May 2011 i DRAFT

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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 ethnici ty.

___________________ 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. Autism 6

- 20

6.2.5.2. Atopy 6

- 21

6.2.5.3. Di abetes

________________________________ ________________________________ _ 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

- 26May 2011 ii DRAFT

– DO NOT CITE OR QUOTE 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

- 32May 2011 6

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# Chapter 6. Susceptible Populations and Lifestages

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

### 1
populations are at increased risk for detrimental effects of ambient exposure to an air pollutant. The 

### 2
NAAQS are intended to provide an adequate margin of safety for both the population as a whole and 

### 3
those individuals potentially at increased r isk for health effects in response to ambient air pollution 

### 4
(Section 1.1). Several studies have evaluated factors to identify populations at greater risk for Pb

- related 

### 5

health effects

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

### 6
an individual to Pb. The definition for both of these terms has been found to vary across studies, but in 

### 7
most instances susceptibility refers to biological or intrinsic factors (e.g., lifestage, sex) while 

### 8
vulnerability refers to non

- b iological or extrinsic factors (e.g., socioeconomic status [SES]) ( U.S. EPA, 

### 9

2009

, 2010 ) . Additionally, in some cases, the terms “at

- risk” and sensitive populations have been used to 

### 10
encompass these concepts more generally. However, in many cases, a factor identified that increases an 

### 11

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

### 12
categorized as either a susceptibility or vulnerability factor. 

### 13

As developed in previous ISAs and reviews ( Sacks et al. ; U.S. EPA, 2009

, 2010 )

, an all 

### 14
encompassing definition for “susceptible population” is used to circumvent the need to distinguish 

### 15

be tween susceptible and vulnerable, and to identify the populations at greater risk for Pb

- induced health 

### 16
effects. This definition identifies susceptible populations as the following: 

### 17

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., educa tional attainment, reduced access to health care), and characteristics that may modify exposure to Pb (e.g., time spent outdoors).

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

### 18
stratified analyses to ident ify the presence or absence of effect measure modification. A thorough 

### 19
evaluation of potential effect measure modifiers may help identify populations that are more susceptible 

### 20

to Pb. T oxicological studies provide support and biological plausibility for fac tors that may lead to 

### 21
increased susceptibility for Pb

- related health effects through the study of animal models of disease

. 

### 22
Therefore, the results from these studies, combined with those results obtained through stratified analyses 

### 23

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)

.May 2011 6

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– DO NOT CITE OR QUOTE in epidemiologic studies

, comprise the overall weight of evidence for the increased susceptibility of 

### 1
specific populations to Pb

- related health effects

. 

### 2
The first section of this chapter summarizes susceptibility of population groups related to 

### 3
differential Pb body burden. The s tudies presented in this section supplement the material provided in 

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

### 5
Pb body burden, as measured by blood Pb or bone Pb. These biomarkers are influen ced to varying 

### 6
degrees by exposure, absorption, biokinetics, and diet. The second section of this chapter discusses the 

### 7
epidemiologic and toxicological studies evaluated in Chapters 5 that provide information on potentially 

### 8
susceptible factors related to P b

- induced health effects. Highlighted studies include only those where the 

### 9
population was stratified into subgroups (e.g., males vs. females) for comparative analysis. In the case of 

### 10
many biomarker studies and the epidemiologic studies considered, this app roach allowed for a 

### 11
comparison between populations exposed to similar Pb concentrations and within the same study design

. 

### 12
Additionally, the section on susceptibility and Pb body burden explores how susceptib ility factors may be 

### 13

related to differential Pb e xpos ures, where data are available

. Numerous studies that focus on only one 

### 14
potentially susceptible population are described in previous chapters, but these studies are not discussed 

### 15
in detail in this chapter because they lack an adequate comparison group

. For example, pregnancy is a 

### 16
potentially susceptible lifestage for mothers and fetuses, but because there are no comparison groups for 

### 17
stratified analyses, these studies are presented in Chapter 5 and are not included here. Included 

### 18
toxicological studies m ay categorize the study population by age, sex, diet, genetics, etc. or are those with 

### 19

animal models of disease. 

### 20
Additionally, it is understood that some of the stratified variables may not be effect measure 

### 21
modifiers but instead may be mediators of Pb

- rel ated health effects. Factors that are mediators are on the 

### 22
causal pathway between Pb and health outcomes, while effect measure modifiers are factors that result in 

### 23
changes in the measured association between Pb and health effects. Because mediators are cau sed by Pb 

### 24
exposure and are also intermediates in the disease pathway that is studied, mediators are not correctly 

### 25
termed susceptibility factors. Some of the factors included in this chapter could be mediators and/or 

### 26

modifiers. These are noted in Table 6

- 3. 

### 27



# 6.1. Susceptibility F actors and Lifestages Related to Lead E xposure and Dose

E levated Pb biomarkers have been shown to be statistically related to several population 

### 28

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

### 29
cases, exposure, absorption, and biokinetics of Pb are all influenced to varying degrees by susceptibility 

### 30

factors

. The relative importance of susceptibility factors on exposure, absorption, and biokinetics varies 

### 31May 2011 6

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– DO NOT CITE OR QUOTE on an individual basis and is difficult to quantify

. The following section distinguishes studies 

### 1
demonstrating a relationship between each susceptibility factor and exposure status from those that are 

### 2

associated with increased biomarker levels without a clear attribution of the rela tive effects of those 

### 3
factors on exposure, absorption, and bioavailability. 

### 4



## 6.1.1. Lifestage

6.1.1.1. Young Children

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

### 5

behaviors and activities include increased hand

- to

- mouth contact, crawling, and poor hand

- washing ( U.S. 

### 6

EPA, 2006 )

. Children can be susceptible to Pb exposure because outdoor play can lead to hand

- to

- mouth 

### 7

contact with contaminated soil

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

### 8
concentration led to a 1.55 μg/dL reduction in median blood Pb lev els (p <0.05) among New Orleans 

### 9

children

. 

### 10
Age of the children may influence blood Pb levels through a combination of behavioral and 

### 11

biokinetic factors

. The 2007

- 2008 NHANES data are presented in Table 6

- 1 by age and gender

. Among 

### 12
children, highest blood P b levels occurred in the 1

- 5 y ear age group, and within this subgroup, 1 y ear old 

### 13
children had the highest blood Pb levels (99th percentile: 16.9 μg/dL) . It is possible that high blood Pb 

### 14
levels among these young children may also be related to in utero ex posures resulting from maternal Pb 

### 15
remobilization from bone stores from historic exposures ( Miranda et al., 2010 )

. Jones et al. ( 2009 ) 

### 16
analyzed the NHANES dataset for the years 1988

- 2004 to study trends in blood Pb among different age 

### 17
groups over time (see Table 6

- 2). They observed greater percentages of children aged 1

- 2 y ear having 

### 18
blood Pb levels between 2.5 and 5 μg/L compare d with 3

- 5 y ear old children

. Similarly, the 1

- 2 y ear old 

### 19
group had larger percentages with blood Pb levels between 5 and 7.5 μg/dL compared with 3

- 5 y ear old 

### 20

children

. These differences may be attributable to differences in exposure, age

- dependent variabi lity in 

### 21
absorption and biokinetics, or diet (milk/formula v ersu s child diets)

. Yapici et al. ( 2006 ) studied the 

### 22
relationship between blood Pb level and age among a cohort of children younger than 73 months living in 

### 23
proximity to a Turkish coal mine

. They observed a low but statistically significant negative correlation 

### 24

between blood Pb and a ge (r =

- 0.38, p <0.001)

. 

### 25

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 y r 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 y r total 2.62 3.26 0.76 1.24 1.80 2.88 6.23 16.94May 2011 6

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– DO NOT CITE OR QUOTE 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 y r 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 y r 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 y r 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 y r 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 y r 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 y r 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 y r 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+ y r 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 ( 2009 a )

.

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 0.8May 2011 6

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– DO NOT CITE OR QUOTE Source: Jones et al. ( 2009 )



### 6.1.1.2. Adults

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

### 1

6

- 1 presents 2007

- 2008 NHANES data broken down by age group and shows that blood Pb levels were 

### 2
highest in the >65

- y ears age group in comparison with adults aged 20

- 64 y ears . In a study of blood Pb 

### 3
and saliva Pb in a mostly fem ale population in Detroit, Nriagu et al. ( 2006 ) found th at age was a 

### 4
statistically significant positive predictor of both blood Pb (p < 0.001) and saliva Pb (p < 0.00 1 ). Average 

### 5
blood Pb levels among 14

- to 24

- y ear

- old subjects was 2.6 μg/dL compared with 4. 3 μg/dL among 

### 6
subjects aged 55 y ears or older; similar ly, average saliva Pb levels among 14

- to 24

- y ears

- old subjects 

### 7

was 2. 5 μg/L compared with 3. 6 μg/L among subjects aged 55 y ears or older. Higher average and median 

### 8
levels among older adults could potentially be due to a shared experience of higher historical Pb 

### 9
exposures stored in bone (see section 4.1 ) in conjunction with remobilization of stored Pb during bone 

### 10
loss ( S ection 4.2). 

### 11
Theppeang et al. ( 2008 ) studied Pb concentrations in the blood, tibia, and patella of subjects age 

### 12

50

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

### 13
age and tibia Pb (β = 0.37, p <0.01 in a model including age, race, Yale energy index, and 2 diet variables; 

### 14
β = 0.57, p <0.01 in a model including age, gender, and an interaction term for gender and age, which was 

### 15

also statistically significant at p = 0.03)

. Theppeang et al. ( 2008 ) also noted that patella Pb concentrations 

### 16
increased with age, although the data qua lity for patella Pb was not as high , so the authors did not present 

### 17
the data or significance levels

. A statistically significant relationship was not observed between the log



### 18

transform of blood Pb and age (β = 0.007, p = 0.11), although the age range of su bjects may not have 

### 19

been sufficient to discern a difference in blood Pb. 

### 20

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

### 21
older studies in the literature are presented in the 2006 AQCD ( U.S. EPA, 2006 )

. Korda s et al. ( 2010 ) 

### 22

observed that maternal hair Pb concentration was a statistically significa nt predictor of child hair Pb 

### 23
concentration (β = 0.37±0.07, p < 0.01)

. Miranda et al. ( 2010 ) observed that pregnant women ages 30

- 34 

### 24

and 35

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

### 25

25

- to 29

- y ears

- old reference age category

. These results could be related to a historical component to Pb 

### 26
exposure among mothers. These findings were also consistent with observations that Pb storage in bones 

### 27
increased with age before subsequent release with bone decay durin g pregnancy , as described in S ection 

### 28

4.2

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

### 29
through breast milk

. 

### 30May 2011 6

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– DO NOT CITE OR QUOTE 

## 6.1.2. Sex

Several studies have suggested that sex influences levels of Pb biomarkers because di fferences in 

### 1
behavior between sexes may cause a differential increase in exposure. The 2007

- 2008 NHANES showed 

### 2
that overall, males have higher blood Pb levels (median: 1.50 μg/dL) than females (median: 1.14 μg/dL) 

### 3
(see Table 6

- 1). Among adults aged 20

- 64 y ears , median blood Pb levels among males was 46% higher 

### 4
than for females, and average levels were 51% higher for males compared with females. Among adults 65 

### 5

y ears or older, median levels were 36% higher, and average levels were 33% higher

. In their study of Pb 

### 6
burden among Baltimore adults aged 50

- 70 y ears , Theppeang et al. ( 2008 ) observed that averag e blood 

### 7

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

### 8
μg/dL)

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

### 9
(18.0 μg/dL) and women (19.4 μg/dL)

. 

### 10
Among U.S. children, the 2007

- 2008 NHANES data show that blood Pb levels are higher among 

### 11
girls than boys for the 1

- to 5

- y ears age group (Table 6

- 1). Blood Pb levels became slightly higher among 

### 12
boys for the 6

- to 11

- y ears age group, and levels were substantially higher among adolescent males in the 

### 13

12

- to 19

- y ears age group

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

### 14

were lower than blood Pb levels for the other age groups. T he 2007

- 2008 NHANES data suggest that 

### 15
gender

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

### 16



## 6.1.3. Ra ce and Ethnicity

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

### 17

EPA, 2006 )

. Recent studies are consistent with those previous findings

. For instance, Levin et al. ( 2008 ) 

### 18

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

### 19

levels

. Data from the Jones et al. ( 2009 ) study, using 2003

- 2004 NHANES data ( CDC, 2011 ) , are shown 

### 20
in Figure 6

- 1

. They found that differences among racial and ethnic groups with regard to the percentage 

### 21

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

- 1980 when 

### 22

NHANES II was conducted . The non

- Hispanic black group stil l had higher percentages with blood Pb 

### 23

levels above 2.5 μ g/dL compared with non

- Hispanic whites and Mexican Americans, with the largest 

### 24

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

### 25
among Mexican A merican and non

- Hispanic white children were nearly identical. Theppeang et al. 

### 26

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

### 27
living in Baltimore

. They observed a statistically significant difference between African American (AA) 

### 28
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 

### 29

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)

. 

### 30
Differences between bone Pb levels in African American and Caucasian subjects could potentially be 

### 31

related to di fferential exposures in the home environment. 

### 32May 2011 6

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– DO NOT CITE OR QUOTE Data used with permission from the American Academy of Pediatrics, Jones et al. ( 2009 ) Figure 6

- 1. Pe rcent 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).

Differences in exposure among ethnic and racial groups have also been noted

. In a study of three 

### 1
parishe s in the greater metropolitan New Orleans area, Campanella and Mielke ( 2008 ) found that, where 

### 2

soil Pb levels were less than 20 m g/ k g, the population was 55% white, 36% black, 3.0% Asian, and 6.0% 

### 3
Hispanic, based on the 2000 Census, with the percentage based on the total number living in Census 

### 4

blocks with the same soil Pb levels

. In contrast, they found that the population was 34% white, 62% 

### 5 0 10 20 30 40 50 60 70

< 1 1

- < 2.5 2.5

- < 5 5

- < 7.5 7.5

- <10 ≥ 10Percent 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 ≥ 10Percent of Children

Blood Pb Level (ug/dL)

Non

- Hispanic black Mexican American Non

- Hispanic white 1999

- 2004May 2011 6

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– DO NOT CITE OR QUOTE black, 1% Asian, and 4% Hispanic on Census blocks in whic h soil Pb levels were between 1,000 and 

### 1
5,000 mg/kg (Figure 6

- 2 ). As described in Section 6.1.4, the differences observed by Campanella and 

### 2

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

### 3
relationship between Pb soil levels and race. 

### 4

Source : Campanella and Mielke ( 2008 )

. Figure 6

- 2. Soil Pb concentration exposure among the population of three parishes withi n greater metropolitan New Orleans, by race and ethnicity.



## 6.1.4. Socioeconomic Status (SES)

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

### 5
relationships have not always been consistent . Nriagu et al. ( 2006 ) performed a multiple regression of 

### 6

blood Pb and saliva Pb levels on va rious socioeconomic, demographic, and exposure variables among an 

### 7
adult population in Detroit . Blood and saliva Pb were both used as indicators of Pb in unbound plasma 

### 8
that is available to organs. Nriagu et al. ( 2006 ) found that education (p <0.001), income (p <0.001) and 

### 9
employment status (p = 0.04) were all s tatistically significant predictors of blood Pb levels, with blood Pb 

### 10
decreasing with some scatter as education and income level increased

. S tatistically s ignificant 

### 11
relationships were also reported by Nriagu et al. ( 2006 ) for saliva Pb level with respect to education (p 

### 12 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 >20,000Population

Soil Pb Concentration ( μ g/g) Black

White

Asian

HispanicMay 2011 6

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– DO NOT CITE OR QUOTE <0.001), income (p < 0.001), and employment (p = 0.06) . However, the highest educational attainment and 

### 1
income categories had higher saliva Pb levels compared with other groups; Nriagu et al. ( 2006 ) attributed 

### 2
these inconsistencies to small sample sizes among the high educational attainment and income categories. 

### 3

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

### 4
For example, Levin et al. ( 2008 ) cite NHANES data analyzed in Pirkle et al. ( 1994 ) that the percentage of 

### 5
children aged 1

- 5 y ears with blood Pb levels above 10 μg/dL was 4.5% for the lowest income group 

### 6
compared with 0.7% for the highest group

. For the 1999

- 2002 NHANES, there was no statistically 

### 7
significant difference between the percent of children with blood Pb levels above 10 μg/dL for Medicaid



### 8
enrolled children (1.7%) compared with non

- e nrolled children (1.3%), although Medicaid

- enrolled 

### 9
children did have higher median blood Pb levels (2.6 μg/dL) compared to children not enrolled in 

### 10
Medicaid (1.7 μg/dL) ( Levin et al., 2008 )

. When adding data for 2003

- 2004 to the analysis (i.e.

, for 1999

- 

### 11
2004), the gap between Medicaid enrolled and non

- enrolled children widened for blood Pb levels 

### 12
exceeding 10 μg/dL (1.9% v ersu s 1.1%), but the difference was still not statistically significant (p > 0.05). 

### 13
Median blood Pb levels with respect to Medica id status did not change when adding the 2003

- 2004 data 

### 14

( R. L. Jones et al., 2009 )

. Likewise, Jones et al. ( 2009 ) analyzed blood Pb levels with respect to poverty



### 15

income ratio (PIR)

. They found statistically significant differences in median blood Pb for PIR ≤ 1.3 

### 16
compared with PIR >1.3 . The p ercent age of 1

- to 5

- y ear0o ld children having blood Pb above 10 μg/dL 

### 17
was higher for PIR ≤ 1.3 (1.8 v ersu s 0.8) ; however, this difference was not statistically significant. 

### 18
Additionally, Campanella and Mielke ( 2008 ) observed a linear increase in soil Pb content outside a home 

### 19
with respect to decreasing average household income, with soil Pb between 2.5 and 20 m g/ k g associated 

### 20
with an average income of $40,000 per year

, while soil Pb be tween 5,000 and 20,000 was associated with 

### 21
an average income of $24,000 per year

. 

### 22



## 6.1.5. Proximity to Lead Sources

Airborne and soil Pb concentrations are higher in some urbanized areas, as described in S ections 

### 23

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

### 24
ambient air Pb in PM tend to occur in the most urbanized areas and in close proximity to traffic in 

### 25
metropolitan areas ( Laidlaw & Filippelli, 2008 ; Mielke et al., 2010 ; Weiss et al., 2006 ) . Moreover, air Pb 

### 26

concentration s exhibit high spatial variability even at low concentrations (~0.01 μ g/m 3 ) ( Martuzevicius et 

### 27

al., 2004 )

. These conditions presen t the potential for additional risk of Pb exposure in urban areas. 

### 28

P roximity to an industrial source likely contribute s to higher Pb exposures , as described in the 2006 

### 29

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

### 30
the observation of higher air concentrations at source oriented Pb monitoring sites compared with non



### 31

source oriented sites in the 2007

- 2009 data presented in Section 3.5. Jones et al. ( 2010 ) found that 

### 32

neonates born near a Pb

- contaminated urban industrial site had statistically significantly higher cord 

### 33May 2011 6

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– DO NOT CITE OR QUOTE blood Pb levels (median: 2.2 μg/dL; 95% CI: 1.5

, 3.3 μg/dL) compared with a reference group of 

### 1
neonates not living near a potentially contaminated site (median: 1.1 μg/dL; 95% CI: 0.8

, 1.3 μg/dL), 

### 2
suggesting that current industrial Pb exposures contribute to neonatal Pb levels

. The population studied in 

### 3

Jones et al. ( 2010 ) was 88% African

- American; 75% had a high school degree or equivalent, while 20% 

### 4
had a college degree and 5% attended but did not graduate from high school. However, the Jones et al. 

### 5

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

### 6
determined if differences in characteristics among the groups with and without industrial exposures 

### 7

confounded these results. 

### 8



# 6.2. Susceptibility F actors and Lifestages Related to Lead Induced He alth Effects

The following section evaluates potential susceptibility factors examined as effect measure 

### 9

modifiers of various Pb

- related health effects. Table 6

- 3 provides an overview of the factors examined and 

### 10
populations identified as susceptible to Pb

- related health effects based on the recent evidence integrated 

### 11
across disciplines. Each characteristic is described in greater detail in the following sections. 

### 12

Table 6

- 3. Summary of new evidence for characteristics examined as potential susceptibility fa ctors and lifestages for lead

- related health effects

Factor Evaluated Susceptible Population

Lifestage Children

Sex Males a Females a

Genetics ALAD a , VDR a *, DRD4 a *, GSTM1 a , TNF

- alpha a , eNOS a , APOE a , HFE a

Pre

- existing Disease Autism ab , Atopy ab

, Hypertension b

Smoking Smokers a

Race/Ethnicity Non

- Hispanic Blacks a , Hispanics a

Socioeconomic Status (SES) Low SES a

Nutrition Iron deficiency

Stress High stress

Cognitive Reserve Low cognitive reserve ab

Other Metals Cd a , As a , Mn a

a Additional evidence is needed to confirm whether the characteristic evaluated results in increased susceptibility to Pb

- related health effects.
b Possible mediatorMay 2011 6

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– DO NOT CITE OR QUOTE 

## 6.2.1. Life s tage

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

### 1
of Pb is often at the same time as development in children. Older adults are more likely to have age



### 2
related degeneration of bones and organ systems and a possible redistribution of Pb. Therefore, increased 

### 3
susceptibility of Pb

- related health effects is a concern for these populations. Below is information from 

### 4
epidemiologic and toxicological studies regarding studies of susceptibility for children and older adults. 

### 5

6.2.1.1. Children

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

### 6
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 

### 7

( SSDAN, 2010a )

. It is recognized that Pb can cross the placenta to affect the developing nervous system 

### 8
of the fetus (Sections 4.2.2.4 and 5.3.2.1) and there is evidence of increased susceptibility to the 

### 9
neurocognitive effects of Pb exposure during several lifestage s throughout childhood and into 

### 10
adolescence (for more detail, see Section 5.3.2.1) . Epidemiologic studies have investigated susceptibility 

### 11
among infants compared to adults or infants to young children. 

### 12
A study including multiple U.S. locations examined associations of blood Pb leve ls with various 

### 13
immune parameters among individuals living near Pb industries and matched controls ( Sarasua et al., 

### 14

2000 )

. For several of the endpoints, the association in the youngest group (6

- 35 months) and the oldest 

### 15

group (16

- 75 years) were in different directions

. For example, among children ages 6

- 35 months, the 

### 16

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

- cell 

### 17
abundance were positive, whereas the associations among 16

- 75 year olds were negative

. The opposite 

### 18
associations were present for T cell abundance

. Ig antibodies, which are produced by activated B cells, are 

### 19
important mediators of the humoral immune respon se to antigens. T cells are important mediators of cell



### 20
mediated immune responses that involve activation of other immune cells and cytokines. These findings 

### 21
by Sarasua et al. ( 2000 ) indicate t hat very young children may be at increased susceptibility for Pb



### 22
associated inappropriate activation of humoral immune responses and perturbations in cell

- to

- cell 

### 23
interactions that underlie allergic, asthma, and inflammatory responses (for more informatio n, see 

### 24
Sections 5.6.2.1 and 5.6.3). 

### 25
A study among Lebanese children examined the association between blood Pb levels and 

### 26
transferrin saturation (TS) less than 12% and iron

- deficiency anemia (IDA) ( Muwakkit et al., 2008 ) . A 

### 27
positive association was detected for blood Pb levels ≥ 10 μ g/dL and both TS less than 12% and IDA 

### 28
among children aged 11

- 23 months old, however null associations were observed among children 24

- 35 

### 29
months old. Calculations were not performed for children aged 36

- 75 months because there were n o 

### 30
children in the highest Pb group (≥ 10 μ g/dL) with either TS <12% or IDA

. The authors note that it is 

### 31May 2011 6

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– DO NOT CITE OR QUOTE difficult to know whether the Pb levels were “a cause or a result of” IDA levels since previous studies 

### 1

linked iron deficiency with Pb toxicity. 

### 2

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

### 3
(i.e., laying down and pruning neuronal circuits) and whose junctional barrier systems in the brain (i.e., 

### 4
the blood brain barrier) and GI system (i.e., gut closure) ar e immature, are more susceptible to Pb 

### 5

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

### 6
exposed to the same dose (mg/kg body weight/day) of Pb ( Berrahal et al., 2011 )

. Additionally, infants 

### 7
may be a susceptible population because Pb easily crosses the placental barrier and accumulates in fetal 

### 8
tissue during gestation ( Pillai et al., 2009 ; Uzbekov et al., 2007 ; Y.

- Y. Wang et al., 2009 )

. 

### 9

Overall evidence indicates young age as a potential susceptibility factor for Pb

- related health 

### 10
effects. Both recent epidemiologic studies summarized above reported associations among the youngest 

### 11
age groups, although different age cut

- points were used with one study inclu ding only infants 35 months 

### 12
of age and younger. Toxicological studies provide support for increased health effects of Pb among 

### 13

younger age groups. 

### 14

6.2.1.2. Older Adults

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

### 15
increase from 12.4% of the U.S. populatio n to 19.7% between 2000 to 2030, which is approximately 35 

### 16
million and 71.5 million individuals, respectively) ( SSDAN, 2010a ; U.S. Census Bureau, 2010 ) . As of the 

### 17

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 

### 18

older ( SSDAN, 2010a )

. 

### 19

A study using the NHANES III cohort examined blood Pb levels a nd mortality among individuals 

### 20
less than 60 years old and individuals 60 years and old er ( Menke et al., 2006 )

. Although the ha zard ratios 

### 21
were greater for all

- cause and cardiovascular mortality among those less than 60 years old, an increase in 

### 22

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

### 23
not statistically significant

. A similar study using the NHANES III cohort examined the relationship 

### 24
between blood Pb levels and mortality from all

- cause, cardiovascular disease, and cancer broken down 

### 25
into more specific age g roups ( Schober et al., 2006 )

. Point estimates were elevated for the association 

### 26
comparing blo od Pb levels of at least 10 μ g/dL to blood Pb levels less than 5 μg/dL and all

- c ause 

### 27
mortality for all age groups (40

- 74, 75

- 84, and 85 + year olds ), although the association for 75

- 84 year 

### 28

olds did n ot reach statistical significance

. The association was also present comparing blood Pb levels of 

### 29

5

- 9 μg/dL to blood Pb levels less than 5 μ g/dL among 40

- 74 year olds and 75

- 84 year olds but not among 

### 30

those 85 years and older. None of the associations betwe en blood Pb and cardiovascular disease

- related 

### 31
mortality reached statistical significance but the point estimates comparing bloo d Pb levels of 10 μ g/dL 

### 32
and greater to those less than 5 μ g/dL were elevated among all age groups

. Finally, the assoc iation 

### 33May 2011 6

- 13 DRAFT

– DO NOT CITE OR QUOTE betw een blood Pb levels 10 μ g/dL and greater and cancer mortality was positive among those 40

- 74 years 

### 1

old and 85 years and older but the association was null for those 75

- 84 years old. Among 75

- 84 year olds 

### 2
the association was positive comparing blood Pb of 5

- 9 μg/dL to less than 5 μ g/dL

. The other age groups 

### 3
had similar point estimates but the associations were not statistically significant

. 

### 4
The NHANES III study cohort was also used to investigate the association between blood Pb and 

### 5
cognitive test scores ( Krieg et a l., 2009 )

. The relationship was examined among adults aged 20

- 59 and 60 

### 6
years and older, but no association was observed in either of the age groups . A study using the Normative 

### 7
Aging Study cohort reported an interaction between Pb and age ( R. O. Wright, Tsaih, et al., 2003 ) . The 

### 8
inverse association between age and cognitive function was greater amo ng those with high blood or 

### 9
patella Pb levels. Effect estimates were in the same direction for tibia Pb but the interaction was not 

### 10
statistically significant. 

### 11
Finally, a study of current and former Pb workers reported that an interaction term of Pb and age 

### 12
(dichotomous cutpoint at 67th percentile but exact age not given) examined in a model of Pb and blood 

### 13

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

### 14
in this study of Pb and blood pressure. 

### 15
Toxicological studies have demonstrated biological plausibility for increased susceptibility among 

### 16
older populations. Demineralization associated with aging may increase the pool of available Pb to the 

### 17
blood. Cory

- Slechta ( 1990 ) administered various doses of Pb for a constant period to y oung animals, 

### 18
adults, or aged animals and found increased susceptibility to Pb in the aged animals due to increased 

### 19
exposure from elevated bone resorption. 

### 20
Also the kidneys of older animals appear to be more susceptible to Pb

- related health effects from 

### 21

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

### 22

et al., 2 011 )

. Susceptibility related to older age is also observed for effects on the brain

. Recent studies 

### 23
have demonstrated the importance of Pb exposure during early development in promoting the emergenc e 

### 24
of Alzheimer’s like pathologies in aged animals. Deve lopment of pathologies of old age in brains of aged 

### 25
animals that were exposed to Pb earlier in life has been documented in multiple species (mice and 

### 26
monkeys)

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

### 27

precu rsor protein and its product beta

- amyloid ( Basha et al., 2005 ; Zawia & Basha, 2005 ) . Some of these 

### 28
findings were seen in animals that no longer had elevated blood Pb levels. 

### 29
Results for age

- related modi fication of the association between Pb and mortality had mixed results 

### 30
and no difference by age was observed for the associations between Pb and other health effects. However, 

### 31
toxicological studies that inform on Pb

- related health effects by age may be rel evant in humans. Future 

### 32
studies will be instrumental in understanding older age as a susceptibility factor. 

### 33May 2011 6

- 14 DRAFT

– DO NOT CITE OR QUOTE 

## 6.2.2. S ex

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

### 1

was male and 50.9% were female

. The distribu tion did vary by age with a greater prevalence of females ≥ 

### 2
65 years old compared to males ( SSDAN, 2010a ) . The 2006 Pb AQCD reported that boys are often found 

### 3
to have higher blood Pb levels than girls, but findings were "less clear" regarding differences in Pb

- related 

### 4

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

. 

### 5
Multiple epidemiologic studies hav e examined Pb

- related effects on cognition stratified by sex. In 

### 6
previous studies using the Cincinnati Lead Study cohort, Dietrich et al. ( 1987 ) and Ris et al. ( 2004 ) 

### 7
observed interactions between blood Pb and sex for both prenatal and postnatal expos ures; associations of 

### 8
prenatal and postnatal blood Pb decrements in memory, attention, and visuoconstruction were observed 

### 9
only among male adolescents. More recently, Wright et al. ( 2008 ) examined early life Pb exposure and 

### 10
criminal arrests in adulthood. The attributable risks were greater among males than females. Additionally, 

### 11

the associat ion between childhood blood Pb levels and gray matter volume loss was greater among males 

### 12

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

### 13
blood Pb levels on adult gray matter, researchers found that inverse associations between yearly mean 

### 14
blood Pb levels and volume of gray matter loss were more pronounced in the frontal lobes of males than 

### 15

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

### 16
examined Pb exposures at various ages throughout childhood and adolescence ( Baghurst et al., 1992 ; 

### 17

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

### 18
in girls throughout childhood and into early adolescence. A study in Poland also investigated th e 

### 19
association between cord Pb levels and cognitive deficits and reported an inverse association for boys at 

### 20
36 months but not for girls ( Jedrychowski et al., 2009 ) . No associa tion was detected for boys or girls at 24 

### 21

months. 

### 22
An epidemiologic study examined the association between blood Pb levels and kidney function 

### 23
among 12

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

### 24
stratified by sex and no effect measure modification was apparent. 

### 25
Similarly, a study of current and former Pb workers examined an interaction term between sex and 

### 26
Pb for the study of Pb and blood pressure ( Weaver et al., 2008 ) . No modification by sex was present. 

### 27
Epidemiologic studies have also been performed to assess differences between males and females 

### 28

for Pb

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

### 29

associations between Pb and total i mmunoglobulin E (IgE ) for women not taking hormone replacement 

### 30
therapy or oral contraceptives ( Pizent et al., 2008 )

. No association was report ed in males, but other 

### 31
associations, such as bronchial reactivity and skin prick tests were observed in the opposite of the 

### 32
expected direction, which questions the validity of the results among the male study participants

. Analysis 

### 33

of an NHANES dataset det ected no association between Pb levels and inflammatory markers ( Songdej et 

### 34May 2011 6

- 15 DRAFT

– DO NOT CITE OR QUOTE al., 2010 )

. Although there was no pattern, a few of the associations were posi tive between Pb and C



### 1
reactive protein for males but not females

. A study of children living at varying distances from a Pb 

### 2
smelter in Mexico reported that blood Pb was associated with increased release of superoxide anion from 

### 3
macrophages, which was great er among males than females ( Pineda

- Zavaleta et al., 2004 )

. Additionally, 

### 4
blood Pb was inversely associated with the release of N O among males but not females

. 

### 5
Epidemiologic investigations of cancer have also examined the associations by sex. A study of the 

### 6

association between occupational exposure Pb and brain tumors reported no sex

- specific associations for 

### 7
gliomas but a positive association for cumulative Pb exposure and meningiomas for males but not females 

### 8

( Rajaraman et al., 2006 )

. An inverse association was observed between ever exposure to Pb and 

### 9
meningiomas for females

. An ecologic analysis of Pb pollution levels and cancer incidence among 

### 10
children reported weak correlations overall and the weak correlations were more apparent among males, 

### 11
whereas no correlation was observed among females ( Absalon & Slesak, 2010 )

. 

### 12
A study of all

- cause and cardiovascular mortality using the NHANES III cohort reported no 

### 13

modification of the association between Pb and all

- cause or cardiovascular mortality by sex ( Menke et al., 

### 14

2006 ) . This did not differ among women when classified as pre

- or post

- menopausal. 

### 15
Toxicological studies have also reported sex differences in Pb

- related effects to various organ 

### 16

systems. Dona ld et al ( 1986 ) reported a different tim e course of enhanced social investigatory behavior 

### 17

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

. ( 1987 ) 

### 18

showed that non

- social behavior de creased in females and increased in males exposed to Pb. Males also 

### 19
had a shorter latency to aggression with Pb treatment versus controls. Pb affected mood disorders 

### 20
differently for males and females. Behavioral testing showed males experienced emotional c hanges and 

### 21
females depression

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

### 22
gestational exposure to Pb impaired memory retrieval in males at all 3 doses of Pb exposure; memory 

### 23
retrieval was only impaired in low

- dose females ( Yang et al., 2003 )

. 

### 24

Sex

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

### 25
and coordination were most affected among males ( Leasure et al., 2008 ) . In addition, obesity in adult 

### 26

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

. 

### 27
Obesity was also found in male offspring exposed in utero to high doses of Pb that persisted to 5 weeks of 

### 28
age/e nd of the study, but among females, body weight remained elevated over controls only to 3 weeks of 

### 29

age ( Yang et al., 2003 )

. Additionally, low

- dose Pb exposure induced retinal decrements in exposed male 

### 30
offspring ( Leasure et al., 2008 )

. 

### 31
A toxicological study of Pb and antioxidant enzymes in heart and kidney tissue reported that male 

### 32

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

### 33

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

### 34
these results could be due to gr eater deposition of Pb in female rats or greater clearance of Pb by males 

### 35

( Sobekova et al., 2009 )

. 

### 36May 2011 6

- 16 DRAFT

– DO NOT CITE OR QUOTE Pb and stress are co

- oc curring factors that act in a sex

- divergent manner to affect behavior, 

### 1
neurochemistry, and corticosterone. Pb and stress act synergistically to affect fixed interval operant 

### 2
behavior and corticosterone in female offspring. Virgolini et al. ( 2008 ) found that effects on the central 

### 3

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

### 4

and fem ales are most susceptible. Behavioral related outcomes after gestational and lactational Pb 

### 5
exposure with and without stress show sex

- differences in exposed offspring ( Virgolini, Rossi

- George, 

### 6

Weston, et al., 2008 ) . Pb

- induced changes in brain neurochemistry with or without concomitant stress 

### 7
exposure are complex with differences varying by brain region, neurotransmitter type and sex of the 

### 8

animal. 

### 9
The brain is known to have a sexually dimorphic area in the hypothalamus termed the sexually 

### 10
dimorphic nucleus (SDN). Lesions in this area affect sex

- specific phenotypes including behavior. Across 

### 11
species the SDN has a greater cell number and l arger size in males versus females. This sexually 

### 12
dichotomous area is especially vulnerable to perturbation during fetal life and the early postnatal period. 

### 13
This may be one area of the brain that could explain some of the sexually dichotomous effects that are 

### 14
seen with Pb exposure. One study supporting this line of thought showed that high dose in utero Pb 

### 15
exposure (pup blood Pb level 64 μg/dL at birth) induced reductions in SDN volume in 35% of Pb



### 16
exposed males { McG ivern, 1991, 49264}. Interestingly, anot her chemical that is known to cause a 

### 17
hypothalamic lesion in this area, monosodium glutamate, is associated with adult onset obesity; adult 

### 18
onset obesity is seen in the Pb literature. 

### 19
Multiple associations between Pb and various health endpoints have been examined for effect 

### 20
measure modification by sex. Although not observed in all endpoints, some studies reported differences 

### 21
between the associations for males and females, especially in neurological studies. However, studies on 

### 22
cognition from the Cincinnati Lead Study cohort and a study in Poland reported males to be the 

### 23
susceptible population, whereas studies from Australia pointed to females as the susceptible population. A 

### 24
difference in sex is also supported by toxicological studies. Further research will confirm the presence or 

### 25

absence of sex

- specific associations between Pb and various health outcomes. 

### 26



## 6.2.3. H ormones

It is possible that hormone levels may affect susceptibility to Pb

- related health effects. Among 

### 27

women, various hormone

- related categories were e xamined for the relationship between blood Pb levels 

### 28

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

### 29
observed between Pb levels and FSH levels among women who were post

- menopausal, who were pre



### 30

menopau sal but not on birth control , menstruating, or pregnant, or who had both ovaries removed ( Krieg, 

### 31

2007 )

. An inverse association was observed for women taking birth control pi lls

. For Pb and LH, there 

### 32May 2011 6

- 17 DRAFT

– DO NOT CITE OR QUOTE was a positive assoc iation among women who were pos t

- menopausal or had both ovaries removed

. No 

### 1

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

### 2
Toxicological studies provide evidence that Pb affects hormones and support the possible 

### 3
susceptibility to Pb

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

### 4

as well as c hanges in the female reproductive tract have been reported in the literature after Pb exposure

. 

### 5
Pb exposu re can also alter e strous cyclicity ( U.S. EPA, 2006 ) , change cervical structure, and lead to 

### 6

o varian dysfunction with altered membrane composition ( Kolesarova et al., 2010 ; Nampoothiri et al., 

### 7

2007 ; Nampoothiri & Gupta, 2006 ; U.S. EPA, 2006 )

. Additionally, embryo development and implantation 

### 8

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

### 9
puberty onset, first estrous, and age of fir st parturition have been repo rted with in utero Pb exposure 

### 10

( Iavicoli et al., 2006 )

. 

### 11



## 6.2.4. G enetics

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

### 12
influencing the absorption, retention, and toxicokinetics of Pb in humans" ( U.S. EPA, 2006 ) . The majority 

### 13

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

### 14
genes, as well as additional genes examined in recent studies, are discussed below. 

### 15

6.2.4.1. Aminolevulinate D ehydratase

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

### 16
produc tion of heme and is also the principal Pb

- binding protein ( U.S. EPA, 2006 ) . ALAD is a 

### 17
polymorphic protein with three isoforms: ALAD 1

- 1, ALAD 1

- 2, and ALAD 2

- 2. Multiple studies have 

### 18
examined the association between ALAD2 polymorp hisms and blood Pb levels ( Y. Chen et al., 2008 ; 

### 19

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

### 20

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

### 21

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

### 22

various health effects. 

### 23
Associations between Pb and brain tumors observed in one study varied by ALAD genotype status 

### 24

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

### 25
among ALAD2 individuals but this association was not found among individuals who had the ALAD1 

### 26
allele. No associations were observed between Pb and glioma regardless of ALAD genotype. 

### 27
A study of current and former workers exposed to Pb examined the association between blood Pb 

### 28
and blood pressure and reported no modification by ALAD genotype ( Weaver et al., 2008 ) . However, 

### 29
another study of blood Pb and blood pressure reported interactions between blood Pb and ALAD, but this 

### 30May 2011 6

- 18 DRAFT

– DO NOT CITE OR QUOTE varied by race (non

- Hispanic white, non

- Hispanic black, and Mexican

- American ) ( Sc inicariello et al., 

### 1

2010 )

. 

### 2
Individuals with ALAD variants had greater associations between Pb and kidney effects; among 

### 3
those with the variant, higher Pb was associated with higher glomerular filtration measures ( Weaver et al., 

### 4

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

### 5
workers with the ALAD2 allele demonstrated greater associations between Pb a nd renal injury ( Gao et al., 

### 6

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

### 7

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

. 

### 8
Studies investigating the association between Pb levels and cognitive functio n have also examined 

### 9
modification by ALAD polymorphisms. In a study using a cohort from NHANES III, slight associations 

### 10
were observed in some cognitive tests for 20

- 59 year olds with CC and CG ALAD genotypes ( Krieg et 

### 11

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

### 12
cognitive function by ALAD variant, although some difference was found when examining bone Pb 

### 13
levels and cognitive function ( Rajan et al., 2008 ; Weisskopf et al., 2007 ; Weuve et al., 2006 )

. 

### 14

6.2.4.2. Vitamin D Receptor

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

### 15
of the NHANES III population examined the association between blood Pb levels and various 

### 16
neurocognitive tests with assessment of effect me asure modification by SNPs and haplotypes of VDR 

### 17

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

### 18
variants being associated with greater modification of the relationship between Pb and one type of 

### 19
neurocognitive test comp ared to the modification of the relationship between Pb and other neurocognitive 

### 20

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

### 21

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

. 

### 22
Three genetic variants or polymorphisms of the vitami n D receptor in humans have been 

### 23
characterized (BsmI, FokI, and ApaI) and have been reported to account for 75% of the differences in 

### 24
bone density in humans ( Morrison et al., 1994 ; Morrison et al., 1992 )

. The Bsm I polymorphisms are 

### 25

denoted as bb (hom ozygote), BB (homozygote), and Bb (heterozygote)

. Bone measurements of Pb levels 

### 26
in exposed workers found that bone Pb was highest in individuals with the BB genotype, intermediate in 

### 27
the heterozygotes and lowest in the bb genotype group ( Schwartz et al., 2000 ; Theppeang et al., 2004 )

. 

### 28
People with the bb genotype or ff (FokI polymorphism) genotype have lower bone Pb than subjects with 

### 29
other genotypes. Subjects with the aa (ApaI polymorphism) or ff genotype have lower plasma Pb than 

### 30
subjects with other genotypes ( Rezende et al., 2008 ) . Plasma Pb is followed to look at bio

- available Pb, 

### 31

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

### 32
haplotype combining a, b and f alleles for the aforementioned respective polymorphisms have lower 

### 33May 2011 6

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– DO NOT CITE OR QUOTE plasma Pb and bone Pb levels ( Rezende et al., 2008 ) . A study of pregnant women examining Pb in 

### 1

maternal and umbilical cord serum and blood found no association betwee n VDR polymorphisms and 

### 2
these parameters. However there was lower Pb in women with the VDR haplotype combining the alleles f 

### 3
a and b, a group that is likely genetically less prone to Pb toxicity during pregnancy ( Rezende et al., 

### 4

2010 )

. 

### 5

6.2.4.3. Methylenetetrahydrofolate reductase

Methylenetetrahydrofolate reducta se ( MTHFR ) catalyzes the conversion of 

### 6

5,10

- methylenetetrahydrofolate to 5

- methyltetrahydrofolate, which in turn, is involved in homocysteine 

### 7
remethylation to the amino acid methionine . A study in Mexico of the association between Pb and 

### 8
Bayley's Mental De velopment Index (MDI) score at 24 months reported no effect measure modification 

### 9
by MTHFR 677T allele ( Pilsner et al., 2010 ) . Another study in Mexico examined the association between 

### 10
maternal Pb and birth weight ( Kordas et al., 2009 ) . No modification of the Pb

- birth weight association by 

### 11

MTHFR was observed. 

### 12

6.2.4.4. Apolipo prot ein E

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

### 13
to regulate synapse formation (connections between neurons) and may be particularly critical in early 

### 14

childhood

. A genetic variant, called the APOE4 al lele is a haplotype between two exonic SNPs and is 

### 15
perhaps the most widely studied genetic variant with respect to increasing risk of neurologic disease. A 

### 16
study of occupationally

- exposed adults observed Pb to be associated with greater decrements in tests such 

### 17
as digit symbol, pegboard assembly, and complex reaction time among adults with at least one APOE

- ε4 

### 18

allele ( Stewart et al., 2002 ) . Conversely, i n a study of children in Mexico, children without the APOE

- ε4 

### 19

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

### 20

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

. 

### 21

6.2.4.5. Hemochromatosis

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

### 22
difference was observed between the association of tibia Pb levels and cognitive function for men with 

### 23

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

### 24
function was present for men with HFE wildtype, but a decline in function associated with Pb levels 

### 25
among men with any HFE allele variant. A study of bone Pb levels and HFE reported no difference in 

### 26

effect estimates f or bone Pb and pulse pressure between different HFE variants and HFE wild

- type 

### 27

( Zhang et al., 2010 )

. 

### 28May 2011 6

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– DO NOT CITE OR QUOTE 

### 6.2.4.6. Other Genetic Polymorphisms

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

- related 

### 1

health effects. These include dopamine 4 r eceptor (DRD4) , g lutathione S

- transferase Mu 1 ( GSTM1 ), 

### 2

t umor necrosis factor

- alpha ( TNF

- alpha ), endothelial nitric oxide synthase ( eNOS ), and various SNPS. 

### 3
A prospective birth cohort reported that increasing blood Pb le vels were associated with poorer rule 

### 4
learning and reversal, spatial span, and planning in their study population ( Froehlich et al., 2007 )

. These 

### 5
inverse associations were exacerbated among those lacking DRD4.7. 

### 6
A study of university students in Korea reported blood Pb levels to be associated with biomarkers 

### 7
of inflammation among individuals with G STM1 null genotype and not among individuals with GSTM1 

### 8

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

. 

### 9
The relationship b etween blood Pb levels and inflammation was examined among individuals with 

### 10

TNF

- alpha GG, GA, or AA alleles. An association was present for those with TNF

- alpha GG but not for 

### 11

those with TNF

- alpha GA or AA ( J. H. Kim et al., 2007 )

. 

### 12
A study of blood Pb and plasma NOx reported no overall association but did report an inverse 

### 13
correlation among subjects with the eNO S TC+CC genotype ( Barbosa et al., 2006 ) . No correlation was 

### 14
observed for subjects with the eNOS TT genotype, however the number of subjects in this group was 

### 15
small, especially for those with high blood Pb levels. 

### 16
One study examined how the association between Pb and brain tumors varied among m ultiple 

### 17
single nucleotide polymorphisms ( SNPs ) ( Bhatti et al., 2009 )

. No effect measure modification of the 

### 18
association between Pb and glioma was observed for any of the SNPs

. GPX1 (the gene encoding for 

### 19
glutathione peroxidase 1) modified the association for glioblastoma multiforme and meningioma

. The 

### 20
association between Pb and glioblastma multiforme was also modified by a RAC2 (the gene encoding for 

### 21

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

### 22
encoding for xanthine dehydrogenase) v ariant. 

### 23



## 6.2.5. Pre

- existing Diseases/Conditions

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

### 24
susceptible to Pb

- related effects on health. Recent studies have explored relationships for autism, atopy, 

### 25
diabetes, and hypertension. 

### 26

6.2.5.1. Autism

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

### 27
per 1,000 population (95% CI : 8 .6

, 9.3) determined from a monitoring network ( Autism and 

### 28
Developmental Disabilities Monitoring Network ) with 11 sites across the U.S. ( CDC, 2009b )

. 

### 29May 2011 6

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– DO NOT CITE OR QUOTE A cross

- sectional study of children with and without autism examin ed the association between 

### 1
blood Pb levels and various immune function and inflammation genes ( Tian et al., 2011 )

. Blood Pb levels 

### 2
among both autistic and non

- autistic children were associate d with expression of the inflammation genes 

### 3
under study, however the associations observed were in opposite directions (positive association among 

### 4

autistic children and inverse among non

- autistic children). 

### 5

6.2.5.2. Atopy

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

### 6
and IgE ( Annesi

- Maesano et al., 2003 )

. The study examined Pb level s (measured via hair) in infants and 

### 7
IgE and reported a positive correlation overall

. However, in stratified analyses, this association remained 

### 8
only among infants of mothers without atopy

. Among atopic mothers, the correlation was positive, 

### 9
although small er, and was not statistically significant. 

### 10

6.2.5.3. Diabetes

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

. A few studies have been 

### 11
conducted to investigate the possibility of diabetes as a susceptibility factor for Pb and various health 

### 12

outcomes

. 

### 13

D ifferenc es in the association between bone and blood Pb levels and renal function for individuals 

### 14
with and without diabetes at baseline was examined using the Normative Aging Study cohort ( Tsaih et al., 

### 15

2004 )

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

### 16

diabetics but not among individuals without diabetes

. However, this association was no longer statistically 

### 17
significant after the exclusion of individuals who were hypertensive or who used diuretic medications

. 

### 18
Another study with this cohort reported no associations bet ween bone Pb and heart rate variability, which 

### 19
did not differ among those with and without diabetes ( Park et al., 2006 )

. 

### 20
The NHANES III study evaluated whether the association between Pb and both all

- cause and 

### 21
cardiovascular mortality varied among individuals with and without diabet es ( Menke et al., 2006 ) . The 

### 22
95% CIs among those with diabetes were large and no difference was apparent among those with and 

### 23

without diabetes. 

### 24

Overall, recent epid emiologic studies found that associations did not differ for individuals with and 

### 25

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

### 26

"increased risk of Pb

- associated declines in renal function" ( U.S. EPA, 2 006 ) . Future research examining 

### 27
associations between Pb and renal function, as well as other health outcomes, among individuals with and 

### 28
without diabetes will inform further on this potential susceptibility factor. 

### 29May 2011 6

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– DO NOT CITE OR QUOTE 

### 6.2.5.4. Hypertension

Hypertension affects appr oximately 24% of adults in the U.S. and the prevalence of hypertension 

### 1
increases with age (61% of individuals 75 years of age and older have hypertension) ( Pleis et al., 2009 )

. 

### 2
The Normative Aging Study cohort mentioned above for modification of the association between 

### 3
Pb levels and renal function by diabetes also examined modifi cation by hypertensive status ( Tsaih et al., 

### 4

2004 )

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

### 5
present among individuals with hypertension but not among individuals that were normotensive. Models 

### 6

of the follow

- up serum creatinine levels demonstrated an association with blood Pb for hypertensive but 

### 7
not normotensive individuals (this association was not present when using tibia or patella Pb). Another 

### 8
study using this population examined modification of the association between bone Pb and heart rate 

### 9

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

. 

### 10
Although a statistically significant association between Pb and heart rate variability was not observed 

### 11
among hypertensive or normotensive individuals, the estimates were different, with greater odds among 

### 12
hypertensive individuals (Pb positively related to low frequency power and the ratio of low fr equency to 

### 13
high frequency power and inverse ly related to high frequency power )

. 

### 14
A study using the NHANES III cohort reported a positive association between Pb and both all



### 15
cause and cardiovascular mortality for hypertensive and normotensive individuals but the associations did 

### 16

not differ based on h ypertensive status ( Menke et al., 2006 )

. 

### 17
The 2006 Pb AQCD reported that individuals with hypertension had increased susceptibility to Pb



### 18

related effects on renal fu nction ( U.S. EPA, 2006 ) . This is supported by recent epidemiologic studies. As 

### 19

described above, studies of Pb

- related effects on renal function and heart rate variability have observed 

### 20
some differences among hypertensive individuals, but the difference betw een hypertensive and 

### 21

normotensive adults is not observed for Pb

- related mortality. 

### 22



## 6.2.6. S moking

T he rate of smoking among adults 18 years and older in the U.S. is approximately 20% and a bout 

### 23

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

### 24
have examined smoking as an effect me asure modifier. 

### 25
A study of Pb and all

- cause and cardiovascular mortality reported no modification of this 

### 26
association by smoking status, measured as current, former, or never smokers ( Menke et al., 2006 ) . The 

### 27
Normative Aging Study examined the association between blood and bone Pb levels and renal function 

### 28
and also reported no interaction with smoking status ( Tsaih et al., 2004 )

. 

### 29
A study of Pb exposed workers and controls reported similar levels of absolute neutroph il counts 

### 30
(ANC) across Pb exposure categories among non

- smokers ( Di Lorenzo et al., 2006 ) . However, among 

### 31
current smokers, higher Pb exposure was associated with higher ANC. Additionally , a positive 

### 32May 2011 6

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– DO NOT CITE OR QUOTE relationship was observed between higher blood Pb levels and TNF

- alpha and g ranulocyte colony



### 1
stimulating factor (G

- CSF) among both smokers and nonsmokers, but this association was greater among 

### 2

smokers ( Di Lorenzo et al., 2007 )

. A recent study of fertile and infertile men examined blood and seminal 

### 3
plasma Pb leve ls for smokers and non

- smokers ( Kiziler et al., 2007 )

. The blood and seminal plasma Pb 

### 4
levels were higher for smokers of both groups

. Additionally, the Pb levels were lowest among non



### 5
smoking fertile men and highest among smoking infertile men

. 

### 6
Prenatal smoking exposure was examined in a study of children’s blood Pb levels and prevalence 

### 7

of attention

- deficit/hyperactivity disorder (ADH D). An interaction was observed between Pb and prenatal 

### 8
tobacco smoke exposure; those children with high Pb levels and prenatal tobacco smoke exposure had the 

### 9
highest odds of ADHD ( Froehlich et al., 2009 )

. 

### 10
Overall, the studies have mixed findings on whether smoking modifies the relationship between Pb 

### 11

and health effects. Future studies of Pb

- related health effects and current, former, and prenatal smoking 

### 12
exposures among various health endpoints will aid in determining susceptibility by this factor. 

### 13



## 6.2.7. R ace /E thnicity

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

- Hispa nic Whites. 

### 14
Approximately 12.1 % of people reported their race/ethnicity as Non

- Hispanic Black and 12.6 % reported 

### 15
being Hispanic ( SSDAN, 2010b ) . Studies of multiple Pb

- related health outcomes examined effect 

### 16
measure modification by race. 

### 17
A study of adults from the NHANES III cohort examined the association between blood Pb levels 

### 18

and all

- cause and cardiova scular mortality ( Menke et al., 2006 ) . Stratified analyses were conducted for 

### 19

non

- Hispanic whites, non

- Hispanic blacks, and Mexican

- Americans and no interaction was reported. 

### 20
Another study using the NHANES III cohort reported on blood Pb levels and hypertension. While no 

### 21

association was observed between blood Pb and non

- Hispanic Whites or Hispanics, a positive association 

### 22
was reported for non

- Hispanic Blacks ( Scinicariell o et al., 2010 ) . Another study using NHANES datasets 

### 23
examined the associations between blood Pb and hypertension ( Muntner et al., 2005 ) . Although none of 

### 24
the associations were statistically significant, increased odds were observed among non

- Hispanic blacks 

### 25

and Mexican

- Americans but not for non

- Hispanic whites. 

### 26
A study of girls aged 8

- 18 years from the NHANES III cohort reported an inverse association 

### 27
between blood Pb levels and pubertal development among African Americans and Mexican Americans 

### 28

( Selevan et al., 2003 ) . For non

- Hispanic Whites, the associations were in the same direction but did not 

### 29
reach statistical significance. Of note, less than 3% of non

- Hispanic Whites had blood Pb levels over 5 

### 30
μg/dL, whereas 11.6% and 12.8% of African Americans and Mexican Americans had blood Pb levels 

### 31
greater than 5 μg/dL, respectively. 

### 32May 2011 6

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– DO NOT CITE OR QUOTE A study linking educational testing data for 4 th grade students in North Carolina reported decline s 

### 1
in reading and mathematics scores with increasing levels of Pb ( Miranda et al., 2007 )

. Although not 

### 2

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

### 3

for white and black children. 

### 4
Blood Pb and asthma was examined for white and black children living in Michigan ( Joseph et al., 

### 5

2005 )

. When utilizing separate referent groups for the two races, the onl y association is an increase 

### 6
among whites (although not statistically significant), but when restricting to the highest blood Pb levels, 

### 7
the association was no longer apparent

. Whites with low blood Pb levels were used as the referent group 

### 8

for both races in additional analysis

. Although the estimates were elevated for black children compared to 

### 9
white children (including at the lowest blood Pb levels), the confidence intervals for the associations 

### 10
overlapped indicating a lack of a difference by race. 

### 11

The r esults of these recent epidemiologic studies suggest that there may be race

- related 

### 12
susceptibility for some outcomes, although the overall understanding of potential effect measure 

### 13
modification by race is limited by the small number of studies. Additionall y, these results may be 

### 14
cofounded by other factors, such as socioeconomic status. 

### 15



## 6.2.8. Socioeconomic Status

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

### 16

of 4 was $17,463) ( SSDAN, 2010c )

. Ris et al. ( 2004 ) examined modification of the associations between 

### 17
early

- life Pb exposure and Learning/IQ among adolescents in the Cincinnati Lead Study

. In models 

### 18
examining the association between Pb and Learning/IQ, prenatal and 78

- month Pb concentrations were 

### 19
associated with larger decrements in Learning/IQ in the lower two quintiles of socioeconomic status 

### 20

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

### 21



## 6.2.9. Body Mass Index

In the U.S. self

- reported rates of obesity were 26.7% in 2009, up from 19.8% in 2000 ( Sherry et al., 

### 22

2010 )

. The NHANES III cohort was utilized in a study of blood Pb levels and all

- cause and 

### 23
cardiovascular mortality, which included assessment of the asso ciations by obesity ( Menke et al., 2006 )

. 

### 24
Positive associations were observed among individuals within the two categories of body mass index 

### 25

( BMI ) ( non

- obese [ <25 kg/m 2 ] and obese [ ≥ 25 kg/m 2 ] ) but there was no difference between the 

### 26
categories

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

### 27
was performed and reported slight changes in the association based on the presenc e of metabolic 

### 28
syndrome, however none of the changes resulted in associations that were statistically significant ( Park et 

### 29

al., 2006 )

. 

### 30May 2011 6

- 25 DRAFT

– DO NOT CITE OR QUOTE No modification by BMI/obesity was observed among recent epidemiologic studies. Future studies 

### 1

of Pb

- related health effects and BMI will aid in dete rmining susceptibility by this factor. 

### 2



## 6.2.10. A lcohol C onsumption

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

### 3
the Normative Aging Study cohort investigated whether the association between blood and bone Pb lev els 

### 4
and renal function would be modified by an individual’s alcohol consumption ( Tsaih et al., 2004 ) . No 

### 5
interaction with alcohol consumption was observed. However, a toxicological study reported that ethanol 

### 6
potentiated the effect of Pb exposure by decreasing renal total protein sulfhydryls (endogenous 

### 7

an tioxidants). Pb and ethanol also decreased other endogenous renal antioxidants (glutathione and non



### 8
protein sulfhydryls) ( Jurczuk et al., 2006 )

. 

### 9



## 6.2.11. N utrition

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

### 10
designed to limit or reduce caloric intake and induce weight loss have been associated with increased 

### 11

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

### 12
such as calcium, iron, and zinc offer some protection from Pb exposure by preventing or competing with 

### 13
Pb for absorption in the GI tract. A recent toxicological study reported negative effects of P b on osmotic 

### 14
fragility, TBARS production, catalase activity, and other oxidative parameters, but most of these effects 

### 15
were reduced to the levels observed in the control group when the rats were given supplementation of 

### 16

zinc and vitamins ( Massó

- González & Antonio

- García, 2009 ) . The previous Pb AQCD ( U.S. EPA, 2006 ) 

### 17
reported lim ited data available to assess modification by nutritional status; however, potential 

### 18
modification by iron and calcium were noted. Recent epidemiologic and toxicological studies of specific 

### 19
mineral intakes/dietary components are detailed below. 

### 20

6.2.11.1. Calcium

Usin g the Normative Aging Study, researchers examined the association between Pb and 

### 21
hypertension by calcium intake ( Elmarsafawy et al., 2006 ) . The associations between Pb (measured and 

### 22
modeled separately for blood, patella, and tibia) and hypertension did not differ based on dichotomized 

### 23
calcium intake (800 mg/day). However, toxicological studies have shown that d ietary calcium deficiency 

### 24
induces increased Pb absorption and retention ( Fullmer, 1992 ; Mykkanen & Wasserman, 1981 ; Six & 

### 25
Goyer, 1970 ) . Also, low calcium levels in the body stimulate the production of vitamin D and increased 

### 26

s ynthesis of calcium

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

### 27
intake reduces accumulation of Pb in bone and mobilization of Pb during pregnancy and lactation 

### 28

( Bogden et al., 1995 )

. 

### 29May 2011 6

- 26 DRAFT

– DO NOT CITE OR QUOTE 

### 6.2.11.2. Iron

The 2006 Pb AQCD included studies that indicated individ uals with iron

- deficiency and 

### 1
malnourishment had greater inverse associations between Pb and cognition/intellect ( U.S. EPA, 2006 ) . A 

### 2
recent epidemiologic study of pubertal development among girls observed inverse associations between 

### 3

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

### 4
deficiency having a stronger inverse association between Pb and inhibin B than those who were iron 

### 5

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

### 6
potentiate the effect of Pb. A study of pregnant rats given an iron deficient diet and exposed to Pb through 

### 7
drinking water over GD 6

- 14 had decreased litter size, pups with reduce d fetal weight and reduced crown



### 8
rump length, increased litter resorption, and a higher dam blood Pb level in the highest exposure groups 

### 9

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

### 10
more susceptible to Pb

- dependent embryo and feto

- toxicity ( Singh et al., 1993 )

. 

### 11

6.2.11.3. Zinc

No epidemiologic studies hav e been performed to examine the effect of zinc on Pb

- related health 

### 12
outcomes. Toxicological studies by Jamieson et al ( 2008 ; 2006 ) reported that a zinc deficient diet 

### 13
increases bone and renal Pb content (deposition in kidney tissue) and impairs skeletal growth and 

### 14

mineralization. A zinc

- supplemented diet attenuated bone and renal Pb content. 

### 15

6.2.11.4. F olate

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

### 16
authors reported no interaction between Pb and folate levels. 

### 17

6.2.11.5. Protein

No recent epidemiologic studies have evaluated protein intake as a suscept ibility factor for Pb



### 18
related health effects. However, a toxicological study demonstrated that differences in maternal protein 

### 19

levels could affect the extent of Pb

- induced immunotoxicity among offspring ( S. Chen et al., 2004 )

. 

### 20



## 6.2.12. S tress

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

### 21

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

### 22

level s on hypertension was present

. Among the same study population, higher stress was also noted to 

### 23
affect the association between Pb levels and cognitive function ; the higher stress group showed a greater 

### 24
inverse association between Pb and cognitive function than those in the low stress group ( Peters et al., 

### 25May 2011 6

- 27 DRAFT

– DO NOT CITE OR QUOTE 2008 )

. In another study, the association between tibia Pb levels and some measures of cognitive function 

### 1
were similarly strengthened by nei ghborhood psychosocial hazards ( Glass et al., 2009 )

. 

### 2
Toxicological studies have demonstrated that early life exposure to Pb and maternal stress can 

### 3
result in toxicity related to multiple systems ( Cory

- Slechta et al., 2008 ; Rossi

- George et al., 2009 ; 

### 4
Virgolini, Rossi

- George, Lisek, et al., 2008 ; Virgolini, Rossi

- George, Weston, et al., 2008 ) , including 

### 5
dysfunctional corticosterone responses ( Rossi

- George et al., 2009 ; Virgolini, Rossi

- George, Weston, et al., 

### 6

2008 )

. Additionally, toxicological studies have demons trated that immune stress also a ffects associations 

### 7

with Pb

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

### 8
and trafficking dysfunction ( Lee et al., 2002 )

. Similarly, mice with neonatal Pb exposure and an immune 

### 9

challe nge had a sickness behavior phenotype, likely driven by IL

- 6 production ( Dyatlov & Lawrence, 

### 10

2002 )

. 

### 11

Similar to studies of stress in animals, maternal self

- esteem has also been shown to modify 

### 12

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

### 13
between children’s blood Pb levels and Bayley’s MDI and Psychomotor Development Index (PDI) among 

### 14

mother

- child pairs. High maternal self

- esteem was independently associated with higher MDI score and 

### 15
also appeared to attenuate the negative effects observed of Pb on MDI and PDI scores; greater decreases 

### 16
in MDI and PDI associated with Pb levels were observed among mothers in the lower quartiles of s elf



### 17
esteem. The investigators indicated that high maternal self

- esteem may serve as a buffer against stress by 

### 18
improving mother

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

### 19
stress responses in the child. 

### 20
Although e xamined in a limited number of studies, recent epidemiologic studies observed 

### 21
modification of the association between Pb and health effects by stress

- level. Susceptibility to Pb

- related 

### 22
health effects by stress is supported by toxicological studies. 

### 23



## 6.2.13. Cognit ive Reserve

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

### 24
function was present among workers with low cognitive reserve but no association was present in workers 

### 25
with high cognitive reserve ( Bleecker et al., 2007 )

. Associations between Pb and motor functions existed 

### 26
among all workers regardless of cognitive reserve

. No other recent epidemiologic studies were performed 

### 27
examining cognitive reserve as a susceptibility factor

. 

### 28



## 6.2.14. O ther M etal E xposure

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

### 29

and not effect measure modifiers ( U.S. EPA, 2006 ) . Recent epi demiologic studies have, however, begun 

### 30May 2011 6

- 28 DRAFT

– DO NOT CITE OR QUOTE to explore the possible interaction between Pb and other metals. These studies, as well as toxicological 

### 1

studies of these metals, are described below. 

### 2

6.2.14.1. Cadmium

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

### 3

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

### 4
girls with high cadmium ( Cd ) and high Pb compared to those with high Pb and low Cd

. Additionally, 

### 5
higher blood Pb and Cd levels together were positively associated with albuminuria and reduced 

### 6
estimated glomerular filtration rate, compared to those with the lowest levels of Pb and Cd ( Navas

- Acien 

### 7

et al., 2009 )

. 

### 8
Toxicological studies have reported that the addition of Cd to Pb treatment of rats reduc ed the 

### 9
histological signs of renal toxicity from each element alone; however, urinary excretion of porphyrins 

### 10
were increased, indicating that although measured tissue burdens of Pb were reduced, the biologically 

### 11
available fraction of Pb was actually increa sed ( G. S. Wang & Fowler, 2008 )

. In other studies, Cd 

### 12
synergistically exacerbated Pb

- dependent renal mitochondrial dysfunction ( L. Wang et al., 2009 )

. 

### 13
Overall, epidemiologic and toxicological studies have reported increased susceptibility to Pb



### 14

rela ted health effects among those with high Cd levels as well. 

### 15

6.2.14.2. Arsenic

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

### 16
Mexico, exposure to both metals were associated with greater decreases in NO and greater incr eases in 

### 17
superoxide anion ( Pineda

- Zavaleta et al., 2004 ) . Recent toxicological studies that have examined the 

### 18

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

### 19

Fowler, 2008 ) . Thus, there is biologic plausibility of in creased susceptibility of Pb

- related health effects 

### 20

when co

- exposed to Pb and As. 

### 21

6.2.14.3. Manganese

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

### 22
manganese (Mn) ( Y. Kim et al., 2009 ) . Compared to children with low blood Mn levels, those with high 

### 23
blood Mn levels had greater decreases in full scal e IQ and verbal IQ associated with blood Pb levels. No 

### 24
effect modification was observed for the association between Pb levels and performance IQ. 

### 25



## 6.2.15. Fluoride

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

### 26
been explored in epidemiologic studies . A recent toxicological study by Sawan et al. ( 2010 ) reported co

- 

### 27May 2011 6

- 29 DRAFT

– DO NOT CITE OR QUOTE exposure with Fl increased Pb deposition in calcified tissues. Future investigation among humans will be 

### 1
important for understanding whether fluoride present in water and other substances increases Pb 

### 2
deposition in humans and modifies the asso ciation between Pb and various health effects. 

### 3



# 6.3. Summary

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

### 4
exposure or biomarkers of Pb exposure. For most studies, relationships between factors and Pb biomarker 

### 5
levels were presented without attribution to exposure, diet, absorption, or biokinetic factors because the 

### 6
studies were not designed to make such conclusions. Where available, studies that shed light on the effect 

### 7
of susceptibility factors on exposure wer e included. The factors examined in Section 6.1 included age, 

### 8
gender, race and ethnicity, SES, and residential proximity to Pb sources. 

### 9
In Section 6.2 of this chapter, epidemiologic and toxicological studies that contributed information 

### 10
on potential susce ptibility factors for Pb

- related health effects were evaluated. Overall, this review 

### 11
provided evidence that various factors may lead to increased susceptibility to Pb

- related health effects 

### 12
(see Table 6

- 3 for evidence from current studies). Section 6.2 inc luded most of the factors from Section 

### 13
6.1, plus various genes, pre

- existing diseases/conditions, smoking, BMI, nutrition, stress, cognitive 

### 14
reserve, and exposure to other metals. 

### 15
Among children, the youngest age groups were observed to be most susceptibl e to having elevated 

### 16
Pb body burden, with blood Pb levels decreasing with increasing age of the children. Recent 

### 17
epidemiologic studies of infants/children detected susceptibility to Pb

- related health effects, and this was 

### 18
supported by toxicological studies

. 

### 19
For adults, elevated Pb biomarkers were associated with increasing age. It is generally thought that 

### 20
these elevated levels are related to remobilization of stored Pb during bone loss (see Section 4.2). Studies 

### 21
of older adults had inconsistent finding s f or effect modification of Pb

- related mortality but no difference 

### 22

was observed for other health effects

. However, toxicological studies support the possibility of age

- related 

### 23
differences in susceptibility to health effects. 

### 24
Some studies suggest that males have higher blood Pb levels than females; this was supported by 

### 25
stratifying the total sample of NHANES subjects. Gender

- based differences appeared to be prominent 

### 26
among the adolescent and adult age groups but were not observed among the youngest age groups (1

- 5 

### 27
years and 6

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

### 28
were mixed, although it appears that there are some differences in associations for males and females. 

### 29
This is also observed in toxicological stud ies. In addition, the associations among females may vary based 

### 30
on hormonal status. Future research will be useful in determining which Pb

- related health effects are 

### 31
greater for males or females and whether hormones play a role in susceptibility. 

### 32May 2011 6

- 30 DRAFT

– DO NOT CITE OR QUOTE Regarding race and ethnicity, recent data suggest that the difference in blood Pb levels between 

### 1
African American and White subjects is decreasing over time, but African Americans still tend to have 

### 2
higher Pb body burden and exposures. Similarly, the gap between so cioeconomic groups with respect to 

### 3
Pb body burden appears to be diminishing, with Pb body burden being higher but not appreciably higher 

### 4
among lower income subjects. Studies of race as a susceptibility factor indicate that some modification of 

### 5

associations between Pb and health effects may be present. Compared to whites, non

- white populations 

### 6
were observed to be more susceptible; however this could be related to confounding by factors such as 

### 7
SES or differential exposure levels, which was noted in some of t he epidemiologic studies. Although 

### 8
limited by the number of studies, lower SES individuals appear to represent a susceptible population. A 

### 9
study of Pb and IQ reported greater inverse associations among those in the lowest SES groups. 

### 10
Additionally, there is evidence associating proximity to areas with Pb sources, including urban areas with 

### 11
large industrial sources, with increased Pb body burden and risk of Pb exposure. 

### 12
Various genes were examined as potentially modifying the associations between Pb and healt h 

### 13
effects. Epidemiologic and toxicological studies reported ALAD and VDR variants may be health

- related 

### 14
susceptibility factors. Other genes examined that may also affect susceptibility to Pb

- related health effects 

### 15

were MTHFR, DRD4, GSTM1, TNF

- alpha, eNOS, APOE, and HFE. 

### 16

Pre

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

### 17
exposure and various health endpoints. Recent epidemiologic studies did not support modification of Pb 

### 18
and health endpoints by diabetes; however, past studies have found diabetics to be a susceptible 

### 19
population with regard to renal function. More research on this population will be important for 

### 20
determining which, if any, health effects related to Pb are different among diabetics. Hypertension was 

### 21

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

### 22
both renal effects and heart rate variability demonstrated greater odds of the association among 

### 23
hypertensive individuals compared to those that are norm otensive. Recent epidemiologic studies also 

### 24
examined autism and atopy as potential susceptibility factors. Future research will allow for a greater 

### 25
understanding of potential modification by these conditions, but current research has shown that autistic 

### 26

ch ildren and infants of mothers without atopy may have increased odds of Pb

- induced health effects. 

### 27
Recent epidemiologic studies examining smoking as a susceptibility factor reported mixed 

### 28
findings. It is possible that smoking modifies the effects of only so me Pb

- related health effects. Further 

### 29
studies of current, former, and prenatal smoking exposures related to Pb and health effects will provide 

### 30

additional information on susceptibility. 

### 31
BMI, alcohol consumption, and nutritional factors were examined in rece nt epidemiologic and 

### 32
toxicological studies. Modification of associations between Pb and various health effects (mortality and 

### 33
heart rate variability) was not observed by BMI/obesity. Also, no modification was observed in an 

### 34
epidemiologic study of renal fun ction examining alcohol consumption as a modifier, but a toxicological 

### 35
study supported the possibility of alcohol as a susceptibility factor. Among nutritional factors, those with 

### 36May 2011 6

- 31 DRAFT

– DO NOT CITE OR QUOTE iron deficiencies were observed to be a susceptible population for Pb

- relate d health effects in both 

### 1
epidemiologic and toxicological studies. Other nutritional factors, such as calcium, zinc, and protein, 

### 2
demonstrated the potential to modify associations between Pb and health effects in toxicological studies. 

### 3
Recent epidemiologic studies of these factors were either not performed or observed no modification. 

### 4
Folate was also examined in a recent epidemiologic study of birth size but no interaction was reported 

### 5
between Pb and folate. Further study of these and other nutritional facto rs will be useful in determining 

### 6
susceptibility among individuals with various nutritional levels/deficiencies. 

### 7
Stress was also evaluated as a susceptibility factor and although there were a small number of 

### 8
recent epidemiologic studies, increased stress wa s observed to negatively impact the association between 

### 9
Pb and health endpoints. Toxicological studies supported this finding. 

### 10
A recent epidemiologic study evaluated cognitive reserve as a modifier of the associations between 

### 11
Pb and cognitive and motor fu nctions. Cognitive reserve was an effect measure modifier for the 

### 12
association between Pb and cognitive function but not motor function. Future studies evaluating Pb



### 13
related health effects and cognitive reserve will provide more information on this possible susceptibility 

### 14

factor. 

### 15
Finally, interactions between Pb and other metals were evaluated in recent epidemiologic and 

### 16
toxicological studies of health effects. High levels of other metals, such as Cd, As, and Mn, were observed 

### 17
to negatively affect the assoc iations between Pb and various health endpoints. 

### 18May 2011 6

- 32 DRAFT

– DO NOT CITE OR QUOTE 

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