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Chapter 6 Contents

Chapter 6. Susceptible Populations and Lifestages ________________________________________________________ 6-1

6.1. Susceptibility Factors and Lifestages Related to Lead Exposure and Dose _______________________________ 6-2

6.1.1. Lifestage__________________________________________________________________________ 6-3

6.1.1.1. Young Children ____________________________________________________________ 6-3

Table 6-1. Blood Pb levels broken down by age and gender, 2007-2008 NHANES ___________6-3

Table 6-2. Percentage of children within six brackets of blood Pb levels, from NHANES 

2003-2004 ________________________________________________________6-4

6.1.1.2. Adults 6-5

6.1.2. Sex ______________________________________________________________________________ 6-6

6.1.3. Race and Ethnicity __________________________________________________________________ 6-6

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

children (1-5 years) from the NHANES survey, 1988-1991 (top) and 1999-

2004 (bottom)._____________________________________________________6-7

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

greater metropolitan New Orleans, by race and ethnicity. ___________________6-8

6.1.4. Socioeconomic Status (SES) __________________________________________________________ 6-8

6.1.5. Proximity to Lead Sources ____________________________________________________________ 6-9

6.2. Susceptibility Factors and Lifestages Related to Lead Induced Health Effects ___________________________ 6-10

Table 6-3. Summary of new evidence for characteristics examined as potential 

susceptibility factors and lifestages for lead-related health effects ____________6-10

6.2.1. Lifestage_________________________________________________________________________ 6-11

6.2.1.1. Children _________________________________________________________________ 6-11

6.2.1.2. Older Adults ______________________________________________________________ 6-12

6.2.2. Sex _____________________________________________________________________________ 6-14

6.2.3. Hormones________________________________________________________________________ 6-16

6.2.4. Genetics _________________________________________________________________________ 6-17

6.2.4.1. Aminolevulinate Dehydratase ________________________________________________ 6-17

6.2.4.2. Vitamin D Receptor ________________________________________________________ 6-18

6.2.4.3. Methylenetetrahydrofolate reductase ___________________________________________ 6-19

6.2.4.4. Apolipoprotein E __________________________________________________________ 6-19

6.2.4.5. Hemochromatosis__________________________________________________________ 6-19

6.2.4.6. Other Genetic Polymorphisms ________________________________________________ 6-20

6.2.5. Pre-existing Diseases/Conditions ______________________________________________________ 6-20

6.2.5.1. Autism6-20

6.2.5.2. Atopy 6-21

6.2.5.3. Diabetes _________________________________________________________________ 6-21

6.2.5.4. Hypertension _____________________________________________________________ 6-22

6.2.6. Smoking _________________________________________________________________________ 6-22

6.2.7. Race/Ethnicity ____________________________________________________________________ 6-23

6.2.8. Socioeconomic Status ______________________________________________________________ 6-24

6.2.9. Body Mass Index __________________________________________________________________ 6-24

6.2.10. Alcohol Consumption ______________________________________________________________ 6-25

6.2.11. Nutrition_________________________________________________________________________ 6-25

6.2.11.1. Calcium _________________________________________________________________ 6-25

6.2.11.2. Iron 6-26

6.2.11.3. Zinc 6-26

6.2.11.4. Folate 6-26

6.2.11.5. Protein 6-26

6.2.12. Stress ___________________________________________________________________________ 6-26
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6.2.13. Cognitive Reserve _________________________________________________________________ 6-27

6.2.14. Other Metal Exposure ______________________________________________________________ 6-27

6.2.14.1. Cadmium ________________________________________________________________ 6-28

6.2.14.2. Arsenic __________________________________________________________________ 6-28

6.2.14.3. Manganese _______________________________________________________________ 6-28

6.2.15. Fluoride _________________________________________________________________________ 6-28

6.3. Summary ________________________________________________________________________________ 6-29

Chapter 6. References ____________________________________________________________________________ 6-32
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Chapter 6. Susceptible Populations

and Lifestages

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

2 populations are at increased risk for detrimental effects of ambient exposure to an air pollutant. The 

3 NAAQS are intended to provide an adequate margin of safety for both the population as a whole and 

4 those individuals potentially at increased risk for health effects in response to ambient air pollution 

5 (Section 1.1). Several studies have evaluated factors to identify populations at greater risk for Pb-related 

6 health effects. Many studies have termed such increased risk as the susceptibility and/or vulnerability of 

7 an individual to Pb. The definition for both of these terms has been found to vary across studies, but in 

8 most instances susceptibility refers to biological or intrinsic factors (e.g., lifestage, sex) while 

9 vulnerability refers to non-biological or extrinsic factors (e.g., socioeconomic status [SES]) (U.S. EPA, 

10 2009, 2010). Additionally, in some cases, the terms “at-risk” and sensitive populations have been used to 

11 encompass these concepts more generally. However, in many cases, a factor identified that increases an 

12 individual's risk for morbidity or mortality effects from exposure to an air pollutant cannot be easily 

13 categorized as either a susceptibility or vulnerability factor. 

14 As developed in previous ISAs and reviews (Sacks et al.; U.S. EPA, 2009, 2010), an all 

15 encompassing definition for “susceptible population” is used to circumvent the need to distinguish 

16 between susceptible and vulnerable, and to identify the populations at greater risk for Pb-induced health 

17 effects. This definition identifies susceptible populations as the following: 

Individual- and population-level characteristics that increase the risk of Pb-related health 

effects in a population including, but not limited to: genetic background, birth outcomes (e.g., low 

birth weight, birth defects), race, sex, lifestage, lifestyle (e.g., smoking status, nutrition), preexisting 

disease, SES (e.g., educational attainment, reduced access to health care), and characteristics that 

may modify exposure to Pb (e.g., time spent outdoors).

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

19 stratified analyses to identify the presence or absence of effect measure modification. A thorough 

20 evaluation of potential effect measure modifiers may help identify populations that are more susceptible 

21 to Pb. Toxicological studies provide support and biological plausibility for factors that may lead to 

22 increased susceptibility for Pb-related health effects through the study of animal models of disease. 

23 Therefore, the results from these studies, combined with those results obtained through stratified analyses 

 

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (Health and Environmental 

Research Online) at http://epa.gov/hero. HERO is a database of scientific literature used by U.S. EPA in the process of developing science 

assessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS).
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1 in epidemiologic studies, comprise the overall weight of evidence for the increased susceptibility of 

2 specific populations to Pb-related health effects. 

3 The first section of this chapter summarizes susceptibility of population groups related to 

4 differential Pb body burden. The studies presented in this section supplement the material provided in 

5 Chapters 3 and 4 by examining how susceptibility factors, such as age, race, ethnicity, and SES may affect 

6 Pb body burden, as measured by blood Pb or bone Pb. These biomarkers are influenced to varying 

7 degrees by exposure, absorption, biokinetics, and diet. The second section of this chapter discusses the 

8 epidemiologic and toxicological studies evaluated in Chapters 5 that provide information on potentially 

9 susceptible factors related to Pb-induced health effects. Highlighted studies include only those where the 

10 population was stratified into subgroups (e.g., males vs. females) for comparative analysis. In the case of 

11 many biomarker studies and the epidemiologic studies considered, this approach allowed for a 

12 comparison between populations exposed to similar Pb concentrations and within the same study design. 

13 Additionally, the section on susceptibility and Pb body burden explores how susceptibility factors may be 

14 related to differential Pb exposures, where data are available. Numerous studies that focus on only one 

15 potentially susceptible population are described in previous chapters, but these studies are not discussed 

16 in detail in this chapter because they lack an adequate comparison group. For example, pregnancy is a 

17 potentially susceptible lifestage for mothers and fetuses, but because there are no comparison groups for 

18 stratified analyses, these studies are presented in Chapter 5 and are not included here. Included 

19 toxicological studies may categorize the study population by age, sex, diet, genetics, etc. or are those with 

20 animal models of disease.

21 Additionally, it is understood that some of the stratified variables may not be effect measure 

22 modifiers but instead may be mediators of Pb-related health effects. Factors that are mediators are on the 

23 causal pathway between Pb and health outcomes, while effect measure modifiers are factors that result in 

24 changes in the measured association between Pb and health effects. Because mediators are caused by Pb 

25 exposure and are also intermediates in the disease pathway that is studied, mediators are not correctly 

26 termed susceptibility factors. Some of the factors included in this chapter could be mediators and/or 

27 modifiers. These are noted in Table 6-3.

6.1. Susceptibility Factors and Lifestages 

Related to Lead Exposure and Dose

28 Elevated Pb biomarkers have been shown to be statistically related to several population 

29 characteristics, including age, gender, race and ethnicity, SES, and urbanization (U.S. EPA, 2006). In most 

30 cases, exposure, absorption, and biokinetics of Pb are all influenced to varying degrees by susceptibility 

31 factors. The relative importance of susceptibility factors on exposure, absorption, and biokinetics varies 
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1 on an individual basis and is difficult to quantify. The following section distinguishes studies 

2 demonstrating a relationship between each susceptibility factor and exposure status from those that are 

3 associated with increased biomarker levels without a clear attribution of the relative effects of those 

4 factors on exposure, absorption, and bioavailability.

6.1.1. Lifestage

6.1.1.1. Young Children

5 Typically, children have increased exposure to Pb compared with adults because children’s 

6 behaviors and activities include increased hand-to-mouth contact, crawling, and poor hand-washing (U.S. 

7 EPA, 2006). Children can be susceptible to Pb exposure because outdoor play can lead to hand-to-mouth 

8 contact with contaminated soil. For example, Zahran et al. (2010) observed that a 1% reduction in soil Pb 

9 concentration led to a 1.55 μg/dL reduction in median blood Pb levels (p <0.05) among New Orleans 

10 children. 

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

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

13 children, highest blood Pb levels occurred in the 1-5 year age group, and within this subgroup, 1 year old 

14 children had the highest blood Pb levels (99th percentile: 16.9 μg/dL). It is possible that high blood Pb 

15 levels among these young children may also be related to in utero exposures resulting from maternal Pb 

16 remobilization from bone stores from historic exposures (Miranda et al., 2010). Jones et al. (2009)

17 analyzed the NHANES dataset for the years 1988-2004 to study trends in blood Pb among different age 

18 groups over time (see Table 6-2). They observed greater percentages of children aged 1-2 year having 

19 blood Pb levels between 2.5 and 5 μg/L compared with 3-5 year old children. Similarly, the 1-2 year old 

20 group had larger percentages with blood Pb levels between 5 and 7.5 μg/dL compared with 3-5 year old 

21 children. These differences may be attributable to differences in exposure, age-dependent variability in 

22 absorption and biokinetics, or diet (milk/formula versus child diets). Yapici et al. (2006) studied the 

23 relationship between blood Pb level and age among a cohort of children younger than 73 months living in 

24 proximity to a Turkish coal mine. They observed a low but statistically significant negative correlation 

25 between blood Pb and age (r = -0.38, p <0.001). 

Table 6-1. Blood Pb levels broken down by age and gender, 2007-2008 NHANES

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

1-5 yr total 2.03 2.01 0.69 1.08 1.54 2.34 4.50 10.56

male 2.01 2.14 0.71 1.10 1.50 2.40 4.21 8.56

female 2.05 1.85 0.66 1.02 1.60 2.28 4.65 10.70

1 yr total 2.62 3.26 0.76 1.24 1.80 2.88 6.23 16.94
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male 2.70 3.98 0.76 1.29 1.80 2.75 5.59 19.82

female 2.53 2.27 0.79 1.22 1.75 2.98 6.42 11.39

2 yr total 2.09 1.52 0.76 1.28 1.77 2.40 4.34 8.40

male 1.99 1.11 0.72 1.30 1.76 2.40 3.82 6.04

female 2.20 1.84 0.82 1.27 1.77 2.35 4.52 10.75

3 yr total 1.99 1.80 0.65 1.04 1.50 2.32 4.92 8.55

male 1.99 1.55 0.68 1.11 1.50 2.35 5.09 8.46

female 1.99 2.08 0.65 0.93 1.40 2.16 4.64 9.81

4 yr total 1.75 1.31 0.69 1.00 1.40 1.90 4.03 6.31

male 1.80 1.47 0.71 1.05 1.30 2.07 4.09 6.89

female 1.66 1.03 0.64 0.98 1.41 1.89 3.78 5.31

5 yr total 1.62 1.22 0.64 0.87 1.29 1.90 3.37 7.29

male 1.58 0.97 0.72 0.95 1.29 1.88 3.38 4.96

female 1.68 1.50 0.62 0.80 1.30 2.04 3.33 8.52

6-11 yr total 1.27 0.87 0.49 0.75 1.06 1.50 2.84 4.80

male 1.29 0.92 0.48 0.74 1.08 1.50 2.90 4.76

female 1.25 0.83 0.50 0.78 1.03 1.49 2.80 4.80

12-19 yr total 0.99 0.73 0.40 0.59 0.81 1.13 2.11 4.00

male 1.13 0.82 0.44 0.69 0.94 1.30 2.41 4.11

female 0.83 0.57 0.37 0.52 0.69 0.91 1.70 3.36

20-64 yr total 1.76 1.57 0.53 0.91 1.40 2.10 4.20 7.42

male 2.13 1.93 0.68 1.12 1.65 2.49 5.22 9.07

female 1.41 1.01 0.47 0.78 1.13 1.73 3.13 5.10

65+ yr total 2.31 1.64 0.80 1.30 1.90 2.70 5.22 8.54

male 2.63 1.66 0.99 1.52 2.19 3.20 5.86 9.03

female 1.98 1.56 0.75 1.17 1.62 2.40 4.14 6.95

Source: CDC (2009a).

Table 6-2. Percentage of children within six brackets of blood Pb levels, from NHANES 

2003-2004 

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 2532 1.9 14.0 55.0 23.6 4.5 1.5 1.4

Gender

Girl 1211 1.9 14.1 54.5 23.9 4.5 1.4 1.7

Boy 1321 1.9 14.0 55.5 23.2 4.6 1.5 1.3

Age

1-2 yr 1231 2.1 10.6 51.0 27.9 6.7 1.4 2.4

3-5 yr 1301 1.7 16.2 57.6 20.7 3.1 1.5 0.9

Race/Ethnicity

Non-Hispanic 

Black 755 2.8 4.0 42.5 36.2 9.4 4.6 3.4

Mexican 

American 812 1.9 10.9 61.0 22.1 3.4 1.3 1.2

Non-Hispanic 

White 731 1.7 17.6 57.1 19.7 3.6 0.8 1.2

PIR

≤ 1.3 1302 2.4 6.7 49.3 32.5 6.9 2.8 1.8

>1.3 1070 1.5 19.9 60.4 16.0 2.3 0.6 0.8
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Source: Jones et al. (2009)

6.1.1.2. Adults

1 Blood Pb levels tend to be higher in the elderly compared with the general adult population. Table 

2 6-1 presents 2007-2008 NHANES data broken down by age group and shows that blood Pb levels were 

3 highest in the >65-years age group in comparison with adults aged 20-64 years. In a study of blood Pb 

4 and saliva Pb in a mostly female population in Detroit, Nriagu et al. (2006) found that age was a 

5 statistically significant positive predictor of both blood Pb (p < 0.001) and saliva Pb (p < 0.001). Average 

6 blood Pb levels among 14- to 24-year-old subjects was 2.6 μg/dL compared with 4.3 μg/dL among 

7 subjects aged 55 years or older; similarly, average saliva Pb levels among 14- to 24-years-old subjects 

8 was 2.5 μg/L compared with 3.6 μg/L among subjects aged 55 years or older. Higher average and median 

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

10 exposures stored in bone (see section 4.1) in conjunction with remobilization of stored Pb during bone 

11 loss (Section 4.2).

12 Theppeang et al. (2008) studied Pb concentrations in the blood, tibia, and patella of subjects age 

13 50-70 as part of the Baltimore Memory Study. They found a statistically significant relationship between 

14 age and tibia Pb (β = 0.37, p <0.01 in a model including age, race, Yale energy index, and 2 diet variables; 

15 β = 0.57, p <0.01 in a model including age, gender, and an interaction term for gender and age, which was 

16 also statistically significant at p = 0.03). Theppeang et al. (2008) also noted that patella Pb concentrations 

17 increased with age, although the data quality for patella Pb was not as high, so the authors did not present 

18 the data or significance levels. A statistically significant relationship was not observed between the log19 transform of blood Pb and age (β = 0.007, p = 0.11), although the age range of subjects may not have 

20 been sufficient to discern a difference in blood Pb.

21 Fetal and child Pb biomarkers have been demonstrated to relate to maternal Pb biomarkers; several 

22 older studies in the literature are presented in the 2006 AQCD (U.S. EPA, 2006). Kordas et al. (2010)

23 observed that maternal hair Pb concentration was a statistically significant predictor of child hair Pb 

24 concentration (β = 0.37±0.07, p < 0.01). Miranda et al. (2010) observed that pregnant women ages 30-34 

25 and 35-39 had statistically significant higher odds of having greater blood Pb levels than women in the 

26 25- to 29-years-old reference age category. These results could be related to a historical component to Pb 

27 exposure among mothers. These findings were also consistent with observations that Pb storage in bones

28 increased with age before subsequent release with bone decay during pregnancy, as described in Section 

29 4.2. Elevated blood Pb levels among mothers also present a potential exposure to their children in utero or 

30 through breast milk. 
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6.1.2. Sex

1 Several studies have suggested that sex influences levels of Pb biomarkers because differences in 

2 behavior between sexes may cause a differential increase in exposure. The 2007-2008 NHANES showed 

3 that overall, males have higher blood Pb levels (median: 1.50 μg/dL) than females (median: 1.14 μg/dL)

4 (see Table 6-1). Among adults aged 20-64 years, median blood Pb levels among males was 46% higher 

5 than for females, and average levels were 51% higher for males compared with females. Among adults 65 

6 years or older, median levels were 36% higher, and average levels were 33% higher. In their study of Pb 

7 burden among Baltimore adults aged 50-70 years, Theppeang et al. (2008) observed that average blood 

8 Pb levels were statistically significantly higher (p <0.01) among men (4.4 μg/dL) than women (3.1 

9 μg/dL). For average tibia Pb levels, Theppeang et al. (2008) noted no difference (p = 0.12) between men 

10 (18.0 μg/dL) and women (19.4 μg/dL). 

11 Among U.S. children, the 2007-2008 NHANES data show that blood Pb levels are higher among 

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

13 boys for the 6- to 11-years age group, and levels were substantially higher among adolescent males in the 

14 12- to 19-years age group. At the same time, blood Pb levels among both adolescent males and females 

15 were lower than blood Pb levels for the other age groups. The 2007-2008 NHANES data suggest that 

16 gender-based differences in blood Pb levels are not substantial until adolescence.

6.1.3. Race and Ethnicity

17 Higher blood Pb and bone Pb levels among African Americans has been well documented (U.S. 

18 EPA, 2006). Recent studies are consistent with those previous findings. For instance, Levin et al. (2008)

19 and Jones et al. (2009) both analyzed NHANES survey data to examine trends in childhood blood Pb 

20 levels. Data from the Jones et al. (2009) study, using 2003-2004 NHANES data (CDC, 2011), are shown 

21 in Figure 6-1. They found that differences among racial and ethnic groups with regard to the percentage 

22 with blood Pb levels greater than 2.5 μg/dL have decreased since the period of 1976-1980 when 

23 NHANES II was conducted. The non-Hispanic black group still had higher percentages with blood Pb 

24 levels above 2.5 μg/dL compared with non-Hispanic whites and Mexican Americans, with the largest 

25 observable differences between 2.5 and 10 μg/dL. It is notable that the distributions of blood Pb levels 

26 among Mexican American and non-Hispanic white children were nearly identical. Theppeang et al. 

27 (2008) also explored the effect of race and ethnicity on several Pb biomarkers in a study of older adults 

28 living in Baltimore. They observed a statistically significant difference between African American (AA) 

29 and Caucasian (C) subjects with respect to tibia Pb (AA: 21.8 μg/g, C: 16.7 μg/g, p <0.01) but not patella 

30 Pb (AA: 7.1 μg/g, C: 7.1 μg/g, p = 0.46) or blood Pb levels (AA: 3.6 μg/dL, C: 3.6 μg/dL, p = 0.69). 

31 Differences between bone Pb levels in African American and Caucasian subjects could potentially be 

32 related to differential exposures in the home environment.
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Data used with permission from the American Academy of Pediatrics, Jones et al. (2009)

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

among U.S. children (1-5 years) from the NHANES survey, 

1988-1991 (top) and 1999-2004 (bottom).

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

2 parishes in the greater metropolitan New Orleans area, Campanella and Mielke (2008) found that, where 

3 soil Pb levels were less than 20 mg/kg, the population was 55% white, 36% black, 3.0% Asian, and 6.0% 

4 Hispanic, based on the 2000 Census, with the percentage based on the total number living in Census 

5 blocks with the same soil Pb levels. In contrast, they found that the population was 34% white, 62% 

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 black, 1% Asian, and 4% Hispanic on Census blocks in which soil Pb levels were between 1,000 and 

2 5,000 mg/kg (Figure 6-2). As described in Section 6.1.4, the differences observed by Campanella and 

3 Mielke (2008) may also be attributable to SES factors, or SES may be a confounding factor in the 

4 relationship between Pb soil levels and race.

Source: Campanella and Mielke (2008).

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

parishes within greater metropolitan New Orleans, by race and 

ethnicity.

6.1.4. Socioeconomic Status (SES)

5 Socioeconomic factors have sometimes been associated with Pb biomarkers, although these 

6 relationships have not always been consistent. Nriagu et al. (2006) performed a multiple regression of 

7 blood Pb and saliva Pb levels on various socioeconomic, demographic, and exposure variables among an 

8 adult population in Detroit. Blood and saliva Pb were both used as indicators of Pb in unbound plasma 

9 that is available to organs. Nriagu et al. (2006) found that education (p <0.001), income (p <0.001) and 

10 employment status (p = 0.04) were all statistically significant predictors of blood Pb levels, with blood Pb 

11 decreasing with some scatter as education and income level increased. Statistically significant 

12 relationships were also reported by Nriagu et al. (2006) for saliva Pb level with respect to education (p 

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

50,000

<20 20-50 50-100 100-200 200-400 400-1,000 1,000-5,000 5,000-20,000 >20,000

Population

Soil Pb Concentration (μg/g)

Black

White

Asian

Hispanic
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1 <0.001), income (p <0.001), and employment (p = 0.06). However, the highest educational attainment and 

2 income categories had higher saliva Pb levels compared with other groups; Nriagu et al. (2006) attributed 

3 these inconsistencies to small sample sizes among the high educational attainment and income categories.

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

5 For example, Levin et al. (2008) cite NHANES data analyzed in Pirkle et al. (1994) that the percentage of 

6 children aged 1-5 years with blood Pb levels above 10 μg/dL was 4.5% for the lowest income group 

7 compared with 0.7% for the highest group. For the 1999-2002 NHANES, there was no statistically 

8 significant difference between the percent of children with blood Pb levels above 10 μg/dL for Medicaid9 enrolled children (1.7%) compared with non-enrolled children (1.3%), although Medicaid-enrolled 

10 children did have higher median blood Pb levels (2.6 μg/dL) compared to children not enrolled in 

11 Medicaid (1.7 μg/dL) (Levin et al., 2008). When adding data for 2003-2004 to the analysis (i.e., for 1999-

12 2004), the gap between Medicaid enrolled and non-enrolled children widened for blood Pb levels 

13 exceeding 10 μg/dL (1.9% versus 1.1%), but the difference was still not statistically significant (p > 0.05). 

14 Median blood Pb levels with respect to Medicaid status did not change when adding the 2003-2004 data 

15 (R. L. Jones et al., 2009). Likewise, Jones et al. (2009) analyzed blood Pb levels with respect to poverty16 income ratio (PIR). They found statistically significant differences in median blood Pb for PIR ≤ 1.3 

17 compared with PIR >1.3. The percentage of 1- to 5-year0old children having blood Pb above 10 μg/dL 

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

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

20 with respect to decreasing average household income, with soil Pb between 2.5 and 20 mg/kg associated 

21 with an average income of $40,000 per year, while soil Pb between 5,000 and 20,000 was associated with 

22 an average income of $24,000 per year. 

6.1.5. Proximity to Lead Sources

23 Airborne and soil Pb concentrations are higher in some urbanized areas, as described in Sections 

24 3.2, 3.3, 3.5 and 4.1, as a result of historical and contemporaneous Pb sources. High concentrations of 

25 ambient air Pb in PM tend to occur in the most urbanized areas and in close proximity to traffic in 

26 metropolitan areas (Laidlaw & Filippelli, 2008; Mielke et al., 2010; Weiss et al., 2006). Moreover, air Pb 

concentrations exhibit high spatial variability even at low concentrations (~0.01 μg/m3 27 ) (Martuzevicius et 

28 al., 2004). These conditions present the potential for additional risk of Pb exposure in urban areas.

29 Proximity to an industrial source likely contributes to higher Pb exposures, as described in the 2006 

30 AQCD (U.S. EPA, 2006) for several studies of superfund and other industrial sites. This is consistent with 

31 the observation of higher air concentrations at source oriented Pb monitoring sites compared with non32 source oriented sites in the 2007-2009 data presented in Section 3.5. Jones et al. (2010) found that 

33 neonates born near a Pb-contaminated urban industrial site had statistically significantly higher cord 
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1 blood Pb levels (median: 2.2 μg/dL; 95% CI: 1.5, 3.3 μg/dL) compared with a reference group of 

2 neonates not living near a potentially contaminated site (median: 1.1 μg/dL; 95% CI: 0.8, 1.3 μg/dL), 

3 suggesting that current industrial Pb exposures contribute to neonatal Pb levels. The population studied in 

4 Jones et al. (2010) was 88% African-American; 75% had a high school degree or equivalent, while 20% 

5 had a college degree and 5% attended but did not graduate from high school. However, the Jones et al. 

6 (2010) study did not analyze covariation between exposure and maternal characteristics, so it cannot be 

7 determined if differences in characteristics among the groups with and without industrial exposures 

8 confounded these results.

6.2. Susceptibility Factors and Lifestages 

Related to Lead Induced Health Effects

9 The following section evaluates potential susceptibility factors examined as effect measure 

10 modifiers of various Pb-related health effects. Table 6-3 provides an overview of the factors examined and 

11 populations identified as susceptible to Pb-related health effects based on the recent evidence integrated 

12 across disciplines. Each characteristic is described in greater detail in the following sections.

Table 6-3. Summary of new evidence for characteristics examined as potential 

susceptibility factors and lifestages for lead-related health effects

Factor Evaluated Susceptible Population

Lifestage Children

Sex Malesa Femalesa

Genetics ALADa, VDRa*, DRD4a*, GSTM1a, TNF-alphaa, eNOSa, APOEa, HFEa

Pre-existing Disease Autismab, Atopyab, Hypertensionb

Smoking Smokersa

Race/Ethnicity Non-Hispanic Blacksa, Hispanicsa

Socioeconomic Status (SES) Low SESa

Nutrition Iron deficiency

Stress High stress

Cognitive Reserve Low cognitive reserveab

Other Metals Cda, Asa, Mna

a

Additional evidence is needed to confirm whether the characteristic evaluated results in increased susceptibility to Pb-related health effects. b

Possible mediator
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6.2.1. Lifestage

1 The previous Pb AQCD reported on susceptibility by age (U.S. EPA, 2006). The greatest ingestion 

2 of Pb is often at the same time as development in children. Older adults are more likely to have age3 related degeneration of bones and organ systems and a possible redistribution of Pb. Therefore, increased 

4 susceptibility of Pb-related health effects is a concern for these populations. Below is information from 

5 epidemiologic and toxicological studies regarding studies of susceptibility for children and older adults. 

6.2.1.1. Children

6 According to the 2000 Census, 28.6% of individuals living in the U.S. were under the age of 20, 

7 with 6.8% aged 0-4 years, 7.3% aged 5-9 years, 7.3% aged 10-14 years, and 7.2% aged 15-19 years 

8 (SSDAN, 2010a). It is recognized that Pb can cross the placenta to affect the developing nervous system

9 of the fetus (Sections 4.2.2.4 and 5.3.2.1) and there is evidence of increased susceptibility to the 

10 neurocognitive effects of Pb exposure during several lifestages throughout childhood and into 

11 adolescence (for more detail, see Section 5.3.2.1). Epidemiologic studies have investigated susceptibility 

12 among infants compared to adults or infants to young children. 

13 A study including multiple U.S. locations examined associations of blood Pb levels with various 

14 immune parameters among individuals living near Pb industries and matched controls (Sarasua et al., 

15 2000). For several of the endpoints, the association in the youngest group (6-35 months) and the oldest 

16 group (16-75 years) were in different directions. For example, among children ages 6-35 months, the 

17 associations between blood Pb levels and Immunoglobulin A (IgA), Immunoglobulin M (IgM), and B-cell 

18 abundance were positive, whereas the associations among 16-75 year olds were negative. The opposite 

19 associations were present for T cell abundance. Ig antibodies, which are produced by activated B cells, are 

20 important mediators of the humoral immune response to antigens. T cells are important mediators of cell21 mediated immune responses that involve activation of other immune cells and cytokines. These findings 

22 by Sarasua et al. (2000) indicate that very young children may be at increased susceptibility for Pb23 associated inappropriate activation of humoral immune responses and perturbations in cell-to-cell 

24 interactions that underlie allergic, asthma, and inflammatory responses (for more information, see 

25 Sections 5.6.2.1 and 5.6.3). 

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

27 transferrin saturation (TS) less than 12% and iron-deficiency anemia (IDA) (Muwakkit et al., 2008). A 

28 positive association was detected for blood Pb levels ≥ 10 μg/dL and both TS less than 12% and IDA 

29 among children aged 11-23 months old, however null associations were observed among children 24-35 

30 months old. Calculations were not performed for children aged 36-75 months because there were no 

31 children in the highest Pb group (≥ 10 μg/dL) with either TS <12% or IDA. The authors note that it is 
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1 difficult to know whether the Pb levels were “a cause or a result of” IDA levels since previous studies 

2 linked iron deficiency with Pb toxicity.

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

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

5 the blood brain barrier) and GI system (i.e., gut closure) are immature, are more susceptible to Pb 

6 exposure (Fullmer et al., 1985). Younger animals tend to attain a higher blood Pb level than older animals 

7 exposed to the same dose (mg/kg body weight/day) of Pb (Berrahal et al., 2011). Additionally, infants 

8 may be a susceptible population because Pb easily crosses the placental barrier and accumulates in fetal 

9 tissue during gestation (Pillai et al., 2009; Uzbekov et al., 2007; Y.-Y. Wang et al., 2009). 

10 Overall evidence indicates young age as a potential susceptibility factor for Pb-related health 

11 effects. Both recent epidemiologic studies summarized above reported associations among the youngest 

12 age groups, although different age cut-points were used with one study including only infants 35 months 

13 of age and younger. Toxicological studies provide support for increased health effects of Pb among 

14 younger age groups.

6.2.1.2. Older Adults

15 The number of Americans over the age of 65 will be increasing in upcoming years (estimated to 

16 increase from 12.4% of the U.S. population to 19.7% between 2000 to 2030, which is approximately 35 

17 million and 71.5 million individuals, respectively) (SSDAN, 2010a; U.S. Census Bureau, 2010). As of the 

18 2000 Census, 7.2% of the U.S. population were ages 60-69, 5.8% were 70-79, and 3.3% were age 80 and 

19 older (SSDAN, 2010a). 

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

21 less than 60 years old and individuals 60 years and older (Menke et al., 2006). Although the hazard ratios 

22 were greater for all-cause and cardiovascular mortality among those less than 60 years old, an increase in 

23 the hazard ratios was also observed among those 60 years of age and older and the interactions terms were 

24 not statistically significant. A similar study using the NHANES III cohort examined the relationship 

25 between blood Pb levels and mortality from all-cause, cardiovascular disease, and cancer broken down 

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

27 comparing blood Pb levels of at least 10 μg/dL to blood Pb levels less than 5 μg/dL and all-cause 

28 mortality for all age groups (40-74, 75-84, and 85+ year olds), although the association for 75-84 year 

29 olds did not reach statistical significance. The association was also present comparing blood Pb levels of 

30 5-9 μg/dL to blood Pb levels less than 5 μg/dL among 40-74 year olds and 75-84 year olds but not among 

31 those 85 years and older. None of the associations between blood Pb and cardiovascular disease-related 

32 mortality reached statistical significance but the point estimates comparing blood Pb levels of 10 μg/dL 

33 and greater to those less than 5 μg/dL were elevated among all age groups. Finally, the association 
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1 between blood Pb levels 10 μg/dL and greater and cancer mortality was positive among those 40-74 years 

2 old and 85 years and older but the association was null for those 75-84 years old. Among 75-84 year olds 

3 the association was positive comparing blood Pb of 5-9 μg/dL to less than 5 μg/dL. The other age groups 

4 had similar point estimates but the associations were not statistically significant. 

5 The NHANES III study cohort was also used to investigate the association between blood Pb and 

6 cognitive test scores (Krieg et al., 2009). The relationship was examined among adults aged 20-59 and 60 

7 years and older, but no association was observed in either of the age groups. A study using the Normative 

8 Aging Study cohort reported an interaction between Pb and age (R. O. Wright, Tsaih, et al., 2003). The 

9 inverse association between age and cognitive function was greater among those with high blood or 

10 patella Pb levels. Effect estimates were in the same direction for tibia Pb but the interaction was not 

11 statistically significant.

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

13 (dichotomous cutpoint at 67th percentile but exact age not given) examined in a model of Pb and blood 

14 pressure was not statistically significant (Weaver et al., 2008). Thus, no modification by age was observed 

15 in this study of Pb and blood pressure.

16 Toxicological studies have demonstrated biological plausibility for increased susceptibility among 

17 older populations. Demineralization associated with aging may increase the pool of available Pb to the 

18 blood. Cory-Slechta (1990) administered various doses of Pb for a constant period to young animals, 

19 adults, or aged animals and found increased susceptibility to Pb in the aged animals due to increased 

20 exposure from elevated bone resorption. 

21 Also the kidneys of older animals appear to be more susceptible to Pb-related health effects from 

22 the same dose of Pb (i.e., continuous 50 mg/L Pb acetate drinking water) than younger animals (Berrahal 

23 et al., 2011). Susceptibility related to older age is also observed for effects on the brain. Recent studies 

24 have demonstrated the importance of Pb exposure during early development in promoting the emergence

25 of Alzheimer’s like pathologies in aged animals. Development of pathologies of old age in brains of aged 

26 animals that were exposed to Pb earlier in life has been documented in multiple species (mice and 

27 monkeys). These pathologies include the development of neurofibrillary tangles and increased amyloid 

28 precursor protein and its product beta-amyloid (Basha et al., 2005; Zawia & Basha, 2005). Some of these 

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

30 Results for age-related modification of the association between Pb and mortality had mixed results 

31 and no difference by age was observed for the associations between Pb and other health effects. However, 

32 toxicological studies that inform on Pb-related health effects by age may be relevant in humans. Future 

33 studies will be instrumental in understanding older age as a susceptibility factor.
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6.2.2. Sex

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

2 was male and 50.9% were female. The distribution did vary by age with a greater prevalence of females ≥

3 65 years old compared to males (SSDAN, 2010a). The 2006 Pb AQCD reported that boys are often found 

4 to have higher blood Pb levels than girls, but findings were "less clear" regarding differences in Pb-related 

5 health effects between males and females (U.S. EPA, 2006).

6 Multiple epidemiologic studies have examined Pb-related effects on cognition stratified by sex. In 

7 previous studies using the Cincinnati Lead Study cohort, Dietrich et al. (1987) and Ris et al. (2004)

8 observed interactions between blood Pb and sex for both prenatal and postnatal exposures; associations of 

9 prenatal and postnatal blood Pb decrements in memory, attention, and visuoconstruction were observed 

10 only among male adolescents. More recently, Wright et al. (2008) examined early life Pb exposure and 

11 criminal arrests in adulthood. The attributable risks were greater among males than females. Additionally, 

12 the association between childhood blood Pb levels and gray matter volume loss was greater among males 

13 than females (Cecil et al., 2008). In an expanded analysis of the developmental trajectory of childhood 

14 blood Pb levels on adult gray matter, researchers found that inverse associations between yearly mean 

15 blood Pb levels and volume of gray matter loss were more pronounced in the frontal lobes of males than 

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

17 examined Pb exposures at various ages throughout childhood and adolescence (Baghurst et al., 1992; 

18 McMichael et al., 1992; Tong et al., 2000). These studies observed Pb effects on cognition were stronger 

19 in girls throughout childhood and into early adolescence. A study in Poland also investigated the 

20 association between cord Pb levels and cognitive deficits and reported an inverse association for boys at 

21 36 months but not for girls (Jedrychowski et al., 2009). No association was detected for boys or girls at 24 

22 months.

23 An epidemiologic study examined the association between blood Pb levels and kidney function 

24 among 12-20 year olds using the NHANES III study cohort (Fadrowski et al., 2010). The results were 

25 stratified by sex and no effect measure modification was apparent.

26 Similarly, a study of current and former Pb workers examined an interaction term between sex and 

27 Pb for the study of Pb and blood pressure (Weaver et al., 2008). No modification by sex was present. 

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

29 for Pb-related effects among biomarkers. A study comprised mostly of females reported positive 

30 associations between Pb and total immunoglobulin E (IgE) for women not taking hormone replacement 

31 therapy or oral contraceptives (Pizent et al., 2008). No association was reported in males, but other 

32 associations, such as bronchial reactivity and skin prick tests were observed in the opposite of the 

33 expected direction, which questions the validity of the results among the male study participants. Analysis 

34 of an NHANES dataset detected no association between Pb levels and inflammatory markers (Songdej et 
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1 al., 2010). Although there was no pattern, a few of the associations were positive between Pb and C2 reactive protein for males but not females. A study of children living at varying distances from a Pb 

3 smelter in Mexico reported that blood Pb was associated with increased release of superoxide anion from 

4 macrophages, which was greater among males than females (Pineda-Zavaleta et al., 2004). Additionally, 

5 blood Pb was inversely associated with the release of NO among males but not females. 

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

7 association between occupational exposure Pb and brain tumors reported no sex-specific associations for 

8 gliomas but a positive association for cumulative Pb exposure and meningiomas for males but not females 

9 (Rajaraman et al., 2006). An inverse association was observed between ever exposure to Pb and 

10 meningiomas for females. An ecologic analysis of Pb pollution levels and cancer incidence among 

11 children reported weak correlations overall and the weak correlations were more apparent among males, 

12 whereas no correlation was observed among females (Absalon & Slesak, 2010).

13 A study of all-cause and cardiovascular mortality using the NHANES III cohort reported no 

14 modification of the association between Pb and all-cause or cardiovascular mortality by sex (Menke et al., 

15 2006). This did not differ among women when classified as pre- or post-menopausal. 

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

17 systems. Donald et al (1986) reported a different time course of enhanced social investigatory behavior 

18 between male and female animals exposed to Pb. In a subsequent publication, Donald et al. (1987)

19 showed that non-social behavior decreased in females and increased in males exposed to Pb. Males also 

20 had a shorter latency to aggression with Pb treatment versus controls. Pb affected mood disorders 

21 differently for males and females. Behavioral testing showed males experienced emotional changes and 

22 females depression-like changes with Pb exposure (de Souza Lisboa et al., 2005). In another study, 

23 gestational exposure to Pb impaired memory retrieval in males at all 3 doses of Pb exposure; memory 

24 retrieval was only impaired in low-dose females (Yang et al., 2003).

25 Sex-specific differences were also observed for gross motor skills; at the lowest Pb dose, balance 

26 and coordination were most affected among males (Leasure et al., 2008). In addition, obesity in adult 

27 offspring exposed to low dose Pb in utero was reported for males but not females (Leasure et al., 2008). 

28 Obesity was also found in male offspring exposed in utero to high doses of Pb that persisted to 5 weeks of 

29 age/end of the study, but among females, body weight remained elevated over controls only to 3 weeks of 

30 age (Yang et al., 2003). Additionally, low-dose Pb exposure induced retinal decrements in exposed male 

31 offspring (Leasure et al., 2008). 

32 A toxicological study of Pb and antioxidant enzymes in heart and kidney tissue reported that male 

33 and female rats had differing enzymatic responses, although the amount of Pb in the heart tissue also 

34 varied between males and females (Alghazal et al., 2008; Sobekova et al., 2009). The authors reported 

35 these results could be due to greater deposition of Pb in female rats or greater clearance of Pb by males 

36 (Sobekova et al., 2009).
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1 Pb and stress are co-occurring factors that act in a sex-divergent manner to affect behavior, 

2 neurochemistry, and corticosterone. Pb and stress act synergistically to affect fixed interval operant 

3 behavior and corticosterone in female offspring. Virgolini et al. (2008) found that effects on the central 

4 nervous system by developmental Pb exposure are enhanced by combined maternal and offspring stress 

5 and females are most susceptible. Behavioral related outcomes after gestational and lactational Pb 

6 exposure with and without stress show sex-differences in exposed offspring (Virgolini, Rossi-George, 

7 Weston, et al., 2008). Pb-induced changes in brain neurochemistry with or without concomitant stress 

8 exposure are complex with differences varying by brain region, neurotransmitter type and sex of the 

9 animal.

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

11 dimorphic nucleus (SDN). Lesions in this area affect sex-specific phenotypes including behavior. Across 

12 species the SDN has a greater cell number and larger size in males versus females. This sexually 

13 dichotomous area is especially vulnerable to perturbation during fetal life and the early postnatal period. 

14 This may be one area of the brain that could explain some of the sexually dichotomous effects that are 

15 seen with Pb exposure. One study supporting this line of thought showed that high dose in utero Pb 

16 exposure (pup blood Pb level 64 μg/dL at birth) induced reductions in SDN volume in 35% of Pb17 exposed males {McGivern, 1991, 49264}. Interestingly, another chemical that is known to cause a 

18 hypothalamic lesion in this area, monosodium glutamate, is associated with adult onset obesity; adult 

19 onset obesity is seen in the Pb literature.

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

21 measure modification by sex. Although not observed in all endpoints, some studies reported differences 

22 between the associations for males and females, especially in neurological studies. However, studies on 

23 cognition from the Cincinnati Lead Study cohort and a study in Poland reported males to be the 

24 susceptible population, whereas studies from Australia pointed to females as the susceptible population. A 

25 difference in sex is also supported by toxicological studies. Further research will confirm the presence or 

26 absence of sex-specific associations between Pb and various health outcomes.

6.2.3. Hormones

27 It is possible that hormone levels may affect susceptibility to Pb-related health effects. Among 

28 women, various hormone-related categories were examined for the relationship between blood Pb levels 

29 and follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels. A positive association was 

30 observed between Pb levels and FSH levels among women who were post-menopausal, who were pre31 menopausal but not on birth control, menstruating, or pregnant, or who had both ovaries removed (Krieg, 

32 2007). An inverse association was observed for women taking birth control pills. For Pb and LH, there 
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1 was a positive association among women who were post-menopausal or had both ovaries removed. No 

2 associations for either hormone were observed for women who were pregnant or menstruating.

3 Toxicological studies provide evidence that Pb affects hormones and support the possible 

4 susceptibility to Pb-related health effects by hormonal status. Delayed onset of puberty (Pine et al., 2006)

5 as well as changes in the female reproductive tract have been reported in the literature after Pb exposure. 

6 Pb exposure can also alter estrous cyclicity (U.S. EPA, 2006), change cervical structure, and lead to 

7 ovarian dysfunction with altered membrane composition (Kolesarova et al., 2010; Nampoothiri et al., 

8 2007; Nampoothiri & Gupta, 2006; U.S. EPA, 2006). Additionally, embryo development and implantation 

9 enzymes are aberrant with Pb exposure (Nandi et al., 2010). In female offspring, delays in F1 and F2 

10 puberty onset, first estrous, and age of first parturition have been reported with in utero Pb exposure

11 (Iavicoli et al., 2006).

6.2.4. Genetics

12 The 2006 AQCD stated that, "genetic polymorphisms in certain genes have been implicated as 

13 influencing the absorption, retention, and toxicokinetics of Pb in humans" (U.S. EPA, 2006). The majority 

14 of discussion focused on aminolevulinate dehydratase (ALAD) and vitamin D receptor (VDR). These two 

15 genes, as well as additional genes examined in recent studies, are discussed below.

6.2.4.1. Aminolevulinate Dehydratase 

16 The aminolevulinate dehydratase gene encodes for an enzyme that catalyzes the second step in the 

17 production of heme and is also the principal Pb-binding protein (U.S. EPA, 2006). ALAD is a 

18 polymorphic protein with three isoforms: ALAD 1-1, ALAD 1-2, and ALAD 2-2. Multiple studies have 

19 examined the association between ALAD2 polymorphisms and blood Pb levels (Y. Chen et al., 2008; 

20 Chia et al., 2007; Chia et al., 2006; Montenegro et al., 2006; Scinicariello et al., 2007; Scinicariello et al., 

21 2010; Sobin et al., 2009; Zhao et al., 2007); ALAD polymorphisms may be biologically related to varying 

22 Pb levels. In addition, studies have examined whether ALAD variants alters associations between Pb and 

23 various health effects.

24 Associations between Pb and brain tumors observed in one study varied by ALAD genotype status 

25 (Rajaraman et al., 2006). Positive associations between Pb exposure and meningioma were reported 

26 among ALAD2 individuals but this association was not found among individuals who had the ALAD1 

27 allele. No associations were observed between Pb and glioma regardless of ALAD genotype. 

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

29 and blood pressure and reported no modification by ALAD genotype (Weaver et al., 2008). However, 

30 another study of blood Pb and blood pressure reported interactions between blood Pb and ALAD, but this 
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1 varied by race (non-Hispanic white, non-Hispanic black, and Mexican-American) (Scinicariello et al., 

2 2010).

3 Individuals with ALAD variants had greater associations between Pb and kidney effects; among 

4 those with the variant, higher Pb was associated with higher glomerular filtration measures (Weaver et al., 

5 2006; Weaver et al., 2003; Weaver et al., 2005). A study of Chinese battery plant storage workers reported 

6 workers with the ALAD2 allele demonstrated greater associations between Pb and renal injury (Gao et al., 

7 2010). Another study of renal function among workers in Asia also reported greater associations between 

8 Pb and renal function by ALAD, especially at high levels of Pb (Chia et al., 2006). 

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

10 modification by ALAD polymorphisms. In a study using a cohort from NHANES III, slight associations 

11 were observed in some cognitive tests for 20-59 year olds with CC and CG ALAD genotypes (Krieg et 

12 al., 2009). However, other studies reported no difference in the association between blood Pb and 

13 cognitive function by ALAD variant, although some difference was found when examining bone Pb 

14 levels and cognitive function (Rajan et al., 2008; Weisskopf et al., 2007; Weuve et al., 2006).

6.2.4.2. Vitamin D Receptor 

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

16 of the NHANES III population examined the association between blood Pb levels and various 

17 neurocognitive tests with assessment of effect measure modification by SNPs and haplotypes of VDR 

18 (Krieg et al., 2010). The results were varied, even among specific SNPs and haplotypes, with some 

19 variants being associated with greater modification of the relationship between Pb and one type of 

20 neurocognitive test compared to the modification of the relationship between Pb and other neurocognitive 

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

22 former Pb exposed workers, no modification was reported by VDR (Weaver et al., 2008). 

23 Three genetic variants or polymorphisms of the vitamin D receptor in humans have been 

24 characterized (BsmI, FokI, and ApaI) and have been reported to account for 75% of the differences in 

25 bone density in humans (Morrison et al., 1994; Morrison et al., 1992). The BsmI polymorphisms are 

26 denoted as bb (homozygote), BB (homozygote), and Bb (heterozygote). Bone measurements of Pb levels 

27 in exposed workers found that bone Pb was highest in individuals with the BB genotype, intermediate in 

28 the heterozygotes and lowest in the bb genotype group (Schwartz et al., 2000; Theppeang et al., 2004). 

29 People with the bb genotype or ff (FokI polymorphism) genotype have lower bone Pb than subjects with 

30 other genotypes. Subjects with the aa (ApaI polymorphism) or ff genotype have lower plasma Pb than 

31 subjects with other genotypes (Rezende et al., 2008). Plasma Pb is followed to look at bio-available Pb, 

32 instead of blood Pb, which largely reports Pb bound to the red blood cell. Thus, subjects with the 

33 haplotype combining a, b and f alleles for the aforementioned respective polymorphisms have lower 
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1 plasma Pb and bone Pb levels (Rezende et al., 2008). A study of pregnant women examining Pb in 

2 maternal and umbilical cord serum and blood found no association between VDR polymorphisms and 

3 these parameters. However there was lower Pb in women with the VDR haplotype combining the alleles f 

4 a and b, a group that is likely genetically less prone to Pb toxicity during pregnancy (Rezende et al., 

5 2010). 

6.2.4.3. Methylenetetrahydrofolate reductase 

6 Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 

7 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which in turn, is involved in homocysteine 

8 remethylation to the amino acid methionine. A study in Mexico of the association between Pb and 

9 Bayley's Mental Development Index (MDI) score at 24 months reported no effect measure modification 

10 by MTHFR 677T allele (Pilsner et al., 2010). Another study in Mexico examined the association between 

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

12 MTHFR was observed.

6.2.4.4. Apolipoprotein E 

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

14 to regulate synapse formation (connections between neurons) and may be particularly critical in early 

15 childhood. A genetic variant, called the APOE4 allele is a haplotype between two exonic SNPs and is 

16 perhaps the most widely studied genetic variant with respect to increasing risk of neurologic disease. A 

17 study of occupationally-exposed adults observed Pb to be associated with greater decrements in tests such 

18 as digit symbol, pegboard assembly, and complex reaction time among adults with at least one APOE-ε4 

19 allele (Stewart et al., 2002). Conversely, in a study of children in Mexico, children without the APOE-ε4

20 allele had a greater inverse association between umbilical cord Pb and Bayley’s MDI than children with

21 this allele, although the interaction term was not statistically significant (R. O. Wright, Hu, et al., 2003). 

6.2.4.5. Hemochromatosis 

22 The Hemochromatosis (HFE) gene encodes a protein believed to be involved in iron absorption. A 

23 difference was observed between the association of tibia Pb levels and cognitive function for men with 

24 and without HFE allele variants (F. T. Wang et al., 2007). No association between tibia Pb and cognitive 

25 function was present for men with HFE wildtype, but a decline in function associated with Pb levels 

26 among men with any HFE allele variant. A study of bone Pb levels and HFE reported no difference in 

27 effect estimates for bone Pb and pulse pressure between different HFE variants and HFE wild-type 

28 (Zhang et al., 2010).
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6.2.4.6. Other Genetic Polymorphisms

1 Some genetic polymorphisms have only one study examining whether they modify Pb-related 

2 health effects. These include dopamine 4 receptor (DRD4), glutathione S-transferase Mu 1 (GSTM1),

3 tumor necrosis factor-alpha (TNF-alpha), endothelial nitric oxide synthase (eNOS), and various SNPS.

4 A prospective birth cohort reported that increasing blood Pb levels were associated with poorer rule 

5 learning and reversal, spatial span, and planning in their study population (Froehlich et al., 2007). These 

6 inverse associations were exacerbated among those lacking DRD4.7.

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

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

9 present (J. H. Kim et al., 2007).

10 The relationship between blood Pb levels and inflammation was examined among individuals with 

11 TNF-alpha GG, GA, or AA alleles. An association was present for those with TNF-alpha GG but not for 

12 those with TNF-alpha GA or AA (J. H. Kim et al., 2007).

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

14 correlation among subjects with the eNOS TC+CC genotype (Barbosa et al., 2006). No correlation was 

15 observed for subjects with the eNOS TT genotype, however the number of subjects in this group was 

16 small, especially for those with high blood Pb levels. 

17 One study examined how the association between Pb and brain tumors varied among multiple 

18 single nucleotide polymorphisms (SNPs) (Bhatti et al., 2009). No effect measure modification of the 

19 association between Pb and glioma was observed for any of the SNPs. GPX1 (the gene encoding for 

20 glutathione peroxidase 1) modified the association for glioblastoma multiforme and meningioma. The 

21 association between Pb and glioblastma multiforme was also modified by a RAC2 (the gene encoding for 

22 Rac2) variant, and the association between Pb and meningioma was also modified by XDH (the gene 

23 encoding for xanthine dehydrogenase) variant. 

6.2.5. Pre-existing Diseases/Conditions

24 Studies have also been performed to examine whether certain morbidities make individuals more 

25 susceptible to Pb-related effects on health. Recent studies have explored relationships for autism, atopy, 

26 diabetes, and hypertension.

6.2.5.1. Autism

27 Rates of autism have increased in recent years. A study reported a prevalence rate in 2006 of 9.0 

28 per 1,000 population (95% CI: 8.6, 9.3) determined from a monitoring network (Autism and 

29 Developmental Disabilities Monitoring Network) with 11 sites across the U.S. (CDC, 2009b).
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1 A cross-sectional study of children with and without autism examined the association between 

2 blood Pb levels and various immune function and inflammation genes (Tian et al., 2011). Blood Pb levels 

3 among both autistic and non-autistic children were associated with expression of the inflammation genes 

4 under study, however the associations observed were in opposite directions (positive association among 

5 autistic children and inverse among non-autistic children).

6.2.5.2. Atopy

6 Atopy, a type of allergic hypersensitivity, was evaluated as a susceptibility factor in a study of Pb 

7 and IgE (Annesi-Maesano et al., 2003). The study examined Pb levels (measured via hair) in infants and 

8 IgE and reported a positive correlation overall. However, in stratified analyses, this association remained 

9 only among infants of mothers without atopy. Among atopic mothers, the correlation was positive, 

10 although smaller, and was not statistically significant.

6.2.5.3. Diabetes

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

12 conducted to investigate the possibility of diabetes as a susceptibility factor for Pb and various health 

13 outcomes. 

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

15 with and without diabetes at baseline was examined using the Normative Aging Study cohort (Tsaih et al., 

16 2004). Tibia and blood Pb levels were positively associated with measures of renal function among 

17 diabetics but not among individuals without diabetes. However, this association was no longer statistically 

18 significant after the exclusion of individuals who were hypertensive or who used diuretic medications. 

19 Another study with this cohort reported no associations between bone Pb and heart rate variability, which 

20 did not differ among those with and without diabetes (Park et al., 2006).

21 The NHANES III study evaluated whether the association between Pb and both all-cause and 

22 cardiovascular mortality varied among individuals with and without diabetes (Menke et al., 2006). The 

23 95% CIs among those with diabetes were large and no difference was apparent among those with and 

24 without diabetes.

25 Overall, recent epidemiologic studies found that associations did not differ for individuals with and 

26 without diabetes. However, results from the previous Pb AQCD found that individuals with diabetes are at 

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

28 associations between Pb and renal function, as well as other health outcomes, among individuals with and 

29 without diabetes will inform further on this potential susceptibility factor.
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6.2.5.4. Hypertension

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

2 increases with age (61% of individuals 75 years of age and older have hypertension) (Pleis et al., 2009). 

3 The Normative Aging Study cohort mentioned above for modification of the association between 

4 Pb levels and renal function by diabetes also examined modification by hypertensive status (Tsaih et al., 

5 2004). The association between tibia Pb and renal function, measured by change in serum creatinine, was 

6 present among individuals with hypertension but not among individuals that were normotensive. Models 

7 of the follow-up serum creatinine levels demonstrated an association with blood Pb for hypertensive but 

8 not normotensive individuals (this association was not present when using tibia or patella Pb). Another 

9 study using this population examined modification of the association between bone Pb and heart rate 

10 variability, measured by low frequency power, high frequency power, and their ratio (Park et al., 2006). 

11 Although a statistically significant association between Pb and heart rate variability was not observed 

12 among hypertensive or normotensive individuals, the estimates were different, with greater odds among 

13 hypertensive individuals (Pb positively related to low frequency power and the ratio of low frequency to 

14 high frequency power and inversely related to high frequency power).

15 A study using the NHANES III cohort reported a positive association between Pb and both all16 cause and cardiovascular mortality for hypertensive and normotensive individuals but the associations did 

17 not differ based on hypertensive status (Menke et al., 2006).

18 The 2006 Pb AQCD reported that individuals with hypertension had increased susceptibility to Pb19 related effects on renal function (U.S. EPA, 2006). This is supported by recent epidemiologic studies. As 

20 described above, studies of Pb-related effects on renal function and heart rate variability have observed 

21 some differences among hypertensive individuals, but the difference between hypertensive and 

22 normotensive adults is not observed for Pb-related mortality.

6.2.6. Smoking

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

24 21% of individuals identify as former smokers (Pleis et al., 2009). Studies of Pb and various health effects 

25 have examined smoking as an effect measure modifier. 

26 A study of Pb and all-cause and cardiovascular mortality reported no modification of this 

27 association by smoking status, measured as current, former, or never smokers (Menke et al., 2006). The 

28 Normative Aging Study examined the association between blood and bone Pb levels and renal function 

29 and also reported no interaction with smoking status (Tsaih et al., 2004).

30 A study of Pb exposed workers and controls reported similar levels of absolute neutrophil counts 

31 (ANC) across Pb exposure categories among non-smokers (Di Lorenzo et al., 2006). However, among 

32 current smokers, higher Pb exposure was associated with higher ANC. Additionally, a positive 
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1 relationship was observed between higher blood Pb levels and TNF-alpha and granulocyte colony2 stimulating factor (G-CSF) among both smokers and nonsmokers, but this association was greater among 

3 smokers (Di Lorenzo et al., 2007). A recent study of fertile and infertile men examined blood and seminal 

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

5 levels were higher for smokers of both groups. Additionally, the Pb levels were lowest among non6 smoking fertile men and highest among smoking infertile men. 

7 Prenatal smoking exposure was examined in a study of children’s blood Pb levels and prevalence 

8 of attention-deficit/hyperactivity disorder (ADHD). An interaction was observed between Pb and prenatal 

9 tobacco smoke exposure; those children with high Pb levels and prenatal tobacco smoke exposure had the 

10 highest odds of ADHD (Froehlich et al., 2009).

11 Overall, the studies have mixed findings on whether smoking modifies the relationship between Pb 

12 and health effects. Future studies of Pb-related health effects and current, former, and prenatal smoking 

13 exposures among various health endpoints will aid in determining susceptibility by this factor.

6.2.7. Race/Ethnicity

14 Based on the 2000 Census, 69.1% of the U.S. population is comprised of Non-Hispanic Whites. 

15 Approximately 12.1% of people reported their race/ethnicity as Non-Hispanic Black and 12.6% reported 

16 being Hispanic (SSDAN, 2010b). Studies of multiple Pb-related health outcomes examined effect 

17 measure modification by race.

18 A study of adults from the NHANES III cohort examined the association between blood Pb levels 

19 and all-cause and cardiovascular mortality (Menke et al., 2006). Stratified analyses were conducted for 

20 non-Hispanic whites, non-Hispanic blacks, and Mexican-Americans and no interaction was reported. 

21 Another study using the NHANES III cohort reported on blood Pb levels and hypertension. While no 

22 association was observed between blood Pb and non-Hispanic Whites or Hispanics, a positive association 

23 was reported for non-Hispanic Blacks (Scinicariello et al., 2010). Another study using NHANES datasets 

24 examined the associations between blood Pb and hypertension (Muntner et al., 2005). Although none of 

25 the associations were statistically significant, increased odds were observed among non-Hispanic blacks 

26 and Mexican-Americans but not for non-Hispanic whites. 

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

28 between blood Pb levels and pubertal development among African Americans and Mexican Americans 

29 (Selevan et al., 2003). For non-Hispanic Whites, the associations were in the same direction but did not 

30 reach statistical significance. Of note, less than 3% of non-Hispanic Whites had blood Pb levels over 5 

31 μg/dL, whereas 11.6% and 12.8% of African Americans and Mexican Americans had blood Pb levels 

32 greater than 5 μg/dL, respectively.
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1 A study linking educational testing data for 4th grade students in North Carolina reported declines 

2 in reading and mathematics scores with increasing levels of Pb (Miranda et al., 2007). Although not 

3 quantitatively reported, a figure depicts the association stratified by race; the slopes appear to be similar 

4 for white and black children.

5 Blood Pb and asthma was examined for white and black children living in Michigan (Joseph et al., 

6 2005). When utilizing separate referent groups for the two races, the only association is an increase 

7 among whites (although not statistically significant), but when restricting to the highest blood Pb levels, 

8 the association was no longer apparent. Whites with low blood Pb levels were used as the referent group 

9 for both races in additional analysis. Although the estimates were elevated for black children compared to 

10 white children (including at the lowest blood Pb levels), the confidence intervals for the associations 

11 overlapped indicating a lack of a difference by race. 

12 The results of these recent epidemiologic studies suggest that there may be race-related 

13 susceptibility for some outcomes, although the overall understanding of potential effect measure 

14 modification by race is limited by the small number of studies. Additionally, these results may be 

15 cofounded by other factors, such as socioeconomic status. 

6.2.8. Socioeconomic Status 

16 Based on the 2000 Census data, 12.4% of Americans live in poverty (poverty threshold for family 

17 of 4 was $17,463) (SSDAN, 2010c). Ris et al. (2004) examined modification of the associations between 

18 early-life Pb exposure and Learning/IQ among adolescents in the Cincinnati Lead Study. In models 

19 examining the association between Pb and Learning/IQ, prenatal and 78-month Pb concentrations were 

20 associated with larger decrements in Learning/IQ in the lower two quintiles of socioeconomic status 

21 (SES) (measured based on family SES levels).

6.2.9. Body Mass Index 

22 In the U.S. self-reported rates of obesity were 26.7% in 2009, up from 19.8% in 2000 (Sherry et al., 

23 2010). The NHANES III cohort was utilized in a study of blood Pb levels and all-cause and 

24 cardiovascular mortality, which included assessment of the associations by obesity (Menke et al., 2006). 

25 Positive associations were observed among individuals within the two categories of body mass index 

(BMI) (non-obese [<25 kg/m2] and obese [≥ 25 kg/m2 26 ]) but there was no difference between the 

27 categories. Using the Normative Aging Study, investigation of bone Pb levels and heart rate variability 

28 was performed and reported slight changes in the association based on the presence of metabolic 

29 syndrome, however none of the changes resulted in associations that were statistically significant (Park et 

30 al., 2006).
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1 No modification by BMI/obesity was observed among recent epidemiologic studies. Future studies 

2 of Pb-related health effects and BMI will aid in determining susceptibility by this factor.

6.2.10. Alcohol Consumption

3 There are a limited number of studies examining alcohol as a susceptibility factor. A study using 

4 the Normative Aging Study cohort investigated whether the association between blood and bone Pb levels 

5 and renal function would be modified by an individual’s alcohol consumption (Tsaih et al., 2004). No 

6 interaction with alcohol consumption was observed. However, a toxicological study reported that ethanol 

7 potentiated the effect of Pb exposure by decreasing renal total protein sulfhydryls (endogenous 

8 antioxidants). Pb and ethanol also decreased other endogenous renal antioxidants (glutathione and non9 protein sulfhydryls) (Jurczuk et al., 2006).

6.2.11. Nutrition

10 Different components of diet may affect the association between Pb and health outcomes. Diets 

11 designed to limit or reduce caloric intake and induce weight loss have been associated with increased 

12 blood Pb levels in adult animals (Han et al., 1999). It is well established that diets sufficient in minerals 

13 such as calcium, iron, and zinc offer some protection from Pb exposure by preventing or competing with 

14 Pb for absorption in the GI tract. A recent toxicological study reported negative effects of Pb on osmotic 

15 fragility, TBARS production, catalase activity, and other oxidative parameters, but most of these effects 

16 were reduced to the levels observed in the control group when the rats were given supplementation of 

17 zinc and vitamins (Massó-González & Antonio-García, 2009). The previous Pb AQCD (U.S. EPA, 2006)

18 reported limited data available to assess modification by nutritional status; however, potential 

19 modification by iron and calcium were noted. Recent epidemiologic and toxicological studies of specific 

20 mineral intakes/dietary components are detailed below.

6.2.11.1. Calcium

21 Using the Normative Aging Study, researchers examined the association between Pb and 

22 hypertension by calcium intake (Elmarsafawy et al., 2006). The associations between Pb (measured and 

23 modeled separately for blood, patella, and tibia) and hypertension did not differ based on dichotomized 

24 calcium intake (800 mg/day). However, toxicological studies have shown that dietary calcium deficiency 

25 induces increased Pb absorption and retention (Fullmer, 1992; Mykkanen & Wasserman, 1981; Six & 

26 Goyer, 1970). Also, low calcium levels in the body stimulate the production of vitamin D and increased 

27 synthesis of calcium-binding proteins to which Pb can bind (Richardt et al., 1986). Increased calcium 

28 intake reduces accumulation of Pb in bone and mobilization of Pb during pregnancy and lactation 

29 (Bogden et al., 1995). 
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6.2.11.2. Iron

1 The 2006 Pb AQCD included studies that indicated individuals with iron-deficiency and 

2 malnourishment had greater inverse associations between Pb and cognition/intellect (U.S. EPA, 2006). A 

3 recent epidemiologic study of pubertal development among girls observed inverse associations between 

4 blood Pb and inhibin B, but this association was modified by iron deficiency, with those girls with iron 

5 deficiency having a stronger inverse association between Pb and inhibin B than those who were iron 

6 sufficient (Gollenberg et al., 2010). Toxicological studies also report that iron deficient diets exacerbate or 

7 potentiate the effect of Pb. A study of pregnant rats given an iron deficient diet and exposed to Pb through 

8 drinking water over GD 6-14 had decreased litter size, pups with reduced fetal weight and reduced crown9 rump length, increased litter resorption, and a higher dam blood Pb level in the highest exposure groups 

10 (Saxena et al., 1991; Singh et al., 1993). Thus, iron deficiency makes female rats of reproductive age 

11 more susceptible to Pb-dependent embryo and feto-toxicity (Singh et al., 1993). 

6.2.11.3. Zinc

12 No epidemiologic studies have been performed to examine the effect of zinc on Pb-related health 

13 outcomes. Toxicological studies by Jamieson et al (2008; 2006) reported that a zinc deficient diet 

14 increases bone and renal Pb content (deposition in kidney tissue) and impairs skeletal growth and 

15 mineralization. A zinc-supplemented diet attenuated bone and renal Pb content. 

6.2.11.4. Folate

16 A study by Kordas et al. (2009) examined Pb and birthsize among term births in Mexico City. The 

17 authors reported no interaction between Pb and folate levels.

6.2.11.5. Protein

18 No recent epidemiologic studies have evaluated protein intake as a susceptibility factor for Pb19 related health effects. However, a toxicological study demonstrated that differences in maternal protein 

20 levels could affect the extent of Pb-induced immunotoxicity among offspring (S. Chen et al., 2004).

6.2.12. Stress

21 A study of bone Pb levels and hypertension reported modification of the association by perceived 

22 stress levels (Peters et al., 2007). Among individuals with greater stress levels, stronger associations of Pb 

23 levels on hypertension was present. Among the same study population, higher stress was also noted to 

24 affect the association between Pb levels and cognitive function; the higher stress group showed a greater 

25 inverse association between Pb and cognitive function than those in the low stress group (Peters et al., 
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1 2008). In another study, the association between tibia Pb levels and some measures of cognitive function 

2 were similarly strengthened by neighborhood psychosocial hazards (Glass et al., 2009). 

3 Toxicological studies have demonstrated that early life exposure to Pb and maternal stress can 

4 result in toxicity related to multiple systems (Cory-Slechta et al., 2008; Rossi-George et al., 2009; 

5 Virgolini, Rossi-George, Lisek, et al., 2008; Virgolini, Rossi-George, Weston, et al., 2008), including 

6 dysfunctional corticosterone responses (Rossi-George et al., 2009; Virgolini, Rossi-George, Weston, et al., 

7 2008). Additionally, toxicological studies have demonstrated that immune stress also affects associations 

8 with Pb. Chicken with low Pb exposure in ovo and viral stressors had increased immune cell mobilization 

9 and trafficking dysfunction (Lee et al., 2002). Similarly, mice with neonatal Pb exposure and an immune 

10 challenge had a sickness behavior phenotype, likely driven by IL-6 production (Dyatlov & Lawrence, 

11 2002).

12 Similar to studies of stress in animals, maternal self-esteem has also been shown to modify 

13 associations between Pb and health effects in children. Surkan et al. (2008) studied the association 

14 between children’s blood Pb levels and Bayley’s MDI and Psychomotor Development Index (PDI) among 

15 mother-child pairs. High maternal self-esteem was independently associated with higher MDI score and 

16 also appeared to attenuate the negative effects observed of Pb on MDI and PDI scores; greater decreases 

17 in MDI and PDI associated with Pb levels were observed among mothers in the lower quartiles of self18 esteem. The investigators indicated that high maternal self-esteem may serve as a buffer against stress by 

19 improving mother-child interactions and care giving practices but also may be a surrogate of biological 

20 stress responses in the child.

21 Although examined in a limited number of studies, recent epidemiologic studies observed 

22 modification of the association between Pb and health effects by stress-level. Susceptibility to Pb-related 

23 health effects by stress is supported by toxicological studies.

6.2.13. Cognitive Reserve

24 A study of Pb smelter workers reported that an inverse association between Pb levels and cognitive 

25 function was present among workers with low cognitive reserve but no association was present in workers 

26 with high cognitive reserve (Bleecker et al., 2007). Associations between Pb and motor functions existed 

27 among all workers regardless of cognitive reserve. No other recent epidemiologic studies were performed 

28 examining cognitive reserve as a susceptibility factor. 

6.2.14. Other Metal Exposure

29 The 2006 Pb AQCD reported that the majority of studies examined other toxicants as confounders 

30 and not effect measure modifiers (U.S. EPA, 2006). Recent epidemiologic studies have, however, begun 
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1 to explore the possible interaction between Pb and other metals. These studies, as well as toxicological 

2 studies of these metals, are described below.

6.2.14.1. Cadmium 

3 In a study of girls in the NHANES III cohort, inverse associations were observed between blood Pb 

4 and inhibin B concentrations (Gollenberg et al., 2010). These inverse associations were stronger among 

5 girls with high cadmium (Cd) and high Pb compared to those with high Pb and low Cd. Additionally, 

6 higher blood Pb and Cd levels together were positively associated with albuminuria and reduced 

7 estimated glomerular filtration rate, compared to those with the lowest levels of Pb and Cd (Navas-Acien 

8 et al., 2009).

9 Toxicological studies have reported that the addition of Cd to Pb treatment of rats reduced the 

10 histological signs of renal toxicity from each element alone; however, urinary excretion of porphyrins 

11 were increased, indicating that although measured tissue burdens of Pb were reduced, the biologically 

12 available fraction of Pb was actually increased (G. S. Wang & Fowler, 2008). In other studies, Cd 

13 synergistically exacerbated Pb-dependent renal mitochondrial dysfunction (L. Wang et al., 2009). 

14 Overall, epidemiologic and toxicological studies have reported increased susceptibility to Pb15 related health effects among those with high Cd levels as well.

6.2.14.2. Arsenic 

16 In a study of immune function among children living at varying distances from a Pb smelter in 

17 Mexico, exposure to both metals were associated with greater decreases in NO and greater increases in 

18 superoxide anion (Pineda-Zavaleta et al., 2004). Recent toxicological studies that have examined the 

19 addition of arsenic (As) to Pb and Cd mixtures report increases in bioavailability of Pb (G. S. Wang & 

20 Fowler, 2008). Thus, there is biologic plausibility of increased susceptibility of Pb-related health effects 

21 when co-exposed to Pb and As.

6.2.14.3. Manganese 

22 Among children in Korea taking part in a study of IQ, an interaction was reported between Pb and 

23 manganese (Mn) (Y. Kim et al., 2009). Compared to children with low blood Mn levels, those with high 

24 blood Mn levels had greater decreases in full scale IQ and verbal IQ associated with blood Pb levels. No 

25 effect modification was observed for the association between Pb levels and performance IQ.

6.2.15. Fluoride

26 Fl has been identified as a potential susceptibility factor in a toxicological study but has not yet 

27 been explored in epidemiologic studies. A recent toxicological study by Sawan et al. (2010) reported co-
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1 exposure with Fl increased Pb deposition in calcified tissues. Future investigation among humans will be 

2 important for understanding whether fluoride present in water and other substances increases Pb 

3 deposition in humans and modifies the association between Pb and various health effects.

6.3. Summary 

4 Section 6.1 of this chapter provides a review of the literature regarding factors influencing Pb 

5 exposure or biomarkers of Pb exposure. For most studies, relationships between factors and Pb biomarker

6 levels were presented without attribution to exposure, diet, absorption, or biokinetic factors because the 

7 studies were not designed to make such conclusions. Where available, studies that shed light on the effect 

8 of susceptibility factors on exposure were included. The factors examined in Section 6.1 included age, 

9 gender, race and ethnicity, SES, and residential proximity to Pb sources. 

10 In Section 6.2 of this chapter, epidemiologic and toxicological studies that contributed information 

11 on potential susceptibility factors for Pb-related health effects were evaluated. Overall, this review 

12 provided evidence that various factors may lead to increased susceptibility to Pb-related health effects 

13 (see Table 6-3 for evidence from current studies). Section 6.2 included most of the factors from Section 

14 6.1, plus various genes, pre-existing diseases/conditions, smoking, BMI, nutrition, stress, cognitive 

15 reserve, and exposure to other metals. 

16 Among children, the youngest age groups were observed to be most susceptible to having elevated 

17 Pb body burden, with blood Pb levels decreasing with increasing age of the children. Recent 

18 epidemiologic studies of infants/children detected susceptibility to Pb-related health effects, and this was 

19 supported by toxicological studies. 

20 For adults, elevated Pb biomarkers were associated with increasing age. It is generally thought that 

21 these elevated levels are related to remobilization of stored Pb during bone loss (see Section 4.2). Studies 

22 of older adults had inconsistent findings for effect modification of Pb-related mortality but no difference 

23 was observed for other health effects. However, toxicological studies support the possibility of age-related 

24 differences in susceptibility to health effects. 

25 Some studies suggest that males have higher blood Pb levels than females; this was supported by 

26 stratifying the total sample of NHANES subjects. Gender-based differences appeared to be prominent 

27 among the adolescent and adult age groups but were not observed among the youngest age groups (1-5 

28 years and 6-11 years). Studies of effect measure modification of Pb and various health endpoints by sex 

29 were mixed, although it appears that there are some differences in associations for males and females. 

30 This is also observed in toxicological studies. In addition, the associations among females may vary based 

31 on hormonal status. Future research will be useful in determining which Pb-related health effects are 

32 greater for males or females and whether hormones play a role in susceptibility.
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1 Regarding race and ethnicity, recent data suggest that the difference in blood Pb levels between 

2 African American and White subjects is decreasing over time, but African Americans still tend to have 

3 higher Pb body burden and exposures. Similarly, the gap between socioeconomic groups with respect to 

4 Pb body burden appears to be diminishing, with Pb body burden being higher but not appreciably higher 

5 among lower income subjects. Studies of race as a susceptibility factor indicate that some modification of 

6 associations between Pb and health effects may be present. Compared to whites, non-white populations 

7 were observed to be more susceptible; however this could be related to confounding by factors such as 

8 SES or differential exposure levels, which was noted in some of the epidemiologic studies. Although 

9 limited by the number of studies, lower SES individuals appear to represent a susceptible population. A 

10 study of Pb and IQ reported greater inverse associations among those in the lowest SES groups. 

11 Additionally, there is evidence associating proximity to areas with Pb sources, including urban areas with 

12 large industrial sources, with increased Pb body burden and risk of Pb exposure.

13 Various genes were examined as potentially modifying the associations between Pb and health 

14 effects. Epidemiologic and toxicological studies reported ALAD and VDR variants may be health-related 

15 susceptibility factors. Other genes examined that may also affect susceptibility to Pb-related health effects 

16 were MTHFR, DRD4, GSTM1, TNF-alpha, eNOS, APOE, and HFE. 

17 Pre-existing diseases/conditions also have the potential to affect the association between Pb 

18 exposure and various health endpoints. Recent epidemiologic studies did not support modification of Pb 

19 and health endpoints by diabetes; however, past studies have found diabetics to be a susceptible 

20 population with regard to renal function. More research on this population will be important for 

21 determining which, if any, health effects related to Pb are different among diabetics. Hypertension was 

22 observed to be a susceptibility factor in both past and recent epidemiologic studies. Studies of Pb and 

23 both renal effects and heart rate variability demonstrated greater odds of the association among 

24 hypertensive individuals compared to those that are normotensive. Recent epidemiologic studies also 

25 examined autism and atopy as potential susceptibility factors. Future research will allow for a greater 

26 understanding of potential modification by these conditions, but current research has shown that autistic 

27 children and infants of mothers without atopy may have increased odds of Pb-induced health effects.

28 Recent epidemiologic studies examining smoking as a susceptibility factor reported mixed 

29 findings. It is possible that smoking modifies the effects of only some Pb-related health effects. Further 

30 studies of current, former, and prenatal smoking exposures related to Pb and health effects will provide 

31 additional information on susceptibility.

32 BMI, alcohol consumption, and nutritional factors were examined in recent epidemiologic and 

33 toxicological studies. Modification of associations between Pb and various health effects (mortality and 

34 heart rate variability) was not observed by BMI/obesity. Also, no modification was observed in an 

35 epidemiologic study of renal function examining alcohol consumption as a modifier, but a toxicological 

36 study supported the possibility of alcohol as a susceptibility factor. Among nutritional factors, those with 
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1 iron deficiencies were observed to be a susceptible population for Pb-related health effects in both 

2 epidemiologic and toxicological studies. Other nutritional factors, such as calcium, zinc, and protein, 

3 demonstrated the potential to modify associations between Pb and health effects in toxicological studies. 

4 Recent epidemiologic studies of these factors were either not performed or observed no modification. 

5 Folate was also examined in a recent epidemiologic study of birth size but no interaction was reported 

6 between Pb and folate. Further study of these and other nutritional factors will be useful in determining 

7 susceptibility among individuals with various nutritional levels/deficiencies.

8 Stress was also evaluated as a susceptibility factor and although there were a small number of 

9 recent epidemiologic studies, increased stress was observed to negatively impact the association between 

10 Pb and health endpoints. Toxicological studies supported this finding. 

11 A recent epidemiologic study evaluated cognitive reserve as a modifier of the associations between 

12 Pb and cognitive and motor functions. Cognitive reserve was an effect measure modifier for the 

13 association between Pb and cognitive function but not motor function. Future studies evaluating Pb14 related health effects and cognitive reserve will provide more information on this possible susceptibility 

15 factor. 

16 Finally, interactions between Pb and other metals were evaluated in recent epidemiologic and 

17 toxicological studies of health effects. High levels of other metals, such as Cd, As, and Mn, were observed 

18 to negatively affect the associations between Pb and various health endpoints.
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