Similar to studies of stress in animals, maternal self-esteem has also been shown to 

5 modify associations between blood Pb levels and health effects in children. Surkan et al.

6 (2008) studied the association between children’s blood Pb levels and Bayley’s MDI and 

7 Psychomotor Development Index (PDI) among mother-child pairs. High maternal self8 esteem was independently associated with higher MDI score and also appeared to 

9 attenuate the negative effects of the child’s increased blood Pb levels on MDI and PDI 

10 scores. Greater decreases in MDI and PDI were associated with increased blood Pb levels 

11 among children whose mothers were in the lower quartiles of self-esteem. The 

12 investigators indicated that high maternal self-esteem may serve as a buffer against stress 

13 by improving mother-child interactions and care giving practices, and maternal self 

14 esteem may also be a surrogate of biological stress responses in the child.

15 Although examined in a limited number of studies, recent epidemiologic studies observed 

16 modification of the association between Pb and various nervous system health effects by 

17 stress-level. Increased risk of Pb-related health effects by stress is further supported by 

18 toxicological studies.

6.3.12 Cognitive Reserve

19 Cognitive reserve has been defined as “the maintenance of cognitive performance in spite 

20 of ongoing underlying brain pathology” (Bleecker et al., 2007b). A study of Pb smelter 

21 workers reported that an inverse association between lifetime weighted blood Pb levels 

22 and cognitive function was present among workers with low cognitive reserve (measured 

23 using a reading achievement test) but no association was present in workers with high 

24 cognitive reserve (Bleecker et al., 2007b). Inverse associations between lifetime-weighted 

25 blood Pb levels and motor functions existed among all workers regardless of cognitive 

26 reserve. No other recent epidemiologic studies were performed examining cognitive 

27 reserve as a factor affecting risk of Pb-related health outcomes. 

6.3.13 Other Metal Exposure

28 The 2006 Pb AQCD reported that the majority of studies that examined other toxicants 

29 did so as confounders and not as effect measure modifiers (U.S. EPA, 2006b). Recent 

30 epidemiologic studies have begun to explore the possible interaction between Pb 
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1 exposure and co-exposures with other metals. These studies, as well as toxicological 

2 studies of these metals, are described below.

6.3.13.1 Cadmium 

3 In a study of girls in the NHANES III cohort, inverse associations were observed 

4 between blood Pb and inhibin B concentrations (Gollenberg et al., 2010). These inverse 

5 associations were stronger among girls with high cadmium (Cd) and high Pb compared to 

6 those with high Pb and low Cd. Additionally, higher blood Pb and Cd levels together 

7 were positively associated with albuminuria and reduced estimated glomerular filtration 

8 rate, compared to those with the lowest levels of Pb and Cd (Navas-Acien et al., 2009).

9 Toxicological studies reported that in rats, the addition of Cd to Pb exposure reduced the 

10 histological signs of renal toxicity from each element alone; however, urinary excretion 

11 of porphyrins were increased, indicating that although measured tissue burdens of Pb 

12 were reduced, the biologically available fraction of Pb was actually increased (Wang and 

13 Fowler, 2008). In other studies, Cd synergistically exacerbated Pb-dependent renal 

14 mitochondrial dysfunction (Wang et al., 2009c).

15 Overall, epidemiologic and toxicological studies have reported increased risk of Pb16 related health effects among those with high Cd levels as well; however, the number of 

17 studies examining both metals is small.

6.3.13.2 Arsenic 

18 In a study of immune function among children living at varying distances from a Pb 

19 smelter in Mexico, higher levels of both Pb and arsenic (As) were associated with greater 

20 decreases in NO and greater increases in superoxide anion (Pineda-Zavaleta et al., 2004).

6.3.13.3 Manganese 

21 Among children in South Korea taking part in a study of IQ, an interaction was reported 

22 between Pb and manganese (Mn) blood levels (Kim et al., 2009b). Compared to children 

23 with low blood Mn levels, those with high blood Mn levels had greater reductions in full 

24 scale IQ and verbal IQ associated with increased blood Pb levels. No effect measure 

25 modification by Mn was observed for the association between blood Pb levels and 

26 performance IQ. A study performed among children in Mexico City observed greater 

27 decreases in neurodevelopment with increases in blood levels of Pb and Mn at 12 
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1 months, compared to decreases in neurodevelopment observed for increased Pb levels

2 with low levels of Mn (Claus Henn et al.). No interaction was observed between the two 

3 metals and neurodevelopment at 24 months. 

6.4 Summary 

4 Among children, the youngest age groups were observed to be most at risk of elevated 

5 blood Pb levels, with levels decreasing with increasing age of the children. Recent 

6 epidemiologic studies of infants/children detected increased risk of Pb-related health 

7 effects, and this was supported by toxicological studies. However, this is based on a 

8 limited number of epidemiologic studies, and more studies are needed for comparing 

9 various age groups and examining adolescents.

10 For adults, elevated Pb biomarkers were associated with increasing age. It is generally 

11 thought that these elevated levels are related to remobilization of stored Pb during bone 

12 loss. Studies of older adults had inconsistent findings for effect measure modification of 

13 Pb-related mortality but no difference was observed for other health effects. However, 

14 toxicological studies support the possibility of age-related differences in Pb-related health 

15 effects. 

16 Some studies suggest that males at some ages have higher blood Pb levels than 

17 comparably aged females; this was supported by stratifying the total sample of NHANES 

18 subjects. Sex-based differences appeared to be prominent among the adolescent and adult 

19 age groups but were not observed among the youngest age groups (1-5 years and 6-11 

20 years). Studies of effect measure modification of Pb and various health endpoints by sex 

21 were inconsistent, although it appears that there are some differences in associations for 

22 males and females. This is also observed in toxicological studies. 

23 Regarding race and ethnicity, recent data suggest that the difference in blood Pb levels 

24 between black and white subjects is decreasing over time, but black subjects still tend to 

25 have higher Pb body burden and Pb exposures than white subjects. Similarly, the gap 

26 between SES groups with respect to Pb body burden appears to be diminishing, with Pb 

27 body burden being higher, but not appreciably higher, among lower income subjects. 

28 Studies of race/ethnicity as a factor affecting risk indicate that some modification of 

29 associations between Pb levels and health effects may be present. Compared to whites, 

30 non-white populations were observed to be more at risk of Pb-related health effects; 

31 however, this could be related to confounding by factors such as SES or differential 

32 exposure levels, which was noted in some of the epidemiologic studies. Although limited 

33 by the number of studies, individuals with lower SES appear to represent an at-risk 

34 population. A study of Pb and IQ reported greater inverse associations among those in the 
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1 lowest SES groups. Additionally, there is evidence associating proximity to areas with Pb 

2 sources, including urban areas with large industrial sources, with increased Pb body 

3 burden and risk of Pb exposure.

4 Various genes were examined as potentially modifying the associations between Pb and 

5 health effects. Epidemiologic and toxicological studies reported that ALAD variants may 

6 increase the risk of Pb-related health effects. Other genes examined that may also affect 

7 risk of Pb-related health effects were VDR, DRD4, GSTM1, TNF-α, eNOS, APOE, and 

8 HFE, although the number of studies examining effect measure modification by these 

9 genes was small. 

10 Evidence for other factors (pre-existing diseases/conditions, smoking, BMI and/or 

11 obesity, alcohol consumption, nutritional factors, stress, cognitive reserve, and co12 exposure with other metals) was limited regarding their effect on Pb-related health 

13 outcomes. Pre-existing diseases/conditions have the potential to affect the risk of Pb14 related health effects. Recent epidemiologic studies did not support modification of 

15 associations between Pb and health endpoints by the prevalence of diabetes; however, 

16 past studies have found individuals with diabetes to be an at-risk population with regard 

17 to renal function. Hypertension was observed to be a factor affecting risk in both past and 

18 recent epidemiologic studies. Studies of Pb levels and both renal effects and heart rate 

19 variability demonstrated greater odds of the associations among hypertensive individuals 

20 compared to those that are normotensive. Epidemiologic studies also examined autism 

21 and atopy as potential factors affecting Pb-related health effects; differences were 

22 observed but few studies were available to examine these factors. Recent epidemiologic 

23 studies examining smoking as a factor potentially affecting risk reported mixed findings. 

24 It is possible that smoking modifies the effects of only some Pb-related health outcomes. 

25 BMI, alcohol consumption, and nutritional factors were also examined in recent 

26 epidemiologic and toxicological studies. Modification of associations between Pb and 

27 various health effects (mortality and heart rate variability) was not observed for 

28 BMI/obesity. Also, no modification was observed in an epidemiologic study of renal 

29 function examining alcohol consumption as a modifier, but a toxicological study 

30 supported the potential of alcohol to affect risk. Among nutritional factors, those with 

31 iron deficiencies were observed to be an at-risk population for Pb-related health effects in 

32 both epidemiologic and toxicological studies. Other nutritional factors, such as calcium, 

33 zinc, and protein intake, demonstrated the potential to modify associations between Pb 

34 and health effects in toxicological studies. Recent epidemiologic studies of these factors 

35 were either not performed or observed no effect modification. Folate was also examined 

36 in an epidemiologic study of birth size but no interaction was reported between Pb and 

37 folate. Stress was evaluated as a factor that potentially increases the risk of Pb-related 

38 health outcomes and although there were a small number of recent epidemiologic studies, 
February 2012 6-38 Draft – Do Not Cite or Quote

1 increased stress was observed to negatively impact the association between Pb and health 

2 endpoints. Toxicological studies supported this finding. An epidemiologic study 

3 evaluated cognitive reserve as a modifier of the associations between Pb and cognitive 

4 and motor functions. Cognitive reserve was an effect measure modifier for the 

5 association between Pb and cognitive function but not motor function. Finally, 

6 interactions between Pb and co-exposure with other metals were evaluated in recent 

7 epidemiologic and toxicological studies of health effects. High levels of other metals, 

8 such as Cd, As, and Mn, were observed to result in greater effects for the associations 

9 between Pb and various health endpoints.

10

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