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# Chapter 4 Contents

Chapter 4. Exposure, Toxicokinetics, and Biomarkers

________________________________ _______________________ 4

- 1

4.1. Exposure Assessment

________________________________ ________________________________ ________ 4

- 1

4.1.1. Pathways for Lead Exposure

________________________________ __________________________ 4

- 1

Figure 4

- 1. Conceptual model of multimedia Pb exposure.

_________________________ 4

- 3

Table 4

- 1. Estimates of Pb measurements for EPA Region 5 from the NHEXAS study.

________________________________ _________________________ 4

- 4

4.1.1.1. Airborne Lead E xposure

________________________________ ______________________ 4

- 4

Table 4

- 2. Estimates of fixed effects multivariate modeling of Pb levels measured during the NHEXAS

- MD study

________________________________ _____ 4

- 5

Table 4

- 3. Comparison of personal, indoor, and outdoor Pb

- bearing PM measurements from several studies.

________________________________ _ 4

- 7

4.1.1.2. Exposure to Lead in Soil and Dust

________________________________ ______________ 4

- 7

Table 4

- 4. M easurements of indoor Pb dust from various studies.

___________________ 4

- 8

4.1.1.3. Dietary Lead Exposure

________________________________ ______________________ 4

- 10

Table 4

- 5. Pb bioaccumulation data for various plants.

__________________________ 4

- 15

4.1.1.4. Occupational

________________________________ ______________________________ 4

- 16

4.1.1.5. Exposure to Lead from Consumer Products

________________________________ ______ 4

- 17

Table 4

- 6. Pb content in various consumer products

____________________________ 4

- 18

4.2. Kinetics

________________________________ ________________________________ _________________ 4

- 19

4.2.1. Absorption

________________________________ ________________________________ _______ 4

- 19

4.2.1.1. Inh alation

________________________________ ________________________________ 4

- 19

4.2.1.2. Ingestion

________________________________ ________________________________ _ 4

- 21

Figure 4

- 2. Estimated relative bioavailability (RBA, compared to Pb

- acetate) of ingested Pb in mineral groups, based on results from juvenile swine

assays.

________________________________ _______________________ 4

- 24

4.2.2. Distribution

________________________________ ________________________________ ______ 4

- 26

4.2.2.1. Blood

________________________________ ________________________________ ___ 4

- 26

Figure 4

- 3. Plot of blood and plasma Pb concentrations in measured in adults and

children.

________________________________ _____________________ 4

- 27
Figure 4

- 4. Relationship between Pb intake and blood Pb concentration in infants (n = 105, age 13 weeks, formula

- fed).

________________________________ _ 4

- 28
Figure 4

- 5

. Simulation of quasi

- steady state blood and plasma Pb concentrations in a child (age 4 years) associated with varyi ng Pb ingestion rates. Simulation based on ICRP Pb biokinetics model (Leggett, 1993).

__________ 4

- 29

4.2.2.2. Bone

________________________________ ________________________________ ____ 4

- 3 0

4.2.2.3. Soft Tissues

________________________________ ______________________________ 4

- 31

4.2.2.4. Fetus

________________________________ ________________________________ ____ 4

- 32

4.2.2.5. Organic Lead

________________________________ _____________________________ 4

- 32

4.2.3. Elimination

________________________________ ________________________________ _______ 4

- 32

4.3. Lead Biomarkers

________________________________ ________________________________ __________ 4

- 34

4.3.1. Bone Lead Measurements

________________________________ ___________________________ 4

- 34

4.3.2. Blood Lead Measurements

________________________________ ___________________________ 4

- 35

Figure 4

- 6. Simulation of temporal relationships between Pb exposure and blood Pb

concentration in children.

________________________________ ________ 4

- 38

4.3.3. Urine Lead Measurements

________________________________ ___________________________ 4

- 39

Figure 4

- 7. Simulation of relationship between urinary Pb excretion and body

burden in adults.

________________________________ _______________ 4

- 40

4.3.4. Lead in Other Potential Biomarkers

________________________________ ____________________ 4

- 41

4.3.4.1. Teeth

________________________________ ________________________________ ____ 4

- 41

4.3.4.2. Hair

________________________________ ________________________________ _____ 4

- 41May 2011 ii DRAFT

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________________________________ ________________________________ ___ 4

- 42

4.3.4.4. Serum δ

- ALA and ALAD

________________________________ ___________________ 4

- 43

4.3.5. Relationship between Lead in Blood and Lead in Bone

________________________________ _____ 4

- 43

4.3.5.1. Children

________________________________ ________________________________ _ 4

- 44

Figure 4

- 8. Simulation of relationship between blood Pb concentration and body burden in children, with a constant Pb intake from age 2 to 5.

____________ 4

- 46
Figure 4

- 9. Simulation of relationship between time

- integrated blood Pb concentration and cumulative Pb absorption in children.

________________ 4

- 47

4.3.5.2. Adults

________________________________ ________________________________ ___ 4

- 47

Figure 4

- 10. Simulation of relationship between blood Pb concentration, bone Pb and body burden in adults.

________________________________ _______ 4

- 49

4.3.6. Relationship Between Lead in Blood and Lead in Soft Tissues

_______________________________ 4

- 52

Figure 4

- 11. Simulation of blood and soft tissue (including brain) Pb in children and adults who experience a period of increased Pb intake. Simulation based

on ICRP Pb biokinetics model (Leggett, 1993)

.

________________________ 4

- 53
Figure 4

- 12

. Simulation of blood and brain Pb in children and adults who experienc e a period of increased Pb intake.

________________________________ ___ 4

- 55

4.3.7. Relationship Between Lead in Blood and Lead in Urine

________________________________ ____ 4

- 55

Figure 4

- 13. Top panel: Predicted relationship between plasma Pb concentration and urinary Pb excretion in an adult (age 40 years). Lower panel: Simulation of blood Pb, bone Pb and urinary excretion of Pb in an adult who experiences a period of increased Pb intake. Simulation based on ICRP Pb biokinetics model (Leggett, 1993).

__________________________ 4

- 57

4.4. Observational Studies of Lead Exposure

________________________________ ________________________ 4

- 58

4.4.1. Lead in Blood

________________________________ ________________________________ _____ 4

- 58

Figure 4

- 14. Temporal trend in blood Pb concentration.

___________________________ 4

- 59

Table 4

- 7. Blood Pb concentrations in the U.S. population

_______________________ 4

- 60
Figure 4

- 1 5. Box plots of blood Pb levels among U.S. children (1

- 5 years old) from the NHANES survey, 1988

- 2008.

________________________________ ___ 4

- 61
Figure 4

- 16. Percent distribution of blood Pb levels by race/ethnicity among U.S. children (1

- 5 years) from the NHANES survey, 1988

- 1991 (top) and

1999

- 2004 (bottom).

________________________________ ____________ 4

- 62
Figure 4

- 17. a) Trends in 206 Pb/ 204 Pb isotope ratio in blood Pb and b) trends in blood Pb levels among Australian study populations during the period 1990

- 2000.

________________________________ ________________________ 4

- 64

4.4.2. Lead in Bone

________________________________ ________________________________ _____ 4

- 64

Table 4

- 8. Epidemiologic studies that provide bone P b measurements for non

occupationally exposed populations

________________________________ 4

- 65

Table 4

- 9. Epidemiologic studies that provide bone Pb measurements for occupationally exposed populations

________________________________ 4

- 73

4.4.3. Lead in Urine

________________________________ ________________________________ _____ 4

- 76

Table 4

- 10. Urine Pb concentrations in the U.S. population

_______________________ 4

- 77

4.4.4. Lead in Teeth

________________________________ ________________________________ _____ 4

- 77

Figure 4

- 18. Comparison of tooth enamel

________________________________ ______ 4

- 78

4.5. Empirical Models of Lead Exposure

- Blood Lead Relationships

________________________________ ______ 4

- 78

4.5.1. Air Lead

- Blood Lead Relationships

________________________________ ____________________ 4

- 79

Table 4

- 11. Summary of estimated slopes for blood Pb to air Pb relationships in

humans

________________________________ ______________________ 4

- 80
Figure 4

- 19. Predicted relationship between air Pb and blood Pb based on a meta analysis of 18 studies.

________________________________ ___________ 4

- 81

4.5.1.1. Children

________________________________ ________________________________ _ 4

- 81

Table 4

- 12. Environmental Pb level s and blood Pb levels in children in Trail, British

Columbia

________________________________ _____________________ 4

- 82

Table 4

- 13. U.S. gasoline Pb consumption and air Pb levels

_______________________ 4

- 84

Table 4

- 14. Air Pb levels and blood Pb levels in children in Mumbai, India

___________ 4

- 85
Figure 4

- 20. Predicted relationship between air Pb and blood Pb based on data from Chicago, IL (1974

– 1988).

________________________________ ________ 4

- 86May 2011 iii DRAFT

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________________________________ ________________________________ ___ 4

- 86

Table 4

- 15. Significant predicto rs of blood Pb concentration in bridge painters

________ 4

- 87

1. 4.5.2.

________________________________ ____ Environmental Lead

- Blood Lead Relationships 4

- 87

Table 4

- 16. Linear model relating environmental Pb exposure and blood Pb

concentration in children a

________________________________ ________ 4

- 89
Figure 4

- 21. Predicted relationship between soil Pb concentration and blood Pb

concentration in children based data collected in the New Orleans child Pb screening program (2000

- 2005) (Mielke et al., 2007).

________________ 4

- 90

Table 4

- 17. General linear model relating blood Pb concentration in children and

environmental Pb levels

— Bunker Hill Superfund Site

___________________ 4

- 92

4.6. Biokinetic Models of Lead Exposure

- Blood Lead Relationships

________________________________ ______ 4

- 92

4.7. Summary

________________________________ ________________________________ ________________ 4

- 93

4.7.1. Exp osure

________________________________ ________________________________ _________ 4

- 93

4.7.2. Kinetics

________________________________ ________________________________ _________ 4

- 94

4.7.3. Lead Biomarkers

________________________________ ________________________________ __ 4

- 96

4.7.4. A ir Lead

- Blood Lead Relationships

________________________________ ____________________ 4

- 97 Chapter 4. References

________________________________ ________________________________ ____________ 4

- 99May 2011 4

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# Chapter 4. Exposure, Toxicokinetics, and Biomarkers

4.1. Exposure Assessment

The purpose of this section is to present recent studies that provide insight about human exposure 

### 1

to Pb through various pathways. The recent information provided here builds upon the conclusions of the 

### 2

2006 Pb AQCD ( 2006 ) , which found that air Pb concentrations and blood Pb l evels have decreased 

### 3

substantially following the 1996 ban on Pb in on

- road vehicle gasoline, the 1978 ban on Pb in household 

### 4

paints, and the 1986 and 1995 restrictions on uses of Pb solder. At the same time, detectable quantities of 

### 5

Pb have still been obse rved to be bioaccessible in various media types. It was reported in the 2006 Pb 

### 6

AQCD ( U.S. EPA, 2006 ) that airborne maximum quarterly Pb concentrations in the U.S. were in the 

### 7

range of 0.03

- 0.05 μg/m 3 for non

- source

- oriented monitors for the years 2000

- 2004 and were 0.10

- 0.22 

### 8

μg/m 3 for source

- oriented monitors during that time period, while blood Pb levels reached a median of 

### 9

1.70 μg/dL among children ages 1

- 5 in 2001

- 2002. It was also observed that Pb exposures were 

### 10

associated with nearby industrial Pb sourc es, presence of Pb

- based paint, and Pb deposited onto food in 

### 11

several of the studies described in the 2006 Pb AQCD. For the current review, Section 4.1. contains a 

### 12

description of studies related to pathways for human exposure to Pb. 

### 13



## 4.1.1. Pathways for Lead Expo sure

Pathways of Pb exposure are difficult to assess because Pb has multiple sources in the environment 

### 14

and passes through various environmental media. These issues are described in detail in Sections 3.2 and 

### 15

3.3. Air

- related pathways of Pb exposure are t he focus of this ISA. Pb can be emitted to air or water. In 

### 16

addition to primary emission of particle

- bound or gaseous Pb to the atmosphere, Pb can be resuspended to 

### 17

the air from soil or dust, and a fraction of that resuspended Pb may even originate from wa ters used to 

### 18

irrigate the soil. Additionally, Pb

- bearing PM can be deposited from the air to soil or water through wet 

### 19

and dry deposition. In general, air

- related pathways include those pathways where Pb passes through 

### 20

ambient air on its path from a source to human exposure. Air

- related Pb exposures include inhalation and 

### 21

ingestion of Pb

- contaminated food, water or other materials including dust and soil . Non

- air

- related 

### 22

exposures include ingestion of indoor Pb paint, Pb in diet as a result of inadvertent a dditions during food 

### 23

Note: Hyperlinks to the reference citations throughout this document will take you to the NCEA HERO database (H ealth and Environmental Research Online) at http://epa.gov/hero . HERO is a database of scientific literature used by U.S. EPA in the process of developing science

a ssessments such as the Integrated Science Assessments (ISA) and the Integrated Risk Information System (IRIS)

.May 2011 4

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– DO NOT CITE OR QUOTE processing, and Pb in drinking water attributable to Pb in distribution systems, as well as other generally 

### 1

less prevalent pathways . The complicated nature of Pb exposure is illustrated Figure 4

- 1, in which the 

### 2

Venn diagram depicts how Pb can cycle through multiple environmental media prior to human exposure. 

### 3

The “air/soil/water” arrows illustrate Pb exposures to plants, animals, and/or humans via contact with Pb



### 4

containing media. The exposures are air

- related if the Pb passed through t he air compartment. When 

### 5

animals consume plant material exposed to Pb that has at some point passed through the air compartment, 

### 6

and when human diet includes animals and/or plants exposed to Pb that has passed through the air 

### 7

compartment, these are also co nsidered air

- related Pb exposures. As a result of the multitude of possible 

### 8

air

- related exposure scenarios and the related difficulty of constructing Pb exposure histories, most 

### 9

studies of Pb exposure through air, water, and soil can be informative to this review. Figure 4

- 1 also 

### 10

illustrates other exposures, such as occupational exposures, contact with consumer goods in which Pb has 

### 11

been used, or ingestion of Pb in drinking water conveyed through Pb pipes. Most Pb biomarker studies do 

### 12

not indicate speciatio n or isotopic signature, and so exposures that are not related to Pb in ambient air are 

### 13

also reviewed in this section because they can contribute to Pb body burden. Many of the studies 

### 14

presented in the subsequent material focus on observations of Pb exposu re via one medium: air, water, 

### 15

soil and dust, diet, or occupation. 

### 16May 2011 4

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– DO NOT CITE OR QUOTE Figure 4

- 1. Conceptual model of multimedia Pb exposure. The Venn diagram is used to illustrate the passage of Pb through multiple environmental media compartments thr ough which

exposure can occur.

The relative importance of different sources or pathways of potential exposure to Pb in the 

### 1

environment is often difficult to discern. Individual factors such as home environment, location, and 

### 2

susceptibility factors (descri bed in more detail in Chapter 6) may influence exposures. The National 

### 3

Human Exposure Assessment Survey (NHEXAS) study sampled Pb, as well as other pollutants and 

### 4

VOCs, in multiple exposure media from subjects across six states in EPA Region 5 (Illinois, I ndiana, 

### 5

Michigan, Minnesota, Ohio, and Wisconsin) ( Clayton et al., 1999 ) as well as in Arizona ( O'Rourke et al., 

### 6

1999 ) and Maryland ( Egeghy et al., 2005 ) . Results from NHEXAS indicate that personal exposure 

### 7

concentrations of Pb are higher than indoor or outdoor concentrations of Pb (Table 4

- 1). It is plausible 

### 8

that local resuspension of Pb

- containing dust due to human activity increased personal ex posure 

### 9

concentrations of airborne Pb relative to indoor or outdoor air Pb concentrations. Pb levels in windowsill 

### 10

dust were higher than Pb levels in surface dust collected from other surfaces. Clayton et al. ( 1999 ) 

### 11

suggested that higher windowsill levels could be attributed to the presence of Pb

- based paint and/or to 

### 12

accumulation of infiltrated outdoor Pb

- bearing PM. Pb levels in food were higher than in beverages, and 

### 13

Pb levels in standing tap water (also refer red to as “first flush ” or “first draw”) were higher than Pb levels 

### 14

obtained after allowing water to run for three minutes to flush out pipes. 

### 15May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 1. Estimates of Pb measurements for EPA Region 5 from the NHEXAS study.

Medium a n Percentage measurable b (CLs) c Mean ( CLs) c 50th ( CLs) c 90 th ( CLs) c

Personal air (ng/m 3 ) d 167 81.6 ( 71.3 ; 92.0 ) 26.83 ( 17.60 ; 36.06 ) 13.01 ( 11.13 ; 18.13 ) 57.20 ( 31.18 ; 85.10 ) Indoor air (ng/m 3 ) d 213 49.8 ( 37.2 ; 62.3 ) 14.37 ( 8.76 ; 19.98 ) 6.61 ( 4.99 ; 8.15 ) 18.50 ( 12.69 ; 30.31 ) Outdoor air (ng/m 3 ) d 87 73.8 ( 56.3 ; 91.3 ) 11.32 ( 8.16 ; 14.47 ) 8.50 ( 7.14 ; 10.35 ) 20.36 ( 12.60 ; 34.91 ) Surface dust (ng/cm 2 ) 245 92.1 ( 87.4 ; 96.8 ) 514.43 (

- 336.6 ; 1365.5 ) 5.96 ( 3.37 ; 10.94 ) 84.23 ( 26.52 ; 442.63 ) Surface dust ( m g/ k g) 244 92.1 ( 87.4 ; 96.8 ) 463.09 ( 188.15 ; 738.04 ) 120.12 ( 83.85 ; 160.59 ) 698.92 ( 411.84 ; 1

, 062.8 ) Window sill dust (ng/cm 2 ) 239 95.8 ( 92.5 ; 99.0 ) 1

, 822.6 ( 481.49 ; 3

, 163.6 ) 16.76 ( 10.44 ; 39.41 ) 439.73 ( 106.34 ; 4

, 436.2 ) Window sill dust ( m g/ k g) 239 95.8 ( 92.5 ; 99.0 ) 954.07 ( 506.70 ; 1

, 401.4 ) 191.43 ( 140.48 ; 256.65 ) 1

, 842.8 ( 1

, 151.3 ; 2

, 782.5 ) Standing tap water (μg/ L ) 444 98.8 ( 97.6 ; 100.0 ) 3.92 ( 3.06 ; 4.79 ) 1.92 ( 1.49 ; 2.74 ) 9.34 ( 7.87 ; 12.35 ) Flushed tap water (μg/ L ) 443 78.7 ( 70.7 ; 86.7 ) 0.84 ( 0.60 ; 1.07 ) 0.33 ( 0.23 ; 0.49 ) 1.85 ( 1.21 ; 3.04 )

Solid food (μg/kg) 159 100.0 ( 100.0 ; 100.0 ) 10.47 ( 6.87 ; 14.07 ) 6.88 ( 6.44 ; 8.04 ) 14.88 ( 10.78 ; 19.08 ) Beverages (μg/kg) 160 91.5 ( 85.2 ; 97.8 ) 1.42 ( 1.13 ; 1.72 ) 0.99 ( 0.84 ; 1.21 ) 2.47 ( 2.06 ; 3.59 ) Food+Beverages (μg/kg) 156 100.0 ( 100.0 ; 100.0 ) 4.48 ( 2.94 ; 6.02 ) 3.10 ( 2.66 ; 3.52 ) 6.37 ( 4.89 ; 8.00 ) Food intake (μg/day) 159 100.0 ( 100.0 ; 100.0 ) 7.96 ( 4.25 ; 11.68 ) 4.56 ( 3.68 ; 5.36 ) 12.61 ( 9.27 ; 16.38 ) Beverage intake (μg/day) 160 91.5 ( 85.2 ; 97.8 ) 2.15 ( 1.66 ; 2.64 ) 1.41 ( 1.18 ; 1.60 ) 4.45 ( 3.15 ; 5.65 ) Food+Beverage intake (μg/day) 156 100.0 ( 100.0 ; 100.0 ) 10.20 ( 6.52 ; 13.89 ) 6.40 ( 5.21 ; 7.78 ) 16.05 ( 13.31 ; 18.85 )

Blood (μg/d L ) 165 94.2 ( 88.2 ; 100.0 ) 2.18 ( 1.78 ; 2.58 ) 1.61 ( 1.41 ; 2.17 ) 4.05 ( 3.24 ; 5.18 )

Note: EPA Region 5 includes six states: Illinois, Indiana, Ohio, Michigan, Minnesota, and Wisconsin. Participants were enrolled using a stratified, four

- stage probability sampling design, and submitted questionnaire and physical measurements data. Summary statistics (percentage measurabl e, mean, median, 90 th percentile) were computed using weighted sample data analysis. The estimates apply to the larger Region 5 target population (all non

- institutionalized residents residing in households).

a Estimates for indoor air, outdoor air, dust me dia, and water media apply to the target population of Region 5 households; estimates for other media apply to the target population of Region 5 residents.
b Percentage measurable is the percentage of the target population of residents (or households) esti mated to have Pb levels above limit of detection (LOD).

c The lower and upper bounds of the 95% confidence limits (CL) are provided.
d PM 50

. Source: Used with permission from Nature Publishing Group, Clayton et al. ( 1999 )



### 4.1.1.1. Airborne Lead Exposure

Limited personal exposure monitoring data for airborne Pb were available for the 2006 AQCD 

### 1

( U.S. EPA, 2006 ) . As described above, the NHEXAS study showed personal air Pb concentrations to be 

### 2

significantly higher than indoor or outdoor air Pb concentrations ( Clayton et al., 1999 ) . Indoor air Pb 

### 3

concentration was shown to be moderately correlated with floor dust and residential yard soil Pb 

### 4

concentration ( M. Rabinowitz et al., 1985 )

. Egeghy et al. ( 2005 ) performed multivariate fixed effects 

### 5

analysis of the NHEXAS

- Maryland data and found that Pb levels measured in indoor air were 

### 6

significantly associated with log

- transformed outdoor air Pb levels, ambient temperature, number of hours 

### 7

in which windows were open, homes built before 1950, and fre quency of fireplace usage (T able 4

- 2 )

. 

### 8May 2011 4

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- 2. Estimates of fixed e ffects multivariate modeling of Pb levels measured during the NHEXAS

- MD study

Pb in Indoor Air Pb in Dust Dermal Pb Blood Pb

Fixed Effect β a p - value β a p - value β a p - value β a p - value

Intercept

- 0.50 0.0051 6.22 <0.0001 6.2 3 <0.0001 0.02 0.91 Outdoor Pb concentration b 0.51 <0.0001 Average weekly t emperature ( ° F) 0.01 0.046 Open w indow period s (h r ) 0.01 0.035

- 0.03 0.0082 House pets (yes)

- 0.15 0.078 Air filter use (yes)

- 0.28 0.087

- 0.12 0.08 8 Home age (<1950) 0.25 0.025 0.96 0.029 Fireplace ( frequency of use) 0.11 0.045 0.46 0.0054 Pb concentration in soil b 0.27 0.037 Interior Pb paint chipping/peeling (yes) 0.43 0.091

Cement at primary entryway (yes) 1.97 0.0064 Indoor pesticide usage last 6 mo (yes) - 0.78 0.0003

Electrostat ic air filter usage (yes)

- 0.91 0.062 Sex of participants (male) 0.41 0.0012 0.43 <0.0001 Ethnic m inority participants (yes) 0.41 0.0063 Washing hands after lawn mo wing (no) 1.04 0.0010
Gasoline power

- equipment usage (yes) 0.61 0.0072
Bathing or showering activities (yes)

- 0.43 0.019 Dust level indoors ( scale: 1

- 3) 0.22 0.019 Residing near commercial areas (yes) 0.32 0.0087
Age of participants (y r ) 0.02 <0.0001 Number cigarettes smoked (count) 0.03 <0.0001 Burning wood or trash (days) 0.58 0.0099 Showering frequency (avg # d ays )

- 0.29 0.0064 Work outside home (yes)

- 0.26 <0.0001 Health status (good) 0.23 0.0009 Adherence to h igh fiber diet (yes)

- 0.15 0.040 Gas or charcoal grill usage (yes )

- 0.17 0.0002

a Estimates of fixed effects in final multiple regression analysis models for Pb in the Maryland investigation data in the Nati onal Human Exposure Assessment Survey (NHEXAS

- MD)
b Log transform

Source: Used with permission from Nature Publishing Group, Egeghy et al. ( 2005 )

.

Some recent studies have measured personal exposure to particle

- bound Pb along with other trace 

### 1

metals. Adgate et al. ( 2007 ) measured the concentrations of several trac e elements in personal, indoor, and 

### 2

outdoor samples of PM 2.5 and found that average personal Pb

- PM 2.5 concentration was roughly three 

### 3

times higher than outdoor Pb

- PM 2.5 concentration and two times higher than indoor Pb

- PM 2.5 

### 4

concentration (Table 4

- 3) . Another study of indoor and outdoor air concentrations of Pb was carried out 

### 5

by Molnar et al. ( 2007 ) . PM 2.5 trace element concentrations were determined in homes, preschools and 

### 6

schools in Stockholm, Sweden. In all sampled locations, Pb

- PM 2.5 concentrations were higher in the 

### 7

outdoor environment than in the proximal indoor environment. The indoor/outdoor ratios for Pb

- PM 2.5 

### 8

suggest an outd oor Pb

- PM 2.5 net infiltration of ~0.6 for these buildings. Outdoor air Pb concentrations did 

### 9

not differ between the central and more rural locations. Indoor air Pb concentrations were higher in spring 

### 10

than in winter , which the authors attributed to greater resuspension of elements that had accumulated in 

### 11

road dust over the winter period and increased roadwear on days with dry surfaces. In a pilot study in 

### 12

Windsor, Ontario, Rasmussen et al

. ( 2007 ) observed that personal exposure to Pb measured using a PM 2.5 

### 13May 2011 4

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– DO NOT CITE OR QUOTE monitor was roughly 40% higher than outdoor Pb concentration and 150% higher than i ndoor Pb 

### 1

concentration. Pekey et al. ( 2010 ) measured indoor and outdoor trace element composition of PM 2.5 and 

### 2

PM 10 in Kocaeli, an industrial region of Turkey, and found that average airborne Pb concentrations were 

### 3

higher outdoors than indoors for both PM 2.5 and PM 10 during summer and for PM 10 during winter, but that 

### 4

indoor Pb concentration was higher than out door Pb concentration for PM 2.5 during winter. The indoor

- to



### 5

outdoor ratio of Pb in PM varied by environment; it tended to be less than one, but the ratio varied from 

### 6

one microenvironment to another. The three studies that included personal samples recorde d 

### 7

measurements that were consistently higher than indoor or outdoor levels. It is likely that a number of 

### 8

factors influenced the indoor

- to

- outdoor ratio of Pb in PM for these studies. These factors may have 

### 9

included seasonal air exchange, which can vary as a function of window opening or air conditioning 

### 10

usage, prevalence and strength of outdoor and indoor Pb sources, and size distribution of airborne Pb



### 11

bearing PM. 

### 12

Several of the studies can be used to develop an understanding of how personal exposure to P M



### 13

bound Pb varies with other exposures. Molnar et al. ( 2007 ) reported Spearman correlations of Pb with 

### 14

PM 2.5 and NO 2 in three outdoor mic roenvironments (residence, school, and preschool) and found that Pb 

### 15

and other trace metals were generally well correlated with PM 2.5 (r = 0.72

- 0.85), but Pb was not always 

### 16

well

- correlated with NO 2 (r = 0.24

- 0.75). In the case where Pb and NO 2 were well

- cor related, it is 

### 17

possible that the Pb was traffic related from resuspended pulverized wheel weights or impurities in 

### 18

unleaded on

- road gasoline. For the other two sites where the correlation between Pb and NO 2 was low, it 

### 19

is possible that they were less affec ted by traffic. Table 3A

- 14 in the Appendix illustrates that Pb 

### 20

exposures are typically well below the level of the NAAQS. The higher exposures occurred in a heavily 

### 21

industrialized area with an incinerator and several industrial facilities including metal processing, cement, 

### 22

petroleum refining, agriculture processing. Otherwise, exposures were all between 0.002 and 0.006 

### 23

μg/m 3 . The proportion of Pb compared with other trace metals varied with location and component. It was 

### 24

typically several times lower than S as well as crustal elements such as Ca and Fe. In the industrial area of 

### 25

Kocaeli, Pb comprised a greater proportion of the PM compared with other areas. 

### 26May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 3. Comparison of personal, indoor, and outdoor Pb

- bearing PM measurements
from several studi es.

Study Location Pb Metric Sampling
Period Personal Pb Indoor Pb Outdoor Pb

Clayton et al. ( 1999 ) IL, IN, MI, MN, OH, WI Med. Pb

- PM 50 (ng/m 3 ) July, 1995

- May, 1997 13 6.6 8.5

Adgate et al. ( 2007 ) Minneapolis

- St. Paul, MN Avg. Pb

- PM 2.5 (ng/m 3 ) Spring, Summer, Fall, 1999 6.2 3.4 2.0

Molnar et al. ( 2007 ) Stockholm, Sweden Avg. Pb

- PM 2.5 (ng/m 3 ) December, 200 3

- July, 2004 Homes: 3.4 Schools: 2.5 Preschools: 1.8 Homes: 4.5 Schools: 4.6 Preschools: 2.6 Tovalin

- Ahumada et al. ( 2007 ) Mexico City, Mexico Med. Pb

- PM 2.5 (ng/m 3 ) April

- May, 2002 26 56

Puebla, Mexico Med. Pb

- PM 2.5 (ng/m 3 ) April

- May, 2002 4 4

Rasmussen et al. ( 2007 ) Windsor, Ontario, Canada Med. Pb

- PM 2.5 ( m g/ k g) April, 2004 311 124 221

Pekey et al. ( 2010 ) Kocaeli, Turkey Avg. Pb

- PM 2.5 (ng/m 3 ) May

- June, 2006, December, 2006

- January 2007 Summer: 34 Winter: 85 Summer: 47 Winter: 72

Avg. Pb

- PM 10 (ng/m 3 ) May

- June, 2006, December, 2006

- January 2007 Summer: 57 Winter: 125 Summer: 78 Winter: 159



### 4.1.1.2. Exposure to Lead in Soil and Dust

The 2006 AQCD ( U.S. EPA, 2006 ) lists indoor Pb dust infiltrated from outdoors as a potential 

### 1

source of exposure to Pb soil and dust. Outdoor soil Pb concentration may present a direct inhalation 

### 2

exposure, or it can be tracked into homes to result in exposure to resuspended Pb PM or to Pb dust during 

### 3

hand

- to

- mouth contact. A detailed description of studies of outdoor Pb concentration is provided in 

### 4

section 3.6.1. Indoor measurements can reflect infiltrated Pb as well as Pb dust derived from debrided 

### 5

paint, consumer products, or soil that has been transported into the home via foot traffic. Table 4

- 4 

### 6

presents indoor Pb levels for several s tudies. 

### 7May 2011 4

- 8 DRAFT

– DO NOT CITE OR QUOTE Table 4

- 4. Measurements of indoor Pb dust from various studies.

Reference Study Location Metric (units) Sample Site Indoor Pb Concentration

Caravanos et al. ( 2006 ) New York City, New York Weekly dust loading (μg/m 2 ) Glass plate Median: 52

Khoder et al. ( 2010 ) Giza, Egypt Weekly dust loading (μg/m 2 ) Glass plate Median: 408

Yu et al. ( 2006 ) Syracuse, New York Dust concentration range (mg/kg) Floor Range: 209

- 1 770

Turner and Simmonds ( 2006 ) Birmingham, Plymouth, and 2 rural sites, UK Dust concentration (mg/kg) Floor Median: 178

Gaitens et al. ( 2009 ) U.S. (nationwide) Dust loading (μg/m 2 ) Smooth floor Median: 1.7 Avg.: 4.4
Rough floor Median: 5.6 Avg.: 16

Smooth windowsill Median: 2.5 Avg.: 190
Rough windowsill Median: 55 Avg.: 480

Mielke et al. ( 2001 ) New Orleans, Louisiana Dust concentration (mg/kg) Multiple locations within homes prepared for painting; sanded house Range: <3

- 28,000

Multiple locations within homes prepared for painting; scraped house Range: 7

- 1,200

Spalinger et al. ( 2007 ) Rural towns, Idaho Dust concentration (mg/kg) Vacuum Median: 120 Max: 830

Floor Median: 95 Max: 1,300 Bunker Hill, Idaho Superfund site Vacuum Median: 470 Max: 2,000

Floor Median: 290 Max: 4,600

Several studies have demonstrated the infiltration of Pb dust into buildings. For example, 

### 1

Caravanos et al. ( 2006 ) collected dust on glass plates at an interior location near an open window, a 

### 2

sheltered exterior location, and an open exterior location for a two

- year period in Manhattan, NY. Median 

### 3

weekly dust loading was reported to be 52 μg/m 2 for the indoor site, 153 μg/m 2 for the unsheltered 

### 4

outdoor site, and 347 μg/m 2 for the sheltered outdoor site. This paper demonstrated the likely role of 

### 5

outdoor Pb in influencing indoor dust Pb loading and indicated that under quiescent conditions (e.g., no 

### 6

cleaning), the indoor dust Pb level might exceed EPA’s hazard level for interior floor dust of 430 μg/m 2 

### 7

(40 μg/ft 2 ). Khoder et al. ( 2010 ) used the same methodology to study Pb dust deposition in Giza, Egypt 

### 8

and found a median weekly deposition rate of 408 μg/m 2 and an exterior median deposition rate of 2,600 

### 9

μg/m 2 . In the latter study, Pb deposition rate correlated with total dust depos ition rate (R=0.92), Cd 

### 10

deposition rate (R=0.95), and Ni deposition rate (R=0.90). Statistically significant differences in Pb 

### 11

deposition rates were observed between old and new homes (p<0.01) in the Khoder et al. ( 2010 ) study, 

### 12

although the only quantitative information provided regarding home age stated that the oldest home was 

### 13

22 years old when the study was performed in 2007. Khoder et al. ( 2010 ) found no statistically significant 

### 14

difference between Pb loadings when segregating the data by proximity to roadways. 

### 15

Residual Pb dust contamination following cleanup has b een documented. For instance, Hunt et al. 

### 16

( 2008 ) performed tests where moderately elevated soil Pb was tracke d onto a tile test surface and then 

### 17

repeatedly cleaned with a moistened wipe and/or vacuumed until visual inspection of the tiles uncovered 

### 18May 2011 4

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– DO NOT CITE OR QUOTE no surface discoloration. The authors then used wet wipe samples to collect residual soil and estimate Pb 

### 1

deposition and concentration. Elevated Pb loadings and concentrations were observed even after multiple 

### 2

cleanings. Scanning electron microscopy (SEM) of the wipe samples revealed that most of the residual 

### 3

dust particles were in the range of 1

- 3 μm in area equivalent diameter. This indicates that Pb

- bearing fine 

### 4

particles are not well captured by home cleaning. Johnson et al. ( 2009 ) surveyed the floors of 488 homes 

### 5

in Syracuse, NY census tracts and fo und that the variability in Pb dust within homes was greater than the 

### 6

variability between homes. A correlation between Pb dust loading on floors and the fraction of homes in 

### 7

census tracts that were renter

- occupied (partial R 2 = 0.48; where total number of homes is the sum of 

### 8

owner

- occupied, renter

- occupied, and vacant homes) was also observed in this study. Yu et al. ( 2006 ) 

### 9

dissolved Pb dust, obtained from vacuuming carpet samples and found that Pb concentration in carpet 

### 10

ranged from 209 to 1 ,770 mg/kg dust. 

### 11

Pb dust on floors, windowsills, and other accessible surfaces are potential exposure sources to 

### 12

small children who use touch to explore their environments. Gaitens et al. ( 2009 ) used National Health 

### 13

and Nutrition Examination Survey (NHANES) data from 1999 through 2004 to exam ine Pb dust in homes 

### 14

of children ages 12

- 60 months. The median value of Pb dust on floors was reported to be 1.7 μg/m 2 

### 15

(mean: 4.4 μg/m 2 ), with floors that were not smooth and cleanable having a median Pb dust value of 5.6 

### 16

μg/m 2 (mean: 16 μg/m 2 ). Floor Pb dust level was modeled against several survey covariates and was 

### 17

significantly associated (p <0.05) with floor surface condition, windowsill Pb dust loading, race and 

### 18

ethnicity, poverty

- to

- income ratio, year of home construction, presence of smokers in the home, and year 

### 19

of survey. It was nearly significantly associated (p = 0.056) with renovations made to pre

- 1950 homes. 

### 20

Median Pb dust on smooth windowsills was 25 μg/m 2 (mean: 190 μg/m 2 ). When windowsills were not 

### 21

smooth, the median Pb dust level was 55 μg /m 2 (mean: 480 μg/m 2 ). Windowsill Pb dust level was also 

### 22

found to be significantly associated (p <0.05) with race and ethnicity, year of home construction, window 

### 23

surface condition, presence of smokers in the home, deterioration of indoor paint, and year o f survey. It 

### 24

was nearly significantly associated (p = 0.076) with deterioration of outdoor paint when homes were built 

### 25

prior to 1950. Dust Pb levels were found by Egeghy et al. ( 2005 ) to be significantly associated with the 

### 26

log

- transform of soil Pb levels, cement cont ent in the home entryway, indoor pesticide use, frequency of 

### 27

fireplace usage, number of hours in which windows were open, and homes built before 1950 (Table 4

- 2)

. 

### 28

Building demolition and renovation activities can create dust from interior and exterior pai nts with 

### 29

Pb content. Mielke and Gonzales ( 2008 ) measured Pb content in paint chips from paint applied prior to 

### 30

1992 and found that median Pb levels were 420 mg/kg for interior paint and 77,000 mg/kg for exterior 

### 31

pa int. Maximum levels were 63,000 mg/kg and 120,000 mg/kg for interior and exterior paint, 

### 32

respectively. Mielke et al. ( 2001 ) compared dust samples from two New Orleans houses that were 

### 33

prepared for painting. One home was power sanded, while the o ther was hand

- scraped. Immediately after 

### 34

sanding, Pb dust samples ranged from <3 to 28,000 mg/kg at the sanded house. Pb dust samples from the 

### 35

scraped house ranged from 7 to 1,200 mg/kg. Pb in dust or paint samples was not quantified. 

### 36May 2011 4

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– DO NOT CITE OR QUOTE Dust Pb concentration s have also been reported for homes in the vicinity of historical metals 

### 1

mining and smelting sources. For example, Spalinger et al. ( 2007 ) measured Pb dust in homes in a 34 km 2 

### 2

area surrounding a designated Superfund site where formerly a Pb and Zn smelter operated at Bunker 

### 3

Hill, ID. Vacuum and floor mat samples were taken from homes in three town s within the 34 km 2 area and 

### 4

five “background” towns further from the Superfund site. For the background towns, Pb concentration in 

### 5

vacuum dust had a median of 120 mg/kg and a maximum of 830 mg/kg, and Pb concentration in floor 

### 6

dust had a median of 95 mg/k g and a maximum of 1,300 mg/kg. The median Pb dust loading rate was 

### 7

measured to be 40 μg/m 2 per day. Among the background homes, median vacuum and floor mat Pb dust 

### 8

samples were 3 and 2.5 times higher, respectively, when comparing homes built before 1960 w ith those 

### 9

built after 1960. Deposition rate of Pb dust was 5 times higher in the older homes. In contrast, Pb in 

### 10

vacuum dust and floor mats for the towns contained within the Bunker Hill Superfund site had a median 

### 11

of 470 mg/kg with a maximum of 2,000 mg/k g and a median of 290 mg/kg with a maximum of 4,600 

### 12

mg/kg, respectively. The median Pb loading rate for these towns was 300 μg/m 2 per day, and the 

### 13

maximum Pb dust loading rate was 51,000 μg/m 2 per day. These results suggest that those living in close 

### 14

proxi mity to an industrial site are at much greater risk of exposure to Pb dust compared to the general 

### 15

population. 

### 16

4.1.1.3. Dietary Lead Exposure

This subsection covers several dietary Pb exposures from a diverse set of sources. Included among 

### 17

those are drinking water , fish and meat, pesticides via vegetables, urban gardening, dietary supplements, 

### 18

tobacco, cultural food sources, and breastfeeding. 

### 19

Drinking W ater

Differences in sources and transport of drinking water may cause variation in Pb levels. For 

### 20

example, Shotyk and Krachler ( 2009 ) measured the Pb concentration in tap water, commercially bottled 

### 21

tap water and bottled natural water. They found that, in many cases, tap water containe d less Pb than 

### 22

bottled water. Excluding bottled water in glass containers that have higher Pb concentrations due to 

### 23

leaching from the glass, the median Pb concentration was 8.5 ng /L (range ≤ 1 to 761 ng / L). This was 

### 24

significantly less than the EU, Health C anada and WHO drinking water maximum admissible 

### 25

concentration of 10 μg /L

. It is now recogn ize d that environmental nanoparticles (NPs) (~1

- 100 nm) can 

### 26

play a key role in determining the chemical characteristics of engineered as well as natural waters 

### 27

( Wigginton et al., 2007 ) . An important question is whether or not NPs from source waters affect the 

### 28

quality of drinking water. For example, if Fe

- oxide NPs are not removed d uring the 

### 29

flocculation/coagulation stage of the treatment process, they may become effective transporters of 

### 30May 2011 4

- 11 DRAFT

– DO NOT CITE OR QUOTE contaminants such as Pb, particularly if these contaminants are leached from piping in the distribution 

### 1

system. Edwards and Dudi ( 2004 ) observed a red

- brown particle

- bound Pb in Washington, DC water that 

### 2

could be confused with innocuous Fe. The source of the particle

- bound Pb was not known but was 

### 3

thought to originate from the source water. 

### 4

Corrosion byproducts can lead to Pb exposures in drinking water. Schock et al. ( 2008 ) 

### 5

character ize d Pb pipe scales from 91 pipes made available from 26 different municipal water systems 

### 6

from across the northern U.S . They found a wide range of elements including Cu, Zn and V as well as Al, 

### 7

Fe and Mn. Interestingly, V was present at nearly one percent levels in pipes from many geographically 

### 8

diverse systems. In a separate study, Gerke et al. ( 2009 ) identified the corrosion product, vanadinite 

### 9

(Pb 5 (VO 4 ) 3 Cl) in Pb pipe corrosion byproducts collected from 15 Pb or Pb

- lined pipes representing 8 

### 10

different municipal drinking water distribution systems in the N ortheastern and M idwest region s of the 

### 11

U

. S. Vanadinite was most frequently found in the surface layers of the corrosion products. The vanadate 

### 12

ion, VO 4 3

- , essentially replaces the phosphate ion in pyromorphite and hydroxyapatite structures. It is not 

### 13

known whether the application of or thophosphate as a corrosion inhibitor would destabil ize vanadinite

, 

### 14

but this would have implications for V release into drinking water. T he stability of vanadinite in the 

### 15

presence of monochloramine is also not known

, and this might have implications for both Pb and V 

### 16

release into drinking water. 

### 17

In recent years, drinking water treatment plants in many municipalities have switched from using 

### 18

chlorine to other disinfecting agents because their disinfection byproducts may be less carcinogenic. 

### 19

However, chloramines are more acidic than chlorine and ca n increase Pb solubility ( Raab et al., 1991 ) and 

### 20

increase Pb concentrations in tap water. For example, after observing elevated Pb concentrations in 

### 21

drinking water samples, Kim and Herrera ( 2010 ) observed Pb oxide corrosion scales potentially occurring 

### 22

after using acidic alum as a disinfection agent. H igh Pb concentrations in Washington, DC drinking water 

### 23

were attributed to leaching of Pb from Pb

- bearing pipes promoted by breakdown products of disinfection 

### 24

agents ( Edwards & Dudi, 2004 )

. Maas et al. ( 2007 ) tested the effect of fluoridation and chlorine

- based 

### 25

(chlorine and chloramines) disinfection agents on Pb leaching from plumbing soldered with Pb. When 

### 26

using chlorine disinfection agents alone, the Pb concentration in water samples doubled duri ng the first 

### 27

week of application (from 100 to 200 ppb) but then decreased over time. When adding fluorosilic acid 

### 28

and ammonia, the Pb concentration spiked to 900 ppb and increased further over time. Similarly, Lasheen 

### 29

et al. ( 2008 ) observed leaching from pipes in Egypt. In this study, the authors tested polyvinyl chloride 

### 30

(PVC), polypropylene (PP), and galvanized iro n pipes and observed leaching from both the PVC and PP 

### 31

pipes when exposed to an acid of pH = 6, with PVC having greatest amount of leaching. Exposure to 

### 32

basic solutions actually resulted in reduction of Pb concentration in the drinking water. 

### 33

Miranda et a l. ( 2007 ) modeled blood Pb levels among children living in Wayne County, NC as a 

### 34

function of household age , use of chloramines and other covariates. It was found that blood Pb level was 

### 35

significantly associated with the year the home was built ( p < 0.00 1 ), use of chloramines ( p < 0.00 1 ), and 

### 36May 2011 4

- 12 DRAFT

– DO NOT CITE OR QUOTE the interaction between these two variables ( p < 0.00 1 ). When year in which the home was built was 

### 1

broken into categories for the independent variables and interaction terms, Miranda et al. ( 2007 ) found 

### 2

that significance increased with the age of the home, based on the assumption that older homes will have 

### 3

more Pb pipes and Pb solder connecting the pipes. However, the study did not control for the presence of 

### 4

Pb paint in the dwellings, so it is difficult to distinguish the effect of Pb pipes from the presence of paint 

### 5

from that variable. 

### 6

Several chemical mechanisms may contribute to release of Pb during use of chloramine 

### 7

disinfection agents. Edwards and Dudi ( 2004 ) hypothesized that Pb leaching through chloramines 

### 8

exposure through the breakd own of brass alloys and solder containing Pb. They also proposed that 

### 9

chloramines may trigger nitrification and hence cause decreasing pH, alkalinity and dissolved oxygen that 

### 10

lead to corrosion after observing that nitrification also leads to increased Pb concentrations in water

. 

### 11

However, Zhang et al. ( 2009 ) found no evidence that nitrification brought about significant lea ching of Pb 

### 12

from Pb pipes. Lytle et al. ( 2009 ) suggested that a lack of increased Pb(II) concentrations in drinking 

### 13

water following a change from free chlorine to chloramine s disinfection is attributed to the formation of 

### 14

the Pb(II) mineral hydroxypyromorphite (Pb 5 (PO 4 ) 3 OH) instead of Pb(IV) oxide. Xie et al. ( 2010 ) further 

### 15

investigated the mechanisms by which Pb(II) release is affected by chloramines. Two opposing 

### 16

mechanisms were proposed : Pb(IV)O 2 reduction by an intermediate species from decomposition of 

### 17

monochloramine ; and increasing redox potential which decreases the thermodynamic driving force for 

### 18

reduction. They suggest that the contact time of monochloramine with PbO 2 and the Cl 2 :N ratio in 

### 19

monochloramine formation will determine which mechanism is more important. Free chlorine can control 

### 20

Pb concentrations from dissolution under flowing conditions but for long stagnation periods, Pb 

### 21

concentrations can exceed the action level: 4

- 10 days were required for Pb concentrations to exceed 15 

### 22

μg / L (for relatively high loadi ngs of PbO 2 of 1 g / L). Thus, under less extreme conditions, it was 

### 23

concluded that chloramination was unlikely to have a major effect on the release of Pb into drinking 

### 24

water. 

### 25

Agriculture

Dietary Pb has the potential to emanate from soil Pb used for agricul tural purposes. For example, 

### 26

Jin et al. ( 2005 ) tested soil Pb, bioaccessibility of soil Pb (determined by CaCl 2 extraction), and P b in tea 

### 27

samples from tea gardens. They observed that the Pb concentration in tea leaves was proportional to the 

### 28

bioaccessible Pb in soil. Fernandez et al. ( 2007 ; 2010 ; 2008 ) measured Pb from atmospheric deposition in 

### 29

two adjacent plots of land having the same soil composition but different uses: one was pasture land and 

### 30

one was agricultural. In the arable land, size distributions of soil particle

- bound Pb, were un iformly 

### 31

distributed. In pasture land, size distributions of Pb were distributed bimodally with peaks around 2

- 20 

### 32

μ m and 50

- 100 μ m ( Fernandez et al., 2010 ) . For the agricultural plot, Pb concentration was constant 

### 33May 2011 4

- 13 DRAFT

– DO NOT CITE OR QUOTE around 70 mg/kg in samples taken over the first 30 cm of soil, at which time it dropped below 10 mg/kg 

### 1

at soil depths between 35 and 100 cm. In contrast, Pb concentration in pasture land peaked at a depth of 

### 2

10 cm at a concentration of roughly 70 mg/kg and then dropped off gradually to approach zero 

### 3

concentration at a depth of approximately 50 cm. The sharp change in concentration for the arable land 

### 4

was attributed to a combination of plowing the so il and use of fertilizers to change the acidity of the soil 

### 5

and hence the bioaccessibility of the Pb within the soil ( Fernandez et al., 2007 ) . They found that the 

### 6

surface layer was acidic (pH: 3.37

- 4.09), as was the subsurface layer (pH: 3.65

- 4.38). 

### 7

There is some evidence that Pb contaminatio n of crops can originate with treatment of crops. For 

### 8

example, compost produced from wastewater sludge has the potential to add Pb to crops. Cai et al. ( 2007 ) 

### 9

demonstrated that production of compost from sludge enriched the Pb content by 15

- 43% prior to its 

### 10

application. Chen et al. ( 2008 ) observed that the median concentration of Pb in California crop soil 

### 11

samples was 16.2 mg/kg (range: 6.0

- 62.2 mg/kg). Factor analysis suggested that the soil was enriched 

### 12

with Pb in c rop soils in the Oxnard/Ventura region. Chen et al. ( 2008 ) further observed that in three of the 

### 13

seven California agricultural regions sampled, concentrations of Pb increased following addition of 

### 14

fertilizer, but sub

- proportionally to the increase in P and Zn indicators of fertilizer. In four regions, there 

### 15

was no increase of Pb at all. Furthermore, Tu et al. ( 2000 ) observed a decrease in Pb fraction with 

### 16

increasing P application. Nziguheba and Smolders ( 2008 ) also surveyed phosphate

- based fertilizers sold 

### 17

in European markets to determine the c ontribution of these fertilizers to heavy metal concentrations in 

### 18

agricultural products. They observed a median Pb concentration of 2.1 mg/kg based on total weight of the 

### 19

fertilizer, with a 95 th percentile concentration of 7.5 mg/kg. Across Europe, Nziguhe ba and Smolders 

### 20

( 2008 ) observed that the amount of Pb applied via fertilizers was only 2.6% of that from atmospheric 

### 21

deposition. Although Pb in on

- road vehicle gasoline has been pha sed out in the U.S., this remains a 

### 22

relevant issue in the U.S. because some imported crops that are produced in countries that still use Pb 

### 23

antiknock agents in on

- road gasoline. For example, high concentrations of Pb have been found in 

### 24

chocolate from beans grown in Nigeria, where leaded gasoline is legal. Rankin et al. ( 2005 ) observed that 

### 25

the ratios of 207 Pb to 206 Pb and 208 Pb to 207 Pb were found to be similar to those of Pb in gasoline. Although 

### 26

this study showed that Pb concentration in the shelled cocoa beans was low (~1 ng/g), manufactured 

### 27

cocoa powder and baking chocolate was observed to have Pb concentrations similar to those of t he cocoa 

### 28

bean shells, on the order of 200 ng/g, and Pb concentration in chocolate products was roughly 50 ng/g 

### 29

( Rankin et al., 2005 ) . It is possible that the increases were attributed to contamination of the coco a by the 

### 30

shells during storage or manufacture, but the authors note that more research is needed to verify the 

### 31

source of contamination. Likewise, it is possible that resuspended Pb that originated from legacy mobile 

### 32

and industrial sources could deposit on crops. 

### 33

Uptake of Pb by plants growing in contaminated soil has been demonstrated in some species during 

### 34

controlled potted plant experiments ( Del Río

- Celestino et al., 2006 ) . In this study, most species retained 

### 35

Pb in the roots with little mobilization to the shoots of the plants. However, certain species Cichorium 

### 36May 2011 4

- 14 DRAFT

– DO NOT CITE OR QUOTE intybus [chicory], Cynodon dactylon [Bermuda grass], Amaranthus blitoides [matweed or mat amaranth], 

### 1

and Silybum marianum [milk thistle]) were able to mobilize Pb from the roots to the shoots of the plant; 

### 2

these specific species could lead to human exposures through consumption of grazing animals. Lima et al. 

### 3

( 2009 ) conducted similar greenhouse experiments with several vegetable crops grown in soil 

### 4

contaminated by P b

- containing residue from battery recycling waste. In this study, carrots were 

### 5

demonstrated to have high bioaccumulation, measured as the percent of Pb concentration measured in the 

### 6

plant compared with the Pb concentration in the soil, with little transloc ation of the Pb to the shoots, 

### 7

measured as the percent of Pb mass in the shoots compared to the Pb mass within the entire plant, of the 

### 8

Pb to the shoots. Conversely, beets, cabbages, sweet peppers, and collard greens had low bioaccumulation 

### 9

but moderate to high translocation. Okra, tomatoes, and eggplants had moderate bioaccumulation and 

### 10

moderate to high translocation. Sesli et al. ( 2008 ) also noted uptake of Pb within wild mushrooms. 

### 11

Vandenhove et al. ( 2009 ) compiled bioaccumulation data for plant groupings from various references; 

### 12

these data are reproduced in Table 4

- 5. Based on this review, grasses had the highest uptake, followed by 

### 13

leafy vegetables and root crops grown in sandy soils; these references also suggested high transfer from 

### 14

roots to shoots among root crops, with shoots having roughly four times higher Pb bioaccumulation than 

### 15

roots. 

### 16May 2011 4

- 15 DRAFT

– DO NOT CITE OR QUOTE Table 4

- 5. Pb bioaccumulation data for various plants. Bioaccumulation is expressed as percent of Pb concentration in the plant to the Pb concentration in the soil.

Plant Group Plant Compartment Soil n GM GSD AM SD Min Max

All 210 2.0% 14 63% 290% 0.015% 2500% Cereals Grain All 9 1.0% 3

. 6 1.8% 1.6% 0.19% 4.8% Straw All 4 2.3% 3

. 5 3.8% 4.0% 0.51% 9.6% Maize Grain All 9 0.12% 2

. 3 0.17% 0.14% 0.052% 0.38% Straw All 3 0.28% 6

. 6 0.85% 1.3% 0.060% 2.3% Rice Grain All 2 2.2% 1.4% 1.2% 3.2% Leafy Vegetables All 31 8.0% 13 210% 610% 0.32% 2500% Sand 4 7.3% 1

. 5 7.8% 3.3% 4.9% 11% Loam 3 82% 1

. 0 82% 3.5% 79% 86% Clay 7 2.8% 4

. 1 5.1% 4.8% 0.41% 12% Non

- Leafy Vegetables Fruits All 5 1.5% 26 78% 170% 0.15% 390% Shoots All 2 0.88% 0.42% 0.58% 1.17% Legumes Pods All 17 0.53% 12 34% 120% 0.046% 490% Sand 3 0.27% 3

. 2 0.42% 0.34% 0.065% 0.89% Loam 5 0.14% 4

. 4 0.42% 0.34% 0.065% 0.89% Clay 4 0.080% 1

. 0 0.33% 0.47% 0.046% 1.0% Shoots All 1 0.080% Root Crops Roots All 27 1.5% 16 41% 98% 0.024% 330% Sand 5 6.4% 1

. 6 7.0% 3.4% 4.2% 12% Loam 5 2.3% 4

. 7 0.50% 0.68% 0.024% 1.7% Shoots All 12 6.3% 15 250% 570% 0.30% 16% Tubers Tubers All 30 0.15% 7

. 4 9.1% 48% 0.015% 260% Sand 5 0.64% 3

. 5 1.2% 1.6% 0.16% 3.9% Loam 17 0.052% 2

. 4 0.073% 0.062% 0.015% 0.23% Fruits Fruits All 5 0.77% 2

. 6 1.0% 0.60% 0.15% 1.7% Leaves All 1 25% Grasses All 17 31% 1

. 8 36% 22% 11% 100% Natural Pastures All 34 92% 4

. 8 23% 29% 0.22% 100% Leguminous Fodder All 1 1.6% All Cereals All 20 0.43% 4

. 7 1.1% 1.4% 0.052% 4.8% Sand 5 0.61% 5

. 3 1.3% 1.3% 0.052% 3.2% Loam 8 0.17% 3

. 9 0.53% 1.1% 0.059% 3.2% Clay 6 0.90% 4

. 0 1.8% 1.8% 0.22% 4.8% Pastures/Grasses All 51 14% 4

. 2 27% 27% 0.22% 100% Fodder All 24 2.5% 12 130% 420% 0.060% 1600% Sand 4 4.5% 2

. 3 5.6% 4.0% 1.6% 11% Clay 4 0.82% 5

. 7 2.7% 4.6% 0.16% 9.6%

Source: Used with permission from Elsevier Publishers, Vandenhove et al. ( 2009 )

.

Findings from Pb uptake studies have implications for urban gardening if urban soils may be 

### 1

contaminated with Pb, as described in Section 4.1.1.2. For instance, Clark et al. ( 2006 ) tested the soil in 

### 2

103 urban gardens in two Boston neighborhoods. They found that Pb

- based paint contributed 40

- 80% of 

### 3

measured Pb in the urban garden soil samples, with the rest coming from historical gasoline emissions. 

### 4

F urthermore, Clark et al. ( 2006 ) estimated that Pb consumption from urban gardens can be responsible for 

### 5

up to 25% of exposure to Pb in drinking water for children living in the Boston neighborhoods studied

. 

### 6

Because soil Pb levels in urban areas will depend on surrounding sources ( Pruvot et al., 2006 ) , Pb 

### 7

exposures in urban garden vegetables will vary. 

### 8

In addition to uptake of Pb through the roots of a plant, deposition of airborne Pb

- bearing PM can 

### 9

also contribute to human dietary Pb exposures, as described in the 2006 Pb AQCD ( 2006 ) . In a recent 

### 10

study, Uzu et al. ( 2010 ) found that Pb deposition from smelter emissions caused a linear increase in Pb 

### 11

concentrations of 7.0 mg/kg per day (R 2 =0.96) in lettuce plants cu ltivated in the courtyard of a smelter. 

### 12May 2011 4

- 16 DRAFT

– DO NOT CITE OR QUOTE They reported that lettuce grown 250

- 400 m from the smelter had concentrations that were 10

- 20 times 

### 1

lower, which is consistent with findings described in Section 3.3 that deposition of Pb containing material 

### 2

drops o ff with distance from a source. 

### 3

Fish

Accumulation in fish could also lead to human exposure to Pb. Ghosh et al. ( 2007 ) demonstrated in 

### 4

laboratory experiments that exposure to Pb in water can lead to linearly inc reasing accumulation in fish. 

### 5

Several studies have documented the potential for human exposure through fish and seafood. Welt et al. 

### 6

( 2003 ) conducted a survey of individu als who fished in Bayou St. John, Louisiana in conjunction with 

### 7

sampling Pb content in sediment. They found that median sediment Pb concentrations ranged from 43 to 

### 8

330 mg/kg in different locations, while maximum Pb concentrations ranged from 580 to 6,500 mg/kg. In 

### 9

total, 65% of those surveyed fished for food from the Bayou, with 86% consuming fish from the Bayou 

### 10

each week. In a study of the effect of coal mining on levels of metals in fish (measured as blood Pb) in 

### 11

northeastern Oklahoma, Schmitt et al. ( 2005 ) found that Pb content varied with respect to species of fish 

### 12

but were found to be elevated in some species. Pb concentrations in fish were higher in areas close to 

### 13

mining activities. Similarly, Besser et al. ( 2008 ) observed higher levels of blood Pb in fish close to mining 

### 14

activities in southeastern M issouri. In a related study of fish species in the same region of Missouri, blood 

### 15

Pb levels in fish were found to be significantly higher in sites within 10 km downstream of active Pb

- Zn 

### 16

mines (p <0.01) compared with fish located further from the mines ( Schmitt et al., 2007 ) , and elevated 

### 17

blood Pb levels in fish were again noted near a Pb

- Zn mine ( Schmitt et al., 2009 ) . It was noted that the 

### 18

Ozark streams where these studies were performed were often used for recreational fishing. There has 

### 19

also been evidence of elevated Pb concentration within large game from mining areas ( Reglero et al., 

### 20

2009 )

. 

### 21

4.1.1.4. Occupational

Occupational environments have t he potential to expose individuals to Pb. Some modern day 

### 22

occupational exposures are briefly discussed below in the context of understanding potential exposures 

### 23

that are not attributed to ambient air. For example, Miller et al. ( 2010 ) obtained personal and area samples 

### 24

of particle

- borne Pb in a precious metals refinery. It was not stated explicitly, but it is likely that Miller et 

### 25

al. ( 2010 ) measured the PM as TSP because the Occupational Safety and Health Administration (OSHA) 

### 26

permissible exposure limit (PEL) for Pb is based on TSP rather than a smaller size cut, and the OSHA 

### 27

PEL was used for comparison. Conce ntrations measured by personal samples ranged from 2 to 6 μg/m 3

, 

### 28

and concentrations from area samples ranged from 4 to 14 μg/m 3 . The OSHA PEL is 5 μg/m 3

. In steel 

### 29

production, sintering was found to be the largest source of airborne Pb exposure in a survey of operations 

### 30May 2011 4

- 17 DRAFT

– DO NOT CITE OR QUOTE ( Sammut et al., 2010 ) , with Pb enrichment in PM reported to be 20,000 mg/kg, although total PM 

### 1

concentration, reported to have 75% below 2.5 μm diameter, was not reported. 

### 2

Operations involving PM in various industries are a source of occupational Pb ex posure, in 

### 3

addition to a residential exposure. Rodrigues et al. ( 2010 ) reported exposures to airborne Pb among New 

### 4

England painters, who regularly use electric grinders to prepare surfaces for painting. Two

- week averaged 

### 5

airborne Pb concentrations, sampled with a n Institute of Medicine inhalable PM sampler designed to 

### 6

capture PM smaller than 100 μm, were reported to be 59 μg/m 3 , with a maximum daily value of 210 

### 7

μg/m 3 . The Pb concentrations reported here were corrected by the National Institute for Occupational 

### 8

Sa fety and Health (NIOSH) respirator protection factors, although the respirator protection factors were 

### 9

not reported by Rodrigues et al. ( 2010 ) . Information on the air Pb

- blood Pb relationship can be found in 

### 10

Section 4.5.1. Nwajei and Iwegbue ( 2007 ) measured Pb contamination in sawdust; such contamination 

### 11

has been reported to occur when trees are gro wn in soil contaminated with Pb ( Andrews et al., 1989 )

. 

### 12

Sawdust samples from fifteen locations in Nigerian sawmills were reported to hav e Pb concentrations 

### 13

ranging from 2.0 to 250 mg/kg. 

### 14

4.1.1.5. Exposure to Lead from Consumer Products

Pb is present in varying amounts in several consumer products including alternative medicines, 

### 15

candies, cosmetics, pottery, tobacco, toys, and vitamins (Table 4

- 6). Several of these categories suggest 

### 16

children may incur regular exposures. Pb concentrations were reported to range from non

- detectable 

### 17

levels up to 77% by mass, for the case of one medicinal product. Exposure to these products, which 

### 18

originate in a range o f different countries, can account for substantial influence on Pb body burden ( Levin 

### 19

et al., 2008 ; Miodovnik & Landrigan, 2009 )

. 

### 20May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 6. Pb content in various consumer products

Product Category Product Location of
Purchase Pb Content (units) Reference

Alternative and Traditional Medicines Cissus quadrangularis, Caulophyllum thalictroides, Turnera diffusa, Centella asiatica, Hoodia gordonii, Sutherlandia frutescens, Curcuma longa, fucoxanthin, Euterpe oleracea (dietary supplements claimed to be from Hoodia gordonii ) U.S. (Mississippi) a Not detected (N.D.)

- 4.21 mg/kg Avula et al ( 2010 )

Malva sylvestris Turkey 1.1

- 2.0 mg/kg Hiçsömnez et al ( 2009 ) Yugmijihwang

- tang, Bojungigki

- tang, Sibjeondaebo

tang, Kuibi

- tang, Ojeogsan Korea 7.9 × 10 - 6 to 2.5 × 10 - 5 mg/kg body weight/d ay Kim et al ( 2009 )

Lemongrass, licorice, holy basil, cloves, ginger India Average: Lemongrass & Holy Basil Leaves: 6.1 mg/kg; Licorice Stolons: 6.1 mg/kg, Clove Dried Flower Buds: 7.8 mg/kg, Ginger Rhizome: 5.8 mg/kg Naithani and Kakkar ( 2006 )

B

- Success 28, Operat ion Sweep, Aloe Vera Plus Bitter Aloes, Zarausmacine, Virgy

- Virgy Computer Worm

- Expeller, Dorasine Powder, Sexual Energy, U&DEE Infection Cleansing Powder, U&DEE Sweet Bitter, Natural Power Stone, Charma Black Stone, Portugal Antiseptic Soap, Edysol Antise ptic Soap, H

- Nal, M

- Reg, Veins Flocher, Diabor, C

- Candi, C

- Cysta, Firas, D

- Diab, P

- Pile, Infecta, Ribacin Forte, Aloe Vera Cure Formula Nigeria 925

- 27,000 μ g Obi et al ( 2006 )

Shell of Hen’s Egg India 14 mg/kg Sharma et al ( 2009 )

Berberis ( B. aristata, B. chitria, B. asiatica, B. lyceum ), Daruharidra India Berberis: Roots: 3.1

- 24.7 mg/kg Stems: 8.0

- 23.8 mg/kg Daruharidra: 16.9

- 49.8 mg/kg Srivastava et al ( 2006 )

Gre t a po wder U.S. (California) 770,000 ppm CDC ( 2002 )

Candy Tamarind Candy U.S. (Oklahoma) Product: 0.15

- 3.61 mg/kg Stems: 0.36

- 2.5 mg/kg Wrappers: 459

- 27,125 mg/kg Lynch et al ( 2000 )

Tamarind Candy U.S. (California) Product: 0.2

- 0.3 mg/kg Stems: 400 mg/kg Wrappers: 16,000

- 21,000 mg/kg CDC ( 2002 )

Cosmetics Lipsticks U.S. Average: 1.07 mg/kg Hepp et al ( 2009 )
Eye Shadows Nigeria N.D.

- 55 mg/kg Omolaoye et al ( 2010a )
Pottery Foods prepared in Pb

- glazed pottery Mexico N.D.

- 3,100 mg/kg Villalobos et al ( 2009 )

Tobacco Smokeless Tobacco United Kingdom 0.15

- 1.56 mg/kg McNeill et al ( 2006 )
Cigarette Tobacco ( 210 Pb concentrations) Pakistan Activity conc.: 7

- 20 Bq/kg Tahir and Alaamer ( 2008 )

Toys Red and yellow painted toy vehicles and tracks Brazil 500

- 6,000 mg/kg Godoi et al ( 2009 )

535 PVC and non

- PVC toys from day care centers U.S. (Nevada) PVC: avg. 325 mg/kg Non

- PVC: avg. 89 mg/kg Yellow: 216 mg/kg Non

- yellow: 94 mg/kg Greenway and Gerstenberger ( 2010 )

Soft plastic toys India Average (by city): 21

- 280 mg/kg Kumar and Pastore ( 2007 ) Toy necklace U.S. 388,000 mg/kg Meyer et al ( 2008 )
Soft plastic toys Nigeria 2.5

- 1,445 mg/kg Omolaoye et al ( 2010b )

Vitamins Vitamins for young children, older children, and pregnant or lactating women U.S. Average: Young children: 2.9 μg/day Older children: 1.8 μg/d ay Pregnant and lactating women: 4.9 μg/day Mindak et al. ( 2008 )

a Hoodia gordonii

, from Eastern Cape, South Africa Euterpe olerace a from Ninole Orchard, Ninole, HawaiiMay 2011 4

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– DO NOT CITE OR QUOTE 

# 4.2. Kinetics

This section summarizes the empirical bases for our understandin g of Pb toxicokinetics in humans. 

### 1

The large amount of empirical information on Pb biokinetics in humans and animal models has been 

### 2

integrated into mechanistic biokinetics models ( U.S. EPA, 2006 ) . These models support pred ictions about 

### 3

the kinetics of Pb in blood and other selected tissues based on the empirically

- based information about Pb 

### 4

biokinetics. In S ection 4. 3 , Pb biokinetics is described from the con text of model predictions. 

### 5



## 4.2.1. Absorption

The focus of the following s ections within absorption is on inhalation and ingestion because these 

### 6

are the major exposure routes of Pb in humans. The 2006 AQCD also presented dermal absorption of 

### 7

inorganic and organic Pb compounds, which is generally considered to be much less than b y inhalation or 

### 8

ingestion. No recent literature has advanced our knowledge of dermal absorption of Pb beyond that which 

### 9

was included in the 2006 AQCD. No additional information provides evidence of dermal absorption being 

### 10

a major exposure route of environm ental Pb. 

### 11

The term absorption refers to the fraction of the amount of Pb ingested or inhaled that is absorbed 

### 12

from the respiratory or gastrointestinal tract . The term bioavailability, as it is used in this section, refers to 

### 13

the fraction of the amount of P b ingested or inhaled that enters the systemic circulation. If properly 

### 14

measured (e.g., time

- integrated blood Pb), under most conditions Pb bioavailability is equivalent (or 

### 15

nearly equivalent) to Pb absorption. Bioaccessibility is a measure of t he physiolo gical solubility of Pb in 

### 16

the respiratory or gastrointestinal tract. Pb must become bioaccessible in order for absorption to occur. 

### 17

Processes that contribute to bioaccessibility include physical transformation of Pb particles and 

### 18

dissolution of Pb compound s into forms that can be absorbed (e.g., Pb 2+ ). 

### 19

4.2.1.1. Inhalation

Systemic absorption of Pb deposited in the respiratory tract is influenced by particle size and 

### 20

solubility, as well as by the pattern of regional deposition within the respiratory tract. Fine parti cles (<1 

### 21

μm) deposited in the bronchiolar and alveolar region can be absorbed after extracellular dissolution or can 

### 22

be ingested by phagocytic cells and transported from the respiratory tract ( Bailey & Roy, 1994 ) . Larger 

### 23

particles (>2.5 μm) that are primarily deposited in the ciliated airways (nasopharyngeal and 

### 24

tracheobronchial regions) can be transferred by mucociliary transport into the esophagus and swallowed, 

### 25

thu s being absorbed via the gut

. 

### 26

Inhaled Pb lodging deep in the respiratory tract seems to be absorbed equally and totally, regardless 

### 27

of chemical form ( Chamberlain et al., 1978 ; Morrow et al., 1980 ; M. B. Rabinowitz et al., 1977 )

. 

### 28

Absorption half

- times ( t 1/2 ) have been estimated for radon decay progeny in adults who inhaled aerosols 

### 29May 2011 4

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– DO NOT CITE OR QUOTE of Pb and bismuth isotopes generated from decay of 220 Rn or 222 Rn. The absorption half

- time f or Pb from 

### 1

the respiratory tract to blood was estimated to be approximately 10 h ours in subjects who inhaled aerosols 

### 2

having an activity median particle diameter of approximately 160 nm (range 50

- 500 nm) ( Marsh & 

### 3

Birchall, 1999 ) , and approximately 68 min for aerosols having diameters of approximately 0.3

– 3 nm 

### 4

( Butterweck et al., 2002 ) . Given the submicron particle size of the exposur e, these rates are thought to 

### 5

represent, primarily, absorption from the bronchiolar and alveolar regions of the respiratory tract. 

### 6

Several studies have attempted to quantify the bioavailability of Pb in atmospheric PM , although 

### 7

different laboratory techniq ues are used throughout the literature, as described in S ection 3.4. Unlike the 

### 8

bioavailability methods described in Section 4.2.1.2, many of these in vitro assays have not been 

### 9

validated with in vivo models. Therefore, any in vitro method can only be a simplistic surrogate of the 

### 10

complex uptake of Pb from the gastrointestinal (GI) tract. Despite this limitation, the studies mentioned 

### 11

below are the only ones to evaluate atmospheric Pb. 

### 12

In a study of PM 10 and PM 2.5 samples from downtown Vienna, Austria, Falta et al. ( 2008 ) used 

### 13

synthetic gastric juice to investigate the bioavailability of heavy metals including Pb. The rat ionale was 

### 14

that inhaled PM in the 2.5

- 10 μm size range are mostly deposited in the tracheal and bronchial regions of 

### 15

the lung from where they are transported within hours by mucociliary clearance, i.e.

, they are mainly 

### 16

swallowed. In contrast, the <2.5 μm p articles are deposited in the pulmonary alveoli where they can stay 

### 17

for months to years. The study aimed to determine the bioavailability of the 2.5

- 10 μm PM . It is important 

### 18

to note that they do not isolate the 2.5

- 10 μm size range; instead, they infer th e characteristics from the 

### 19

difference between the PM 2.5 and PM 10 fractions. The Pb concentrations associated with the two fractions 

### 20

were almost identical

, as was the percentage extracted by synthetic gastric juice (86% and 83% Pb for 

### 21

PM 2.5 and PM 10 fractio ns, respectively). The mean daily bioavailable mass was calculated to be 16 ng for 

### 22

the PM 2.5

- 10 size range. Since the quantitative clearance of these particles to the stomach was assumed, 

### 23

this value represents an upper estimate for the amount of bioavailab le Pb. Niu et al. ( 2010 ) determined the 

### 24

bioavailability of Pb fine (100

- 1,000 nm) and ultrafine

- sized (<100 nm) urban airborne PM from two sites 

### 25

within the city of Ott a wa, Canada. For all size fractions, the median Pb concentrations for PM smaller 

### 26

than 10 μm were 8,800 and 7,800 mg/kg for the two different loc ations. The bioavailability was based on 

### 27

ammonium acetate extractability and it was found that, within the fine and nano

- size ranges, 13

- 28% Pb 

### 28

was extracted. The Falta et al. ( 2008 ) and Niu et al. ( 2010 ) results illustrate that different extraction 

### 29

techniques result in different bioavailable fractions. The main finding from Niu et al. ( 2010 ) was that the 

### 30

highest values (~28% and ~19% for the two different locations) were found for the <57 nm PM

, with 

### 31

percent bioavailability decreasing with increasing PM size. This indicat ed that Pb was p otentially most 

### 32

bioavailable in the nano

- size range. 

### 33

A recent study by Barrett et al. ( 2010 ) investigated the solid phase speciation of Pb in urban road 

### 34

dust in Manchester, UK, and considered the health implications of inhalation and ingestion of such 

### 35

material. Human exposure via inhalation is likely to involve only the finest grained fractions (up to 10 

### 36May 2011 4

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– DO NOT CITE OR QUOTE μm) and unfortunately this study charact eri z ed only the <38 μm fraction. Pb

- goethite and PbCrO 4 

### 1

comprised the largest fractions, 45% and 21% respectively, of Pb in the <38 μm fraction. These forms 

### 2

tend to be less bioavailable if ingested compared with PbO or Pb

- acetate because they are less soluble. 

### 3

Organic Lead

Alkyl Pb compounds can exist in ambient air as vapors

. Inhaled tetraalkyl Pb vapor is nearly 

### 4

completely absorbed following dep osition in the respiratory tract . As reported in the 2006 AQCD, a single 

### 5

exposure to vapors of radioactive ( 203 Pb) tetraethyl Pb resulted in 37% initially deposited in the 

### 6

respiratory tract, of which ~20% was exhaled in the subsequent 48 h ours ( Heard et al., 1979 )

. In a similar 

### 7

experiment conducted with 203 Pb tetramethyl Pb, 51% of the inhaled 203 Pb dose was initially deposited in 

### 8

the respiratory tract, of which ~40% was exhaled in 48 h ours ( Heard et al., 1979 )

. 

### 9

Estimation of bioavailability of organic Pb is relevant to some aviation fuel exposures (i.e., piston



### 10

engine aircraft). Mahaffey ( 1977 ) estimated that 40% of inhaled Pb is bioavailable to adults. Chamberlain 

### 11

et al. ( 1975 ) suggested that 35% of inhaled combustion products of tetraethyl 203 Pb fuel are deposited and 

### 12

then retained in adult lungs with a half

- life of 6 hours. Fifty percent of that 203 Pb was detectable in the 

### 13

blood within 50 hour s of inhalation, and the rest was found to deposit in bone or tissue. Chamberlain et al. 

### 14

( 1975 ) estimated that continuous inhalation of Pb at a concentration of 0.001 μg/m 3 could produce a 1 

### 15

μg/dL increment in blood Pb. 

### 16

4.2.1.2. Ingestion

The extent and rate of G I absorption of ingested inorganic Pb are influenced by physiological states 

### 17

of the exposed indiv idual (e.g., age, fasting, nutritional calcium and iron status, pregnancy) and 

### 18

physicochemical characteristics of the Pb

- bearing material ingested (e.g., particle size, mineralogy, 

### 19

solubility). Pb absorption in humans may be a capacity

- limited process, in which case the percentage of 

### 20

ingested Pb that is absorbed may decrease with increasing rate of Pb intake. Numerous observations of 

### 21

nonlinear relationships between blood Pb concentration and Pb intake in humans provide support for the 

### 22

likely existence of a saturable absorption mechanism or some other capacity

- limited process in the 

### 23

distribution of Pb in humans ( Pocock et al ., 1983 ; J. Sherlock et al., 1982 ; J. C. Sherlock et al., 1984 ; J. C. 

### 24

Sherlock & Quinn, 1986 ) . While evidence for capacity

- limited processes at the level of the intestinal 

### 25

epithelium is compelling, the dose at which absorption becomes appreciably limited in humans is not 

### 26

known. 

### 27

In adults, estimates of absorption of ingested water

- soluble Pb compounds (e.g., Pb chloride, Pb 

### 28

nitrate, Pb

- acetate ) range from 3 to 10% in fed subjects ( Heard & Chamberlain, 1982 ; James et al., 1985 ; 

### 29

Maddaloni et al., 1998 ; M. B. Rabinowitz et al., 1980 ; Watson et al., 1986 ) . The absence of food in the GI 

### 30

tract in creases absorption of water

- soluble Pb in adults. Reported estimates of soluble Pb absorption range 

### 31May 2011 4

- 22 DRAFT

– DO NOT CITE OR QUOTE from 26 to 70% in fasted adults ( Blake et al., 1983 ; Heard & Chamberlain, 1982 ; James et al., 1985 ; 

### 1

Maddaloni et al., 1998 ; M. B. Rabinowitz et al., 1980 ) . Reported fed:fasted ratios for soluble Pb 

### 2

absorption in adults range from 0.04 to 0.2 ( Bla ke et al., 1983 ; Heard & Chamberlain, 1982 ; James et al., 

### 3

1985 ; M. B. Rabinowitz et al., 1980 )

. 

### 4

Limited evidence demonstrates that GI absorption of water

- soluble Pb is higher in children than in 

### 5

adults. Estimates derived from dietary balance studies conducted in infants and children (ages 2 weeks to 

### 6

8 years) indicate that ~ 40

- 50% of ingest ed Pb is absorbed ( Alexander et al., 1974 ; Ziegler et al., 1978 )

. 

### 7

Experimental studies provide further evidence for greater absorption of Pb from the gut in young animals 

### 8

compared to adult animals ( Aungst et al., 1981 ; Forbes & Reina, 1972 ; Kostial et al., 1978 ; Pounds et al., 

### 9

1978 ) . The mechanisms for an apparent age difference in GI absorption of Pb have not been completely 

### 10

elucidated and may include both physiological and dietary factors ( Mushak, 1991 )

. 

### 11

Nutritional deficiencies have also been linked to Pb absorption in the GI tract, particularly in 

### 12

children. Children who are iron

- deficient have higher blood Pb concentrations than similarly exposed 

### 13

iron

- replete children, suggesting that iron deficiency may result in higher Pb absorption or, possibly, other 

### 14

changes in Pb biokinetics that contribute to altered blood Pb concentrations ( Mahaffey & Annest, 1986 ; 

### 15

Marcus & Schwartz, 1987 ; Schell et al., 2004 ) . Studies conducted in animal models have provided direct 

### 16

evidence for interactions between iron deficiency and increased Pb absorption , perhaps by enhancing 

### 17

binding of Pb to iron

- binding proteins in the intestine ( Bannon et al., 2003 ; Barton, Conrad, Nuby, et al., 

### 18

1978 ; Morrison & Quarterman, 1987 )

. 

### 19

The effects of iron nutritional status on blood Pb in clude changes in blood Pb concentrations in 

### 20

association with genetic variation in genes involved in iron metabolism. For example, genetic variants in 

### 21

the hemochromatosis (HFE) and transferrin genes are associated with higher blood Pb concentrations in 

### 22

chil dren ( Hopkins et al., 2008 ) . In contrast, HFE gene variants are associated with lower bone and blood 

### 23

Pb levels in elderly men ( Wright et al., 2004 )

. 

### 24

Several studies have suggested that dietary calcium may have a protectiv e role against Pb by 

### 25

decreasing absorption of Pb in the GI tract and by decreasing the mobilization of Pb from bone stores to 

### 26

blood. In experimental studies of adults, absorption of a single dose of Pb (100

- 300 μg Pb chloride) was 

### 27

lower when the Pb was ing ested together with calcium carbonate (0.2 g calcium carbonate) than when the 

### 28

Pb was ingested without additional calcium ( Blake & Mann, 1983 ; Heard & Chamberlain, 1982 ) . A 

### 29

similar effect of calcium occurs in rats ( Barton, Conrad, Harrison, et al., 1978 ) . Similarly, an inverse 

### 30

relationship was observed between dietary calcium intake and blood Pb concentration in children, 

### 31

suggesting that children who are calcium

- deficient may absorb more Pb than calcium

- replete children 

### 32

( Elias et al., 2007 ; Mahaffey et al., 1986 ; Schell et al., 2004 ; Ziegl er et al., 1978 ) . These observations 

### 33

suggest that calcium and Pb share and may compete for common binding and transport mechanism s in the 

### 34

small intestine which are regulated in response to dietary calcium and calcium body stores ( Bronner et al., 

### 35

1986 ; Fullmer & Rosen, 1990 ) . However, animal studies have also shown that multiple aspects of Pb 

### 36May 2011 4

- 23 DRAFT

– DO NOT CITE OR QUOTE toxicokinetics are affected by calcium nutritional status. For example, feeding rats a calcium deficient diet 

### 1

is associated with increased Pb absorption, decreased whole body Pb clearance, and increased volume of 

### 2

distribution of Pb ( Aungst & Fung, 1985 )

. These studies suggest that associations between calcium 

### 3

nutrition and blood Pb that have been observed in human populations may not be solely attributable to 

### 4

effects of calcium nutrition on Pb absorption. Other pot ential mechanisms by which calcium nutrition 

### 5

may affect blood Pb and Pb biokinetics include effects on bone mineral metabolism and renal function. 

### 6

Blood Pb concentrations in young children have also been shown to increase in association with 

### 7

lower dietary Zn levels ( Schell et al., 2004 )

. Mechanisms for how Zn a ffect s blood Pb concentration

, i.e.

, 

### 8

whether it involves changes in absorption or changes in distribution and/or elimination of Pb

, have not 

### 9

been determined. 

### 10

Dissolution of Pb from the soil/mineralogical matrix in the stomach appears to be the major process 

### 11

that renders soil Pb bioaccessibl e for absorption in the GI tract. Relative bioavailability (RBA) of Pb in 

### 12

soils and dust has been most extensively studied in animal models. Relative bioavailability is the ratio of 

### 13

the absorbed fraction (AF) of ingested dose of soil Pb to that of a water

- soluble form of Pb (e.g., Pb



### 14

acetate ) that is considered to be completely bioaccessible (e.g., RBA = AF Soil Pb /AF Pb

- acetate ). In typical 

### 15

studies, the absorbed fraction of the Pb dose is estimated based measurements of Pb measured in blood 

### 16

and/or other tiss ues (e.g., kidney, liver, bone) after dosing . Gastric function of swine is thought to be 

### 17

sufficiently similar to that of humans to justify use of swine as a model for assessing RBA of Pb in soils 

### 18

( Casteel et al., 1997 ; Casteel et al., 2006 ; Juhasz et al., 2009 ; U.S. EPA, 2007a ; Weis & Lavelle, 1991 )

. 

### 19

Other practical advantages of the swine model over rodent models have been described

, and include : 

### 20

absence of coprophagia ; ease with which Pb dosing can be administered and controlled ; and higher 

### 21

bioavailability of soluble Pb (e.g., Pb

- acetate) in swine, which is more similar to humans than rats ( D. M. 

### 22

Smith et al., 2009 )

. Relative bioavailability of Pb has been shown to vary depending upon the Pb 

### 23

mineralogy and physical characteristics of the Pb in the soil (e.g.

, encapsulated or exposed) and size of the 

### 24

Pb

- bearing grains. G I absorption of larger Pb

- containing particles (>100 μm) tends to be lower than 

### 25

smaller particles ( Barltrop & Meek, 1979 ; Healy et al. , 1992 )

. 

### 26

Collectively, published studies conducted in swine have provided 39 estimates of Pb RBA for 37 

### 27

different soil or “ soil

- like ” test materials ( Bannon et al., 2009 ; Casteel et al., 2006 ; Marschner et al., 2006 ; 

### 28

D. M. Smith et al., 2009 ) . The mean of RBA estimates from 25 soils is 49% ( ± 29 [SD ] ), median is 51%, 

### 29

and 5 th to 95 th percentile range is 12 to

- 89%. RBA estimates for soils collected from 8 firing ranges were 

### 30

approximately 100% ( Bannon et al., 2009 ) . The relatively high RBA for the firing range soils may reflect 

### 31

the high abundance of relatively un

- encapsulate d Pb carbonate (30

- 90% abundance) and Pb oxide (1

- 

### 32

60%) in these soils. Similarly, a soil sample (low Pb concentration) mixed with a NIST paint standard 

### 33

(55% Pb carbonate, 44% Pb oxide) also had a relatively high bioavailability (72% ) ( Casteel et al., 2006 )

. 

### 34

Samples of smelter slag, or soils in which the dominant source of Pb was smelter slag, had relati vely low 

### 35May 2011 4

- 24 DRAFT

– DO NOT CITE OR QUOTE RBA (14

- 40%, n = 3)

, as did a sample from a mine tailings pile (RBA = 6%), and a sample of finely 

### 1

ground galena mixed with soil ( Casteel et al., 2006 )

. 

### 2

Based on data for 18 soil materials assayed in swine, RBA of Pb mineral phases were categorized 

### 3

into “ low ” (<0.25 [25%] ), “ medium ” (0.25

- 0.75 [25 to 75%] ), and “ high ” (>0.75 [75%] ) categor ies 

### 4

( Casteel et al., 2006 )

. Figure 4

- 2 shows some of the materials that fall into these three cate gories. Mineral 

### 5

phases observed in mineralogical wastes can be expected to change over time (i.e., weathering), which 

### 6

could change the RBA over time. The above observations in swine are supported by various studies 

### 7

conducted in rats that have found RBA of Pb in soils to vary considerably and to be less that 100% 

### 8

( Freeman et al., 1996 ; Freeman et al., 1992 ; Freeman et al., 1994 ; D. M. Smith et al., 2008

, 2009 )

. 

### 9

Source: Casteel et al. ( 2006 )

. Figure 4

- 2

. Estimated relative bioavailability (RBA, compared to Pb

acetate ) of ingested Pb in mine ral groups, based on results from juvenile swine assays.

Drexler and Brattin ( 2007 ) developed an in vitro bioaccessibility (IVBA) assay for soil Pb that 

### 10

utilizes extraction fluid comprised of glycine, deionized water, and hydrochloric acid at a pH of 1.50 that 

### 11

is combined with sieved test material (<250 μm) for 1 hour. The assay was tested for predictin g in vivo 

### 12

RBA of 18 soil

- like test materials that were assayed in a juvenile swine assay ( Casteel et al., 2006 ) . A 

### 13

regression model relating IVBA and RBA was derived based on these data (Equation 4

- 1): 

### 14May 2011 4

- 25 DRAFT

– DO NOT CITE OR QUOTE RBA = (0.878 • IVBA)

– 0.028 

### 1

Equation 4

- 1

where RBA and IVBA are expressed as fractions (i.e., not as percent ). The weighted r 2 for the relationship 

### 2

(weighted for error in the IVBA and RBA estimates) was 0.924 (p<0.001). The IVBA assay reported in 

### 3

Drexler and Brattin ( 2007 ) has been identified by the U.S. EPA as a validated method for predicting RBA 

### 4

of Pb in soils for use in risk assessment ( U.S. EPA, 2007b ) . A review of soil Pb RBA estimates made 

### 5

using the IVBA assay described above and Equation 4

- 1 identified 270 estimates of Pb RBA in soils 

### 6

obtained from 11 hazardous waste sites. The mean for the site

- wide RBA estimates ( n = 11 sites) was 57% 

### 7

(SD 15), median was 63%, and 5 th to 95 th percentile range was 34 to 71%. 

### 8

Equation 4

- 1 cannot be reliably extrapolated to other in vitro assays that have been developed for 

### 9

estimating Pb bioaccessibility without validation against in vivo RBA measurements ma de on the same 

### 10

test materials. Comparisons of outcomes of in vitro assay s applied to the same soil test materials have 

### 11

found considerable variability in IVBA estimates ( Saikat et al., 2007 ; Van de Wiele et al., 2007 ) . This 

### 12

variability has been attributed to differences in assay conditions, including pH, liquid:soil ratios, inclusion 

### 13

or absence of food material, and differences in methods used to separate dissolved and particle

- bound Pb 

### 14

(e.g., centrifugation v ersu s filtration). Given the dependence of IVBA outcomes on assay conditions, in 

### 15

vitro assays used to predict in vivo RBA should be evaluated against in vivo RBA estimates to 

### 16

quantitatively assess uncertainty in RBA predictions ( U.S. EPA, 2007b )

. 

### 17

Absorption of Pb in house dusts has not been rigorously evaluated quantitatively in humans or in 

### 18

experimental animal mode ls. The RBA for paint Pb mixed with soil has been reported to be 

### 19

approximately 72% (95% CI: 44

, 98) in juvenile swine, suggesting that paint Pb dust maybe highly 

### 20

bioavailable ( Casteel et al., 2006 ) . The same material yielded a bioaccessibility value (based on IVBA 

### 21

assay) of 75% ( Drexler & Brattin, 2007 ) , which corresponds to a predicted RBA of 63%, based on 

### 22

Equation 4

- 1. A review of indoor Pb RBA estimates made usi ng the IVBA assay and Equation 4

- 1 

### 23

identified 100 estimates of Pb RBA in dusts obtained from two hazardous waste sites. Mean Pb RBAs for 

### 24

the Herculaneum site were 47% (SD 7, 10 samples) for indoor dust and 69 % (SD 3, 12 samples) for soil. 

### 25

At the Omaha site , mean Pb RBAs were 73% (SD 10, 90 samples) for indoor dust and 70% (SD 10, 45 

### 26

samples) for soil. Yu et al. ( 2006 ) applied an IVBA method to estimate bioaccessibility of Pb in house 

### 27

dust samples collected from 15 urban homes. Homes were sele cted for inclusion in this study based on 

### 28

reporting to the state department of health of at least on child with a blood Pb concentration >15 μg/dL 

### 29

and Pb paint dust may have contributed to indoor dust Pb. The mean IVBA was 64.8% (SD 8.2, age: 52.5 

### 30

to 77.2 months ). 

### 31

The above results, and the IVBA assays used in studies of interior dust, have not been evaluated 

### 32

against in vivo RBA estimates for dust samples. Although, expectations would be that a validated IVBA 

### 33

methodology for soil would perform well for pre dicting RBA of interior dust, this has not actually been 

### 34May 2011 4

- 26 DRAFT

– DO NOT CITE OR QUOTE experimentally confirmed. Factors that may affect in vitro predictions of RBA of interior dust Pb could 

### 1

include particle size distribution of interior dust Pb and the composition of the dust matrix, which may be 

### 2

quite different from that of soil. 

### 3

Other estimates of “bioavailability” of Pb exposure samples are derived from less validated in vitro 

### 4

methods. Roussel et al. ( 2010 ) estimated that 63% of soil Pb is bioavailable in the stomach, while 39% is 

### 5

bioavailable in the intestines, using different acidities of solutions to simulate acids in the digestive 

### 6

system. Yu et al. ( 2006 ) dissolved Pb dust, obtained from vacuuming carpet samples, in to simulated 

### 7

gastric and intestinal acids. The carpet samples were obtained from homes located in northern New 

### 8

Jersey. Pb concentration in carpet ranged from 209 to 1,770 mg/kg dust, with 52

- 77% of Pb dissolving in 

### 9

simulated gastric acid and 5

- 32% dissolvi ng in simulated intestinal acids. In a similar test in the U.K., 

### 10

Turner and Simmonds ( 2006 ) observed median Pb dust concentrations of 178 mg/kg with approximately 

### 11

80% bioavailability in simulated gastric acid. Jin et al. ( 2005 ) observed that bioaccessibility of Pb in soil 

### 12

was proportional to the soil acidity and organic matter conte nt of the soil. 

### 13



## 4.2.2. Distribution

A simple conceptual representation of Pb distribution is that it contains a fast turnover pool, 

### 14

comprising mainly soft tissue, and a slow pool, comprising mainly skeletal tissues ( M. B. Rabinowitz et 

### 15

al., 1976 )

. The highest soft tissue concentrations in adults occur in liver and kidney cortex ( Barry, 1975 ; 

### 16

Gerhardsson et al., 1986 ; Gerhardsson et al., 1995 ; Gross et al., 1975 ; Oldereid et al., 1993 )

. Pb in blood 

### 17

(i.e., plasma) exchanges with both of these compartments. 

### 18

4.2.2.1. Blood

Blood comprises ~1% of total Pb body burden. Pb in blood is found primarily (>99%) in the RBC s 

### 19

( Ber gdahl, Grubb, et al., 1997 ; Bergdahl et al., 1998 ; Bergdahl et al., 1999 ; Hernandez

- Avila et al., 1998 ; 

### 20

Manton et al., 2001 ; Schutz et al., 1996 ; D. Smith et al., 2002 ) . δ

- aminolevulinic acid dehydratase 

### 21

(ALAD) is the primary binding ligand for Pb in erythrocytes ( Bergdahl, Grubb, et al., 1997 ; Bergdahl et 

### 22

al., 19 98 ; Sakai et al., 1982 ; Xie et al., 1998 ) . Two other Pb

- binding proteins have been identified in the 

### 23

RBC , a 45 kDa protein (K

max 700 μg/dL; K d 5.5 μg/L) and a smaller protein(s) having a molecular weight 

### 24

<10 kDa ( Bergdahl, Grubb, et al., 1997 ; Bergdahl et al., 1996 ; Bergdahl et al., 1998 ) . Of the three 

### 25

principal Pb

- binding proteins identified in RBCs , ALAD has the strongest affinity for Pb ( Bergdahl et al., 

### 26

1998 ) and appears to dominate the ligand distribution of Pb (35 to 84% of total erythrocyte Pb) at blood 

### 27

Pb levels below 40 μg/dL ( Bergdahl et al., 1996 ; Bergdah l et al., 1998 ; Sakai et al., 1982 ) . Pb binding to 

### 28

ALAD is saturable; the binding capacity has been estimated to be ~850 μg/dL RBCs (or ~40 μg/dL whole 

### 29

blood) and the apparent dissociation constant has been estimated to be ~1.5 μg/L ( Bergdahl et al., 1998 )

. 

### 30May 2011 4

- 27 DRAFT

– DO NOT CITE OR QUOTE Saturable binding to RBC proteins contributes to an increase in the plasma/blood Pb ratio with 

### 1

increasing blood Pb concentratio n and curvature to the blood Pb

– plasma Pb relationship ( Barbosa, 

### 2

Ramires, et al., 2006 ; Bergdahl, Schut z, et al., 1997 ; Bergdahl et al., 1998 ; Bergdahl et al., 1999 ; DeSilva, 

### 3

1981 ; C. Jin et al., 2008 ; K ang et al., 2009 ; Manton et al., 2001 ; D. Smith et al., 2002 ) . An example of this 

### 4

is shown in Figure 4

- 3

. Saturable binding of Pb to RBC proteins has several important consequences. As 

### 5

blood Pb increases and the higher affinity binding sites for Pb in RBC s become saturated at 

### 6

approximately 40 μg/dL blood , a larger fraction of the blood Pb is available in plasm a to distribute to 

### 7

brain and other Pb

- responsive tissues. This change in distribution of Pb contributes to a curvature in the 

### 8

relationship between Pb intake (at constant absorption fraction) and blood Pb concentration. 

### 9

Typically, at blood Pb concentration s <100 μg/dL, only a small fraction (<1%) of blood Pb is found 

### 10

in plasma ( DeSilva, 1981 ; Manton & Cook, 1984 ; Marcus, 1985 ) . However, as previously noted, plasma 

### 11

Pb may be the more biologically labile and toxicologically active fraction of the circulating Pb. 

### 12

Ap proximately 40

- 75% of Pb in the plasma is bound to proteins, of which albumin appears to be the 

### 13

dominant ligand ( Al

- Modhefer et al., 1991 ; Ong & Lee, 1980 )

. Pb in serum that is not bound to protein 

### 14

exists largely as complexes with low molecular weight sulfhydryl compounds (e.g., cys teine, 

### 15

homocysteine) and other ligands ( Al

- Modhefer et al., 1991 )

. 

### 16

Source: Adapted, with permission from Elsevier Publishing and the Finland Institute of Occupational Health, from Bergdahl et al. ( 1997 ; 1999 )

. Figure 4

- 3

. Plot of blood and plasma Pb concentrations in measured in
adults and ch ildren.

As shown in Figure 4

- 3, the limited binding capacity of Pb binding proteins in RBCs produces a 

### 17

curvilinear relationship between bloo d and plasma Pb concentrat ion. The l imited binding capacity of RBC 

### 18 

### 0.0 0.5 1.0 1.5 2.0

0 20 40 60 80 100Plasma Pb (μg/dL)



### Blood Pb ( μ g/dL) Adults ChildrenMay 2011 4

- 28 DRAFT

– DO NOT CITE OR QUOTE binding proteins also confers, or at least contributes, to a curvilinear relationship between Pb intake and 

### 1

blood Pb concentration

. A curvilinear relationship between Pb intake and blood Pb concentration has been 

### 2

ob served in children ( Lacey et al., 1985 ; Ryu et al., 1983 ; J. C. Sherlock & Quinn, 1986 ) . As shown in 

### 3

Figure 4

- 4, t he relationship becomes pseudo

- linear at relatively low daily Pb intakes (i.e., <10 μg/ day/ kg) 

### 4

an d at blood Pb concentrations < 25 μg/dL. 

### 5

Source: Adapted, with permission from Taylor & Francis Publishing, from Sherlock and Quinn ( 1986 )

. Figure 4

- 4

. Relationship between Pb intake and blood Pb concentration in infants ( n = 1 05, age 13 weeks, formula

- fed). Data represent mean and standard errors for intake; the line is the regression model (blood Pb = 3.9 + 2.43 (Pb intake [μg/week] 1/3 )

.

Figure 4

- 5 shows the predicted relationship between quasi

- steady state blood and plasma Pb 

### 6

concentrations in a 4

- year old chil d using the ICRP model ( ICRP, 1994 ; Leggett, 1993 ; Pounds & Leggett, 

### 7

1998 ) . The abrupt inflection point that occurs at approximately 25 μg/dL blood Pb is an artifact of the 

### 8

numerical approach to simulate the s aturation of binding using discontinuous first

- order rate constants for 

### 9

uptake and exit of Pb from the RBC. A continuous function of binding sites and affinity, using empirical 

### 10

estimates of both parameters, yield a similar but continuous curvature in the r elationship ( Bergdahl et al., 

### 11

1998 ; O'Flaherty, 1995 ) . Nevertheless, either approach predicts a pseudo

- linear relationship at blood Pb 

### 12

concentrations below approximately 25 μg/dL which, in this model, corresponds to an intake of 

### 13

ap proximately 100 μg/day (absorption rate ≈ 30 μg/day) (upper panel) . An important consequence of the 

### 14

limited Pb binding capacity of RBC proteins is that the plasma Pb concentration will continue to grow at 

### 15

a linear rate above the saturation point for RBC pr otein binding. One implication of this is that a larger 

### 16 0 5 10 15 20 25 30 35 40 45

0 100 200 300 400Blood Pb (μg/dL)



### Pb Intake ( μ g/day)May 2011 4

- 29 DRAFT

– DO NOT CITE OR QUOTE fraction of the Pb in blood will become available to distribute to brain and other Pb

- responsive tissues as 

### 1

blood Pb increases. This could potentially contribute to non

- linearity in dose

- response rela tionships in 

### 2

studies in which blood Pb is the used as the internal dose metric. 

### 3

Figure 4

- 5

. Simulation of quasi

- steady state blood and plasma Pb concentrations in a child (age 4 years) associated with varying Pb ingestion rates. S imulation based on ICRP Pb biokinetics
model ( Leggett, 1993 )

. 0.00 0.10 0.20 0.30 0.40 0.50 0.60

0 10 20 30 40 50Plasma Pb (μg/dL)

Blood Pb ( μg/dL )

0.0 0.2 0.4 0.6 0.8 1.0

0 10 20 30 40 50 60

0 100 200 300 400Plasma Pb (μg/dL)Blood Pb (μg/dL)

Intake ( μg/day ) Blood PlasmaMay 2011 4

- 30 DRAFT

– DO NOT CITE OR QUOTE Studies conducted in swine provide additional evidence in support of RBC binding kinetics 

### 1

influenc ing distribution of Pb to tissues. In these studies, the relationship between the ingested dose of Pb 

### 2

and tissue Pb concentrations (e.g., liver, kidney, bone) was linear, whereas, the relationship between dose 

### 3

and blood Pb was curvilinear with the slope de creasing as the dose increased ( Casteel et al., 2006 )

. 

### 4

Saturable binding of Pb to RBC proteins als o contributes to a curvilinear relationship between urinary Pb 

### 5

excretion and plasma Pb concentration (Section 4.2.3) ( Bergdahl, Schutz, et al., 1997 ; Besser et al., 2008 )

. 

### 6

4.2.2.2. Bone

The dominant compartment for Pb in the body is in bone. In human adults, 94% of the total body 

### 7

burden of Pb is found in the bones, whereas bone Pb accounts for 73% of the body burden in ch ildren 

### 8

( Barry, 1975 ) . Bone is comprised of two main types, cortical (or compact) and trabecular (or spongy or 

### 9

calcellous). The proportion of cortical to trabecular bone in the human body varies by age, but on average 

### 10

is about 80 to 20 ( ICRP, 1973 ; Leggett, 1993 ; O'Flaherty, 1998 )

. 

### 11

The exchange of Pb from plasma to the bone surface is a rapid process ( i.e., adult t 1/2 =0.19 and 

### 12

0.23 h ours for trabecular and cortical bone, respectively) ( Leggett, 1993 ) . Some Pb diffuses from the bone 

### 13

surface to deeper bone regions (adult t 1/2 = 150 days) where it is relatively inert (in adults) and part of a 

### 14

“ nonexcha n ge a ble ” pool of Pb in bone ( Legge tt, 1993 )

. 

### 15

Pb distribution in bone includes uptake into cells that populate bone (e.g., osteoblasts, osteoclasts, 

### 16

osteocytes) and exchanges with proteins and minerals in the extracellular matrix ( Pounds et al., 1991 ) . Pb 

### 17

forms highly stable complexes with phosphate and can replace calcium in the calcium

- phosphate salt, 

### 18

hydroxyapatite, which comprises the primary crystalline matrix of bone ( Brès et al., 1986 ; Miyake, 1986 ; 

### 19

Verbeeck et al., 1981 )

. Several intracellular kinetic pools of Pb have been described in isolated cultures of 

### 20

osteo blasts and osteoclasts which appear to reflect physiological compartmentalization within the cell, 

### 21

including membranes, mitochondria, soluble intracellular binding proteins, mineralized Pb (i.e., 

### 22

hydroxyapatite) and inclusion bodies ( Long et al., 1990 ; Pounds & Rosen, 1986 ; Rosen, 1983 )

. 

### 23

Approximately 70

- 80% of Pb taken up into isolated primary c ultures of osteoblasts or osteocytes is 

### 24

associated with mitochondria and mineralized Pb ( Pounds et al., 1991 )

. 

### 25

Pb accumulates in bone regions having the most active calcification at the time of exposure . Pb 

### 26

accumulation is thought to occur predominantly in trabecular bone during childhood and in both cortical 

### 27

and trabecular bone in adulthood ( Aufderheide & Wittmers, 1992 ) . Early Pb uptake in children is greater 

### 28

in trabecular bone due to its larger surface area and higher metabolic rate. With continued exposure, Pb 

### 29

concentrations in bone may increas e with age throughout the lifetime beginning in childhood , indicative 

### 30

of a relatively slow turnover of Pb in adult bone ( Barry, 1975 ; Barry & Connolly, 1981 ; Gross et al., 

### 31

1975 ; Park, Mukherjee, et al., 2009 ; Schroeder & Tipton, 1968 ) . The cortical and trabecular bones have 

### 32May 2011 4

- 31 DRAFT

– DO NOT CITE OR QUOTE distinct rates of turnover and Pb release. For example, tibia has a turnover rate of about 2% per year 

### 1

whereas trabecular bone has a turnover rate of more than 8% per year in adults ( M. B. Rabinowitz, 1991 )

. 

### 2

A high bone format ion rate in early childhood results in the rapid uptake of circulating Pb into 

### 3

mineralizing bone; however, bone Pb is also recycled to other tissue compartments or excreted in 

### 4

accordance with a high bone resorption rate ( O'Flaherty, 1995 ) . Thus, most of the Pb acquired early in life 

### 5

is not permanently fixed in the bone (60

- 65%) ( ICRP, 1973 ; Leggett, 1993 ; O'Flaherty, 1995 ) . However, 

### 6

some Pb accumulated in bone does persist into later life

. McNeill et al. ( 2000 ) compared tibia Pb levels 

### 7

and cumulative blood Pb indices in a population of 19

- to 29

- year

- olds who had been highly exposed to 

### 8

Pb in childhood from the Bunker Hill, Idaho smelter ; t hey concluded that Pb from exposure in early 

### 9

childhood had persisted in the bone matrix until adulthood. 

### 10

A key factor affecting Pb uptake into bone is the fraction of bone surface in trabecular and cortic al 

### 11

bone adjacent to active bone marrow. Of the total bone surface against red marrow, 76% is trabecular and 

### 12

24% is cortical endosteal ( Salmon et al., 1999 ) . The fraction of total bone marrow that is red and active 

### 13

decreases from 100% at birth to about 32% in adulthood ( Cristy, 1981 ) . However, bone marrow has much 

### 14

lower Pb concentrations than bone matrix ( Skerfving et al., 1983 )

. 

### 15

4.2.2.3. Soft Tissues

Most of the Pb in so ft tissue is in liver and kidney ( Barry, 1975 ; Gerhardsson et al., 1986 ; 

### 16

Gerhardsson et al., 1995 ; Gross et al., 1975 ; Oldereid et al., 1993 ) . Pb in these soft tissues (i.e., kidney, 

### 17

liver, and brain) exists predominantly bound to protein. High affinity cytosolic Pb

- binding proteins have 

### 18

been identified in rat kidney and brain ( DuVal & Fowler, 1989 ; Fowler, 1989 ) . The Pb

- binding proteins in 

### 19

rat are cleavage products of α2μ globulin, a member of the protein superfamily known as retinol

- binding 

### 20

proteins that are generally observed only in male rats ( Fowler & DuVal, 1991 ) . Other hig h

- affinity 

### 21

Pb

- binding proteins (K d ~14 nM) have been isolated in human kidney, two of which have been identified 

### 22

as a 5 kD a peptide, thymosin 4 and a 9 kD a peptide, acyl

- CoA binding protein ( D. R. Smith et al., 1998 )

. 

### 23

Pb also binds to metallothionein, but does not appear to be a sign ificant inducer of the protein in 

### 24

comparison with the inducers Cd and Zn ( Eaton et al., 1980 ; Waalkes & Klaassen, 1985 )

. 

### 25

The liver and kidneys rapidly accumulate systemic Pb (t 1/2 =0.21 and 0.41 h ou r s , respectively), 

### 26

which amounts to 10

- 15% and 15

- 20% of intravenously injected Pb, respectively ( Leggett, 1993 ) . A 

### 27

linear relationship in dose

- tissue Pb concentrations for kidney and liver has been demonstrated in swine, 

### 28

dogs, and rats ( Azar et al., 1973 ; Casteel et al., 1997 ; Casteel et al., 2006 ; D. M. Smith et al., 2008 ) . In 

### 29

contrast to Pb in bone, which accumulates Pb with continued exposure in adulthood, concentrations in 

### 30

soft tissues (e.g., liver and kidney) are relatively con stant in adults ( Barry, 1975 ; Treble & Thompson, 

### 31

1997 ) , reflecting a faster turnover of Pb in soft tissue relative to bone. 

### 32May 2011 4

- 32 DRAFT

– DO NOT CITE OR QUOTE 

### 4.2.2.4. Fetus

Evidence for maternal

- to

- fetal transfer of Pb in humans is derived from cord blood to maternal 

### 1

blood Pb rat ios. These ratios range from about 0.6 to 1.0 at the time of delivery ( Carbone et al., 1998 ; 

### 2

Goyer, 1990 ; Graziano et al., 1990 ; B. Gulson, Jameson, et al., 1998 ; Kordas et al., 2009 ; Manton, 1985 )

. 

### 3

In addition, the similarity of isotopic ratios in maternal blood and in blood and urine of newly

- born 

### 4

infants provide further evidence for placental trans fer of Pb to the fetus ( B. Gulson et al., 1999 )

. 

### 5

Transplacental transfer of Pb may be facilitated by an increase in the plasma/blood Pb 

### 6

concentration ratio during pregnancy ( Lamadrid

- Figueroa et al., 2006 ; Montenegro et al., 2008 )

. 

### 7

Maternal

- to

- fetal transfer of Pb appears to be related partly to the mobilization of Pb from the maternal 

### 8

skeleton. Evidence for transfer of maternal bone Pb to the fetus has been provided by stable Pb isotope 

### 9

studies in cynomolgus monkeys exposed during pregnancy . Approximately 7

- 39% of the maternal Pb 

### 10

burden transferred to the fetus was derive d from the maternal skeleton , with the remainder derived from 

### 11

contemporaneous exposure ( Franklin et al., 1997 ; O'Flaherty, 1998 )

. 

### 12

4.2.2.5. Organic Lead

Information on the distribution of Pb in humans following exposures to organic Pb is extremely 

### 13

limited . However, as reported in the 2006 AQCD, the available evidence demonstrates near complete 

### 14

absorption following inhalation of tetraalkyl Pb vapor and subsequent transformation to trialkyl Pb 

### 15

metabolites. One hour following brief inhalation exposures to 203 Pb tetraethyl or tetramethyl Pb (1 

### 16

mg/m 3 ), ~50% of the 203 Pb body burden was associated with liver and 5% with kidney; the remaining 

### 17

203 Pb was widely distributed throughout the body ( Heard et al., 1979 )

. The kinetics of 203 Pb in blood 

### 18

showed an initial declining phase during the first 4 h ou rs (tetramethyl Pb) or 10 h ours (tetraethyl Pb) after 

### 19

the exposure, f ollowed by a reappearance of radioactivity back into the blood after ~20 h ours . The high 

### 20

level of radioactivity initially in the plasma indicates the presence of tetraalkyl/trialkyl Pb

. T he 

### 21

subsequent rise in blood radioactivity, however, probably represents water

- soluble inorganic Pb and 

### 22

trialkyl and dialkyl Pb compounds that were formed from the metabolic conversion of the volatile parent 

### 23

compounds ( Heard et al., 1979 )

. 

### 24

Alkyl Pb compounds undergo oxidative dealkylation catalyzed by cytochrome P450 in liver and, 

### 25

possibly, in other tissues

. Trialkyl Pb metabolites have been found in the liver, kidney, and brain 

### 26

following exp osure to the tetraalkyl compounds in workers ( Bolanowska et al., 1967 ) ; these metabolites 

### 27

have also been detected in brain tissue of nonoccupational subjects ( Nielsen et al., 1978 )

. 

### 28



## 4.2.3. Elimination

The rapid

- phase (30

- 40 days) of Pb excretion amounts to 50

- 60% of the absorbed fraction 

### 29

( Chamberlain et al., 1978 ; Kehoe, 1961a

, 1961b

, 1961c ; M. B. Rabinowitz et al., 1976 ) . Absorbed Pb is 

### 30May 2011 4

- 33 DRAFT

– DO NOT CITE OR QUOTE excreted primarily in urine and feces, with sweat, saliva, hair, nails, and breast milk being minor routes of 

### 1

excretion ( Chamberlain et al., 1978 ; Griffin et al., 1975 ; Hursh et al., 1969 ; Hursh & Suomela, 1968 ; 

### 2

Kehoe, 1987 ; M. B. Rabinowitz et al., 1976 )

. 

### 3

Approximately 30% of Pb excretion during the first 20 days after exposure is due to urinary and 

### 4

fecal losses ( Leggett, 1993 ) . The kinetics of urinary excretion following a single dose of Pb is similar to 

### 5

that of blood ( Chamberlain et al., 1978 ) , likely due to the fact that Pb in urine derives largely from Pb in 

### 6

plasma. Evidence for this is the observation that urinary Pb excretion is strongly correlated with the 

### 7

rate of glomerular filtration of Pb ( Araki et al., 1986 ) and plasma Pb concentration ( Bergdahl, Schutz, et 

### 8

al., 1997 ) (i.e., glomerular filtration rate × plasma Pb concentration), and both relationships are linear. 

### 9

While the relationship between urinary Pb excretion and plasma Pb concentration has been shown to be 

### 10

linear, the plasma Pb relationship to blood Pb concentrati on is curvilinear (as described in Section 4.2.2.1 

### 11

and demonstrated in Figure 4

- 5). This contributes to an increase in the renal clearance of Pb from blood 

### 12

with increasing blood Pb concentrations ( Chamberlain, 1983 ) . Similarly, a linear relationship between 

### 13

plasma Pb concentration and urinary excretion rate predicts a linear relationship between Pb intake (at 

### 14

constant absorption fraction) and urinary Pb excretion rate, whereas the relationship with blood Pb 

### 15

conce ntration would be expected to be curvilinear (Section 4.2. 7 ). 

### 16

Estimates of urinary filtration of Pb from serum (or plasma) range from 13

- 22 L/day, with a mean 

### 17

of 18 L/day ( Araki et al., 1986 ; Chamberlain et al., 1978 ; Manton & Cook, 1984 ; Manton & Malloy, 

### 18

1983 ) , which corresponds to half

- time for transfer of Pb from plasma to urine of 0.1

- 0.16 day s for a 70

- kg 

### 19

adult who has a plasma volume of ~3 L. The rate of urinary excretion of Pb was less than the rate of 

### 20

glomerular filtration of ultrafilterable Pb, suggesting that urinary Pb is the result of incomplete renal 

### 21

tubular reabsorption of Pb in the glomerular filtrate ( Araki et al., 198 6 ) ; although, net tubular secretion of 

### 22

Pb has been demonstrated in animals ( Vander et al., 1977 ; Victery et al., 1979 ) . On the other hand, 

### 23

estimates of blood

- to

- urine clearance range from 0.03

- 0.3 L/day with a mean of 0.18 L/day ( Araki et al., 

### 24

1990 ; Berger et al., 1990 ; Chamberlain et al., 1978 ; Koster et al., 1989 ; Manton & Malloy, 1983 ; M. B. 

### 25

Rabinow itz et al., 1973 ; Ryu et al., 1983 ) ( Diamond, 1992 ) , consistent with a plasma Pb to blood Pb 

### 26

concentration ratio of ~0.005

– 0.01 L/day ( Klotzback et al., 2003 ) . Based on the above differences, 

### 27

urinary excretion of Pb can be expected to reflect the concentration of Pb in plasma and variables that 

### 28

affect delivery of Pb from plasma to urine (e.g., glomerular filtration and other transfer processes in the 

### 29

kidney). 

### 30

The value for fecal:urinary excretion ratio ( ~0.5) was observed during days 2

- 14 following 

### 31

intravenous injection of Pb in humans ( Booke r et al., 1969 ; Chamberlain et al., 1978 ; Hursh et al., 1969 )

. 

### 32

This ratio is slightly higher (0.7

- 0.8) with inhalation of submi cron Pb

- bearing PM due to ciliary clearance 

### 33

and subsequent ingestion. The transfer of Pb from blood plasma to the small intestine by biliary secretion 

### 34

in the liver is rapid (adult t 1/2 = 10 days), and accounts for 70% of the total plasma clearance ( O'Flaherty, 

### 35

1995 )

. 

### 36May 2011 4

- 34 DRAFT

– DO NOT CITE OR QUOTE Organic Lead

Pb absorbed after inhalation of tetraethyl and tetramethyl Pb is excreted in exhaled air, urine, and 

### 1

feces ( Heard et al., 1979 ) . Fecal:urinary excretion ratios were 1.8 following exposure to tetraethyl Pb and 

### 2

1.0 following exposure to tetramethyl Pb ( Heard et al., 1979 ) . Occupational monitoring studies of 

### 3

workers who were exposed to tetraethyl Pb have shown that tetraethyl Pb is excreted in the urine as 

### 4

diethyl Pb, ethyl Pb, and inorganic Pb ( Turlakiewicz & Chmielnicka, 1985 ; Vural & Duydu, 1995 ; W. 

### 5

Zhang et al., 1994 )

. 

### 6



# 4.3. Lead Biomarkers

This section describes the biological measurements of Pb and their interpreta tion as indicators of 

### 7

exposure or body burden. The focus is on blood Pb and bone Pb and the interplay between them, as these 

### 8

are the most commonly measured biomarkers in recent epidemiologic and toxicological studies. 

### 9

M echanistic models are used throughou t the section as a means to describe basic concepts that 

### 10

derive from the wealth of information on Pb toxicokinetics. Although predictions from models are 

### 11

inherently uncertain, models can serve to illustrate expected interrelationships between Pb intake and 

### 12

tissue distribution that are important in interpreting human clinical and epidemiolog ic studies. Thus, 

### 13

models serve as the only means we have for synthesizing our extensive, but incomplete, knowledge of Pb 

### 14

biokinetics into a holistic representation of Pb biokinetics. Furthermore, models can also be used to make 

### 15

predictions about biokinetics relationships that have not been thoroughly evaluated in experiments or 

### 16

epidemiologic studies. In this way, models can serve as heuristic tools for shaping data collect ion to 

### 17

improve our u nderstanding of Pb biokinetics. 

### 18

Numerous mechanistic models of Pb biokinetics in humans have been proposed, and these are 

### 19

described in the 2006 Pb AQCD ( U.S. EPA, 2006 ) and in the supporting literature cited in that report. In 

### 20

this sectio n, for simplicity and for internal consistency, we have limited the discussion to predictions from 

### 21

a single model, the ICRP Pb biokinetics model ( ICRP, 1994 ; Leggett, 1993 ; Pounds & Leggett, 1998 )

. 

### 22

This model wa s originally developed for the purpose of supporting radiation dosimetry predictions; 

### 23

however, it has also been applied in Pb risk assessment ( Abrahams et al., 2006 ; Khoury & Diamond, 

### 24

2003 ; Lorenzana et al., 2005 ) . Portions of the model have been incorporated into an All Ages Lead Model 

### 25

(AALM) that i s being developed by EPA ( 2005 )

. 

### 26



## 4.3.1. Bone Lead Measurements

For Pb measurements in bone, the most commonly examined bones are the tibia, calcane us, patella, 

### 27

and finger bone. For cortical bone, the midpoint of the tibia is measured. For trabecular bone, both the 

### 28May 2011 4

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– DO NOT CITE OR QUOTE patella and calcaneus are measured. The tibia consists of more than 95% cortical bone, the calcaneus and 

### 1

patella comprise more than 95% tr abecular bone, and finger bone is a mixed cortical and trabecular bone 

### 2

although the second phalanx is dominantly cortical. Recent studies favor measurement of the patella, 

### 3

because it has more bone mass and may afford better measurement precision than the c alcaneus. Bone 

### 4

analysis methods have included flame atomic absorption spectrometry (AAS), anode stripping 

### 5

voltammetry (ASV), inductively coupled plasma atomic emission spectroscopy (ICP

- AES), inductively 

### 6

coupled plasma mass spectrometry (ICP

- MS), laser abl ation inductively coupled plasma mass 

### 7

spectrometry (LA

- ICP

- MS), thermal ionization mass spectrometry (TIMS), synchrotron radiation induced 

### 8

X

- ray emission (SRIXE), particle induced X

- ray emission (PIXE), and X

- ray fluorescence (XRF). The 

### 9

upsurge in populari ty of the XRF method has paralleled a decline in the use of the other methods. More 

### 10

information on the precision, accuracy, and variability in bone Pb measurements can be found in the 2006 

### 11

Pb AQCD ( U.S. EPA, 2006 )

. 

### 12

T wo main approaches for XRF measurements have been used to measure Pb concentrations in 

### 13

bone, the K

- shell and L

- shell methods

. The K

- shell method is the most widely used, as there have been 

### 14

relatively few developments in L

- shell devices since the early 1990s . However, Nie et al. ( 2011 ) recently 

### 15

reported on the use of a new portable L

- shell device for human in vivo Pb measurements. Advances in L



### 16

shell device technology resulted in much higher sensitivity than previous L

- shell devices. The new L



### 17

shell device showed sensitivity similar to that of K

- shell methods and a high correlation with results 

### 18

obtained from K

- shell methods (intraclass correlation = 0 .65). 

### 19

Bone Pb measurements are typically expressed in units of Pb/g bone mineral. This may potentially 

### 20

introduce variability into the bone Pb measurements related to variation in bone density. Typically, 

### 21

potential associations between bone density and bone Pb concentration are not evaluated in epidemiolog ic 

### 22

studies ( Hu et al., 2007 ; Theppeang et al., 2008 )

. 

### 23



## 4.3.2. Blood Lead Measurements

Analytical methods for measuring Pb in blood include AAS, graphite furnace atomic absorption 

### 24

spectrometry (GFAAS), ASV, ICP

- AES, and ICP

- MS. GFAAS and ASV are generally considered to be 

### 25

the methods of choice ( Flegal & Smith, 1995 ) . Limits of detection for Pb using AAS are on the order of 

### 26

5

- 10 μg/dL for flame AAS measurements and approximately 0.1 μg/dL for flameless AAS measuremen ts 

### 27

( Flegal & Smith, 1995 ; NIOSH, 1994 ) . A detection limit of 0.005 μg/dL has been achieved for Pb in 

### 28

blood samples analyzed by GFAAS. 

### 29

For measurement of Pb i n plasma, ICP

- MS provides sufficient sensitivity ( Schutz et al., 1996 )

. 

### 30

While the technique has been applied to assessing Pb exposures in adults, it has not received widespread 

### 31

use in epidemiologic st udies. 

### 32May 2011 4

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– DO NOT CITE OR QUOTE The primary binding ligand for Pb in RBC, ALAD, is encoded by a single gene in humans that is 

### 1

polymorphic in two alleles (ALAD1 and ALAD2) ( Scinicariello et al., 2007 ) . Since the ALAD1 and 

### 2

ALAD2 alleles can be codominantly expressed, 3 different genotypes (ALAD 1

- 1, ALAD 1

- 2, and ALAD 

### 3

2

- 2) are possible. The ALAD 1

- 1 genotype is the most common. Scinicariello et al. ( 2010 ) tested 

### 4

genotypes in civilian, noninstitutionalized U.S. individuals that participated as part of NHANES III from 

### 5

1988

– 1994 and found that 15.6% of non

- Hispanic whites, 2.6% non

- Hispanic black s, and 8.8% Mexican 

### 6

Americans carried the ALAD2 allele. 

### 7

The 2006 AQCD document reports that many studies have shown that, with similar exposures to 

### 8

Pb, individuals with the ALAD

- 2 allele have higher blood Pb levels than those without ( Astrin et al., 

### 9

1987 ; Bergdahl, Schutz, et al., 1997 ; H.

- S. Kim et al., 2004 ; Pérez

- Bravo et al., 2004 ; C. M. Smith et al., 

### 10

1995 ; Wetmur, 1994 ; Wetmur, Lehner t, et al., 1991 ) . More recent meta analy ses provide further support 

### 11

for ALAD2 carriers having higher blood Pb levels than ALAD1

- 1 homozygotes ( Scinicariello et al., 

### 12

2007 ; Zhao et al. , 2007 ) . The mechanism for this association may be higher Pb binding affinity of 

### 13

ALAD2. Although, this would be consistent with the structural differences that result in greater 

### 14

electronegativity of ALAD1 compared to ALAD2 ( Wetmur, 1994 ; Wetmur, Kaya, et al., 1991 )

, 

### 15

measurements of Pb binding affinity to ALAD1 and ALAD2 (i.e., Pb 2+ displacement of Zn 2+ binding to 

### 16

recombinant ALAD1 and ALAD2) have not revealed differences in Pb binding affinity ( Jaffe et al., 2000 )

. 

### 17

Both analyses reported the greatest differences for ALAD2 compared to ALAD1 in highly exposed adults 

### 18

and little difference among environmentally

- exposed adults; large differences were also observed for 

### 19

children at low exposures. However, there were few studies that evaluated children and the largest study 

### 20

contributing to the meta analysis may have been influenced by selection bias ( Scinicariello et al., 2007 )

. 

### 21

Individual studies find similar results, with blood Pb levels being higher in individuals with ALAD2 

### 22

alleles ( Miyaki et al., 2009 ; Shaik & Jamil, 2009 ) . A subsequent meta analysis of adult data from 

### 23

NHANES III did not find any differences in blood Pb level between all carriers of either the ALAD 1

- 1 or 

### 24

ALAD 1

- 2/2

- 2 allele ( Scinicariello et al., 2010 ) . Other studies provid e further support for no blood Pb 

### 25

differences among ALAD1 and ALAD2 carriers ( Montenegro et al., 2006 ; Rabstein et al., 2008 ; 

### 26

Wananukul et al., 2006 ) or lower blood Pb levels for individuals with ALAD 1

- 2/2

- 2 ( Chia et al., 2006 )

. 

### 27

Analyses of serial blood Pb concentrations measured in longitudinal epidemiologic studies have 

### 28

found relatively strong correlations (e.g., r = 0.5

- 0.8) between individual blood Pb concentrations 

### 29

measured after 6

- 12 months of age ( Dietrich et al., 1993 ; McMichael et al., 1988 ; Otto et al., 1985 ; M. 

### 30

Rabinowitz et al., 1984 ; Schnaas et al., 2000 ) . These observations suggest that, in general, exposure 

### 31

characteristics of an individual child (e.g., exposure levels and/or exposure behaviors) tend to be 

### 32

relatively constant across age. However, a single blood Pb mea surement may not distinguish between a 

### 33

history of long

- term lower

- level Pb exposure from a history that includes higher acute exposures 

### 34

( Mushak, 1998 ) . This is illustrated in Figure 4

- 6 . Two hypothetical children are simulated. Child A has a 

### 35

relatively constant Pb intake from birth, whereas Child B has the same long

- term Pb intake as Child A, 

### 36May 2011 4

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– DO NOT CITE OR QUOTE but with a 1

- year elevated intake beg inning at age 24 months (Figure 4

- 6, upper panel). The absorption 

### 1

fraction is assumed to be the same for both children. Blood Pb samples 1 and 5 for Child A and B, or 2 

### 2

and 4 for Child B, will yield similar blood Pb concentrations (~3 or 10 μg/dL, respecti vely), yet the 

### 3

exposure contexts for these samples are very different. Two samples (e.g., 1 and 2, or 4 and 5), at a 

### 4

minimum, are needed to ascertain if the blood Pb concentration is changing over time. The rate of change 

### 5

can provide information about the magnitude of change in exposure, but not necessarily about the time 

### 6

history of the change (Figure 4

- 6 , lower panel). Time

- integrated measurements of Pb concentration may 

### 7

provide a means for accounting for some of these factors and, thereby, provide a bette r measure of long



### 8

term Pb exposure. 

### 9May 2011 4

- 38 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 6

. Simulation of temporal relationships between Pb exposure
and blood Pb concentration in children. Child A and Child B have a relatively constant basal Pb intake (μg/day/kg body weight) from birth; Child B experiences 1

- year elevated intake beginning at age 24 months (upper panel). Blood Pb samples 1 and 5 for Child A and B, or 2 and 4 for Child B, will yield similar blood Pb concentrations (~3 or 10 μg/dL, respectively), yet the exposure scenarios for these samples are very different. As shown in the example of Child C and Child D, two samples can provide information about the magnitude of change in exposure, but not necessarily the temporal history of the change (lower panel). Simulation based on ICRP Pb
bi okinetics model ( Leggett, 1993 )

.May 2011 4

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– DO NOT CITE OR QUOTE 

## 4.3.3. Urine Lead Measurements

Standard methods that have been reported for urine Pb analysis are, in general, the same as those 

### 1

analyses noted for determination of Pb in blood. Reported detection limits are ~50 μg/L for AAS, 5

- 10 

### 2

μg/L for ICP AES, and 4 μg/L for ASV for urine Pb analyses. 

### 3

T he concentration of Pb in urine is a function of the urinary Pb excretion (Sect ion 4.2.3) and the 

### 4

urine flow rate. Urine flow rate requires collection of a timed urine sample, which is often problematic in 

### 5

epidemio logic studies. Collection of un timed ( “ spot ” ) urine samples, a common alternative to timed 

### 6

samples, requires adjustment o f the Pb measurement in urine to account for variation in urine flow 

### 7

( Diamond, 1988 ) . Several approaches to this adjustment have been explored, including adjusting the 

### 8

measured urine Pb concentration by the urine creatinine concentration, urine osmolality, o r specific 

### 9

gravity ( Araki et al., 1990 ; Fukui et al., 1999 )

. Urine flow rate can vary by a factor or more than 10, 

### 10

depending on the state of hydration and other factors that affect glomerular filtration rate and renal tubular 

### 11

reabsorption of the glomerular filtrate. All of these factors can be affected by Pb exposur e at levels that 

### 12

produce nephrotoxicity (i.e., decreased glomerular filtration rate, impaired renal tubular transport 

### 13

function). Therefore, urine Pb concentration measurements provide little reliable information about 

### 14

exposure (or Pb body burden), unless t hey can be adjusted to account for unmeasured variability in urine 

### 15

flow rate ( Araki et al., 1990 )

. 

### 16

Urinary Pb concentration reflects, mainly, the exposure history of the previous few months; thus, a 

### 17

single urinary Pb measurement cannot distinguish between a long

- term low level of exposure or a higher 

### 18

acute expo sure. Urinary Pb measurements would be expected to correlate with concurrent blood Pb

. 

### 19

Chiang et al. ( 2008 ) reported a significant, but relatively weak correlation between urinary Pb levels 

### 20

(μg/dg creatinine) and individual Pb intakes (μg/day) estimated in a group of 10

- to 12

- year

- old children 

### 21

(β: 0.053, R = 0.320, p = 0.02, n = 57). A contributing factor to the relatively weak correlatio n may have 

### 22

been the temporal displacement between the urine sampling and measurements used to estimate intake, 

### 23

which may have been as long as six months for some children. 

### 24

Thus, a single urine Pb measurement, or a series of measurements taken over short

- t ime span, is 

### 25

likely a relatively poor index of Pb body burden for the same reasons that blood Pb is not a good indicator 

### 26

of body burden. On the other hand, long

- term average measurements of urinary Pb can be expected to be 

### 27

a better in dex of body burden (Fi gure 4

- 7). 

### 28May 2011 4

- 40 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 7

. Simulation of relationship between urinary Pb excre tion and body burden in adults. A change in Pb uptake results in a relatively rapid change in urinary excretion of Pb, to a new quasi

- steady state, and a relatively small change in body burden (upper panel). The long

- term average urinary Pb excretion more closely tracks the pattern of change in body burden (lower panel). Simulation based on ICRP Pb
biok i netics model ( Leggett, 1993 )

. 0 5 10 15 20

0 2 4 6 8 10

25 30 35 40 45 50 55 60 65 70Body Burden (mg)Urine Pb (μg/day)

Age (year) Urine
Body



### 0 5 10 15 20

0 1 2 3 4 5 6

25 30 35 40 45 50 55 60 65 70Body Burden (mg)Time-Averaged Urine Pb(μg/day)



### Age (year) Urine
BodyMay 2011 4

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– DO NOT CITE OR QUOTE 

## 4.3.4. Lead in Other Potential Biomarkers

There was extensive discussion in the 2006 Pb AQCD regarding the utility of other Pb biomarkers 

### 1

as indicators of exposure or body burden. Due to the fac t that most epidemiologic studies continue to use 

### 2

blood Pb or bone Pb as biomarkers of exposure or body burden, and other potential biomarkers (i.e., teeth, 

### 3

hair, and saliva) have not been established to the same extent as blood or bone Pb, only summaries are 

### 4

provided below. 

### 5

4.3.4.1. Teeth

Tooth Pb is a minor contributor to the total body burden of Pb. As teeth accumulate Pb, tooth Pb 

### 6

levels are generally considered an estimate of cumulative Pb exposure. The tooth Pb

- blood Pb 

### 7

relationship is more complex than the bo ne Pb

- blood Pb relationship because of differences in tooth type, 

### 8

location, and analytical method. Although mobilization of Pb from bone appears well established, this is 

### 9

not the case for Pb in teeth. Conventional wisdom has Pb fixed once it enters the too th. Although that may 

### 10

be the case for the bulk of enamel, it is not true for the surface of the enamel and dentine ( B. L. Gulson et 

### 11

al., 1997 ; M. B. Rabinowitz et al., 1993 ) . Limited studies have demonstrated m oderate

- to

- high 

### 12

correlations between tooth Pb levels and blood Pb levels ( M. B. Rabinowitz, 1995 ; M. B. Rabinowitz et 

### 13

al., 1989 )

. 

### 14

Teeth are composed of several tissues formed pre

- and postnatal . Therefore, if a child ’ s Pb exposure 

### 15

during the years of tooth formation varied widely, different amounts of Pb would be deposited at different 

### 16

rates ( M. B. Rabinowitz et al., 1993 ) . This may allow investigators to elucidate the history of Pb exposure 

### 17

in a child. Robbins et al. ( 2010 ) found a significant association between environmental Pb measures that 

### 18

correlated with leaded ga soline use and tooth enamel Pb in permanent teeth. Costa de Almeida et al. 

### 19

( 2007 ) was able to discern differences between tooth enamel Pb concentration in biopsy samples from 

### 20

children who lived in areas having higher or lower levels of Pb contamination. Gulson and Wilson ( 1994 ) 

### 21

advocated the use of sections of ena mel and dentine to obtain additional information compared with 

### 22

analysis of the whole tooth (e.g., ( Fosse et al., 1995 ; Tvinnereim et al., 1997 ) . For example, deciduous 

### 23

tooth Pb in the enamel provides information about in utero exposure whereas that in dentine from the 

### 24

same tooth provides information about postnatal exposure until the tooth exfoliates at about 6

- 7 years of 

### 25

age. 

### 26

4.3.4.2. Hair

The 2006 Pb AQCD discussed applications of hair Pb measurements for assessing Pb bo dy burden 

### 27

or exposure and noted methodological limitations (e.g., external contamination) and lack of a strong 

### 28

empirical basis for relating hair Pb levels to body burden or exposure. No new methodological or 

### 29May 2011 4

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– DO NOT CITE OR QUOTE conceptual advances regarding hair Pb measuremen ts have occurred since 2006, and widespread 

### 1

application of hair Pb measurements in epidemiologic studies has not occurred. 

### 2

Pb is incorporated into human hair and hair roots ( Bos et al., 1985 ; M. B. Rabinowitz et al., 1976 ) 

### 3

a nd has been explored as a possibly noninvasive approach for estimating Pb body burden ( Gerhardsson et 

### 4

al., 1995 ; Wilhelm et al., 1989 ; Wilhelm et al., 2002 )

. Hair Pb measurements are subject to error from 

### 5

contamination of the surface with environmental Pb and contaminants in artificial hair treatments (i.e., 

### 6

dyeing, bleaching, permanents) and are a relatively poor predictor of blood Pb concentrations, particularly 

### 7

at low levels (<1 0

- 12 μg/dL) ( Campbell & Toribara, 2001 ; G. Drasch et al ., 1997 ; Esteban et al., 1999 ; J. 

### 8

L. Rodrigues et al., 2008 )

. Temporal relationships between Pb exposure and hair Pb levels, and kinetics of 

### 9

deposition and retention of Pb in hair have not been evaluated

. Although hair Pb measurements have been 

### 10

used in some epidemiolog ic studies, an empirical basis for interpreting hair Pb measurements in terms of 

### 11

body burden or exposure has not been firmly established. 

### 12

4.3.4.3. Saliva

A growing body of literature on the utility of measurements of salivary Pb has developed since th e 

### 13

completion o f the 2006 AQCD ( U.S. EPA, 2006 ) . Earlier reports suggested a relatively strong correlation 

### 14

between salivary Pb concentration and blood Pb concentration ( Brodeur et al., 1983 ; Omokhodion & 

### 15

Crockford, 1991 ; P'an, 1981 ) ; however, more recent assessments have shown relatively weak or 

### 16

inconsis tent associations ( Barbosa, Heloisa, et al., 2006 ; Costa de Almeida et al., 2009 ; Nriagu et al., 

### 17

2006 ) . The differences in these outcomes may reflect differences in blood Pb concentrations, exposure 

### 18

history and/or dental health (i.e., transfer of Pb between dentin and saliva) and possibly methods for 

### 19

determining Pb in saliva. Barbosa et al. ( 2006 ) found a significant but relatively weak correlation 

### 20

(log[blood PB] v ersu s log[saliva Pb], r = 0.277, p = 0.008) in a sample of adults, ages 18

- 60 years ( n = 

### 21

88). The correlation was similar for salivary and plasma Pb. Nriagu et al. ( 2006 ) found also found a 

### 22

relatively weak association (R 2

= 0.026) between blood Pb (μg/dL) and salivary Pb (μg/L) in a sample of 

### 23

adults who resi d ed in Detroit, MI ( n = 904). Costa de Almeida et al. ( 2009 ) found a significant correlation 

### 24

between salivary and blood Pb con centr ations in children in a Pb

- contaminated region in Sao Paulo State, 

### 25

Br azil (r = 0. 76. p = 0.04, n = 7) prior to site remediation; however, the correlation degenerated (r = 0.03, 

### 26

p = 0.94, n = 9) following remediation. Nevertheless, salivary Pb concentration s in the group of children 

### 27

who lived in the contaminated area were significantly elevated compared to a reference population. It is 

### 28

possible, that salivary Pb measurements may be a useful non

- invasive biomarker for detecting elevated Pb 

### 29

exposure; however, it is not clear based on currently available data, if salivary Pb measurements would be 

### 30

a more reliable measure of exposure than blood Pb measurements. 

### 31May 2011 4

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– DO NOT CITE OR QUOTE 

### 4.3.4.4. Serum δ

- ALA and ALAD

The association between blood Pb and blood ALAD activity and serum δ

- aminolevulinc acid ( δ



### 1

ALA) levels was recognized decades ago as having potential use as a biomarker of Pb exposure 

### 2

( Hernberg et al., 1970 ; Mitchell et al., 1977 ) . More recently reference values for blood ALAD activity 

### 3

ratio (the ratio of ALAD activity in the blood sample to that measured after fully activating the enzyme i n 

### 4

the sample) have been reported ( Gultepe et al., 2009 )

. Inhibition of erythrocyte ALAD by Pb results in a 

### 5

rise in the plasma concentration of the ALAD substrate δ

- ALA. The δ

- ALA biomarker can be measured 

### 6

in serum and has been used as a surrogate for Pb measurements in studies in which whole blood samples 

### 7

or adequately prepared plasma or serum samples were not available for Pb measurements ( Opler et al., 

### 8

2004 ; Opler et al., 2008 )

. 

### 9



## 4.3.5. Relationship between Lead in Blood and Lead in Bone

The kinetics of elimination of Pb from the body reflects the existence of fast and slow pools of Pb 

### 10

in the body. The dominant phase of Pb kinetics in the blood, exhibited shortly after a change in exposure 

### 11

occurs, has a half

- life of ~20

- 30 days ( Leggett, 1993 ) . A slower phase becomes evident with longer 

### 12

observation periods following a decrease in exposure. Slow transfer rates for the movement of Pb from 

### 13

nonexchangeable bone pools to the plasma are the dominant transfer process determining long

- term 

### 14

accumulation and elimination of bone Pb burden. 

### 15

Bone Pb stores can contribute 40

- 70% to blood Pb ( B. Gulson et al., 1995 ; Manton, 1985 ; D. R. 

### 16

Smith et al., 1996 ) . Bone Pb burdens in adults are slowly lost by diffusion (heteroionic exchange) as well 

### 17

as by resorption ( O'Flaherty, 1995 ) . Half

- times for the release of Pb in bone is dependent on age and 

### 18

intensity of exposure. Slow bone volume compartments are much more labile in infants and children than 

### 19

in adults as reflected by half

- times for movement into the plasma (e.g., cortical t 1/2 = 0.23 y ea rs at birth, 

### 20

1.2 y ea r s at 5 years of age, 3.7 y ea rs at 15 years of age, and 23 y ea rs in adults; trabecular t 1/2 = 0.23 y ea rs 

### 21

at birth, 1.0 y ea rs at 5 years of age, 2.0 y ea rs at 15 y ea rs of age, a nd 3.9 y ea rs in adults) ( Leggett, 1993 )

. 

### 22

Children who have been removed from a relatively brief exposure to elevated environmental Pb exhibit 

### 23

faster slow

- phase kinetics than children removed from exposures that lasted several years, with half

- times 

### 24

of 10 and 20

- 38 months, respectively ( Manton et al., 2000 ) . The longer half

- times measured under the 

### 25

latter conditions reflect the contribution of bone Pb stores to blood Pb following a change in exposure. 

### 26

T he longer h alf

- life of Pb in bone compared to blood Pb, allows a more cumulative measure of Pb 

### 27

dose . Pb in adult bone can serve to maintain blood Pb levels long after external exposure has ceased 

### 28

( Fleming et al., 1997 ; Inskip et al., 1996 ; Kehoe, 1987 ; O'Flaherty et al., 1982 ; D. R. Smith et al., 1996 )

, 

### 29

even for exposures that occurred during childhood ( F. E. McNeill et al., 2000 ) . The more widespread use 

### 30

of in vivo XRF Pb measurements in bone and indirect measure ments of bone processes with stable Pb 

### 31

isotopes have enhanced the use of bone Pb as a biomarker of Pb body burden. 

### 32May 2011 4

- 44 DRAFT

– DO NOT CITE OR QUOTE T here is a stronger relationship between patella Pb and blood Pb than tibia Pb and blood Pb 

### 1

( Hernandez

- Avila et al., 1996 ; Hu et al., 1996 ; Hu et al., 1998 ; Park, Mukherjee, et al., 2009 )

. Hu et al. 

### 2

( 1998 ) suggest that trabecular bone is the predominant bone type providing Pb back into circulation under 

### 3

steady

- state and pathologic conditions. The stronger relationships between blood Pb and trabecu lar Pb 

### 4

compared with cortical bone is probably associated with the larger surface area of trabecular bone 

### 5

allowing for more Pb to bind via ion exchange mechanisms and more rapid turnover making it more 

### 6

sensitive to changing patterns of exposure. 

### 7

4.3.5.1. Children

A s mentioned in Section 4.2.2. 2 , bone growth in children will contribute to accumulation of Pb in 

### 8

bone, which will comprise most of the Pb body burden. As a result, Pb in bone will more closely reflect 

### 9

Pb body burden than blood Pb. However, changes in blood Pb concentration in children (i.e., associated 

### 10

with changing exposures) are thought to more closely parallel changes in total body burden. Figure 4

- 8 

### 11

shows a simulation of the temporal profile of Pb in blood and bone in a child who experience s a period of 

### 12

constant Pb intake (from age 2

- 5) via ingestion (μg Pb /day) followed by an abrupt decline in intake. The 

### 13

figure illustrates several important general concepts about the relationship between Pb in blood and bone. 

### 14

While blood Pb approaches a quasi

- steady st ate after a period of a few months with a constant rate of Pb 

### 15

intake (as demonstrated by the vertical dashed line), Pb continues to accumulate in bone with continued 

### 16

Pb intake after the quasi

- steady state is achieved in blood. The model also predicts that the rate of release 

### 17

of Pb from bone after cessation of exposure is faster than in adults. This difference has been attributed to 

### 18

accelerated growth

- related bone mineral turnover in children, which is the primary mechanism for release 

### 19

of Pb that has been in corporated in to the bone mineral matrix. 

### 20

Empirical evidence in support of this comes from longitudinal studies in which relatively high 

### 21

correlations (r = 0.85) were found between concurrent (r = 0.75) or lifetime average blood Pb 

### 22

concentrations (r = 0.85) and tibia bone Pb concentrations (measured by XRF) in a sample of children in 

### 23

which average blood Pb concentrations exceeded 20 μg/dL; the correlations was much weaker (r <0.15) 

### 24

among children who had average blood Pb concentration <10 μg/dL ( Wasserman et al., 1994 )

. 

### 25

Two alternativ e blood Pb metrics depicted in Figure 4

- 8 include the time

- averaged and time



### 26

integrated blood Pb concentrations. Both the time

- averaged and time

- integrated blood Pb metrics display 

### 27

rates of change in response to the exposure event that more closely approxi mate the slower kinetics of 

### 28

bone Pb and body burden, than the kinetics of blood Pb concentration, with notable differences. The time



### 29

averaged blood Pb concentration increases during the exposure event and decays following the event, 

### 30

consistent with the changing body burden. The time

- integrated blood Pb concentration ( conceptually 

### 31

identical to cumulative blood lead index [CBLI] used in epidemiologic studies ) is a cumulative function 

### 32

and increases throughout childhood; however, the slope of the increase is higher during the exposure 

### 33May 2011 4

- 45 DRAFT

– DO NOT CITE OR QUOTE event than prior to or following the event. Following cessation of exposure, the time

- integrated blood Pb 

### 1

and body burden diverge. This is expected, as the time

- integrated blood Pb curve is a cumulative function 

### 2

which cannot dec rease over time and bone Pb levels will decrease with cessation of exposure. 

### 3

The time

- integrated blood Pb concentration will be a better reflection of the total amount of Pb that 

### 4

has been absorbed, than the body burden at any given time. The time

- integrate d blood Pb concentration 

### 5

will also reflect cumulative Pb absorption, and cumulative exposure if the absorption fraction is constant. 

### 6

This is illustrated in the hypothetical simulations of an exposure event experienced by a child (Figure 4

- 

### 7

9). This pattern is similar for adults. 

### 8May 2011

Figure 4-8. S i mulation of relationship between blood Pb concentrat ion

and body burden in c age 2 to 5. burden more closely in children than in adults, due to more rapid turnover of bone and bone panel). Nevertheless, the time concentration more closely tracks t body burden (middle panel). The time concentration increases over time (lower panel). Simul ation based on ICRP Pb biokinetics model

4-46 DR AFT S i mulation of relationship between blood Pb concentra t ion

burden in children, with a constant Pb intake from age 2 to 5.Blood Pb concentration is thought to parallel body burden more closely in children than in adults, due to more rapid turnover of bone and bone-Pb stores in children (upper panel). Nevertheless, the time-averaged blood Pb concentration more closely tracks the pattern of change in body burden (middle panel). The time-integrated blood Pb concentration increases over time (lower panel). Simul ation based on ICRP Pb biokinetics model ( Leggett, 1993 ).

DO NOT CITE OR QUOTE S i mulation of relationship between blood Pb concentrat ion hildren, with a constant Pb intake from Blood Pb concentration is thought to parallel body burden more closely in children than in adults, due to more Pb stores in children (upper

he pattern of change in integrated blood Pb concentration increases over time (lower panel). Simul ationMay 2011 4

- 47 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 9

. Simulation of relationship between time

- integrated blood Pb concentration and cumula tive Pb absorption in children. The simulations include a 3

- year period of elevated Pb intake during age s 2

- 5 years. The time

- integrated blood Pb concentration closely parallels cumulative Pb absorption. Simulation based on ICRP Pb biokinetics model ( Leggett,
1993 )

.



### 4.3.5.2. Adults

In adults, where a relatively large fraction of the body burden residing in bone has a slower 

### 1

turnover compared to blood, a constant Pb uptake (or constant intake and fractional absorption) gives rise 

### 2

to a quasi

- steady state b lood Pb concentration, while the body burden continues to increase over a much 

### 3

longer period, largely as a consequence of continued accumulation of Pb in bone. This pattern is 

### 4

illustrated in Figure 4

- 10 which depicts a hypothetical simulation of an exposure event consisting of a 20

- 

### 5

year period of daily ingestion of Pb in an adult. The exposure event shown in the simulations gives rise to 

### 6

a relatively rapid increase in blood Pb concentration, to a new qua si

- steady state, achieved in ~75

- 100 

### 7

days (i.e., approximately 3

- 4 times the blood elimination half

- life). In contrast, the body burden continues 

### 8

to increase during this period. Following cessation of the exposure, blood Pb concentration declines 

### 9

relativel y rapidly compared to the slower decline in body burden. Careful examination of th e simulation 

### 10

shown in Figure 4

- 10 reveals that the acc umulation and elimination phases of blood Pb kinetics are not 

### 11

symmetrical; elimination is slower than accumulation as a result of the gradual release of bone Pb stores 

### 12 0 5 10 15 20

0 10 20 30 40 50

0 2 4 6 8 10Cumulative Absorption (mg)Time-Integrated Blood Lead(μg/dL x yr )



### Age (year) Blood AbsorptionMay 2011 4

- 48 DRAFT

– DO NOT CITE OR QUOTE to blood

. This response, known as t he prolonged terminal elimination phase of Pb from blood

, has been 

### 1

observed in retired Pb workers and in workers who continued to work after improved industrial hygiene 

### 2

stan dards reduced their exposures. In the adult simulation shown in Figure 4

- 10 , the initial phase of 

### 3

elimination (the first 5 years following cessation of exposure at 50 years) has a half

- time of approximately 

### 4

14 years; however, the half

- time increases to app roximately 60 years during the period 5

- 30 years after 

### 5

cessation of exposure. These model predictions are consistent with the slow elimination of Pb from blood 

### 6

and elimination half

- times of severa l decades for bone Pb (e.g., 16

- 98 years) that have been est imated 

### 7

from observations made on Pb workers ( Fleming et al., 1997 ; Gerhardsson et al., 1 995 )

. Based on this 

### 8

hypothetic al simulation, a blood Pb concentration measured 1 year following cessation of a period of 

### 9

increased Pb uptake would show little or no appreciable change from prior to the exposure event, 

### 10

whereas, the body burden would remain elevated. This illustrates how a single blood Pb concentration 

### 11

measurement, or a series of measurements taken over a short

- time span, could be a relatively poor index 

### 12

of Pb body burden. 

### 13

One important potential implication of the profoundly different kinetics of Pb in blood and bone is 

### 14

that, for a constant Pb exposure, bone Pb will increase with increasing duration of exposure and, 

### 15

therefore, with age. In contrast, blood Pb will achieve a quasi

- steady state. As a result, the relationship 

### 16

between blood Pb and bone Pb will diverge with in creasing exposure duration and age. This divergence 

### 17

can impart different degrees of age

- confounding when either blood Pb or bone Pb is used as an internal 

### 18

dose metric in dose

- response models. In a review of epidemiologic studies that evaluated the associat ions 

### 19

between blood Pb, bone Pb and cognitive function, the effects of bone Pb were more pronounced than 

### 20

blood Pb (particularly for longitudinal studies) for older individuals with environmental Pb exposures and 

### 21

low blood Pb levels ( Shih et al., 2007 ) . In contrast, occupational workers with high current Pb exposures 

### 22

had the strongest associations for blood Pb levels with cognitive function, thus provi ding evidence for this 

### 23

divergence ( Shih et al., 2007 )

. 

### 24May 2011

Figure 4-10. S i mulation of relationship between blood Pb concentrat ion,

bone Pb and body burden in adults. results in a quasi body burden (upper panel). A change in Pb uptake gives rise to a relatively rapid change in blood Pb, to a new qua si state, and a slower change in body burden. The long time-averaged blood Pb co slower pattern of change in body burden (middle panel) . The time-integrated blood Pb concentration increases over the
li fetime, with a greater rate of increase during perio ds of higher Pb
biokinetics model

Tibia bone Pb has been shown to be correlated with tim e 

### 1

CBLI). McNeill et al. ( 20 00 ) compared tibia Pb levels and cumulative blood Pb indic es in a population of 

### 2

19- to 29-year-o l ds who had been highly exposed 

### 3

They concluded that Pb from exposure in early childhood had persisted in the bone matrix until 

### 4

adulthood. The bone Pb/CBLI slopes from vario 

### 5

4-49 Simulation of relationship between blood Pb concentration,

e Pb and body burden in adults.A constant baseline intake n a quasi-steady state blood Pb concentration and body burden (upper panel). A change in Pb uptake gives rise to a relatively rapid change in blood Pb, to a new qua si state, and a slower change in body burden. The long-term averaged blood Pb concentration more closely tracks the slower pattern of change in body burden (middle panel) . The integrated blood Pb concentration increases over the
li fetime, with a greater rate of increase during perio ds of

uptake (lower panel). Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 ).

Tibia bone Pb has been shown to be correlated with tim e-integrated blood Pb concentration (i.e.,

compared tibia Pb levels and cumulative blood Pb indic es in a population of

olds who had been highly exposed to Pb in childhood from the Bunker Hill, Idaho smelte r

. They concluded that Pb from exposure in early childhoo d had persisted in the bone matrix until

adulthood. The bone Pb/CBLI slopes from various studies range from 0.022 to 0.067 μ g/g bone mineral

DO NOT CITE OR QUOTE S i mulation of relationship between blood Pb concentrat ion,
A constant baseline intake steady state blood Pb concentration and body burden (upper panel). A change in Pb uptake gives rise to a relatively rapid change in blood Pb, to a new qua si-steady
term ncentration more closely tracks the slower pattern of change in body burden (middle panel) . The integrated blood Pb concentration increases over the
li fetime, with a greater rate of increase during perio ds of based on ICRP Pb

integrated blood Pb concentration (i.e.,

compared tibia Pb levels and cumulative blood Pb indic es in a population of

to Pb in childhood from the Bunker Hill, Idaho smelte r

. They concluded that Pb from exposure in early childhoo d had persisted in the bone matrix until

μ g/g bone mineralMay 2011 4

- 50 DRAFT

– DO NOT CITE OR QUOTE per μg

- year/dL ( Healey et al., 2008 ; Hu et al., 2007 ) . Because the CBLI is a cumulative function which 

### 1

cannot decrease over time, CBLI and bone Pb would be expected to diverge following cessation of 

### 2

exposure, as bone Pb levels de crease. This has been observed as a lower bone Pb/CBLI slope in retired Pb 

### 3

workers compared to active workers and in worker populations whose exposures declined over time as a 

### 4

result of improved industrial hygiene ( Fleming et al., 1997 ; Gerhardsson et al., 1993 )

. 

### 5

Although, differences in kinetics of blood and bone Pb degrade the predictive value of blood Pb as 

### 6

a metric of Pb body burden, within a population that has similar exposure histories and age demographics

, 

### 7

blood and bone P b may show relatively strong associations

. A recent analysis of a subset of data from the 

### 8

Normative Aging Study showed that cross

- sectional measurements of blood Pb concentration accounted 

### 9

for approximately 9% (tibia) to 13% (patella) of the variability in bone Pb levels

. Inclusion of age in the 

### 10

regression model accounted for an additional 7

- 10% of the variability in bone Pb ( Park, Mukherj ee, et al., 

### 11

2009 )

. 

### 12

Mobilization of Lead from Bone in Adulthood

Potential mobilization of Pb from the skeleton increases this contribution of bone Pb to blood Pb, 

### 13

which occurs at times of physiological stress associated with enhanced bone remodeling suc h as during 

### 14

pregnancy and lactation ( Hertz

- Picciotto et al., 2000 ; Manton, 1985 ; Silbergeld, 1991 ) , menopause or in 

### 15

the elderly ( Silbergeld et al., 1988 ) , extended bed rest ( Markowitz & Weinberger, 1990 )

, 

### 16

hyperparathyroidism ( Kessler et al., 1999 ) and severe weight loss ( Riedt et al., 2009 )

. 

### 17

During pregnancy, bone Pb can serve as a Pb source as maternal bone is resorbed for the 

### 18

production of the fetal skeleton ( Franklin et al., 1997 ; B. Gulson et al., 1999 ; B. Gulson et al., 2003 ; B. L. 

### 19

Gulson et al., 1997 ) . Increased blood Pb during pregnancy has been demonstrated in numerous studies 

### 20

and these changes have been characterized as a “U

- shaped ” pattern of lower blood Pb concentrations 

### 21

during the sec ond trimester compared to the first and third trimesters ( B. Gulson et al., 2004 ; B. L. Gulson 

### 22

et al., 1997 ; Hertz

- Picciotto et al., 2000 ; Lagerkvist et al., 1996 ; Lamadrid

- Figueroa et al., 2006 ; 

### 23

Rothenberg et al., 1994 ; Schuhmacher et al., 1996 ) . The U

- shaped relationship re flects the relatively 

### 24

higher impact of hemodilution in the second trimester versus the rate of bone Pb resorption accompanying 

### 25

calcium releases for establishing the fetal skeleton. In the third trimester, fetal skeletal growth on calcium 

### 26

demand is greater, and Pb released from maternal skeleton offset s hemodilution. Gulson et al. ( 1998 ) 

### 27

reported that, during pregnancy, blood Pb concentrations in the first immigrant Australian cohort (n = 15) 

### 28

increased by an average of about 20% compared to non

- pregnant migrant controls (n = 7). Skeletal 

### 29

contribution to blood Pb, based on the isotopic composition for the immigrant subjects, increased in an 

### 30

approximately linear manner during pregnancy. The mean increases for each individual during pregnancy 

### 31

varied from 26% to 99%. Interestingly, the percent change in blood Pb c oncentration was significantly 

### 32

greater during the post

- pregnancy period than during the second and third trimesters. The contribution of 

### 33May 2011 4

- 51 DRAFT

– DO NOT CITE OR QUOTE skeletal Pb to blood Pb during the post

- pregnancy period remained essentially constant at the increased 

### 1

level of Pb mob ilization. 

### 2

Gulson et al. ( 2004 ) observed that calcium supplementation was found to d elay increased 

### 3

mobilization of Pb from bone during pregnancy and halved the flux of Pb release from bone during late 

### 4

pregnancy and postpartum. In another study, women whose daily calcium intake was 850 mg per day 

### 5

showed lower amounts of bone resorption dur ing late pregnancy and postpartum than those whose intake 

### 6

was 560 mg calcium per day ( Manton et al., 2003 ) . Similarly, calcium supplementation (1200 mg/day) in 

### 7

pregnant Mexican women resulted in an 11% reduction in blood Pb level compared to placebo and a 24% 

### 8

average reduction for the most compliant women ( Ettinger et al., 2009 ) . When considering baseline blood 

### 9

Pb levels in women who were more compliant in taking calcium supplementation, the reductions were 

### 10

si milar for those <5 μg/dL and those ≥ 5 μg/dL (14% and 17%, respectively). This is in contrast to a study 

### 11

of women who had blood Pb concentrations <5 μg/dL, where calcium supplementation had no effect on 

### 12

blood Pb concentrations ( B. Gulson et al., 2006b ) . These investigators attributed their results to changes 

### 13

in bone resorption with decoupling of trabecular and cortical b one sites. 

### 14

Miranda et al. ( 2010 ) studied blood Pb level among pregnant women aged 18

- 44 years old. The 

### 15

older age segments in the study presumably had greater historic Pb exposures and associated stored Pb 

### 16

than the younger age segments. Compared with the bloo d Pb levels of a reference group in the 25

- 29 

### 17

years old age category, women ≥ 30 years old had significant odds of having higher blood Pb levels (aged 

### 18

30

- 34: OR = 2.39, p <0.001; aged 35

- 39: OR = 2.98, p <0.001; aged 40

- 44: OR = 7.69, p <0.001). 

### 19

Similarly, younger women had less chance of having higher blood Pb levels compared with the reference 

### 20

group (aged 18

- 19: OR = 0.60, p = 0.179; aged 20

- 24: OR = 0.54, p = 0.015). These findings indicate that 

### 21

maternal blood Pb levels are more likely the result of Pb r emobilization from bone stores from historic 

### 22

exposures as opposed to contemporaneous exposures. 

### 23

L actation can affect the endogenous bone Pb release rate. After adjusting for patella Pb 

### 24

concentration, an increase in blood Pb levels of 12.7% (95% CI: 6.2, 19 .6) was observed for women who 

### 25

practiced partial lactation and an increase of 18.6% (95% CI: 7.1, 31.4) for women who practiced 

### 26

exclusive lactation compared to those who stopped lactation ( Tellez

- Rojo et al., 2002 ) . In another Mexico 

### 27

City study, Ettinger et al. ( 2004 ; 2006 ) concluded that an interquartile increase in patella Pb was 

### 28

associat ed with a 14% increase in breast milk Pb, whereas for tibia Pb the increase was ~5%. Breast 

### 29

milk:maternal blood Pb concentration ratios are general ly <0.1, although values of 0.9 have been reported 

### 30

( Ettinger et al., 2006 ; B. Gulson, Jameson, et al., 1998 ; Koyashiki et al., 2010 )

. Dietary intake of 

### 31

polyunsaturated fatty acids (PUFA) has been shown to weaken the association between Pb levels in 

### 32

patella and breast milk, perhaps indicating decreased transfer of Pb from bone to breast milk with PUFA 

### 33

consumption ( Arora et al., 2008 )

. 

### 34

The Pb content in s ome bones (i.e., mid femur and pelvic bone) plateau at middle age and then 

### 35

decreases at older ages ( G. A. Drasch et al., 1987 ) . This decrease is most pronounced in females and may 

### 36May 2011 4

- 52 DRAFT

– DO NOT CITE OR QUOTE be due to ost eoporosis and release of Pb from resorbed bone to blood ( B. Gulson et al., 2002 ) . Two 

### 1

studies indicate that the endogenous release rate in postmenopausal women ranges from 0.13

- 0.14 μg/dL 

### 2

in blood per μg/g bone and is nearly double the rate found in premenopausal women (0.07

- 0.08 μg/dL per 

### 3

μg/g bone) ( Garrido Latorre et al., 2003 ; Popovic et al., 2005 )

. 

### 4

S tudies of the effect of hormone replacement therapy on bone Pb mobilization have yielded 

### 5

conflicting results ( Berkowitz et al., 2004 ; Garrido Latorre et al., 2003 ; Korrick et al., 2002 ; Popovic et 

### 6

al. , 2005 ; Webber et al., 1995 ) . In women with sev ere weight loss (28% of BMI in 6 months) sufficient to 

### 7

increase bone turnover, increased blood Pb levels of approximat ely 2.1 μg/dL (250%) were reported , and 

### 8

these blood Pb increases were associated with biomarkers of increased bone turnover (e.g., urinary 

### 9

pyridinoline cross

- links) ( Riedt et al., 2009 )

. 

### 10



## 4.3.6. Relationship Between Lead in Blood and Lead in Soft
Tissues

Figure 4

- 11 shows simulations of blood and soft tissues Pb (including brain) for the same exposure 

### 11

scenario s previously displayed . Pb uptake and elimination in soft tissues is much faster than bone. As a 

### 12

result, foll owing cessation of a period of elevated exposure, Pb in soft tissues is more quickly returned to 

### 13

blood. The terminal elimination phase from soft tissue mimics that of blood, and it is similarly influenced 

### 14

by the contribution of bone Pb returned to blood an d being redistributed to soft tissue. 

### 15May 2011 4

- 53 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 11

. Simulation of blood and soft tissue (including brain) Pb in children and adults who experience a period of increased Pb intake. Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

.

Information on Pb levels in human brain are limited to autopsy data and the simulation of brain Pb 

### 1

shown in Figure 4

- 12 reflects general concepts de rived from observations made in non

- human primates, 

### 2

dogs and rodents. These observations suggest that peak Pb levels in the brain are reached 6 months 

### 3

following a bolus exposure and within two months approximately 80% of steady state brain Pb levels are 

### 4

reached ( Leggett, 1993 ) . There is a relatively slow elimination of Pb from brain ( t 1/2 ≈ 2 years) compared 

### 5

to other soft tissues ( Leggett, 1993 ) . This slow elimination rate is reflected in the slower elimination 

### 6 0.0 0.2 0.4 0.6 0.8 1.0

0 2 4 6 8 10

0 2 4 6 8 10Total Soft Tissue Pb (mg)Blood Pb (μg/dL)

Age (year) Blood
Soft Tissue

0.0 0.4 0.8 1.2 1.6 2.0 2.4

0 2 4 6 8 10

25 30 35 40 45 50 55 60 65 70Total Soft Tissue Pb (mg)Blood Pb (μg/dL)

Age (year) Blood

Soft TissueMay 2011 4

- 54 DRAFT

– DO NOT CITE OR QUOTE phase kinetics in shown Figure 4

- 12 . Although in this model, brain Pb to blood Pb transfer half

- times are 

### 1

assumed to be the same in children and adults, uptake kinetics are assumed to be faster during infancy and 

### 2

childhood, which achieves a higher fraction of the soft tissue burd en in brain, consistent with higher 

### 3

brain/body mass relationships. This is reflected in the simulation as slower brain Pb accumulation in 

### 4

childre n. The uptake half times predicted by Leggett ( 1993 ) vary from 0.9 to 3.7 days, depending on age. 

### 5

Brain Pb kinetics represented in the simulations are simple outcomes of modeling assumptions and cannot 

### 6

currently be verified with available observations in humans. 

### 7May 2011 4

- 55 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 12

. Simulation of blood and brain Pb in children and adults who experience a period of in creased Pb intake. Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

.



## 4.3.7. Relationship Between Lead in Blood and Lead in
Urine

Urinary filtering and excretion of Pb is associated w ith plasma Pb concentration s. Given the 

### 1

curvilinear relationship between blood Pb and plasma Pb, a secondary expectation is for a curvilinear 

### 2

relationship between blood Pb and urinary Pb excretion that may become evident only at relatively high 

### 3 0 8 16 24 32 40 48

0 2 4 6 8 10

25 30 35 40 45 50 55 60 65 70Total Brain Pb (μg)Blood Pb (μg/dL)

Age (year) Blood

BrainMay 2011 4

- 56 DRAFT

– DO NOT CITE OR QUOTE blood Pb co n centrations (e.g., >25 μg/dL). Figure 4

- 13 shows these relationships predicted from the 

### 1

model. In this case, the exposure scenario shown is for an adult (age 40 years) at a quasi

- steady state 

### 2

blood Pb concentration; the same relationships hold for childre n. At low blood Pb concentrations ( < 25 

### 3

μg/dL), urinary Pb excretion is predicted to closely parallel plasma Pb concentration for any given blood 

### 4

Pb level (Figure 4

- 13

, top panel). It follows from this that, similar to blood Pb, urinary Pb will respond 

### 5

much more rapidly to an abrupt change in Pb exposure than will bone Pb. One important implication of 

### 6

this relationship is that, as described previously for blood Pb, the r elationships between urinary Pb and 

### 7

bone Pb will diverge with increasing exposure duratio n and age, even if exposure remains constant. 

### 8

Furthermore, following an abrupt cessation of exposure, urine Pb (i.e., not provoked by administration of 

### 9

chelating agents) will quickly decrease while bone Pb will remain elevated (Figure 4

- 13 , lower panel). 

### 10May 2011 4

- 57 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 13

. Top panel: Predicted relationship between plasma Pb concentration and urinary Pb excretion in an adult (age 40 years). Lower panel: Simulation of blood Pb, bone Pb and urinary excretion of Pb in an adult who experience s a period of increase d Pb intake. Simulation based on ICRP Pb
biokinetics model ( Leggett, 1993 )

. 0.00 0.05 0.10 0.15 0.20 0.25 0.30

0 20 40 60 80

0 10 20 30 40 50Plasma Pb (μg/dL)Urine Pb (μg/day)

Blood Pb ( μg/dL ) Urine Plasma



### 0 2 4 6 8 10

0 4 8 12 16

25 30 35 40 45 50 55 60 65 70Bone Pb (mg)Urine Pb (μg/day)Blood Pb (μg/dL)



### Age (year) Bone Urine BloodMay 2011 4

- 58 DRAFT

– DO NOT CITE OR QUOTE 

# 4.4. Observational S tudies of Lead E xposure

4.4.1. Lead in Blood

Overall, trends in blood Pb levels have been decreasing among U.S. residents over the past twenty 

### 1

years. Blood Pb concentrations in the U.S. general population have been monitored in the NHANES. 

### 2

Analyses of these data have shown a progressive downward tren d in blood Pb concentrat ions during the 

### 3

period 1976

- 2008 , with the most dramatic declines coincident with the phase out of leaded gasoline 

### 4

( Brody et al., 1994 ; Pirkle et al., 1994 ; Pirkle et al., 1998 ; J. Schwartz & Pitcher, 1989 ) . The temporal 

### 5

trend for the period 1988

- 2008 is shown in Figure 4

- 14. Summary statistics from the most recent 

### 6

publ ically available data (1999

- 2008 ) are presented in Table 4

- 7 ( CDC, 2011 )

. The geometric mean Pb 

### 7

concentration among children 1

- 5 years of age, based on the sample collected during the period 200 7

- 

### 8

2008 , was 1. 51 μg/dL (95% CI : 1. 37, 1.66 ) , which was a slight increase from the previous year (1.46 

### 9

μg/dL , 95% CI: 1.36, 1.57)

. Figure 4

- 15 uses NHANES data to illustrate the distribution of blood Pb 

### 10

levels among U.S. children aged 12

- 60 months. The median blood Pb in this age group was 1.4 μg/dL 

### 11

with a 95 th percentile value of 4.1 μg/dL ( NCHS, 2010 )

. For 2005

- 2008, 95% of childhood blood Pb 

### 12

levels were less than 5 μg/dL. 

### 13

When data wer e aggregated for years 1999

- 2004 , Pb concentrations in children were highest in the 

### 14

ethnicity category non

- Hispanic black (GM 2.8, 95% CI: 2.5, 3.0) compared to the categories Mexican



### 15

American (GM 1.9, 95% CI : 1.7, 2.0) and non

- Hispanic white (GM 1.7, 95% CI: 1.6, 1.8) ( Jones et al., 

### 16

2009 )

. Figure 4

- 16 demonstrates the change in percent of children with various blood Pb levels by 

### 17

race/ethnicity from 1988

- 1991 and 1999

- 2004. When these da ta were aggregated for the years 1988

- 2004, 

### 18

residence in older housing, poverty, age, and being non

- Hispanic black were significant risk factors for 

### 19

higher Pb levels ( Jones et al., 2009 )

. The geometric mean blood Pb concentration among adults ≥ 20 years 

### 20

of age was 1.38 μg/dL (95% CI: 1.31, 1.46 ) based on the sample collected during the period 2007

- 200 8 

### 21

( CDC, 2011 ) . Based on these same data, the geometr ic mean for all males was 1.47 μg/dL (95% CI: 1.39, 

### 22

1.56), and for fema les was 1.11 μg/dL (95% CI: 1.06, 1.16 ). 

### 23May 2011 4

- 59 DRAFT

– DO NOT CITE OR QUOTE Figure 4

- 14

. Temporal trend in blood Pb concentration. Shown are geometric means and 95% CIs based on data from NHANES III
Phase 1 ( Brody et al., 1 994 ; Pirkle et al., 1994 ) ; NHANES III
Phase 2 ( Pirkle et al., 1998 ) ; and NHANES IV ( CDC, 2011 ) . Data for adults during the period 1988

- 1994 are for ages 20

- 49 years, and ≥ 20 years for the period 1999

- 2008. 0 1 2 3 4 5

88

- 91 91

- 94 99

- 00 01

- 02 03

- 04 05

- 06 07

- 08Blood Lead (μg/dL)

Survey Period Children 1

- 5 yrs

Adults ≥ 20 yrsMay 2011 4

- 60 DRAFT

– DO NOT CITE OR QUOTE Table 4

- 7

. Blood Pb c oncentrations in the U.S

. p opulation

Survey Stratum Period Geometric Mean (μg/dL) 95% Confidence Interval Number of Subjects

All 1999

- 2000 1.66 1.60, 1.72 7970 2001

- 2002 1.45 1.39, 1.51 8945 2003

- 2004 1.43 1.36, 1.50 8373 2005

- 2006 1.29 1.23, 1.36 8407 2007

- 2008 1.27 1.21, 1.34 8266
1

- 5 yr 1999

- 2000 2.23 1.96, 2.53 723 2001

- 2002 1.70 1.55, 1.87 898 2003

- 2004 1.77 1.60, 1.95 911 2005

- 2006 1.46 1.36, 1.57 968 2007

- 2008 1.51 1.37, 1.66 817 6

- 11 yr 1999

- 2000 1.51 1.36, 1.66 905 2001

- 2002 1.25 1.14

, 1.36 1044 2003

- 2004 1.25 1.12

, 1.39 856 2005

- 2006 1.02 0.95, 1.01 934 2007

- 2008 0.99 0.91, 1.07 1011
12

- 19 yr 1999

- 2000 1.10 1.04, 1.17 2135 2001

- 2002 0.94 0.90, 0.99 2231 2003

- 2004 0.95 0.88, 1.02 2081 2005

- 2006 0.80 0.75, 0.85 1996 2007

- 2008 0.80 0.74, 0.86 1074

≥ 20 yr 1999

- 2000 1.75 1.68, 1.81 4207 2001

- 2002 1.56 1.49, 1.62 4772 2003

- 2004 1.52 1.45, 1.60 4525 2005

- 2006 1.41 1.34, 1.48 4509 2007

- 2008 1.38 1.31, 1.46 5364 Males 1999

- 2000 2.01 1.93, 2.09 3913 2001

- 2002 1.78 1.71, 1.86 4339 2003

- 2004 1.69 1.62, 1.75 4132 2005

- 2006 1.52 1.42, 1.62 4092 2007

- 2008 1.47 1.39, 1.56 4147 Females 1999

- 2000 1.37 1.32, 1.43 4057 2001

- 2002 1.19 1.14, 1.25 4606 2003

- 2004 1.22 1.14, 1.31 4241 2005

- 2006 1.11 1.05, 1.17 4315 2007

- 2008 1.11 1.06, 1.16 4119 Mexican

- Americans 1999

- 2000 1.83 1.75, 1.91 2742 2001

- 2002 1.46 1.34, 1.60 2268 2003

- 2004 1.55 1.43, 1.69 2085 2005

- 2006 1.29 1.21, 1.38 2236 2007

- 2008 1.25 1.15, 1.36 1712 Non

- Hispanic blacks 1999

- 2000 1.87 1.75, 2.00 1842 2001

- 2002 1.65 1.52, 1.80 2219 2003

- 2004 1.69 1.52, 1.89 2293 2005

- 2006 1.39 1.26, 1.53 2193 2007

- 2008 1.39 1.30, 1.48 1746 Non

- Hispanic whites 1999

- 2000 1.62 1.55, 1.69 2716 2001

- 2002 1.43 1.37, 1.48 3806 2003

- 2004 1.37 1.32, 1.43 3478 2005

- 2006 1.28 1.19, 1.37 3310 2007

- 2008 1.24 1.16, 1.33 3461

Source: Adapted from data from the NHANES ( CDC, 2011 )May 2011 4

- 61 DRAFT

– DO NOT CITE OR QUOTE Source: Adapted from data from the NHANES ( NCHS, 2010 ) Figure 4

- 15. Box plots of blood Pb levels among U.S. children (1

- 5 years old) from the NHANES survey, 1988

- 2008. Top : all data

. Bottom : data for subjects having blood Pb levels less than 15 μg/dL.May 2011 4

- 62 DRAFT

– DO NOT CITE OR QUOTE Data use d with permission from the American Academy of Pediatrics, Jones et al. ( 2009 ) Figure 4

- 16. Percent distribution of blood Pb levels by race/ethn icity among U.S. children (1

- 5 years) from the NHANES survey,
1988

- 1991 (top) and 1999

- 2004 (bottom).

Several studies have shown seasonal variation in blood Pb concentrations in children ( B. Gulson et 

### 1

al., 2008 ; D. L. Johnson et al., 1996 ; Laidlaw et al., 2005 ) . Seasonal variation in blood Pb concentration 

### 2

was also evident in individual children when repeated blood Pb measurements were made over a 5

- year 

### 3 0 10 20 30 40 50 60 70

< 1 1

- < 2.5 2.5

- < 5 5

- < 7.5 7.5

- <10 ≥ 10Percent of Children 1988

- 1991

0 10 20 30 40 50 60 70

< 1 1

- < 2.5 2.5

- < 5 5

- < 7.5 7.5

- <10 ≥ 10Percent of Children

Blood Pb Level (ug/dL)

Non

- Hispanic black Mexican American Non

- Hispanic white 1999

- 2004May 2011 4

- 63 DRAFT

– DO NOT CITE OR QUOTE period ( B. Gulson et al., 2008 ) . Meteor o logical factors appear to contribute to blood Pb seasonality. 

### 1

Laidlaw et al. ( 2005 ) analyzed the temporal relationships between child blood Pb concentrations and 

### 2

various atmospheric variables in three cites (Indianapolis, IN; Syracuse, NY; New Orleans, LA). Blood 

### 3

Pb data was obtained from public hea lth screening programs conducted in the three cities during 

### 4

1998

- 2003. B lood Pb sample s were domina ted by children <5 years of age and age distribution v aried 

### 5

across the three cities. The number of blood Pb measurements included in the analyses were as fol lows: 

### 6

Indianapolis, 15,969; Syracuse, 14,457 ( D. Johnson & Bretsch, 2002 ; D. L. Johnson et al., 1996 ) ; New 

### 7

Orleans, 2,295 ( Mielke et al., 2007 ) . The temporal variation in blood Pb concentrations in each city were 

### 8

predicted by multivariate regression models that included th e following significant variables: PM 10 , wind 

### 9

speed, air temperature, and soil moisture; as well as dummy variables accounting for temporal 

### 10

displacement of the effects of each independent variable on blood Pb. Laidlaw et al. ( 2005 ) reported R 2 

### 11

values for the regression models

, but did not report the actual regression coefficients. The R 2 values were 

### 12

as follows: Indianapolis 0.87 (p = 0.004); Syracuse 0.61 (p = 0.0012); New Orleans 0.59 (p <0.00001). 

### 13

This analysis provides a possibl e explanation for the seasonal patterns of blood Pb concentrations in 

### 14

children that involves weather

- dependent entrainment and air transport of surface dusts. 

### 15

Trends in blood Pb levels have been accompanied by changes in Pb isotope ratios within blood Pb. 

### 16

Isotopic ratios, described in Sections 3.2 and 3.3 as a tool for source apportionment, have been used to 

### 17

associate blood Pb measurements with anthropogenic sources of Pb in the environment. Changes in Pb 

### 18

isotopic ratios in blood samples reflect the changin g influence of sources of Pb following the phase

- out of 

### 19

tetraethyl Pb antiknock agents in automotive gasoline and changes in Pb usage in paints and other 

### 20

industrial and consumer products ( B. Gulson et al., 2006a ; B. Gulson et al., 2008 ; Ranft et al., 2006

, 

### 21

2008 )

. Gulson et al. ( 2006a ) illustrated how a linear increase in the isotopic ratio 206 Pb/ 204 Pb occurred in 

### 22

concert with a decrease in blood Pb levels among various study populations in Aust ralia during the period 

### 23

1990

- 2000 (Figure 4

- 17). Gulson et al. ( 2006a ) point out that the isotopic signature of 206 Pb/ 204 Pb derived 

### 24

from Australian mines (median ~16.8) differs from that of European and Asian mines, where 206 Pb/ 204 Pb 

### 25

varies between ~17.4 and ~18.1. Liang et al. ( 2010 ) also examined the trends in blood Pb level over the 

### 26

period 1990 to 2006 in Shanghai and saw a reduction corresponding to the phase out of Pb in gasoline. A 

### 27

plot of 208 Pb/ 206 Pb to 207 Pb/ 206 Pb for blood and environmental samples showed overlap between the 

### 28

isotopic signature for coal combustion ash and that measured in blood. This result suggests a growing 

### 29

influence of Pb from coal ash i n Shanghai in the absence of Pb in automobile emissions. 

### 30May 2011 4

- 64 DRAFT

– DO NOT CITE OR QUOTE Source: Used with permission from Academic Press, Gulson et al. ( 2006 a ) Figure 4

- 17. a) Trends in 206 Pb/ 204 Pb isotope ratio in blood Pb and b) trends in blood Pb levels among Australian study populations during the period 1990

- 2000.



## 4.4.2. Lead in Bone

An extensive national database (i.e., NHANES) is available for blood Pb con centrations in children 

### 1

and adults, as described in Section 4.4.1. Bone Pb concentrations are less well characterized. Tables 4

- 8 

### 2

and 4

- 9 are compilations of data from epidemiologic studies that provided bone Pb concentrations and/or 

### 3

variability in concent rations among individuals without reported occupational exposure and those with 

### 4

occupational exposures, respectively. In non

- occupationally exposed individuals, typical group mean tibia 

### 5

bone Pb concentrations ranged from 10 to 30 μg/g. Patella bone Pb leve ls are typically higher than tibia 

### 6

bone Pb levels in the studies considered (Table 4

- 8). For example, in the Normative Aging Study, patella 

### 7

bone Pb concentrations were approximately 32 μg/g, whereas tibia bone Pb concentrations were about 22 

### 8

μg/g. Occupati onally exposed individuals generally had greater bone Pb concentrations than seen in 

### 9

control groups (i.e., unexposed). Bone Pb data in Table 4

- 9 for occupationally exposed individuals were 

### 10

also generally higher compared to non

- occupationally exposed indivi duals (Table 4

- 8). 

### 11May 2011 4

- 65 DRAFT

– DO NOT CITE OR QUOTE Table 4

- 8. Epidemiologic studies that provide bone Pb measurements for non

occupationally exposed populations

Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Bandeen

- Roche et al. ( 2009 ) Baltimore Memory Study cohort 50

- 70 1140 Baltimore, MD 2001

- 2005 Cumulative Tibia Mean ± SD Tibia: 18.8 ± 11.6 Not reported

Bellinger et al. ( 1994 ) Not reported 5

- 8 (recruited) 19

- 20 (follow

- up) 79 Boston, MA 1989

- 1990 Cumulative Tibia Patella Mean (Range) : Tibia: 5.4 (3

- 16)

Patella: 9.2 (4

- 18) High
exposure: >24 Low
exposure: <8.7

Cheng et al. ( 2001 ) Normative Aging Study cohort Mean ± SD: Normotensive : 65.49 ± 7.17 Borderline hypertension: 68.3 ± 7.79 Definite hypertension: 67.93 ± 6.79 833 males Boston, MA 8/1/1991

- 12/31/1997 Cumulative Tibia Patella Mean ± SD Tibia: Normotensive : 20.27 ± 11.55 Borderline hypertension: 23.46 ± 15.02 Definite hypertension: 22.69 ± 14.71

Patella : Normotensive : 28.95 ± 18.01 Borderline hypertension: 33.73 ± 21.76 Definite hypertension: 32.72 ± 19.55 Lowest quintile: Tibia: 8.5 Patella: 12.0

Highest quintile: Tibia: 36.0 Patella: 53.0

Coon et al. ( 2006 ) Participants from Henry Ford Health System (HFHS) ≥ 50 Mean: 69.9 121

cases 414 controls Southeastern Michigan 1995

- 1999 (participants received primary health care services) Cumulative Tibia Calcaneu

s Mean ± SD: Tibia: 12.5 ± 7.8 Calcaneus : 20.5 ± 10.2 Tibia Q1: 0

- 5.91 Q2: 5.92

- 10.40 Q3: 10.41

- 15.50 Q4: ≥ 15.51

Calcaneus Q1: 0

- 11.70 Q2: 11.71

- 19.07 Q3: 19.08

- 25.28 Q4: ≥ 25.29 Elmarsafaw y et al. ( 2006 ) Normative Aging Study Not reported 471 elderly

m ales Greater Boston area, MA 6/1991

- 12/1994 Not reported Tibia Patella Mean ± SD: Tibia: 21.6 ± 1 2.0 Patella: 31.7

± 18.3 Not reported

Glass et al., ( 2009 ) Baltimore Memory Study Mean: 59.4 Range: 50

- 70 1,001 Baltimore, MD 2001

- 2005 Cumulative (lifetime) Tibia Mean ± SD: Tibia: 18.8 ± 11.1 NPH Scale: Lowest tertile: Mean Tibia level: 16.3 ± 11.0

Middle tertile: Mean Tibia level: 19.3 ± 10.7

Highest tertile: Mean Tibia level: 20.3 ± 11.4May 2011 4

- 66 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Hsieh et al. ( 2009 ) Not reported Mean: Control: 46.06 18 controls Not reported Not reported Control group for occupational
exposure group Tibia Patella Mean ± SD Tibia Control: 18.51 ± 22.40 Patella Control: 7.14

± 9.81 Not reported

Hu et al. ( 1996 ) (As reported in Navas

Acien et al., ( 2008 ) ) Normative Aging Study 48

- 92 Mean ± SD: 66.6 ± 7.2 590 males Boston, MA 8/1991

- 12/1994 Cumulative Tibia Patella Mean ±SD : Tibia: 21.8 ± 12.1 Patella: 32.1

± 18.7

Range: Tibia: <1

- 96 Patella: 1

- 142 Figures 1 and 2 show both types of bone Pb levels increasing with age

Jain et al. ( 2 007 ) VA

Normative Aging Study Not reported 837 males Greater Boston, MA 9/1/1991

- 12/31/2001 Not reported Tibia Patella Mean ± SD Tibia: Non

- Cases: 21.4 ± 13.6 C ases : 24.2 ± 15.9

Patella: Non

- cases : 30.6 ± 19.7 Cases : 36.8 ± 20.8

Range: Tibia: Noncases:

- 3

- 126 Cases:

- 5

- 75

Patella: Noncases:

- 10

- 165 Cases: 5

- 101 Mean ± SD (Range):

Tibia: Non

- cases: Tertile 1: 10.2 ± 3.8 (

- 3

- 15) Tertile 2: 19.1 ± 2.3 (16

- 23) Tertile 3: 35.5

± 14.4 (24

- 126)

Cases: Tertile 1: 10.1

± 5.3 (

- 5

- 15) Tertile 2: 19.8 ± 2.2 (16

- 23) Tertile 3: 39.5 ± 14.9 (25

- 75)

Patella: Non

- cases: Tertile 1: 13.9 ± 4.9 (

- 10

- 20) Tertile 2: 27.1 ±4.1 (21

- 34) Tertile 3: 52.5 ± 20.7 (35

- 165)

Cases: Tertile 1: 15.3 ± 4.3 (5

- 19) Tertile 2: 25.7 ± 3.8 (21

- 33) Tertile 3: 53.3

± 17.3 (35

- 101) Kamel et al. ( 2002 ) ; Kamel et al. ( 2005 ) ; Kamel et al. ( 2008 ) Not reported 30

- 80 256 controls (Bone samples collecte d from 41 controls ) New England (Boston, MA) 1993

- 1996 Cumulative Control group for occupational
exposure group Tibia Patella Mean ± SE Tibia Controls: 11.1

± 1.6 Patella Controls: 16.7 ± 2.0 Controls Tibia: N (%)

- 7

- 7: 14 (34) 8

- 14: 12 (29) 15

- 61: 15 (37)

Patella: N (%)

- 4

- 9: 14 (34) 10

- 20: 14 (34) 21

- 107: 13 (32) Khalil et al. ( 20 09 ) 1982 Pb Occupational Study Control mean: 55 51 controls Eastern Pennsylvania 1982

- 2004 Control group for occupational
exposure group Tibia Median (IQR) Tibia Control : 12 (

- 8

- 32) Not reportedMay 2011 4

- 67 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Korrick et al. ( 1999 ) (As reported in from Navas

Acien et al., ( 2008 ) Nurses’ Health Study Combined: 47

- 74 Mean ± SD: Combined: 58.7 ± 7.2 Cases: 61.1 ± 7.1 High controls: 61.1 ± 7.2 Low controls: 58.7 ± 7.1 284 females (89

cases; 195 controls ) Boston, MA 7/1993

- 7/1995 Nonoccupationall y exposed Tibia Patella Mean ± SD Tibia: Combined: 13.3 ± 9.0 Cases: 13.0 ± 9.4 High controls: 14.7 ± 10 Low controls: 12.7 ± 8.1

Patella: Combined: 17.3 ± 11.1 Cases: 19.5 ± 12.9 High controls: 17.2 ± 9 Low controls: 15.8 ± 10.6

Range Ti bia Combined:

- 5

- 69 Patella Combined:

- 5

- 87 Patella: 10th percentile: 6 90th percentile: 31

Lee et al. ( 2001 ) (As reported in Navas

- Acien et al., ( 2008 ) ) Not reported 22.0

- 60.2 Mean ± SD: Contr ols: 34.5 ± 9.1 135 controls Republic of Korea 10/24/1997

- 8/19/1999 Control group for occupational
exposure group Tibia Mean ± SD Tibia Controls: 5.8

± 7.0

Range Tibia Controls:

- 11

- 27 Not reported

Martin et al. ( 2006 ) Baltimore Memory Study 50

- 70 Mean: 59.4 964 Baltimore, MD 5/2001

- 9/2002 (1 st study visit) 8/2002

- 3/2004 (2 nd study visit

– tibia Pb measured) Cumulative (lifetime) Tibia Mean ± SD Tibia: 18.8 ± 12.4 Tibia IQR: 11.9

- 24.8

Needleman et al. ( 2002 ) Not reported 12

- 18 Mean age ± SD : African American cases: 15.8 ± 1.4 African American controls: 15.5 ± 1.1 White cases: 15.7 ± 1.3 White controls: 15.8 ± 1.1 194 male youth

cases 146 male youth controls Allegheny County, PA (cases); Pittsburgh, PA (controls) 4/1996

- 8/1998 Not reported Tibia Mean ± SD Tibia Cases ( ppm) : All subjects: 11.0 ± 32.7 African American: 9.0 ± 33.6 White: 20 ± 27.5 Tibia Controls (ppm) : All subjects: 1.5 ± 32.1 African American:

- 1.4 ± 31.9 White: 3.5 ± 32.6 Table 4 distributes bone Pb by ≥ 25 or <25 for race, two parental figures, and parent occupation

Osterberg et al. ( 1997 ) ( As reported in Shih et al., ( 2007 ) ) Not reported Median: 41.5 19 male controls Not reported Not reported Control group for occupational exposure group Finger bone Median (range) Finger Bone Controls: 4 (

- 19

- 18) Not reportedMay 2011 4

- 68 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Park et al. ( 2006 ) Normative Aging Study Mean: 72.9 ± 6.5 413 males Greater Boston, MA 11/14/2000

- 12/22/2004 (HRV
measurement s taken) 1991

- 2002 (bone Pb measurement s taken) Not reported Tibia Patella M edian (IQR)

Tibia: 19.0 (11

- 28) Patella: 23.0 (15

- 34) Estimated Patella a : 16.3 (10.4

- 25.8) Median (IQR) for No. of metabolic abnormalities

:

Tibia: 0: 18.5 (10.5

- 23) 1: 19 (11

- 28) 2: 19 (12

- 26)

Patella: 0: 22 (13.5

- 32) 1: 25 (16

- 36) 2: 20 (15

- 32)

Estimated Patella: 0: 16.3 (10.8

- 24.8) 1: 17.1 (11

- 29.3) 2: 15.1 (9.4

- 22.1) Park et al. ( 2009 ) Normative Aging Study Mean: 67.3 ± 7.2 613 males Greater Boston, MA 8/1991

- 12/1995 Not reported Tibia Patella Median (IQR)

Tibia: 19 (14

- 27) Patella: 26 (18

- 37) Table 1 distributes tibia and patella Pb by genotype; Table 2 distributes tibia and patella Pb by number of gene variants Park et al. ( 2010 ) VA Normative Aging Study cohort Mean: 64.9 (at bone Pb
measurement ) 448 males Eastern Massachusett

s 1991

- 1996 Cumulative (chronic exposure) Tibia Patella Mean ± SD Tibia: 22.5 ± 14.2 Patella: 32.5

± 20.4 Tibia IQR: 15 Patella IQR: 21

Table 2 provides age

adjusted mean bone Pb levels (age, race, education, smoking [pack

- yr], occupational noise, noise notch, BMI, hypertension, diabetes) Payton et al. ( 1998 ) VA Normative Aging Study cohort Mean: 66.8 141

m ales Boston, MA 4/1993

- 3/1994 Not reported Tibia Patella Mean ± SD Tibia: 22.5 ± 12.2 Patella: 31.7 ± 19.2 Not reported

Peters et al. ( 2007 ) Normative Aging Study cohort Mean: 66.9 513 male

cases Boston, MA 1991

- 1996 Cumulative Tibia Patella Mean ± SD Tibia: 21.5 ± 13.4 Patella: 31.5

± 19.3 Not reported

Rajan et al. ( 2007 ) VA Normative Aging Study Cohort Mean: 67.5 (at bone scan) 1075 males Boston, MA 1991

- 2002 Not reported Tibia Patella Mean ± SD Tibia : 22.1 ± 13.8 Patella: 31.4

± 19.6 Not reportedMay 2011 4

- 69 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g) Rajan et al. ( 2008 ) VA Normative Aging Study Cohort ≥ 45 720 males Boston, MA 1993

- 2001 Current and cumulative Tibia Patella Mean ± SD ALAD 1

- 1 Tibia: 21.9 ± 13.8 Patella: 29.3

± 19.1 ALAD 1

- 2/2

- 2 Tibia: 21.2 ± 11.6 Patella: 27.9

± 17.3 Not reported

Rhodes et al. ( 2003 ) VA Normative Aging Study Cohort Mean: 67.1 526 males Boston, MA 1/1/1991

- 12/31/1995 Not reported Tibia Patella Mean ± SD Tibia: 21.9 ± 13.5 Patella: 32.1

± 19.8 No. of participants (%) Tibia: <1

- 15: 173 (33) 16

- 24: 186 (35) 25

- 126: 167 (32)

Patella: <1

- 22: 189 (36) 23

- 35: 165 (31) 36

- 165: 172 (33) Roels et al. ( 1994 ) Not reported 30

- 60 68 males Belgium Not reporte d Control group for occupational
exposure group Tibia Geometric Mean (Range)

Tibia Controls: Normotensive : 21.7 (<15.2

- 69.3) Hypertensive: 20.2 (<15.2

- 52.9) Total: 21.4 (<15.2

- 69.3) Not reported

Rothenberg et al. ( 2002 ) (As reported in Navas

Acien et al., ( 2008 ) ) Not reported 15

- 44 Mean ± SD: 31.0 ± 7.7 720 females Los Angeles, CA 6/1995

- 5/2001 Not reported Tibia Calcaneu

s Mean ± SD Tibia: 8.0 ± 11.4 Calcaneus: 10.7 ± 11.9 Tibia quartiles: Q1:

- 33.7

- 0.9 Q2: 1.0

- 8.0 Q3: 8.1

- 16.1 Q4: 16.2

- 42.5

Calcaneus quartiles: Q1:

- 30.6

- 3.0 Q2: 3.1

- 10.0 Q3: 10.1

- 18.7 Q4: 18.8

- 49.0 Shih et al., ( 2006 ) Baltimore Memory Study cohort Mean: 59.39 985 Balti more, MD Not reported Not reported Tibia Mean ± SD : Tibia: 18.7 ± 11.2 Not reportedMay 2011 4

- 70 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Stokes et al. ( 1998 )

, a s reported in Shih et al., ( 2007 ) Not reported 19

- 29 (in 1994) Mean ± SD: Cases: 24.3 ± 3.18 Control: 24.2

± 3.02 Cases: 9 months

- 9 yr (during 1/1/1974

- 12/31/1975) 257

cases 276 controls Silver Valley, ID; Spokane, WA 7/10/1994

- 8/7/1994 Cumulative (lifelong) Environmental (resided near Pb smelter during childhood) Tibia Mean (Range) : Tibia Cases: 4.6 (

- 28.9

- 37) Tibia Controls: 0.6 (

- 46.4

- 17.4) Tibia No. of Cases: <1 μ g/g: 31.5 % 1

- 5 μ g/g: 24.4% 5

- 10 μ g/g: 22.3% >10 μ g/g: 21.8%

No. of Controls: <1 μ g/g: 50.4% 1

- 5 μ g/g: 25.6% 5

- 10 μ g/g: 19.4% >10 μ g/g: 4.7%

Mean ± SD Tibia concentration by age group: Cases: 19

- 21: 1.47 ± 8.35 22

- 24: 4.48 ± 7.45 25

- 27: 4.82 ± 8.92 28

- 30: 6.64 ± 9.53

Controls: 19

- 21: 1.27 ± 6.60 22

- 24:

- 0.61

± 6.19 25

- 27: 0.60 ± 8.60 28

- 30: 1.74 ± 6.42 Van Wijngaarde n et al. ( 2009 ) Not reported Mean: 61.5 47 Rochester, NY Not reported Cumulative Tibia Calcaneu

s Mean ± SD Tibia : 2.0 ± 5.2 Calcaneus : 6.1 ± 8.5 Not reported

Wasserman et al. ( 2003 ) Yugoslavia Prospective Study of Environment al Pb Exposure 10

- 12 167 children Kosovska, Mi trovica, Kosovo, Yugoslavia; Pristina, Kosovo, Yugoslavia 5/1985

- 12/1986 (mother’s enrollment) 1986

- 1999 (follow

- up through age 12 yr) Tibia Pb measured 11

- 13 yr old Cumulative (lifetime) Environmental (Pb smelter, refinery, battery plant) Tibia Mean ± SD: Tibia Pristina: 1.36

± 6.5 Mitrovica: 39.09 ± 24.55 Tibia quartiles: Q1:

- 14.4

- 1.85 Q2: 1.85

- 10.5 Q3: 10.5

- 35 Q4: 35

- 193.5

Table 3 distributes tibia Pb by sex, ethnicity, address at birth relative to factory, and maternal educationMay 2011 4

- 71 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g) Weisskopf et al. ( 2004 ) , as reported in Shih et al. 194225 ( 2007 ) Normative Aging Study Mean ± SD: 67.4 ± 6.6 466 males Boston, MA 1991

- 2002 Environmental Tibia Patella Median (IQR) Tibia: 19 (12,26) Patella: 23 (15, 35) Tibia IQR: 14 Patella IQR: 20

Table 3 shows mean Pb levels across cate

gor ical variables (yr of education,

smo king status, computer exper ience, first language English) Weisskopf et al. ( 2007 ) VA Normative Aging Study cohort Mean: Lowest Patella quintile: 73.2 Highest Patella quintile: 80.7 31 males Boston, MA Bone Pb measured: 1994

- 1999 Scans performed: 2002

- 2004 Not reported Tibia Patella Median (IQR) Tibia Lowest quin

tile: 13 (9

- 17) Highest quin

- tile: 41 (38

- 59)

Patella Lowest quin

tile: 9 (5

- 15) Highest quin

tile: 63 (43

- 86) Not reported

Weisskopf et al. ( 2007 ) VA Normative Aging Study cohort Mean: 68.7 1,089 males Boston, MA 1993

- 2001 Concurrent and cumulative Tibia Patella Median (IQR) Tibia : 20 (13

- 28) Patella: 25 (17

- 37) Table 1 shows the distribution of Pb biomarkers by ca te gories of co var iates (age, edu

cation, smo

king status, alco hol intake, physi

cal activity,

com pu ter experience, first language English) Weisskopf et al. ( 2009 ) Normative Aging Stud y (95% white) Mean ± SD (at Patella baseline) Tertile 1: 65.2

± 7.1 Tertile 2: 66.5

± 6.5 Tertile 3: 70.2

± 7.2 868 males Greater Boston area, MA 1991

- 1999 Cumulative Tibia Patella Mean ± SD Tibia: 21.8 ± 13.6 Patella: 31.2

± 19.4 Patella tertiles: 1: <22 2: 22

- 35 3: >35

Weisskopf et al. ( 2010 ) BUMC, BWH, BIDMC, HVMA, Normative Aging Study (NAS), Harvard Cooperative Program on Aging (HCPOA) Mean: Cases: 66.5 Controls: 69.4 330

cases 308 controls Boston, MA 2003

- 2007 1991

- 1999 (NAS patients bone Pb measured) Cumulative Tibia Patella Mean ± SD: Tibia: 10.7 ± 12.1 Patella: 13.6

± 15.9 Tibia quartiles: Q1: <3.1 Q2: 3.5

- 9.6 Q3: 10.0

- 17.0 Q4: >17.3

Patella quartiles: Q1: <2.7 Q2: 3.5

- 11.0 Q3: 11.3

- 20.9 Q4: > 20.9May 2011 4

- 72 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (yrs) N Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. ( μ g/g) Distribution of Bon e Pb

( μ g/g)
Weuve et al. ( 2006 ) VA Normative Aging Study cohort ≥ 45 720 males Boston, M A 1991 (measuring bone Pb levels) End date not reported Cumulative Tibia Patella Median ( 1st

- 3rd quartile): Tibia: 19 (13

- 28) Patella: 27 (18

- 39) Table 1 shows distribution of mean Pb bio

- marker levels by characteristic s of participants (age, education,

com pu ter exper ience, smoking status, alcohol
consump tion, tertile of cal

cium intake, tertile of physical activity, diabetes) Weuve et al. ( 2009 ) Nurses’ Health Study cohort 47

- 74 587 females Boston, MA 1995

- 2005 Recent and cumulative Tibia Patella Mean ± SD: Tibia: 10.5 ± 9.7 Patella: 12.6 ± 11.6 Not reported

Wright et al. ( 2003 ) , a s reported in Shih et al. 194225 ( 2007 ) Normative Aging Study Mean ± SD: 68.2 ± 6.9 736 males Boston, MA 1991

- 1997 Environmental Tibia Patella Mean ± SD:

Tibia: 22.4 ± 15.3 Patella: 29.5

± 21.2 Tibia: Difference in

mean from Lowest

- highest quartile: 34.2

Patella: Difference in mean from lowest

highest quartile: 47May 2011 4

- 73 DRAFT

– DO NOT CITE OR QUOTE Table 4

- 9. Epidemiologic studies that provide bone Pb measurements for occupationally exposed populations

Reference Cohort Age (years) Number of Subjects Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration ( μ g/g) Distribution of Bone Pb

( μ g/g)

Bleecker et al. ( 1997 ) ( As reported in Shih et al., ( 2007 ) ) Canada Lead Study Cumulative: 24

- 64 Younger: 24

- 43 Older: 44

- 64 Mean ± SD: Cumulative: 44.1 ± 8.36 Younger: 37.2 ± 4.57 Older: 50.9

± 4.86 80 males Canada Not reported Occupational (Pb smelter workers) Tibia Mean ± SD (Tibia) : Cumulative: 41.0

± 24.44 Younger: 35 ± 24.11 Older: 46.9 ± 23.59

R ange (Tibia) : Cumulative:

- 12

- 90 Younger:

- 12

- 80 Older: 3

- 90 Not reported

Bleecker et al. ( 2007 ) Not reported Mean: 39.7 61 Northern Canada Not reported Occupational (primary Pb smelter workers) Tibia Mean: Tibia: 38 .6 Not reported

Caffo et al. ( 2008 ) Not reported Mean: 60.39 513 males Delaware and New Jersey, US 1994

- 1997 (Phase 1 recruitment ) 2001

- 2003 (Phase 2 recruitment ) Cumulative Occupational (Former organolead manufacturin g workers) Tibia Mean ± SD: Peak Tibia: 23.99 ± 18.46 Not reported

Dorsey et al. ( 2006 ) Not reported Mean: 43.4 652 Korea 10/24/1997

- 8/19/1999 (enrolled) Occupational (Pb workers) Tibia Patella Mean ± SD: Tibia : 33.5 ± 43.4 Patella : 75.1 ± 101.1 Not reported

Glenn et al. ( 2003 ) , as reported in Navas

- Acien et al., ( 2008 ) Not reported 40

- 70 Mean: 55.8 (baseline) 496 males Eastern U.S. 6/1994

- 6/1996 (enrolled) 6/1998 (follow

- up period ended) Occupational (Chemical manufacturin g facility; inorganic and organic Pb) Tibia Mean ± SD: Tibia: 14.7 ± 9.4 (at yr 3) Peak Tibia: 24.3 ± 18.1

Range: Tibia:

- 1.6

- 52 (at year 3) Peak Tibia:

- 2.2

- 118.8 Not reported

Glenn et al. ( 2006 ) Not reported 0

- 36.2 (baseline) Mean ± SD: 41.4 ± 9.5 (baseline) 575 (76% male; 24% female) South Korea 10/1997

- 6/2001 Cumulative and recent Occupational (Pb

- using facilities) Tibia Mean ± SD: Tibia: 38.4 ± 42.9

Tibia

- Women: Visit 1: 28.2 ± 19.7 Visit 2: 22.8 ± 20.9

Tibia

- Men: Visit 1: 41.7 ± 47.6 Visit 2: 37.1 ± 48.1 Not reportedMay 2011 4

- 74 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (years) Number of Subjects Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration ( μ g/g) Distribution of Bone Pb

( μ g/g)

Hanninen et al. ( 1998 ) , as reported in Shih et al., ( 2007 ) Not reporte d Mean ±SD : Male: 43 Female: 48 BPb(max)
≤ 2.4
μ mol/L: 41.7

± 9.3 BPb (max) >2.4 μ mol/L: 46.6 ± 6.2 54 (43 males, 11 females) Helsinki, Finland Not reported Occupational (Pb acid battery factory workers) Tibia Calcaneus Mean ± SD:

Tibia: BPb (max)
≤ 2.4 μ mol/L: 19.8 ± 13.7 BPb (max) >2.4 μ mol/L: 35.3 ± 16.6

Calcaneus: BPb (max)

≤ 2.4 μ mol/L: 78.6 ± 62.4 BPb (max) >2.4 μ mol/L: 100.4 ± 43.1 Not reported

Hsieh et al. 2009 ( 2009 ) Not reported Mean: Cases: 45.71 Controls: 46.06 22 cases 18 controls Location NR Not reported Occupational (Pb paint factory workers) Tibia Patella Mean ± SD Tibia Case: 61.55 ± 30.21 Control: 18.51 ± 22.40

Patella Case: 66.29 ± 19.48 Control: 7.14 ± 9.81 Not reported

Kamel et al. ( 2002 ) ; Kamel et al. ( 2005 ) ; Kamel et al. ( 2008 ) Not reported 30

- 80 109 cases 256 controls (Bone samples collected from 104 cases and 41 controls) New England (Boston, MA) 1993

- 1996 Cumulative Occupational (Pb fumes, dust, or particles) Tibia Patella Mean ± SE Tibia Cases: 14.9 ± 1.6 Controls: 11.1 ± 1.6

Patella Cases: 20.5 ± 2.1 Controls: 16.7 ± 2.0 Cases Tibia Pb: N (%)

- 7

- 7: 21 (20) 8

- 14: 35 (34) 15

- 61: 48 (46)

Patella Pb: N (%)

- 4

- 9: 27 (26) 10

- 20: 40 (38) 21

- 107: 37 (36)

Controls Tibia Pb: N (%)

- 7

- 7: 14 (34) 8

- 14: 12 (29) 15

- 61: 15 (37)

Patella Pb: N (%)

- 4

- 9: 14 (34) 10

- 20: 14 (34) 21

- 107: 13 (32) Khalil et al. ( 2009 ) 1982 Pb Occupationa l Study cohort Mean: Cases: 54 Controls: 55 83 cases 51 controls Eastern Pennsylvani

a 1982

- 2004 Occupational (Pb battery plant workers) Tibia Median (IQR) Tibia Cases: 57 (20

- 86) Controls: 12 (

- 8

- 32) Not reported

Osterberg et al. ( 1997 ) , as reported in Shih et al. ( 2007 ) Not reported Median: 41.5 38 male

cases 19 male controls Not reported Not reported Occupational (secondary Pb smelter

– inorganic Pb) Finger bone Median Finger Bone: High Cases: 32 Low cases: 16 Control: 4

Range Finger Bone: High Cases: 17

- 101 Low cases:

- 7

- 49 Control:

- 19

- 18 Not reportedMay 2011 4

- 75 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (years) Number of Subjects Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration ( μ g/g) Distribution of Bone Pb

( μ g/g)

Roels et al. ( 1994 ) Not reported 30

- 60 76 male

cases 68 male controls Belgium Not reported Occupational (Pb smelter workers) Mean case exposure: 18 yr (range: 6 to 36 yr) Tibia Geometric Mean (Range)

Tibia Cases: Normotensive: 64.0 (19.6

- 167.1) Hypertensive: 69.0 (21.7

- 162.3) Total: 65.8 (19.6

- 167.1)

Tibia Controls: Normotensive: 21.7 (<15.2

- 69.3) Hypertensive: 20.2 (<15.2

- 52.9) Total: 21.4 (<15.2

- 69.3) Not reported

Schwar tz ( 2000 ) et al.

, as reported in Shih et al., ( 2007 ) U. S. Organolead Study Mean ± SD: Cases: 55.6

± 7.4 Controls: 58.6 ± 7.0 535 male

cases 118 male controls Eastern U.S. 6/1994

- 10/1997 (enrolled) Completed 2

- 4 annual follow

- up visits Tibia Pb taken in 3 rd year Occupational (tetraethyl and tetramethyl Pb manufacturin g facility) Tibia Mean ± SD Current Tibia: Cases: 14.4 ± 9.3

Peak Tibia: Cases: 22.6 ± 16.5 Not reported

Schwartz et al. ( 2000 ) , as reported in Navas

- Acien et al. ( 2008 ) Not reported 41.7

- 73.7 (Combined) Mean ± SD: Combined: 57.6 ± 7.6 Hypertensiv e: 60.2 ± 6.9 Nonhyperte nsive: 56.6

± 7.5 543 males Eastern U.S. 1995 (recruited) 1996

- 1997 (Tibia Pb taken during the 3rd yr) Occupational (former organolead manufacturin g workers) Tibia Mean ± SD Tibia: Combined: 14.4

± 9.3 Hypertensive: 15.4 ± 9.1 Nonhypertensive : 14.0 ± 9.3

Range Tibia: Combined :

- 1.6

- 52 Not reported

Schwartz et al. ( 2001 ) ; Lee et al. ( 2001 ) Not reported Mean: Exposed: 40.4 Control: 34.5 803 cases 135 controls South Korea 10/24/1997

- 8/19/1999 Occupational (battery manufacturin g, secondary smelting, Pb oxide manufacturin g, car radiator manufacturin g) Tibia Mean ± SD Tibia Cases: 37.1 ± 40.3 Control: 5.8 ± 7.0 Range: Tibia Cases:

- 7

- 338 Controls:

- 11

- 27 Not repor ted

Schwartz et al. ( 2005 ) Not reported Mean at 1 st

v isit: 41.4 576 South Korea 10/1997

- 6/2001 Occupational (current and former Pb workers) Tibia Mean ± SD Tibia: 38.4 ± 43 Tibia: 25 th percentile at V1: 14.4 75 th percentile at V1: 47.1May 2011 4

- 76 DRAFT

– DO NOT CITE OR QUOTE Reference Cohort Age (years) Number of Subjects Location Study Period Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration ( μ g/g) Distribution of Bone Pb

( μ g/g)

Stewart et al. ( 1999 ) , as reported in Shih et al., ( 2007 ) U.S. Organolead Study 40

- 70 (in 1995) 38% ≥ 60 yrs Mean: 58 534 males Eastern U.S. Not reported Occupational (tetraethyl and tetramethyl Pb manufacturin g facility) Tibia Mean ± SD Tibia: Current: 14.4 ± 9.3 Peak: 23.7 ± 17.4

Range: Tibia Current:

- 1.6

- 52 Peak:

- 2.2

- 105.9 Current Tibia Pb: N (%) <5: 77 (14.2) 5

- 9.99: 113 (20.8) 10

- 14.99: 119 (21.9) 15

- 19.99: 117 (21.5)

≥ 20: 118 (21.7)

Peak Tibia Pb: N (%) <5: 49 (9.1) 5

- 9.99: 64 (11.8) 1 0

- 14.99: 70 (12.9) 15

- 19.99: 87 (16.1) 20

- 24.99: 79 (14.6) 25

- 29.99: 55 (10.2)
≥ 30: 137 (26.1) Stewart et al. ( 2006 ) Not reported Mean: 56.1 532 males Eastern U.S. 1994

- 1997; 2001

- 2003 Cumulative Occupational (Organolead workers

- not occupationall y exposed to Pb at time of enrollment) Tibia Mean ± SD Current Tibia: 14.5 ± 9.6 Peak Tibia: 23.9

± 18.3 Not reported

Weaver et al. ( 2008 ) Not reported Mean ± SD : 43.3 ± 9.8 652 South Korea 12/1999

- 6/2001 Occupational (Current and former Pb workers; plants produced Pb batteries, Pb oxide, Pb crystal, or radiators, or

were secondary Pb smelters) Patella Mean ± SD Patella: 37.5 ± 41.8 Not reported



## 4.4.3. Lead in Urine

Urine Pb concentrations in the U.S. general population have been monitored in the NHANES. Data 

### 1

from the most recent survey ( CDC, 2011 ) are shown in Table 4

- 10 . The geometric mean for the entire 

### 2

sam ple for the period 2007

- 2008 (n = 2, 627 ) was 0. 52 μg/g creatinine (95% CI: 0. 48 , 0. 5 5 ). The 

### 3

geometric means for males (n = 1, 327 ) and females (n = 1,300 ) were 0. 50 μg/g creatinine (95% CI: 0.47, 

### 4

0.53) and 0.53 μg/g creatinine (95% CI: 0.49, 0.57 ), respectively. 

### 5May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 10

. Urine Pb concentrations in the U.S. p opulation

Survey Stratum Period Geometric Mean (μg/g CR ) 95% Confidence Interval Number of Subjects
All 1999

- 2000 0.721 0.700, 0.742 2465 2001

- 2002 0.639 0.603, 0.677 2689 2003

- 2004 0.632 0.603, 0.662 2558 2005

- 2006 0.546 0.502, 0.573 2576 2007

- 2008 0.515 0.483, 0.549 2627 6

- 11 yr 1999

- 2000 1.170 0.975, 1.41 340 2001

- 2002 0.918 0.841, 1.00 368 2003

- 2004 0.926 0.812, 1.06 290 2005

- 2006 0.628 0.563, 0.701 355 2007

- 2008 0.644 0.543, 0.763 394 12

- 19 yr 1999

- 2000 0.496 0.460, 0.535 719 2001

- 2002 0.404 0.380, 0.428 762 2003

- 2004 0.432 0.404, 0.461 725 2005

- 2006 0.363 0.333, 0.395 701 2007

- 2008 0.301 0.270, 0.336 376

≥ 20 yr 1999

- 2000 0.720 0.683, 0.758 1406 2001

- 2002 0.658 0.617, 0.703 1559 2003

- 2004 0.641 0.606, 0.679 1543 2005

- 2006 0.573 0.548, 0.600 1520 2007

- 2008 0.546 0.513, 0.580 1857 Males 1999

- 2000 0.720 0.679, 0.763 1227 2001

- 2002 0.639 0.607, 0.673 1334 2003

- 2004 0.615 0.588, 0.644 1281 2005

- 2006 0.551 0.522, 0.582 1271 2007

- 2008 0.502 0.471, 0.534 1327 Females 1999

- 2000 0.722 0.681, 0.765 1238 2001

- 2002 0.639 0.594, 0.688 1355 2003

- 2004 0.648 0.601, 0.698 1277 2005

- 2006 0.541 0.507, 0.577 1305 2007

- 2008 0.527 0.489, 0.568 1300 Mexican

- Americans 1999

- 2000 0.940 0.876, 1.01 884 2001

- 2002 0.810 0.731, 0.898 682 2003

- 2004 0.755 0.681, 0.838 618 2005

- 2006 0.686 0.638, 0.737 652 2007

- 2008 0.614 0.521, 0.722 515 Non

- Hispanic blacks 1999

- 2000 0.722 0.659, 0.790 568 2001

- 2002 0.644 0.559, 0.742 667 2003

- 2004 0.609 0.529, 0.701 723 2005

- 2006 0.483 0.459, 0.508 692 2007

- 2008 0.452 0.414, 0.492 589 Non

- Hispanic whites 1999

- 2000 0.696 0.668, 0.725 822 2001

- 2002 0.615 0.579, 0.654 1132 2003

- 2004 0.623 0.592, 0.655 1074 2005

- 2006 0.541 0.500, 0.585 1041 2007

- 2008 0.506 0.466, 0.550 1095

Values are μg Pb/g creatinine

Source: Based on data from the NHANES ( CDC, 2011 )



## 4.4.4. Lead in Teeth

The influence of historical Pb exposures was recently studied by Robbins et al. ( 2010 ) . Tooth 

### 1

enamel samples from 127 subjects born between 1936 and 1993 were analyzed for Pb concentration and 

### 2

Pb isotope ratios of the tooth enamel and compared with those parameters for sediment cores and 

### 3

estimates of Pb emissions from gasoline during the years when 50% enamel formation was estimated to 

### 4

occur. They found that the log

- transform of tooth enamel conce ntration was significantly predicted by the 

### 5

log

- transform of Lake Erie sediment core data obtained by Graney et al. ( 1995 ) ( p <0.00001) and by the 

### 6

log

- transform of U.S. consumption of Pb in gasoline ( p <0.00001); Figure 4

- 18. Additionally, Robbins et 

### 7May 2011 4

- 78 DRAFT

– DO NOT CITE OR QUOTE al. ( 2010 ) found that 207 Pb/ 206 Pb was significantly predicted by the 207 Pb/ 20 6 Pb observed in the Lake Erie 

### 1

sediment cores obtained by Graney et al. ( 1995 ) ( p <0.0001) and for this study ( p <0.0002). 

### 2

Source: Used with permission from Elsevier Publishing, Robbins et al. ( 2010 )

. Figure 4

- 18. Comparison of tooth enamel 50% formation (solid line) with newly obtained Pb sediment Lake Erie cores (open trian gles), previously obtained Lake Erie sediment (open circles, Graney
et al. ( 1995 ) ) , and U.S. gasoline usage (closed circles). All values are normalized by the peak observation for that parameter.



# 4.5. Empirical Models of Lead Exposure

- Blood Lead Relationships

Multivariate regression models, commonly used in epidemiology, provide estimates of the 

### 3

contribution of variance in the internal dose metric to various determinants or control variables (e.g., air 

### 4

Pb concentration, surface dust Pb concentration). Structura l equation modeling links several regression 

### 5

models together to estimate the influence of determinants on the internal dose metric. Regression models 

### 6

can provide estimates of the rate of change of blood or bone Pb concentration in response to an 

### 7

incrementa l change in exposure level (i.e., slope factor). One strength of regression models is that they are 

### 8

empirically verified within the domain of observation and have quantitative estimates of uncertainty 

### 9

im bedded in the model structure. However, regression mo dels are based on (and require) paired predictor



### 10

outcome data, and, therefore, the resulting predictions are confined to the domain of observations and are 

### 11

typically not generalizable to other populations. Regression models also frequently exclude numerous 

### 12

parameters that are known to influence human Pb exposures (e.g., soil and dust ingestion rates) and the 

### 13May 2011 4

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– DO NOT CITE OR QUOTE relationship between human exposure and tissue Pb levels, parameters which are expected to vary 

### 1

spatially and temporally. Thus, extrapolation of regres sion models to other spatial or temporal contexts, 

### 2

which is often necessary for regulatory applications of the models, can be problematic. 

### 3



## 4.5.1. Air Lead

- Blood Lead Relationships

The 2006 AQCD and its 1986 predecessor ( U.S. EPA, 1986

, 2006 ) described epidemiological 

### 4

studies of relationships between air Pb and b lood Pb. Much of the pertinent earlier literature (e.g.

, prior to 

### 5

1984) was summarized by Brunekreef ( 1984 ) . Based on meta

- analysis of 18 studies of urban or industrial



### 6

urban populations, Brunekreef ( 1984 ) estimated the blood Pb

- air Pb slope for children to be 0.3485 

### 7

ln[μg/dl blood Pb] per ln[μg/m 3 air Pb] ( R 2 = 0.69; Figure 4

- 19 ). This corresponds to an increase of 6.3 

### 8

μg/dL blood Pb for an increase in air Pb co ncentration from 0.15 to1.5 μg/m 3

. When the analysis was 

### 9

limited to children whose blood Pb concentrations were <20 μg/dL, the regression coefficient was 0.2159 

### 10

(R 2

= 0.33)

, which corresponds to an increase of 3.2 μg/dL blood Pb for an increase in air Pb from 0.15 

### 11

to1.5 μg/m 3

. Blood Pb

- air Pb slopes are presented for recent studies in the following paragraphs. These 

### 12

data are summarized in Table 4

- 11. 

### 13May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 11

. Summary of estimated slopes for blood Pb to a ir Pb re lationships in humans

Reference Study Methods Model Description Blood Pb

– Air Pb Slope (μg/dL/ μg/m 3 )

Children Populations

Brunekreef et al. ( 1984 ) Location: Various countries Years: 1974

- 1983 Subjects: C hildren (varying age ranges) Analysis : Meta analysis of 18 studies Model: Log

- Log Blood Pb: 5

- 41 μg/dL (mean range for studies) Air Pb: 0.2

- 10 μg/m 3 (mean range for studies) All children: 18 a , 6.1 b Children <20 μg/dl: 13 a

, 3.0 b

Hayes et al. ( 1994 ) Location: Chicago, IL Years: 1974

- 1988 Subjects: 0.5

- 6 yr (9,604 blood Pb measurements) A nalysis: Regression of blood Pb screening and quarterly average air Pb Model: Log

- Log Blood Pb: 12

- 30 μg/dL (annual GM range) Air Pb: 0.5

- 1.2 μg/m 3 (annual GM range) 24 a , 5.7 b

Hilts et al. ( 2003 ) Location: Trail, BC Years: 1989

- 2001 Subjects: 0.5

- 6 yr (292

- 536 blood Pb measurements/yr) A nalysis: Regression of blood Pb screening and community air Pb following upgrading of a local smelter Model: Linear Blood Pb: 4.7

- 11.5 μg/dL (annual median range) Air Pb: 0.03

- 1.1 μg/m 3 (annual median range) 6.5

Ranft et al. ( 2008 ) Location: Germany Years: 1983

- 2000 Subjects: 6

- 11 yr (n = 843) A nalysis: Pooled regression 5 cross

- sectional studies Model: Log

- Linear Bloo d Pb: 2.2

- 13.6 μg/dL (5th

95th percentile) Air Pb: 0.03

- 0.47 μg/m 3 (5th

95th percentile) 3.2 c

Schna a s et al. ( 2004 ) Location: Mexico City Years: 1987

- 2002 Subjects: 0.5

- 10 yr (n = 321) A nalysis: Regression of longitudinal blood Pb measurements and annual average air Pb data Model: Log

- Log Blood Pb: 5

- 12 μg/dL (annual GM range) Air Pb: 0.7

- 2.8 μg/m 3 (annual mean range) 4.8 a , 1.1 b

Schwartz and Pitcher ( 1989 ) , U.S. EPA ( 1986 ) Location: US Years: 1976

- 1980 Subjects: 0.5

- 7 yr (n = 7,000) A nalysis: NHANES blood Pb, gasoline consumption data and Pb concentrations in gasoline Model: Linear Blood Pb: 11

- 18 μg/dL (mean range) Air Pb: 0.36

- 1.22 μg/m 3 (annual maximum quarterly mean) 9.3

Schwartz and Pitcher ( 1989 ) , U.S. EPA ( 1986 ) Location: Chicago, IL Years: 1976

- 1980 Subjects: 0

- 5 yr (n = 7,000) A nalysis: Chicago blood Pb screening, gasoline consumption data, and Pb concentrations in gasoline Model: Linear Blood Pb: 18

- 27 μg/dL (mean range) Air Pb : 0.36

- 1.22 μg/m 3 (annual maximum quarterly mean) 7.7

Tripathi et al. ( 2001 ) Location: Mumbai, India Years: 1984

- 1996 Subjects: 6

- 10 yr (n = 544) Analysis : Regression of blood Pb and air Pb data Model: Linear Blood Pb: 8.6

- 14.4 μg/dL (regional GM range) Air Pb: 0.11

- 1.18 μg/m 3 (regional GM range) 3.6

Adult Po pulations

Rodrigues et al. ( 2010 ) Location: New England, U.S. Years: 1994

- 1995 Subjects: Adult bridge painters (n

- 84, 1 female) Analysis: Regression analysis of blood Pb and air Pb data (personal monitors) collected during wo rk performing various job

- related tasks Model: Log

- log Blood Pb: 16.1 μg/dL (GM, 1,7 GSD) A ir Pb: 58 μg/m 3 (GM, 2.8 GSD) 5.4 a , 4.2 b

a At an air concentration of 0.15 μg/m 3

b At an air concentration of 1 μg/m 3

c For a change in air Pb concentration from 0.025 to 0.465 μg/m 3

GM, geometric mean; GSD, geometric standard deviationMay 2011 4

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– DO NOT CITE OR QUOTE Data provided from Brunekreef ( 1984 )

. Figure 4

- 19

. Predicted relationship between air Pb and blood Pb based on a meta analysis of 18 studies. The regression model is: ln[μg/dL blood Pb] = 0.3485

⋅ ln[μg/m 3 air Pb] + 2.85 for all
children and ln[μg/dL blood Pb] = 0.2159

⋅ ln[μg/m 3 air Pb] + 2.62 when the sample was restricted to populations that had blood Pb concentrations <20 μg/dL

.



### 4.5.1.1. Children

Hilts et al. ( 2003 ) reported child blood Pb and air Pb trends for the city of Trail, British Columb ia, 

### 1

over a period preceding and following installation of a new smelter process in 1997 which resulted in 

### 2

lower air Pb concentrations . Blood Pb data were obtained from annual (1989

- 2001) surveys of children 6

- 

### 3

60 months of age (n: 292

- 536 per year) who live d within 4 km from the smelter. Air Pb concentrations 

### 4

were obtained from high volume suspended particulate samplers place d within 2 km of the smelter that 

### 5

operated 24 hours every 6th day. Data on Pb levels in air, residential soil, interior dust, and blood for three 

### 6

sampling periods are summarized in Table 4

- 12 . Based on these data, blood Pb decreased 6.5 μg/dL per 1 

### 7

μg/m 3 air Pb and by 0.068 μg/dL per mg/kg soil Pb (based on linear regression with air or soil Pb as the 

### 8

sole independent variable). Several u ncertainties apply to these estimates. Potential mismatching of air Pb 

### 9

concentrations (often termed misclassification) with individual blood Pb levels may have occurred as a 

### 10

result of air Pb being measured within 2 km of the smelter, whereas, the blood Pb data included children 

### 11

who resided >2 km from the smelter. The regression estimates were based on group mean estimates for 

### 12

three sampling dates, rather than on the individual blood Pb estimates, which included repeated measures 

### 13 0 10 20 30 40 50 60

0 5 10 15 20 25Blood Pb (μg/dL)



### Air Pb ( μ g/m 3 

### ) All children < 20 ug/dLMay 2011 4

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– DO NOT CITE OR QUOTE on an unreported fraction of the sample. The limited number of data pairs ( three ) constrained parameter 

### 1

estimates to simple regression coefficients. Other important factors probably contributed to blood Pb 

### 2

declines in this population that may have been correlated with air, soil and d ust Pb levels. These include 

### 3

aggressive public education and exposure intervention programs ( Hilts, 1996 ; Hilts et al., 1998 )

. 

### 4

Therefore, the coefficients shown in Table 4

- 12 are likely to overestimate the influence of air, dust, or soil 

### 5

Pb on blood Pb concentrations at this site. 

### 6

Table 4

- 12

. Environmental Pb levels and blood P b levels in children in Trail, British Columbia

Date 1996 1999 2001 Regression Coefficient (μg/dL per μg/m 3 ) Blood Pb (μg/dL) 11.5 5.9 4.7 NA Air Pb (μg/m 3 ) 1.1 0.3 0.03 6.5 ± 0.52 (R 2 =0.99, p=0.050) Soil Pb ( m g/ k g) 844 756 750 0.068 ± 0.008 (R 2 =0.99, p=0.069) Interior Dust Pb ( m g/ k g) 758 583 580 0.035 ± 0.005 (R 2 =0.98, p=0.097)

A new smelter process began operation in 1997. Values for air, soil and dust Pb are annual averages; values for blood Pb are annual geometr ic means. Regression coefficients are for simple linear regression of each exposure variable on blood Pb.

Source: Data from Hilts e t al. ( 2003 )

.

Ranft et al. ( 2008 ) reported a meta

- analysis of five cross

- sectional surveys of air and soil Pb levels 

### 7

and blood Pb concentrati ons in children living in Duisburg, Germany. The analysis included observations 

### 8

on 843 children (6

- 11 years of age) made during the period 1983

- 2000 . Pb was measured in PM 10 samples 

### 9

collected in a 200 m eter by 200 m eter grid that encompassed the city . Pb in surface soil (0

- 10 cm) was 

### 10

measured at 145 locations in the city. Air and soil Pb concentrations were assigned to each participant by 

### 11

spatial interpolation from the sampling grid data to each home residence. The 5 th

- 95th percentile ranges 

### 12

were 0.025

- 0. 465 μg Pb/m 3 for air and 72

- 877 mg Pb/kg for soil. T he results of multivariate regression 

### 13

analyses were reported in terms of the relative increase (the geometric mean blood Pb ratio, GMR) for an 

### 14

increase in air or soil Pb from the 5 th to 95 th percentile va lue. In a multivariate linear regression model (R 2 

### 15

= 0.586) that included air and soil Pb in the same model and adjusted for co variates, the GMR values 

### 16

were: 2. 55 per 0.44 μg/m 3 increase in air Pb (95% CI: 2.40, 2.71, R 2

= 0.484, p<0.001) and 1.30 per 800 

### 17

mg /kg soil Pb (95% CI: 1.19, 1.43, R 2 = 0.017, p <0.001). Based on the values for R 2 , the regression 

### 18

model accounted for approximately 59% of the total variance in blood Pb and, of this, 83% was attributed 

### 19

to air Pb. Values for GMR for soil Pb varied dependi ng on the sampling data and ranged from 1.41 to 

### 20

2.89, with most recent data (2000) yielding a value of 1.63 per 800 mg/kg increase in soil Pb. The GMR 

### 21

values can be converted to regression slopes (slope = starting blood Pb× ln(GMR)/ 5th

- 95th percentile air 

### 22

o r soil Pb) for calculating equivalent air:blood Pb ratios. The model predicts an increase of 3.2 μg/dL 

### 23

blood Pb per 1 μg/m 3 increase in air Pb. Based on the GMR estimate of 1.63 for soil Pb, a 1

, 000 mg/kg 

### 24

increase in soil Pb would be associated with an inc rease in blood Pb of 0

. 6 μg/dL per mg/kg soil. The 

### 25

degree of confounding of the GMR and estimates resulting from the air and soil Pb correlation was not 

### 26May 2011 4

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– DO NOT CITE OR QUOTE reported

, although the correlation coefficient for the two variables was 0.136 for the whole data set a nd 

### 1

0.703 when data collected in 1983 was omitted. T he Ranft et al. ( 2008 ) model is log

- linear, with the 

### 2

natural logarithm of blood Pb being a function of linear increa se in air Pb. This results an upward 

### 3

curvature of the blood Pb

- air Pb relationship (i.e., in linear scale, the blood Pb

- air Pb slope inc reases with 

### 4

increasing air Pb concentration). By comparison, log

- log models predict an increase in the blood Pb

- air 

### 5

Pb s lope with decreasing air Pb concentration, whereas linear models predict a constant blood Pb

- air Pb 

### 6

slope across all air Pb concentrations. 

### 7

Schnaas et al. ( 2004 ) analyzed data on blood Pb and air Pb concentrations during and after the 

### 8

phase out of leaded gasoline use in Mexico (1986

- 1997) in children as part of a prospective study 

### 9

conducted in Mexico City. The sample included 321 children b orn during the period 1987 through 1992. 

### 10

Repeated blood Pb measurements were made on each child at 6

- month intervals up to age 10 years. Air 

### 11

Pb measurements in PM 10 (annual average of quarterly means) were derived from three area monitors 

### 12

which represented distinct study zones. Children were assigned to study zones based on their current 

### 13

address and were assigned the corresponding annual average air Pb concentrations for appropriate air 

### 14

monitoring zones. Associations between blood Pb concentration, air Pb c oncentration and other variables 

### 15

(e.g., age, year of birth, family use of glazed pottery) were evaluated using multivariate regression 

### 16

models. The regression model (r 2 = 0.96) predicted blood Pb

- air Pb slopes that decreased with year of 

### 17

birth. The largest slope occurred in the cohort born in 1987, who experienced the largest decline in air Pb 

### 18

(from 2.8 to <0.1 μg/m 3 ); the predicted slope for this group of children was 0.213 (95% CI: 0.114

- 0.312) 

### 19

ln [μg/dL blood] per ln[μg/m 3 air]. This slope corresponds to an increase of 2.1 μg/dL blood Pb for an 

### 20

increase in air Pb from 0.15 to1.5 μg/m 3

. 

### 21

Schwartz and Pitcher ( 1989 ) reported a multivariate regression analysis of a ssociations between 

### 22

U.S. gasoline Pb consumption (i.e., sales) and blood Pb concentrations in the U.S. population during the 

### 23

period 1976

- 1980 when use of Pb in gasoline was being phased out. Although this analysis did not 

### 24

directly derive a slope for the ai r Pb

- blood Pb relationships, other analyses have shown a strong 

### 25

correlation between U.S. gasoline Pb consumption and ambient air Pb levels during this same period 

### 26

( U.S. EPA, 1986 ) . Therefore, it is possible to infer an air Pb

- blood Pb relationship from these data

. T wo 

### 27

sources of blood Pb data were used in Schwartz and Pitcher ( 1989 ) : NH ANES II provided measurements 

### 28

for U.S. children 6 months to 7 years of age (n = 9,996) during 1976

- 1980 , and the City of Chicago blood 

### 29

Pb screening program provided approximately 7,000 blood Pb measurements in black children during 

### 30

1976

- 1980. Gasoline Pb c onsumption was estimated as the product of monthly gasoline sales in the U.S. 

### 31

and quarterly estimates of Pb concentrations in gasoline reported to U.S. EPA. Based on the NHANES 

### 32

blood Pb data for white children , the regression coefficient was 2.14 μg/dL blo od per 100 metric tons of 

### 33

gasoline Pb/day (SE=0.19, p=0.0000 ) ; results for black children were essentially identical . Based on the 

### 34

Chicago blood Pb data the regression coefficient was 16.12 (μg/dL per 1

, 000 metric tons gasoline 

### 35

Pb/quarter (SE=1.37, p=0.000 1) , which is roughly equivalent to 1.79 μg/dL blood per 100 me tric tons of 

### 36May 2011 4

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– DO NOT CITE OR QUOTE gasoline Pb/day. U.S. EPA ( 1986 ) reported data on gasoline Pb consumption (sales) and ambient Pb levels 

### 1

in the U.S. during the per iod 1976

- 1984 (Table 4

- 13 ). Based on these data, air Pb concentrations 

### 2

decreased in association with gasoline Pb consumption. The linear regression coefficient for the air Pb 

### 3

decrease was 0.23 μg/m 3 per 100 metric tons gasoline Pb/day (SE = 0.02, R 2 = 0.95 , p < 0.0001). If this 

### 4

regression coefficient is used to convert the blood Pb slopes from Schwartz and Pitcher ( 1989 ) , the 

### 5

corresponding air Pb

- blood Pb slopes would be 9.3 and 7.8 μg/dL per μg/m 3 , based on the NHANES and 

### 6

Chicago data, r espectively (e.g., 2.14/0.23 = 9.3 ). 

### 7

Table 4

- 13

. U.S. g asoline Pb c onsumption and a ir Pb l evels

Date Total Gasoline Pb (103 metric tons/yr) Total Gasoline Pb (102 metri c tons/day) a Air Pb (μg/m 3 )

1976 171.4 4.70 1.22 1977 168.9 4.63 1.20 1978 153 4.19 1.13 1979 129 3.53 0.74 1980 78.8 2.16 0.66 1981 60.7 1.66 0.51 1982 59.9 1.64 0.53 1983 52.3 1.43 0.40 1984 46 1.26 0.36

The linear regression coefficient is 0.23 μg/m 3 air per 100 metric tons/day (SE= 0.020, R 2 = 0.95, p<0.0001)

. a C onversion factor is 10/365 days/year

.

Source: U .S. EPA ( 1986 )

.

Tripathi et al. ( 2001 ) reported child blood Pb and air Pb trends for the city and suburbs of Mumbai, 

### 8

India over the period 1984

- 1996. Blood Pb data were obtained from child ren 6

- 10 years of age (n = 544) 

### 9

who lived in 13 locations within the Mumbai area. Air Pb concentrations were measured from high 

### 10

volume PM samplers (with the majority of Pb in the respirable size range) placed at a height of 1.6 meters 

### 11

that operated 24 hours. Data on Pb concentrations in air, residential soil, interior dust, and blood for three 

### 12

sampling periods are summarized in Table 4

- 14 . Based on these data, blood Pb increased 3.6 μg/dL per 1 

### 13

μg/m 3 air Pb (base d on linear regression with air or soil Pb as the sole independent variable). Several 

### 14

uncertainties apply to these estimates , including p otential exposure misclassification since the mean air Pb 

### 15

concentration was used for each suburb over the entire study period. The regression estimates were based 

### 16

on group mean blood Pb estimates for the 13 sampling locations, rather than on the individual blood Pb 

### 17

estimates, which included repeated measures on an unreported fraction of the sample. 

### 18May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 14

. Air Pb l evel s and b lood Pb l evels in c hildren in Mumbai, India

Blood Pb (μg/dL) Air Pb (μg/m 3 )

Location N GM GSD N GM GSD

Borivilli 12 10.4 1.67 10 0.32 1.51 Byculla 117 11.0 1.99 30 0.99 1.73 Deonar 46 9.5 2.29 93 0.11 3.21 Goregaon 21 9.1 1.30 24 0.35 1.77 Govandi 20 8.9 1.42 10 0.10 1.52 Jogeshwari 20 8.6 1.32 24 0.11 2.47 Khar 17 9.0 1.53 22 0.18 3.15 Parel 168 10.4 1.91 37 0.44 1.48 Sion 34 9.6 1.49 96 0.39 1.75 Thans (SS) 37 12.0 1.86 4 1.18 1.04 Vile Parle 19 9.1 1.46 7 0.37 1.34 Colaba 12 9.2 1.86 9 0.14 1.63 Vakola 21 14.4 1.64 7 1.12 1.12

The linear regression coefficient is 3.62 μg/dL blood per μg/m 3 air (SE= 0.61, R 2 = 0.76, p<0.001)

. GM, geometric mean; GSD, geometric standard deviation; N, number of subjects

.

Source: Data are from Tripathi et al. ( 2001 )

.

Hayes et al. ( 1994 ) analyzed data collected as part of the Chicago, IL blood Pb screenin g program 

### 1

for the period 1974

- 1988, following the phase

- out of leaded gasoline. The data included 9

, 604 blood Pb 

### 2

measurements in children (age : 6 months to 6 years) and quarterly average air Pb concentrations 

### 3

measured at 12 mon itoring stations in Cook Coun ty, IL. Quarterly median blood Pb levels declined in 

### 4

association with quarterly mean air Pb concentrations. The regression model predicted a slope of 0.24 ln 

### 5

[μg/dL blood] per ln[μg/m 3 air] , as illustrated in Figure 4

- 20 . This corresponds to an increase of 11.1 

### 6

μg/dL blood Pb for an increase in air Pb from 0.15 to1.5 μg/m 3

. 

### 7May 2011 4

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– DO NOT CITE OR QUOTE Modified from Hayes et al. ( 1994 )

. Figure 4

- 20

. Predicted relationship between air Pb and blood Pb based o n data from Chicago, IL (1974

– 1988). The regression model is: ln[μg/dL blood Pb] = 0.24

⋅ ln[μg/m 3 air Pb] + 3.17

.



### 4.5.1.2. Adults

Rodrigues et al. ( 2010 ) exam ined factors contributing to variability in blood Pb concentration in 

### 1

New England bridge painters

, who regularly use electric grinders to prepare surfaces for painting . The 

### 2

study included 84 adults (1 female) who were observed during a 2

- week period in 1994 or 1995. Subjects 

### 3

wore personal inhalable PM samplers designed to capture PM smaller than 100 μm, while performing 

### 4

various job

- related tasks. The geometric mean air Pb concentration for the 2

- week period was 58 μg/m 3 

### 5

(GSD 2.8) , with a maximum daily value of 210 μg/m 3 . The Pb concentrations reported were corrected by 

### 6

the National Institute for Occupational Safety and Health (NIOSH) respirator protection factors, which 

### 7

were not reported by the authors. Hand wipe samples were collected at the mid

- shift break and at the end 

### 8

of the shift (after the subjects had reportedly cleaned up for the day; GM = 793 μg, GSD 3.7). Blood Pb 

### 9

samples were collected at the be ginning of the 2

- week period (GM = 16.1 μg/dL, GSD 1. 7). Associations 

### 10

between exposure variables and blood Pb concentrations were explored with multivariate regression 

### 11

models (Table 4

- 15 ). When the model excluded hand

- wipe data (not all participants who wore the 

### 12

personal air samplers agreed to provide hand

- wipes)

, the regression coefficient for the relationship 

### 13

between ln[blood Pb concentration (μg/dL)] and ln [air Pb (μg/m 3 ) ] was 0.11 (SE = 0. 05, p = 0.03). This 

### 14

corresponds to a 1.3

- fold increase in blood Pb concentration for a 10

- fold increase in air Pb concentration. 

### 15 

### 0 5 10 15 20 25 30

0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6Blood Pb (μg/dL)



### Air Pb ( μ g/m 3 

### )May 2011 4

- 87 DRAFT

– DO NOT CITE OR QUOTE A second regression model included hand wipe Pb (n = 54) and yielded a regression coefficient of 0.05 

### 1

(SE = 0.07, p = 0.45) , which corresponds to a 1.12

- fold increase in blood Pb concentration per 10

- fold 

### 2

in crease in air Pb concentration. 

### 3

Table 4

- 15

. Significant predictors of blood Pb concentration in bridge painters

Parameters Blood Pb (Air Only) Blood Pb (Air and Hand Wipe)
β(SE) p - value β(SE) p - value

Intercept 1.90 (0.24) <0.0001 2.12 (0.44) 0.0007 Time of blood Pb (end vs start of study) 0.16 (0.04) <0.0001

– 0.31 (0.11) 0.005 Mean air Pb (μg/m 3 ) 0.11 (0.05) 0.03 0.05 (0.07) 0.45 Hand wipe at break (μg Pb )

— 0.007 (0.06) 0.91 Hand wipe at break * time of blood Pb

— 0.07 (0.01) <0.0001 Months on bridge painting crews 0.001 (0.0004) 0.03 0.001 (0.0006) 0.04 Education
≤ High school > High school 0.38 (0.10) Reference 0.0002 0.29 (0.13) Reference 0.03
Respirator fit test No Yes – 0.14 (0.14) Reference 0.32 – 0.13 (0.21) Reference 0.53
Respirator fit test * time of blood Pb No Yes 0.18 (0.06) Reference 0.003 0.17 (0.07) Reference 0.01

Smoke on site No Yes 0.14 (0.09) Reference 0.14 0.15 (0.10) Reference 0.14

Smoke on site * time of blood Pb No Yes – 0.15 (0.05) Reference 0.002 – 0.11 (0.04) Reference 0.009
Personal hygiene index Low High 0.27 (0.11) Reference 0.02 0.29 (0.12) Reference 0.02

Site

- level variables Containment facility Poor Good – 0.59 (0.18) Reference 0.001 – 0.57 (0.22) Reference 0.01

Air Pb , hand wipe, and blood Pb levels are natural log

- transformed.
B lood Pb concentration in units of μg/dL

. Source: Data from Rodrigues et al. ( 2010 )

.



## 4.5.2. Environmental Lead

- Blood Lead Relationships

Empirically

- based relationships between blood Pb levels and Pb intakes and/or Pb concentrations 

### 4

in environmental media have provided the basis for what has become known as slope factor models. 

### 5

Slope factor models are highly simplified representations of empirically based regression models in which 

### 6

the slope pa rameter represents the change in blood Pb concentration projected to occur in association with 

### 7

a change in Pb intake or uptake. The slope parameter is factored by exposure parameters (e.g., exposure 

### 8

concentrations, environmental media intake rates) that re late exposure to blood Pb concentration ( Abadin 

### 9

& Wheeler, 1997 ; Bowers et al., 1994 ; Carlisle & Wade, 1992 ; Maddaloni et al., 2005 ; Stern, 1994

, 1996 ; 

### 10

U.S. EPA, 2003 ) . In slope factor models, Pb bi okinetics are represented as a linear function between the 

### 11

blood Pb concentration and either Pb uptake (uptake slope factor, USF) or Pb intake (intake slope factor, 

### 12

ISF). The models take the general mathematical forms: 

### 13May 2011 4

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– DO NOT CITE OR QUOTE 

### ISF E PbB



## ⋅ = Equation 4

- 2



### USF AF E PbB



## ⋅ ⋅ = Equation 4

- 3
where PbB is the blood Pb concentration, E is an expression for exposure (e.g., soil intake × soil Pb 

### 1

concentration) and AF is the absorption fraction for Pb in the specific exposure medium of interest. Intake 

### 2

slope fac tors are based on ingested rather than absorbed Pb and, therefore, integrate both absorption and 

### 3

biokinetics into a single slope factor, whereas models that utilize an uptake slope factor include a separate 

### 4

absorption parameter. In contrast to mechanistic models, slope factor models predict quasi

- steady state 

### 5

blood Pb concentrations that correspond to time

- averaged daily Pb intakes (or uptakes) that occur over 

### 6

sufficiently long periods to produce a quasi

- steady state (i.e., >75 days, ~3 times the t 1/2 for elimination of 

### 7

Pb in blood). 

### 8

The U.S. EPA Adult Lead Methodology (ALM) is a example of a slope factor model that has had 

### 9

extensive regulatory use in the EPA Superfund program for assessing health risks to adults associated with 

### 10

non

- residential exposur es to Pb in contaminated soils ( Maddaloni et al., 2005 ; U.S. EPA, 1996a ) . The 

### 11

model was developed to predict maternal and fetal blood Pb concentrations that might occur in relation to 

### 12

maternal exposures to contaminated soils. The model assumes an uptake slope factor of 0.4 μg/dL blood 

### 13

per μ g/day Pb uptake. Additional discussion of slope factor models that have been used or proposed for 

### 14

regulatory use can be found in the 2006 AQCD ( U.S. EPA, 2006 )

. 

### 15

Previous studies included in the 2006 AQCD ( U.S. EPA, 2006 ) explored the relationship between 

### 16

blood Pb in children and environmental Pb concentra tions. In a pooled analysis of 12 epidemiologic 

### 17

studies, interior dust Pb loading, exterior soil/dust Pb, age, mouthing behavior, and race were all 

### 18

statistically significant variables included in the regression model for blood Pb concentration ( Lanphear et 

### 19

al., 1998 ) . Significant interactions were found for age and dust Pb loading, mouthing behavior and 

### 20

exterior soil/dust level, and SES and water Pb level. In a meta

- analysis of 11 epidemiologic studies, 

### 21

among children the most common expos ure pathway influencing blood Pb concentration in structural 

### 22

equation modeling was exterior soil, operating through its effect on interior dust Pb and hand Pb ( Succop 

### 23

et al., 1998 ) . Similar to Lanphear et al. ( 1998 ) , in the linear regressi on model, interior dust Pb loading had 

### 24

the strongest relationships with blood Pb concentration. Individual studies conducted in Rochester, NY, 

### 25

Cincinnati, OH, and Baltimore, MD report similar relationships between children ’ s blood Pb and interior 

### 26

dust conc entrations ( Bornschein et al., 1985 ; Lanphe ar & Roghmann, 1997 ; U.S. EPA, 1996b )

. 

### 27

Dixon et al. ( 2009 ) reported a mu ltivariate analysis of associations between environmental Pb 

### 28

concentrations and blood Pb concentrations, based on data collected in the NHANES (1999

- 2004). The 

### 29

analyses included 2,155 children, age 12

- 60 months. The population

- weighted geometric mean blood Pb 

### 30

concentration was 2.03 μg/dL ( GSD 1.03 ). A linear model applied to these data yielded an R 2 of 40% 

### 31

(Table 4

- 16 ). The regression coefficient for th e relationship between ln[blood Pb concentration (μg/dL) ] 

### 32May 2011 4

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– DO NOT CITE OR QUOTE and ln[floor dust Pb concentration (μg/ft 2 ) ] was 0.386 (SE 0.089) for “ not smooth and cleanable ” surfaces 

### 1

(e.g., h igh

- pile carpets) and 0.205 (SE 0.032) for “ smooth and cleanable ” surfaces (e.g., uncarpeted or 

### 2

low

- pile carpets). These coefficients correspond to a 2.4

- fold or 1.6

- fold increase in blood P b 

### 3

concentration, respectively, for a 10

- fold increase in floor dust Pb concentration. 

### 4

Table 4

- 16

. Linear model relating environmental P b exposure and blood P b concentration
in children a

Variables Overall p

- value Levels Estimate (SE) p - Value Intercept 0.172

- 0.517 (0.373 0.172

Age (in yr) < 0.001 Age Age2 Age3 Age4 2.620 (0.628)

– 1.353 (0.354) 0.273 (0.083)

– 0.019 (0.007) < 0.001 < 0.001 0.002 0.008

Yr of construction 0.014 Intercept for missing 1990

– present 1978

– 1989 1960

– 1977 1950

– 1959 1940

– 1949 Before 1940 – 0.121 (0.052)

– 0.198 (0.058)

– 0.196 (0.060)

– 0.174 (0.056)

– 0.207 (0.065)

– 0.012 (0.072) 0.000 0.024 0.001 0.002 0.003 0.003 0.870

-

PIR < 0.001 Intercept for missing Slope 0.053 (0.065

– 0.053 (0.012) 0.420 < 0.001

Race/ethnicity < 0.001 Non

- Hispanic white Non

- Hispanic black Hispanic Other 0.000 0.247 (0.035

– 0.035 (0.030) 0.128 (0.070) - < 0.001 0.251 0.073

Country of birth 0.002 Missing United States b
Mexico Elsewhere – 0.077 (0.219) 0.000 0.353 (0.097) 0.154 (0.121 0.728

- < 0.001 0.209

Floor surface/condition × log floor PbD < 0.001 Intercept for missing Not smooth and cleanable Smooth and cleanable or carpeted 0.178 (0.094) 0.386 (0.089) 0.205 (0.032) 0.065 < 0.001 < 0.001

Floor surface/condition × log floor PbD) 2 Not smooth and cleanable Smooth and cleanable or carpeted 0.023 (0.015) 0.027 (0.008) 0.124 0.001

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

– 0.009 (0.004) 0.159

0.012

Log windowsill PbD 0.002 Intercept for missing Slope 0.053 (0.040 0.041 (0.011 0.186 < 0.001

Home

- apartment type < 0.001 Intercept for missing Mobile home or trailer One family house, detached One family house, attached Apartment (1

– 9 units) Apartment (≥ 10 units) – 0.064 (0.097 0.127 (0.067)

– 0.025 (0.046) 0.000 0.069 (0.060)

– 0.133 (0.056) 0.511 0.066 0.596

- 0.256 0.022

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

- Log cotinine concentration (ng/dL) 0.004 Intercept for missing Slope – 0.150 (0.063) 0.039 (0.012) 0.023 0.002

Window, cabinet, or wall renovation in a pre

- 1978 home 0.045 Missing Yes No – 0.008 (0.061) 0.097 (0.047) 0.000 0.896 0.045

-

a n = 2,155 (age 10

- 60 mo); R 2 = 40%

b Includes the 50 states and the District of Columbia

Source: D ixon et al. ( 2009 )

.May 2011 4

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– DO NOT CITE OR QUOTE Mielke et al. ( 2007 ) analyzed data on blood Pb and soil Pb concentration collected as part of a 

### 1

universal blood Pb screening program in New Orleans (2000

- 2005). The data set included 55,551 blood 

### 2

Pb measure ments for children 0

- 6 years of age and 5,467 soil Pb measurements. B lood Pb and soil Pb 

### 3

concentrations were matched at the level of census tracts. The association between blood Pb 

### 4

concentration and soil Pb concentration was evaluated using non

- p arametric permutation methods. The 

### 5

resulting best

- fit model (R 2 =0.528) was: 

### 6

Equation 4

- 4

where PbB is the median blood Pb concentration and PbS is the median soil Pb concentration. The 

### 7

resulting curvilinear relationship predicts a two fold increase in blood Pb conc entration for an increase in 

### 8

soil Pb concentration from 100 to 1000 ppm (Figure 4

- 21 ). 

### 9

Figure 4

- 21

. Predicted relationship between soil Pb concentration and
blood Pb concentration in children based data collected in the New Orleans child Pb screening pro gram (2000

- 2005) ( Mielke et al., 2007 )

. Th e data set included 55,551 blood Pb measurements for children 0

- 6 years of age and 5 ,467 soil Pb
measurements. B lood Pb and soil Pb concentrations were
matched at the level of census tracts.

In a subsequent re

- analysis of the New Orleans (2000

- 2005) data, individual child blood Pb 

### 10

observations were matched to census tract soil concentrations ( Zahran et al., 2011 )

. This analysis 

### 11

confirmed the association between blood Pb and both soil Pb and age reported in Mielke et al. ( 2007 )

. 

### 12 0 2 4 6 8 10

0 400 800 1200 1600 2000Blood Pb (μg/dL)

Soil Pb (ppm) Blood=2.038+0.172 x Soil 0.5May 2011 4

- 91 DRAFT

– DO NOT CITE OR QUOTE Regression co e ffic i ents for soil Pb (random effects generalized least squares regression) ranged from 

### 1

0.217 to 0.214 (per soil Pb 0.5 ), which is equivalent to appro ximately a 2

- fold increase in blood Pb 

### 2

concentration for an increase in soil Pb concentration from 100 to 1000 ppm. 

### 3

Several studies have linked elevated blood Pb levels to residential soil exposures for populations 

### 4

living nearby industrial or mining facili ties. Gulson et al. ( 2009 ) studied the blood Pb and isotopic Pb 

### 5

ratios of children younger than 5 years old and adults older than 18 years old living in the vicinity of a 

### 6

mine producing Magellan Pb ore in western Australia. They observed a median blood Pb level of 6 .6 

### 7

μg/dL for the children, with isotopic ratios indicating contributions from the mine ranging from 27 to 

### 8

93%. A weak but significant linear association between blood Pb level and percent Magellan Pb was 

### 9

observed (R 2 = 0.12, p = 0.018). Among children with blood Pb levels over 9 μg/dL and among adults, the 

### 10

isotopic ratios revealed Pb exposures from a variety of sources. Garavan et al. ( 2008 ) measured soil Pb 

### 11

and blood Pb lev els among children aged 1 month to 17.7 years old in an Irish town near a coal mine. The 

### 12

blood Pb measurements were instituted as part of a screening and community education program given 

### 13

that the presence of Pb had been documented in the environment. Gara van et al. ( 2008 ) found that over 3 

### 14

years of the screening period, median blood Pb levels reduced by roughly 22% from 2.7 to 2.1 μg/dL. 

### 15

An extensive discussion of the rela tionships between environmental Pb levels and blood Pb 

### 16

concentrations in children at the Bunker Hill Superfund Site, a former Pb mining and smelting site, was 

### 17

provided in the 2006 AQCD. In the most recent analysis ( TerraGraphics Environmental Engineering, 

### 18

2004 ) of the data on environmental Pb levels and child blood Pb concentrations (1988

- 2002), blood Pb 

### 19

concentrations (annual GM ) ranged from 2.6 to 9.9 μg/dL. Environmental Pb levels (e.g., dust, soil, paint 

### 20

Pb levels) data were collected at ~3

, 000 residences, with interior dust Pb concentrations (annual GM ) 

### 21

ranging from ~400 to 4

, 200 mg/kg and ya rd soil Pb concentration (annual GM ) ranging from ~150 to 

### 22

2

, 300 mg/kg . Several multivariate regression models relating environmental Pb levels and blood Pb 

### 23

concentration were explored; the model having the highest R 2 ( 0.26) is shown in Table 4

- 17. The mode l 

### 24

predicts significant associations between blood Pb concentration, age, interior dust, yard soil, 

### 25

neighborhood soil (geometric mean soil Pb concentration for areas within 200 ft of the residence), and 

### 26

community soil Pb concentration (community GM ). Based on the standardized regression coefficients, the 

### 27

community soil Pb concentration had the largest effect on blood Pb concentration, followed by 

### 28

neighborhood soil Pb concentration, interior dust Pb concentration, and yard soil Pb concentration (Table 

### 29

4

- 17 ). The model predicted a 1.8 μg/dL decrease in blood Pb concentration in association with a decrease 

### 30

in community soil Pb concentration from 2

, 000 to 1

, 000 mg/kg . The same decrease in neighborhood soil 

### 31

Pb concentration, interior dust Pb concentration, or yard soil Pb concentration was predicted to result in a 

### 32

0.8, 0.5, or 0.2 μg/dL decrease in blood Pb concentration, respectively. 

### 33May 2011 4

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– DO NOT CITE OR QUOTE Table 4

- 17

. General linear model relating blood Pb concentration in children and
environmental Pb levels

— Bunker Hill Superfund Site

Parameter Coefficient P

- value Standardized Coefficient Intercept

- 0.1801 0.7916 0.00000 Age (yr)

- 0.4075 <0.0001

- 0.2497 ln(interior dust Pb) ( mg/kg ) 0.7288 <0.0001 0.1515 ln(yard soil Pb) ( mg/kg ) 0.2555 0.0002 0.0777 GM soil Pb within 200 ft of residence ( mg/kg ) 0.0008 <0.0001 0.1380 GM community soil Pb ( mg/kg ) 0.0018 <0.0001 0.2250

R 2 = 0.264; p <0.0001; based on data from Bunker Hill Superfund Site collected over the period 1988

- 2002

. GM : geometric mean; ln : natural log

.

Source: TerraGraphics ( 2004 )

.

Malcoe et al. ( 2002 ) analyzed 1997 data on blood Pb and environmental Pb concentrations in a 

### 1

re presentative sample of Native American and white children (n = 224, age 1

- 6 years) who resided in a 

### 2

former Pb minin g region in Ottawa County, OK. The data set included measurements of blood Pb, yard 

### 3

soil Pb, residential interior dust Pb loading, first

- draw water Pb, paint Pb assessment and other behavioral 

### 4

( i.e., hand

- to

- mouth activity, hygiene rating ) and demographic variables (i.e. , hand

- to

- mouth activity, 

### 5

hygiene rat ing, poverty level, caregiver education). A multivariate regression model accounted for 34% of 

### 6

the observed variability in blood Pb. Yard soil Pb and interior dust Pb loading accounted for 10% and 3% 

### 7

of the blood Pb variability, respectfully. The regressio n m odel predicted a slope of 0.74 μg/dL blood Pb 

### 8

per ln[μg/g soil Pb] and a slope of 0.45 μg/dL blood Pb per ln[μg/ft 2 ] dust Pb loading. 

### 9



# 4.6. Biokinetic Models of Lead Exposure

- Blood Lead Relationships

An alternative to regression models are mechanistic models, which attempt to specify all 

### 10

parameters needed to describe the mechanisms (or processes) of transfer of Pb from the environment to 

### 11

human tissues. Such mechanistic models are more complex than regression models; this added 

### 12

complexity introduces challenges in terms of their mathematical solution and empirical verification. 

### 13

However, by incorporating parameters that can be expected to vary spatially or temporally, or across 

### 14

individuals or populations, mechanistic models can be extrapolated to a wide range of e xposure scenarios, 

### 15

including those that may be outside of the domain of paired predictor

- outcome data used to develop the 

### 16

model. Exposure

- intake models, a type of mechanistic models, are highly simplified mathematical 

### 17

representations of relationships betwe en levels of Pb in environmental media and human Pb intakes (e.g., 

### 18

μg Pb ingested per day). These models include parameters representing processes of Pb transfer between 

### 19

environmental media (e.g., air to surface dust) and to humans, including rates of huma n contact with the 

### 20

media and intakes of the media (e .g., g soil ingested per day). Intake

- biokinetic models provide the 

### 21May 2011 4

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– DO NOT CITE OR QUOTE analogous mathematical representation of relationships between Pb intakes and Pb levels in body tissues 

### 1

(e.g., blood Pb concentration). T hey include parameters that represent processes of Pb transfer (a) from 

### 2

portals of entry into the body and (b) from blood to tissues and excreta. Linked together, exposure

- intake 

### 3

and intake

- biokinetics models (i.e., integrated exposure

- intake

- biokinetics models) provide an approach 

### 4

for predicting blood Pb concentrations (or Pb concentrations in other tissues) that corresponds to a 

### 5

specified exposure (medium, concentration , and duration). Detailed information on exposure and internal 

### 6

dose can be obtained fr om controlled experiments, but almost never from epidemiological observations or 

### 7

from public health monitoring programs. Exposure intake

- biokinetics models can provide these 

### 8

predictions in the absence of complete information on the exposure history and blo od Pb concentrations 

### 9

for an individual (or population) of interest. Therefore, these models are critical to applying 

### 10

epidemiologi c

- based information on blood Pb

- response relationships to the quantification and 

### 11

characterization of human health risk. They are also critical for assessing the potential impacts of public 

### 12

health programs directed at mitigation of Pb exposure or of remediat ion of contaminated sites. 

### 13

However, they are not without their limitations. Human exposure

- biokinetics models include large 

### 14

numbers of parameters, which are required to describe the many processes that contribute to Pb intake, 

### 15

absorption, distribution, an d elimination . The large number of parameters complicates the assessment of 

### 16

confidence in parameter values, many of which cannot be directly measured. Statistical procedures can be 

### 17

used to evaluate the degree to which model outputs conform to “ real

- world ” observations and values of 

### 18

influential parameters can be statistically estimated to achieve good agreement with observations. Still, 

### 19

large uncertainty can be expected to remain about many, or even most, parameters in complex exposure



### 20

biokinetic models. Suc h uncertainties need to be identified and their impacts on model predictions 

### 21

quantified (i.e., sensitivity analysis or probabilistic methods). 

### 22

Modeling of human Pb exposures and biokinetics has advanced considerably during the past 

### 23

several decades, althoug h there have been relatively few developments since the 200 6 Pb AQCD was 

### 24

published. Still in use is the Integrated Exposure Uptake Biokinetic (IEUBK) Model for Lead in Childre n 

### 25

( U.S. EPA, 1994 ) and models that simulate Pb b iokinetics in humans from birth through adulthood 

### 26

( Leggett, 1993 ; O'Flaherty , 1993

, 1995 )

. The EPA AALM is still in development. A complete and 

### 27

extensive discussion of these models can be found in the 2006 Pb AQCD ( U.S. EPA, 2006 )

. 

### 28



# 4.7. Summary

4.7.1. Exposure

Exposure data consider ed in this assessment build upon the conclusions of the 2006 AQCD for Pb 

### 29

( 2006 ) , which found air Pb concentrations in the U.S. and associated biomarkers of exposure to Pb have 

### 30

decreased substantially following the ban on Pb in gasoline, house

- hol d paints, and solder. Pb exposure is 

### 31May 2011 4

- 94 DRAFT

– DO NOT CITE OR QUOTE difficult to assess because Pb has multiple sources in the environment and passes through various media. 

### 1

Air

- related pathways of Pb exposure are the focus of this assessment. Pb can be emitted to air, water, or 

### 2

soil. In addition to primary emission of particle

- b ound or gaseous Pb to the atmosphere, Pb can be 

### 3

suspended to the air from disturbance of soil or dust, and a fraction of that suspended Pb may even 

### 4

originate from waters used to irrigate the soil. Pb

- bearing PM ca n be deposited from the air to soil or 

### 5

water through wet and dry deposition. In general, air

- related pathways include those pathways where Pb 

### 6

passes through ambient air on its path from a source to human exposure. Air

- related Pb exposures include 

### 7

inhalatio n and ingestion of Pb

- contaminated food, water or other materials including dust and soil . Non



### 8

air

- related Pb exposures may include ingestion of indoor Pb paint, Pb in diet as a result of inadvertent 

### 9

additions during food processing, and Pb in drinking wat er attributable to Pb in distribution systems, as 

### 10

well as other generally less prevalent pathways . Pb can cycle through multiple media prior to human 

### 11

exposure. Given the multitude of possible air

- related exposure scenarios and the related difficulty of 

### 12

con structing Pb exposure histories, most studies of Pb exposure through air, water, and soil can be 

### 13

informative to this review. Other exposures, such as occupational exposures, contact with consumer goods 

### 14

in which Pb has been used, or ingestion of Pb in drink ing water conveyed through Pb pipes may also 

### 15

contribute to Pb body burden. 

### 16

Section 4.1 presents data illustrating potential exposure mechanisms. Several studies suggested that 

### 17

soil can act as a reservoir for Pb emissions from industrial or and other activi ties

. Exposure to soil 

### 18

contaminated with deposited Pb can occur through hand

- to

- mouth contact as well as inhalation of 

### 19

resuspen ded Pb

- bearing PM . In general, soil Pb concentrations tended to be higher within inner

- city 

### 20

communities compared with neighborhoo ds surrounding city outskirts. Infiltration of Pb dust has been 

### 21

demonstrated, and Pb dust has been shown to persist in indoor environments even after repeated 

### 22

cleanings. Measurements of particle

- bound Pb exposures reported in this assessment have shown tha t 

### 23

personal exposure concentrations for Pb are typically higher than indoor or outdoor ambient Pb 

### 24

concentrations. These findings may be related to local resuspension with body movement. 

### 25



## 4.7.2. Kinetics

The majority of Pb in the body is found in bone (roughly 90% in adults, 70% in children); only 

### 26

about 1% of Pb is found in the blood. Pb in blood is primarily (~99%) bound to RBC s. It has been 

### 27

suggested that the small fraction of Pb in plasma (<1%) may be t he more biologically labile and 

### 28

toxicologically active fraction of the circulating Pb. Saturable binding to RBC proteins contributes to an 

### 29

increase in the plasma/blood Pb ratio with increasing blood Pb concentration and curvature to the blood 

### 30

Pb

– plasma Pb relationship. As blood Pb increases and the higher affinity binding sites for Pb in RBCs 

### 31

become saturated at approximately 40 μg/dL blood, a larger fraction of the blood Pb is available in 

### 32

plasma to distribute to brain and other Pb

- responsive tissues. 

### 33May 2011 4

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– DO NOT CITE OR QUOTE The burden of Pb in the body may be viewed as divided between a dominant slow compartment 

### 1

(bone) and a smaller fast compartment (soft tissues) . Pb uptake and elimination in soft tissues is much 

### 2

faster than in bone. Pb accumulates in bone regions undergoing the most active calcification at the time of 

### 3

exposure. During infancy and childhood, bone calcification is most active in trabecular bone (e.g. patella) ; 

### 4

whereas, in adulthood, calcification occurs at sites of remodeling in cortical (e.g. tibia) and trabecula r 

### 5

bone ( Aufderheide & Wittmers, 1992 )

. A high bone formation rate in early childhood results in the rapid 

### 6

uptake of circulating Pb into mineralizing bone; however, bone Pb is also recycled to other tissue 

### 7

compartments or excreted in accordance with a high bone resorption rate ( O'Flaherty, 1995 ) . Thus, most 

### 8

of the Pb acquired early in life is not permanently fixed in the bone. 

### 9

The exchange of Pb from plasma to the bone surface is a relatively rapid process. Pb in bone 

### 10

becomes distributed in trabecular and the more d ense cortical bone. The proportion of cortical to 

### 11

trabecular bone in the human body varies by age, but on average is about 80 to 20

. Of the bone types, 

### 12

trabecular bone is more reflective of recent exposures than is cortical bone due to the slow turnover ra te 

### 13

and lower blood perfusion of cortical bone. Some Pb diffuses to deeper bone regions where it is relatively 

### 14

inert, particularly in adults. These bone compartments are much more labile in infants and children than in 

### 15

adults as reflected by half

- times for movement to the plasma (e.g., cortical t 1/2 = 0.23 y ea rs at birth, 3.7 

### 16

y ea rs at 15 years of age, and 23 y ea rs in adults; trabecular t 1/2 = 0.23 y ea rs at birth, 2.0 y ea rs at 15 years of 

### 17

age, and 3.8 y ea rs in adults) ( Leggett, 1993 )

. D ue to the more rapid turnover of bone mineral in children

, 

### 18

changes in blood Pb concentration are thought to more closely parallel changes in total body burd en. 

### 19

However, some Pb accumulated in bone during childhood does persist into later life

. Potential 

### 20

mobilization of Pb from the skeleton could occur in adults at times of physiological stress associated with 

### 21

enhanced bone remodeling such as during pregnancy and lactation, menopause or in the elderly, extended 

### 22

bed rest, hyperparathyroidism, and weightlessness. Regardless of age, however, similar blood Pb 

### 23

concentrations in two individuals (or populations) do not necessarily translate to similar body burdens or 

### 24

similar exposure histories. 

### 25

The kinetics of elimination of Pb from the body reflects the existence of fast and slow pools of Pb 

### 26

in the body. The dominant phase of Pb kinetics in the blood, exhibited shortly after a change in exposure 

### 27

occurs, has an elimina tion half

- life of ~20

- 30 days. An abrupt change in Pb uptake gives rise to a 

### 28

relatively rapid change in blood Pb, to a new quasi

- steady state, achieved in ~75

- 100 days (i.e., 3

- 4 times 

### 29

the blood elimination half

- life). A slower phase may become evident wit h longer observation periods 

### 30

following a decrease in exposure due to the gradual redistribution of Pb among other compartments via 

### 31

the blood. Therefore, a single blood Pb concentration may reflect the near

- term or longer

- term history of 

### 32

the individual to v arying degrees, depending on the relative contributions of internal (e.g., bone) and 

### 33

external sources of Pb to blood Pb, which in turn will depend on the exposure history and possibly age



### 34

related and individual

- specific (e.g., pregnancy, lactation) charact eristics of bone turnover. In general, 

### 35May 2011 4

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– DO NOT CITE OR QUOTE higher blood Pb concentrations can be interpreted as indicating higher exposures (or Pb uptakes); 

### 1

however, they do not necessarily predict higher body burdens, especially in adults. 

### 2



## 4.7.3. Lead Biomarkers

Observational stud ies using biomarkers of Pb are included in Section 4.4

. The median blood Pb 

### 3

level for the entire U.S. population is 1.2 μg/dL and the 95 th percentile blood Pb level was 3.7 μg/dL, 

### 4

based on the 2007

- 2008 NHANES data ( NCHS, 2010 ) . Among children aged 1

- 5 years, the median and 

### 5

95 th percentiles were slightly higher at 1.4 μg/dL and 4.1 μg/dL, respectively. Overall, trends in blood Pb 

### 6

levels have been decreasing among U.S. children and adults over the past twenty years. Concurrent 

### 7

changes in isotopic ratios of blood Pb samples reflect changes in source composition over the past several 

### 8

decades. Recent studies have observed a relationship between blood Pb and soil Pb concentration. 

### 9

Additionally, studies have shown that blood Pb is also associated with non

- air

- related, non

- policy



### 10

relevan t exposure to Pb paints in older homes, Pb released into drinking water, and occupational work 

### 11

with materials containing Pb. 

### 12

Blood Pb is dependent on both the recent exposure history of the individual, as well as the long



### 13

term exposure history that determi nes body burden and Pb in bone. The contribution of bone Pb to blood 

### 14

Pb changes depending on the duration and intensity of the exposure, age, and various other physiological 

### 15

variables that may affect bone remodeling (e.g., nutritional status, pregnancy, me nopause). Blood Pb in 

### 16

adults is typically more an index of recent exposures than body burden, whereas bone Pb is an index of 

### 17

cumulative exposure and body burden. In children, due to faster exchange of Pb to and from bone, blood 

### 18

Pb is both an index of recen t exposure and potentially an index of body burden. In some physiological 

### 19

circumstances (e.g., osteoporosis), bone Pb may contribute to blood Pb in adults. The disparity between 

### 20

blood Pb and body burden may have important implications for the interpretatio n of blood Pb 

### 21

measurements in some epidemiology studies. Conceptually, measurement of long

- term Pb body burden 

### 22

(i.e., based on tibia Pb) may be the appropriate metric if the effects of Pb on a particular outcome are 

### 23

lasting and cumulative. However, if the effects of Pb on the outcome represent the acute effects of current 

### 24

exposure, then blood Pb may be the preferred metric. In the absence of clear evidence as to whether a 

### 25

particular outcome is an acute effect of recent Pb dose or a chronic effect of cumulat ive Pb exposure, both 

### 26

blood and bone metrics should be considered

. 

### 27

Cross

- sectional studies that sample blood Pb once generally provide an index of recent exposures. 

### 28

In contrast, cross

- sectional studies of bone Pb and longitudinal samples of blood Pb conce ntrations over 

### 29

time provide an index of cumulative exposure and are more reflective of average Pb body burdens over 

### 30

time. The degree to which repeated sampling will reflect the actual long

- term time

- weighted average 

### 31

blood Pb concentration depends on the sa mpling frequency in relation to variability in exposure. High 

### 32May 2011 4

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– DO NOT CITE OR QUOTE variability in Pb exposures can produce episodic (or periodic) oscillations in blood Pb concentration that 

### 1

may not be captured with low sampling frequencies. 

### 2

The concentration of Pb in urine is a function of the urinary Pb excretion and the urine flow rate. 

### 3

Urine flow rate requires collection of a timed urine sample, which is often problematic in epidemiologic 

### 4

studies. Collection of un

- timed ( “ spot ” ) urine samples, a common alternative to timed s amples, requires 

### 5

adjustment of the Pb measurement in urine to account for variation in urine flow ( Diamond, 1988 )

. 

### 6

Urinary Pb concentration reflects, mainly, the exposure history of the previous few months; thus, a single 

### 7

urinary Pb measurement cannot distin guish between a long

- term low level of exposure or a higher acute 

### 8

exposure. Thus, a single urine Pb measurement, or a series of measurements taken over short

- time span, is 

### 9

likely a relatively poor index of Pb body burden for the same reasons that blood Pb is not a good indicator 

### 10

of body burden. On the other hand, long

- term average measurements of urinary Pb can be expected to 

### 11

better reflect body burden. 

### 12



## 4.7.4. Air Lead

- Blood Lead Relationships

The 1986 Pb AQCD described epidemiological studies of relationships bet ween air Pb and blood 

### 13

Pb. Much of the pertinent earlier literature described in the AQCD was drawn from a meta

- analysis by 

### 14

Brunekreef ( 1984 ) . In addition to the meta

- analysis of Brunekreef ( 1984 )

, seven more recent studies have 

### 15

provided data from which estimates of the blood Pb

- air Pb slope can be derived for children (Table 4

- 11 ). 

### 16

The range of estimates from these seven studies is 1

- 9 μg/dL per μg/m 3 , w hich encompasses the estimate 

### 17

from the Brunekreef ( 1984 ) meta

- analysis of (3

- 6 μg/dL per μg/m 3 ). The Schnaas et al. (2004) had a 

### 18

particularly strong experimental design in that is the only longitudinal study in which blood Pb 

### 19

concentration was monitored repeatedly in individual children from age 6 months to 10 years. For 

### 20

children wh o experienced the largest declines in air Pb (i.e., from 2.8 to <0.1 μg/m 3 ), the predicted blood 

### 21

Pb

- air Pb slope (adjusted for age, year of birth, SES, and use of glazed pottery) was 0.213 ln [μg/dL 

### 22

blood] per ln[μg/m 3 air]. The cross

- sectional study done b y Ranft et al. ( 2008 ) attempted to account for 

### 23

potential co

- variates that influence blood Pb (e.g., soil Pb concentration, gender, environmental tobacco 

### 24

smoke, fossil heating sys tem and parental education). It is the only study that reported a logarithmic blood 

### 25

Pb

- linear air Pb relationship , which results in an upward curvature of the blood Pb

- air Pb relationship 

### 26

(i.e., the blood Pb

- air Pb slope increases with increasing air Pb co ncentration) . In other studies (or based 

### 27

on other studies), the blood Pb

- air Pb relationship was either log

- log ( Brunekreef, 1984 ; Hayes et al., 

### 28

1994 ; Schnaas et al., 2004 ) , which predicts an increase in the blood Pb

- air Pb slope with decreasing air Pb 

### 29

concentration or linear ( Hilts, 2003 ; J. Schwartz & Pitcher, 1989 ; Tripathi et al., 2001 ) , which predicts a 

### 30

constant blood Pb

- air Pb slope across all air Pb concentrations . These differences may simply reflect 

### 31

model selection by the investigators; alternative models are not reported in these studies. Because air Pb 

### 32May 2011 4

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– DO NOT CITE OR QUOTE contributes to Pb in soil and indoor dusts, adjustment for the correlated co

- variate s such as soil Pb would 

### 1

introduce a downward bias in the slope estimate. 

### 2May 2011 4

- 99 DRAFT

– DO NOT CITE OR QUOTE 

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