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# CHAPTER 6 POTENTIALLY AT - RISK POPULATIONS
The NAAQS are intended to provide an adequate margin of safety for both the population 1 

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

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

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

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

### pollutant. To facilitate the identification of popula tions at greater risk for Pb

- related 6 

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

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

### studies, but in most instances “su sceptibility” refers to biological or intrinsic factors 9 

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

### ( e.g., socioeconomic status [SES]) ( U.S. EPA, 2010a , 2009 )

. Additionally, in some cases, 11 

### the terms “at

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

### concepts more generally. In this ISA, “at

- risk” groups are defined as those with 13 

### characteristics that increase the risk of Pb

- related health eff ects in a population. These 14 

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

### sex, age, diet, pre

- existing disease, SES, and characteristics that may modify exposure or 16 

### the response to Pb. 17 

### To examine whether Pb differ entially affects certain populations, epidemiologic studies 18 

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

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

### identify populations that are a t greater risk for Pb

- related health effects. Toxicological 21 

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

### factors that may lead to increased risk for Pb

- related health effects. These epidemiologic 23 

### and toxicologi cal studies provide the scientific basis for an overall weight of the evidence 24 

### evaluation for the increased risk of specific populations to Pb

- related health effects. 25 

### The first section of this chapter summarizes physiological factors that possibly influen ce 26 

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

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

### section supplement the material provided in Chapters 3 and 4 by examining how fact ors 29 

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

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

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

### related to increased risk of Pb

- induced health effects. Highlighted studies include only 33 

### those where the population was stratif ied into subgroups ( e.g., males versus females or 34February 2012 6

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### smokers versus nonsmokers) for comparative analysis. In the case of many biomarker 1 

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

### between populations exposed to sim ilar Pb concentrations and within the same study 3 

### design. Numerous studies that focused on only one potentially at

- risk population were 4 

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

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

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

### becaus e there are no comparison groups for stratified analyses, these studies were 8 

### presented in Chapter 5 but are not included here. Included toxicologic al studies may have 9 

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

### those that examined animal models of disease. 11 

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

### thi rd section may not be effect measure modifiers but instead may be mediators of Pb

13 

### related health effects. Mediators are factors that fall on the causal pathway between Pb 14 

### and health outcomes, whereas effect measure modifiers are factors that result in chan ges 15 

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

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

### mediators are not correctly termed “at

- risk” factors. Some of the factors discuss ed in this 18 

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

- 4

. 19



## 6.1 Physiological Factors that Influence th e Internal Distribu tion of Lead Blood and bone Pb measures are influenced to varying degrees by biokinetic processes 20 

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

### processes can be affected by multiple factors, such as age, genetics, diet, and co

- exposure 22 

### with other metals and non - metals. 23 

### Age influences the biokinetic response to Pb within the b ody. Infants may be an at

- risk 24 

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

### during gestation ( Pill ai et al., 2009 ; Wang et al., 2009e ; Uzbekov et al., 2007 )

. This 26 

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

### bone stores ( O'Flaherty, 1998 ; Franklin et al., 1997 )

. This also results in increased 28 

### maternal blood Pb levels ( Lamadrid

- Figueroa et al., 2006 ; Gulson et al., 2004a ; Hertz

29 

### Picciotto et al., 2000 ; Gulson et al., 1997 ; Lagerkvi st et al., 1996 ; Schuhmacher et al., 30 

### 1996 ; Rothenberg et al., 1994a )

. Bone growth rate is high during childhood. The majori ty 31 

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

### does remain in the bone until older age ( McNeill et al., 2000 ; O'Flaherty, 1995 ; Legg ett, 33February 2012 6

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### 1993 )

. Older adults are more likely to have age

- related degeneration of bones and organ 1 

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

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

. 3 

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

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

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

. Multiple 6 

### studies have also examined the association between the aminolevulinate dehydratase 7 

### (ALAD) polymorphism and blood Pb levels and found that the ALAD

- 2 polymorphism 8 

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

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

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

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

. 12 

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

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

### the GI tract. A study in China reported that children who regularly consumed br eakfast 15 

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

### 2011b )

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

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

. A 18 

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

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

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

### supplementation of zinc and vitamins ( Massó

- González and Antonio

- García, 2009 )

. 22 

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

- deficient 23 

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

### A zinc

- supple mented diet attenuated bone and renal Pb content. Toxicological studies 25 

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

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

. 27 

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

### during pregnancy and lactation ( Bogden et al., 1995 )

. Additionally, studies have reported 29 

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

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

. 31 

### Finally, co

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

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

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

### increased bioavailability of Pb ( Wang and Fowler, 2008 )

. A toxicological study by 35 

### Sawan et al. ( 2010 ) reported co

- exposure with fluoride increased Pb deposition in 36 

### calcified tissues. 37February 2012 6

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### In summary, age, genetics, diet , and other exposures affect the biokinetics of Pb, which in 1 

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

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

### distribution was provided. 4



## 6.2 Population Characteristics Potentially Related to Differential Lead Exposure Elevated or differential Pb exposure and related biomar ker levels (such as blood Pb), 5 

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

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

### EPA, 2006b )

. In most cases, exposure, absorption, and biokinetics of Pb are all 8 

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

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

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

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

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

### that p opulation characteristics differentially influence Pb exposure; the new literature 14 

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

### characteristics on Pb exposure. Differential response to given Pb ex posures is discusse d 16 

### in Section 6. 3

. 17



### 6.2.1 Age

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

### children’s behaviors and activi ties include increased hand

- to

- mouth contact, crawling, 19 

### and poor hand

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

### ( U.S. EPA, 2006b )

. Children can also be susceptible to Pb exposure because outdoor pl ay 21 

### can lead to hand

- to

- mouth contact with contaminated soil. For example, Zahran et al. 22 

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

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

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

### and biokinetic factors. The 2007

- 2008 N HANES data are presented in Table 6

- 1 by age 26 

### and sex. Among children, highest blood Pb levels occurred in the 1

- 5 year age group 27February 2012 6

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### (children under age 1 were not included), and within this subgroup (not shown on the 1 

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

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

### utero ex posures resulting from maternal Pb remobilization from bone stores from historic 4 

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

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

### years 1999

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

### over time (see Table 6

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

- 2 years 8 

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

### with 3

- 5 year

- old children, but no age difference was noted for the 7.5 to <10 μ g/dL 10 

### bracket. These distribut ion differences may be attributable to differences in exposure, 11 

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

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

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

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

### (r =

- 0.38, p <0.001). 16



### Table 6 - 1 Blood Pb levels by age and sex, 2007 - 2008 NHANES Age Sex N Avg. Std. Dev. 5% 25% 50% 75% 95% 99% 1 - 5 yr Total 811 2.03 2.01 0.69 1.08 1.54 2.34 4.50 10.60 Male 440 2.01 2.14 0.71 1.10 1.50 2.40 4.21 8.56 Female 371 2.05 1.85 0.66 1.02 1.60 2.28 4.65 10.70 6 - 11 yr Total 1 , 002 1.27 0.87 0.49 0.75 1.06 1.50 2.84 4.80 Male 500 1.29 0.92 0.48 0.74 1.08 1.50 2.90 4.76 Female 502 1.25 0.83 0.50 0.78 1.03 1.49 2.80 4.80 12 - 19 yr Total 1 , 089 0.99 0.73 0.40 0.59 0.81 1.13 2.11 4.00 Male 586 1.13 0.82 0.44 0.69 0.94 1.30 2.41 4.11 Female 503 0.83 0.57 0.37 0.52 0.69 0.91 1.70 3.36 20 - 64 yr Total 4 , 278 1.76 1.57 0.53 0.91 1.40 2.10 4.20 7.42 Male 2 , 079 2.13 1.93 0.68 1.12 1.65 2.49 5.22 9.07 Female 2 , 199 1.41 1.01 0.47 0.78 1.13 1.73 3.13 5.10 65+ yr Total 1 , 086 2.31 1.64 0.80 1.30 1.90 2.70 5.22 8.54 Male 542 2.63 1.66 0.99 1.52 2.19 3.20 5.86 9.03 Female 544 1.98 1.56 0.75 1.17 1.62 2.40 4.14 6.95February 2012 6

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– Do Not Cite or Quote Age Sex N Avg. Std. Dev. 5% 25% 50% 75% 95% 99% Overall Total 8 , 266 1.70 1.53 0.51 0.86 1.30 2.04 4.10 7.20 Male 4 , 147 1.94 1.77 0.58 0.99 1.5 2.3 4.72 8.69 Female 4 , 119 1.45 1.19 0.46 0.76 1.14 1.78 3.35 5.77 Source: ( NCHS, 2010 )

.



### Table 6 - 2 Percentage of children within six categories/brackets of blood Pb levels, 1999 - 2004 NHANES
Pb Units:

μg/dL (95% CI) n Geometric mean <1 μg/dL, % 1 to <2.5 μg/dL, % 2.5 to <5 μg/dL, % 5 to <7.5 μg/dL, % 7.5 to <10 μg/dL, % ≥ 10 μg/dL, %
Overall 2,532 1.9 (1.8
- 2.0) 14.0 (11.6
- 16.6) 55.0 (52.1
- 57.9) 23.6 (21.1
- 26.1) 4.5 (3.3
- 5.9) 1.5 (1.0
- 2.1) 1.4 (1.0
- 2.0) Sex

Female 1,211 1.9 (1.7
- 2.0) 14.1 (10.8
- 17.7) 54.5 (51.1
- 57.8) 23.9 (20.3
- 27.8) 4.5 (3.3
- 5.8) 1.4 (0.8
- 2.3) 1.7 (0.9
- 2.6) Male 1,321 1.9 (1.7
- 2.0) 14.0 (11.4
- 16.7) 55.5 (51.4
- 59.5) 23.2 20.3
- 26.3) 4.6 (3.0
- 6.5) 1.5 (0.9
- 2.3) 1.3 (0.7
- 2.6) Age

1
- 2 yr 1,231 2.1 (2.0
- 2.2) 10.6 (7.7
- 13.9) 51.0 (46.7
- 55.3) 27.9 (24.9
- 31.0) 6.7 (5.0
- 8.6) 1.4 (0.8
- 2.2) 2.4 (1.4
- 3.5) 3
- 5 yr 1,301 1.7 (1.6
- 1.9) 16.2 (12.9
- 19.9) 57.6 (53.8
- 61.4) 20.7 (17.9
- 23.7) 3.1 (1.9
- 4.6) 1.5 (0.8
- 2.3) 0.9 (0.4
- 1.5) Race/Ethnicityc

Non
- Hispanic Black 755 2.8 (2.5
- 3.0) 4.0 (2.5
- 5.7) 42.5 (37.8
- 47.2) 36.2 (33.1
- 39.3) 9.4 (6.9
- 12.2) 4.6 (3.0
- 6.5) 3.4 (1.8
- 5.5)
Mexican American 812 1.9 (1.7
- 2.0) 10.9 (8.6
- 13.4) 61.0 (56.9
- 65.1) 22.1 (18.0
- 26.5) 3.4 (2.2
- 5.0) 1.3 (0.6
- 2.2) 1.2 (0.4
- 2.6)
Non
- Hispanic White 731 1.7 (1.6
- 1.8) 17.6 (14.0
- 21.5) 57.1 (52.4
- 61.7) 19.7 (16.1
- 23.5) 3.6 (1.9
- 5.8) 0.8 (0.3
- 1.6) 1.2 (0.6
- 2.0) Poverty
- Income Ratio (PIR)c

≤ 1.3 1,302 2.4 (2.2
- 2.5) 6.7 (4.6
- 9.2) 49.3 (44.9
- 53.7) 32.5 (28.6
- 36.4) 6.9 (2.2
- 8.8) 2.8 (1.7
- 4.1) 1.8 (1.1
- 2.7) >1.3 1,070 1.5 (1.4
- 1.6) 19.9 (16.3
- 23.8) 60.4 (56.9
- 63.8) 16.0 (12.9
- 19.3) 2.3 (1.2
- 3.7) 0.6 (0.1
- 1.4) 0.8 (0.3
- 1.6) Source: Reprinted with permission of the American Acedemy of Pediatrics; Jones et al. ( 2009a ) 

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

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

### ( U.S. EPA, 2006b )

. Kordas et al. ( 2010 ) observed that maternal hair Pb conc entration 3 

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

### p < 0.01). Miranda et al. ( 2010 ) observed that pregnant women (ages 30

- 34 years and 35

- 5 

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

### young er pregnant women in the (25

- to 29

- year - olds) reference age category. These 7 

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

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

### age before subsequent release with bone loss occurring during pre gnancy, as described in 10 

### Section 4.2 and summarized in Section 6.1 . Elevated blood Pb levels among mothers 11February 2012 6

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### present a pot ential exposure route to their children in utero or through breast milk. 1 

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

### ( Hamilton et al., 2001 )

. 3



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

### population ( U.S. EPA, 2006b )

. Table 6

- 1 presents 2007

- 2008 NHANES data broken 5 

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

### group in comparison with adults aged 20

- 64 years. In a study of blood Pb and saliva Pb in 7 

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

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

### levels among 14

- to 24

- year - old subjects was 2.60 ± 0.16 μg/dL compared with 4.29 ± 10 

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

### among older adults could potentially b e due to a shared experience of higher historical Pb 12 

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

### ( Section 4.2 ). 14 

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

### subjects age 50

- 70 as part of the Baltimore Memory St udy. They found a statistically 16 

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

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

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

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

### concentrations increased w ith age, although the data quality for patella Pb was not as 21 

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

### significant relationship was not observed between the log

- transform of blood Pb and age 23 

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

### discern a difference in blood Pb level. 25



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

### differences in behavior between sexes may cause a differenti al increase in exposure. The 27 

### 2007

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

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

### adults aged 20

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

### with females (p < 0.0001). Among adults 65 years or older, average blood Pb levels were 31February 2012 6

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### 33% higher for males compared with females (p < 0.0001). In their study of Pb burden 1 

### among Baltimore adults aged 50

- 70 years, Theppeang et al. ( 2008b ) observed that 2 

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

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

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

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

- 2008 NHANES data showed that blood Pb levels were 6 

### higher among girls than boys for the 1

- to 5

- years age group ( Table 6

- 1 ). Blood Pb levels 7 

### became slig htly higher among boys for the 6

- to 11

- years age group, and levels were 8 

### substantially higher among adolescent males than females in the 12

- to 19

- years age 9 

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

### lower than bl ood Pb levels for the other age groups. The 2007

- 2008 NHANES data 11 

### suggest that sex

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

### adolescence. 13



### 6.2.3 Race and Ethnicity Higher blood Pb and bone Pb levels among African Americans has been well 14 

### docum ented ( U.S. EPA, 2006b )

. Recent studies are consistent with those previous 15 

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

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

### Jones et al. ( 2009a ) study, using NHANES data ( NCHS, 2010 ) from 1988

- 1991 and 18 

### 1999

- 2004 are shown in Figure 6

- 1 . The authors found that differences among children 19 

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

### 2.5 μg/dL over the period 1999

- 2004 have de creased since the period of 1988

- 1991 . The 21 

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

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

### differences for blood Pb levels between 2.5 an d <10 μ g/dL. It is notable that the 24 

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

### children were nearly identical in the 1999

- 2004 dataset. Theppeang et al. ( 2008b ) also 26 

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

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

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

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

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

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

### compared to Caucasians in the Baltimore population studied by Theppeang et al. ( 2008b )

. 33February 2012 6

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– Do Not Cite or Quote Data used with permission of the American Academy of Pediatrics, Jones et al. ( 2009a ) Note: from the NHANES survey, 1988
- 1991 (top) and 1999
- 2004 (bottom). 

### Figure 6 - 1 Percent distribution of blood Pb levels by race/ethnicity among U.S. children (1 - 5 years). Differences in exposure among ethnic and racial groups have also been noted. In a study 1 

### of three parishes in the greater metropolitan New Orleans area, Campanella and Mielk e 2 

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

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

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

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

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

- 2004February 2012 6

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### and 4% Hispanic ( Figure 6

- 2 ). As described in Section 6.2.4 , the differences observed by 1 

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

### confounding factor in the relationship between Pb soil leve ls and race/ethnicity of nearby 3 

### residents. 4

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

. Note: By Census 2000 race/ethnicity demographic groups. 

### Figure 6 - 2 Soil Pb concentration exposure among the population of three parishes within greater metropolitan New Orleans.

6.2.4 Socioeconomic Status (SES) Socioeconomic factors have sometimes been associated with Pb exposure biomarkers, 5 

### althou gh these relationships have not always been consistent ( U.S. EPA, 2006b )

. Nriagu 6 

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

### various socioeconomic, demographic, and exposure variables among an adult population 8 0 5,000 10,000 15,000 20,000 25,000 30,000 35,000 40,000 45,000 50,000Population

Soil Pb Concentration (mg/kg) Black White Asian HispanicFebruary 2012 6

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### in Detroit, Michigan. Blood and saliva Pb we re both used as indicators of Pb in unbound 1 

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

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

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

### and income level inc reased. Statistically significant relationships were also reported by 5 

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

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

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

### ( 2006 ) attributed these incon sistencies to small sample sizes among the high educational 9 

### attainment and income categories. 10 

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

### decreasing. For example, Levin et al. ( 2008 ) cited 1991

- 1994 NHANES data [analyzed in 12 

### Pirkle et al. ( 1994 ) ] that the percentage of children aged 1

- 5 years with blood Pb levels ≥ 13 

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

### income group. Levin et al. ( 2008 ) also analyzed data from the 1999

- 2002 NHANES and 15 

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

### levels above 10 μg/dL for Medicaid

- enrolled children (1.7%) compared with 17 

### non - enrolled children (1.3%). However, Me dicaid

- enrolled children did have higher 18 

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

### μg/dL). When adding data for 2003

- 2004 to the analysis ( i.e., for 1999

- 2004), the gap 20 

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

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

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

### adding the 2003

- 2004 data ( Levin et al., 2008 )

. Likewise, Jones et al. ( 2009a ) analyzed 24 

### blood Pb levels with respect to poverty

- income ratio (PIR), which is the ratio of family 25 

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

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

### >1.3. T he percentage of 1

- to 5

- year - old children having blood Pb ≥ 10 μg/dL was higher 28 

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

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

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

### between 2.5 and 20 mg /kg associated with a Census block

- averaged median household 32 

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

### associated with a Census block

- averaged median household income of $24,000 per year. 34February 2012 6

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### 6.2.5 Proximity to Lead Sources Airborne and soil Pb concentrations are higher in some industrialized and urbanized 1 

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

### contemporaneous Pb sources. The highest air Pb concentrations measured using the Pb

3 

### TSP monitoring network have been measured at monitors located near sources emitting 4 

### Pb. Elevated soil Pb concentrations have also been measu red in urbanized areas 5 

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

### Filippelli, 2008 ; Weiss et al., 2006 )

. Several studies describe mechanisms by which larger 7 

### particles present in soil can become resuspended to the air by perturbation from traffic

8 

### and wind

- generated turbulence ( Harris and Davidson, 2008 ; Lough et al., 2005 ; Zereini et 9 

### al., 2005 ; Nicholson, 1988 ; Gillette et al., 1974 )

. However, there are no recent monitoring 10 

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

### assessment of the specific contribution of resuspension to ambient air concentrati ons. Air 12 

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

### μ g/m 3 

### ) ( Martuzevicius et al., 2004 )

. Proximity to an industrial source likely contributes to 14 

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

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

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

### non - source oriented sites in the 2007

- 2009 data presented in Section 3.5

. 18 

### Jones et al. ( 2010 ) found that neonate s born near a Pb

- contaminated hazardous waste site 19 

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

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

### contaminated site (median: 1.1 μg/dL [95% CI: 0.8, 1.3 μg/dL]), suggesting that Pb

22 

### contaminated hazardous waste sites contribute to neonatal Pb levels. The population 23 

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

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

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

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

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

### hazardous waste sites) confounded these results. 29 

### Studies have suggested that soil Pb exposure is related to land us e type and historical 30 

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

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

### associated with traffic

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

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

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

### Pb levels dropped following Hurricanes Katrina and Rita, from 329 mg /kg to 203 mg /kg 36February 2012 6

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### when comparing samples from 2000 with those from 2006. The reduction in soil Pb was 1 

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

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

### Pb levels obtained from children ages 0

- 6 years at the same time periods declined by 4 

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

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

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

### was covered with geotextile material topped with 15 cm of river alluvium. Median so il 8 

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



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

### ( 2009 ) , which drew inference from the NHANES national survey for 1999

- 2004, is 11 

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

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

### 1987 )

. Dixon et al. ( 2009 ) used NHANES data from 1999

- 2004 to perform a linear 14 

### regression of b lood Pb among children 12

- 60 months old on several factors including 15 

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

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

### transformed) was sig nificantly associated with homes built after 1950 (p = 0.014), 18 

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

### homes (p = 0.045). Detailed results of this regression are shown in Table 6

- 3 . As part of 20 

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

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

### significantly associated with the following housing

- related factors: floor surface 23 

### condition (p < 0.0 01), windowsill dust Pb (log transformed) (p < 0.001), year of 24 

### construction (p < 0.001), and renovation in a pre

- 1950 home (p < 0.001). Windowsill 25 

### dust Pb (log transformed) was significantly associated with the following housing

- related 26 

### factors: year of co nstruction (p < 0.001), window surface condition (0.001), and 27 

### deteriorated indoor paint (p = 0.028). 28February 2012 6

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### Table 6 - 3 Regression of log - transformed blood Pb level of children 12 - 60 months old on various factors re lated to housing condition, from 1999 - 2004 NHANES dataset

Variables Overall **p** - value Levels Estimate (SE) **p** - Value Intercept 0.172

– 0.517 (0.373) 0.172 Age (in years) < 0.001 Age 2.620 (0.628) < 0.001 Age 2

– 1.353 (0.354) < 0.001 Age 3 0.273 (0.083) 0.002 Age 4

– 0.019 (0.007) 0.008 Year of construction 0.014 Intercept for missing

– 0.121 (0.052) 0.024 1990

– present

– 0.198 (0.058) 0.001 1978

– 1989

– 0.196 (0.060) 0.002 1960

– 1977

– 0.174 (0.056) 0.003 1950

– 1959

– 0.207 (0.065) 0.003 1940

– 1949

– 0.012 (0.072) 0.870 Before 1940 0.000

— PIR < 0.001 Intercept for missing 0.053 (0.065) 0.420 Slope

– 0.053 (0.012) < 0.001 Race/ethnicity < 0.001 Non
- Hispanic white 0.000

— Non
- Hispanic black 0.247 (0.035) < 0.001 Hispanic

– 0.035 (0.030) 0.251 Other 0.128 (0.070) 0.073 Country of birth 0.002 Missing

– 0.077 (0.219) 0.728 U.S. b 0.000

— Mexico 0.353 (0.097) < 0.001 Elsewhere 0.154 (0.121) 0.209 Floor surface/condition × log floor PbD < 0.001 Intercept for missing 0.178 (0.094) 0.065 Not smooth and cleanable 0.386 (0.089) < 0.001 Smooth and cleanable or carpeted 0.205 (0.032) < 0.001 Floor surface/condition × (log floor PbD) 2 Not smooth and cleanable 0.023 (0.015) 0.124 Smooth and cleanable or carpeted 0.027 (0.008) 0.001 Floor surface/condition × (log floor PbD) 3 Uncarpeted not smooth and cleanable

– 0.020 (0.014) 0.159 Smooth and cleanable or carpeted

– 0.009 (0.004) 0.012 Log windowsill PbD 0.002 Intercept for missing 0.053 (0.040) 0.186 Slope 0.041 (0.011) < 0.001 Home
- apartment type < 0.001 Intercept for missing

– 0.064 (0.097) 0.511 Mobile home or trailer 0.127 (0.067) 0.066 One family house detached

– 0.025 (0.046) 0.596 One family house attached 0.000

— Apartment (1

– 9 units) 0.069 (0.060) 0.256 Apartment (≥ 10 units)

– 0.133 (0.056) 0.022 Anyone smoke inside the home 0.015 Missing 0.138 (0.140) 0.331 Yes 0.100 (0.040) 0.015 No 0.000

— Log cotinine concentration (ng/dL) in blood 0.004 Intercept for missing

– 0.150 (0.063) 0.023 Slope 0.039 (0.012) 0.002 Window cabinet or wall renovation in a pre - 1978 home 0.045 Missing

– 0.008 (0.061) 0.896 Yes 0.097 (0.047) 0.045 No 0.000

— n = 2,155; R 2 = 40%. Source: ( Dixon et al., 2009 ) 

### Renovation activities on older homes have be en shown to produce excess Pb dust 1 

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

### concentrations from 1994

- 2004 NHANES on demographic and housing variables and 3 

### found that renovation of windows, cabinets, or walls in a pre

- 1950 home was 4February 2012 6

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### significantly associated with floor dust Pb concentration (p < 0.001). Paint scra ping 1 

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

### concentration (p = 0.053). Dixon et al. ( 2009 ) performed a regression analysis on log

3 

### transformed blood Pb levels from NHANES (1999

- 2004) on several demographic and 4 

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

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

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

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

### the house ranged from 390

- 27,600 mg /kg after the first sampling. Fo llowing several 9 

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

### concentrations were < 3 mg /kg, but five sites ranged from 17

- 1,340 mg /kg. Two children 11 

### had blood Pb tested as pa rt of this study. A 33 month

- old child exhibited no change in 12 

### blood Pb before or after renovation (blood Pb = 4 μ g/dL), while a twelve

- month old child 13 

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

### manners from the children because the younger child had smal ler veins; the older child 15 

### had a venous sample while the younger child had a finger

- stick. It is unclear if either of 16 

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

### men performing home renovations in the U.K., wind ow renovation and wood

- stripping 18 

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

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

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

. 21



## 6.3 Factors Potentially Related to Increased Risk of Lead Induced Health Effects
This section evaluates factors examined in recent studies as effect measure modifiers that 22 

### potentially increase the risk of various Pb

- related health effects. Table 6

- 4 provides an 23 

### overview of the factors examined and populations identified as “at

- risk” of Pb

- related 24 

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

### characte ristic is described in greater detail in the following subsections. 26February 2012 6

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### Table 6 - 4 Summary of evidence for factors that potentially increase the risk of lead - related health effects

Factor Evaluated Potentially Related to Increased Risk Age (Section 6.3.1 ) Children Sex (Section 6.3.2 ) Males, a Females a Genetics (Section 6.3.3 ) ALAD a , VDR a *, DRD4 a *, GSTM1 a , TNF
- α a , eNOS a , APOE a , HFE a
Pre
- existing Disease (Section 6.3.4 ) Autism a , Atopy a , b , Hypertension b Smoking (Section 6.3.5 ) Smokers a Race/Ethnicity (Section 6.3.6 ) Non
- Hispanic Blacks a , Hispanics a Socioeconomic Status (SES) (Section 6.3.7 ) Low SES a Nutrition (Section 6.3.10 ) Iron deficiency a Stress (Section 6.3.11 ) High stress a Cognitive Reserve (Section 6.3.12 ) Low cognitive reserve a , b Other Metals (Section 6.3.13 ) High/co
- exposure to Cd a , As a , Mn a

a Evidence for this factor was limited. b Possible mediator



### 6.3.1 Age Below is information from epidemiologic and toxicological studies regarding studies of 1 

### increased risk for Pb

- related health effects among children and older adults. Other age 2 

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

### stratified studies of lifestage. 4



### 6.3.1.1 Children According to the 2000 Census, 28.6% of ind ividuals living in the U.S. were under the age 5 

### of 20, with 6.8% aged 0

- 4 years, 7.3% aged 5

- 9 years, 7.3% aged 10

- 14 years, and 7.2% 6 

### aged 15

- 19 years ( SSDAN CensusScope, 2010a )

. It is recognized that Pb can cross the 7 

### placenta and affect the developing nervous system of the fet us ( Sections 4.2.2.4 and 8 

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

### exposure during several lifestages throughout gestation, childhood, and into a dolescence 10 

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

### have adequate comparison groups between children o f various age groups or between 12 

### children and adults, and were ther efore only presented in Chapter 5

. 13February 2012 6

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### A study including multiple U.S. locations exa mined associations of blood Pb levels with 1 

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

### matched controls ( Sarasua et al., 2000 )

. For several of these endpoints, the association in 3 

### t he youngest group (ages 6

- 35 months) and the oldest group (ages 16

- 75 years) were in 4 

### opposite directions. For example, among children ages 6

- 35 months, the associations 5 

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

### B

- cell abundance were positive, whereas the associations among 16

- 75 year olds were 7 

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

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

### r esponse to antigens. T cells are important mediators of cell

- mediated immune responses 10 

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

### al. ( 2000 ) indicate that very young chi ldren may be at increased risk for Pb

- associated 12 

### activation of humoral immune responses and perturbations in cell

- to

- cell interactions that 13 

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

### Sections 5.6.2.1 and 5.6.3). 15 

### A stu dy among Lebanese children examined the association between blood Pb levels and 16 

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

- deficiency anemia (IDA) ( Muwakkit et 17 

### al., 2008 )

. A positive association was detected for blood Pb levels ≥ 10 μ g/dL and both 18 

### TS less than 12% and IDA among children aged 11

- 23 months old; however, null 19 

### associations were observed among children 24

- 35 months old. Calculations were not 20 

### performed for children aged 36

- 75 months because there were no children in the highest 21 

### Pb group (≥ 10 μ g/dL) with either TS <12% or IDA. The authors noted that it is difficul t 22 

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

### studies linked iron deficiency with Pb toxicity. 24 

### Overall evidence indicates early childhood as a lifestage of increased risk for Pb

- related 25 

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

### among the youngest age groups, although different age cut

- points were used with one 27 

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

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

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

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

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

### more at risk from the effects Pb exposure ( Fullmer et al., 1985 )

. 33February 2012 6

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### 6.3.1.2 Older Adults
The number of Americans over the age of 65 will be increasing in upcoming years 1 

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

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

### ( SSDAN CensusScope, 2010a ; U.S. Census Bureau, 2010 )

. As of the 2000 Census, 7.2% 4 

### of the U.S. population were age s 60

- 69, 5.8% were 70

- 79, and 3.3% were age 80 and 5 

### older ( SSDAN CensusScope, 2010a )

. 6 

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

### individuals le ss than 60 years old and individuals 60 years and older ( Menke et al., 2006 )

. 8 

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

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

### simila r study using the NHANES III cohort examined the relationship between blood Pb 11 

### levels and mortality from all

- cause, cardiovascular disease, and cancer broken down into 12 

### more specific age groups ( Schober et al., 2006 )

. Point estimates were elevated for the 13 

### association comparing blood Pb levels ≥ 10 μ g/dL to blood Pb levels <5 μ g/dL and all

14 

### cause mortality for all age groups (40

- 74, 75

- 84, and 85+ year olds), although the 15 

### association for 75

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

### also present when comparing blood Pb levels of 5

- 9 μ g/dL to blood Pb levels <5 μ g/dL 17 

### among 40

- 74 year olds and 75

- 84 year ol ds, but not among those 85 years and older. 18 

### None of the associations between blood Pb and cardiovascular disease

- related mortality 19 

### reached statistical significance but the point estimates for cardiovascular disease

- related 20 

### mortality comparing blood Pb leve ls ≥ 1 0 μ g/dL to blood Pb levels <5 μ g/dL were 21 

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

### ≥ 1 0 μ g/dL and cancer mortality was positive among those 40

- 74 years old and 85 years 23 

### and older but the association was null for those 75

- 84 years old. Among 75

- 84 year olds 24 

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

- 9 μ g/dL to <5 μ g/dL. The 25 

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

### significant. 27 

### A study using the Norma tive Aging Study cohort reported an interaction between Pb and 28 

### age ( Wright et al., 2003b )

. The inverse association between age and cognitive function 29 

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

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

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

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

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

### significant ( Weaver et al., 2008 )

. Thus, no modification by age was observed in this study 35 

### of Pb and blood pressure. 36February 2012 6

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### Toxicological studies have demonstrated Pb

- related health effects among older 1 

### populations. The kidneys of older animals appear to be more at

- risk for Pb

- related hea lth 2 

### effects from the same dose of Pb ( i.e., continuous 50 mg /L Pb

- acetate drinking water) 3 

### than younger animals ( Berrahal et al., 2011 )

. Increased risk related to older age is also 4 

### observed for effec ts on the brain. Recent studies have demonstrated the importance of Pb 5 

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

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

### animals that were e xposed to Pb earlier in life has been documented in multiple species 8 

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

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

### product beta

- amyloid ( Basha et al., 2005 ; Zawia and Basha, 2005 )

. Some of these 11 

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

### In summary, results for age

- related m odification of the association between Pb and 13 

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

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

### studies have shown increases in Pb

- re lated health effects by age that may be relevant in 16 

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

### potentially affects the risk of Pb

- related outcomes. 18



### 6.3.2 Sex
The distribution of males and females in the U.S. is simila r. In 2000, 49.1% of the U.S. 19 

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

### greater prevalence of females ≥ 65 years old compared to males ( SSD AN CensusScope, 21 

### 2010a )

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

### levels than girls, but findings were "less clear" regarding differences in Pb

- related health 23 

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

. 24 

### Multiple epidemiologic studies have examined Pb

- related effects on cognition stratified 25 

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

### and Ris et al. ( 2004 ) observed interactions betwe en blood Pb (prenatal and postnatal) and 27 

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

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

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

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

### Additionally, the association between childhoo d blood Pb levels and adult gray matter 32 

### volume loss was greater among males than females ( Cecil et al., 2008 )

. In an expand ed 33 

### analysis of the developmental trajectory of childhood blood Pb levels on adult gray 34February 2012 6

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### matter, researchers found that associations between yearly mean blood Pb levels and 1 

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

### fe males ( Brubaker et al., 2010 )

. Multiple studies were also conducted in Port Pirie, 3 

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

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

. These 5 

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

### childhood and into e arly adolescence. A study in Poland also investigated the association 7 

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

### association for boys at 36 months but not for girls ( Jedrychowski et al., 2009a )

. No 9 

### association was detected f or boys or girls at 24 months. 10 

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

### and kidney function among 12

- 20 year olds using the NHANES III study cohort 12 

### ( Fadrowski et al., 2010 )

. The results were stratified by sex and no effect measure 13 

### modification was apparent. 14 

### Similarly, a study of current and former Pb workers examined an in teraction term 15 

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

. 16 

### No modification by sex was present. 17 

### Epi demiologic studies have also been performed to assess differences between males and 18 

### females for Pb

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

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

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

### et al., 2008 )

. No ass ociation was reported in males, but other associations, such as 22 

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

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

### participants. Analy sis of an NHANES dataset detected no association between blood Pb 25 

### levels and inflammatory markers ( Songdej et al., 2010 )

. Although there was no clear 26 

### pattern, a few of the associations were positive between blood Pb and C

- reactive protein 27 

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

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

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

### ( Pineda

- Zavaleta et al., 2004 )

. 31 

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

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

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

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

. An 35 

### ecologic analysis of Pb pollution levels and cancer incidence among children reported 36February 2012 6

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### weak correlations overall and the weak correlations were more apparent among males, 1 

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

. 2 

### A study of all

- cause and cardiovascular mortality using the NHANES III cohort reported 3 

### no modification of the association between blood Pb and all

- cause or cardiovascular 4 

### mortality by sex ( Menke et al., 2006 )

. This did not differ among women when classified 5 

### as pre - or post

- menopausal. 6 

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

- related effects to various 7 

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

### investigatory behavior between male and female mice exposed to Pb. In a su bsequent 9 

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

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

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

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

### changes and females depression

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

### 2005 )

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

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

- dose 16 

### female rats ( Yang et al., 2003 )

. Sex

- specific differences in mice were also observed for 17 

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

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

. 19 

### Pb and stress are co

- occurring factors that act in a sex

- divergent manner to affect 20 

### behavior, neurochemistry, and co rticosterone levels. Pb and stress act synergistically to 21 

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

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

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

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

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

### (with and without stress) exhibited sex

- differences in exposed offspring ( Virgolini et al., 27 

### 2008b )

. Pb

- induced changes in brain neurochemistry, with or without concomitant stress 28 

### exposure, a re complex with differences varying by brain region, neurotransmitter type, 29 

### and sex of the animal. 30 

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

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

- specif ic phenotypes 32 

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

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

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

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

### exposure. One study supporting this line of thought showed that high

- dose in utero Pb 37February 2012 6

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### exposure (pup blood Pb level 64 μ g/dL at birth) induced reductio ns in SDN volume in 1 

### 35% of Pb

- exposed male rats ( McGivern et al., 1991 )

. Interestingly, another chemical 2 

### that is known to ca use a hypothalamic lesion in this area, monosodium glutamate, is 3 

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

### literature. 5 

### Obesity in adult offspring exposed to low

- dose Pb in utero was reported for male but not 6 

### female mice ( Leasure et al., 2008 )

. Obesity was also found in male rat offspring exposed 7 

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

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

### al., 2003 )

. Additionally, low

- dose Pb exposure indu ced retinal decrements in exposed 10 

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

. 11 

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

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

### in the heart tissue or the disposition of P b also varied between males and females 14 

### ( Sobekova et al., 2009 ; Alghazal et al., 2008a )

. The authors reported these results could 15 

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

### ( Sobekova et al., 2009 )

. 17 

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

### effect measure modification by sex. Although not o bserved in all endpoints, some studies 19 

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

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

### cohort and a study in Poland reported males to be a n at

- risk population, whereas studies 22 

### from Australia pointed to females as an at

- risk population. A difference in sex is 23 

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

### absence of sex

- specific associations between Pb and various health outcomes and in 25 

### which sex the associations are greater. 26



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

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

### ( U.S. EPA, 2006b )

. The majority of discussion there focused on the aminolevulinate 29 

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

### well as additional genes examined in recent studies, are discussed below. 31February 2012 6

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### 6.3.3.1 Aminolevulinate Dehydratase
The a minolevulinate dehydratase (ALAD) gene encodes for an enzyme that catalyzes the 1 

### second step in the production of heme and is also the principal Pb

- binding protein ( U.S. 2 

### EPA, 2006b )

. Studies have examined whether ALAD variants alt ered associations 3 

### between Pb and various health effects. 4 

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

### ALAD genotype status ( Rajaraman et al., 2006 )

. Positive associations between Pb 6 

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

### reported among ALAD2 indi viduals, but this association was not found among 8 

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

### glioma regardless of ALAD genotype. 10 

### Studies investigating the association between Pb levels and cognitive function have al so 11 

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

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

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

. In 14 

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

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

### and CG ALAD genotypes ( i.e., ALAD2 carriers) ( Krieg et al., 2009 )

. In the NAS cohort 17 

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

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

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

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

### effect modification by ALAD genotype across tests ( Rajan et al., 2008 )

. For example, 22 

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

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

### index and no difference in the a ssociations with other cognitive tests. For tibia and patella 25 

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

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

### effect modification wou ld vary among different cognitive domains. The limited number 28 

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

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

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

### generally associated with lower cognitive function in ALAD2 carriers. 32 

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

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

### et al., 2008 )

. However, another study of blood Pb and blood pressure reported 35February 2012 6

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### interactions b etween blood Pb and ALAD, but this varied by race/ethnicity ( non - Hispanic 1 

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

. 2 

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

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

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

. A 5 

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

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

### injury ( Gao et al., 2010a )

. Another study of renal function among Pb workers in Asia also 8 

### reported greater associations between blood Pb concentrations and re nal function by 9 

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

. 10



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

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

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

### by SNPs and haplotypes of VDR ( Krieg et al., 20 10 )

. The results were varied, even 14 

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

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

### compared to the modification of the relationship betw een Pb and other neurocognitive 17 

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

### current and former Pb

- exposed workers, no modification was reported by VDR ( Weaver 19 

### et al., 2008 )

. 20



### 6.3.3.3 Methylenetetrahydrofolate reductase Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 21 

### 5,10

- methylenetetrahydrofolate to 5

- methyltetrahydrofolate, which in t urn, is involved in 22 

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

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

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

### 2010 )

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

### weight ( Kordas et al., 2009 )

. No modification of the Pb

- birth weight association by 27 

### MTHFR was observed. 28February 2012 6

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

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

### particularly critical in early childhood. A genetic variant, called the APOE 4 allele is a 3 

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

### variant with respect to increasing risk of neurologic disease. A study of occupationally

5 

### exposed adults observed tibia Pb levels to be associated with greater co gnitive 6 

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

### assembly, and complex reaction time) among adults with at least one APOE

- ε4 allele 8 

### ( Stewar t et al., 2002 )

. Conversely, in a study of children in Mexico, children without the 9 

### APOE

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

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

### s tatistically significant ( Wright et al., 2003a )

. 12



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

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

### cognitive function for men with and without HFE allele variants ( Wang et al., 2 007a )

. No 15 

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

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

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

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

### wild

- type ( Zhang et al., 2010a )

. An interaction was observed between an HFE variant in 20 

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

### al., 2010b )

. The inverse association between maternal tibia Pb levels and birth weight 22 

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

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

### concentrations. 25



### 6.3.3.6 Other Genetic Polymorphisms Some other genetic polymorphisms were also examined as to whether they modify Pb

26 

### related healt h effects, but only limited data were available for these polymorphisms. 27 

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

### transporter (DAT1), glutathione S

- transferase Mu 1 (GSTM1), tumor necrosis factor

29 

### alpha ( TNF

- α ), endot helial nitric oxide synthase (eNOS), and various SNPS. 30February 2012 6

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### A prospective birth cohort reported that increasing blood Pb levels were associated with 1 

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

### ( Froehlich et al., 2007 )

. These inverse associations were exacerbated among those 3 

### lacking DRD4

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

### modification of the associations be tween Pb levels and neurocognitive development by 5 

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

. 6 

### A stud y of university students in South Korea reported blood Pb levels to be associated 7 

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

### among individuals with GSTM1 present ( Kim et al., 2007 )

. This study of blood Pb levels 9 

### and inflammation also examined individuals with TNF

- α GG, GA, or AA alleles. An 10 

### association was present for those with TNF

- α GG but not for those with TNF

- α GA or 11 

### AA. 12 

### A study of blood Pb and plasma NO X 

### reported no overall association but did report an 13 

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

### 2006a )

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

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

### levels. 17 

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

### tumors varied am ong multiple single nucleotide polymorphisms (SNPs) ( Bhatti et al., 19 

### 2009 )

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

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

### modified the asso ciation for glioblastoma multiforme and meningioma. The association 22 

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

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

### modified by XDH (the gene en coding for xanthine dehydrogenase) variant. 25 

### Overall, studies of ALAD observed increased Pb

- related health effects associated with 26 

### certain gene variants. Other genes, such as VDR, APOE, HFE, DRD4, GSTM1, TNF

- α , 27 

### and eNOS, may also affect the risk of Pb

- rela ted health effects but conclusions are 28 

### limited due to the small number of studies. 29



### 6.3.4 Pre - existing Diseases/Conditions Studies have also been performed to examine whether certain morbidities increase an 30 

### individual’s risk of Pb

- related effects on health. Rece nt studies have explored 31 

### relationships for autism, atopy, diabetes, and hypertension. 32February 2012 6

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

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

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

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

. 4 

### A cross

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

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

### al., 2011 )

. Blood Pb levels of children with and without autism were associated with 7 

### expression of the genes unde r study; however, the associations observed were in opposite 8 

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

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

### were associated with decr eased expression). 11



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

### study of Pb and IgE ( Annesi

- Maesano et al., 2003 )

. The study examined hair Pb levels in 13 

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

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

### mothers with atopy, the correlation was positiv e, although smaller, and was not 16 

### statistically significant. 17



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

. A few studies have 18 

### been conducted to investigate the poss ibility of diabetes as a modifying factor for Pb and 19 

### various health outcomes. 20 

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

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

### Aging S tudy cohort ( Tsaih et al., 2004 )

. Tibia and blood Pb levels were positively 23 

### associated with measures of poor renal function among i ndividuals with diabetes but not 24 

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

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

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

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

### ( Park et al., 2006 )

. 29February 2012 6

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### The NHANES III data were used to evaluate w hether the association between blood Pb 1 

### and both all

- cause and cardiovascular mortality varied among individuals with and 2 

### without diabetes ( Menke et al., 2006 )

. The 95% CIs among those with diabetes were 3 

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

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

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

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

### risk of Pb

- associated declines in renal function" ( U.S. EPA, 2006b )

. Future research 8 

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

### among individuals with and without diabet es will inform further on the potential for 10 

### increased risk among individuals with diabetes. 11



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

### hypertension increases with age (61% of individuals ≥ 75 years old h ave hypertension) 13 

### ( Pleis et al., 2009 )

. 14 

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

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

### hypertensive status ( Tsaih et al., 2004 )

. The association between tibia Pb and renal 17 

### functio n, measured by change in serum creatinine, was present among individuals with 18 

### hypertension but not among individuals that were normotensive. Models of the follow

- up 19 

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

### hype rtension but not individuals without hypertension (this association was not present 21 

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

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

### low fr equency power, high frequency power, and their ratio ( Park et al., 2006 )

. Although 24 

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

### observed among indi viduals with or without hypertension, the estimates were different, 26 

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

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

### and were inversely related to high frequency power). 29 

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

### levels and both all

- cause and cardiovascular mortality for individuals with and without 31 

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

### al., 2006 )

. 33February 2012 6

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### The 2006 Pb AQCD reported that individuals with hypertension had increased risk of Pb

1 

### related effects on renal function ( U.S. EPA, 2006b )

. This is supported by recent 2 

### epidemiologic studies. As described above, studies of Pb

- related effects on renal function 3 

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

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

### observed for Pb

- relat ed mortality. 6



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

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

. Studies o f 8 

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

### A study of blood Pb levels and all

- cause and cardiovascular mortality reported no 10 

### modification of this association by smoking status, measured as current, former, or neve r 11 

### smokers ( Menke et al., 2006 )

. The Normative Aging Study also examined the association 12 

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

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

. 14 

### A study of Pb

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

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

### 2006 )

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

### ANC. Additionally, a positive relationship was observed between high er blood Pb levels 18 

### and TNF

- α and granulocyte colony

- stimulating factor (G

- CSF) among both smokers an d 19 

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

. A 20 

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

### smokers and non - smokers ( Kiziler et al., 200 7 )

. The blood and seminal plasma Pb levels 22 

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

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

### Prenatal smoking exposure was examin ed in a study of children’s concurrent blood Pb 25 

### levels and prevalence of attention

- deficit/hyperactivity disorder (ADHD) among children 26 

### aged 8

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

### and prenatal tobacco smoke expos ure; those children with high Pb levels and prenatal 28 

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

. 29 

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

### bet ween Pb levels and health effects. Future studies of Pb

- related health effects and 31 

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

### in determining changes in risk by this factor. 33February 2012 6

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### 6.3.6 Race/Ethnicity
Based on the 2000 Censu s, 69.1% of the U.S. population is comprised of non - Hispanic 1 

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

### black and 12.6% reported being Hispanic ( SSDAN CensusScope, 2010b )

. Studies of 3 

### multiple Pb

- related health outcomes examined effect measure modification by 4 

### race/ethnicity. 5 

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

### Pb levels and all

- cause and cardiovascular mortality ( Menke et al., 2006 )

. Stratified 7 

### analyses were condu cted for non - Hispanic whites, non - Hispanic blacks, and Mexican 8 

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

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

### 2010 ; Muntner et al., 2005 )

. While no association was observed between blood Pb and 11 

### hypertension for non - Hispanic whites or His panics, a positive association was reported 12 

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

### 2010 )

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

### hypertension were statistically significant, increased odds were observed among 15 

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

### et al., 2005 )

. 17 

### A study of girls aged 8

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

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

### Mexican Americans ( Selevan et al., 2003 )

. For non - Hispanic whites, the associations 20 

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

### of non - Hispanic whites had blood Pb levels over 5 μ g/dL, whereas 11.6% and 12.8% of 22 

### blacks and Mexican Americans, respectively, had blood Pb levels greater than 5 μ g/dL. 23 

### A study linking educational testing data for 4th grade students in North Carolina reported 24 

### declines in reading and mathematics scores with increasing levels of blood Pb ( Miranda 25 

### et al., 2007b )

. Although not quantitatively reported, a figure in the study depicted the 26 

### association stratified b y race, and the slopes appeared to be similar for white and black 27 

### children. 28 

### Blood Pb and asthma incidence was examined for white and black children living in 29 

### Michigan ( Joseph et al., 2005 )

. When utilizing separate referent groups for the two races, 30 

### the only association is an increase among whites (although not statistically significant), 31 

### but when restricting to the highest blood Pb l evels, the association was no longer 32 

### apparent. Whites with low blood Pb levels were used as the referent group for both races 33 

### in additional analysis. Although the estimates were elevated for black children compared 34February 2012 6

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### to white children (including at the lowes t blood Pb levels), the confidence intervals for 1 

### the associations overlapped indicating a lack of a difference by race. 2 

### The results of these recent epidemiologic studies suggest that there may be race/ethnicity

3 

### related increased risk for some outcomes, al though the overall understanding of potential 4 

### effect measure modification by race/ethnicity is limited by the small number of studies. 5 

### Additionally, these results may be confounded by other factors, such as socioeconomic 6 

### status. 7



### 6.3.7 Socioeconomic Status
Base d on the 2000 Census data, 12.4% of Americans live in poverty (poverty threshold 8 

### for family of 4 was $17,463) ( SSDAN CensusScope, 2010c )

. Ris et al. ( 2004 ) examined 9 

### modification of the associations between early

- life Pb levels and Learning/IQ among 10 

### adolescents in the Cincinnati Lead Study. In models examining the association between 11 

### Pb and Learning/IQ, the prenatal and 78

- month blood Pb levels were associated with 12 

### larger decrements in Learning/IQ in the lower two quintiles of socioeconomic status 13 

### (SES) (measured based on family SES levels). 14



### 6.3.8 Body Mass Index
In the U.S. self

- reported r ates of obesity were 26.7% in 2009, up from 19.8% in 2000 15 

### ( Sherry et al., 2010 )

. The NHANES III cohort was utilized in a study of blood Pb levels 16 

### and all

- cause and cardiovascular mortality, which included assessment of the associations 17 

### by obesity ( Menke et al., 2006 )

. Positive asso ciations were observed among individuals 18 

### within both categories of body mass index (BMI; normal [<25 kg/m 2 

### ] and 19 

### overweight/obese [≥ 25 kg/m 2 

### ], determined using measured values of height and weight) 20 

### but there was no difference in the association between the two categories. Using the 21 

### Normative Aging Study data, an investigation of bone Pb levels and heart rate variability 22 

### was performed and reported slight changes in the association based on the presence of 23 

### metabolic syndrome; however, none of the changes resu lted in associations that were 24 

### statistically significant ( Park et al., 2006 )

. Overall, no modification by BMI or obesity 25 

### was observed among recent epidemiologic studies. 26February 2012 6

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### 6.3.9 Alcohol Consumption
Th ere are a limited number of studies examining alcohol as a factor affecting Pb

- related 1 

### risk. A study using the Normative Aging Study cohort investigated whether the 2 

### association between blood and bone Pb levels and renal function would be modified by 3 

### an ind ividual’s alcohol consumption ( Tsaih et al., 2004 )

. No interaction with alcohol 4 

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

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

### (endogenous antioxidants) in rats. Pb and ethanol also decreased other endogenous renal 7 

### antioxidants (glutathione and non - protein sulfhydryls) ( Jurczuk et al., 2006 )

. 8



### 6.3.10 Nutritional Fac tors Different components of diet may affect the association between Pb concentrations and 9 

### health outcomes. Recent epidemiologic and toxicological studies of specific mineral 10 

### intakes/dietary components are detailed below. 11



### 6.3.10.1 Calcium Using the Normative Aging Study cohort, researchers examined the association between 12 

### Pb levels and hypertension, modified by calcium intake ( Elmarsafawy et al., 2006 )

. The 13 

### associations between Pb levels (measured and modeled separately f or blood, patella, and 14 

### tibia) and hypertension did not differ based on dichotomized calcium intake 15 

### (800 mg /day). 16



### 6.3.10.2 Iron The 2006 Pb AQCD included studies that indicated individuals with iron

- deficiency and 17 

### malnourishment had greater inverse associations bet ween Pb and cognition ( U.S. EPA, 18 

### 2006b )

. A recent epidemiologic study of pubertal development among girls observed 19 

### inverse associations between blood Pb and inhibin B, but this association was modified 20 

### by iron deficiency; girls w ith iron deficiency had a stronger inverse association between 21 

### Pb and inhibin B than those who were iron sufficient ( Gollenberg et al., 2010 )

. 22 

### Toxicological studies also reported that iron

- deficient diets exacerbate or potentiate the 23 

### effect of Pb. A study of pregnant rats given an iron

- deficient diet and exposed to Pb 24 

### through drinking water over GD6

- GD14, had decreased litter size, more pups w ith 25 

### reduced fetal weight and reduced crown

- rump length, increased litter resorption, and a 26February 2012 6

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### higher damblood Pb level in the highest exposure groups ( Singh et al., 1993 ; Saxena et 1 

### al., 1991 )

. Thus, in this model, iron deficiency makes rat dams more at risk for Pb

2 

### dependent embryo and fetotoxicity ( Singh et al., 1993 )

. 3



### 6.3.10.3 Folate A study by Kordas et al. ( 2009 ) examined Pb levels and birth size among term births in 4 

### Mexico City. The authors reported no interaction betw een maternal tibia Pb and folate 5 

### levels. 6



### 6.3.10.4 Protein No recent epidemiologic studies have evaluated protein intake as a factor affecting Pb

7 

### related health effects. However, a toxicological study demonstrated that differences in 8 

### maternal protein intake levels c ould affect the extent of Pb

- induced immunotoxicity 9 

### among offspring ( Chen et al., 2004 )

. 10



### 6.3.11 Stress A study of bone (tibia and patella) Pb levels and hypertension reported modification of 11 

### the association by perceived stress levels ( Peters et al., 2007 )

. Among individuals with 12 

### greater perceived stress levels, stronger associations betwee n blood Pb levels and 13 

### hypertension were present. Among the same study population, higher perceived stress 14 

### was also reported to affect the association between blood Pb levels and cognitive 15 

### function; the higher stress group showed a greater inverse associati on between Pb and 16 

### cognitive function than those in the low stress group ( Peters et al., 2008 )

. In another 17 

### study, the inverse association between tibia Pb levels and some measures of cognitive 18 

### function were similarly strengthened by neighborhood psychosocial hazards ( Glass et al., 19 

### 2009 )

. 20 

### Toxicological studies have demonstrated that early life exposure to Pb and maternal 21 

### stress can result in toxicity related to multiple systems ( Rossi

- George et al., 2009 ; Co ry 22 

### Slechta et al., 2008 ; Virgolini et al., 2008a ; Virgolini et al., 2008b ) , including 23 

### dysfunctional corticosterone responses ( Rossi

- George et al., 2009 ; Virgolini et al., 24 

### 2008b )

. Additionally, toxicological studies have demonstrated that stressors to the 25 

### immune system can also affect associations with Pb exposure. C hickens with low Pb 26 

### exposure in ovo, with additional viral stressors, had increased immune cell mobilization 27February 2012 6

- 34 Draft

– Do Not Cite or Quote 

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

. Similarly, mice with neonatal Pb exposure, 1 

### and an additional immune challenge, had a sickness behavior phenotype, likely driven by 2 

### IL

- 6 production ( Dyatlov and Lawrence, 2002 )

. 3 

### Similar to studies of stress in animals, maternal self

- esteem has also been sh own to 4 

### modify associations between blood Pb levels and health effects in children. Surkan et al. 5 

### ( 2008 ) studied the association between children’s blood Pb levels and Bayley’s MDI and 6 

### Psychomotor Development Index (PDI) among mother

- child pairs. High maternal self

7 

### esteem was independently associated with higher MDI score and a lso appeared to 8 

### attenuate the negative effects of the child’s increased blood Pb levels on MDI and PDI 9 

### scores. Greater decreases in MDI and PDI were associated with increased blood Pb levels 10 

### among children whose mothers were in the lower quartiles of self

- esteem. The 11 

### investigators indicated that high maternal self

- esteem may serve as a buffer against stress 12 

### by improving mother

- child interactions and care giving practices, and maternal self 13 

### esteem may also be a surrogate of biological stress responses in the child. 14 

### Although examined in a limited number of studies, recent epidemiologic studies observed 15 

### modification of the association between Pb and various nervous system health effects by 16 

### stress

- level. Increased risk of Pb

- related health effects by stress is f urther supported by 17 

### toxicological studies. 18



### 6.3.12 Cognitive Reserve Cognitive reserve has been defined as “ the maintenance of cognitive performance in spite 19 

### of ongoing underlying brain pathology” ( Bleecker et al., 2007b )

. A study of Pb smelter 20 

### workers report ed that an inverse association between lifetime weighted blood Pb levels 21 

### and cognitive function was present among workers with low cognitive reserve (measured 22 

### using a reading achievement test) but no association was present in workers with high 23 

### cognitive r eserve ( Bleecker et al., 2007b )

. Inverse associations between lifetime

- weighted 24 

### blood Pb levels and motor functions existed among all workers regardless of cognitive 25 

### reserve. No ot her recent epidemiologic studies were performed examining cognitive 26 

### reserve as a factor affecting risk of Pb

- related health outcomes. 27



### 6.3.13 Other Metal Exposure The 2006 Pb AQCD reported that the majority of studies that examined other toxicants 28 

### did so as confo unders and not as effect measure modifiers ( U.S. EPA, 2006b )

. Recent 29 

### epidemiologic studies have begun to explore the possible interaction between Pb 30February 2012 6

- 35 Draft

– Do Not Cite or Quote 

### exposure and co

- exposures with other metals. These studies, as well as toxicolog ical 1 

### studies of these metals, are described below. 2



### 6.3.13.1 Cadmium In a study of girls in the NHANES III cohort, inverse associations were observed 3 

### between blood Pb and inhibin B concentrations ( Gollenberg et al., 2010 )

. These inverse 4 

### associations were stronger among girls with high cadmium (Cd) and high Pb compared to 5 

### those with high Pb and low Cd. Additionally, higher blood Pb and Cd levels togethe r 6 

### were positively associated with albuminuria and reduced estimated glomerular filtration 7 

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

- Acien et al., 2009 )

. 8 

### Toxicological studies reported that in rats, the addition of Cd to Pb exposure reduced the 9 

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

### of porphyrins were increased, indicating that although measured tissue burdens of Pb 11 

### were reduced, the biologically available fraction of Pb was actually increased ( Wang and 12 

### Fowler, 2008 )

. In other studies, Cd synergistically exacerbated Pb

- dependent renal 13 

### mit ochondrial dysfunction ( Wang et al., 2009c )

. 14 

### Overall, epidemiologic and toxicological studies have reported increased risk of Pb

15 

### related health effects among those with high Cd levels as well; however, the n umber of 16 

### studies examining both metals is small. 17



### 6.3.13.2 Arsenic In a study of immune function among children living at varying distances from a Pb 18 

### smelter in Mexico, higher levels of both Pb and arsenic (As) were associated with greater 19 

### decreases in NO and great er increases in superoxide anion ( Pineda

- Zavaleta et al., 2004 )

. 20



### 6.3.13.3 Manganese Among children in South Korea taking part in a study of IQ, an interaction was reported 21 

### between Pb and manganese (Mn) blood leve ls ( Kim et al., 2009b )

. Compared to children 22 

### with low blood Mn levels, those with high blood Mn levels had greater reductions in full 23 

### scale IQ and verbal IQ associated with increased blood Pb levels. No effect measure 24 

### modification by Mn was observed for the association between blood Pb levels and 25 

### performance IQ. A study performed among children in Mexico City observed greater 26 

### decreases in neurodevelopment with increases in blood levels of Pb and Mn at 12 27February 2012 6

- 36 Draft

– Do Not Cite or Quote 

### months, compared to decreases in neurodevelopment observed for increased Pb levels 1 

### with low levels of Mn ( Claus Henn et al. )

. No interaction was observed between the two 2 

### metals and neurodevelopment at 24 months. 3



## 6.4 Summary Among children, the youngest age groups were observed to be most at risk of elevated 4 

### blood Pb levels, with levels decreasing with increasing age of the children. Recent 5 

### epidemiologic studies of in fants/children detected increased risk of Pb

- related health 6 

### effects, and this was supported by toxicological studies. However, this is based on a 7 

### limited number of epidemiologic studies, and more studies are needed for comparing 8 

### various age groups and exam ining adolescents. 9 

### For adults, elevated Pb biomarkers were associated with increasing age. It is generally 10 

### thought that these elevated levels are related to remobilization of stored Pb during bone 11 

### loss. Studies of older adults had inconsistent findings for effect measure mod ification of 12 

### Pb

- related mortality but no difference was observed for other health effects. However, 13 

### toxicological studies support the possibility of age

- related differences in Pb

- related health 14 

### effects. 15 

### Some studies suggest that males at some ages have hi gher blood Pb levels than 16 

### comparably aged females; this was supported by stratifying the total sample of NHANES 17 

### subjects. Sex

- based differences appeared to be prominent among the adolescent and adult 18 

### age groups but were not observed among the youngest age groups (1

- 5 years and 6

- 11 19 

### years). Studies of effect measure modification of Pb and various health endpoints by sex 20 

### were inconsistent, although it appears that there are some differences in associations for 21 

### males and females. This is also observed in toxic ological studies. 22 

### Regarding race and ethnicity, recent data suggest that the difference in blood Pb levels 23 

### between black and white subjects is decreasing over time, but black subjects still tend to 24 

### have higher Pb body burden and Pb exposures than white su bjects. Similarly, the gap 25 

### between SES groups with respect to Pb body burden appears to be diminishing, with Pb 26 

### body burden being higher, but not appreciably higher, among lower income subjects. 27 

### Studies of race/ethnicity as a factor affecting risk indicate that some modification of 28 

### associations between Pb levels and health effects may be present. Compared to whites, 29 

### non - white populations were observed to be more at risk of Pb

- related health effects; 30 

### however, this could be related to confounding by factors s uch as SES or differential 31 

### exposure levels, which was noted in some of the epidemiologic studies. Although limited 32 

### by the number of studies, individuals with lower SES appear to represent an at

- risk 33 

### population. A study of Pb and IQ reported greater inverse associations among those in the 34February 2012 6

- 37 Draft

– Do Not Cite or Quote 

### lowest SES groups. Additionally, there is evidence associating proximity to areas with Pb 1 

### sources, including urban areas with large industrial sources, with increased Pb body 2 

### burden and risk of Pb exposure. 3 

### Various genes we re examined as potentially modifying the associations between Pb and 4 

### health effects. Epidemiologic and toxicological studies reported that ALAD variants may 5 

### increase the risk of Pb

- related health effects. Other genes examined that may also affect 6 

### risk of P b

- related health effects were VDR, DRD4, GSTM1, TNF

- α , eNOS, APOE, and 7 

### HFE, although the number of studies examining effect measure modification by these 8 

### genes was small. 9 

### Evidence for other factors (pre

- existing diseases/conditions, smoking, BMI and/or 10 

### ob esity, alcohol consumption, nutritional factors, stress, cognitive reserve, and co

11 

### exposure with other metals) was limited regarding their effect on Pb

- related health 12 

### outcomes. Pre

- existing diseases/conditions have the potential to affect the risk of Pb

13 

### re lated health effects. Recent epidemiologic studies did not support modification of 14 

### associations between Pb and health endpoints by the prevalence of diabetes; however, 15 

### past studies have found individuals with diabetes to be an at

- risk population with regar d 16 

### to renal function. Hypertension was observed to be a factor affecting risk in both past and 17 

### recent epidemiologic studies. Studies of Pb levels and both renal effects and heart rate 18 

### variability demonstrated greater odds of the associations among hypertens ive individuals 19 

### compared to those that are normotensive. Epidemiologic studies also examined autism 20 

### and atopy as potential factors affecting Pb

- related health effects; differences were 21 

### observed but few studies were available to examine these factors. Recen t epidemiologic 22 

### studies examining smoking as a factor potentially affecting risk reported mixed findings. 23 

### It is possible that smoking modifies the effects of only some Pb

- related health outcomes. 24 

### BMI, alcohol consumption, and nutritional factors were also examined in recent 25 

### epidemiologic and toxicological studies. Modification of associations between Pb and 26 

### various health effects (mortality and heart rate variability) was not observed for 27 

### BMI/obesity. Also, no modification was observed in an epidemiologic s tudy of renal 28 

### function examining alcohol consumption as a modifier, but a toxicological study 29 

### supported the potential of alcohol to affect risk. Among nutritional factors, those with 30 

### iron deficiencies were observed to be an at

- risk population for Pb

- relate d health effects in 31 

### both epidemiologic and toxicological studies. Other nutritional factors, such as calcium, 32 

### zinc, and protein intake, demonstrated the potential to modify associations between Pb 33 

### and health effects in toxicological studies. Recent epidemi ologic studies of these factors 34 

### were either not performed or observed no effect modification. Folate was also examined 35 

### in an epidemiologic study of birth size but no interaction was reported between Pb and 36 

### folate. Stress was evaluated as a factor that pote ntially increases the risk of Pb

- related 37 

### health outcomes and although there were a small number of recent epidemiologic studies, 38February 2012 6

- 38 Draft

– Do Not Cite or Quote 

### increased stress was observed to negatively impact the association between Pb and health 1 

### endpoints. Toxicological studies suppo rted this finding. An epidemiologic study 2 

### evaluated cognitive reserve as a modifier of the associations between Pb and cognitive 3 

### and motor functions. Cognitive reserve was an effect measure modifier for the 4 

### association between Pb and cognitive function but not motor function. Finally, 5 

### interactions between Pb and co

- exposure with other metals were evaluated in recent 6 

### epidemiologic and toxicological studies of health effects. High levels of other metals, 7 

### such as Cd, As, and Mn, were observed to result in grea ter effects for the associations 8 

### between Pb and various health endpoints. 9 10


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