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# CHAPTER 4 EXPOSURE, TOXICOKINE TICS, AND BIOMARKERS

4.1 Exposure Assessment

The purpose of this section is to present recent studies that provide insight about human 1 

### exposure to Pb through various pathways. Pb is considered to be a multimedia 2 

### contaminant with multiple pathways of exposure. The relative importance of various 3



### media in affecting Pb exposure changes with source strength and location, location and 4 

### time activity of the exposed individuals, behavior of the exposed individuals, and risk 5 

### factors such as age and socioeconomic factors (risk factors are discussed in detail in 6 

### Chapter 6 ). Blood Pb and bone Pb b iomarkers (discussed in Section 4.3 , Section 4.4

, 7



### Section 4.5 , and Section 4.6 ) , are often used to indica te composite Pb exposure resulting 8



### from multiple media and pathways of exposure

. 9



### The recent information provided here builds upon the conclusions of the 2006 Pb AQCD 10 

### ( 2006b )

, which found that air Pb concentrations and blood Pb levels have decreased 11 

### substantially following the restrictions on Pb in on

- road vehicle gasoline, Pb in household 12 

### paints, the use of Pb solder, and reductions in indust rial Pb emissions that have occurred 13 

### since the late 1970s. Nevertheless, detectable quantities of Pb have still been observed to 14 

### be bioaccessible in various media types. It was reported in the 2006 Pb AQCD ( U.S. 15 

### EPA, 2006b ) that airborne maximum quarterly Pb concentrations in the U.S. were in the 16 

### range of 0.03

- 0.05 μg/m 3 

### for non

- source

- oriented monitors for the years 2000

- 2004 and 17



### were 0.10

- 0.22 μg/m 3 

### for source

- oriented monitors during that time period, while blood 18



### Pb levels reached a median of 1.70 μg/dL among children (1

- 5 years of age) in 19



### 2001

- 2002. It was also observed that Pb exposures were associated with nearby industrial 20 

### Pb sources, presence o f Pb

- based paint, and Pb deposited onto food in several of the 21 

### studies described in the 2006 Pb AQCD. 22



### 4.1.1 Pathways for Lead Exposure

Pathways of Pb exposure are difficult to assess because Pb has multiple sources in the 23 

### environment and passes through various environmental media. These issues are described 24



### in detail in Sections 3.2 and 3.3 . Air

- related pathways of Pb exposure are the focus of this 25 

### ISA. Pb can be emitted to air, soil, or water and then cycle through any or all of these 26 

### media. In addition to primary emission of particle

- bound or gaseo us Pb to the 27 

### atmosphere, Pb can be resuspended to the air from soil or dust. Additionally, Pb

- bearing 28 

### PM can be deposited from the air to soil or water through wet and dry deposition. Air

- 29February 2012 4

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### related Pb exposures also include inhalation and ingestion of Pb

- con taminated food, 1 

### water or other materials including dust and soil via hand

- to

- mouth contact. In general, 2



### air

- related pathways include those pathways where Pb passes through ambient air on its 3 

### path from a source to human exposure. Some non

- air

- related exposu res of Pb include 4 

### ingestion of indoor Pb paint, Pb in diet as a result of inadvertent additions during food 5 

### processing, and Pb in drinking water attributable to Pb in distribution systems, as well as 6 

### other generally less prevalent pathways. 7



### Particle size of Pb

- PM is relevant to transport through various media leading to exposure. 8 

### The inhalability of airborne particles is a gradually decreasing function of particle size. 9 

### Inhalability criteria established from experimental data obtained at wind speeds of 1

- 8 10 

### m/s describe PM inhalability of 77% for particles <10 μ m (d ae 

### , aerodynamic diameter). 11 

### Inhalability of particles ranging in size from 40 to 100 μ m d ae 

### is 50%; above 100 μ m, 12 

### inhalability data are lacking ( Soderholm, 1989 ; ACGIH, 1985 )

. Of the particles that are 13 

### not inhaled, their settling to surfaces makes them available for subsequent ingestion. The 14 

### main pathway for Pb ingestion by children is by hand to mouth ( Lanphear et al., 1998 )

. In 15 

### a playground environment in London, U.K. , Duggan et al. ( 1985 ) reported that hand to 16 

### mouth transfer was effectively limited to par ticles smaller than 10 μm, even when the soil 17 

### itself exhibited a much larger particle size distribut ion. More recently, Yamamoto et al. 18 

### ( 2006 ) reported for a cohort of children in Kanagawa Prefecture, Japan (greater Tokyo 19 

### area) that the mode of size distributions of particles adhering to children’s hands was 39 20



### ± 26 μ m, with t he upper tail ranging from 200

- 300 μ m. Differences in the size 21 

### distribution results may be related to differences in the soil between the two locations 22 

### and/or to differences between the analytical methods used to measure size distribution; 23 

### Duggan and Inski p ( 1985 ) used optical microscopy of the dust wipes, while Yamamoto et 24



### al. ( 2006 ) used a laser scattering device measuring sampled particles suspended in an 25 

### aqueous solution. Similar studies focusing on particle size distributions of ingestion of 26 

### house dust are lacking. Ingestion of house dust has been reported to be the major source 27 

### of lead intake during early childhood ( Lanphear et al., 2002 )

. If a similar particle size 28



### distribution holds for househol d dust, then ingestion of indoor Pb of atmospheric origin 29 

### could also be strongly dependent on dust particle size. Therefore, larger particles of 30 

### atmospheric origin, which may not be considered relevant for exposure by inhalation 31 

### exposure, are still relevan t for Pb exposure by ingestion. However, no studies in the 32 

### literature have presented information on the relative contributions of Pb from different 33



### PM size fractions to blood Pb concentrations. 34



### The complicated nature of Pb exposure is illustrated Figure 4

- 1 , in which the Venn 35 

### diagram depicts how Pb can cycle through multiple environmental media prior to human 36 

### exposure. The “air/soil/water” arrows illus trate Pb exposures to plants, animals, and/or 37



### humans via contact with Pb

- containing media. The exposures are air

- related if the Pb 38February 2012 4

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### passed through the air compartment. When animals consume plant material exposed to 1 

### Pb that has at some point passed through t he air compartment, and when human diet 2 

### includes animals and/or plants exposed to Pb that has passed through the air 3 

### compartment, these are also considered air

- related Pb exposures. As a result of the 4 

### multitude of possible air

- related exposure scenarios an d the related difficulty of 5 

### constructing Pb exposure histories, most studies of Pb exposure through air, water, and 6


### soil can be informative to this review. Figure 4

- 1 also illustrates other exposures, such as 7 

### occupational exposures, contact with consumer goods in which Pb has been used, or 8 

### ingestion of Pb in drinking water conveyed through Pb pipes. Most Pb biomarker studies 9 

### do not indicate speciation o r isotopic signature, and so exposures that are not related to 10 

### Pb in ambient air are also reviewed in this section because they can contribute to Pb body 11 

### burden. Many of the studies presented in the subsequent material focus on observations 12 

### of Pb exposure via one medium: air, water, soil and dust, diet, or occupation. 13

Note: The Venn diagram is used to illustrate the passage of Pb through multiple environmental media compartments through whic h
exposure can occur.


### Figure 4

- 1 Conceptual model of multimedia Pb exposure.

The relative importance of different sources or pathways of potential exposure to Pb in 14



### the environment is often difficult to discern. Individual factors such as home 15February 2012 4

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### environment, lo cation, and risk factors (described in more detail in Chapter 6 ) may 1 

### influence exposures. The National Human Exposure Assessment Survey (NHEXAS) 2



### st udy sampled Pb, as well as other pollutants and VOCs, in multiple exposure media from 3 

### subjects across six states in EPA Region 5 (Illinois, Indiana, Michigan, Minnesota, Ohio, 4 

### and Wisconsin) ( Clayton et al., 1999 ) as well as in Arizona ( O'Rourke et al., 1999 ) and 5 

### Maryland ( Egeghy et al., 2005 )

. Results from NHEXAS indicate t hat personal exposure 6 

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

- 1 ). 7 

### Pb levels in windowsill dust were higher than Pb levels in surface dust collected from 8 

### other surfaces. Clayton et al. ( 1999 ) suggested that higher windowsill levels could be 9 

### attributed to the presence of Pb

- based paint and/or to accumulation of infiltrated outdoor 10



### Pb

- bearing PM. Pb levels in food were higher than in beverages, and Pb levels in 11 

### standing tap water (also referred to as “first flush” or “first draw”) were higher than Pb 12



### levels obtained after allo wing water to run for three minute s to flush out pipes. 13February 2012 4

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### 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 90th (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 (mg/kg) 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 (mg/kg) 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/dL) 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 enroll ed using a stratified, four

- stage probability sampling design, and submitted questionnaire and physical measurements data. Summary statistics (percentage measurable, mean, median, 90th 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 i ndoor air, outdoor air, dust media, and water media apply to the target population of Region 5 households; estimates for othe r media apply to the target population of Region 5 residents.

b Percentage measurable is the percentage of the target population of residents (or households) estimated 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: Reprinted with permission of Nature Publishing Group, Clayton et al. ( 1999 )



### Several s tudies have used a combination of measured values and default model values to 1 

### represent exposures and determine their relative contributions to blood Pb. Cornelis et al. 2 

### ( 2006 ) used the Integrated Exposure Uptake Biokinetic model (IEUBK), described in 3 

### detail in the 2006 Pb AQCD ( U.S. EPA, 2006b ) to model children’s exposures to Pb 4



### emissions from a non

- ferrous smelter in Hoboken, Belgium. They point out that ambient 5 

### air Pb concentrations decrease with distance from the smelter while IEUBK is fairly 6 

### insensitive to changes in ambient air concentration. They input the average ambient air 7 

### Pb concentration of 0.81μg/m3 and assumed that the indoor air Pb concentrat ion was 8 

### 30% of the outdoor Pb. In the absence of indoor air Pb samples, the default assumption 9 

### was adopted for the Cornelis et al. ( 2006 ) study. Similarly, Carrizales et al. ( 2006 ) 10 

### analyzed exposures to children living near a copper smelter in S an Luis Potosi, Mexico. 11 

### They employed the IEUBK default options for assignment of Pb dust concentration as 12February 2012 4

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### 70% of the soil Pb concentration, while air Pb concentration was assigned based on 1 

### measurements by the Mexican government. Based on these assumptions , they attributed 2 

### 87% of blood Pb to soil and dust exposure. Input soil and dust Pb levels were obtained 3 

### from an average of 28 sites. Using defaults for all IEUBK values, the soil/dust Pb 4 

### ingestion pathway has been predicted to contribute 63

- 75% (depending of a child’s age) 5 

### of blood Pb, whereas the air Pb inhalation pathway contributed <1% ( SRC, 2007 )

. This 6 

### analysis did not specifically estimated the portion of the soil/dust Pb ingestion pathway 7 

### that derives from air Pb, such as recently airborne Pb deposited to soil and dust which 8



### remains av ailable for inhalation and ingestion. In the 1986 Pb AQCD, blood Pb

- air Pb 9 

### slopes were examined that included both direct (inhalation) and indirect (via soil, dust, 10 

### etc.) air Pb contributions, resulting in the conclusion that slopes for the total air Pb 11



### co ntribution were roughly twice that of the slope due to inhaled air Pb alone. This “recent 12



### air” Pb was described in the 2007 Pb Risk Assessment ( U.S. EPA, 2007f ) to include 13 

### those pathways involving Pb that is or has recently been in the outdoor ambient air, 14 

### including inhalation and ingestion of indoor dust Pb derived from recent amb ient air 15 

### ( e.g., air Pb that has penetrated into the residence recently and loaded indoor dust). 16 

### Beyond the direct inhalation pathway (outdoor and indoor ambient air Pb), Appendix I of 17



### the 2007 Pb Risk Assessment ( U.S. EPA, 2007f ) provides estimates of the contribution of 18 

### various other pathways ( e.g., diet, drinking water, out door soil ingestion) as well as those 19 

### involving recent air Pb to blood Pb. Estimates of recent air Pb contributions were highly 20 

### dependent on the exposure scenario evaluated. For the General Urban Case Study in that 21 

### assessment, “current conditions” at the t ime of the risk assessment (0.14 μ g/m3, mean of 22 

### maximum quarterly average concentration of Pb in TSP) were modeled as remaining 23 

### constant throughout the 7 years of the exposure modeled in the biokinetic model. A 24



### median concurrent blood Pb concentration of 1 .8

- 2.8 μ g/dL (depending on the exposure 25 

### and risk model) was estimated as the average of the results at 75 and 81 months of age. 26 

### The recent air Pb ingestion pathways contributed a median of 12

- 28% (depending on the 27 

### exposure model) to blood Pb beyond the 0.5

- 0.6% attributable to inhalation of recent 28 

### airborne Pb. In simulations for the 95th percentile of current conditions (0.87 μ g/m3, 29 

### 95th percentile of maximum quarterly average concentration of Pb in TSP), median 30



### children’s blood Pb increased to 2.0

- 3.1 μ g/d L and the contribution of recent air Pb 31 

### ingestion pathways increased to 22

- 37% of blood Pb. Results of other exposure scenarios 32 

### for which greater or lesser contributions of recent air Pb to blood Pb were predicted are 33 

### available in Appendix I of the 2007 Pb Risk Assessment ( U.S. EPA, 2007f )

. 34February 2012 4

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### 4.1.2 Environmental Exposure Assessment Methodo logies

A number of monitoring and modeling techniques have been employed for exposure 1 

### assessment. These are detailed in either the 2006 Pb AQCD ( U.S. EPA, 2006b ) or in the 2 

### subsequent Risk and Exposure Assessment performed as part of the same NAAQS 3



### review ( U.S. EPA, 2007g )

. Some of these methods are briefly described here to provide a 4 

### context for the exposure studi es described in Section 4.1.3 . Blood Pb sampling is 5



### described in detail in Section 4.3.2

. 6



### Data collection to assess Pb exposure pathways may involve air, soil, and dust samples. 7 

### Methods used for digesting air Pb samples are described in Section 3.4 , as are ambient air 8 

### Pb monitoring techniques. Factors affecting collection of ambient air Pb samples are 9



### described in detail in Section 3.4 . For the monitors in the FRM network, the primary role 10 

### is compliance assessment. Accordingly, this network includes monitors in locations near 11 

### sources of air Pb emissions which are expect ed to or have been shown to contribute to 12 

### ambient air Pb concentrations in excess of the Pb NAAQS. In such locations, Pb may be 13 

### associated with relatively larger size particles, contributing to air Pb concentration 14 

### gradients with distance from the source a nd greater deposition in the near

- source 15



### locations. The FRM network also includes non

- source

- oriented monitors for which the 16 

### main objective is to gather information on neighborhood

- scale lead concentrations that 17 

### are typical in urban areas so to better unde rstand ambient air

- related Pb exposures for 18 

### populations in these areas. This part of the Pb NAAQS network, is required to be 19 

### operational as of December 27, 2011. These monitor locations are distributed across a 20 

### broad geographic area, representing approxima tely 63 large urban areas which contain 21 

### approximately half of the total U.S. population (based on recently published 2010 Census 22 

### Bureau data). In lieu of more detailed analysis of population proximity for these newly 23 

### established monitors, population counts were calculated near previously existing 24 

### monitors for which data are presented in Section 3.5 . For the monitors in that limited 25 

### dataset, among the total population of 311,127,619 people in the 2010 Census ( ESRI, 26



### 2011 )

, 181,100 (0.06%) lived within 1 km of a source

- oriented monitor, while 918,351 27 

### (0.30%) lived within 1 km of a non

- source

- oriented monitor. 28



### Dust sampling has not changed drastically since it was first proposed by Sayre et al. 29 

### ( 1974 )

, in which a disposable paper towel was soaked in 20% denatured alcohol and 30 

### 1:750 benzalkonium chloride and then used to wipe a 1 ft 2 

### sampling area in a systematic 31 

### fashion. Que Hee et al. ( 1985 ) and Sterling et al. ( 1999 ) compared wipe testing with 32 

### vacuum methods. Sampling efficiency for the first attempt varied between 53

- 76% with 33 

### vacuum pump flow rate and tube type and was 52% for the wipe method for the Que Hee 34



### et al. ( 1985 ) study, with 100% efficiency aft er five consecutive samples were obtained. 35 

### Sterling et al. ( 1999 ) observed that two of three vacuuming methods had significantly 36February 2012 4

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### higher geometric mean collection (vacuum 1: 94. 3 μ g/ft 2 

### ; vacuum 2: 23.5 μ g/ft 2 

### ) 1 

### compared with dust wipes (5.6 μ g/ft 2 

### ). 2



### Models may also be used in exposure assessment. For example, two dispersion models, 3 

### the American Meteorological Society/Environmental Protection Agency Regulatory 4 

### Model (AERMOD), and I ndustrial Source Complex

- Plume Rise Model Enhancements 5 

### (ISC

- PRIME) were employed to model dispersion of Pb emissions from specific 6



### industrial facilities ( Cimorelli et al., 2005 ; Perry et al., 2005 ; EPRI, 1997 )

, and to 7



### estimate ambient air Pb concentrations at some of the case studies included in the 2007 8 

### Risk and Exposure Assessment ( U.S. EPA, 2007g )

. These models assume plume 9 

### dispersion follows a Gaussian distribution from a point source. For the two point source 10 

### case studies included in the 2007 risk assessment, the plume models were used to track 11



### e missions to ambient air near homes located within a few miles of emitting facilities. 12 

### However, dispersion models can also be used to track long distance transport of Pb 13 

### emissions, as performed by Krell and Roeckner ( 1988 ) to model the dispersion and 14 

### deposition of Pb and Cd from European nations into the North Sea. 15



### Several models esti mate blood Pb levels resulting from estimated exposure to Pb in 16 

### environmental media. These models, which are described in detail in the 2006 Pb AQCD 17 

### ( U.S. EPA, 2006b ) include the IEUBK model, and the EPA All Ages Lead Model 18 

### (AALM), which combines and expands the thorough exposure and absorption modules of 19 

### the IEUBK model with the comprehensive biokinetic model of Leggett ( 1993 )

. 20



### The Stochastic Human Exposure and Dose (SHEDS) and NORMTOX models also are 21 

### capable of modeling metals exposures through various routes including inhalation, 22 

### ingestion, and dermal exposure ( Loos et al., 2010 ; Burke et al., 2002 )

. Pb exposure 23 

### modeling can also be accomplished using the Modeling Environment for Total Risk 24 

### (MENTOR) framework, in which airborne Pb levels could be modeled using AQS, 25 

### dispersion modeling, or ch emical transport modeling, while human exposure is modeled 26 

### with SHEDS or a similar exposure model ( Georgopoulos and Lioy, 2006 )

. Additionally, 27



### h ousing data and time

- activity data from the Consolidated Human Activity Database 28 

### (CHAD) are incorporated into MENTOR to develop refined estimates of Pb exposure and 29 

### tissue burden. However, a literature search did not produce any Pb exposure studies using 30



### t he SHEDS, NORMTOX, or MENTOR modeling systems. In general, these models take 31 

### input for several environmental Pb exposure media including soil, dust, food and water, 32 

### outdoor air, and indoor air. The models are designed to evaluate different exposure 33



### scenari os based on specification of particular conditions. 34February 2012 4

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### 4.1.3 Exposure Studies

4.1.3.1 Airborne Lead Exposure

Limited personal exposure monitoring data for airborne Pb were available for the 2006 1 

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

. As described above, the NHEXAS study showed personal 2 

### air Pb concentrations to be significantly higher than indoor or outdoor air Pb 3



### concentrations ( Clayton et al., 1999 )

. Indoor air Pb concentration was moderately 4 

### correlated with floor dust and residential yard soil Pb concentration ( Rabinowitz et al., 5



### 1985 )

. Egeghy et al. ( 2005 ) performed multivariate fixed effects analysis of the 6



### NHEXAS

- Maryland data and found that Pb levels measured in indoor air were 7 

### signi ficantly associated with log

- transformed outdoor air Pb levels, ambient temperature, 8 

### number of hours in which windows were open, homes built before 1950, and frequency 9 

### of fireplace usage ( Table 4

- 2 ). 10February 2012 4

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### Table 4

- 2 Estimates of fixed effects 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 6.23 <0.0001 0.02 0.91
Outdoor Pb concentration b 0.51 <0.0001 Average weekly temperature (°F) 0.01 0.046 Open window periods (hr) 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 0.088 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 Electrostatic air filter usage (yes)

- 0.91 0.062 Sex of participants (male) 0.41 0.0012 0.43 <0.0001 Ethnic minority participants (yes) 0.41 0.0063 Washing hands after lawn mowing (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 (yr) 0.02 <0.0001 Number cigarettes smoked (count) 0.03 <0.0001 Burning wood or trash (days) 0.58 0.0099 Showering frequency (avg # days)

- 0.29 0.0064 Work outside home (yes)

- 0.26 <0.0001 Health status (good) 0.23 0.0009 Adherence to high 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 National Human Exposure Assessment Survey (NHEXAS

- MD)

. b Log transform
Source: Reprinted with permission of Nature Publishing Group, Egeghy et al. ( 2005 )

.



### Some recent studies have measured persona l exposure to particle

- bound Pb along with 1 

### other trace metals. Adgate et al. ( 2007 ) measured the concentrations of several trace 2 

### elements in personal, indoor, and outdoor air samples of PM 2.5 

### and found that average 3 

### personal Pb

- PM 2.5 

### concentration was roughly three times higher than outdoor air Pb

4



### PM 2.5 

### concentration and two times higher than indoor Pb

- PM 2.5 

### concentration ( Table 5



### 4

- 3 ). Another study of indoor and outdoor air concentrations of Pb was carried out by 6


### Molnar et al. ( 2007 )

. PM 2.5 

### trace element concentrations were determined in homes, 7 

### preschools and schools in Stockholm, Sweden. In all sampled locations, Pb

- PM 2.5 8 

### concentrations were higher in the outdoor environment than in the pro ximal indoor 9



### environment. The indoor/outdoor ratios for Pb

- PM 2.5 

### suggest an outdoor Pb

- PM 2.5 

### net 10February 2012 4

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### infiltration of ~0.6 for these buildings. Outdoor air Pb concentrations did not differ 1



### between the central and more rural locations. Indoor air Pb concentratio ns were higher in 2 

### spring than in winter, which the authors attributed to greater resuspension of elements 3 

### that had accumulated in road dust over the winter period and increased roadwear on days 4 

### with dry surfaces. Pekey et al. ( 2010 ) measured indoor and outdoor trace element 5 

### composition of PM 2.5 

### and PM 10 

### in Kocaeli, an industrial region of Turkey, and found that 6 

### average airborne Pb concentrations were higher outdoors than indoors for both PM 2.5 

### and 7



### PM 10 

### during summer and for PM 10 

### during winter, but that indoor Pb concentration was 8 

### higher than outdoor Pb concentration for PM 2.5 

### during winter. The indoor

- to

- outdoor 9 

### ratio of airborne Pb varied by environment; it tended to be less than one, but the ratio 10 

### varied from one microenvironment to another. In a pilot study in Windsor, Ontario, 11



### Rasmussen et al. ( 2007 ) observed that the concentration of Pb in PM 2.5 

### from a personal 12 

### exposure sample was roughly 40% higher than the concentration of Pb in outdoor PM 2.5 13 

### and 150% higher than Pb in indoor PM 2.5 

### . The three studies that included personal 14 

### samples recorded measurements that were consistently higher than indoor o r outdoor 15



### levels. 16



### Domestic wood burning is a potential source of Pb compounds ( Section 3.2.2.5 ). Molnar 17



### et al. ( 2005 ) measured trace element concentration in indoor and personal exposure PM 2.5 18 

### samples for homes in which wood is burned and in a reference group where no wood 19 

### burning occurs in the home. For both indoor and personal samples, Molnar e t al. ( 2005 ) 20 

### observed that Pb concentrations were higher for the wood burning group, but that the 21 

### differences were not significant (indoor concentration: 6.0 μ g/m 3 

### vs. 4.3 μ g/m 3 

### , p = 0.26; 22 

### personal exposure: 4.6 μ g/m 3 

### vs. 3.0 μ g/m 3 

### , p = 0.06). 23



### Indoor activity has been associated with resuspension of settled dust, which could cause 24 

### airborne contact with particle

- bound Pb. Qian et al. ( 2008 ) estimated a PM 10 

### resuspension 25



### rate of 1.4x10 - 4 

### hr - 1 

### for one person walking across a carpeted floor. Measurements of 26 

### submicron particles illustrated a roughly two

- fold increase of airborne particle 27 

### concentration for particles smaller than 1.8 μ m for activity vs. low activity periods, with 28 

### maximum concentrations reaching 4

- 11 times the maximum value during low activity 29 

### periods. For PM 10 

### , average concentration was 2.5 times higher than background levels 30 

### during activity periods, while peak co ncentration was 4.5 times higher. Qian and Ferro 31 

### ( 2008 ) observed that resuspension rates depend on particle size, floor material, and 32 

### ventilation position. Increases in walking speed and weight of the walker did not 33 

### consistently produce increases in resuspension. 5

- 10 μ m par ticles produced a higher 34 

### resuspension rate compared with smaller particles. Newly carpeted areas produced 35 

### significantly higher resuspension rates than vinyl floors. Zhang et al. ( 2008 ) modeled and 36 

### conducted experiments of particle dispersion from walking and observed that human 37 

### activity did affect resuspension. They found that larger particles were more readily 38February 2012 4

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– Do Not Cite or Quote 

### detached from the carpet by walking motion, but that smaller parti cles are more easily 1 

### resuspended once detached. Hunt and Johnson ( In Press ) studied the duration and spatial 2 

### extent of resuspension of 0.3

- 5.0 μ m particles following walking by a soiled shoe. 3



### 0.3

- 0.5 μ m particle concentration remained increased over a time period of 23 min, while 4



### 1

- 5 μ m particles declined in concentration over the same time period. Experiments and 5 

### computational fluid dynamics simulations by Eisner et al. ( 2010 ) for a mechanical foot 6 

### moving on carpeting suggested that the rotating motion of the moving foo t on the carpet 7 

### induced rotating air movement beneath the foot that re

- entrained the particles. If Pb 8 

### adsorption onto particles varies with sources, size selectivity of resuspension processes 9 

### could lead to enhanced Pb exposure from one source relative to a nother. 10



### Several of the studies can be used to develop an understanding of how personal exposure 11



### to PM

- bound Pb varies with other exposures. Molnar et al. ( 2007 ) reported Spearman 12



### correlations of Pb with PM 2.5 

### and NO 2 

### in three outdoor microenvironments (residence, 13 

### school, and preschool) and found that Pb and other trace metals were generally well 14



### correlated with PM 2.5 

### (r = 0.72

- 0.85), but Pb was not always well

- correlated with NO 2 

### (r 15



### = 0.24

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

### were well

- correlated, it is possible that the Pb 16 

### was traffic related from resuspended pulverized wheel weights or impurities in unleaded 17



### on

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

### was 18



### low , it is possible that they were less affected by traffic. Table 3

- 26 in the Appendix to 19 

### Chapter 3 illustrates that Pb concentrations in the four studies summarized there are 20 

### typically well below the level of the NAAQS. The higher personal air concentratoins 21 

### occurred in a heavily industria lized area of Kocaeli, Turkey with an incinerator and 22 

### several industrial facilities including metal processing, cement, petroleum refining, 23 

### agriculture processing. Otherwise, concentrations were all between 0.002 and 24



### 0.006 μg/m 3 

### . The proportion of Pb compa red with other trace metals varied with location 25 

### and component. It was typically several times lower than S as well as crustal elements 26 

### such as Ca and Fe. In the industrial area of Kocaeli, Pb comprised a greater proportion of 27 

### the PM compared with other ar eas. 28February 2012 4

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### Table 4

- 3 Comparison of personal, indoor, and outdoor Pb

- PM measurements from several studies

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 ) Minneap olis

St. Paul, M N 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, 2003

- 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

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

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

- PM 2.5 ( mg/kg) April, 2004 311 124 221



### 4.1.3.2 Exposure to Lead in Soil and Dust

The 2006 Pb AQCD ( U.S. EPA, 2006b ) lists indoor Pb dust infiltrated from outdoors as a 1 

### potential source of exposure to Pb soil and dust. Thus, outdoor soil Pb may present an 2 

### inhalation exposure if resuspended indoors or an ingestion exposure during hand

- to

3 

### mouth contact. A detailed description of studies of outdoor soil Pb concentration is 4 

### provided in Section 3.6.1 . Indoor measurements can reflect infiltrated Pb as well as Pb 5 

### dust derived from debrided paint, consumer products, or soil that has been transported 6


### into the home via foot traffic. Table 4

- 4 presents indoor dust Pb concentrations for 7



### 2006

- 2011 observational studies in which indoor dust Pb was measured. 8February 2012 4

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### Table 4

- 4 Measurements of ind oor dust Pb concentration from 2006

- 2011 studies

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

Caravanos et al. ( 2006a ) New York City, New York Weekly dust loading (μg/m 2 ) Glass plate next to open window of academic building Median: 52

Khoder et al. ( 2010 ) Giza, Egypt (extensive leaded gasoline use; industrial area) Weekly dust loading (μg/m 2 ) Glass plate in second

- floor living room of apartments Median: 408

Brattin and Griffin ( 2011 ) Eureka, Utah near Eureka Mills Superfund Site Dust concentration (mg/kg) Indoor home site (not specified) 160

- 2000

Denver, CO, near VBI70 Superfund Site Indoor home site (not specified) 11

- 660
East Helena, MT, near East Helena Superfund Site Indoor home site (not specified) 68

- 1000

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

- 1770

Turner and Simmonds ( 2006 ) Birmingham, Plymouth, and 2 rural sites, UK Dust concentration (mg/kg) Floor Median: 17 8

Gaitens et al. ( 2009 ) U.S. (nationwide) Dust loading (μg/m 2 ) Smooth f loor 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

Wilson et al. ( 2007 ) Milwaukee, Wisconsin Dust concentration (μg/m 2 ) Central perimeter Avg.: 107
Entry Avg.: 140

Window Avg.: 151

Zota et al. ( 2011 ) Ottawa County, Oklahoma (area surrounding the Tar Creek Superfund Site) Dust concentration (mg/kg) Indoor (site not specifi ed) Avg.: 109
Median: 63
Max.: 881

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 Dust concentration (mg/kg) Vacuum Median: 470 Max: 2,000

Floor Median: 290 Max: 4,600



### Several studies suggested the infiltration of Pb dust into buildings. For example, 1



### Caravanos et al. ( 2006a ) collected dust on glass plates at an interior location near an open 2 

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

- year period 3 

### in Manhattan, NY. Median weekly dust loading was reported to be 52 μ g/m 2 

### for the 4 

### indoor site, 153 μg/m 2 

### for the unsheltered outdoor site, and 347 μg/m 2 

### for the sheltered 5 

### outdoor site. This paper demonstrated the likely role of outdoor Pb in influencing indoor 6 

### dust Pb loading and indicated that under quiescent conditions ( e.g., no cleaning) near an 7February 2012 4

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### ope n second

- story window, the indoor dust Pb level might exceed EPA’s hazard level for 1



### interior floor dust of 430 μg/m 2 

### (40 μg/ft 2 

### ). Khoder et al. ( 2010 ) used the sam e 2 

### methodology to study Pb dust deposition in residential households in the town of Giza, 3 

### Egypt, located between two industrial areas and where leaded gasoline is still in use; the 4 

### investigators reported a median weekly deposition rate of 408 μg/m 2 

### and an e xterior 5 

### median deposition rate of 2,600 μg/m 2 

### . In the latter study, Pb deposition rate correlated 6 

### with total dust deposition rate (R=0.92), Cd deposition rate (R=0.95), and Ni deposition 7 

### rate (R=0.90). Statistically significant differences in Pb deposition rates were observed 8 

### between old and new homes ( p <0 .01) in the Khoder et al. ( 2010 ) study, although the 9 

### only quantitative information provided regarding home age stated that the oldest home 10



### was 22 years old when the study was performed in 2007. Khoder et al. ( 2010 ) found no 11 

### statistically significant difference between Pb loadings when segregating the data by 12 

### proximity to roadways. Recently, Brattin and Griffin ( 2011 ) performed linear regressions 13 

### of dust Pb on soil Pb based on data collected previously for outdoor soil Pb and indoor 14 

### dust Pb near mining a nd/or smelting Superfund sites in Utah, Colorado, and Montana 15 

### ( U.S. EPA, 2005f

, 2002a

, 2001 )

. They observed that the dust Pb concentration was 16



### 4

- 35% of outdoor soil Pb. Excluding outlier s on the regression, dust Pb concentration 17 

### ranged from 160

- 2,000 mg/kg, 11

- 660 mg/kg, and 68

- 1

, 000 mg/kg at three sites. 18



### Correlations between indoor and outdoor Pb content in dust can be partially explained 19 

### with speciation. Beauchemin et al. ( 2011 ) used XANES to speciate in

- home paint 20 

### samples to assess the contributions of indoor paint and outdoor material to indoor dust Pb 21 

### concentrations. In indoor dust samples of parti cles <150 μm in size, Pb oxide, Pb sulfate, 22 

### and Pb carbonate were measured. These materials commonly were used in white paint. In 23 

### the size fraction of particles <36 μm, half of the measured Pb was associated with Fe

24 

### oxyhydroxides such as ferrihydrite and g oethite and presumably adsorbed onto these 25 

### species. This finding suggested that a mix of indoor and outdoor sources may affect the 26 

### composition of dust in this size fraction. 27



### Residual Pb dust contamination following cleaning activities has been documented. For 28 

### instance, Hunt et al. ( 2008 ) performed tests where a test soil prepared by drying, 29 

### grinding, and sieving Pb

- contaminated yard soil samples from Herculaneum, MO was 30 

### tracked onto a tile test surface and then repeatedly cleaned with a moistened wipe and/or 31 

### vacuumed until visual inspection of the tiles uncovered no surface discoloration. The 32 

### authors then used wet wipe samples to collect residual soil and estimate Pb deposition 33 

### and concentration. After the first walk, tile Pb dust loading was 2,670 μg/m 2 

### ; after the 34 

### first vacuuming, it decreased to 398 μg/m 2 

### . After multiple walks, tile Pb dust loading was 35 

### 7,100 μg/m 2 

### , and it decreased to 1,400 μg/m 2 

### after multiple vacuu ming. Scanning 36 

### electron microscopy (SEM) of the wipe samples revealed that most of the residual dust 37 

### particles were in the range of 1

- 3 μm in area equivalent diameter. This result indicates 38February 2012 4

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### that Pb

- bearing fine particles are not completely captured by home cleaning. Yu et al. 1 

### ( 2006 ) analyzed dust samples from 50 homes in n orthern New Jersey (typically of older 2 

### housing stock, although the study does not specify housing age). The investigators 3 

### obtained dust from vacuuming carpet samples and found that total Pb concentration in 4 

### carpet ranged from 209 to 1,770 mg/kg dust. 5



### Pb d ust on floors, windowsills, and other accessible surfaces are potential exposure 6 

### sources to small children who use touch to explore their environments. Gaitens et al. 7 

### ( 2009 ) used National Health and Nutrition Examination Survey (NHANES) data from 8 

### 1999 through 2004 to examine Pb in dust in homes of children ages 12

- 60 months. The 9



### median value of Pb d ust loading on floors was reported to be 1.7 μg/m 2 

### (mean: 10



### 4.4 μg/m 2 

### ), with floors that were not smooth and cleanable having a median Pb dust 11 

### loading value of 5.6 μg/m 2 

### (mean: 16 μg/m 2 

### ). Floor Pb dust loading value was modeled 12 

### against several survey covaria tes and was significantly associated (p <0.05) with floor 13 

### surface condition, windowsill Pb dust loading, race and ethnicity, poverty

- to

- income 14 

### ratio, year of home construction, presence of smokers in the home, and year of survey. It 15 

### was nearly significantl y associated (p = 0.056) with renovations made to pre

- 1950 homes. 16 

### Median Pb dust loading on smooth windowsills was 25 μg/m 2 

### (mean: 190 μg/m 2 

### ). When 17 

### windowsills were not smooth, the median Pb dust loading was 55 μg/m 2 

### (mean: 18



### 480 μg/m 2 

### ). Windowsill Pb dust l evel was also significantly associated (p <0.05) with 19 

### race and ethnicity, year of home construction, window surface condition, presence of 20 

### smokers in the home, deterioration of indoor paint, and year of survey. Sill surface was 21 

### nearly significantly associa ted (p = 0.076) with deterioration of outdoor paint when 22 

### homes were built prior to 1950. Dust Pb loading was found by Egeghy et al. ( 2005 ) to be 23 

### significantly associated with the log

- transform of soil Pb concentration, cement content in 24 

### the home entryway, indoor pesticide use, frequency of fireplace usage , number of hours 25 

### in which windows were open, and homes built before 1950 ( Table 4

- 2 ). Wilson et al. 26 

### ( 2007 ) studied Pb dust samples from homes in Milwaukee, WI children with and without 27



### elevated blood Pb ≥ 1 0 μg/dL. They found that Pb dust samples obtained from the floor 28 

### were always significantly higher in residences of children with elevated blood Pb, with 29 

### the exception of samples from the bathroom floor. Windowsill dust was not significantly 30 

### higher in residences of children with elevated blood Pb. 31



### Building demolition and renovation activities can create dust from interior and exterior 32 

### paints with Pb content . Mielke and Gonzales ( 2008 ) measured Pb content in paint chips 33 

### from paint applied prior to 1992 and found that medi an Pb levels were 420 mg/kg for 34 

### interior paint and 77,000 mg/kg for exterior paint. Maximum levels were 63,000 mg/kg 35 

### and 120,000 mg/kg for interior and exterior paint, respectively. Mielke et al. ( 2001 ) 36 

### compared dust samples from two New Orleans houses that were prepared for painting. 37 

### One home was power sanded, while the other was hand

- scraped. Immediately after 38February 2012 4

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### sanding, Pb dust samples ranged from <3 to 28,000 mg/kg at the sanded house. Pb dust 1 

### samples from the scraped house ranged from 7 to 1,200 mg/kg. Pb in dust or paint 2 

### samples was not quantified. 3



### Dust Pb concentrations have also been reported for homes in the vicinity of historic and 4



### activ e metals mining and smelting sources. Near an active smelter in Port Pirie, Australia, 5 

### median hand dust Pb loadings increased with age among a cohort of fourteen children 6 

### followed over age 0

- 36 months (2

- 5 months: 54 μg/m 2 

### , 6

- 9 months: 173 μg/m 2 

### , 10

- 15 7



### mon ths: 424 μg/m 2 

### , > 15 months: 336 μg/m 2 

### ) ( Simon et al., 2007 )

. Zota et al. ( 2011 ) 8



### studied Pb dust and indoor Pb

- PM 2.5 

### concentration in Ottawa County, OK near the Tar 9 

### Creek Superfund Site, in which a metals mine had closed. Statistically significant 10 

### correlations among outdoor soil Pb concentration, indoor dust Pb concentration, indoor 11 

### dust Pb loading, and indoor air Pb

- PM 2.5 

### concentrations were observed (r = 0.25

- 0.65), 12 

### with an average dust Pb concentration of 109 mg/kg, dust Pb loading of 54 μg/m 2 

### , soil Pb 13



### concentration of 201 mg/kg, and indoor Pb

- PM 2.5 

### concentration of 1 ng/m 3 

### . Dust Pb 14



### concentrations were found to increa se significantly with proximity to two chat ( i.e., dry 15 

### mining waste) sources and to decrease with distance to the street and presence of central 16 

### air conditioning. Spalinger et al. ( 2007 ) measured Pb in dust in homes in a 34 km 2 

### area 17 

### surrounding a designated Superfund site where formerly a Pb and Zn smelter operated at 18 

### Bunker Hill, ID. During spring of 1999, vacuum and floor mat samples were taken from 19



### homes in three towns within the 34 km 2 

### area and five “background” towns further from 20 

### the Superfund site. For the background towns, Pb concentration in vacuum dust had a 21



### median of 120 mg/kg and a maximum of 830 mg/kg, and Pb concentration in floor dust 22


### had a median of 95 mg/kg and a maximum of 1,300 mg/kg. The median Pb dust loading 23



### rate was measured to be 40 μg/m 2 

### per day. Among the background homes, median 24 

### vacuum and floor mat Pb dust samples were 3 and 2.5 times higher, respectively, when 25 

### comparing h omes built before 1960 with those built after 1960. Deposition rate of Pb 26 

### dust was 5 times higher in the older homes. In contrast, Pb in vacuum dust and floor mats 27 

### for the towns contained within the Bunker Hill Superfund site had a median Pb 28



### concentration of 470 mg/kg with a maximum of 2,000 mg/kg and a median of 290 mg/kg 29 

### with a maximum of 4,600 mg/kg, respectively. The median Pb loading rate for indoor 30



### dust in houses in these towns was 300 μg/m 2 

### per day, and the maximum Pb dust loading 31 

### rate was 51,000 μg/ m 2 

### per day. These results suggest that those living in close proximity 32 

### to large Pb and Zn smelters or mines that are now Superfund sites are at much greater 33 

### risk of exposure to Pb dust compared to the general population. 34



### Pb exposure has been reported on ch ildren’s playgrounds. Mielke et al. ( 2011b ) reported 35



### median soil Pb concentration of 558 mg/kg on playground soils at eleven New Orleans 36 

### daycare or community centers. Fo llowing remediation efforts to cover playground soil 37 

### with clean soil, median concentration dropped to 4.1 mg/kg. Duggan et al. ( 1985 ) 38February 2012 4

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### reported on the concentration and size distribution of wipe samples on the hands of 368 1



### pre

- school children from eleven schools in London, UK. Hand Pb residue (PbH) values 2 

### were modeled as linear and power functions of Pb dust (PbD) from this study to obtain 3



### PbH = 16.1 + 0.0064PbD or PbH = 0.393PbD 0.533 

### . Given that the Duggan et al. ( 1985 ) 4 

### study was performed when Pb additives were used in gasoline, dust Pb concentration 5 

### values are not reported here. Measurements of the size distribution produced geometric 6


### mean diameters of 4.5 μm and 1.5 μm depending on the anal ysis method. The hand wipe 7 

### samples were effectively limited to particles smaller than 10 μm, even when the soil itself 8 

### exhibited a much larger particle size distribution. However, these studies focused on 9 

### playground lead exposure. Que Hee et al. ( 1985 ) performed repeated wipe sampling of 10 

### hands after rubbing in a reference dust sample and in reporting results for a “small adult 11 

### hand” observed that loose particles up to 246 μm in diameter adhered, which is similar to 12 

### the upper limit of 200

- 300 μm observed by Yamamoto et al. ( 2006 )

. If a similar 13 

### relationship holds for household dust, then exposure to Pb in dust by hand

- to

- mouth 14 

### activity may be influenced by the dust particle size distribution and the relationship of Pb 15 

### content to particle siz e fraction. 16



### 4.1.3.3 Dietary Lead Exposure

This subsection covers several dietary Pb exposures from a diverse set of sources. 17 

### Included among those are drinking water, fish and meat, agriculture, urban gardening, 18 

### dietary supplements, tobacco, cultural food sources, and breastfeeding. The breadth of 19 

### dietary Pb exposures is illustrated in Figure 4

- 2 , which illustrates the data obtained in the 20 

### 2008 FDA Total Diet Study market basket survey ( FDA, 2008 )

. Among the highest Pb 21 

### concentrations were those for noodles, baby food carrots, baby food oatmeal, S wiss 22 

### cheese, beef tacos from a Mexican restaurant, and fruit

- flavored cereal. The source of the 23 

### Pb in each case is unclear. Possible sources of Pb in food samples include introduction 24 

### during processing or preparation with drinking water contaminated with Pb, deposition of 25 

### Pb onto raw materials for each food, and Pb exposure in livestock that produce dairy or 26 

### meat ingredients. Manton et al. ( 2005 ) used Pb isotope ratios to estimate sources of 27 

### dietary Pb among a cohort of mothers and children from O m ah a, NE using a combination 28 

### of food samples, hand wipes, house dust wipes, and aerosol samples collected between 29 

### 1990 and 1997 and speciated for Pb isotopes. Drinking water Pb was not included in this 30 

### study. The authors cited results from Egan et al. ( 2002 ) that imported vegetables 31 

### contributed 55% of Pb dietary intake for infants, 30% for 2

- 6 y old children, and 20% for 32



### 25

- 30 y old women. Imported candy contributed 10% of Pb dietary intake for 2

- 6 y old 33


### children and 9% for 25

- 30 y old women. Isotopic data from Manton et al. ( 2005 ) 34 

### suggested that, with the exception of children age 0

- 12 mos, house dust is a large 35February 2012 4

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### contributor to dietary Pb . The pattern of certain Pb

- isotope ratios observed in the diet of 1



### children 0

- 12 mos are suggested to derive from Ca salts in limes t one that may have been 2 

### used in dietary supplements in baby formula. The contribution of ambient Pb aerosols to 3 

### dietary Pb sa mples was not statistically significant for this urban exposure study. 4

Source Data: ( FDA, 2008 ) Note: from the 2008 FDA Total Diet Study. “BF” denotes baby food.


### Figure 4

- 2 Market basket survey results for Pb concentration in foods.February 2012 4

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### Drinking Water

Differences in sources and transport of drinking water m ay cause variation in water Pb 1 

### levels. For example, Shotyk and Krachler ( 2009 ) measured the Pb concentration in tap 2 

### water, commercially bottled tap water and bottled natural water. They found that, in 3 

### many cases, tap water containe d less Pb than bottled water. Excluding bottled water in 4 

### glass containers because Pb can be leached from the glass, the median Pb concentration 5 

### in the bottled water samples was 8.5 ng/L (range ≤ 1 to 761 ng/L). This level ( i.e., 8.5 6 

### ng/L) is significantly less than the Maximum Contaminant Level for Pb of 15 μg/L. Pb in 7 

### drinking water supplies can derive from atmospheric deposition onto surface waters, as 8



### described in Section 3.3.1.2 , or via corrosion of Pb in the distribution network 9 

### exacerbated by contact with acidic disinfection byproducts, as described in the following 10 

### paragraphs. 11



### It is now recognized that environmental nanoparticles (NPs) (~1

- 100 nm) can play a key 12 

### role in determining the chemical characteristics of engineered as well as natural waters 13 

### ( Wigginton et al., 2007 )

. An important question is whether or not NPs from source waters 14 

### affect the quality of drinking water. For example, if Fe

- oxide NPs are not remove d during 15 

### the flocculation/coagulation stage of the treatment process, they may become effective 16 

### transporters of contaminants such as Pb, particularly if these contaminants are leached 17 

### from piping in the distribution system. Edwards and Dudi ( 2004 ) observed a red

- brown 18 

### particle

- bound Pb in Washington, DC water that could be confused with innocuous Fe. 19 

### The source of the particle

- bound Pb was not known but was thought to originate from the 20



### source water. 21



### Corrosion byproducts can influence Pb concentrations in drinking water. Schock et al. 22 

### ( 2008 ) characterized Pb pipe scales fr om 91 pipes made available from 26 different 23 

### municipal water systems from across the northern U.S. They found a wide range of 24 

### elements including Cu, Zn and V as well as Al, Fe and Mn. Interestingly, V was present 25 

### at nearly one percent levels in pipes from many geographically diverse systems. In a 26 

### separate study, Gerke et al. ( 2009 ) identified the corrosion product, vanadinite 27 

### (Pb 5 

### (VO 4 

### ) 3 

### Cl) in Pb pipe corrosion byproducts collected from 15 Pb or Pb

- lined pipes 28



### r epresenting 8 different municipal drinking water distribution systems in the Northeastern 29 

### and Midwest regions of the U.S. Vanadinite was most frequently found in the surface 30 

### layers of the corrosion products. The vanadate ion, VO 4 3

- 

### , essentially replaces th e 31 

### phosphate ion in pyromorphite and hydroxyapatite structures. It is not known whether the 32 

### application of orthophosphate as a corrosion inhibitor would destabilize vanadinite, but 33 

### this substitution would have implications for V release into drinking water. The stability 34 

### of vanadinite in the presence of monochloramine is also not known, and its stability 35 

### might have implications for both Pb and V release into drinking water. 36February 2012 4

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### In recent years, drinking water treatment plants in many municipalities have switched 1 

### from using chlorine to other disinfecting agents because their disinfection byproducts 2 

### may be less carcinogenic. However, chloramines are more acidic than chlorine and can 3 

### increase Pb solubility ( Raab et al., 1991 ) and increase Pb concentrations in tap water. For 4 

### example, after observing elevated Pb concentrations in drinking water samples, Kim and 5



### Herrera ( 2010 ) observed Pb oxide corrosion scales occurring after using acidic alum as a 6 

### disinfection agent. High Pb concentrations in Washington, DC drinking water were 7 

### attributed to leaching of Pb from Pb

- bearing pipes promoted by breakdown products of 8 

### disinfection agents ( Edwards and Dudi, 2004 )

. Maas et al. ( 2007 ) tested the effec t of 9



### fluoridation and chlorine

- based (chlorine and chloramines) disinfection agents on Pb 10 

### leaching from plumbing soldered with Pb. When using chlorine disinfection agents alone, 11 

### the Pb concentration in water samples doubled during the first week of applica tion (from 12



### 100 to 200 ppb ) but then decreased over time. When adding fluorosilic ic acid and 13 

### ammonia, the Pb concentration spiked to 900 ppb and increased further over time. 14 

### Similarly, Lasheen et al. ( 2008 ) observed leaching from pipes in Egypt. In this study, the 15 

### authors tested polyvinyl chloride (PVC), polypropylene (PP), and galvanized iron pipes 16 

### and observed leaching from both the PVC and PP pipes when exposed to an acid of pH = 17 

### 6, with PVC having greatest amount of leaching. Exposure to basic solutions actually 18 

### resulted in reduction of Pb concentration in the drinking water. 19



### Miranda et al. ( 2007a ) modeled blood Pb levels among children living in Wayne County, 20 

### NC as a function of household age, use of chloramines and other covariates. Blood Pb 21 

### levels were significantly associated with the year the home was built (p <0.001), use of 22



### ch loramines (p <0.001), and the interaction between these two variables (p <0.001). 23 

### When year in which the home was built was broken into categories for the independent 24 

### variables and interaction terms, Miranda et al. ( 2007a ) found that significance increased 25 

### with the age of the home. However, the study did not control for the presence of Pb paint 26 

### in the dwellings, so it is difficult to d istinguish the influence of Pb pipes from Pb in paint 27



### on blood Pb levels. 28



### Several chemical mechanisms may contribute to release of Pb during use of chloramine 29 

### disinfection agents. Edwards and Dudi ( 2004 ) hypothesized that Pb leaching occurs when 30 

### chloramines cause the breakdown of brass alloys and solder containing Pb. After 31 

### observing that nitrification also leads to increased P b concentrations in water, they also 32 

### proposed that chloramines may trigger nitrification and hence cause decreasing pH, 33 

### alkalinity and dissolved oxygen that lead to corrosion after observing that nitrification 34



### also leads to increased Pb concentrations in w ater. However, Zhang et al. ( 2009b ) found 35 

### no evidence that nitrification brought about significant leaching of Pb from Pb pipes. 36 

### Lytle et al. ( 2009 ) suggested that a lack of i ncreased Pb(II) concentrations in drinking 37 

### water following a change from free chlorine to chloramines disinfection is attributed to 38February 2012 4

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### the formation of the Pb(II) mineral hydroxypyromorphite (Pb 5 

### (PO 4 

### ) 3 

### OH) instead of 1 

### Pb(IV) oxide. Xie et al. ( 2 010 ) further investigated the mechanisms by which Pb(II) 2 

### release is affected by chloramines. Two opposing mechanisms were proposed: Pb(IV)O 2 3 

### reduction by an intermediate species from decomposition of monochloramine; and 4 

### increasing redox potential which decreases the thermodynamic driving force for 5 

### reduction. They suggest that the contact time of monochloramine with PbO 2 

### and the 6


### Cl 2 

### :N ratio in monochloramine formation will determine which mechanism is more 7 

### important. Free chlorine can control Pb concentra tions from dissolution under flowing 8 

### conditions but for long stagnation periods, Pb concentrations can exceed the action level: 9



### 4

- 10 days were required for Pb concentrations to exceed 15 μg/L (for relatively high 10 

### loadings of PbO 2 

### of 1 g/L). Thus, under les s extreme conditions, it was concluded that 11 

### chloramination was unlikely to have a major effect on the release of Pb into drinking 12



### water. 13



### Agriculture

The 2006 Pb AQCD ( 2006b ) states that surface deposition “represents a sig nificant 14 

### contribution to the total Pb in and on the plant”, while uptake through a plants roots can 15 

### also contribute to a plant’s Pb concentration. Consequently, Pb content in plants may 16 

### contribute to human dietary exposure. Uptake of Pb by plants growing i n contaminated 17 

### soil has been repeatedly demonstrated in some species during controlled potted plant 18 

### experiments ( Del Río

- Celestino et al., 2006 )

. In this study, most species retained Pb in 19



### the roots with little mobilizati on to the shoots of the plants. However, certain species 20 

### Cichorium intybus [chicory], Cynodon dactylon [Bermuda grass], Amaranthus blitoides 21 

### [matweed or mat amaranth], and Silybum marianum [milk thistle]) were able to mobilize 22



### Pb from the roots to the shoo ts of the plant; these specific species could lead to human 23 

### exposures through consumption of grazing animals. Lima et al. ( 2009 ) conducted similar 24 

### greenhouse ex periments with several vegetable crops grown in soil contaminated by Pb

25 

### containing residue from battery recycling waste. In this study, carrots had high 26 

### bioaccumulation, measured as the percent of Pb concentration measured in the plant 27 

### compared with the Pb concentration in the soil, with little translocation of the Pb to the 28 

### shoots, measured as the percent of Pb mass in the shoots compared to the Pb mass within 29 

### the entire plant, of the Pb to the shoots. Conversely, beets, cabbages, sweet peppers, and 30



### collar d greens had low bioaccumulation but moderate to high translocation. Okra, 31 

### tomatoes, and eggplants had moderate bioaccumulation and moderate to high 32



### translocation. Sesli et al. ( 2008 ) also noted uptake of Pb within wild mushrooms. 33



### Vandenhove et al. ( 2009 ) compiled bioaccumulation data for plant groupings from 34 

### various references; these data are repro duced in Table 4

- 5 . Based on this review, grasses 35 

### had the highest uptake, followed by leafy vegetables and root crops grown in sandy soils; 36February 2012 4

- 23 Draft

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### these references also suggested high transfer from roots to shoots amo ng root crops, with 1 

### shoots having roughly four times higher Pb bioaccumulation than roots. This is consistent 2 

### with the 2006 Pb AQCD ( 2006b )

, which reported that Pb deposition onto leafy 3 

### vegetables accounted for most Pb. 4



### Uzu et al. ( 2010 ) found that Pb deposition from smelter emissions caused a linear 5



### increase in Pb concentrations of 7.0 mg/kg per day (R 2 

### =0.96) in lettuce plants cultivated 6 

### in the courtyard of a smelter. They re ported that lettuce grown 250

- 400 m from the 7



### smelter had concentrations that were 10

- 20 times lower, which is consistent with findings 8



### described in Section 3.3 that deposition of Pb containing material drops off with distance 9 

### from a source. Pb contamination of crops can occur through Pb emissions during aerial 10 

### application of fertilizers and pesticides. In 2009, the U.S. Federal Aviation 11



### Administratio n (FAA) recorded 960,000 hours of flight time for aerial application. This 12 

### term encompasses crop and timber production including seeding cropland and fertilizer 13 

### and pesticide application. It is estimated that 42% of these flight

- hours involved piston 14 

### engin e aircraft utilizing leaded fuel ( FAA, 2009 )

. 15



### Fernandez et al. ( 2010 ; 2008 ; 2007 ) measured Pb from atmospheric deposition in two 16 

### adjacent plots of land having the same soil composition bu t different uses: one was 17 

### pasture land and one was agricultural. In the arable land, size distributions of soil 18 

### particle

- bound Pb, were uniformly distributed. In pasture land, size distributions of soil 19 

### particle

- bound Pb were bimodal with peaks around 2

- 20 μm and 50

- 100 μm ( Fernandez 20 

### et al., 2010 )

. For the agricultural plot, Pb concentration was constant around 70 mg/kg in 21 

### samples taken over the first 30 cm of soil, at which time it dropped below 10 mg/kg at 22 

### soil depths between 35 and 100 cm. In contrast, Pb concen tration in pasture land peaked 23 

### at a depth of 10 cm at a concentration of roughly 70 mg/kg and then dropped off 24 

### gradually to approach zero concentration at a depth of approximately 50 cm. The sharp 25 

### change in concentration for the arable land was attributed to a combination of plowing 26 

### the soil and use of fertilizers to change the acidity of the soil and hence the 27 

### bioaccessibility of the Pb within the soil ( Fernandez et al., 2007 )

. They found that the 28 

### surface layer was acidic (pH: 3.37

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

- 4.38). 29



### There is some evidence that Pb in crops can originate with treatment of crops. For 30 

### example, compost produced from wastewater sludge has the potential to add Pb to crops. 31



### Cai et al. ( 2007 ) demonstrated that production of compost from sludge enriched the Pb 32 

### content by 15

- 43% prior to its application. Chen et al. ( 2008a ) observed that the median 33 

### concentration of Pb in California crop soil samples was 16.2 mg/kg (range: 34



### 6.0

- 62.2 mg/kg). Chen et al. ( 2008b ) further observed that in three of the seven California 35 

### agricultural regions sampled, concentrations of Pb increased following addition of 36 

### fertilizer, but the increase was less than that for P and Zn indicators of fertilizer. In four 37February 2012 4

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### regions, there was no increase of Pb at all. Furthermore, Tu et al. ( 2000 ) observed a 1 

### decrease in Pb fraction with increasing P application. Nziguheba and Smolders ( 2008 ) 2 

### also surveyed phosphate

- based fertilizers sold in European markets to determine the 3



### contri bution of these fertilizers to heavy metal concentrations in agricultural products. 4 

### They reported a median fertilizer Pb concentration of 2.1 mg/kg based on total weight of 5 

### the fertilizer, with a 95th percentile concentration of 7.5 mg/kg. Across Europe, 6



### N ziguheba and Smolders ( 2008 ) estimated that the amount of Pb applied via fertilizers to 7 

### be only 2.6% of that resulting from atmospheric deposition. 8



### Although Pb in on

- road vehicle gasoline has been phased out in the U.S., some imported 9



### cr ops are produced in countries that still use Pb antiknock agents in on

- road gasoline. For 10 

### example, high concentrations of Pb have been found in chocolate from beans grown in 11 

### Nigeria, during the time when leaded gasoline was still legally sold. Rankin et al

. ( 2005 ) 12



### observed that the ratios of 207 

### Pb to 206 

### Pb and 208 

### Pb to 207 

### Pb were similar to those of Pb in 13 

### gasoline. Although this study showed that Pb concentration in the shelled cocoa beans 14 

### was low (~1 ng/g), manufactured cocoa powder and baking chocolate had Pb 15 

### concentrations similar to those of the cocoa bean shells, on the order of 200 ng/g, and Pb 16 

### concentration in chocolate products was roughly 50 ng/g ( Rankin et al., 2005 )

. It is 17 

### possible that the increases were attributed to contamination of the cocoa by the shells 18 

### during storage or manufacture , but the authors note that more research is needed to verify 19 

### the source of contamination. Likewise, it is possible that resuspended Pb that originated 20 

### from legacy mobile and industrial sources could deposit on crops. 21



### The extent to which soil Pb contribut es Pb to agricultural crops varies with soil 22 

### characteristics. For example, Jin et al. ( 2005 ) tested soil Pb, bioaccessibility of soil Pb 23 

### (determined by CaCl 2 

### extraction), and Pb in tea samples from tea gardens. They observed 24 

### that the Pb concentration in tea leaves was proportional to the bioacce ssible Pb in soil. 25February 2012 4

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### 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% 2

, 500%

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% 2,500%
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% 1,600%
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: Reprinted with permission of Elsevier Publishers, Vandenhove et al. ( 2009 )

.



### Findings from Pb uptake studies have implications for urban gardening if urban soils may 1



### be contaminated with Pb, as described in Section 4.1.3.2 . For instance, Clark et al. ( 2006 ) 2 

### tested the soil in 103 urban gardens in two Boston neighborhoods. They found that Pb

3 

### based paint contributed 40

- 80% of Pb in the urban garden soil samples, with the rest 4 

### coming from historical gasoline emissions. Furthermore, Clark et al. ( 2006 ) estimated 5February 2012 4

- 26 Draft

– Do Not Cite or Quote 

### that Pb consumption from urban gardens can be equivalent to 10

- 25% of the expos ure to 1 

### Pb from drinking water for children living in the Boston neighborhoods studied. Because 2 

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

, Pb 3 

### exposures in urban garden vegetables will vary. 4



### Game

Game meat consumption also may pose a risk of Pb exposure. In Pb mining or smelting 5 

### areas, several studies have docume nted Pb concentrations in game [ e.g., ( Nwude et al., 6



### 2010 ; Reglero et al., 2009a ) ] . Jankovská et al. ( 2010 ) studied Pb accumulation in sheep 7 

### infected with tapeworm and found that sheep harboring the parasites contained 8 

### significantly less Pb compared with their uninfected counterparts (p ≤ 0.05). 9



### Potential Pb exposure through co nsumption of animals exposed to or killed with Pb shot 10



### has also been well documented ( Hunt et al., 2009 ; Tsuji et al., 2009 ; Tsuji et al., 2008 ; 11 

### Hunt et al., 2006 )

. For example, Martínez

- Haro et al. ( 2010 ) observed Pb in the feces of 12 

### mallards that ingested gun shot of 34

- 13,930 mg/kg with a median of 1

, 104 mg/kg, while 13



### m allards that did not ingest gun shot had feces Pb levels < 12.5 mg/kg. Mateo et al. ( 2011 ) 14 

### studied Pb bioaccessibility as a function of cooking method for breast meat from 15 

### partridges killed with gun shot. The y observed that preparation in cold or hot vinegar 16 

### increased bioaccessibility compared with total Pb in the samples. 17



### Fish

Accumulation in fish could also lead to human exposure to Pb ( U.S. EPA, 2006b

, 1986a )

. 18



### Ghosh et al. ( 2007 ) demonstrated in laboratory experiments that exposure to Pb in water 19 

### can lead to linearly increasing accumulation in fish. Several studies have documented the 20


### poten tial for human exposure through fish and seafood. Welt et al. ( 2003 ) conducted a 21 

### survey of individuals who fished in Bayou St. John, Louisiana in conjunction with 22 

### sampling Pb content in sediment. They found that median sediment Pb concentrations 23 

### ranged from 43 to 330 mg/kg in different locations, while maximum sediment Pb 24 

### concentrations ranged from 580 to 6,500 mg/kg. In total, 65% of the surveyed individuals 25 

### fished for food from the Bayou, with 86% consuming fish from the Bayou each week. In 26 

### a study of the effect of coal mining on levels of metals in fish (measured as blood Pb) in 27 

### northeastern Oklahoma, Schmitt et al. ( 2005 ) found that Pb concentrations i n blood 28 

### varied with respect to species of fish, but Pb concentrations were higher in fish in areas 29 

### close to mining activities. Similarly, Besser et al. ( 2008 ) observed higher levels of blood 30



### Pb in fish close to minin g activities in southeastern Missouri. In a related study of fish 31 

### species in the same region of Missouri, blood Pb levels in fish were found to be 32 

### significantly higher in sites within 10 km downstream of active Pb

- Zn mines (p <0.01) 33February 2012 4

- 27 Draft

– Do Not Cite or Quote 

### compared with fish loca ted further from the mines ( Schmitt et al., 2007a )

, and elevated 1 

### blood Pb levels in fish were again noted near a Pb

- Zn mine ( Schmitt et al., 2009 )

. It was 2



### noted that the Ozark streams where these studies were performed were often used for 3 

### recreational fishing. 4



### Breast Milk

Studies breastfeeding women suggest that infants may be exposed to Pb in breast milk. 5 

### Ettinger et al. ( 2004a ) observed among Mexico City women studied in 1994

- 1995 that at 6



### 1 month postpartum, 88 women breastfeeding exclusively (with mean blood Pb level of 7



### 9.4 μg/dL) had breast milk Pb concentrations of 1.4 ± 1.1 μg/L, and 165 women 8 

### breastfeeding partially (with mean blood Pb level of 9.5 μg /dL) had breast milk Pb 9



### concentrations of 1.5 ± 1.2 μg/L. During the same time period, Ettinger et al. ( 2006 ) 10 

### studied breastfeeding women in Mexico City over a child’s first year of life and sampled 11 

### Pb concentration in breast milk at 1, 4, and 7 mo post

- partum. They observed that mean 12



### breast milk concentrations dro pped from 1.4 μg/L at 1 mo (mean maternal blood Pb = 13



### 9.3 μg/dL) to a mean of 1.2 μg/L at 4 mo (mean maternal blood Pb = 9.0 μg/dL) to 14



### 0.9 μg/L at 7 mo (mean maternal blood Pb = 8.1 μg/dL); this reduction was statistically 15 

### significant (p < 0.00001). Among t he 310 women included in the study, 181 had previous 16 

### pregnancies. In one study of nursing mothers living in Pb contaminated city in Australia, 17



### 10 of the 11 mothers had breast milk concentrations <5 μg/L ( Simon et al., 2007 )

. The 18 

### authors hypothesized that breast milk concentration was too low to be a major contributor 19 

### to blood Pb level in these infants relative to other factors such as hand loading of lead. 20 

### However, one mother with a blood Pb level of 25 μg/dL had a breast mil k Pb level of 21



### 28 μg/L ( Simon et al., 2007 )

. 22



### 4.1.3.4 Occupational

Occupational environments have the potentia l to expose individuals to Pb. Some modern 23 

### day occupational exposures are briefly discussed below in the context of understanding 24 

### potential exposures that are not attributed to ambient air. For example, Miller et al. 25 

### ( 2010 ) obtained personal and area samples of particle

- borne Pb in a precious metals 26 

### refinery; year of the study was not reported. It was not stated explicitly, but it is likely 27



### that Miller et al. ( 2010 ) measured the PM as TSP because the Occupational Safety and 28



### Health Admini stration (OSHA) permissible exposure limit (PEL) for Pb is based on TSP 29 

### rather than a smaller size cut, and the OSHA PEL was used for comparison. 30 

### Concentrations measured by personal samples ranged from 2 to 6 μg/m 3 

### , and 31 

### concentrations from area samples ran ged from 4 to 14 μg/m 3 

### . The OSHA PEL is 5 μg/m 3



### . 32February 2012 4

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– Do Not Cite or Quote 

### In steel production, sintering was found to be the largest source of airborne Pb exposure 1 

### in a survey of operations ( Sammut et al., 2010 )

, with Pb enrichment in PM report ed to be 2 

### 20,000 mg/kg, although total PM concentration, reported to have 75% of particulate mass 3



### below 2.5 μm diameter, was not reported; year of the study was also not reported. 4



### Operations involving PM in various industries are a source of occupational Pb exposure, 5 

### in addition to a residential exposure. Rodrigues et al. ( 2010 ) re ported exposures to 6 

### airborne Pb among New England painters, who regularly use electric grinders to prepare 7 

### surfaces for painting. Two

- week averaged airborne Pb concentrations, sampled with an 8 

### Institute of Medicine inhalable PM sampler designed to capture PM smaller than 100 μm, 9 

### were reported to be 59 μg/m 3 

### , with a maximum daily value of 210 μg/m 3 

### . The Pb 10 

### concentrations reported here were corrected by the National Institute for Occupational 11 

### Safety and Health (NIOSH) respirator protection factors, although t he respirator 12 

### protection factors were not reported by Rodrigues et al. ( 2010 )

. Information on the air Pb

13 

### blood Pb relationship can be found in Section 4.5.1 . Nwajei and Iwegbue ( 2007 ) 14



### measured Pb contam ination in sawdust; such contamination has been reported to occur 15 

### when trees are grown in soil contaminated with Pb ( Andrews et al., 1989 )

. Sawdust 16 

### samples from fifteen locations in Nigerian sawmills were reported to have Pb 17



### con centrations ranging from 2.0 to 250 mg/kg. 18



### 4.1.3.5 Exposure to Lead from Consumer Products

Pb is present in varying amounts in several consumer products including alternative 19 

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

- 6 ). Several 20 

### of these categories suggest children may incur regular exposures. Pb concentrations were 21 

### reported to range from non

- detectable levels up to 77% by mass, for the case of one 22 

### medicinal product. Exposure to these products, which originate in a range of different 23 

### countries, can account for substantial influence on Pb body burden ( Miodovnik and 24 

### Landrigan, 2009 ; Levin et al., 2008 )

. 25



### 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 )February 2012 4

- 29 Draft

– Do Not Cite or Quote Product Category Product Location of Purchase Pb Content (units) Reference Yugmijihwang

- tang, Bojungigki

- tang, Sibjeondaebo

- tang, Kuibi

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

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, Operation 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, Chama Black Stone, Portugal Antiseptic So ap, Edysol Antiseptic 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 μg Obi et al. ( 2006 )

Shell of Hen’s Egg India 14 mg/kg Sh arma 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 )

Greta powder 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 U.K. 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 Vitamin s for young children, older children, and pregnant or lactating

women U.S. Average: Young children: 2.9 μg/day Older children: 1.8 μg/day Pregnant and lactating women: 4.9 μg/day Mindak et al. ( 2008 )

a Hoodia gordonii , from Eastern Cape, South Africa Euterpe oleracea from Ninole Orchard, Ninole, Hawaii Note that the country of origin is not provided because it was not published in the references cited

.February 2012 4

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## 4.2 Kinetics

This section summarizes the empirical bases for our understanding of Pb toxicokinetics in 1 

### humans. The large amount of empirical information on Pb biokinetics in humans and 2 

### animal models has been integrated into mechanistic biokinetics models ( U.S. EPA, 3



### 2006b )

. These models sup port predictions about the kinetics of Pb in blood and other 4 

### selected tissues based on the empirically

- based information about Pb biokinetics. In 5



### Section 4.3 (and Section 4.2.2.1 ), Pb biokinetics is described from the context of model 6 

### predictions. 7



### 4.2.1 Absorption

The focus of the following sections within absorption is on inhalation and ingestion 8 

### because these are the major exposure routes of Pb in humans. The 2006 Pb AQCD also 9 

### presented dermal absorption of inorganic and organic Pb compounds, which is generally 10 

### considered to be much less than by in halation or ingestion. A study published subsequent 11 

### to the 2006 Pb AQCD measured rates of absorption of Pb in skin patches harvested from 12



### nude mice ( Pan et al., 2010 )

. Following application of 12 mg Pb as Pb

- acetate or Pb 13 

### nitrate, the absorption rate (measured over a 10

- hour observation period) was 14 

### approximately 0.02 μg Pb/cm 2 

### per hour. Absorbed Pb was detected in liver and kidney of 15 

### nude mice following a 120

- hr occluded dermal application of approximately 14 mg Pb as 16



### either Pb

- acetate or Pb nitrate. Uptake of Pb into the skin at the site of application was 17 

### greater when Pb

- acetate was applied to the skin compared to lead nitrate; however, liver 18 

### and kidney Pb concentrations observed at the conclusion of the stud y (120 hours 19 

### following the application of Pb) were not different for the two Pb compound. No 20 

### additional information provides evidence of dermal absorption being a major exposure 21



### route of environmental Pb. 22



### The term absorption refers to the fraction of the a mount of Pb ingested or inhaled that is 23 

### absorbed from the respiratory or gastrointestinal tract. The term bioavailability, as it is 24 

### used in this section, refers to the fraction of the amount of Pb ingested or inhaled that 25 

### enters the systemic circulation. I f properly measured ( e.g., time

- integrated blood Pb), 26 

### under most conditions Pb bioavailability is equivalent (or nearly equivalent) to Pb 27 

### absorption. Bioaccessibility is a measure of the physiological solubility of Pb in the 28 

### respiratory or gastrointestinal tract. Pb must become bioaccessible in order for absorption 29 

### to occur. Processes that contribute to bioaccessibility include physical transformation of 30 

### Pb particles and dissolution of Pb compounds into forms that can be absorbed ( e.g., Pb 2+ 

### ). 31



### Bioaccessibil ity is typically assessed by measuring the fraction of Pb in a sample that can 32February 2012 4

- 31 Draft

– Do Not Cite or Quote 

### be extracted into a physiological or physiological

- like solution ( e.g., gastric juice or 1 

### solution similar to gastric juice). 2



### 4.2.1.1 Inhalation

Systemic absorption of Pb deposited in the respiratory tract is influenced by particle size 3 

### and solubility, as well as by the pattern of regional deposition within the respiratory tract. 4 

### Fine particles (<1 μm) deposited in the bronchiolar and alveolar region can be absorbed 5



### after extracellular dissolution or can be ingested by phagocytic cells and transported from 6 

### the respiratory tract ( Bailey and Roy, 1994 )

. Larger particles (>2.5 μm) that are primarily 7 

### deposited in the ciliated airways (nasopharyngeal and tracheobronchial regions) can be 8 

### transferred by mucociliary transport into the esophagus and swallowed, thus being 9 

### absorbed via the gut. 10



### Inhaled Pb lodging deep in the respiratory tract seems to be absorbed equall y and totally, 11 

### regardless of chemical form ( Morrow et al ., 1980 ; Chamberlain et al., 1978 ; Rabinowitz 12 

### et al., 1977 )

. Absorption half

- times ( t1/2 

### ) have been estimated for radon decay progeny in 13 

### adults who inhaled aerosols of Pb and bismuth isotopes generated from decay of 220 

### Rn or 14

222 

### Rn. The absorption half

- time for Pb from the respiratory tract to blood was estimated 15 

### to be approximately 10 hours in subjects who inhaled aerosols having an activity median 16 

### particle diameter of approximately 160 nm (range 50

- 500 nm) ( Marsh and Birchall, 17



### 1999 )

, and approximately 68 min for aerosols having diameters of approximately 0.3

– 18



### 3 nm ( Butterweck et al., 2002 )

. Given the submicron particle size of the exposure, these 19 

### rates are thought to represent, primarily, absorption from the bronchiolar and alveolar 20 

### regions of the respiratory tract. 21



### Several studies have quantified the bio accessibility of Pb in atmospheric PM, based on 22



### various in vitro extraction methods. In a study of PM 10 

### and PM 2.5 

### samples from 23 

### downtown Vienna, Austria, Falta et al. ( 2008 ) used synthetic gastric juice to investigate 24 

### the bioaccessibility of metals including Pb. The rationale was that inhaled particles in the 25



### 2.5

- 10 μm size range are mostly deposited in the tracheal and bronchial regions of the 26 

### lung from where they are transported within hours by mucociliary clearance, i.e., they are 27 

### mainly swallowed. In contrast, the <2.5 μm particles are deposited in the pulmonary 28 

### alveoli where they can stay for months to years. The study aimed to determine the 29 

### bioaccessibility of the 2.5

- 10 μm PM. It is important to note that they do not isolate the 30



### 2.5

- 10 μm size range; instead, th ey infer the characteristics from the difference between 31



### the PM 2.5 

### and PM 10 

### fractions. The Pb concentrations associated with the two fractions 32 

### were almost identical, as was the percentage extracted by synthetic gastric juice (86% and 33


### 83% Pb for PM 2.5 

### and PM 10 

### fractions, respectively). The mean daily bioavailable mass 34February 2012 4

- 32 Draft

– Do Not Cite or Quote 

### was calculated to be 16 ng for the PM 2.5

- 10 

### size range. Since the quantitative clearance of 1 

### these particles to the stomach was assumed, this value represents an upper estimate for 2



### the amo unt of bioavailable Pb. Niu et al. ( 2010 ) determined the bioaccessibility of Pb in 3 

### fine (100

- 1,000 nm) and ultrafine

- sized (<100 nm) urban airborne PM from two sites 4 

### within the city of Ottawa, Canada. For all size fractions, the median Pb concentrations for 5 

### particles smaller than 10 μm were 8,800 and 7,800 mg/kg for the two different locations. 6 

### The bioaccessibility was based on ammonium acetate extrac tability and it was found that, 7



### within the fine and ultrafine

- size ranges, 13

- 28% Pb was extracted. The Falta et al. 8 

### ( 2008 ) and Niu et al. ( 2010 ) results illustrate that different extraction techniques result in 9 

### different bioavailable fractions. The main finding from Niu et al. ( 2010 ) was that the 10 

### highest values (~28% and ~19% for the two different locations) were found for the 11



### <57 nm particles, with percent bioaccessibility decreasing with increasing particle size. 12



### Th is result indicated that Pb was potentially most bioavailable in the ultrafine

- size range. 13



### A recent study by Barrett et al. ( 2010 ) investigated the solid phase speciation of Pb in 14



### urban road dust in Manchester, UK, and considered the health implications of inhalation 15 

### and ingestion of such material. Human exposure via inhalation is likely to involve only 16 

### the finest grained fractions (up to 10 μm) and unfortunately this study characterized only 17



### the < 38 μm fraction. Pb

- goethite and PbCrO 4 

### comprised the largest fractions, 45% and 18 

### 21% respectively, of Pb in the <38 μm fraction. These forms tend to be less 19 

### bioaccessibility if ingested compared with PbO or Pb

- acetate because they are less 20



### soluble. 21



### The abov e considerations indicate that the relationship between air Pb exposure and 22 

### blood Pb will depend on numerous exposure variables ( e.g., particle size, solubility, 23 

### exposure frequency and duration) and physiological variables (age, activity level, 24


### transport a nd absorption in the respiratory tract, blood Pb kinetics). Mechanistic models 25 

### provide one means for integrating these variable into predictions of blood Pb

– air Pb 26 

### relationships; although, predictions are subject to simplifications and generalizations 27



### ma de in constructing the models. As an example, the ICRP ( Pounds and Leggett, 1998 ; 28 

### ICRP, 1994 ; Leggett, 1993 ) model ( Section 4.3 for a brief description) can be used to 29 

### predict blood Pb

– air Pb slopes for specific direct Pb inhalation exposure scenarios. For a 30 

### long

- term continuous (24 h ou r s /day) exposure of a typical adult male engaged in light 31 

### exercise ( ventilation rate 20

- 22 m 3 

### /day) to Pb

- bearing particles having a 1 μm uniform 32 

### particle size, the predicted blood Pb

– air Pb slopes range from 0.7 μg/dL per μg/m 3 

### (for 33 

### low solubility particles; e.g., Pb oxide) to 3 μg/dL per μg/m 3 

### (for highly soluble Pb; 34



### e. g., Pb salts). Empirical estimates of blood Pb

– air Pb slopes for various populations, 35 

### derived from epidemiological studies , are summarized in Section 4.5.1

. 36February 2012 4

- 33 Draft

– Do Not Cite or Quote 

### Organic Lead

Alkyl Pb compounds can exist in ambient air as vapors. Inhaled tetraalkyl Pb vapor is 1 

### nearly completely absorbed following deposition in the respiratory tract. As reported in 2 

### the 2006 Pb AQCD, a single exposure to vapors of radioactive ( 203 

### Pb) tetraethyl Pb 3 

### resulted in 37% initially deposited in the respiratory tract, of which ~20% was exhaled in 4 

### the subsequent 48 hours ( Heard et al., 1979 )

. In a similar experiment conducted with 5

203 

### Pb tetramethyl Pb, 51% of the inhaled 203 

### Pb dose was initially deposited in the 6 

### respiratory tract, of which ~40% was exhaled in 48 hours ( Heard et al., 1979 )

. 7



### Estimation of bioavailability of organic Pb is relevant to some aviation fuel exposures 8 

### ( e. g., persons exposed to leaded gasoline used piston

- engine aircraft). Mahaffey ( 1977 ) 9 

### estimated that 40% of inhaled Pb in urban air (largely attributed to combustion of 10 

### gasoline containing tetraethyllead) is bioavailable to adults. Chamberlain et al. ( 1975 ) 11 

### suggested that 35% of inhaled combustion prod ucts of tetraethyl 203 

### Pb fuel are deposited 12 

### and then retained in adult lungs with a half

- life of 6 hours. Fifty percent of that 203 

### Pb was 13 

### detectable in the blood within 50 hours of inhalation, and the rest was found to deposit in 14



### bone or tissue. Chamberlai n et al. ( 1975 ) estimated that continuous inhalation of Pb in 15 

### engine exhaust from fuel containing tetraethyllead at a concentration of 0.001 μg/m 3 

### for a 16 

### period of months could produce a 1 μg/dL increment in blood Pb. 17



### 4.2.1.2 Ingestion

The extent and rate of GI absorption of ingested inorganic Pb are influenced by 18 

### physiological states of the exposed individual ( e.g., age, fasting, nutritional calcium and 19 

### iron status, pregnancy) and physicochemi cal characteristics of the Pb

- bearing material 20 

### ingested ( e.g., particle size, mineralogy, solubility). Pb absorption in humans may be a 21 

### capacity

- limited process, in which case the percentage of ingested Pb that is absorbed 22 

### may decrease with increasing rate of Pb intake. Numerous observations of nonlinear 23 

### relationships between blood Pb concentration and Pb intake in humans provide support 24 

### for the likely existence of a saturable absorption mechanism or some other capacity

25 

### limited process in the distribution o f Pb in humans ( Sherlock and Quinn, 1986 ; Sherlock 26 

### et al., 1984 ; Pocock et al., 1983 ; Sherlock et al., 1982 )

. While evidence for capacity

27 

### limited processes at the level of the intestinal epitheliu m is compelling, the dose at which 28 

### absorption becomes appreciably limited in humans is not known. 29



### In adults, estimates of absorption of ingested water

- soluble Pb compounds ( e.g., Pb 30 

### chloride, Pb nitrate, Pb

- acetate) range from 3 to 10% in fed subjects ( Maddaloni et al., 31



### 1998 ; Watson et al., 1986 ; James et al., 1985 ; Heard and Chamberlain, 1982 ; Rabinowitz 32 

### et al., 1980 )

. The absence of food in the GI tract increases absorption of water

- soluble Pb 33February 2012 4

- 34 Draft

– Do Not Cite or Quote 

### in adults. Reported estimates of soluble Pb absorption range from 26 to 70% in fasted 1



### adults ( Maddaloni et al., 1998 ; James et al., 1985 ; Blake et al., 1983 ; Heard and 2 

### Chamberlain, 1982 ; Rabinowitz et al., 1980 )

. Reported fed:fasted ratios for soluble Pb 3 

### absorption in adults range from 0.04 to 0.2 ( James et al., 1985 ; Blake et al., 1983 ; Heard 4 

### and Chamberlain, 1982 ; Rabinowitz et al., 1980 )

. 5



### Limited evidence demonstrates that GI absorption of water

- soluble Pb is higher in 6



### children t han in adults. Estimates derived from dietary balance studies conducted in 7 

### infants and children (ages 2 weeks to 8 years) indicate that ~ 40

- 50% of ingested Pb is 8



### absorbed ( Ziegler et al., 1978 ; Alexander et al., 1974 )

. Experimental studies provide 9 

### further evidence for greater absorption of Pb from the gut in young animals compared to 10



### adult animals ( Aungst et al., 1981 ; Kostial et al., 1978 ; Pounds et al., 1978 ; Forbes and 11 

### Reina, 1972 )

. The mechanisms for an apparent age difference in GI absorption of Pb have 12 

### not been completely elucidated and may include both physiological and dietary factors 13 

### ( Mushak, 1991 )

. Eating breakfast was shown to be significant predictor of blood Pb 14



### concentrations in 1 ,344 children 3

- 5 year s old ( Liu et a l., 2011b )

. Blood Pb 15 

### concentrations were lower in children who regularly ate breakfast compared to children 16 

### who did not eat breakfast, and the difference persisted after controlling for nutritional 17 

### variables (blood iron, calcium, copper, magnesium, zinc ). This observation may be 18 

### explained by lower GI absorption of Pb ingested with or in close temporal proximity to 19 

### meals. Direct evidence for meals lowering GI absorption of Pb has been reported for 20



### adults ( Maddaloni et al., 1998 ; James et al., 1985 )

. 21



### Nutritional deficiencies have also been linked to Pb absorption in the GI tract, 22 

### particularly in children. Children who are iron

- deficient have higher blood Pb 23 

### concentrations than similarly exposed iron

- replete children, suggesting that iron 24 

### deficiency may result in higher Pb abso rption or, possibly, other changes in Pb 25



### biokinetics that contribute to altered blood Pb concentrations ( Schell et al., 2004 ; Marcus 26 

### and Schwartz, 1987 ; Mahaffey and Annest, 1986 )

. Studies conducted in animal models 27 

### have provided direct evidence for interac tions between iron deficiency and increased Pb 28 

### absorption, perhaps by enhancing binding of Pb to iron

- binding proteins in the intestine 29 

### ( Bannon et al., 2003 ; Morrison and Quarterman, 1987 ; Barton et al., 1978b )

. An analysis 30 

### of data from a sample 448 woman (age 20

- 55 years) did not find a significant association 31 

### between iron body stores (indicated from serum ferritin concentration) and blood Pb 32



### concen trations, although depleted irons stores (serum ferritin of <12 μg/L) was associated 33 

### with higher blood concentrations of cadmium, cobalt and manganese higher ( Meltzer et 34 

### al., 2010 )

. The effects of iron nutritional status on blood Pb include changes in blood Pb 35 

### concentrations in association with genetic variation in ge nes involved in iron metabolism. 36 

### For example, genetic variants in the hemochromatosis (HFE) and transferrin genes are 37 

### associated with higher blood Pb concentrations in children ( Hopkins et al., 2008 )

. In 38February 2012 4

- 35 Draft

– Do Not Cite or Quote 

### contrast, HFE gene variants are associated with lower bone and blood Pb levels in elderly 1



### men ( Wright et al., 2004 )

. 2



### Several studies have suggested that dietary calcium may have a protective role against Pb 3 

### by decreasing absorption of Pb in the GI tract and by decr easing the mobilization of Pb 4 

### from bone stores to blood. In experimental studies of adults, absorption of a single dose 5 

### of Pb (100

- 300 μg Pb chloride) was lower when the Pb was ingested together with 6 

### calcium carbonate (0.2 g calcium carbonate) than when th e Pb was ingested without 7



### additional calcium ( Blake and Mann, 1983 ; Heard and Chamberlain, 1982 )

. A similar 8



### effect of calcium occurs in rats ( Barton et al., 1978a )

. Similarly, an inverse relationship 9 

### was observed between dietary calcium intake and blood Pb concentration in children, 10 

### suggesting that children who are calcium

- deficient may absorb more P b than calcium

11 

### replete children ( Elias et al., 2007 ; Schell et al., 2004 ; Mahaffey et al., 1986 ; Ziegler et 12 

### al., 1978 )

. These observations suggest that calcium and Pb share and may compete for 13 

### common binding and transport mechanisms in the small intestine which are regulated in 14 

### response to dietary calcium and calcium body stores ( Fullmer and Rosen, 1990 ; Bronner 15 

### et al., 1986 )

. However, animal st udies have also shown that multiple aspects of Pb 16 

### toxicokinetics are affected by calcium nutritional status. For example, feeding rats a 17 

### calcium deficient diet is associated with increased Pb absorption, decreased whole body 18 

### Pb clearance, and increased vol ume of distribution of Pb ( Aungst and Fung, 1985 )

. These 19 

### studies suggest that associations between calcium nutrition and blood Pb that have been 20 

### observed in human populations may not be solely attributable to effects of calcium 21 

### nutrition on Pb absorption. Other potential mechanisms by which calcium nutrition may 22



### affect blood Pb and Pb biokinetics include effects on bone mineral metabolism and renal 23



### function. 24



### Blood Pb concentrat ions in young children have also been shown to increase in 25 

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

. Mechanisms for how Zn 26 

### affects blood Pb concentration, i.e., whether it involves changes in absorption or changes 27 

### in distribution and/or elimination of Pb, have not been determined. 28



### Dissolution of Pb from the soil/mineralogical matrix in the stomach appears to be the 29 

### major process that renders soil Pb bioaccessible for absorption in the GI tract. Absorption 30 

### of Pb has been shown to vary depending upon the Pb mineralogy and physical 31 

### characteristics of the Pb in the soil ( e.g., encapsulated or exposed) and size of the Pb

32 

### bearing grains. GI absorption of larger Pb

- contai ning particles (>100 μm) tends to be 33 

### lower than smaller particles ( Healy et al., 1992 ; Barltrop and Meek, 1979 )

. Absorption of 34 

### Pb in soils and dust has been most extensively studied in the in vivo swine model. Gastric 35



### function of swine is thou ght to be sufficiently similar to that of humans to justify use of 36 

### swine as a model for assessing factors that may affect GI absorption of Pb from soils in 37February 2012 4

- 36 Draft

– Do Not Cite or Quote 

### humans ( Juhasz et al., 2009 ; U.S. EPA, 2007b ; Casteel et al., 2006 ; Casteel et al., 1997 ; 1 

### Weis and Lavelle, 1991 )

. Other practical advantages of the swine model over rodent 2 

### models have been described, and include: absence of coprophagia; ease with which Pb 3 

### dosing can be administered and controlled; and higher absorption fraction of soluble Pb 4 

### ( e.g., Pb

- acetate) in swine, which is more similar to humans than rats ( Smith et al., 5



### 2009a )

. The swine studies measure bloo d and/or tissue Pb ( e.g., kidney, liver, bone) 6 

### concentrations following oral dosing of swine with either soil or with a highly water 7 

### soluble and fully bioaccessible form of Pb ( e.g., Pb

- acetate ). A comparison of the internal 8



### concentrations of Pb under thes e two conditions provides a measure of the bioavailability 9 

### ( i.e., absorption) of Pb in soil relative to that of Pb

- acetate , which is typically referred to 10 

### as relative bioavailability (RBA). Relative bioavailability measured in the swine assay is 11 

### equivalent to the ratio of the absorbed fraction (AF) of ingested dose of soil Pb to that of 12



### water

- soluble Pb

- acetate ( e.g., RBA = AF Soil Pb 

### /AF Pb

- acetate 

### ). 13



### Collectively, published studies conducted in swine have provided 39 estimates of Pb 14



### RBA for 38 different soil or “soil

- like” test materials ( Bannon et al., 2009 ; Smith et al., 15



### 2009a ; Casteel et al., 2006 ; Marschner et al., 2006 )

. The mean of RBA estimates from 25 16 

### soils is 49% (± 29[SD]), median is 51%, and 5 th to 95 th percentile range is 12 to

- 89%. 17



### RBA estimate s for soils collected from 8 firing ranges were approximately 100% 18 

### ( Bannon et al., 2009 )

. The relative ly high RBA for the firing range soils may reflect the 19 

### high abundance of relatively un

- encapsulated Pb carbonate (30

- 90% abundance) and Pb 20 

### oxide (1

- 60%) in these soils. Similarly, a soil sample (low Pb concentration) mixed with 21 

### a NIST paint standard (55% P b carbonate, 44% Pb oxide) also had a relatively high 22 

### bioavailability (72%) ( Casteel et al., 2006 )

. Samples of smelter slag, or soils in which the 23



### dominant source of Pb was smelter slag, had relatively low RBA (14

- 40%, n = 3), as did 24 

### a sample from a mine tailings pile (RBA = 6%), and a sample of finely ground galena 25



### mixed with soil ( Casteel et al., 2006 )

. 26



### Bas ed on data for 18 soil materials assayed in swine, RBA of Pb mineral phases were 27 

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

- 0.75 [25 to 75%]), and “high” 28 

### (>0.75 [75%]) categories ( Casteel et al., 2006 )

. Figure 4

- 3 shows some of the materials 29 

### that fall into these three categories. Mineral phases observed in mineralogical wastes can 30 

### be expected to change over time ( i.e., weathering), which could change t he RBA over 31 

### time. The above observations in swine are supported by various studies conducted in rats 32 

### that have found RBA of Pb in soils to vary considerably and to be less that 100% ( Smith 33 

### et al., 2009a

, 2008 ; Freeman et al., 1996 ; Freeman et al., 1994 ; Freeman et al., 1992 )

. 34February 2012 4

- 37 Draft

– Do Not Cite or Quote Source: Casteel et al. ( 2006 )

. Note: based on results from juvenile swine assays.


### Figure 4

- 3 Estimated relative bioavailability (RBA, compared to Pb

- acetate) of ingested Pb in mineral groups.

Drexler and Brattin ( 2007 ) developed an in vitro bioaccessibility (IVBA) assay for soil 1 

### Pb that utilizes extraction fluid comprised of glycine, deionized water, and hydrochloric 2 

### acid at a pH of 1.50 that is combined with sieved test material (< 250 μm) for 1 hour. The 3 

### assay was tested for predicting in vivo RBA of 18 soil

- like test materials that were 4 

### assayed in a juvenile swine assay ( Casteel et al., 2006 )

. A regression m odel relating 5 

### IVBA and RBA was derived based on these data (Equation 4

- 1): 6



### RBA = ( 0

. 878 × IVBA )

− 0

. 028

Equation 4

- 1



### where RBA and IVBA are expressed as fractions ( i.e., not as percent). The weighted r 2 7 

### for the relationship (weighted for error in the IVBA and RBA estimates) was 0.924 8 

### ( p <0 .001). The IVBA assay reported in Drexler and Brattin ( 2007 ) has been identified by 9 

### the U.S. EPA as a validated method for predicting RBA of Pb in soi ls for use in risk 10



### assessment ( U.S. EPA, 2007e )

. A review of soil Pb RBA estimates made using the IVBA 11 

### assay described above and Equation 4

- 1 identified 270 estimates of Pb RBA in soils 12



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

- wide RBA estimates (n = 13February 2012 4

- 38 Draft

– Do Not Cite or Quote 

### 11 sites) was 57% (SD 15), median was 63%, and 5 th to 95 th percentile range was 34 to 1


### 71%. 2



### Equation 4

- 1 cannot be reliably e xtrapolated to other in vitro assays that have been 3 

### developed for estimating Pb bioaccessibility without validation against in vivo RBA 4 

### measurements made on the same test materials. Comparisons of outcomes among 5



### different in vitro assays applied to the sam e soil test materials have found considerable 6 

### variability in IVBA estimates ( Juhasz et al., 2011 ; Smith et al., 2011 ; Saikat et al., 2007 ; 7 

### Van de Wiele et al., 2007 )

. This variability has been attributed to differences in assay 8 

### conditions, including pH, liquid:soil ratios, inclusion or absence of fo od material, and 9 

### differences in methods used to separate dissolved and particle

- bound Pb 10 

### ( e.g., centrifugation versus filtration). Smith et al. ( 2011 ) found that algorithms for 11 

### predicting RBA based on two different IVBA assays did not yield similar predictions of 12 

### RBA when applied to the same material. Given the dependence of IVBA outcomes on 13 

### assay conditions, in vitro assays used to predict in vivo RBA s hould be evaluated against 14



### in vivo RBA estimates to quantitatively assess uncertainty in RBA predictions ( U.S. 15 

### EPA, 2007e )

. 16



### Absorption of Pb in house dusts has not been rigorously evaluat ed quantitatively in 17 

### humans or in experimental animal models. The RBA for paint Pb mixed with soil was 18 

### reported to be approximately 72% (95% CI: 44, 98) in juvenile swine, suggesting that 19 

### paint Pb dust reaching the gastrointestinal tract maybe highly bioav ailable ( Casteel et al., 20



### 2006 )

. The same material yielded a bioaccessibility value (based on IVBA assay) of 75% 21 

### ( Drexler and Brattin, 2007 )

, which corresponds to a predicted RBA of 63%, based on 22 

### Equation 4

- 1. A review of indoor Pb RBA estimates made using the IVBA assay and 23 

### Equation 4

- 1 identified 100 estimates of Pb RBA in dusts obtained from two hazardous 24



### waste sites. Mean Pb RBAs for the Herculaneum site wer e 47% (SD 7, 10 samples) for 25 

### indoor dust and 69% (SD 3, 12 samples) for soil. At the Omaha site, mean Pb RBAs were 26 

### 73% (SD 10, 90 samples) for indoor dust and 70% (SD 10, 45 samples) for soil. Yu et al. 27 

### ( 2006 ) applied an IVBA method to estimate bioaccessibility of Pb in house dust samples 28



### collected from 15 urban homes. Hom es were selected for inclusion in this study based on 29 

### reporting to the state department of health of at least on child with a blood Pb 30



### concentration >15 μg/dL and Pb paint dust may have contributed to indoor dust Pb. The 31 

### mean IVBA was 64.8% (SD 8.2, age: 5 2.5 to 77.2 months). 32



### The above results, and the IVBA assays used in studies of interior dust, have not been 33 

### evaluated against in vivo RBA estimates for dust samples. Although, expectations are 34 

### that a validated IVBA methodology for soil would perform well for predicting RBA of 35 

### interior dust, this validation has not actually been experimentally confirmed. Factors that 36 

### may affect in vitro predictions of RBA of interior dust Pb could include particle size 37February 2012 4

- 39 Draft

– Do Not Cite or Quote 

### distribution of interior dust Pb and the composition of the dust matrix, which may be 1 

### quite different from that of soil. 2



### Other estimates of bioaccessibility of Pb in house dusts have been reported, based on 3 

### results from in vitro extraction assays that have not been validated for predicting in vivo 4



### bioavailabil ity. Bioaccessibility assays that sequentially extract soil at gastric pH 5 

### followed by intestinal pH tend to show higher bioaccessibility of soil and dust Pb when 6 

### incubated at gastric conditions ( Juhasz et al., 2011 ; Lu et al., 2011 ; Smith et al., 2011 ; 7 

### Roussel et al., 2010 ; Yu et al., 2006 )

. Yu et al. ( 2006 ) dissolved Pb dust, obtained from 8 

### vacuuming carpet samples into simulated gastric and intestinal acids (also 9



### Section 4.1.3.2 ). The carpet samples were obtaine d from homes located in northern New 10 

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

- 77% of 11 

### Pb dissolving in simulated gastric acid and 5

- 32% dissolving in simulated intestinal 12 

### acids. In a similar test in the U.K., Turner an d Simmonds ( 2006 ) observed median Pb 13



### dust concentrations of 178 mg/kg with approximately 80% bioaccessibility in simulated 14 

### gastric acid. Jin et al. ( 2005 ) observed that bioaccessibility of Pb in soil was proportional 15 

### to the soil acidity and organic matter content of the soil. 16



### 4.2.2 Distribution

A simple conceptual representation of Pb distribution is that it contains a fast turnover 17 

### pool, comprising mainly soft tissue, and a slow pool, comprising mainly skeletal tissues 18 

### ( Rabinowitz et al., 1976 )

. The highest soft tissue concentrations in adults occur in liver 19 

### and kidney cort ex ( Gerhardsson et al., 1995 ; Oldereid et al., 1993 ; Gerhardsson et al., 20



### 1986 ; Barry, 1975 ; Gross et al., 1975 )

. Pb in blood ( i.e., plasma) exchanges with both of 21 

### these compartments. 22



### 4.2.2.1 Blood

Blood comprises ~1% of total Pb body burden. Pb in blood is found primarily (>99%) in 23



### the RBCs ( Smith et al., 2002 ; Manton et al., 2001 ; Bergdahl et al., 1999 ; Bergdahl et al., 24



### 1998 ; Hernandez

- Avila et al., 1998 ; Bergdahl et al., 1997a ; Schu tz et al., 1996 )

. δ

25 

### aminolevulinic acid dehydratase (ALAD) is the primary binding ligand for Pb in 26 

### erythrocytes ( Bergdahl et al., 1998 ; Xie et al., 1998 ; Bergdahl et al., 1997a ; Sakai et al., 27



### 1982 )

. Two other Pb

- binding proteins have been identified in the RBC, a 45 kDa protein 28 

### (K max 

### 700 μg/dL; K d 

### 5.5 μg/L) and a smaller protein(s) having a molecular weight 29



### <10 kDa ( Bergdahl et al., 1998 ; Bergdahl et al., 1997a ; Bergdahl et al., 1996 )

. Of the 30



### thr ee principal Pb

- binding proteins identified in RBCs, ALAD has the strongest affinity 31February 2012 4

- 40 Draft

– Do Not Cite or Quote 

### for Pb ( Bergdahl et al., 1998 ) and appears to dominate the ligand distribution of Pb (35 to 1


### 84% of total erythrocyte Pb) at blood Pb levels below 40 μg/dL ( Bergdahl et al., 1998 ; 2 

### Bergdahl et al., 1996 ; Sakai et al., 1982 )

. Pb binding to ALAD is saturable; the binding 3 

### capacity was estimated to be ~850 μg/dL RBCs (or ~40 μg/dL whole blood) and the 4 

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

. 5 

### Binding to fetal hemoglobin within the RBC has a higher affinity for Pb than adult 6 

### hemoglobi n. This suggests that erythrocytes of neonates should be able to store more Pb 7



### than infants ( Simon et a l., 2007 )

. Hematocrit is somewhat higher in the neonate at birth 8 

### (51%) than in later infancy (35% at 6 months), which may lead to a decrease in the total 9 

### binding capacity of blood over the first 6 months of life that results in a redistribution of 10



### Pb am ong other tissues ( Simon et al., 2007 )

. 11



### Saturable binding to RBC proteins contributes to an increase in the plasma/blood Pb ratio 12 

### with increasing blood Pb concentration and curvature to the blood Pb

– plasma Pb 13 

### relationship ( Kang et al., 2009 ; Jin et al., 2008 ; Barbosa et al., 2006b ; Smith et al., 2002 ; 14 

### Manton et al., 2001 ; Bergdahl et al., 1999 ; Bergdahl et al., 1998 ; Bergdahl et al., 1997b ; 15 

### DeSilva, 1981 ; Rentschler et al., In Press )

. An example of this is shown in Figure 4

- 4

. 16



### Saturabl e binding of Pb to RBC proteins has several important consequences. As blood 17 

### Pb increases and the higher affinity binding sites for Pb in RBCs become saturated, a 18 

### larger fraction of the blood Pb is available in plasma to distribute to brain and other Pb

19



### re sponsive tissues. This change in distribution of Pb contributes to a curvature in the 20 

### relationship between Pb intake (at constant absorption fraction) and blood Pb 21 

### concentration. Plasma Pb also exhibits faster kinetics. Following exposures of 5 adults 22



### that resulted in relatively high blood Pb concentrations (56

- 110 μg/dL), the initial (fast

23 

### phase) elimination half

- time for plasma Pb (38 ± 20 [SD] days) was approximately half 24 

### that of blood (81 ± 25 days) ( Rentschler et al., In Press )

. 25



### Typically, at blood Pb concentrations <100 μg/dL, only a small fraction (<1%) of blood 26 

### Pb is found in plasma ( Marcus, 1985 ; Manton and Cook, 1984 ; DeSilva, 1981 )

. However, 27 

### as previ ously noted, plasma Pb may be the more biologically labile and toxicologically 28 

### active fraction of the circulating Pb. Approximately 40

- 75% of Pb in the plasma is bound 29 

### to proteins, of which albumin appears to be the dominant ligand ( Al

- Modhefer et al., 30



### 1991 ; Ong and Lee, 1980 a )

. Pb in serum that is not bound to protein exists largely as 31 

### complexes with low molecular weight sulfhydryl compounds ( e.g., cysteine, 32 

### homocysteine) and other ligands ( Al

- Modhefe r et al., 1991 )

. 33February 2012 4

- 41 Draft

– Do Not Cite or Quote Source: Adapted with permission of Elsevier Publishing and the Finland Institute of Occupa tional Health, Bergdahl et al. ( 1999 ; 1997b )

. 

### Figure 4

- 4 Plot of blo od and plasma Pb concentrations measured in adults and children.

As shown in Figure 4

- 4 , the limited binding capacity of Pb binding proteins in RBCs 1



### pr oduces a curvilinear relationship between blood and plasma Pb concentration. The 2 

### limited binding capacity of RBC binding proteins also confers, or at least contributes, to a 3 

### curvilinear relationship between Pb intake and blood Pb concentration. A curviline ar 4 

### relationship between Pb intake and blood Pb concentration has been observed in children 5 

### ( Sherlock and Quinn, 1986 ; Lacey et al., 1985 ; Ryu et al., 1983 )

. As shown in Figure 4

- 5

, 6 

### the relationship becomes pseudo

- linear at relativ ely low daily Pb intakes 7 

### ( i.e., <10 μg/day/kg) and at blood Pb concentrations <25 μg/dL. 8 

### 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 ChildrenFebruary 2012 4

- 42 Draft

– Do Not Cite or Quote Source: Adapted with permission of Taylor & Francis Publishing

, Sherlock and Quinn ( 1986 )

. 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 Relationship between Pb intake and bloo d Pb concentration in infants (n = 105, age 13 weeks, formula

- fed).

Figure 4

- 6 shows the predicted relationship between quasi

- steady state blood and plasma 1



### Pb concentrations in a 4

- year old child using the ICRP model ( Pounds and Leggett, 1998 ; 2 

### ICRP, 1994 ; Leggett, 1993 )

, s ee Section 4.3 for a brief description of the ICRP model ]

. 3 

### The abrupt inflection point that occurs at approximately 25 μg/dL blood Pb is an artifact 4 

### of the numerical approach to simulate the saturation of binding using discontinuous first

5 

### order rate constants for uptake and exit of Pb from the RBC. A continuous function of 6 

### binding sites and affinity, using empirical estimates of both parameters, yield a similar 7 

### but continuous curvature in the relationship ( Bergdahl et al., 1998 ; O'Flaherty, 1995 )

. 8 

### Nevertheless, either approach p redicts a pseudo

- linear relationship at blood Pb 9 

### concentrations below approximately 25 μg/dL which, in this model, corresponds to an 10 

### intake of approximately 100 μg/day (absorption rate ≈ 30 μg/day) (upper panel). An 11 

### important consequence of the limited Pb binding capacity of RBC proteins is that the 12 

### plasma Pb concentration will continue to grow at a linear rate above the saturation point 13 

### for RBC protein binding. One implication of this is that a larger fraction of the Pb in 14



### blood will become available to di stribute to brain and other Pb

- responsive tissues as 15 

### blood Pb increases. This could potentially contribute to non

- linearity in dose

- response 16 

### relationships in studies in which blood Pb is the used as the internal dose metric. 17 

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

0 100 200 300 400Blood Pb (μg/dL)



### Pb Intake ( μ g/day)February 2012 4

- 43 Draft

– Do Not Cite or Quote Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

- 6 Simulation of quasi

- steady state blood and plasma Pb concentrations in a child (age 4 years) associated with varying Pb ingesti on rates.

Studies conducted in swine provide additional evidence in support of RBC binding 1 

### kinetics influencing distribution of Pb to tissues. In these studies, the relationship 2 

### between the ingested dose of Pb and tissue Pb concentrations ( e.g., liver, kidney, bone) 3 

### was linear, whereas, the relationship between dose and blood Pb was curvilinear with the 4 

### 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 PlasmaFebruary 2012 4

- 44 Draft

– Do Not Cite or Quote 

### slope decreasing as the dose increased ( Casteel et al., 2006 )

. Saturabl e binding of Pb to 1 

### RBC proteins also contributes to a curvilinear relationship between urinary Pb excretion 2 

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

. 3



### 4.2.2.2 Bone

The dominant compartment for Pb in the body is in bone. In human adults, 94% of the 4 

### total body burden of Pb is found in the bones, whereas bone Pb accounts for 73% of the 5 

### body burden in ch ildren ( Barry, 1975 )

. Bone is comprised of two main types, cortical (or 6 

### compact) and trabecular (or spongy or ca n cellous). The proportion of cortical to 7 

### trabecular bone in the human body varies by age, but on average is about 80 to 20 percent 8 

### ( O'Flaherty, 1998 ; Leggett, 1993 ; ICRP, 1973 )

. 9



### The exchange of Pb from plasma t o the bone surface is a rapid process ( i.e., adult t 1/2 10 

### =0.19 and 0.23 hours for trabecular and cortical bone, respectively) ( Leggett, 1993 )

. 11 

### Some Pb diffuses from the bone surface to deeper bone regions (adult t 1/2 

### =150 days ) 12 

### where it is relatively inert (in adults) and part of a “nonexchangeable” pool of Pb in bone 13 

### ( Leggett, 1993 )

. 14



### Pb distribution in bone includes uptake into cells that populate bone ( e.g., osteoblasts, 15 

### osteoclasts, osteocytes ) and exchanges with proteins and minerals in the extracellular 16



### matrix ( Pounds et al., 1991 )

. Pb forms highly stable complexes with phosphate and can 17 

### replace calcium in the calcium

- phosphate salt, hydroxyapatite, which comprises the 18 

### primary crys talline matrix of bone ( Meirer et al., 2011 ; Brès et al., 1986 ; Miyake, 1986 ; 19 

### Verbeeck et al., 1981 )

. Several intracellular kinetic pools of Pb have been described in 20



### isolated cultures of osteobla sts and osteoclasts which appear to reflect physiological 21 

### compartmentalization within the cell, including membranes, mitochondria, soluble 22 

### intracellular binding proteins, mineralized Pb ( i.e., hydroxyapatite) and inclusion bodies 23 

### ( Long et al., 1990 ; Pounds and Rosen, 1986 ; Rosen, 1983 )

. Approximately 70

- 80% of Pb 24 

### taken up into isolated primary cultures of osteoblasts or osteocytes is associated with 25



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

. 26



### Pb accumulates in bone regions having the most active calcification at the time of 27 

### exposure. Pb accumulation is thought to occur predominantly in trabecular bone during 28



### childhood and in both cortical and trabecular bone in adulthood ( Aufderheide and 29



### Wit tmers, 1992 )

. Early Pb uptake in children is greater in trabecular bone due to its larger 30 

### surface area and higher metabolic rate. With continued exposure, Pb concentrations in 31 

### bone may increase with age throughout the lifetime beginning in childhood, in dicative of 32 

### a relatively slow turnover of Pb in adult bone ( Park et al., 2009a ; Barry and Connolly, 33



### 1981 ; Barry, 1975 ; Gross et al., 1975 ; Schroeder and Tipton, 1968 )

. The cortical and 34February 2012 4

- 45 Draft

– Do Not Cite or Quote 

### trabecular bones have distinct rates of turnover and Pb release. For example, tibia has a 1 

### turnover rate of about 2% per year whereas trabecular bone has a turnover rate of more 2 

### than 8% per year in adults ( Rabinowitz, 1991 )

. 3



### A high bone formation rate in early childhood results in the rapid uptake of circulating Pb 4 

### into mineralizing bone; however, bone Pb is also recycled to other tissue compartments 5 

### or excreted in accordance with a high bone resorption rate ( O'Flaherty, 1995 )

. Thus, most 6 

### of the Pb acquired early in life is not per manently fixed in the bone (60

- 65%) 7 

### ( O'Flaherty, 1995 ; Leggett, 1993 ; ICRP, 1973 )

. However, some Pb accumulated i n bone 8 

### does persist into later life. McNeill et al. ( 2000 ) compared tibia Pb levels and cumulative 9 

### blood Pb indices in a population of 19

- to 29

- year

- olds who had been highly exposed to 10 

### Pb in childhood from the Bunker Hill, Idaho smelter; they concluded that Pb from 11 

### exposure in early childhood had persisted in the bone matrix until adulthood. 12



### A key factor affecting Pb uptake into bone is the fraction of bone su rface in trabecular 13 

### and cortical bone adjacent to active bone marrow. Of the total bone surface against red 14 

### marrow, 76% is trabecular and 24% is cortical endosteal ( Salmon et al., 1999 )

. The 15


### fraction of total bone marrow that is red and active decreases from 100% at birth to about 16


### 32% in adulthood ( Cristy, 1981 )

. However, bone marrow has much lower Pb 17



### concentrations than bone matrix ( Skerfving et al., 1983 )

. 18



### 4.2.2.3 Soft Tissues

Most of the Pb in soft tissue is in liver and kidney ( Gerhardsson et al., 1995 ; Oldereid et 19 

### al., 1993 ; Gerhardsson et al., 1986 ; Barry, 1975 ; Gr oss et al., 1975 )

. Presumably, the Pb 20 

### in these soft tissues ( i.e., kidney, liver, and brain) exists predominantly bound to protein. 21 

### High affinity cytosolic Pb

- binding proteins have been identified in rat kidney and brain 22 

### ( DuVal and Fowler, 1989 ; Fowler, 1989 )

. The Pb

- binding proteins in rat are cleavage 23 

### products of α2μ globulin, a member of the pr otein superfamily known as retinol

- binding 24 

### proteins that are generally observed only in male rats ( Fowler and DuVal, 1991 )

. Other 25 

### high

- affinity Pb

- binding proteins (K d 

### ~14 nM) have been isolated in human kidney, two 26 

### of which have been identified as a 5 kDa peptide, thym osin 4 and a 9 kDa peptide, acyl

27 

### CoA binding protein ( Smith et al., 1998 )

. Pb also binds to metallothionein, but does not 28 

### appear to be a significant inducer of the protein in comparison with the inducers Cd and 29



### Zn ( Waalkes and Klaassen, 1985 ; Eaton et al., 198 0 )

. 30



### The liver and kidneys rapidly accumulate systemic Pb (t 1/2 

### =0.21 and 0.41 hours, 31 

### respectively), which amounts to 10

- 15% and 15

- 20% of intravenously injected Pb, 32 

### respectively ( Leggett, 1993 )

. A linear relationship in dose

- tissue Pb concentrations for 33 

### kidney and liver has been demonstrated in swine, dogs, and rats ( Smith et al., 2008 ; 34February 2012 4

- 46 Draft

– Do Not Cite or Quote 

### Casteel et al., 2006 ; Casteel et al., 1997 ; Azar et al., 1973 )

. In contrast to Pb in bone, 1 

### which accumulates Pb with continued exposure in adulthood, concentrations in soft 2 

### tissues ( e.g., liver and kidney) are relativel y constant in adults ( Treble and Thompson, 3



### 1 997 ; Barry, 1975 )

, reflecting a faster turnover of Pb in soft tissue relative to bone. 4



### 4.2.2.4 Fetus

Evidence for maternal

- to

- fetal transfer of Pb in humans is derived from cord blood to 5 

### maternal blood Pb ratios. Group mean ratios range from about 0.7 to 1.0 at the time of 6 

### delivery for mean maternal blood Pb levels ranging from 1.7 to 8.6 μ g/dL ( Amaral et al., 7



### 2010 ; Kordas et al., 2009 ; Patel and Prabhu, 2009 ; Carbone et al., 1998 ; Goyer, 1990 ; 8 

### Graziano et al., 1990 )

. In a study of mothers having blood Pb levels of <14 μg/dL, the 9 

### ratio of cord blood Pb to maternal blood Pb decreased with decreasing maternal b lood Pb 10 

### (r=0.82) ( Carbone et al., 1998 )

. In addition, the similarity of isotopic ratios in maternal 11 

### blood and in blood and urine of newly

- born infants provide further evidence for placental 12



### transfer of Pb to the fetus ( Gulson et al., 1999 )

. 13



### Transplacental transfer of P b may be facilitated by an increase in the plasma/blood Pb 14 

### concentration ratio during pregnancy ( Montenegro et al., 2008 ; Lamadrid

- Figueroa et al., 15



### 2006 )

. Maternal

- to

- fetal transfer of Pb appears to be related partly to the mobilization of 16



### Pb from the maternal skeleton. Evidence for transfer of maternal bone Pb to the fetus has 17 

### been provided by stable Pb isotope studies in cynomolgus monkeys exposed during 18 

### pregnancy. Approximately 7

- 39% of the maternal Pb burden transferred to the fetus was 19 

### derived from the maternal skeleton, with the remainder derived from contemporaneous 20



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

. 21



### 4.2.2.5 Organic Lead

Information on the distribution of Pb in humans following exposures to organic Pb is 22 

### extremely limited. However, as reported in the 2006 Pb AQCD, the available evidence 23 

### demonstrates near complete absorption following inhala tion of tetraalkyl Pb vapor and 24 

### subsequent transformation to trialkyl Pb metabolites. One hour following brief inhalation 25


### exposures to 203 

### Pb tetraethyl or tetramethyl Pb (1 mg/m 3 

### ), ~50% of the 203 

### Pb body burden 26 

### was associated with liver and 5% with kidney; the remaining 203 

### Pb was widely distributed 27 

### throughout the body ( Heard et al., 1979 )

. The kinetics of 20 3 

### Pb in blood showed an initial 28 

### declining phase during the first 4 hours (tetramethyl Pb) or 10 hours (tetraethyl Pb) after 29 

### the exposure, followed by a reappearance of radioactivity back into the blood after ~20 30 

### hours. The high level of radioactivity initia lly in the plasma indicates the presence of 31February 2012 4

- 47 Draft

– Do Not Cite or Quote 

### tetraalkyl/trialkyl Pb. The subsequent rise in blood radioactivity, however, probably 1


### represents water

- soluble inorganic Pb and trialkyl and dialkyl Pb compounds that were 2



### formed from the metabolic conversion of the volatile parent compounds ( Heard et al., 3



### 1979 )

. 4



### Alkyl Pb compounds undergo oxidative dealkylation ca talyzed by cytochrome P450 in 5 

### liver and, possibly, in other tissues. Trialkyl Pb metabolites have been found in the liver, 6 

### kidney, and brain following exposure to the tetraalkyl compounds in workers 7 

### ( Bolanowska et al., 1967 ) ; these metabolites have also been detected in brain tissue of 8



### nonoccupa tional subjects ( Nielsen et al., 1978 )

. 9



### 4.2.3 Elimination

The rapid

- phase (30

- 40 days) of Pb excretion amounts to 50

- 60% of the absorbed 10



### fraction ( Chamberlain et al., 1978 ; Rabinowitz et al., 1976 ; Kehoe, 1961a

, b

, c )

. 11 

### Absorbed Pb is excreted primarily in urine and feces, with sweat, saliva, hair, nails, and 12 

### breast milk being minor routes of excretion ( Kehoe, 1987 ; Chamberlain et al., 1978 ; 13 

### Rabinowitz et al., 1976 ; Griffin et al., 1975 ; Hursh et al., 1969 ; Hursh and Suomela, 14



### 1968 )

. 15



### Approximately 30% of intravenously injected Pb in humans (40

- 50% in beagles and 16 

### baboons) is excreted via urine and feces during the first 20 days following adminis tration 17 

### ( Leggett, 1993 )

. The kinetics of urinary excretion following a single dose of Pb is similar 18



### to that of blood ( Chamberlain et al., 1978 )

, likely due to the fact that Pb in urine derives 19 

### largely from Pb in plasma. Evidence for this is the observation that urinary Pb excretion 20 

### is strongly correlated with the rate of glomerular filtration of Pb ( Araki et al., 1986 ) and 21 

### plasma Pb concentration ( Bergdahl et al., 1997b ; Rentschler et al., In Press ) 22 

### ( i.e., glomerular filtration rate × plasma Pb concentration), and bot h relationships are 23 

### linear. While the relationship between urinary Pb excretion and plasma Pb concentration 24 

### is linear, the plasma Pb relationship to blood Pb concentration is curviline ar (as described 25



### in Section 4.2.2.1 and demonstrated in Figure 4

- 6 ). This relationship contributes to an 26



### increase in the renal clearance of Pb from blood with increasing blood Pb concentrations 27 

### ( Chamberlain, 1983 )

. Similarly, a linear relationship between plasma Pb concentration 28 

### and urinary excretion rate predicts a linear relationship between Pb intake (at constant 29 

### absorption fraction) and urinary Pb excretion rate, whereas the relationship with blood Pb 30



### concentrat ion would be expected to be curvilinear (Section 4.3.7 ). 31



### Estimates of urinary filtration of Pb from serum (or plasma) range from 13

- 22 L/day, 32



### with a mean of 18 L/day ( Araki et al., 1986 ; Manton and Cook, 1984 ; Manton and 33 

### Malloy, 1983 ; Chamberlain et al., 1978 )

, which corresponds to half

- time for transfer of 34February 2012 4

- 48 Draft

– Do Not Cite or Quote 

### Pb from plasma to urine of 0.1

- 0.16 days for a 70

- kg adult who has a plasma volume of 1 

### ~3 L. The rate of urinary excretion of Pb was less than the rate of glomerular filtration of 2 

### ultrafilterable Pb, suggesting that urinary Pb is the result of incomplet e renal tubular 3



### re

- absorption of Pb in the glomerular filtrate ( Araki et al., 1986 ) ; although, net tubular 4



### secretion of Pb has been demonstrated in animals ( Victery et al., 1979 ; Vander et al., 5



### 1977 )

. On the other hand, estimates of blood

- to

- urine clearance range from 6



### 0.03

- 0.3 L/day with a mean of 0.18 L/day ( Diamond, 1992 ; Araki et al., 1990 ; Berger et 7 

### al., 19 90 ; Koster et al., 1989 ; Manton and Malloy, 1983 ; Ryu et al., 1983 ; Chamberlain et 8 

### al., 1978 ; Rabinowi tz et al., 1973 )

, consistent with a plasma Pb to blood Pb concentration 9



### ratio of ~0.005

– 0.01 L/day ( Klotzback et al., 2003 )

. Based on the above differences, 10 

### urinary excretion of Pb can be expected to reflect the concentratio n of Pb in plasma and 11 

### variables that affect delivery of Pb from plasma to urine ( e.g., glomerular filtration and 12 

### other transfer processes in the kidney). 13



### The value for fecal:urinary excretion ratio (~0.5) was observed during days 2

- 14 14 

### following intravenous injection of Pb in humans ( Chamberlain et al., 1978 ; Booker et al., 15



### 1969 ; Hursh et al., 1969 )

. This ratio is slightly higher (0.7

- 0.8) with inhalation of 16



### submicron Pb

- bearing PM due to ciliary clearance and subsequent ingestion. The transfer 17 

### of Pb from blood plasma to the small intestine by biliary secretion in the liver is rapid 18 

### (adult t 1/2 

### = 10 days), and accounts for 70% of the total plasma clearance ( O'Flaherty, 19



### 1995 )

. 20



### Organic Lead

Pb absorbed after inhalation of tetraethyl and tetramethyl Pb is excreted in exhaled air, 21 

### urine, and feces ( Heard et al., 1979 )

. Fecal:urinary excretion ratios were 1.8 following 22 

### exposure to tetraethyl Pb and 1.0 following exposure to tetramethyl Pb ( Heard et al., 23



### 1979 )

. Occupational monitoring studies of workers exposed to tetraethyl Pb showed that 24 

### tetraethyl Pb is excreted in the urine as diethyl Pb, ethyl Pb, and inorganic Pb ( Vural and 25 

### Duydu, 1995 ; Zhang et al., 1994 ; Turlakiewicz and Chmielnicka, 1985 )

. 26



## 4.3 Lead Biomarkers

This section describes the biological measurements of Pb and their interpretation as 27 

### indicators of exposure or body burden. 28



### For any health endpoint of interest, the most useful biomark er of exposure is one that 29 

### provides information about the Pb dose at the critical target organ and, moreover, reflects 30 

### the exposure averaging time that is appropriate to the underlying pathogenetic processes 31February 2012 4

- 49 Draft

– Do Not Cite or Quote 

### ( e.g., instantaneous, cumulative over lifetime, or cumulative over a circumscribed age 1 

### range). In recent studies of Pb and health, the exposure biomarkers most frequently used 2 

### are Pb in blood and bone. For outcomes other than those relating to hematopoiesis and 3 

### bone health, these biomarkers provide info rmation about Pb dose that is some distance 4 

### from the target organ. For example, given that the central nervous system is considered 5 

### the critical target organ for childhood Pb toxicity, it would be most helpful to be able to 6 

### measure, in vivo, the Pb concent rations at the cellular site(s) of action in the brain. 7 

### However, because such measurements are not currently feasible, investigators must rely 8 

### on measurements of Pb in the more readily accessible but peripheral tissues. The 9 

### relationship between brain Pb an d Pb in each of these surrogate tissues is still poorly 10 

### understood, although the pharmacokinetics clearly differs among these compartments. 11



### As an exposure biomarker, blood Pb concentration has other limitations. Only about 5% 12 

### of an individual’s total body Pb burden resides in blood. Furthermore, blood consists of 13 

### several subcompartments. More than 90% of Pb in whole blood is bound to red cell 14 

### proteins such as hemoglobin, with the balance in plasma. From a toxicological 15 

### perspective, the unbound fraction is likely to be the most important subcompartment of 16 

### blood Pb because it distributes into soft tissues. The concentration of Pb in plasma is 17



### muc h lower than in whole blood (<1%). The greater relative abundance of Pb in whole 18 

### blood makes its measurement much easier (and more affordable) than measurement of Pb 19 

### in plasma. The use of whole blood Pb as a surrogate for plasma Pb could be justified if 20



### th e ratio of whole blood Pb to plasma Pb were well characterized, but this is not so. At 21 

### least some studies suggest that it varies several

- fold among individuals with the same 22 

### blood Pb level. Moreover, binding Pb in red blood cells is limited, so the ratio o f blood 23 

### Pb to plasma Pb would be expected to be nonlinear. Thus, interpreting whole blood Pb 24 

### level as a proxy for plasma Pb level, which, itself, is a proxy for brain Pb level, will result 25 

### in some exposure misclassification. 26



### Another limitation of blood Pb as an exposure biomarker is that the kinetics of Pb in 27 

### blood is relatively fast compared to the kinetics of Pb in bone, and therefore, of the whole 28 

### body burden. Thus, a high blood Pb concentration measured at any given time does not 29 

### necessarily indicate a high body Pb burden. Similarly, individuals who have the same 30 

### blood Pb level will not necessarily have similar body burdens or exposure histories. The 31 

### rate at which blood Pb changes with time/age depends on exposure history due to re

32 

### equilibration of Pb s tored in the various body pools. 33



### The development of X

- ray

- fluorescence (XRF) methods for measuring Pb in mineralized 34 

### tissues offers another approach for characterization and reconstruction of exposure 35 

### history. Such tissues are long

- term Pb storage sites, with a half

- life measured in decades 36February 2012 4

- 50 Draft

– Do Not Cite or Quote 

### and contain ~90% of the total body Pb burden in adults and 70% in children. Thus, bone 1 

### Pb reflects a long exposure averaging time. 2



### Mechanistic models are used throughout the section as a means to describe basic 3


### concepts that derive from the wealth of information on Pb toxicokinetics. Although 4 

### predictions from models are inherently uncertain, models can serve to illustrate expected 5 

### interrelationships between Pb intake and tissue distribution that are important in 6 

### interpre ting human clinical and epidemiologic studies. Thus, models serve as the only 7 

### means we have for synthesizing our extensive, but incomplete, knowledge of Pb 8 

### biokinetics into a holistic representation of Pb biokinetics. Furthermore, models can also 9



### be used t o make predictions about biokinetics relationships that have not been thoroughly 10 

### evaluated in experiments or epidemiologic studies. In this way, models can serve as 11 

### heuristic tools for shaping data collection to improve our understanding of Pb biokinetics. 12



### Mechanistic toxicokinetics models can make predictions about hypothetical populations 13 

### and exposure scenarios. When a model is run as a single simulation, the output represents 14 

### average outcomes from what is in reality a distribution of possible outcomes th at would 15 

### be expected in the population (or in any single individual) where intra

- individual and 16



### inter

- individual variability in exposure and toxicokinetics exist. More realistic predictions 17 

### for the population can be developed by running a series of model s imulations in which 18 

### ranges ( i.e., distributions) of parameter values are considered that may better represent 19 

### the population of interest. In this section, only single simulations are used to demonstrate 20 

### relationships between various biomarkers ( e.g., blood Pb and bone Pb) that would apply 21 

### to a population having “typical” or “average” exposure and toxicokinetics. These single 22 

### simulations are used for illustrative purposes to describe general concepts and patterns. 23 

### Variability would be expected in real popula tions. 24



### Numerous mechanistic models of Pb biokinetics in humans have been proposed, and 25 

### these are described in the 2006 Pb AQCD ( U.S. EPA, 2006b ) and in the supporting 26 

### literature cited in that report. In this section, for simplic ity and for internal consistency, 27 

### we have limited the discussion to predictions from a single model, the ICRP Pb 28



### biokinetics model ( Pounds and Leggett, 1998 ; ICRP, 1994 ; Leggett, 1993 )

. The ICRP 29



### model consists of a systemic biokinetics model ( Leggett, 1993 ) and a human respiratory 30



### tract model ( ICRP, 1994 )

. The Leggett model simulates age

- dependent kinetics of tissue 31



### d istribution and excretion of lead ingestion and inhalation intakes. This model was 32 

### originally developed for the purpose of supporting radiation dosimetry predictions and it 33 

### has been used to develop cancer risk coefficients for internal radiation exposures to lead 34



### and other alkaline earth elements that have biokinetics similar to those of calcium ( ICRP, 35



### 1993 )

. Although the ICRP model has not be en validated by U.S. EPA as a regulatory 36 

### model for lead risk assessment, it has been applied in Pb risk assessment ( Abrahams et 37February 2012 4

- 51 Draft

– Do Not Cite or Quote 

### al., 2006 ; Lorenzana et al., 2005 ; Khou ry and Diamond, 2003 )

. Portions of the model 1 

### have been incorporated into an AALM that is being developed by EPA ( 2005a )

. In 2



### addition to the above consider ations regarding previous applications of the ICRP model, 3



### the model was selected for use in the ISA because it has several useful features for 4 

### predicting exposure

- body burden relationships. The model simulates blood Pb and tissue 5 

### Pb concentration dynamics associated with the uptake and elimination phases of 6 

### exposures of ≥ 1 day in duration; and it simulates age

- dependent and particle size

7 

### dependent deposition and clearance of inhaled lead in the respiratory tract. These types of 8 

### simulations can only be appr oximated with the U.S. EPA IEUBK Model for lead in 9 

### children because it simulates exposures in time steps of 1 year ( i.e., age

- year average 10 

### exposures); lumps the simulation of deposition, mechanical clearance, and absorption of 11 

### inhaled lead into a single ab sorption term representing the combined processes of 12 

### gastrointestinal and respiratory tract absorption of inhaled lead; simulates steady state 13 

### blood Pb concentrations and was does not allow access to the underlying simulations of 14



### tissue Pb concentrations w hich serve as intermediate variables in the model for predicting 15 

### steady state blood Pb concentrations. Other models have been developed that allow 16



### simulations of tissue Pb concentrations (e.g., O'Flaherty, 1995 ; Leggett, 1993 ) and 17 

### comparisons of these models have been previously described ( Maddaloni et al., 2005 )

. 18



### Pb bioki netics in adolescents is poorly characterized by all existing Pb biokin e tics 19 

### models. Individuals undergo rapid changes in sexual development, growth, food and 20 

### water intake, bone growth and turnover, behavior, etc. during adolescence. There is a 21 

### paucity of experimental measurements of Pb biomarkers during this time developmental 22 

### window. The individual biological and kinetic parameters for adolescents are largely 23 

### interpolated rather than based on solid experimental and toxicological measurements. 24



### These defici encies limit the validity of model predictions in this age group. 25



### 4.3.1 Bone Lead Measurements

For Pb measurements in bone, the most commonly examined bones are the tibia, 26 

### calcaneus, patella, and finger bone. For cortical bone, the midpoint of the tibia is 27



### measu red. For trabecular bone, both the patella and calcaneus are measured. The tibia 28 

### consists of more than 95% cortical bone, the calcaneus and patella comprise more than 29 

### 95% trabecular bone, and finger bone is a mixed cortical and trabecular bone although 30



### the second phalanx is dominantly cortical. Recent studies favor measurement of the 31 

### patella for estimating trabecular bone Pb, because it has more bone mass and may afford 32 

### better measurement precision than the calcaneus. 33February 2012 4

- 52 Draft

– Do Not Cite or Quote 

### Bone Pb measurements are typically exp ressed in units of Pb/g bone mineral. This 1 

### convention may potentially introduce variability into the bone Pb measurements related 2 

### to variation in bone density. Typically, potential associations between bone density and 3



### bone Pb concentration are not evaluat ed in epidemiologic studies ( Theppeang et al., 4



### 2008a ; Hu et al., 2007a )

. 

### An important consequence of expressing bone Pb measures 5


### relative to bone mineral content is that lower bone mineral de nsity is associated with 6 

### greater measurement uncertainty in bone Pb. This can have important implications for 7 

### studies in older women for whom low bone mineral density is more common than in 8 

### other populations including men and younger adults. 9



### Methods of dir ect analysis of bone tissue samples include flame atomic absorption 10 

### spectrometry (AAS), anode stripping voltammetry (ASV), inductively coupled plasma 11 

### atomic emission spectroscopy (ICP

- AES), inductively coupled plasma mass spectrometry 12 

### (ICP

- MS), laser ablat ion inductively coupled plasma mass spectrometry (LA

- ICP

- MS), 13 

### thermal ionization mass spectrometry (TIMS), synchrotron radiation induced X

- ray 14 

### emission (SRIXE), particle induced X

- ray emission (PIXE), and X

- ray fluorescence 15 

### (XRF). Non

- invasive, in vivo mea surements of bone Pb is achieved with XRF. The 16 

### upsurge in popularity of the XRF method has paralleled a decline in the use of the other 17 

### methods. More information on the precision, accuracy, and variability in bone Pb 18



### measurements can be found in the 2006 P b AQCD ( U.S. EPA, 2006b )

. 19



### Two main approaches for XRF measurements have been used to measure Pb 20 

### concentrations in bone, the K

- shell and L

- shell methods. The K

- shell method is the most 21 

### widely used, as there have been relatively fe w developments in L

- shell devices since the 22 

### early 1990s. However, Nie et al. ( 2011 ) recently reported on the use of a new portable L

23



### shell device for human in vivo Pb measurements. Advances in L

- shell device technology 24 

### resulted in much higher sensitivity than previous L

- shell devices. The new L

- shell device 25 

### showed sensitivity similar to that of K

- shell methods (detection limit was approximately 26



### 8 μ g/g bone mineral with 2 mm of soft tissue overlay targeted bone) and a high 27



### correlation with results obtained from K

- shell methods (intraclass correlation = 0.65). 28



### Behinaen et al. ( 2011 ) described application of a 4

- detector system ( “clover leaf array” ) 29



### for the K

- shell method that provided higher precision and lower minimum detection 30 

### limits (MDL) for tibia and calcaneus Pb measurements (3.25 and 4.78 μg/g bone mineral, 31 

### respectively) compared to measurements made with single detectors (8

- 12 μg/g and 32



### 14

- 15 μg/g, respectively). 33



### Since 1986, several investigator s have reported refinements to hardware and software to 34 

### improve the precision and accuracy of XRF measurements and there have been a number 35 

### of investigations into the precision, accuracy and v ariability in XRF measurements 36


### [ e.g., ( Todd et al., 2002 ; Todd et al., 2001 ; Aro et al., 2000 ; Todd et al., 2000 ) ] . Todd 37February 2012 4

- 53 Draft

– Do Not Cite or Quote 

### et al. ( 2000 ) provided a detailed discussion of factors that influence the variability and 1 

### measurement uncertainty, including reposition ing, sample measurement duration, 2 

### overlying tissue, operator expertise, detector resolution, and changes to measurement 3 

### process over time. Some of these aspects were also discussed by Hu et al. ( 1995 )

. From 4 

### their cadaver and in vivo measurements, Todd et al. ( 2000 ) concluded that the uncertainty 5 

### in an individual measurement was an underestimate of the standard deviation of replicate 6 

### measurements, suggesting a methodological defic iency probably shared by most current 7

109 

### Cd

- based K

- shell XRF Pb measurement systems. In examining the reproducibility of 8



### the bone Pb measurements over a 41⁄2 month period, Todd et al. found the average 9



### difference between the XRF results from short term and longer term measurements was 10



### 1.2 μg/g, indicating only a small amount of variability in the XRF results over a sustained 11 

### period of time. 12



### In the epidemiologic literature, XRF bone Pb data have typically been reported in two 13 

### ways: one that involves a methodo logical approach to assessing the minimum detection 14 

### limit and the other termed an epidemiologic approach by Rosen and Pounds ( 1998 )

. In 15 

### the former approach, a minimum detection limit is defined using various methods, 16 

### including two or three times the square r oot of the background counts; one, two, or three 17 

### times the SD of the background; or two times the observed median error. This approach 18 

### relies upon the minimum detection limit to define a quantitative estimate that is of 19 

### sufficient precision to be included in the statistical analysis, as demonstrated by Bellinger 20



### et al. ( 1994a )

, Gerhardsson et al. ( 1993 )

, and Christoffersson et al. ( 1986 )

. 21



### With the epidemiologic approach, all values are used (including negative values) to 22



### deter mine the minimum detection limit of an instrument that results in extremely low 23



### detection limits. Rosen and Pounds ( 1998 ) noted that this approach yields population 24 

### bone Pb averages that were artificially low. However, not including values that are 25 

### negative or below the detection limit, or assigning these values a fixed number is also of 26 

### concern. Using the epidemiologic approach of retaining all point estimates of measured 27 

### bone Pb concentrations provided the least amount of bias and the greatest efficiency in 28 

### comparing the mean or median levels of bone Pb of different populations ( Kim et al., 29



### 1995 )

. 30



### 4.3.2 Blood Lead Measurements

Analytical methods for measuring Pb in blood include AAS, graphite furnace atomic 31 

### absorption spectrometry (GFAAS), ASV, ICP

- AES, and ICP

- MS. GFAAS and ASV are 32 

### generally considered to be the methods of choice ( Flegal and Smith, 1995 )

. Limits of 33 

### detection for Pb using AAS are on the order of 5

- 10 μg/dL for flame AAS measurements 34February 2012 4

- 54 Draft

– Do Not Cite or Quote 

### and approximately 0.1 μg/dL for fl ameless AAS measurements ( Flegal and Smith, 1995 ; 1 

### NIOSH, 1994 )

. A detection limit of 0.005 μ g/dL has been achieved for Pb in blood 2 

### samples analyzed by GFAAS. 3



### For measurement of Pb in plasma, ICP

- MS provides sufficient sensitivity ( Schutz et al., 4



### 1996 )

. While the technique has been applied to assessing Pb exposures in adults, ICP

- MS 5 

### has not received widespread use in epidemiologic studies. 6



### The primary binding ligand for Pb in RBC, ALAD, is encoded by a single gene in 7 

### humans that is polymorphic in two alleles (ALAD1 and ALAD2) ( Scinicariello et al., 8



### 2007 )

. Since the ALAD1 and ALAD 2 alleles can be co

- dominantly expressed, 3 9 

### different genot ypes (ALAD 1

- 1, ALAD 1

- 2, and ALAD 2

- 2) are possible. The ALAD 10



### 1

- 1 genotype is the most common. Scinicariello et al. ( 2010 ) tested genotypes in civilian, 11



### non

- institutionalized U.S. individuals that participated as part of NHANES III from 12



### 1988

– 1994 and found that 15.6% of non

- Hispanic whites, 2.6% non

- Hispanic blacks, and 13


### 8.8% Mexican Americans carried the ALAD2 allele. 14



### The 2006 Pb AQCD document reports that many studies have shown that, with similar 15 

### exposures to Pb, individuals with the ALAD

- 2 allele have higher blood Pb levels than 16



### those without ( Kim et al., 2004 ; Pérez

- Bravo et al., 2004 ; Bergdahl et al., 1997b ; Smith et 17 

### al., 1995a ; Wetmur, 1994 ; Wetmur et al., 1991a ; Astrin et al., 1987 )

. More recent meta 18 

### analyses provide further support fo r ALAD2 carriers having higher blood Pb levels than 19



### ALAD1

- 1 homozygotes ( Scinicariello et al., 2007 ; Zhao et al., 2007 )

. The mechanism for 20 

### this association may be higher Pb binding affinity of ALAD2. Although, this 21 

### interpretation would be consistent with the structural differences that result in greater 22 

### electronegativity of ALAD1 compared to ALAD2 ( Wetmur, 1994 ; Wetmur et al., 23


### 1991b )

, measurements of Pb binding affinity to ALAD1 and ALAD2 ( i.e.

, Pb 2+ 24 

### displacement of Zn 2+ 

### binding to recombinant ALAD1 and ALAD2) have not revealed 25 

### differences in Pb binding affinity ( Jaffe et al., 2000 )

. In a meta

- analysis of 24 studies, 26



### Scinicariello et al. ( 2007 )

, observed the greatest differences for ALAD2 compared to 27 

### ALAD1 in highly exposed adults with little difference among environmentally

- exposed 28 

### adults; large differ ences were also observed for children at low exposures. However, 29 

### there are few studies that evaluated children and the largest study contributing to the meta 30 

### analysis may have been influenced by selection bias ( Scinicariello et al., 2007 )

. 31 

### Individual studies find similar results in occupationally

- exposed adults, with blood Pb 32 

### levels being higher in individuals w ith ALAD2 alleles ( Miyaki et al., 2009 ; Shaik and 33 

### Jamil, 2009 )

. A subsequent meta analysis of adult data from NHANES III did not find 34 

### any differences in blood Pb level between all carriers of either the ALAD 1

- 1 or ALAD 35



### 1

- 2/2

- 2 allele ( Scinicariello et al., 2010 )

. Other studies provide further support for no 36 

### blood Pb differences among ALAD1 and ALAD2 carriers ( Sobin et al., 2009 ; Rabstein et 37February 2012 4

- 55 Draft

– Do Not Cite or Quote 

### al., 2008 ; Montenegro et al., 2006 ; Wananukul et al., 2006 ) or lower blood Pb levels for 1



### individuals with ALAD 1

- 2/2

- 2 ( Krieg et al., 2009 ; Chia et al., 2006 )

. 2



### Genetic polymorphism in the gene that encodes for peptide transporter 2 (PEPT2) has 3 

### been associated with variability in blood Pb concentrations in children ( Sobin et al., 4



### 2009 )

. PE PT2 expression in the brain and renal proximal tubule has been associated with 5 

### transport of di

- and tri

- peptides and may function in the transport of δ

- ALA into brain 6



### and renal tubular re

- absorption of peptides. The PRPT2*2 polymorphism was associated 7



### with increased blood Pb concentrations in a sample of 116 children of Mexican

8 

### American/Hispanic (age 4

- 12 years, mean blood Pb concentration 3

- 6 μg/dL). 9



### Analyses of serial blood Pb concentrations measured in longitudinal epidemiologic 10 

### studies found relatively strong correlations ( e.g., r = 0.5

- 0.8) between individual blood 11



### Pb concentrations measured after 6

- 12 months of age ( Schnaas et al., 2000 ; Dietrich et 12 

### al., 1993b ; McMichael et al., 1988 ; Otto et al., 1985a ; Rabinowitz et al., 1984 )

. These 13 

### observations suggest that, in general, exposure characteristics of an individual child 14 

### ( e.g., exposure levels and/or exposure behaviors) tend to be relatively constant across 15 

### age. However, a single blood Pb measurement may not distinguish between a history of 16 

### long

- term lower

- level Pb exposure from a history that includes hi gher acute exposures 17 

### ( Mushak, 1998 )

. This concept is illustrated in Figur e 4

- 7 . Two hypothetical children are 18 

### simulated. Child A has a relatively constant Pb intake from birth, whereas Child B has 19



### the same Pb intake as Child A for the first two years of life, then a 1

- y ear elevated intake 20 

### beginning at age 24 months ( Figur e 4

- 7 , upper panel) that returns to the same intake as 21



### Child A at 36 months. The absorption fract ion is assumed to be the same for both 22 

### children. Blood Pb samples 1 and 5 for Child A and B, or 2 and 4 for Child B, will yield 23 

### similar blood Pb concentrations (~3 or 10 μg/dL, respectively), yet the exposure contexts 24 

### for these samples are very different. Two samples ( e.g., 1 and 2, or 4 and 5), at a 25 

### minimum, are needed to ascertain if the blood Pb concentration is changing over time. 26



### The rate of change can provide information about the magnitude of change in exposure, 27 

### but not necessarily about the time his tory of the change ( Figur e 4

- 7 , lower panel). Time

28 

### integrated measurements of Pb concentration may provide a means for accounting for 29



### some of these fa ctors and, thereby, provide a better measure of long

- term Pb exposure. 30February 2012 4

- 56 Draft

– Do Not Cite or Quote Note: 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 p anel). 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 Ch ild 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 biokinetics model ( Leggett, 1993 )

. 

### Figur e 4

- 7 Simulation of temporal relationships between Pb exposure and blood Pb concentration in children.February 2012 4

- 57 Draft

– 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 1 

### as those analyses noted for determination of Pb in blood. Reported detection limits are 2



### ~50 μg/L for AAS, 5

- 10 μg/L for ICP AES, and 4 μg/L for ASV for urine Pb analyses. 3



### The concentration of Pb in urine is a function of the urinary Pb excretion ( Section 4.2.3 ) 4 

### and the urine flow rate. Urine flow rate requires collection of a timed urine sample, which 5 

### is often problematic in epidemiologic st udies. Collection of untimed (“spot”) urine 6 

### samples, a common alternative to timed samples, requires adjustment of the Pb 7



### measurement in urine to account for variation in urine flow ( Diamond, 1988 )

. Several 8 

### approaches to this adjustment have been explored, including adjusti ng the measured urine 9 

### Pb concentration by the urine creatinine concentration, urine osmolality, or specific 10 

### gravity ( Fukui et al., 1999 ; Araki et al., 1990 )

. Urine flow rate can vary by a factor or 11 

### more than 10, depending on the state of hydration and other factors that affect glomerular 12



### filtration rate an d renal tubular reabsorption of the glomerular filtrate. All of these factors 13 

### can be affected by Pb exposure at levels that produce nephrotoxicity ( i.e., decreased 14 

### glomerular filtration rate, impaired renal tubular transport function). Therefore, urine Pb 15 

### concentration measurements provide little reliable information about exposure (or Pb 16 

### body burden), unless they can be adjusted to account for unmeasured variability in urine 17



### flow rate ( Araki et al., 1990 )

. 18



### Urinary Pb concentration reflects, mainly, the concentration of Pb in the blood. As such, 19 

### urinary concentrations by reflect both recent and past exposur es to Pb (see Section 4.3.5 ). 20 

### A single urinary Pb measurement cannot distinguish between a long

- term low level of 21 

### exposure or a higher acute exposu re. Urinary Pb measurements would be expected to 22 

### correlate with concurrent blood Pb (see Section 4.3.6 for additional discussion of the 23 

### relationship between blood and urine Pb). Chiang et al. ( 2008 ) reported a significant, but 24 

### relatively weak correlation between urinary Pb levels (μg/dg creatinine) and individual 25 

### Pb intakes (μg/day) estimated in a group of 10

- to 1 2

- year

- old children (β: 0.053, R = 26 

### 0.320, p = 0.02, n = 57). A contributing factor to the relatively weak correlation may have 27 

### been the temporal displacement between the urine sampling and measurements used to 28 

### estimate intake, which may have been as long a s 6 months for some children. 29



### Thus, a single urine Pb measurement, or a series of measurements taken over short

- time 30 

### span, is likely a relatively poor index of Pb body burden for the same reasons that blood 31 

### Pb is not a good indicator of body burden. On th e other hand, long

- term average 32 

### measurements of urinary Pb can be expected to be a better index of body burden ( Figure 33



### 4

- 8 ). 34February 2012 4

- 58 Draft

– Do Not Cite or Quote Note: 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 bu rden (lower panel). Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

- 8 Simulation of relationship between urinary Pb excretion and body burden in adults. 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 BodyFebruary 2012 4

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– Do Not Cite or Quote 

### 4.3.4 Lead in Other Biomarkers

There was extensive discussion in the 2006 Pb AQCD regarding the utility of other Pb 1 

### biomarkers as indicators of exposure or body burden. Due to the fact that most 2 

### epidemiologic studies continue to use blood Pb or bone P b, and other potential 3 

### biomarkers ( i.e., teeth, hair, and saliva) have not been established to the same extent as 4 

### blood or bone Pb, only summaries are 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, 6 

### tooth Pb levels are generally considered an estimate of cumulative Pb exposure. The 7



### tooth Pb

- blood Pb relationship is more complex than the bone Pb

- blood Pb relationship 8 

### because of differences in tooth type, location, and analytical method. Although 9



### m obilization of Pb from bone appears well established, this is not the case for Pb in teeth. 10 

### Conventional wisdom has Pb fixed once it enters the tooth. Although that may be the case 11 

### for the bulk of enamel, it is not true for the surface of the enamel and de ntine ( Gulson et 12 

### al., 1997 ; Rabinowitz et al., 1993 )

. Limited studies have demonstrated moderate

- to

- high 13



### correlations between tooth Pb levels and blood Pb levels ( Rabinowitz, 1995 ; Rabinowitz 14 

### et al., 1989 )

. 15



### Teeth are composed of several tissues formed pre

- and postnatal . Therefore, if a child’s 16 

### Pb exposure during the years of tooth formation varied widely, different amounts of Pb 17 

### would be deposited at different rates ( Rabinowitz et al., 1993 )

. This difference may allow 18 

### investigators to elucidate the history of Pb exposure in a child. Robbins et al. ( 2010 ) 19 

### found a significant association betwe en environmental Pb measures that correlated with 20 

### leaded gasoline use and tooth enamel Pb in permanent teeth. Costa de Almeida et al. 21 

### ( 2007 ) discerned differences between tooth enamel Pb concentration in biopsy samples 22 

### from children who lived in areas having higher or lower levels of Pb con tamination. 23



### Gulson and Wilson ( 1994 ) advocated the use of sections of enamel and dentine to obtain 24 

### additional information compared with analysis of the whole tooth ( e.g., ( Tvinnereim et 25 

### al., 1997 ; Fosse et al., 1995 )

. For example, deciduous tooth Pb in the enamel provides 26



### information about in utero exposure whereas that in dentine from the same tooth provides 27 

### information about postnatal exposure until the tooth exfoliates at about 6

- 7 years of age. 28February 2012 4

- 60 Draft

– Do Not Cite or Quote 

### 4.3.4.2 Hair

The 2006 Pb AQCD discussed applications of hair Pb measurements for assessing Pb 1 

### body burden or exposure and noted methodological limitations ( e.g., external 2 

### contamination) and lack of a strong empirical basis for relating hair Pb level s to body 3 

### burden or exposure. No new methodological or conceptual advances regarding hair Pb 4 

### measurements have occurred since 2006, and widespread application of hair Pb 5 

### measurements in epidemiologic studies has not occurred. 6



### Pb is incorporated into human hair and hair roots ( B os et al., 1985 ; Rabinowitz et al., 7



### 1976 ) and has been ex plored as a noninvasive approach for estimating Pb body burden 8 

### ( Wilhelm et al., 2002 ; Gerhardsson et al., 1995 ; Wilhelm et al., 1989 )

. Hair Pb 9



### measurements are sub ject to error from contamination of the surface with environmental 10 

### Pb and contaminants in artificial hair treatments ( i.e., dyeing, bleaching, permanents) and 11 

### are a relatively poor predictor of blood Pb concentrations, particularly at blood Pb levels 12



### less than 10

- 12 μg/dL ( Rodrigues et al., 2008 ; Campbell and Toribara, 2001 ; Esteban et 13 

### al., 1999 ; Drasch et al., 1997 )

. Temporal relationships between Pb exposure and hair Pb 14 

### levels, and kinetics of deposition and retention of Pb in hair have not been evaluated. 15



### Al though hair Pb measurements have been used in some epidemiologic studies ( Shah et 16 

### al., 2011 ; U.S. EPA, 2006b )

, an empirical basis for interpreting hair Pb measurements in 17 

### terms of body burden or exposure has not been firmly established. 18



### 4.3.4.3 Saliva

A growing body of literature on the utility of measurements of salivary Pb has developed 19 

### since the completion of the 2006 Pb AQCD ( U.S. EPA, 2006b )

. Earlier reports suggested 20 

### a relatively strong correlation between salivary Pb conc entration and blood Pb 21



### concentration ( Omokhodion an d Crockford, 1991 ; Brodeur et al., 1983 ; P'an, 1981 ) ; 22 

### however, more recent assessments have shown relatively weak or inconsistent 23



### associations ( 2011 ; 2010 ; Costa de Almeida et al., 2009 ; Barbosa et al., 2006c ; Nriagu et 24 

### al., 2006 )

. The differences in these outcomes may reflect differences in blood Pb 25 

### concentrations, exposure history and/or dental health ( i.e., transfer of Pb between dentin 26 

### and saliva) and possibly methods for determ ining Pb in saliva. Barbosa et al. ( 2006c ) 27 

### found a significant but relatively weak correlation (log[blood PB] versus log [saliva Pb], r 28 

### = 0.277, p = 0.008) in a sample of adults, ages 18

- 60 years (n = 88). The correlation was 29 

### similar for salivary and plasma Pb. Nriagu et al. ( 2006 ) found also found a relatively 30 

### weak association (R 2 

### = 0.026) between blood Pb (μg/dL) and salivary Pb (μg/L) in a 31 

### sample of adults who resided in Detroit, MI (n = 904). Costa de Almeida et al. ( 2009 ) 32 

### found a significant correlation between salivary and blood Pb concentrations in children 33February 2012 4

- 61 Draft

– Do Not Cite or Quote 

### in a Pb

- contaminated region in Sao Paulo State, Brazil ( r = 0.76. p = 0.04, n = 7) prior to 1 

### site remediation; however, the correlation degenerated (r = 0.03, p = 0.94, n = 9) 2 

### following remediation. Nevertheless, salivary Pb concentrations in the group of children 3 

### who lived in the contaminated area were signific antly elevated compared to a reference 4 

### population. It is possible, that salivary Pb measurements may be a useful non

- invasive 5 

### biomarker for detecting elevated Pb exposure; however, it is not clear based on currently 6 

### available data, if salivary Pb measureme nts would be a more reliable measure of 7 

### exposure than blood Pb measurements. 8



### 4.3.4.4 Serum δ

- ALA and ALAD

The association between blood Pb and blood ALAD activity and serum δ

- aminolevulin i c 9 

### acid ( δ

- ALA) levels was recognized decades ago as having potential use as a biomarker 10 

### of Pb exposure ( Mitchell et al., 1977 ; Hernberg et al., 1970 )

. More recently reference 11 

### values for blood ALAD activity ratio (the ratio of ALAD activity in the blood sample to 12 

### that measured after fully activating the enzyme in the sample) have been reported 13 

### ( Gultepe et al., 2009 )

. Inhibition of erythrocyte ALAD by Pb results in a rise in the 14 

### plasma concentration of the ALAD substrate δ

- ALA. The δ

- ALA biomarker can be 15



### measured in serum and has been used as a surrogate for Pb measurements in studies in 16 

### which whole blood samples or adequately prepared plasma or serum samples were not 17



### available for Pb measurements ( Opler et al., 2008 ; Opler et al., 2004 )

. 18



### 4.3.5 Relationship between Lead in Blood and Lead in Bone

The kinetics of elim ination of Pb from the body reflects the existence of fast and slow 19 

### pools of Pb in the body. The dominant phase of Pb kinetics in the blood, exhibited shortly 20 

### after a change in exposure occurs, has a half

- life of ~20

- 30 days ( Leggett, 1993 ; 21 

### Rabinowitz et al., 1976 )

. Studies of a limited number of adults (four individuals with hip 22 

### or knee replacement, a married couple, and 10 female Australian immigrants) in which 23 

### the Pb exposure was from historical environmental sour ces have found that bone Pb 24



### stores can contribute 40

- 70% to blood Pb ( Smith et al., 1996 ; Gulson et al., 1995 ; 25 

### Manton, 1985 )

. Bone Pb burdens in adults are slowly lost by diffusion (heteroionic 26 

### exchange) as well as by resorption ( O'Flaherty, 1995 )

. Half

- times for the release of Pb in 27 

### bone are dependent on age and intensity of exposure. Bone compartments are much more 28 

### labile in infants and children than in adults as reflected by half

- times for movement of Pb 29



### from bone into the plasma ( e.g., cortical t 1/2 

### = 0.23 years at birth, 1.2 years at 5 years of 30 

### age, 3.7 years at 15 years of age, and 23 years in adults; trabecular t 1/2 

### = 0.23 years at 31February 2012 4

- 62 Draft

– Do Not Cite or Quote 

### birth, 1.0 years at 5 years of age, 2.0 years at 15 years of age, and 3.9 y ears in adults) 1 

### ( Leggett, 1993 )

. Slow transfer rates for the movement of Pb from nonexchangeable bone 2 

### pools to the plasma are the dominant transfer process determining long

- term 3



### accumulation and elimination of bone Pb burden

. 4



### The apparent slow clearance of Pb from the blood over months and years following the 5 

### cessation or reduction in exposures reflects elimination of Pb stores in bone. Longer fast

6 

### phase elimination half

- times (60

- 120 days) were reported for five adults with lead 7 

### poisoning following roughly a month to 12 years of exposure and relatively high blood 8



### Pb concentrations of 70

- 110 μg/dL ( Rentschler et al., In Press )

. A slower phase becomes 9 

### evident with longer observation periods following a decrease in exposure. Nilsson et al. 10 

### ( 1991 ) reported in tri

- exponential decay in the blood Pb concentrations of 14 individuals 11 

### having a median occupational exposure period of 26 year s. Representing 22% of blood 12 

### Pb, the fast compartment had a clearance half time of 34 day. The intermediate 13 

### compartment, 27% of blood Pb, had a clearance half time of 1 .12 year . And, the slow 14 

### compartment, 50% of blood Pb, had a clearance half time of 13 year s. The authors 15 

### attributed the fast, intermediate, and slow compartment clearance to elimination of Pb 16 

### from blood and some soft tissues, from trabecular bone, and cort ical bone, respectively. 17 

### Children who have been removed from a relatively brief exposure to elevated 18



### environmental Pb also exhibit faster slow

- phase kinetics than children removed from 19 

### exposures that lasted several years, with half

- times of 10 and 20

- 38 mo nths, respectively 20 

### ( Man ton et al., 2000 )

. Rothenberg et al. ( 1998 ) also showed that exposures in the first 6 21 

### months of life could contribute to elevated blood lead through at least 3 years relative to 22



### children with lo wer early life exposures, despite similar environmental exposures at later 23 

### time points. In both adults and children, the longer half

- times measured under the latter 24 

### conditions reflect the contribution of bone Pb stores to blood Pb following a change in 25



### exp osure. 26



### The longer half

- life of Pb in bone compared to blood Pb, allows a more cumulative 27 

### measure of Pb dose. Pb in adult bone can serve to maintain blood Pb levels long after 28 

### external exposure has ceased ( Fleming et al., 1997 ; Inskip et al., 1996 ; Smith et al., 1996 ; 29 

### Kehoe, 1987 ; O'Flaherty et al., 1982 )

, even for exposures that occurred during childhood 30 

### ( McNeill et al., 2000 )

. The more widespread use of in vivo XRF Pb measurements in 31 

### bone and indirect measurements of bone processes with stabl e Pb isotopes have enhanced 32 

### the use of bone Pb as a biomarker of Pb body burden. 33



### Several studies have found a stronger relationship between patella Pb and blood Pb than 34



### tibia Pb and blood Pb ( Park et al., 2009a ; Hu e t al., 1998 ; Hernandez

- Avila et al., 1996 ; 35 

### Hu et al., 1996b )

. Hu et al. ( 1998 ) suggest that trabecular bone is the predominant bone 36 

### type providing Pb back into circulation under steady

- state and pathologic conditions. The 37February 2012 4

- 63 Draft

– Do Not Cite or Quote 

### stronger relationship between blood Pb and trabecular Pb compared with cortical bone is 1 

### probably associated with the larger surface area of trabecular bone allowing for more Pb 2 

### to bind via ion exchange mechanisms and more rapid turnover making it more sensitive 3 

### to changing patt erns of exposure. 4



### 4.3.5.1 Children

As mentioned in Section 4.2.2.2 , bone growth in children will contribute to accumulation 5 

### of Pb in bone, which will compri se most of the Pb body burden. As a result, Pb in bone 6 

### will more closely reflect Pb body burden than blood Pb. However, changes in blood Pb 7 

### concentration in children ( i.e., associated with changing exposures) are thought to more 8 

### closely parallel changes in total body burden. Figure 4

- 9 shows a simulation of the 9 

### temporal profile of Pb in blood and bone in a child who experiences a period of constant 10



### Pb i ntake (from age 2

- 5) via ingestion (μg Pb/day) followed by an abrupt decline in 11 

### intake. The figure illustrates several important general concepts about the relationship 12 

### between Pb in blood and bone. While blood Pb approaches a quasi

- steady state after a 13



### pe riod of a few months with a constant rate of Pb intake (as demonstrated by the vertical 14 

### dashed line), Pb continues to accumulate in bone with continued Pb intake after the 15 

### quasi

- steady state is achieved in blood. The model also predicts that the rate of re lease of 16 

### Pb from bone after cessation of exposure is faster than in adults. This difference has been 17 

### attributed to accelerated growth

- related bone mineral turnover in children, which is the 18 

### primary mechanism for release of Pb that has been incorporated int o the bone mineral 19



### matrix. 20



### Empirical evidence in support of this conclusion comes from longitudinal studies in 21 

### which relatively high correlations were found between concurrent (r = 0.75) or average 22 

### lifetime (obtained at 6

- month intervals from birth to age 10 or 12) blood Pb 23 

### concentrations (r = 0.85) and tibia bone Pb concentrations (measured by XRF) in a 24 

### sample of children in which the group mean concurrent blood Pb concentration exceeded 25



### 20 μg/dL; the correlations was much weaker (r <0.15) among the group of children with 26



### a mean concurrent blood Pb concentration <10 μg/dL ( Wasserman et al., 2003 )

. 27



### Two alternative blood Pb metrics depicted in Figure 4

- 9 include the time

- averaged and 28



### time

- integrated blood Pb concentrations. Both the time

- averaged and time

- integrated 29 

### blood Pb metrics display rates of change in response to the exposure event that more 30 

### closely approximate the slower kinetics of bone Pb and body burden, than the kinetics of 31 

### blood Pb concentration, with notable differences. The time

- averaged blood Pb 32 

### concentration increases during the exposure event and decays fol lowing the event, 33 

### consistent with the changing body burden. The time

- integrated blood Pb concentration 34February 2012 4

- 64 Draft

– Do Not Cite or Quote 

### (conceptually identical to cumulative blood lead index [CBLI] used in epidemiologic 1 

### studies) is a cumulative function and increases throughout childhood; however, the slope 2 

### of the increase is higher during the exposure event than prior to or following the event. 3 

### Following cessation of exposure, the time

- integrated blood Pb and body burden diverge. 4 

### This result is expected, as the time

- integrated blood Pb cu rve is a cumulative function 5



### which cannot decrease over time and bone Pb levels will decrease with cessation of 6



### exposure. 7



### The time

- integrated blood Pb concentration will be a better reflection of the total amount 8 

### of Pb that has been absorbed, than the body burden at any given time. The time

9 

### integrated blood Pb concentration will also reflect cumulative Pb absorption, and 10 

### cumulative exposure if the absorption fraction is constant. This is illustrated in the 11 

### hypothetical simulations of an exposure event exper ienced by a child ( Figure 4

- 10 ). This 12 

### pattern is similar for adults. 13February 2012 4

- 65 Draft

– Do Not Cite or Quote Note: 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 b lood Pb concentration increases over time (lower panel). Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

- 9 Simulation of relationship between blood Pb c oncentration and body burden in children, with a constant Pb intake from age 2 to 5.February 2012 4

- 66 Draft

– Do Not Cite or Quote Note: The simulations include a 3

- year period of elevated Pb intake during ages 2

- 5 years. The time

- integrated blood Pb concentration closely parallels cumulative Pb abs orption. Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

- 10 Simulation of relationship between time

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

4.3.5.2 Adults

In adults, where a relatively large fraction of the body burden residing in bone has a 1 

### slower turnover compared to blood, a constant Pb uptake (or constant intake and 2 

### fractional absorption) gives rise to a quasi

- steady state blood Pb concentration, while t he 3 

### body burden continues to increase over a much longer period, largely as a consequence of 4 

### continued accumulation of Pb in bone. This pattern is illustrated in Figure 4

- 11 which 5 

### depicts a hypothetical simulation of an exposure event consisting of a 20

- year period of 6 

### daily ingestion of Pb in an adult. The exposure event shown in the simulations gives rise 7 

### to a relatively rapid increase in blood Pb conce ntration, to a new quasi

- steady state, 8



### achieved in ~75

- 100 days ( i.e., approximately 3

- 4 times the blood elimination half

- life). 9 

### In contrast, the body burden continues to increase during this period. Following cessation 10 

### of the exposure, blood Pb concentrat ion declines relatively rapidly compared to the 11 

### slower decline in body burden. Careful examination of the simulation shown in Figure 12



### 4

- 11 reveals that the accumulation and elimination phases of blood Pb kinetics are not 13 

### 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 AbsorptionFebruary 2012 4

- 67 Draft

– Do Not Cite or Quote 

### symmetrical; elimination is slower than accumulation as a result of the gradual release of 1 

### bone Pb stores to blood. This response, known as the prolonged terminal elimination 2 

### phase of Pb from blood, has been observed in retired Pb workers and in workers who 3 

### continued to work after improved industrial hygiene standards reduced their exposures. In 4



### the adult simulation shown in Figure 4

- 11 , the initial phase of elimination (the first 5



### 5 years following cessation of exposure at 50 years) has a half

- time of approximately 6



### 14 years; however, the half

- time increases to approximately 60 years dur ing the period 7



### 5

- 30 years after cessation of exposure. These model predictions are consistent with the 8



### slow elimination of Pb from blood and elimination half

- times of several decades for bone 9 

### Pb ( e.g., 16

- 98 years) that have been estimated from observation s made on Pb workers 10 

### ( Wilker et al., 2011 ; Fleming et al., 1997 ; Gerhardsson et al., 1995 )

. Based on this 11 

### hypothetical simulation, a blood Pb concentra tion measured 1 year following cessation of 12 

### a period of increased Pb uptake would show little or no appreciable change from prior to 13 

### the exposure event, whereas, the body burden would remain elevated. These simulations 14



### in Figure 4

- 11 illustrate how a single blood Pb concentration measurement, or a series of 15



### measurements taken over a short

- time span, could be a relatively poor index of Pb body 16



### burden. 17



### On e important potential implication of the profoundly different kinetics of Pb in blood 18 

### and bone is that, for a constant Pb exposure, Pb in bone will increase with increasing 19 

### duration of exposure and, therefore, with age. In contrast, blood Pb concentration will 20 

### achieve a quasi

- steady state. As a result, the relationship between blood Pb and bone Pb 21 

### will diverge with increasing exposure duration and age. This divergence can impart 22 

### different degrees of age

- confounding when either blood Pb or bone Pb is used as an 23



### internal dose metric in dose

- response models. In a review of epidemiologic studies that 24 

### evaluated the associations between blood Pb, bone Pb and cognitive function, the effects 25 

### of bone Pb were more pronounced than blood Pb (particularly for longitudina l studies) 26 

### for older individuals with environmental Pb exposures and low blood Pb levels ( Shih et 27 

### al., 2007 )

. In contrast, occupational workers with high current Pb exposu res had the 28 

### strongest associations for blood Pb levels with cognitive function, thus providing 29 

### evidence for this divergence ( Shih et al., 2007 )

. 30



### The aforementioned expecta tion for an increase in bone Pb and body burden with age 31 

### applies to scenarios of constant exposure but not necessarily to real world populations in 32 

### which individual and population exposures have changed over time. Longitudinal studies 33



### of blood and bone Pb trends have not always found strong dependence on age ( Nie et al., 34



### 2009 ; Kim et al., 1997 )

. Kim et al. ( 1997 ) found that bone Pb levels increased with 35 

### increasing age in elderly adults (age 52

- 83) years), only when the data were analyzed 36



### cross

- sectionally. When analyzed longitudinally, the trend for individual patella Pb was a 37


### 23% decrease over a 3

- ye ar period (approximate t 1/2 

### of 8 years), whereas tibia Pb levels 38February 2012 4

- 68 Draft

– Do Not Cite or Quote 

### did not change with over the same period. Therefore, although older individuals tended to 1 

### have higher bone Pb levels, the 3

- year temporal trend for individuals was a loss of Pb 2



### from the more labile Pb stores in trabecular bone. Nie et al. ( 2011 ) observed that 3 

### longitudinal observations of blood and bone Pb in elderly adults did not sho w a 4 

### significant age effect on the association between blood Pb and bone Pb (patella and tibia), 5 

### when the sample population (n=776) was stratified into age tertiles (mean age 62, 69 or 6



### 77 years). Nie et al. ( 2009 ) did find that regressed function bone Pb and appeared to level 7



### off at bone Pb levels > 20 μg/g bone mineral. 8

Note: A constant baseline intake results in 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 quasi

- steady state, and a slo wer change in body burden. The long

- term time

- averaged blood Pb concentration more closely tracks the slower pattern of change in body burden (middle panel). The time

- integrated blood Pb concentration increases over the lifetime, with a greater rate of inc rease during periods of higher Pb uptake (lower panel). Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

- 11 Simulation of relationship between blood Pb concentration, bone Pb and body burden in adults.February 2012 4

- 69 Draft

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### Tibia bone Pb is correlated with time

- integrated blood Pb concentration ( i.e., CBLI). 1



### McNeill et al. ( 2000 ) compared tibia Pb levels and cumulative blood Pb indices in a 2 

### population of 19

- to 29

- year

- olds who had been highly exposed to Pb in childhood from 3 

### the Bunker Hill, Idaho smelter. They concluded that Pb from exposure in early childhood 4 

### had persisted in the bone matrix until adulthood. The bone Pb/CBLI slopes from various 5 

### studies range from 0.022 to 0.067 μg/g bone mineral per μg

- year/dL ( Healey et al., 2008 ; 6 

### Hu et al., 2007a )

. Because the CBLI is a cumulative function which cannot decrease over 7 

### time, CBLI and bone Pb would be expected to diverge following cessation of exposure, 8



### as bone Pb levels decrease. T his divergence was observed as a lower bone Pb/CBLI slope 9 

### in retired Pb workers compared to active workers and in worker populations whose 10 

### exposures declined over time as a result of improved industrial hygiene ( Fleming et al., 11



### 1997 ; Gerhardsson et al., 1993 )

. 12



### Although differences in kinetics of blood and bone Pb degrade the predictive value of 13 

### blood Pb as a metric of Pb body burden, within a population that has similar exposure 14 

### histories and age demographics, blood and bone Pb may show relatively strong 15 

### associations. A recent analysis of a subset of da ta from the Normative Aging Study (an 16 

### all male cohort) showed that cross

- sectional measurements of blood Pb concentration 17 

### accounted for approximately 9% (tibia) to 13% (patella) of the variability in bone Pb 18 

### levels. Inclusion of age in the regression model accounted for an additional 7

- 10% of the 19 

### variability in bone Pb ( Park et al., 2009a )

. 20



### Mobilization of Lead from Bone in Adulthood

In addition to changes in exposure ( e.g., declines in exposure discussed in p rior section), 21 

### there are physiological processes during different life circumstances that can increase the 22



### contribution of bone Pb to blood Pb. These life circumstances include times of 23 

### physiological stress associated with enhanced bone remodeling such as during pregnancy 24



### and lactation ( Hertz

- Picciotto et al., 2000 ; Silbergeld, 1991 ; Manton, 1985 )

, menopause 25 

### or in the elderly ( Silbergeld et al., 1988 )

, extended bed rest ( Markowitz and Weinberger, 26



### 1990 )

, hyperparathyroidism ( Kessler et al., 1999 ) and severe weight loss ( Riedt et al., 27



### 2009 )

. 28



### During pregnancy, bone Pb can serve as a Pb source as maternal bone is resorbed for the 29 

### production of the fetal skel eton ( Gulson et al., 2003 ; Gulson et al ., 1999 ; Franklin et al., 30



### 1997 ; Gulson et al., 1997 )

. Increased blood Pb during pregnancy has been demonstrated 31 

### in numerous studies and these changes have been characterized as a “U

- shaped” pattern 32 

### of lower blood Pb concentrations during the second trimester compared to the first and 33



### third t rimesters ( Lamadrid

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

- Picciotto et 34 

### al., 2000 ; Gulson et al., 1997 ; Lagerkvist et al., 1996 ; Schuhmacher et al., 1996 ; 35February 2012 4

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### Rothenberg et al., 1994 a )

. The U

- shaped relationship r eflects the relatively higher impact 1 

### of hemodilution in the second trimester versus the rate of bone Pb resorption 2 

### accompanying calcium releases for establishing the fetal skeleton. In the third trimester, 3 

### fetal skeletal growth on calcium demand is greater , and Pb released from maternal 4



### skeleton offsets hemodilution. Gulson et al. ( 1998a ) reported that, during pregnancy, 5 

### blood Pb concentrations in the first immigrant Australian cohort (n = 15) increased by an 6 

### average of about 20% compared to non

- pregnant migrant controls (n = 7). Skeletal 7 

### contribution to blood Pb, based on the isotopic comp osition for the immigrant subjects, 8 

### increased in an approximately linear manner during pregnancy. The mean increases for 9 

### each individual during pregnancy varied from 26% to 99%. Interestingly, the percent 10 

### change in blood Pb concentration was significantly greater during the post

- pregnancy 11 

### period than during the second and third trimesters. This is consistent with Hansen et al. 12 

### ( 2011b ) that demonstrated the greatest blood Pb levels at 6 weeks postpartum compared 13 

### to the second trimester in 211 Norwegian women. Increased calcium demands of 14 

### lactation (relative to pregnancy) may contribute to the greater change in blood Pb 15 

### observed post pregnanc y compared to the second and th i r d trimesters. The contribution of 16 

### skeletal Pb to blood Pb during the post

- pregnancy period remained essentially constant at 17



### the increased level of Pb mobilization. 18



### Gulson et al. ( 2004a ) observed that calcium supplementation was found to delay 19 

### increased mobilization of Pb from bone during pregnancy and halved the flux of Pb 20 

### release from bone during late pregnancy and postpartum. In another study, women whose 21 

### daily calcium intake was 850 mg per day showed lower amounts of bone resorption 22 

### during late pregnancy and postpartum than those whose intake was 560 mg calcium per 23 

### day ( Manton et al., 2003 )

. Similarly, calcium supplementation (1

, 200 mg/day) in 24 

### pregnant Mexican women resulted in an 11% reduction in blood Pb level compared to 25 

### placebo and a 24% average reduction for the most compliant women ( Ettinger et al., 26



### 2009 )

. When considering baseline blood Pb levels in women who were more compliant 27 

### in taking calcium supplementation, the reductions were similar for those <5 μg/dL and 28


### those ≥ 5 μg/dL (14% and 17%, respectively). This result is in contrast to a study of 29



### women wh o had blood Pb concentrations <5 μg/dL, where calcium supplementation had 30



### no effect on blood Pb concentrations ( Gulson et al., 2006b )

. These investigators 31 

### attributed their results to changes in bone res orption with decoupling of trabecular and 32



### cortical bone sites. 33



### Miranda et al. ( 2010 ) studied blood Pb level among pregnant women aged 18

- 44 years 34 

### old. The older age segments in the study presumably had greater historic Pb exposures 35 

### and associated stored Pb than the younger age segmen ts. Compared with the blood Pb 36 

### levels of a reference group in the 25

- 29 years old age category, pregnant women ≥ 37



### 30 years old had significant odds of having higher blood Pb levels (aged 30

- 34: OR = 38February 2012 4

- 71 Draft

– Do Not Cite or Quote 

### 2.39, p <0.001; aged 35

- 39: OR = 2.98, p <0.001; aged 40

- 4 4: OR = 7.69, p <0.001). 1 

### Similarly, younger women had less chance of having higher blood Pb levels compared 2 

### with the reference group (aged 18

- 19: OR = 0.60, p = 0.179; aged 20

- 24: OR = 0.54, p = 3 

### 0.015). These findings indicate that maternal blood Pb levels are more likely the result of 4 

### Pb mobilization of bone stores from historic exposures as opposed to contemporaneous 5



### exposures. 6



### Blood Pb levels increase during lactation due to alterations in the endogenous bone Pb 7 

### release rate. After adjusting for patella Pb concentration, an increase in blood Pb levels of 8 

### 12.7% (95% CI: 6.2, 19.6) was observed for women who practiced partial lactation and 9 

### an increase of 18.6% (95% CI: 7.1, 31.4) for women who practiced exclusive lactation 10 

### compared to those who stopped lact ation ( Tellez

- Rojo et al., 2002 )

. In another Mexico 11 

### City study, Ettinger et al. ( 2006 ; 2004b ) concluded that an interquartile increase in patella 12 

### Pb was associated with a 14% increase in breast milk Pb, whereas for tibia Pb the 13 

### increase was ~5%. Breast milk:maternal blood Pb concentration ratios are generally <0.1, 14 

### although values of 0.9 ha ve been reported ( Koyashiki et al., 2010 ; Ettinger et al., 2006 ; 15 

### Gulson et al., 1998b )

. Dietary intake of polyunsaturated fatty acids (PU FA) has been 16 

### shown to weaken the association between Pb levels in patella and breast milk, perhaps 17 

### indicating decreased transfer of Pb from bone to breast milk with PUFA consumption 18 

### ( Arora et al., 2008 )

. 19



### The Pb content in some bones ( i.e., mid femur and pelvic bone) plateau at midd le age and 20 

### then decreases at older ages ( Drasch et al., 1987 )

. This decrease is most pronounced in 21 

### females and may be due to osteoporosis and release of Pb from resorbed bone to blood 22 

### ( Gulson et al., 2002 )

. Two studies indicate that the endogenous release rate in 23 

### postmenopausal women ranges from 0.13

- 0.14 μg/dL in blood per μg/g bone and is 24 

### nearly double the rate found in premenopausal women (0.07

- 0.08 μg/dL per μg/g bone) 25 

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

. An analysis of data on blood lead 26



### concentrations and markers of bone formation (serum alkaline phosphatase) and 27 

### resorption (urinary cross

- linked N

- telopeptides, NTx) in a sample of U.S. found that 28 

### blood Pb concentrations were higher in women (pre

- or post

- menopausal) who exhibited 29 

### the highest bone formation or resorption ac tivities ( Jackson et al., 2010 )

. Calcium or 30 

### vitamin D supplementation decreased the blood lead concentrations in the highest bone 31 

### formation and resorption tertiles of the population of post

- menopausal women. 32 

### Significant associations between increasing NTx and increasing blood Pb levels 33 

### ( i.e., increased intercept of regression model relating the change in blood Pb per change 34 

### in bone Pb) has also been observed in elde rly males ( Nie et al., 2009 )

. 35



### Studies of the effect of hormone replacement therapy on bone Pb mobilization have 36 

### yielded conflicting results ( Popovic et al., 2005 ; Berkowitz et al., 2004 ; Garrido Latorre 37February 2012 4

- 72 Draft

– Do Not Cite or Quote 

### et al., 2003 ; Korrick et al., 2002 ; Webber et al., 1995 )

. In women with severe w eight loss 1 

### (28% of BMI in 6 months) sufficient to increase bone turnover, increased blood Pb levels 2 

### of approximately 2.1 μg/dL (250%) were reported, and these blood Pb increases were 3 

### associated with biomarkers of increased bone turnover ( e.g., urinary pyri dinoline cross

4 

### links) ( Riedt et al., 200 9 )

. 5



### 4.3.6 Relationship between Lead in Blood and Lead in Soft Tissues

Figure 4

- 12 shows simulations of blood and soft tissues Pb (including brain) for th e same 6 

### exposure scenarios previously displayed. Pb uptake and elimination in soft tissues is 7 

### much faster than bone. As a result, following cessation of a period of elevated exposure, 8 

### Pb in soft tissues is more quickly returned to blood. The terminal elimin ation phase from 9 

### soft tissue mimics that of blood, and it is similarly influenced by the contribution of bone 10 

### Pb returned to blood and being redistributed to soft tissue. 11February 2012 4

- 73 Draft

– Do Not Cite or Quote Note: Simulation based on ICRP Pb biokinetics model ( Leggett, 1993 )

. 

### Figure 4

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

Information on Pb levels in human brain are limited to autopsy data and the simulation of 1



### brain Pb shown in Figure 4

- 13 reflects general concepts derived from observations made 2



### in non

- human prima tes, dogs and rodents. These observations suggest that peak Pb levels 3



### in the brain are reached 6 months following a bolus exposure and within two months 4 

### approximately 80% of steady state brain Pb levels are reached ( Leggett, 19 93 )

. There is a 5 

### relatively slow elimination of Pb from brain (t 1/2 

### ≈ 2 years) compared to other soft tissues 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 TissueFebruary 2012 4

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### ( Leggett, 1993 )

. This slow elimination rate is reflected in the slower elimination phase 1



### kinetics in shown Figure 4

- 13 . Although in this model, brain Pb to blood Pb transfer half

2 

### times are assumed to be the same in children and adults, uptake kinetics are assume d to 3 

### be faster during infancy and childhood, which achieves a higher fraction of the soft tissue 4 

### burden in brain, consistent with higher brain/body mass relationships. The uptake half 5 

### times predicted by Leggett ( 1993 ) vary from 0.9 to 3.7 days, depending on age. Brain Pb 6 

### kinetics represented in the simulations are simple outcomes of modeling assumptions and 7 

### cannot currently be verified with available observations in humans. 8February 2012 4

- 75 Draft

– Do Not Cite or Quote Note: Simulation based on ICRP Pb biokin etics model ( Leggett, 1993 )

. 

### Figure 4

- 13 Simulation of blood and brain Pb in children and adults who experience a period of increased Pb intake.

Urinary filtering and excretion of Pb is associated with plasma Pb concentrations. Given 1 

### the curvilinear relationship between blood Pb and plasma Pb, a secondary expectation is 2 

### for a curvilinear relationship between blood Pb and urinary Pb excretion that may 3 

### become evident only at relat ively high blood Pb concentrations ( e.g., >25 μg/dL). Figure 4



### 4

- 14 shows these relationships predicted from the model. In this case, the exposure 5 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

BrainFebruary 2012 4

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### scenar io shown is for an adult (age 40 years) at a quasi

- steady state blood Pb 1 

### concentration; the same relationships hold for children. At lower blood Pb concentrations 2 

### (<25 μg/dL), urinary Pb excretion is predicted to closely parallel plasma Pb concentration 3



### fo r any given blood Pb level ( Figure 4

- 14 , top panel). It follows from this that, similar to 4 

### blood Pb, urinary Pb will respond much more rapidly to an ab rupt change in Pb exposure 5 

### than will bone Pb. One important implication of this relationship is that, as described 6 

### previously for blood Pb, the relationships between urinary Pb and bone Pb will diverge 7 

### with increasing exposure duration and age, even if exp osure remains constant. 8 

### Furthermore, following an abrupt cessation of exposure, urine Pb will quickly decrease 9 

### while bone Pb will remain elevated ( Figure 4

- 14 , lower panel). 10February 2012 4

- 77 Draft

– Do Not Cite or Quote Note: 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 )

. 

### Figure 4

- 14 Relationship between Pb in urine and Pb in blood. 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 BloodFebruary 2012 4

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## 4.4 Observational Studies of Lead Biomarker Levels

4.4.1 Lead in Blood

Overall, trends in blood Pb levels have been decreasing among U.S. residen ts over the 1 

### past 20 years. Blood Pb concentrations in the U.S. general population have been 2 

### monitored in the NHANES. Analyses of these data show a progressive downward trend 3 

### in blood Pb concentrations during the period 1976

- 2008, with the most dramatic dec lines 4 

### coincident with the phase out of leaded gasoline ( Pirkle et al., 1998 ; Brody et al., 1994 ; 5 

### Pirkle et al., 1994 ; Schwartz and Pitcher, 1989 )

. The temporal trend for the period 6


### 1988

- 2008 is shown in Figure 4

- 15 . Summary statistics from the most recent publically 7 

### available data (1999

- 2008) ar e presented in Table 4

- 7 ( CDC, 2011 )

. The geometric mean 8 

### Pb concentration among children 1

- 5 years of age, based on the sample colle cted during 9 

### the period 2007

- 2008, was 1.51 μg/dL (95% CI: 1.37, 1.66), which was a slight increase 10 

### from the previous year (1.46 μg/dL, 95% CI: 1.36, 1.57). Figure 4

- 16 uses NHANES data 11 

### to illustrate temporal trends in the distribution of blood Pb levels among U.S. children 12 

### aged 12

- 60 months. The median blood Pb in this age group was 1.4 μg/dL with a 95 th 13 

### percentile value of 4.1 μg/dL in 2007

- 2008 ( NCHS, 2010 )

. For 2005

- 2008, 95% of 14



### childhood blood Pb levels were less than 5 μg/dL. The geometric mean blood Pb 15 

### concentration among adults ≥ 20 years of age was 1.38 μg/dL (95% CI: 1.31, 1.46) for 16 

### the sample collected during the period 2007

- 2008 ( CDC, 2011 )

. Based on these same 17 

### data, the geometric mean for all males (aged ≥ 1 y) was 1.47 μg/dL (95% CI: 1.39, 1.56), 18



### an d for females (aged ≥ 1 y) was 1.11 μg/dL (95% CI: 1.06, 1.16). 19



### There has been a steep decline in mean blood Pb levels from 1975 through 2010 among 20



### all birth cohorts from 1975 to 2010; Figure 4

- 17 . For all cohorts, blood Pb generally 21 

### decreases with age during childhood until adolescence; following adolescence (in the 22 

### early 20s), blood Pb generally levels off or even increases with age. It is possible th at 23 

### bone growth in young people and occupational exposure for adults influences the shape 24 

### of these curves. For the 1960 to 1970 birth cohort, the mean blood Pb is the highest of the 25 

### cohorts in the 1970s, but beginning in 1993 the mean blood Pb is one of the lowest of the 26 

### cohorts. This interaction between time and cohort may be due to the faster release of Pb 27 

### from bone in younger people ( Rabinowitz, 1991 )

. This interaction is also apparent for 28 

### some of the other more recently born cohorts. In comparison, the slopes of blood Pb over 29 

### time are nearly parallel among the cohorts born before 1930. This suggests that t he time

30



### cohort

- interaction diminishes among older people. Also, the leveling of the blood Pb in 31 

### the 2000s could be due to aging of the birth cohort and consequent slowing of their Pb 32



### release from bone. 33February 2012 4

- 79 Draft

– Do Not Cite or Quote 

### When race/ethnicity groups were compared for years 199 9

- 2004, blood Pb levels in 1 

### children were highest in the ethnicity category non

- Hispanic black (GM 2.8, 95% CI: 2.5, 2 

### 3.0) compared to the categories Mexican

- American (GM 1.9, 95% CI: 1.7, 2.0) and 3



### non

- Hispanic white (GM 1.7, 95% CI: 1.6, 1.8) ( Jones et al., 2009a )

. Figure 4

- 18 4 

### demonstrates the change in percent of children (aged 1

- 5 years) with various blood Pb 5 

### levels by race/ethnicity between the survey during 1988

- 1991 and that during 1999

- 2004. 6 

### When these data for children aged 1

- 5 years were aggregated for all survey years from 7 

### 1988 to 2004, residence in older housing, poverty, age, and being non

- Hispanic black 8 

### were significant predi ctors of higher Pb levels ( Jones et al., 2009a )

. 9

Note: Shown are geometric means and 95% CIs based on data from NHANES III Phase 1 ( Brody et al., 1994 ; P irkle 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.


### Figure 4

- 15 Temporal trend in blood Pb concentration. 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 yrsFebruary 2012 4

- 80 Draft

– Do Not Cite or Quote 

### Table 4

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

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 8,945

2003

- 2004 1.43 1.36, 1.50 8,373

2005

- 2006 1.29 1.23, 1.36 8,407

2007

- 2008 1.27 1.21, 1.34 8,266

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 1,044

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 1,011

12

- 19 yr 1999

- 2000 1.10 1.04, 1.17 2,135

2001

- 2002 0.94 0.90, 0.99 2,231

2003

- 2004 0.95 0.88, 1.02 2,081

2005

- 2006 0.80 0.75, 0.85 1,996

2007

- 2008 0.80 0.74, 0.86 1,074

≥ 20 yr 1999

- 2000 1.75 1.68, 1.81 4,207

2001

- 2002 1.56 1.49, 1.62 4,772

2003

- 2004 1.52 1.45, 1.60 4,525

2005

- 2006 1.41 1.34, 1.48 4,509

2007

- 2008 1.38 1.31, 1.46 5,364

Males 1999

- 2000 2.01 1.93, 2.09 3,913

2001

- 2002 1.78 1.71, 1.86 4,339

2003

- 2004 1.69 1.62, 1.75 4,132

2005

- 2006 1.52 1.42, 1.62 4,092

2007

- 2008 1.47 1.39, 1.56 4,147

Females 1999

- 2000 1.37 1.32, 1.43 4,057

2001

- 2002 1.19 1.14, 1.25 4,606

2003

- 2004 1.22 1.14, 1.31 4,241

2005

- 2006 1.11 1.05, 1.17 4,315

2007

- 2008 1.11 1.06, 1.16 4,119

Mexican

- Americans 1999

- 2000 1.83 1.75, 1.91 2,742

2001

- 2002 1.46 1.34, 1.60 2,268

2003

- 2004 1.55 1.43, 1.69 2,085

2005

- 2006 1.29 1.21, 1.38 2,236

2007

- 2008 1.25 1.15, 1.36 1,712

Non

- Hispanic blacks 1999

- 2000 1.87 1.75, 2.00 1,842

2001

- 2002 1.65 1.52, 1.80 2,219

2003

- 2004 1.69 1.52, 1.89 2,293

2005

- 2006 1.39 1.26, 1.53 2,193

2007

- 2008 1.39 1.30, 1.48 1,746February 2012 4

- 81 Draft

– Do Not Cite or Quote Survey Stratum Period Geometric Mean (μg/dL) 95% Confidence Interval Number of Subjects

Non

- Hispanic whites 1999

- 2000 1.62 1.55, 1.69 2,716

2001

- 2002 1.43 1.37, 1.48 3,806

2003

- 2004 1.37 1.32, 1.43 3,478

2005

- 2006 1.28 1.19, 1.37 3,310

2007

- 2008 1.24 1.16, 1.33 3,461 Source: Adapted from data from the NHANES ( CDC, 2011 )

. Age strata correspond to the NHANES study design

.

Source: Adapted from data from the NHANES ( NCHS, 2010 )February 2012 4

- 82 Draft

– Do Not Cite or Quote Note: Top: all data. Bottom: data for subjects having blood Pb levels less than 15 μg/dL.


### Figure 4

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

- 5 years old) from the NHANES survey, 1988

- 2008.

Source: Adapted from data from the NHANES ( NCHS, 2010 ) Note: The means of logged blood Pb were weighted to represent national averages. Data were from the publically NHANES II, NHANES III for 1988

- 1991 and 1992

- 1994, and the continuous NHANES in 1999

- 2000, 2003

- 2004, 2005

- 2006, 2007

- 2008. Continuous NHANES data from 2001

- 2002 and 2009

- 2010 are not included because there were only 551 blood Pb samples in each of those data sets. The year plotted for exam year was the reported e xam year for NHANES II, the middle year of each of the phases of NHANES III, and the second year of each of the continuous NHANES.


### Figure 4

- 17 Blood Pb cohort means versus year of exam.February 2012 4

- 83 Draft

– Do Not Cite or Quote Source: D ata used with permission of the American Academy of Pediatrics, Jones et al. ( 2009a )


### Figure 4

- 18 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).

Several studies have shown seasonal variation in blood Pb concentrations in children 1


### [ e.g., ( Gulson et al., 2008 ; Laidlaw et al., 2005 ; Haley and Talbot, 2004 ; Johnson et al., 2



### 1996 ) ] . Seasonal variation in blood Pb concentration was evident in Australian children 3 

### (n=107) with a group mean blood Pb level of 2.57 μg/dL when repeated blood Pb 4



### measurements were made over a 5

- year period, with lower levels in summer compared 5 0 10 20 30 40 50 60 70

< 1 1

- < 2.5 2.5

- < 5 5

- < 7.5 7.5

- <10 ≥ 10Percent of Children 

### 1988

- 1991

0 10 20 30 40 50 60 70

< 1 1

- < 2.5 2.5

- < 5 5

- < 7.5 7.5

- <10 ≥ 10Percent of Children



### Blood Pb Level (ug/dL)

Non

- Hispanic black Mexican American Non

- Hispanic white 

### 1999

- 2004February 2012 4

- 84 Draft

– Do Not Cite or Quote 

### with winte r ( Gulson et al., 2008 )

. A cross

- sectional study conducted in New York State 1


### from 1995

- 1998 demonstrated seasonality, with the greatest percent of one and two year 2



### old children with blood Pb ≥ 1 0 μg/dL (n=262,687) occurring in August and the lowest 3 

### percent in March and April ( Haley and Talbot, 2004 )

. Meteorological factors appear to 4 

### contribute to blood Pb seasonality. Laidlaw et al. ( 2005 ) analyzed the temporal 5 

### relationships between chil d blood Pb concentrations and various atmospheric variables in 6 

### three cites (Indianapolis, IN: 1999

- 2002; Syracuse, NY: 1994

- 1998; New Orleans, LA: 7



### 1998

- 2003). Blood Pb data was obtained from public health screening programs 8



### conducted in the three cities. B lood Pb samples were dominated by children <5 years of 9 

### age and age distribution varied across the three cities. The number of blood Pb 10 

### measurements included in the analyses were as follows: Indianapolis, 15,969; Syracuse, 11 

### 14,457 ( Johnson and Bretsch, 2002 ; Johnson et al., 1996 ) ; New Orleans, 2,295 ( Mielke et 12 

### al., 2007a )

. The temporal variation in blood Pb concentrations in each city were predicted 13 

### by multivariate regression models that included the following significa nt variables: PM 10 

### , 14 

### wind speed, air temperature, and soil moisture; as well as dummy variables accounting 15 

### for temporal displacement of the effects of each independent variable on blood Pb. 16



### Laidlaw et al. ( 2005 ) reported R 2 

### values for the regression models, but did not report the 17



### actual r egression coefficients. The R 2 

### values were as follows: Indianapolis 0.87 (p = 18 

### 0.004); Syracuse 0.61 (p = 0.0012); New Orleans 0.59 (p <0.00001). 19



### Studies have examined the change in blood Pb with changes in potential Pb sources. 20



### Gulson et al. ( 2004b ) observed that children living near a Zn

- Pb smelter in Australia had 21 

### blood Pb levels ranging from 10 to 42 μg/dL, with 55

- 100% of Pb attributed to the 22



### smelter based on isoto pe ratio analysis. Rubio

- Andrade et al. ( 2011 ) followed a cohort of 23



### 6

- 8 y old children living within 3.5 km of a Mexican smelter at 0, 6, 12, and 60 months 24 

### after environmental intervention took place. Soil Pb was concurrently obtained but not 25 

### reported at 6, 12, or 60 months. Me dian blood Pb level at initiation of the study was 26



### 10.1 μg/dL for the 598 initial participants, and median soil Pb was 3,300 mg/kg at the 27 

### start of the study. After 60 months, median blood Pb level was 4.4 μg/dL for the 28 

### remaining 232 participants, and media n soil Pb concentration was 370 mg/kg at that time. 29



### Bonnard and McKone ( 2009 ) modeled blood Pb of French children ages 21

- 74 months 30 

### living within a village containing a Pb smelter and estimated blo od Pb levels of 31



### 3.2

- 10.9 μg/dL. It should be noted that these studies are suggestive but not conclusive in 32 

### showing that exposure to sources elevates blood Pb because these studies do not control 33



### for factors such as non

- ambient in

- home exposures. For this r eason, Newhook et al. 34 

### ( 2003 ) point out that they utilize World Health Organiza tion guidelines on fenceline 35 

### concentrations in lieu of blood Pb levels in the vicinity of industrial sources to quantify 36 

### exposures related to the sources. Lanphear et al. ( 1998 ) noted that the probability of 37 

### children having blood Pb ≥ 10 μg/dL increases both with exterior soil Pb content and 38 

### interior Pb dust loading. Mielke et al. ( 2011a ) noted signi ficant increases in percentages 39February 2012 4

- 85 Draft

– Do Not Cite or Quote 

### of children younger than 7 y old with blood Pb level ≥ 10 μg/dL for those living in inner 1 

### city New Orleans housing developments (22.9%) compared with children living in 2 

### communities located on the city outskirts (9.1%). At th e same time, median soil Pb was 3 

### significantly higher in the inner city (438 mg/kg) compared with the city outskirts 4 

### (117 mg/kg). 5



### For infants <1 year old, very little data are available on blood Pb levels. Simon et al. 6 

### ( 2007 ) followed a cohort of 13 children living near an Australian smelter from birth 7 

### through 36 months. In general, immediately after birth blood Pb levels f ell for 1

- 2 months 8 

### to approximately 47% of birth blood Pb level. After this initial fall, all infants' blood Pb 9 

### levels rose with age until approximately 12 months old ( Simon et al., 2007 )

. Median 10 

### blood Pb level among the children was 1.9 μg/dL at 2 months and increased to 11



### 13.6 μg/dL at 16 months. Geometric mean hand

- Pb loading of the child and the mother 12 

### were significant contributors to the area under the curve for infant blood Pb, with 46% 13 

### and 60% of the variance being explained by these variables, respectively; geometric 14 

### mean mothers' blood Pb explained 46% of the variance ( Simon et al., 2007 )

. Across all 15 

### the data, there was a good correlation between child blood Pb level and child hand Pb 16 

### loading (R 2 

### = 0.70). In another study, blood Pb levels of 15 infants aged 6

- 12 months 17 

### were compared with cord blood Pb levels, resulting in significantly lower blood Pb levels 18 

### later in life (2.24 μg/dL vs. 4.87 μg/dL) ( Carbone et al. , 1998 ) 19



### Pb body burden has been reported among individuals known to consume wild game 20 

### hunted with Pb shot. For example, fifty men from Nuuk, Greenland participated in a 21 

### study in which they recorded their diet and produced blood samples ( Johansen et al., 22



### 2006 )

. Men wh o regularly ate hunted game had an average blood Pb concentration of 23



### 12.8 μg/dL, in contrast with those who did not and had an average blood Pb 24



### concentration of 1.5 μg/dL. Umbilical cord blood was collected from a cohort of Inuit 25 

### newborns from northern Que bec, where the Inuit population consumes game killed with 26



### Pb shot ( Lévesque et al., 2003 )

. The geometric mean cord blood Pb level was 27



### 0.19 μmol/L, with a range of 0.01

- 1.31 μmol/L; the Canadian level of concern for cord 28



### blood Pb is 0.48 μmol/L. The authors cont r asted the finding that 7% of Inuit newborns 29


### had cord blood Pb concentration ≥ 0.48 μmol/L in contrast with 0.16% of the Caucasi an 30 

### population in southern Quebec. 31



### Recent studies have sought to characterize human exposure to Pb from piston

- engine 32



### aircraft emissions. Section 3.2.2.1 describes a study by Carr et al. ( 2011 ) in which Pb 33 

### concentrations, both modeled and monitored, extended beyond airport property. Miranda 34



### et al. ( 2011 ) used GIS to study the association between blood Pb level and distance from 35 

### airports in six North Carolina Counties. They observed that the trend in blood Pb level 36 

### decreases monotonically with distance class from the airports, with subjects within 500 m 37February 2012 4

- 86 Draft

– Do Not Cite or Quote 

### of the airports having significantly increased blood Pb levels with residential proximity to 1 

### airports (β = 0.043, 95% CI (0.006,0.080), p < 0.05) compared with the general 2 

### population for a given county after controlling for proportion of black, Hispanic, perc ent 3 

### receiving public assistance, and household median income at the census block group 4 

### level and including dummy variables for season during which the children were screened 5



### for blood Pb. 6



### Trends in blood Pb levels have been accompanied by changes in Pb iso tope ratios for 7 

### blood Pb. Isotopic ratios, described in Sections 3.2 and 3.3 as a tool for source 8 

### apportionment, have been used to associate blood Pb measurements with anthropogenic 9 

### sources of Pb in the environment. Changes in Pb isotopic ratios in blood samples reflect 10 

### the changing influence of sources of Pb following the phase

- out of tetraethyl Pb 11 

### antiknock agents in automotive gasoline and changes in Pb usage in paints and other 12 

### industrial and consumer products ( Gulson et al., 2008 ; Ranft et al., 2008 ; Gulson et al., 13



### 2006a ; Ranft et al., 2006 )

. Gulson et al. ( 2006a ) illustrated how a linear increase in the 14 

### isotopic ratio 206 

### Pb/ 204 

### Pb occurred in concert with a decrease in blood Pb levels among 15 

### selected study populations in Australia during the period 1990

- 2000 ( Figure 4

- 19 ). 16



### Gulson et al. ( 2006a ) point out that the isotopic signature of 206 

### Pb/ 204 

### Pb derived from 17 

### Australian mines (median ~16.8) differs from that of European and Asian mines, where 18

206 

### Pb/ 204 

### Pb varies between ~17.4 and ~18.1. Liang et al. ( 201 0 ) also examined the trends 19 

### in blood Pb level over the period 1990 to 2006 in Shanghai and saw a reduction 20 

### corresponding to the phase out of Pb in gasoline. A plot of 208 

### Pb/ 206 

### Pb to 207 

### Pb/ 206 

### Pb for 21 

### blood and environmental samples showed overlap between the isotopic signature for coal 22 

### combustion ash and that measured in blood. This result suggests a growing influence of 23 

### Pb from coal ash in Shanghai in the absence of Pb in automobile emissions. Oulhote et al. 24 

### ( 2011 ) examined Pb isotope ratios in blood Pb samples of 125 French children aged 6 m

25 

### 6 y. The study found that Pb isotope ratios could be used to attribute Pb exposure to o ne 26 

### source for 32% of children and to eliminate an unlikely source of Pb exposure in 30% of 27



### children. 28February 2012 4

- 87 Draft

– Do Not Cite or Quote Source: Reprinted with permission of Academic Press, Gulson et al. ( 2006a )


### Figure 4

- 19 Trends in 206 

### Pb/ 204 

### Pb isotope ratio in blood Pb (a) and trends in blood Pb levels (b) 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 concentrations 1 

### in children and adults, as described in Section 4.4.1 . Bone Pb concentrations are less well 2



### characterized. Table 4

- 8 and Table 4

- 9 are compilations of dat a from epidemiologic 3 

### studies that provided bone Pb concentrations by K

- XRF and/or variability in 4 

### concentrations among individuals without reported occupational exposure and those with 5 

### occupational exposures, respectively. In non

- occupationally exposed indi viduals, typical 6 

### group mean tibia bone Pb concentrations ranged from 10 to 30 μg/g. Patella bone Pb 7 

### levels are typically higher than tibia bone Pb levels in the studies considered ( Table 4

- 8 ). 8 

### For example, in the Normative Aging Study, patella bone Pb concentrations were 9 

### approximately 32 μg/g, whereas tibia bone Pb concentrations were about 22 μg/g. 10 

### Occupationally exposed individuals generally had great er bone Pb concentrations than 11 

### seen in control groups ( i.e., unexposed). Bone Pb data in Table 4

- 9 for occupationally 12 

### exposed individuals were also generally higher compared to non

- occupationally exposed 13 

### individuals ( Table 4

- 8 ). 14February 2012 4

- 88 Draft

– Do Not Cite or Quote 

### Table 4

- 8 Epidemiologic studies that provide bone Pb measurements for non

occupationally exposed populations

Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Bandeen

Roche et al. ( 2009 ) Cohort: Baltimore Memory Study cohort Age (yrs): 50

- 70 N: 1140 Location: Baltimore, MD Study Period :2001

- 2005 Cumulative Tibia Mean±SD Tibia: 18.8 ± 11.6 Not reported

Bellinger et al. ( 1994a ) Cohort: No t reported Age (yrs): 5

- 8 (recruited); 19

- 20 (follow

- up)
N: 79 Location: Boston, MA Study Period: 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 ) Cohort: Normative Aging Study cohort Age (yrs): Mean± SD:

Normotensive: 65.49 ± 7.17 Borderline hypertension: 68.3 ± 7.79 Definite hypertension: 67.93 ± 6.79 N: 833 males Location: Boston, MA Study Period: 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 B orderline 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 ) Cohort: Part icipants from Henry Ford Health System (HFHS) Age (yrs): ≥ 50; Mean: 69.9
N: 121 cases; 414 controls Location: Southeastern Michigan Study Period: 1995

- 1999 (participants

received primary health care services) Cumulative Tibia Calcaneus 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 Elmarsafawy et al. ( 2006 ) Cohort: Normative Aging Study Age (yrs): Not reported
N: 471 elderly males Location: Greater Boston area, MA Study Period: 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 ) Cohort: Baltimore Memory Study Age (yrs): Mean: 59.4; Range: 50

- 70 N: 1,001 Location: Baltimore, MD Study Period: 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 ± 11.4 Hsieh et al. ( 2009b ) Cohort: Not reported Age (yrs): Mean: Control: 46.06
N: 18 controls Lo cation: Not reported Study Period: 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. ( 1996b ) [As reported in Navas

- Acien et al., ( 2008 ) ] Cohort: Normative Aging Study Age (yrs): 48

- 92; Mean ± SD: 66.6 ± 7.2
N: 590 males Location: Boston, MA Study Period: 8/1991

- 12/1994 Cumul ative 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 ageFebruary 2012 4

- 89 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Jain et al. ( 2007 ) Cohort: VA

- Normative Aging Study Age (yrs): Not reported
N: 837 males Location: Greater Boston, MA Study Period: 9/1/1991

- 12/31/2001 Not reported Tibia Patella Mean ± SD Tibia: Non

- Cases: 21.4 ± 13.6 Cases: 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 ) Cohort: Not reported Age (yrs): 30

- 80 N: 256 controls (Bone samples collected from

41 controls) Location: New England (Boston, MA) Study Period: 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. ( 2009b ) Cohort: 1982 Pb Occupational Study Age (yrs): Control mean: 55
N: 51 controls Location: Eastern Pennsylvania Study Period: 1982

- 2004 Control group for occupational exposure group Tibia Median (IQR) Tibia Control: 12 (

- 8

- 32) Not reported

Korrick et al. ( 1999 ) (As reported in from Navas

- Acien et al., ( 2008 ) Cohort: Nurses’ Health Study Age (yrs): Combined: 47

- 74; Mean± SD:

Combined: 58.7 ± 7.2; Cases: 61.1 ± 7.1; High control s: 61.1 ± 7.2; Low controls: 58.7 ± 7.1 N: 284 females; (89 cases; 195 controls) Location: Boston, MA Study Period: 7/1993

- 7/1995 Nonoccupationally 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 Tibia Combined:

- 5

- 69 Patella Combined:

- 5

- 87 Patella: 10th percentile: 6 90th percentile: 31

Lee et al. ( 2001a ) [As reported in Navas

- Acien et al., ( 2008 ) ] Cohort: Not reported Age (yrs): 22.0

- 60.2 Mean ± SD: Controls:

34.5 ± 9.1 N: 135 controls Location: South Korea Study Period: 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 reportedFebruary 2012 4

- 90 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Martin et al. ( 2006 ) Cohort: Baltimore Memory Study Age (yrs): 50

- 70; Mean: 59.4
N: 964 Location: Baltimore, MD Study Period: 5/2001

- 9/2002 (1st study visit) 8/2002

- 3/2004 (2nd 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 ) Cohort: Not reported Age (yrs): 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
N: 194 male youth cases; 146 male youth

controls Location: Allegheny County, PA (cases);

Pittsburgh, PA (controls) Study Period: 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 of paper distributes bone P b by ≥ 25 or <25 for race, two parental figures, and parent occupation

Osterberg et al. ( 1997 ) [As reported in Shih et al., ( 2007 ) ] Cohort: Not reported Age (yrs): Median: 41.5
N: 19 male controls Location: Not reported Study Period: Not reported Control group for occupational exposure group Finger bone Median (range) Finger Bone Controls: 4 (

- 19

- 18) Not reported

Park et al. ( 2006 ) Cohort: Normative Aging Study Age (yrs): Mean: 72.9 ± 6.5
N: 413 males Location: Greater Boston, MA Study Period: 11/14/2000

- 12/22/2 004; (HRV

measurements taken); 1991

- 2002 (bone Pb measurements taken) Not reported Tibia Patella Median (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. ( 2009b ) Cohort: Normative Aging Study Age (yrs): Mean: 67.3 ± 7.2
N: 613 males Location: Greater Boston, MA Study Period: 8/1991

- 12/1995 Not reported Tibia Patella Median (IQR)

Tibia: 19 (14

- 27) Patella: 26 (18

- 37) Table 1 of p aper distributes tibia and patella Pb by genotype; Table 2 of paper distributes tibia and patella Pb by number of gene variants Park et al. ( 2010 ) Cohort: VA Normative Agi ng Study cohort Age (yrs): Mean: 64.9 (at bone

Pb measurement)
N: 448 males Location: Eastern Massachusetts Study Period: 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 of paper provides age

adjusted mean bone Pb levels (age, race, education, smoking [pack

- yr], occupational noise, noise notch, BMI, hypertension, diabetes) Payton et al. ( 1998 ) Cohort: VA Normative Aging Study cohort Age (yrs): Mean: 66.8
N: 141 males Location: Boston, MA Study Period: 4/1993

- 3/1994 Not reported Tibia Patella Mean ± SD Tibia: 22.5 ± 12.2 Patella: 31.7 ± 19.2 Not reportedFebruary 2012 4

- 91 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Peters et al. ( 2007 ) Cohort: Normative Aging Study cohort Age (yrs): Mean: 66.9
N: 513 male cases Location: Boston, MA Study Period: 1991

- 1996 Cumulative Tibia Patella Mean ± SD Tibia: 21.5 ± 13.4 Patella: 31.5 ± 19.3 Not reported

Rajan et al. ( 2007 ) Cohort: VA Normative Aging Study Cohort Age (yrs): Mean: 67.5 (at bone scan)
N: 1075 males Location: Boston, MA Study Period: 1991

- 2002 Not reported Tibia Patella Mean ± SD Tibia: 22.1 ± 13.8 Patella: 31.4 ± 19.6 Not reported

Rajan et al. ( 2008 ) Cohort: VA Normative A ging Study Cohort Age (yrs): ≥ 45
N: 720 males Location: Boston, MA Study Period: 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 ) Cohort: VA Normative Aging Study Cohort Age (yrs): Mean: 67.1
N : 526 males Location: Boston, MA Study Period: 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 ) Cohort: Not reported Age (yrs): 30

- 60 N: 68 males Location: Belgium Study Period: Not reported 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. ( 2002b )

, as reported in Navas

- Acien et al. ( 2008 ) Cohort: Not reported Age (yrs): 15

- 44; Mean ± SD: 31.0 ± 7.7 N: 720 females Location: Los Angeles, CA Study Period: 6/1995

- 5/2001 Not reported Tibia Calcaneus 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 ) Cohort: Baltimore Memory Study cohort Age (yrs): Mean: 59.39
N: 985 Location: Baltimore, MD Study Period: Not reported Not reported Tibia Mean ± SD: Tibia: 18.7 ± 11.2 Not reportedFebruary 2012 4

- 92 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Stokes et al. ( 1998 )

, as reported in Shih et al. ( 2007 ) Cohort: Not reported Age (yrs): 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)
N: 257 cases; 276 controls Location: Silver Valley, ID; Spokane, WA Study Period: 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 μg/g: 31.5% 1

- 5 μg/g: 24.4% 5

- 10 μg/g: 2 2.3% >10 μg/g: 21.8%

No. of Controls: <1 μg/g: 50.4% 1

- 5 μg/g: 25.6% 5

- 10 μg/g: 19.4% >10 μg/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 Wijngaarden et al. ( 2009 ) Cohort: Not reported Age (yrs): Mean: 61.5
N: 47 Location: Rochester, NY Study Period: Not reported Cumulative Tibia Calcaneus Mean ± SD Tibia: 2.0 ± 5.2 Calcaneus: 6.1 ± 8.5 Not reported

Wasserman et al. ( 2003 ) Cohort: Yugoslavia Prospective Study of Environmental Pb Exposure Age (yrs): 1 0

- 12 N: 167 children Location: Kosovska, Mitrovica, Kosovo

,

Yugoslavia; Pristina, Kosovo, Yugoslavia Study Period: 5/1985

- 12/1986

(mother’s enroll ment); 1986

- 199 9 (follow

- up through age 12 yr); Tibia Pb measured 11

- 13 yr old Cumulative (lifetime) Environmental (Pb smelter, refinery, battery plant) Tibia Mea n ± 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 of paper distributes tibia Pb by sex, ethnicity, address at birth relative to factory, and maternal education Weisskopf et al. ( 2004 )

, as reported in Shih et al. ( 2007 ) Cohort: Normative Aging Study Age (yrs): Mean ± SD: 67.4 ± 6.6
N: 466 males Location: Boston, MA Study Period: 1991

- 2002 Environmental Tibia Patella Median (IQR) Tibia: 19 (12,26) Patella: 23 (15, 35) Tibia IQR: 14 Patella IQR: 20

Table 3 of paper

s hows mean Pb levels across cate gor

ical variables (yr of education, smoking status, computer exper ience, first language English) Weisskopf et al. ( 2007b ) Cohort: VA Normative Aging Study cohort Age (yrs): Mean:

Lowest Patella quintile: 73.2; Highest Patella quintile: 80.7
N: 31 males Location: Boston, MA Study Period : 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. ( 2007a ) Cohort: VA Normative Aging Study cohort Age (yrs): Mean: 68.7
N: 1,089 males Location: Boston, MA Study Period: 1993

- 2001 Concurrent and cumulative Tibia Patella Median (IQR) Tibia: 20 (13

- 28) Patella: 25 (17

- 37) Table 1 of paper shows distrib ution of Pb biomarkers by categories of covar

iates (age, education,

smo king status, alco

- hol intake, physical activity, compu ter experience, first language English)February 2012 4

- 93 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Conc. (μg/g) Distribution of Bone Pb (μg/g) Weisskopf et al. ( 2009 ) Cohort: Normative Aging Study ; (95% white) Age (yrs): Mean ± SD (at Pat ella baseline);

Tertile 1: 65.2 ± 7.1; Tertile 2: 66.5 ± 6.5 Tertile 3: 70.2 ± 7.2
N: 868 males Location: Greater Boston area, MA Study Period: 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 ) Cohort: BUMC, BWH, BIDMC, HVMA, Normative Aging Study (NAS), Harvard Cooperativ e Program on Aging (HCPOA) Age (yrs): Mean:

Cases: 66.5; Controls: 69.4
N: 330 cases; 308 controls Location: Boston, MA Study Period: 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: >20.9

Weuve et al. ( 2006 ) Cohort: VA Normative Aging Study cohort Age (yrs): ≥ 45
N: 720 males Location: Boston, MA Study Period: 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 of paper shows distri bution of mean Pb bio marker levels by characteristics of pa rticipants (age, education, computer exper ience, smoking status, alcohol consumption, tertile of cal cium intake, tertile of physical activity, diabetes) Weuve et al. ( 2009 ) Cohort: Nurses’ Health Study cohort Age (yrs): 47

- 74 N: 587 females Location: Boston, MA Study Period: 1995

- 2005 Recent and cumulative Tibia Patella Mean ± SD: Tibia: 10.5 ± 9.7 Patella: 12.6 ± 11.6 Not reported

Wright et al. ( 2003b )

, as reported in Shih et al. ( 2007 ) Cohort: Normative Aging Study Age (yrs): Mean ± SD: 68.2 ± 6.9
N: 736 males Location: Boston, MA Study Period: 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: 47February 2012 4

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– Do Not Cite or Quote 

### Table 4

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

Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration (μg/g) Distribution of Bone Pb (μg/g)

Bleecker et al. ( 1997 )

, as reported in Shih et al. ( 2007 ) Cohort: Canada Lead Study Age (yrs): 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
N: 80 males Location: Canada Study Period: Not Reported Occupational (Pb smelter workers) Tibia Mean ± SD (Tibia): Cumulative: 41.0 ± 24.44 Younger: 35 ± 24.11 Older: 46.9 ± 23.59

Range (Tibia): Cumulative:

- 12

- 90 Younger:

- 12

- 80 Older: 3

- 90 Not reported

Bleecker et al. ( 2007a ) Cohort: Not reported Age (yrs): Mean: 39.7 N: 61 Location: Northern Canada Study Period: Not Reported Occupational (primary Pb smelter workers) Tibia Mean: Tibia: 38.6 Not reported

Caffo et al. ( 2008 ) Cohort: Not reported Age (yrs): Mean: 60.39 N: 513 males Location: Delaware and New Jersey, U.S. Study Period: 1994

- 1997

(Phase 1 recruitment) ; 2001

- 2003 (Phase 2 recruitment) Cumulative Occupational (Former organolead manufacturing workers) Tibia Mean ± SD: Peak Tibia: 23.99 ± 18.46 Not reported

Dorsey et al. ( 2006 ) Coho rt: Not reported Age (yrs): Mean: 43.4 N: 652 Location: Korea Study Period: 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 ) Cohort: Not reported Age (yrs): 40

- 70; Mean: 55.8 (baseline) N: 496 males Location: Eastern U.S. Study Period: 6/1994

- 6/1996 (enrolled);

6/1998 (follow

- up period ended) Occupational (Chemical manufacturing 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 ) Cohort: Not reported Age (yrs): 0

- 36.2 (baseline);

Mean ± SD: 41.4 ± 9.5 (baseline) N: 575; (76% male; 24% female) Location: South Korea Study Period: 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 reported

Hanninen et al. ( 1998 )

, as reported in Shih et al. ( 2007 ) Cohort: Not reported Age (yrs): Mean±SD:

Male: 43; Female: 48 BPb (max) ≤ 2.4 μmol/L: 41.7 ± 9.3 BPb (max) >2.4 μmol/L: 46.6 ± 6.2 N: 54; (43 males, 11 females) Location: Helsinki, Finland Study Period: Not reported Occupational (Pb acid battery factory workers) Tibia Calcaneus Mean±SD:

Tibia: BPb (max) ≤ 2.4 μmol/L: 19.8 ± 13.7 BPb (max) >2.4 μmol/L: 35.3 ± 16.6

Calcaneus: BPb (max) ≤ 2.4 μmol/L: 78.6 ± 62.4 BPb (max) >2.4 μmol/L: 100.4 ± 43.1 Not reportedFebruary 2012 4

- 95 Draft

– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration (μg/g) Distribution of Bone Pb (μg/g)

Hsieh et al. 2009 ( 2009b ) Cohort: Not reported Age (yrs): Mean:

Cases: 45.71 Controls: 46.06 N: 22 cases; 18 controls Location: Not Reported Study Period: 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 ) Cohort: Not reported Age (yrs): 30

- 80 N: 109 cases; 256 controls;

(Bone samples collected from 104 cases and 41 controls) Location: New England (Boston, MA) Study Period: 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. ( 2009b ) Cohort: 1982 Pb Occupational Study cohort Age (yrs): Mean:

Cases: 54 Controls: 55 N: 83 cases; 51 controls Location: Eastern Pennsylvania Study Period: 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 ) Cohort: Not reported Age (yrs): Median: 41.5 N: 38 male cases; 19 male controls Location : Not reported Study Period: 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 reported

Roels et al. ( 1994 ) Cohort: Not reported Age (yrs): 30

- 60 N : 76 male cases; 68 male controls Location: Belgium Study Period: 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 reportedFebruary 2012 4

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– Do Not Cite or Quote Reference Study Methods Prior Pb Exposure Bone Pb biomarker Bone Pb Concentration (μg/g) Distribution of Bone Pb (μg/g)
Schwartz ( 2000c ) et al., as reported in Shih et al., ( 2007 ) Cohort: U.S. Organolead Study Age (yrs): Mean ± SD:

Cases: 55.6 ± 7 .4 Controls: 58.6 ± 7.0 N: 535 male cases

118 male controls Location: Eastern U.S. Study Period: 6/ 1994

- 10/1997 (enrolled);

Comple ted 2

- 4 annual follow

- up visits; Tibia Pb taken in 3rd year Occupational (tetraethyl and tetramethyl Pb manufacturing facility) Tibia Mean ± SD Current Tibia: Cases: 14.4 ± 9.3

Peak Tibia: Cases: 22.6 ± 16.5 Not reported

Schwartz et al. ( 2000b )

, as reported in Navas

- Acien et al. ( 2008 ) Cohort: Not reported Age (yrs): 41.7

- 73.7 (Combined)

Mean ± SD: Combined: 57.6 ± 7.6 Hypertensive: 60.2 ± 6.9 Nonhypertensive: 56.6 ± 7.5 N: 543 males Location: Eastern U.S. Study Period: 1995 (recruited);

1996

- 1997 (Tibia Pb taken during the 3rd yr) Occupational (former organolead manufacturing 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. ( 2001a ) Cohort: Not reported Age (yrs): Mean:

Exposed: 40.4 Control: 34.5 N: 803 cases; 135 controls Location: South Korea Study Period: 10/24/1997

- 8/19/1999 Occupational (battery manufacturing, secondary smelting, Pb oxide manufacturing, car radiator manufacturing) Tibia Mean ± SD Tibia Cases: 37.1 ± 40.3 Control: 5.8 ± 7.0 Range: Tibia Cases:

- 7

- 338 Controls:

- 11

- 27 Not reported

Schwartz et al. ( 2005 ) Cohort: Not reported Age (yrs): Mean at 1st visit: 41.4 N: 576 Location: South Korea Study Period: 10/1997

- 6/2001 Occupational (current and former Pb workers) Tibia Mean ± SD Tibia: 38.4 ± 43 Tibia: 25th percentile at V1: 14.4 75th percentile at V1: 47.1
Stewart et al. ( 1999 )

, as reported in Shih et al., ( 2007 ) Cohort: U.S. Organolead Study Age (yrs): 40

- 70 (in 1995)

38% ≥ 60 yrs Mean: 58 N: 534 males Location: Eastern U.S. Study Period: Not Reported Occupational (tetraethyl and tetramethyl Pb manufacturing 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) 10

- 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 ) Cohort: Not reported Age (yrs): Mean: 56.1 N: 532 males Location: Eastern U.S. Study Period: 1994

- 1997; 2001

- 2003 Cumulative Occupational (Organolead workers

- not occupationally 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 ) Cohort: Not reported Age (y rs): Mean ± SD: 43.3 ± 9.8 N: 652 Location: South Korea Study Period: 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 UrineFebruary 2012 4

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– Do Not Cite or Quote 

### Urine Pb concentrations in the U.S. general population have been monitored in the 1 

### NHANES. Data from the most recent survey ( CDC, 2011 ) are shown in Table 4

- 10 . The 2 

### geometric mean for the entire sample for the period 2007

- 2008 (n = 2,627) was 0.52 μ g/g 3 

### creatinine (95% CI: 0.48, 0.55). The geometric means for males (n = 1,327) and females 4 

### (n = 1,300) were 0.50 μ g/g creatinine (95% CI: 0.47, 0.53) and 0.53 μ g/g creatinine (95% 5 

### CI: 0.49, 0.57), respectively. 6



### Table 4

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

Survey Stratum Period Geometric Mean (μg/g CR) a 95% Confidence Interval Number of Subjects

All 1999

- 2000 0.721 0.700, 0.742 2,465

2001

- 2002 0.639 0.603, 0.677 2,689

2003

- 2004 0.632 0.603, 0.662 2,558

2005

- 2006 0.546 0.502, 0.573 2,576

2007

- 2008 0.515 0.483, 0.549 2,627

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 1,406

2001

- 2002 0.658 0.617, 0.703 1,559

2003

- 2004 0.641 0.606, 0.679 1,543

2005

- 2006 0.573 0.548, 0.600 1,520

2007

- 2008 0.546 0.513, 0.580 1,857

Males 1999

- 2000 0.720 0.679, 0.763 1,227

2001

- 2002 0.639 0.607, 0.673 1,334

2003

- 2004 0.615 0.588, 0.644 1,281

2005

- 2006 0.551 0.522, 0.582 1,271

2007

- 2008 0.502 0.471, 0.534 1,327

Females 1999

- 2000 0.722 0.681, 0.765 1,238

2001

- 2002 0.639 0.594, 0.688 1,355

2003

- 2004 0.648 0.601, 0.698 1,277

2005

- 2006 0.541 0.507, 0.577 1,305

2007

- 2008 0.527 0.489, 0.568 1,300

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 723February 2012 4

- 98 Draft

– Do Not Cite or Quote Survey Stratum Period Geometric Mean (μg/g CR) a 95% Confidence Interval Number of Subjects

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 1,132

2003

- 2004 0.623 0.592, 0.655 1,074

2005

- 2006 0.541 0.500, 0.585 1,041

2007

- 2008 0.506 0.466, 0.550 1,095

a Values are μg Pb/g creatinine (CR)

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 )

. 1 

### Tooth enamel samples from 127 subjects born between 1936 and 1993 were analyzed for 2 

### Pb concentration and Pb isotope ratios of the tooth enamel and compared with those 3 

### parameters f or sediment cores and estimates of Pb emissions from gasoline during the 4 

### years when 50% enamel formation was estimated to occur. They found that the log

5 

### transform of tooth enamel concentration was significantly predicted by the log

- transform 6



### of Lake Erie s ediment core data obtained by Graney et al. ( 1995 ) (p <0.00001) and by the 7 

### log

- tra nsform of U.S. consumption of Pb in gasoline (p <0.00001); Figure 4

- 20

. 8 

### Additionally, Robbins et al. ( 2010 ) found that 207 

### Pb/ 206 

### Pb was significantly predicted by 9



### the 207 

### Pb/ 206 

### Pb observed in the Lake Erie sediment cores obtained by Graney et al. ( 1995 ) 10 

### (p <0.0001) and for this study (p <0.0002). 11February 2012 4

- 99 Draft

– Do Not Cite or Quote Source: Reprinted with permission of Elsevier Publishing, Robbins et al. ( 2010 )

. Note: (solid line) with newly obtained Pb sediment Lake Erie cores (open triangles), previous ly 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.


### Figure 4

- 20 Comparison of relative temporal changes in tooth enamel Pb concentration.

Several Brazillian studies have found increased levels of Pb in teeth in areas where Pb 1 

### sources are present. For example, Costa de Almeida et al. ( 2007 ) reported Pb 2 

### concentration in tooth enamel among 4

- 6 y old kindergarteners in São Paulo, Brazil to be 3 

### significantly higher f or children living near a Pb

- acid battery processing plant in the 4 

### Baruru neighborhood compared with 4

- 6 y old children in other parts of the city 5 

### ( non

- exposed median: 206 mg/kg, n = 247; exposed median: 786 mg/kg, n = 26; p < 6 

### 0.0001). Subsequent analysis r evealed that 55% of 4

- 6 y old children from Baruru had 7 

### tooth enamel Pb concentrations greater than 600 mg/kg, forming a significant comparison 8 

### with other neighborhoods having 0

- 33% of 4

- 6 y old children with tooth enamel Pb 9 

### greater than 600 mg/kg (p < 0.00 01) ( de Almeida et al., 2008 )

. The authors did not 10 

### describe controlling for additional factors , such as socioeconomics or housing conditions. 11



### Arruda

- Neto et al. ( 2009 ) studied Pb in tooth samples among São Paulo children to 12 

### compare exposures of children age 4

- 12 livi ng near a dam with heavy metal sediments 13 

### with those of children ages 4

- 13 living in a control area thought to have few exposures. 14 

### They observed a significant comparison (near dam: avg 1.28 ± 0.11 mg/kg, n = 50; 15 

### control region: avg 0.91 mg/kg, n = 24). In a related study of Pb measures in teeth among 16 

### the general population ages 7

- 60 y, Arruda

- Neto et al. ( 2009 ) observed peak Pb 17 

### concentrations of 115% of age 7 y concentrations at age 10 y followed by a steep drop to 18 

### 50% among 20 y old subjects. Tooth Pb concentrations stayed fairly constant throughout 19 

### adulthood but then dropped to just above 30% among 65 y old subjects. Note that the 20February 2012 4

- 100 Draft

– Do Not Cite or Quote 

### authors did not clarify if average or median values were presented, nor did they adjust for 1 

### potentially confounding factors. 2



## 4.5 Empirical Models of Lead Exposure

- Blood Lead Relationships

Multivariate regression models, commonly used in epidemiology, provide estimates of 3



### the contribution of variance in t he internal dose metric to various determinants or control 4 

### variables ( e.g., air Pb concentration, surface dust Pb concentration). Structural equation 5 

### modeling links several regression models together to estimate the influence of 6



### determinants on the interna l dose metric. Regression models can provide estimates of the 7 

### rate of change of blood or bone Pb concentration in response to an incremental change in 8 

### exposure level ( i.e., slope factor). One strength of regression models is that they are 9 

### empirically verif ied within the domain of observation and have quantitative estimates of 10 

### uncertainty imbedded in the model structure. However, regression models are based on 11 

### (and require) paired predictor

- outcome data, and, therefore, the resulting predictions are 12



### confined to the domain of observations and are typically not generalizable to other 13 

### populations. Regression models also frequently exclude numerous parameters that are 14 

### known to influence human Pb exposures ( e.g., soil and dust ingestion rates) and the 15 

### relationship between human exposure and tissue Pb levels, parameters which are 16 

### expected to vary spatially and temporally. Thus, extrapolation of regression models to 17 

### other spatial or temporal contexts, which is often necessary for regulatory applications of 18



### the models , can be problematic. 19



### 4.5.1 Air Lead

- Blood Lead Relationships

The 1986 Pb AQCD ( U.S. EPA, 1986a ) described epidemiological studies of 20 

### relationships between air Pb and blood Pb. Of the studies examined, the total blood Pb

- air 21 

### Pb slope (when considering both direct and indirect exposures derived from air) was 22 

### estimated to be approximately double the slope estimated from the direct contribution due 23



### to inhaled air alone ( U.S. EPA, 1986a )

. Much of the pertinent earlier litera ture ( e.g., prior 24 

### to 1984) was summarized by Brunekreef ( 1984 )

. Based on the studies available at that 25 

### time that considered multiple air

- related Pb exposure pathways in the aggregate, the 1986 26 

### Pb AQCD concluded that “the blood Pb versus air Pb slope β is much smaller at high 27



### blood and air levels.” This is to say that the slope β was much smaller for occupational 28 

### exposures where high blood Pb levels (>40 μg/dL) and high air Pb levels (much greater 29



### than 10 μg/m 3 

### ) prevailed relative to lower environmental exposures which showed lower 30



### b lood Pb and air Pb concentrations (<30 μg/dL and <3 μg/m 3 

### ). For those environmental 31 

### exposures, it was concluded that the relationship between blood Pb and air Pb “ for direct 32February 2012 4- 101 Draft
– Do Not Cite or Quote 

### inhalation appears to be approximately linear in the range of normal ambient exposures 1 

### (0.1-2.0 μg/m 3 

### )” (pp 1–98 of the 1986 Pb AQCD). Based on meta- analysis of 18 studies of 2



### urban or industrial -urban populations, Brunekreef ( 1984 ) estimated the blood Pb-air Pb slope 3 

### for children to be 0.3485 ln[μg/dL blood Pb] per ln[μg/m 3 

### air Pb] (R 2 

### = 0.69; Figure 4-21). 4 

### This slope corresponds to an increase of 4.6 μg/dL blood Pb per μg/m 3 

### air Pb at an air Pb 5



### concentration of 1.5 μg/m 3 

### for all groups included in the study ( n= 96). The 1.5 μg/m 3 

### value 6


### is the median of the air Pb concentrations that match the 96 blood Pb concentrations in 7 

### Figure 3 of Brunekreef et al. (1984), taken from the Appendix to the same paper . When the 8 

### analysis was limited to children whose blood Pb concentrations were <20 μg/dL, the slope 9 

### was 0.2159 (R 2 

### =0.33), which corresponds to an increase of 4.8 μg/dL blood Pb per μg/m 3 

### air 10 

### Pb at the median air concentration (0.54 μg/m 3 

### , n=43)

Newer stu dies that provide estimates for the blood Pb- air Pb slope are described below . In 12 

### some studies, the blood Pb-air Pb relationship was described with a non

- linear regression 13 

### function, in which the blood Pb-air Pb slope varied with air Pb concentration. In Table 4-11, 14 

### slopes corresponding to the central estimate of the air Pb concentrations are provided, which 15 

### are considered to be the best estimate of the slope from each study. These were calculated by 16 

### evaluating each regression function at ± 0.01 μg/m . 11

3 

### from the central estimate of the air Pb 17 

### concentration. Air Pb concentration ranges and central estimates varied across studies, 18 

### making it difficult to inter pret comparisons based solely on the central estimates of the 19 

### slopes; therefore, Figure 4-21 depicts the relationship between the blood Pb-air Pb slop e as a 20 

### function of air Pb concentration for the range of air Pb concentrations evaluated in each 21 

### study (the central estimate is also shown). Figure 4-21 provides a more informative picture 22 

### of the extent to which slope estimates vary (and overlap) within and between stu dies. In the 23


### Schna as et al. ( 2004 ) analysis, the effect of air Pb on blood Pb may have been 24 

### underestimated due to inclusion of location and SES terms in their regression model. It was 25 

### specifically noted by the authors that air Pb differed significantly between the locations and 26 

### the p oorer residential areas were usually the more i ndustrialized areas with higher pollution. 27 

### Hence, the inclusion of these terms may have accounted for some of the variance in blood Pb 28



### attributable to air Pb

. With th e exception of Ranft et al. ( 2008 ), all studies included in Table 29



### 4-11 and Figure 4-22 include a blood Pb- air Pb relationship that reflects all air

- related 30 

### pathways of exposure. The Ranft et al. ( 2008 )study includes a separate term for soil Pb, so 31



### the blood Pb- air Pb slope presen ted for that study underestimates the slope that would reflect 32



### all air

- related pathways, since soil Pb encompasses deposited ambient air Pb. The Ranft et al. 33 

### ( 2008 ) model is log- linear, with the natura l logarithm of blood Pb being a function of linear 34 

### increase in air Pb. This results an upward curvature of the blood Pb- air Pb relationship

. By 35 

### comparison, log -log models predict an increase in the blood Pb- air Pb slope with decreasing 36



### air Pb concentration , whereas linear models predict a constant blood Pb- air Pb slope across 37



### all air Pb concentrations. 38February 2012 4

- 102 Draft

– Do Not Cite or Quote 

### Table 4

- 11 Summary of estimated slopes for bloo d Pb to air Pb relationships in humans

Reference Study Methods Model Description Blood Pb

– Air Pb Slopea

Children Populations

Brunekreef et al. ( 1984 ) Location: Various countries
Years: 1974

- 1983 Subjects : Children (varying age ranges; n>190,000) Analysis: Meta analysis of 18 studies Model: Log

- Log
Blood Pb: 5

- 41 μg/dL (mean range for studies)
Air Pb: 0.1

- 24 μg/m 3 (mean range for studies) All children:
4.6 (1.5) c

Children <20 μg/ dL : 4.8 (0.54) d

Hayes et al. ( 1994 ) Location: Chicago, IL
Years: 1974

- 1988 Subjects: 0.5

- 6 yr (n = 9,604) Analysis: Regression of quarterly med ian blood Pb and quarterly mean air Pb Model: Log

- Log
Blood Pb: 12

- 30 μg/dL (annual median range)
Air Pb: 0.05

- 1.2 μg/m 3 (annual mean r ange) 8.2 (0.62) e

Hilts et al. ( 2 003 ) Location: Trail, BC
Years: 1989

- 2001 Subjects: 0.5

- 6 yr (Estimated n = 220

- 460, based on 292

- 536 blood Pb measure ments/yr with 75

- 85% participation ) Analysis: Regression of blood Pb screening and community air Pb following upgrading of a local smelter Model: Linear
B lood Pb: 4.7

- 11.5 μg/dL (annual geometric mean range)
Air Pb: 0.03

- 1.1 μg/m 3 (annual geometric mean range) 6.5 (0.48) f

Ranft et al. ( 2008 ) Location: Germany
Years: 1983

- 2000 Subjects: 6

- 11 yr (n = 843) Analysis: Pooled regression 5 cross

- sectional studies Model: multivariate Log

- Linear
Blood Pb: 2.2

- 13.6 μg/dL (5th

- 95th percentile)
Air Pb: 0.03

- 0.47 μg/m 3 (5th

- 95th percentile) 3.2 (0.1) g

Schnaas et al. ( 2004 ) Location: Mexico City
Years : 1987

- 2002 Subjects : 0.5

- 10 yr (n = 321) Analysis: Regression of lifetime blood Pb from longitudinal blood Pb measurements and annual average air Pb data Model: Log

- Log
Blood Pb: 5

- 12 μg/dL (annual GM range)
Air Pb: 0.07

- 2.8 μg/m 3 (annual mean range in yr of birth) 2.2 (0.4) h

Schwartz and Pitcher ( 1989 )

, U.S. EPA ( 1986a ) Location: Chicago, IL
Years: 1976

- 1980 Subjects : Black children, 0

- 5 yr (n = 5,476) Analysis : 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) b 8.6 (0.75) i

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 (0.45) j

Adult Populations

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 work performing various job

- related tasks Model: Log

- log
Blood Pb: 16.1 μg/dL (GM, 1,7 GSD)
Air Pb: 58 μg/m 3 (GM, 2.8 GSD) 0.01 (58) kFebruary 2012 4

- 103 Draft

– Do Not Cite or Quote Mixed Child

- Adult Populations

Schwartz and Pitcher ( 1989 )

, U.S. EPA ( 1986a ) Location: U

. S

. Years: 1976

- 1980 Subjects : 0.5

- 74 yr (n = 9,987) Analysis: 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 (0.75) l

a Slope is predicted change in blood Pb (μg/dL per μg/m3) evaluated at ± 0.01 μg/m3 from central estimate of air Pb for the stu dy (shown in parentheses)

b Based on data for U.S. (1986 Pb AQCD )

c ln(PbB) = ln(PbA) x 0.3485 +2.853

d ln(PbB) = ln(PbA) x 0.2159 + 2.620

e ln( Pb B) = ln(PbA) x 0.24 +3.17

f PbB = PbA x 6.5

g PbB =1.5 x EXP(0.9361 x (PbA

- 0.1)/0.44), where 1.5 μg/dL is the background PbB, and 0.1 μg/m 3 is the median PbA for the study; model also adjusted for soil Pb concentration, which may reduce estimated slope

h ln(PbB) = Ln(PbA) x 0.213 +1.615 for the 1987 cohort , see text for more study details.

i PbB = PbA x 8.6
j PbB =Pb A x 3.6

k ln(PbB) = ln(PbA) x 0.05 +2.12

l PbB = PbA x 9.63 GM, geometric mean; GSD, geometric standard deviation; PbB, blood Pb concentration (μg/dL); PbA, air lead concentration (μg/m 3 )

Data provided from Brunekreef ( 1984 )

. Note: The regression model is: (ln[μg/dL blood Pb] = 0.3485

⋅ ln[μg/m 3 air Pb] + 2.85) for all children (n=96 subject groups) 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 (n=44 subject groups).


### Fig ure 4

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

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 μg/dLFebruary 2012 4

- 104 Draft

– Do Not Cite or Quote Note: Slopes are calculated for a change in air Pb (±0.01 μg/m 3 ) over ranges of air Pb concentrations repo rted in each study (lines). The air Pb axis is truncated at 2 μg/m 3 ; the actual range for the Brunkreefe et al. ( 1984 ) study was 0.1

- 6.4 μg/dL per μg/m 3 and for the Schnaas et al. ( 2004 ) study was 0.08

- 2.8 μg/dL per μg/m 3 . The slope axis has been truncated at 40; the actual range for the Hayes et al. ( 1994 ) study was 5

- 56 μg/dL per μg/m 3 (the high end of the range was estimated for the minimum annual average air Pb of 0.05 μg/m 3 ). The two estimates for Schwartz and Pitcher ( 1989 ) represent data for U.S. and Chicago. Models are log

- log (solid line s), log

- linear (dashed line), and linear (dotted lines). Symbols show the slope at the central estimate of air Pb ( e.g., mean or median reported for each study).


### Figure 4

- 22 Blood Pb

– air Pb slope (μg/dL per μg/m 3 

### ) predicted from various epidemiologic studies (links available in Table 4

- 11 ).

4.5.1.1 Children

Hilts et al. ( 2003 ) reported child blood Pb and air Pb trends for the city of Trail, British 1 

### Columbia, over a period preceding and following installation of a new smelter process in 2


### 1997 which resulted in lower air Pb conc entrations. Blood Pb data were obtained from 3 

### annual (1989

- 2001) surveys of children 6

- 60 months of age who lived within 4 km from 4 

### the smelter (n: 292

- 536 eligible per year, 75

- 85% participation). Air Pb concentrations 5 

### were obtained from high volume suspend ed particulate samplers placed within 2 km of 6 

### the smelter that operated 24 hours every 6th day. Data on Pb levels in air, residential soil, 7 

### interior dust, and blood for three sampling periods are summarized in Table 4

- 12 . Based 8 

### on these data, blood Pb decreased 6.5 μg/dL per 1 μg/m 3 

### air Pb and by 0.068 μg/dL per 9 

### mg/kg soil Pb (based on linear regression with air or soil Pb as the sole independent 10



### variab le). Several uncertainties apply to these estimates. Potential mismatching of air Pb 11 

### concentrations (often termed misclassification) with individual blood Pb levels may have 12 

### occurred as a result of air Pb being measured within 2 km of the smelter, whereas, the 13 0 10 20 30 40

0.0 0.5 1.0 1.5 2.0Blood Pb Slope (μg/dLperμg/m3)

Air Pb (μ g/m 3 ) Brunekreef (1984) <20 μg/ dL
Hayes (1994)

Hilts (2003)

Ranft (2008)

Schnaas (2004)

Schwartz (1989) Chicago

Schwartz (1989) U.S.

Tripathi (2001)February 2012 4

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### blood Pb data included children who resided >2 km from the smelter. The regression 1 

### estimates were based on group mean estimates for three sampling dates, rather than on 2 

### the individual blood Pb estimates, which included repeated measures on an unreport ed 3 

### fraction of the sample. The limited number of data pairs (three) constrained parameter 4 

### estimates to simple regression coefficients. Other important factors probably contributed 5 

### to blood Pb declines in this population that may have been correlated with a ir, soil and 6 

### dust Pb levels. These factors include aggressive public education and exposure 7 

### intervention programs ( Hilts et al., 1998 ; Hilts, 1996 )

. Therefore, the coefficients shown 8



### in Table 4

- 12 are likely to overestimate the influence of air, dust, or soil Pb on blood Pb 9



### concentrations at this site. 10



### Table 4

- 12 Environmen tal Pb levels and blood Pb levels in children in Trail, British Columbia

Date 1996 1999 2001 Regression Coefficient (μg/dL per μg/m3)

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 (mg/kg) 844 756 750 0.069 ± 0.008 (R 2 =0.99, p=0.069)
Interior Dust Pb (mg/kg) 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 geometric means; values for blood Pb are annual geometric means. Regression coefficients are for simple linear regression of each exposure variable on blood Pb.
Source: Data from Hilts et al. ( 2003 )

.



### Ranft et al. ( 2008 ) reported a meta

- analysis of five cross

- sectional surveys of air and soil 11



### Pb leve ls and blood Pb concentrations in children living in Duisburg, Germany. The 12 

### analysis included observations on 843 children (6

- 11 years of age) made during the 13 

### period 1983

- 2000. Pb was measured in PM 10 

### samples collected in a 200 meter by 200 14 

### meter grid that encompassed the city. Pb in surface soil (0

- 10 cm) was measured at 145 15 

### locations in the city. Air and soil Pb concentrations were assigned to each participant by 16 

### spatial interpolation from the sampling grid data to each home residence. The 5 th

- 95th 17



### percen tile ranges were 0.025

- 0.465 μg Pb/m 3 

### for air and 72

- 877 mg Pb/kg for soil. The 18 

### results of multivariate regression analyses were reported in terms of the relative increase 19 

### (the geometric mean blood Pb ratio, GMR) for an increase in air or soil Pb from the 5 th 20



### to 95 th percentile value. In a multivariate linear regression model (R 2 

### = 0.586) that 21 

### included air and soil Pb in the same model and adjusted for covariates, the GMR values 22 

### 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) 23 

### and 1.30 per 800 mg/kg soil Pb (95% CI: 1.19, 1.43, R 2 

### = 0.017, p <0.001). Based on the 24



### values for R 2 

### , the regression model accounted for approximately 59% of the total 25 

### variance in blood Pb and, of this, 83% was attributed to air Pb. Values for GMR for soil 26February 2012 4

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– Do Not Cite or Quote 

### Pb varied depending on the sampling data and ranged from 1.41 to 2.89, with most recent 1 

### data ( from the year 2000) yielding a value of 1.63 per 800 mg/kg increase in soil Pb. The 2 

### GMR values can be converted to regression slopes (slope = [ starting b lood 3 

### Pb×ln(GMR) ] / [ 95 th

− 5th percentile air or soil Pb ] ) for calculating equivalent air:blood 4 

### Pb ratios. The model predicts an increase of 3.2 μg/dL blood Pb per 1 μg/m 3 

### increase in 5 

### air Pb at the median air Pb concentration for the study (0.1 μg/m 3 

### ) and as suming a 6 

### background blood Pb concentration of 1.5 μg/dL. Based on the GMR estimate of 1.63 for 7 

### soil Pb, a 1,000 mg/kg increase in soil Pb would be associated with an increase in blood 8


### Pb of 0.9 μg/dL per mg/kg soil at the median soil Pb concentration of 20 6 mg/kg and 9 

### assuming a background blood Pb concentration of 1.5 μg/dL. The degree of confounding 10 

### of the GMR and estimates resulting from the air and soil Pb correlation was not reported, 11 

### although the correlation coefficient for the two variables was 0.136 for the whole data set 12


### and 0.703 when data collected in 1983 was omitted. Because the model also included Pb 13 

### levels in soil, the blood Pb

- air Pb ratio may be underestimated since some of the Pb in 14 

### soil was likely derived from air. The blood Pb

- air Pb slope does not include the portion of 15 

### the soil/dust Pb ingestion pathway that derives from air Pb, such as recently airborne Pb 16 

### deposited to soil and dust which remains available for inhalation and ingestion. To 17



### estimate the blood Pb

- air Pb ratio that included all air

- related pathways, data for 18 

### geometric mean of blood Pb and air Pb among the cohort of children studied were 19 

### extracted from Figure 1 in Ranft et al. ( 2008 ) for each of the five study years. The 20



### e xtracted values of the geometric mean of blood Pb and air Pb were used in regressions 21 

### employing linear and log

- log fits. The linear model obtained was: PbB = (13.65×PbA) + 22 

### 2.96 (R 2 

### = 0.92); i.e., the linear regression produced a constant slope of 14 μ g/dL per 23 

### μg/m 3 

### . The log

- log model was: ln(PbB) = (0.48×ln(PbA) + 2.61 (R 2 

### = 0.91), resulting in 24 

### an inverse curve for dPbB/dPbA vs. PbA with a slope of 22 μ g/dL per μg/m 3 

### at PbA = 25



### 0.1 μ g/m 3



### . 26



### Schnaas et al. ( 2004 ) analyzed data on blood Pb and air Pb concentrations during and 27 

### after the phase out of leaded gasoline use in Mexico (1986

- 1997) in children as part of a 28 

### prospective study conducted in Mexico City. The sample includ ed 321 children born 29 

### during the period 1987 through 1992. Repeated blood Pb measurements were made on 30



### each child at 6

- month intervals up to age 10 years. Air Pb measurements in PM 10 

### (annual 31 

### average of quarterly means) were derived from three area monitors which represented 32 

### distinct study zones. Children were assigned to study zones based on their current address 33 

### and were assigned the corresponding annual average air Pb concentrations for their year 34 

### of birth and appropriate air monitoring zones. Associations between lifetime (across the 35 

### first 10 years of life) blood Pb concentration, air Pb concentration for year of birth and 36 

### other variables ( e.g., age, year of birth, family use of glazed pottery) were evaluated 37 

### using multivariate regression models. The large st slope occurred in the cohort born in 38 

### 1987, who experienced the largest decline in air Pb (from 2.8 to <0.1 μ g/m 3 

### ); the 39February 2012 4

- 107 Draft

– Do Not Cite or Quote 

### predicted slope for this group of children was 0.213 (95% CI: 0.114

- 0.312) ln [μg/dL 1 

### blood] per ln[μg/m 3 

### air]. This slope corresponds to an increase of 2.2 μ g/dL blood Pb per 2 

### μg/m 3 

### at the median annual air Pb concentration of 0.4 μg/m 3 

### estimated over the years of 3 

### the study . Slopes for other birth cohorts ranged from

- 0.003 (1992) to 0.166 (1988) with a 4 

### median of 0.153 for all six cohorts. This median slope corresponds to an increase of 5



### 1.7 μ g/dL blood Pb per μg/m 3 

### at the median annual air Pb concentration of 0.4 μ g/m 3 6 

### estimated over the years of the study. Considering all cohorts simultaneously, data for 7 

### annual g eometric mean of blood Pb and air Pb were extracted from Figure 1 in Schnaas et 8



### al. ( 2004 )

. However, in employing this approach, blood Pb is confoun ded by age and year 9 

### because in the early years of the study, only younger children were available and in the 10 

### later years of the study, only older children contributed data. The extracted values of the 11 

### geometric mean of blood Pb and mean air Pb were used in regressions employing linear 12 

### and log

- log models for comparison to other studies and a log

- linear model as employeed 13 

### by the authors. The linear model obtained was: PbB = (2.50×PbA) + 5.61 (R 2 

### = 0.84), 14 

### i.e., the linear model produced a constant slope of 2.5 0 μ g/dL per μg/m 3 

### . However, 15 

### inspection of the graph (not shown here) suggested a bi

- linear fit. Regression of the data 16



### over the interval 0.1

- 0.4 μ g/m 3 

### produced a slope of 9.0 μ g/dL per μg/m 3 

### (R 2 

### = 0.83), and 17 

### regression of the data over the interval 0.4

- 2.8 μ g/m 3 

### produced a slope of 1.52 μ g/dL per 18 

### μg/m 3 

### (R 2 

### = 0.83). The log

- log model was: ln(PbB) = (0.26×ln(PbA)) + 2.20 (R 2 

### = 0.94), 19 

### resulting in an inverse curve for dPbB/dPbA vs. PbA, with a slope of 4.5 μ g/dL per 20 

### μg/m 3 

### at PbA = 0.4 μ g/m 3 

### . The log

- linear model as employed by the authors was: 21 

### ln(PbB) = (0.32×PbA) + 1.73 (R 2 

### = 0.77) ; and described the data least well . The log

22 

### linear model produced an exponential curve of dPbB/dPbA vs. PbA, with a slope of 23



### 2.04 μ g/dL per μg/m 3 

### at PbA = 0.4 μ g/m 3



### . 24



### Schwartz and Pitcher ( 1989 ) reported a multivariate regression analysis of associations 25 

### between U.S. gasoline Pb consumption ( i.e., sales) and blood Pb concentrations in the 26 

### U.S. population during the period 1976

- 1980 when use of P b in gasoline was being 27 

### phased out. Although this analysis did not directly derive a slope for the air Pb

- blood Pb 28 

### relationships, other analyses have shown a strong correlation between U.S. gasoline Pb 29 

### consumption and ambient air Pb levels during this same period ( U.S. EPA, 1986a )

. 30 

### Therefore, it is possible to infer an air Pb

- blood Pb relationship from these data. Two 31



### sources of blood Pb data were used in Schwartz and Pitcher ( 1989 ) : NHANES II 32 

### provided measurements for U.S. children 6 months to 74 years of age (n = 9,996) during 33



### 1976

- 1980, and the City of Chicago blood Pb screening program provided approximately 34 

### 7,000 blood Pb measurements in black children during 1976

- 1980. Gasoline Pb 35 

### consumption was estimated as the product of monthly gasoline sales in the U.S. and 36 

### quarterly estimates of Pb concentrations in gasoline reported to U.S. EPA. Based on the 37 

### NHANES blood Pb data for white children, the regression coefficient was 2.14 μ g/dL 38 

### blood per 100 metric tons of gasoline Pb/day (SE=0.19, p=0.0000); results for black 39February 2012 4

- 108 Draft

– Do Not Cite or Quote 

### children were essentially identical. Based on the Chicago blood Pb data the regression 1 

### coefficient was 16.12 (μg/dL per 1,000 metric tons gasoline Pb/quarter (SE=1.37, 2 

### p=0 .0001), which is roughly equivalent to 1.79 μ g/dL blood per 100 metric tons of 3 

### gasoline Pb/day (the value cited in Schwartz and Pitcher ( 1989 ) is 1.97 μ g/dL blood per 4 

### 100 metric tons of gasoline Pb/day). U.S. EPA ( 1986a ) reported data on gasoline Pb 5 

### consumption (sales) and ambient Pb levels in the U.S. during the period 1976

- 1984 6 

### ( Table 4

- 13 ). Based on these data, air Pb concentrations decreased in association with 7 

### gasoline Pb consumption. The linear regression coefficient for the air Pb decrease was 8



### 0.23 μ g/m 3 

### per 100 metric tons gasoline Pb/day (SE = 0.02, R 2 

### = 0.95, p <0.0001). If this 9



### reg ression coefficient is used to convert the blood Pb slopes from Schwartz and Pitcher 10 

### ( 1989 )

, the corresponding air Pb

- blood Pb slopes would be 9.3 and 8.6 μ g/dL per μg/m 3



### , 11 

### based on the NHANES and Chicago data, respectively ( e.g., 2.14/0.23 = 9.3 and 12 

### 1.97/0.23=8.6). 13



### Table 4

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

Date Total Gasoline Pb (103 metric tons/yr) Total Gasoline Pb (102 metric 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 Conversion factor is 10/365 days/year.

Source: U.S. EPA ( 1986a )

.



### Tripathi et al. ( 2001 ) reported child blood Pb and air Pb trends for the city and suburbs of 14 

### Mumbai, India over the period 1984

- 1996. Blood Pb data were obtained from children 15



### 6

- 10 years of age (n = 544) who lived in 13 lo cations within the Mumbai area. Air Pb 16 

### concentrations were measured from high volume PM samplers (with the majority of Pb in 17 

### the respirable size range) placed at a height of 1.6 meters that operated 24 hours. Data on 18 

### Pb concentrations in air, residential s oil, interior dust, and blood for three sampling 19 

### periods are summarized in Table 4

- 14 . Based on these data, blood Pb increased 3.6 μg/dL 20 

### per 1 μg/m 3 

### ai r Pb (based on linear regression with air or soil Pb as the sole independent 21 

### variable). Several uncertainties apply to these estimates, including potential exposure 22



### misclassification since the mean air Pb concentration was used for each suburb over the 23



### ent ire study period. The regression estimates were based on group mean blood Pb 24February 2012 4

- 109 Draft

– Do Not Cite or Quote 

### estimates for the 13 sampling locations, rather than on the individual blood Pb estimates, 1 

### which included repeated measures on an unreported fraction of the sample. 2



### Table 4

- 14 Air Pb levels and blood Pb levels in children 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 screening 3 

### program for the period 1974

- 1988, following the phase

- out of leaded gasoline. The data 4



### included 9,604 blood Pb measurements in children (age: 6 months to 6 years) and 5 

### quarterly average air Pb concentrations measured at 12 monitoring stations in Cook 6 

### County, IL. Quarterly median blood Pb levels declined in association with quarterly mean 7



### air Pb conce ntrations. The regression model predicted a slope of 0.24 ln [μg/dL blood] 8 

### per ln[μg/m 3 

### air], as illustrated in Figure 4

- 23 . This slope corresponds to an increase of 9



### 8.2 μg/dL blood Pb per μg/m 3 

### at the average annual mean air Pb concentration of 10



### 0.62 μg/m 3



### . 11February 2012 4

- 110 Draft

– Do Not Cite or Quote Modified from Hayes et al. ( 1994 )

. Note: The regression model is: (ln[μg/dL blood Pb] = 0.24

⋅ ln[μg/m 3 air Pb] + 3.17).


### Figure 4

- 23 Predicted relationship between air Pb and blood Pb based on data from Chicago, IL in children age 0

- 5 y (1974

– 1988).

4.5.1.2 Adults

Rodrigues et al. ( 2010 ) examined factors contributing to variability in blood Pb 1



### concentration in New England bridge painters, who regularly use electric grinders to 2 

### prepare surfaces for painting. The study included 84 adults (1 fe male) who were observed 3 

### during a 2

- week period in 1994 or 1995. Subjects wore personal inhalable PM samplers 4 

### designed to capture PM smaller than 100 μm, while performing various job

- related tasks. 5 

### The geometric mean air Pb concentration for the 2

- week peri od was 58 μg/m 3 

### (GSD 2.8), 6 

### with a maximum daily value of 210 μg/m 3 

### . These Pb concentrations were reported to 7 

### have been corrected by the National Institute for Occupational Safety and Health 8 

### (NIOSH) respirator protection factors, which were not reported by the authors. Hand 9 

### wipe samples were collected at the mid

- shift break and at the end of the shift (after the 10 

### subjects had reportedly cleaned up for the day; GM = 793 μg, GSD 3.7). Blood Pb 11 

### samples were collected at the beginning of the 2

- week period (GM = 1 6.1 μg/dL, GSD 12 

### 1.7). Associations between exposure variables and blood Pb concentrations were 13 

### explored with multivariate regression models ( Table 4

- 15 ). When the model excluded 14 

### 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 

### )February 2012 4

- 111 Draft

– Do Not Cite or Quote 

### hand

- wipe data (not all participants who wore the personal air samplers agreed to provide 1



### hand

- wipes), the regression coefficient for the relationship between ln[blo od Pb 2 

### concentration (μg/dL)] and ln[air Pb (μg/m 3 

### )] was 0.11 (SE = 0.05, p = 0.03). This slope 3 

### corresponds to a 1.3

- fold increase in blood Pb concentration for a 10

- fold increase in air 4 

### Pb concentration and a slope of 0.009 μg/dL per μg/m 3 

### , at the average occupational air 5 

### Pb concentration for the study (58 μg/m 3 

### ); non

- occupational exposures were not included 6 

### in the slope calculation. A second regression model included hand wipe Pb (n = 54) and 7 

### yielded a regression coefficient of 0.05 (SE = 0.07, p = 0.45), which corresponds to a 8



### 1.12

- fold increase in blood Pb concentration per 10

- fold increase in air Pb concentration 9 

### and a slope of 0.02 μg/dL per μg/m 3 

### , at the average occupational air Pb concentration for 10 

### the study (58 μg/m 3 

### ). 11



### 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. Blood Pb concentration in units of μg/dL.

Source: Data from Rodrigues et al. ( 2010 )

.February 2012 4

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### 4.5.2 Environmental Lead

- Blood Lead Relationships

Empirically

- based relationships between blood Pb levels and Pb intakes and/or Pb 1 

### concentrations in environmental media have provided the basis for what has become 2 

### known as slope factor models. Slope factor models are highly simplified representations 3 

### of empirically based regression models in which the slope parameter represents the 4 

### change in blood Pb concentration projected to occur in association with a change in Pb 5 

### intake or uptake. The slope parameter is factored by exposure parameters ( e.g., exposure 6 

### concentrations, environmental media intake rates) that relate exposure to blood Pb 7



### concentration ( M addaloni et al., 2005 ; U.S. EPA, 2003c ; Abadin and Wheeler, 1997 ; 8 

### Stern, 1996 ; Bowers et al., 1994 ; Ste rn, 1994 ; Carlisle and Wade, 1992 )

. In slope factor 9 

### models, Pb biokinetics are represented as a linear function between the blood Pb 10 

### concentration and either Pb uptake (uptake slope factor, USF) or Pb intake (intake slope 11 

### factor, ISF). The models take the general mathematical forms: 12



### PbB = E × ISF

Equation 4

- 2



### PbB = E × AF × USF

Equation 4

- 3



### where PbB is the blood Pb concentration, E is an expression for exposure ( e.g., soil 13 

### intake × soil Pb concentration) and AF is the absorption fraction for Pb in the specific 14 

### exposure medium of i nterest. Intake slope factors are based on ingested rather than 15 

### absorbed Pb and, therefore, integrate both absorption and biokinetics into a single slope 16 

### factor, whereas models that utilize an uptake slope factor include a separate absorption 17 

### parameter. In contrast to mechanistic models, slope factor models predict quasi

- steady 18 

### state blood Pb concentrations that correspond to time

- averaged daily Pb intakes (or 19 

### uptakes) that occur over sufficiently long periods to produce a quasi

- steady state 20 

### ( i.e., >75 days , ~3 times the t 1/2 

### for elimination of Pb in blood). 21



### The U.S. EPA Adult Lead Methodology (ALM) is an example of a slope factor model 22 

### that has had extensive regulatory use in the EPA Superfund program for assessing health 23



### risks to adults associated with non

- residential exposures to Pb in contaminated soils 24 

### ( Maddaloni et al. , 2005 ; U.S. EPA, 1996a )

. The model was developed to predict maternal 25 

### and fetal blood Pb concentrations that might occur in relation to maternal exposures to 26 

### contaminated soils. The model assumes an uptake slope factor of 0.4 μg/dL blood per 27 

### μg/day Pb uptake. Additional discussion of slope factor models that have been used or 28 

### proposed for regulatory use can be found in the 2006 Pb AQCD ( U.S. EPA, 2006b )

. 29February 2012 4

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### Previous studies included in the 2006 Pb AQCD ( U.S. EPA, 2006b ) explored th e 1 

### relationship between blood Pb in children and environmental Pb concentrations. In a 2 

### pooled analysis of 12 epidemiologic studies, interior dust Pb loading, exterior soil/dust 3 

### Pb, age, mouthing behavior, and race were all statistically significant variable s included 4 

### in the regression model for blood Pb concentration ( Lanphear et al., 1998 )

. Significant 5



### interactions we re found for age and dust Pb loading, mouthing behavior and exterior 6 

### soil/dust level, and SES and water Pb level. In a meta

- analysis of 11 epidemiologic 7 

### studies, among children the most common exposure pathway influencing blood Pb 8



### concentration in structur al equation modeling was exterior soil, operating through its 9



### effect on interior dust Pb and hand Pb ( Succop et al., 1998 )

. Similar to Lanphear et al. 10 

### ( 1998 )

, in the linear regression model, interior dust Pb loading had the strongest 11 

### relationships with blood Pb concentration. Individual studies conducted in Rochester, 12 

### NY, Cincinnati, OH, and Baltimore, MD report similar relationships between children’s 13



### blood Pb and interior dust concentrations ( Lanphear and Roghmann, 1997 ; U.S. EPA, 14


### 1996b ; Bornschein et al., 1985 )

. 15



### Dixon et al. ( 2009 ) reported a multivariate analysis of associations between 16 

### environmental Pb concentrations and blood Pb concentrations, based on data collected in 17 

### the NHANES (1999

- 2004). The analyses included 2,155 children, age 12

- 60 months. The 18 

### population

- weighted geometric mean blood Pb concentration was 2.03 μg/dL 19 

### (GSD 1.03). A linear model applied to these data yielded an R 2 

### of 40% ( Table 4

- 16 ). The 20 

### regression coefficient for the relationship between ln[blood Pb concentration (μg/dL)] 21 

### and ln[floor dust Pb concentration (μg/ft 2 

### )] was 0.386 (SE 0.089) for “not smooth and 22



### cleanable” surfa ces ( e.g., high

- pile carpets) and 0.205 (SE 0.032) for “smooth and 23 

### cleanable” surfaces ( e.g., uncarpeted or low

- pile carpets). These coefficients correspond 24



### to a 2.4

- fold or 1.6

- fold increase in blood Pb concentration, respectively, for a 10

- fold 25



### increase in floor dust Pb concentration. 26February 2012 4

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### Table 4

- 16 Linear model relating environmental Pb exposure and blood Pb concentration in children

Variables Overall p

- value Levels a Estimate (SE) p - Value Intercept 0.172

- 0.517 (0.373 ) 0.172

Age (in yr) < 0.001 Age Age 2 Age 3 Age 4 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 U .S. 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 Floo r 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 Children: n = 2,155 (age 10

- 60 months); R 2 = 40%
b Includes the 50 states and the District of Columbia Source: Dixon et al. ( 2009 )

.


### Mielke et al. ( 2007a ) analyzed blood Pb and soil Pb concentration data collected as par t 1 

### of a blood Pb screening program in New Orleans (2000

- 2005). The data set included 2 

### 55,551 blood Pb measurements for children 0

- 6 years of age and 5,467 soil Pb 3



### measurements. Blood Pb and soil Pb concentrations were matched at the level of census 4



### tracts. T he association between blood Pb concentration and soil Pb concentration was 5 

### evaluated using non

- parametric permutation methods. The resulting best

- fit model 6 

### (R 2 

### =0.528) was: 7February 2012 4

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### PbB = 2

. 038 + ( 0

. 172 × PbS 0

. 5 

### )

Equation 4

- 4



### where PbB is the median blood Pb concentration and PbS is the median soil Pb 1 

### concentration. The resulting curvilinear relationship predicts a twofold increase in blood 2



### Pb concentration for an increase in soil Pb concentration from 100 to 1

, 000 ppm ( Figure 3



### 4

- 24 ). 4

Note: The data set included 55,551 blood Pb measurements for children 0

- 6 years of age and 5,467 soil Pb measurements. Blood Pb and soil Pb concentrations were match ed at the level of census tracts ( Mielke et al., 2007a )

. 

### Figure 4

- 24 Predicted relationship between soil Pb concentration and blood Pb concentration in children based on data collected in the New

In a subsequent re

- analysis of the New Orleans (2000

- 2005) data, individual child blood 5



### Pb observations were matched to census tract soil concentrations ( Zahran et al., 2011 )

. 6 

### This analysis confirmed the association between blood Pb and both soil Pb and age 7 

### reported in Mielke et al. ( 2007a )

. Regression coefficients for soil Pb (random effects 8 

### generalized least squares regression) ranged from 0.217 to 0.214 (per soil Pb 0.5 

### ), which is 9 

### equivalent to approximately a 2

- fold increase in blood Pb concentration for an increase in 10



### soil Pb concentration from 100 to 1

, 000 ppm

. 11



### Several studies have linked elevated blood Pb levels to residential soil exposures for 12 

### populations living nearby industrial or mining facilities. Gulson et al. ( 2009 ) studied the 13 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 0.5February 2012 4

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### blood Pb and isotopic Pb ratios of children younger than 5 years old and adults older than 1



### 18 years old living in the vicinity of a mine producing Magellan Pb ore in western 2 

### Australia. They observed a median blood Pb level of 6.6 μg/dL for the children, with 3 

### isotopic ratios indicating contributions from the mine ranging from 27 to 93%. A weak 4 

### but significant linear association between blood Pb level and percent Magellan Pb was 5 

### observed (R 2 

### = 0.12, p = 0.018). Among children with blood Pb levels over 9 μg/dL and 6 

### among adults, the isotopic ratios revealed Pb exposures from a variety of sources. 7



### Garavan et al. ( 2008 ) measured soil Pb and blood Pb levels among children aged 1 month 8



### to 17.7 years old in an Irish town near a coal mine. The blood Pb measurements were 9 

### instituted as part of a screening and community education program given that the 10 

### presence of Pb had been documented in the environment. Garavan et al. ( 2008 ) found that 11



### over 3 years of the screening period, median blood Pb levels reduced by roughly 22% 12



### from 2.7 to 2.1 μg/dL. 13



### An extensive discussion of the relationships between environmental Pb levels and blood 14



### Pb concentrations in chil dren at the Bunker Hill Superfund Site, a former Pb mining and 15 

### smelting site, was provided in the 2006 Pb AQCD. In the most recent analysis 16 

### ( TerraGraphics Environmental Engineering, 2004 ) of the data on en vironmental Pb levels 17 

### and child blood Pb concentrations (1988

- 2002), blood Pb concentrations (annual GM) 18 

### ranged from 2.6 to 9.9 μg/dL. Environmental Pb levels ( e.g., dust, soil, paint Pb levels) 19 

### data were collected at ~3,000 residences, with interior dust Pb concentrations (annual 20 

### GM) ranging from ~400 to 4,200 mg/kg and yard soil Pb concentration (annual GM) 21 

### ranging from ~150 to 2,300 mg/kg. Several multivariate regression models relating 22 

### environmental Pb levels and blood Pb concentration were explored; th e model having the 23 

### highest R 2 

### (0.26) is shown in Table 4

- 17 . The model predicts significant associations 24 

### between blood Pb concentration, age, interior dust, yard soil, neighborhood soil 25 

### (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 27 

### coefficients, the community soil Pb concentration h ad the largest effect on blood Pb 28 

### concentration, followed by neighborhood soil Pb concentration, interior dust Pb 29 

### concentration, and yard soil Pb concentration ( Table 4

- 17 ). The model predicted a 30



### 1.8 μg/dL decrease in blood Pb concentration in association with a decrease in 31 

### community soil Pb concentration from 2,000 to 1,000 mg/kg. The same decrease in 32 

### neighborhood soil Pb concentration, interior dust Pb concentration, or yard soil Pb 33 

### concentration was predicted to result in a 0.8, 0.5, or 0.2 μg/dL decrease in blood Pb 34 

### concentration, respectively. Note that the soil Pb component of the model was similar to 35 

### that derived by Lewin et al. ( 1999 )

, in which a model of blood Pb as a function of soil Pb 36 

### among 0

- 6 y old children living near one of four industrial si tes was given as PbB = 37 

### 0.2438ln( PbS } + 0.2758. 38February 2012 4

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### 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 1 

### concentrations in a representative sample of Native American and white children (n = 2 

### 224, age 1

- 6 years) who resided in a former Pb mining region in Ottawa County, OK. 3 

### The data set included measurements of blood Pb, yard soil Pb, residential interior dust Pb 4 

### loading, first

- draw water Pb, paint Pb assessment and other behavioral ( i.e., hand

- to

5



### mouth ac tivity, hygiene rating) and demographic variables ( i.e., hand

- to

- mouth activity, 6 

### hygiene rating, poverty level, caregiver education). A multivariate regression model 7 

### accounted for 34% of the observed variability in blood Pb. Yard soil Pb and interior dust 8 

### Pb loading accounted for 10% and 3% of the blood Pb variability, respectfully. The 9 

### regression model predicted a slope of 0.74 μg/dL blood Pb per ln[μg/g soil Pb] and a 10 

### slope of 0.45 μg/dL blood Pb per ln[μg/ft 2 

### ] dust Pb loading. 11



## 4.6 Biokinetic Models of Lead E xposure - Blood Lead Relationships

An alternative to regression models are mechanistic models, which attempt to specify all 12 

### parameters needed to describe the mechanisms (or processes) of transfer of Pb from the 13



### environment to human tissues. Such mechanistic models are more complex than 14 

### regression models; this added complexity introduces challenges in terms of their 15 

### mathematical solution and empirical verification. However, by incorporating parameters 16 

### that can be expected to vary spatially or temporally, or ac ross individuals or populations, 17 

### mechanistic models can be extrapolated to a wide range of exposure scenarios, including 18 

### those that may be outside of the domain of paired predictor

- outcome data used to develop 19 

### the model. Exposure

- intake models, a type of m echanistic models, are highly simplified 20February 2012 4

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### mathematical representations of relationships between levels of Pb in environmental 1 

### media and human Pb intakes ( e.g., μg Pb ingested per day). These models include 2 

### parameters representing processes of Pb transfer be tween environmental media ( e.g., air 3 

### to surface dust) and to humans, including rates of human contact with the media and 4 

### intakes of the media ( e.g., g soil ingested per day). Intake

- biokinetic models provide the 5 

### analogous mathematical representation of rel ationships between Pb intakes and Pb levels 6 

### in body tissues ( e.g., blood Pb concentration). Biokinetic models include parameters that 7 

### represent processes of Pb transfer (a) from portals of entry into the body and (b) from 8



### blood to tissues and excreta. Link ed together, exposure

- intake and intake

- biokinetics 9 

### models ( i.e., integrated exposure

- intake

- biokinetics models) provide an approach for 10 

### predicting blood Pb concentrations (or Pb concentrations in other tissues) that 11 

### corresponds to a specified exposure (me dium, concentration, and duration). Detailed 12 

### information on exposure and internal dose can be obtained from controlled experiments, 13 

### but almost never from epidemiological observations or from public health monitoring 14 

### programs. Exposure intake

- biokinetics mo dels can provide these predictions in the 15 

### absence of complete information on the exposure history and blood Pb concentrations for 16 

### an individual (or population) of interest. Therefore, these models are critical to applying 17 

### epidemiologic

- based information on blood Pb

- response relationships to the quantification 18 

### and characterization of human health risk. They are also critical for assessing the 19 

### potential impacts of public health programs directed at mitigation of Pb exposure or of 20



### remediation of contaminated s ites. 21



### However, they are not without their limitations. Human exposure

- biokinetics models 22 

### include large numbers of parameters, which are required to describe the many processes 23 

### that contribute to Pb intake, absorption, distribution, and elimination. The la rge number 24 

### of parameters complicates the assessment of confidence in parameter values, many of 25 

### which cannot be directly measured. Statistical procedures can be used to evaluate the 26 

### degree to which model outputs conform to “real

- world” observations and valu es of 27 

### influential parameters can be statistically estimated to achieve good agreement with 28 

### observations. Still, large uncertainty can be expected to remain about many, or even 29 

### most, parameters in complex exposure

- biokinetic models. Such uncertainties need to be 30 

### identified and their impacts on model predictions quantified ( i.e., sensitivity analysis or 31 

### probabilistic methods). 32



### Modeling of human Pb exposures and biokinetics has advanced considerably during the 33 

### past several decades, although there have been rel atively few developments since the 34 

### 2006 Pb AQCD was published. Still in use is the Integrated Exposure Uptake Biokinetic 35 

### (IEUBK) Model for Lead in Childre n ( U.S. EPA, 1994 ) and models that simulate Pb 36



### bio kinetics in humans from birth through adulthood ( O'Flaherty, 1995 ; Leggett, 1993 ; 37February 2012 4

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### O'Flaherty, 1993 )

. The EPA AALM is still in development. A complete and exte nsive 1 

### discussion of these models can be found in the 2006 Pb AQCD ( U.S. EPA, 2006b )

. 2



## 4.7 Summary and Conclusions

4.7.1 Exposure

Exposure data considered in this assessment build upon the conclusions of the 2006 Pb 3 

### AQCD ( 2006b )

, which found air Pb concentrations in the U.S. and associated biomarkers 4 

### of exposure to Pb have decreased substantially following the ban on Pb in gasoline, 5



### house

- hold paints, and solder. Pb exposure is difficult to assess because Pb h as multiple 6 

### sources in the environment and passes through various media. The atmosphere is the 7 

### main environmental transport pathway for Pb, and, on a global scale, atmospheric Pb is 8 

### primarily associated with fine particulate matter, which can deposit to so il and water. In 9 

### addition to primary emission of particle

- bearing or gaseous Pb to the atmosphere, Pb can 10 

### be suspended to the air from soil or dust. Air

- related pathways of Pb exposure are the 11



### focus of this assessment. In addition to inhalation of Pb from ambient air, air

- related Pb 12 

### exposure pathways include inhalation and ingestion of Pb from indoor dust and/or 13 

### outdoor soil that originated from recent or historic ambient air ( e.g., air Pb that has 14 

### penetrated into the residence either via the air or trackin g of soil). Non

- air

- related Pb 15 

### exposures may include occupational exposures, hand

- to

- mouth contact with Pb

16 

### containing consumer goods, hand

- to

- mouth contact with dust or chips of peeling Pb

17 

### containing paint, or ingestion of Pb in drinking water conveyed thr ough Pb pipes. Pb can 18 

### cycle through multiple media prior to human exposure. Given the multitude of possible 19



### air

- related exposure scenarios and the related difficulty of constructing Pb exposure 20 

### histories, most studies of Pb exposure through air, water, and soil can be informative to 21 

### this review. Other exposures, such as occupational exposures, contact with consumer 22 

### goods in which Pb has been used, or ingestion of Pb in drinking water conveyed through 23 

### Pb pipes may also contribute to Pb body burden. 24



### A number of monitoring and modeling techniques have been employed for ambient Pb 25 

### exposure assessment. Environmental Pb concentration data can be collected from 26 

### ambient air Pb monitors, soil Pb samples, dust Pb samples, and dietary Pb samples to 27 

### estimate human expos ure. Exposure estimation error depends in part on the collection 28 

### efficiency of these methods; collection efficiency for ambient air Pb FRM samplers is 29



### described in Section 3.4 . Additionally, high spatial variability of the Pb concentrations in 30 

### various media also can contribute to exposure error, as described in the 2009 PM ISA 31 

### ( U.S. EPA, 2009 )

. Models, such as the Integrated Exposure Uptake B iokinetic (IEUBK) 32February 2012 4

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– Do Not Cite or Quote 

### model, simulate human exposure to Pb from multiple sources and through various routes 1 

### including inhalation, ingestion, and dermal exposure. IEUBK model inputs include soil 2 

### Pb concentration, air Pb concentration, dietary Pb intake includin g drinking water, Pb 3 

### dust ingestion, human activity, and biokinetic factors. Measurements and/or assumptions 4 

### can be utilized when formulating the model inputs; errors in measurements and 5 

### assumptions thus have the potential to propagate through the exposure models. 6



### Section 4.1 presents data illustrating potential exposure pathways. Soil can act as a 7 

### reservoir for deposited Pb emissions, and exposure to soil contaminated with deposited 8 

### Pb can occur through resuspended PM as well as shoe tracking and hand

- to

- mouth 9 

### contact, which is the main pathway of childhood exposure to Pb. In general, soil Pb 10 

### concentrations tended to be higher within inner

- city commun ities compared with 11 

### neighborhoods surrounding the city. Recent data by Yamamoto et al. ( 2006 ) have shown 12 

### that the size distribution of particles collected on children’s hands have a mode around 13



### 40 μm with the upper tail of the distribution extending to 200

- 300 μm. Infiltration of Pb 14



### dust into indoor environments has been demon strated, and Pb dust has been shown to 15 

### persist in indoor environments even after repeated cleanings. Measurements of particle

16 

### bound Pb exposures reported in this assessment have shown that personal exposure 17 

### measurements for Pb concentration are typically h igher than indoor or outdoor ambient 18 

### Pb concentrations. These findings may be related to local resuspension with body 19



### movement. 20



### 4.7.2 Toxicokinetics

The majority of Pb in the body is found in bone (roughly 90% in adults, 70% in children); 21 

### only about 1% of Pb is found in the blood. Pb in blood is primarily (~99%) bound to red 22 

### blood cells (RBCs). It has been suggested that the small fraction of Pb in plasma (<1%) 23 

### may be the more biologically labile and toxicologically active fraction of the circulating 24



### Pb. The rela tionship between Pb in blood and plasma is pseudo

- linear at relatively low 25 

### daily Pb intakes ( i.e., <10 μg/day/kg) and at blood Pb concentrations <25 μg/dL, and 26 

### becomes curvilinear at higher blood Pb concentrations due to saturable binding to RBC 27 

### proteins. As blood Pb level increases and the higher affinity binding sites for Pb in RBCs 28 

### become saturated, a larger fraction of the blood Pb is available in plasma to distribute to 29



### brain and other Pb

- responsive tissues. 30



### The burden of Pb in the body may be viewed a s divided between a dominant slow 31 

### ( i.e., uptake and elimination) compartment (bone) and smaller fast compartment(s) (soft 32 

### tissues). Pb uptake and elimination in soft tissues is much faster than in bone. Pb 33 

### accumulates in bone regions undergoing the most ac tive calcification at the time of 34February 2012 4

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### exposure. During infancy and childhood, bone calcification is most active in trabecular 1 

### bone ( e.g., patella); whereas, in adulthood, calcification occurs at sites of remodeling in 2 

### cortical ( e.g., tibia) and trabecular bone ( Aufder heide and Wittmers, 1992 )

. A high bone 3 

### formation rate in early childhood results in the rapid uptake of circulating Pb into 4 

### mineralizing bone; however, in early childhood bone Pb is also recycled to other tissue 5 

### compartments or excreted in accordance with a high bone resorption rate ( O'Flaherty, 6


### 1995 )

. Thus, much of the Pb acquired early in life is not permanently fixed in the bone. 7



### The exchange of Pb from plasma to the bone surface is a relatively rapid process. Pb in 8



### bone becomes distributed in trabecular and the more dense cortical bone. The proportion 9 

### of cortical to trabecular bone in the human body varies by age, but on average is about 10


### 80% cortical to 20% trabecular. Of the bone types, trabecular bone is more reflective of 11



### rec ent exposures than is cortical bone due to the slow turnover rate and lower blood 12 

### perfusion of cortical bone. Some Pb diffuses to deeper bone regions where it is relatively 13 

### inert, particularly in adults. These bone compartments are much more labile in infa nts 14 

### and children than in adults as reflected by half

- times for movement of Pb from bone into 15 

### to the plasma ( e.g., cortical half

- time = 0.23 years at birth, 3.7 years at 15 years of age, 16



### and 23 years in adults; trabecular half

- time = 0.23 years at birth, 2. 0 years at 15 years of 17 

### age, and 3.8 years in adults) ( Leggett, 1993 )

. 18



### Evidence for maternal

- to

- fetal transfer of Pb in humans is derived from cord blood to 19 

### maternal blood Pb ratios. Group mean ratios range from about 0.7 to 1.0 at the time of 20 

### delivery for mean maternal blood Pb levels ranging from 1.7 to 8.6 μg/dL. Transplacental 21 

### transfer of Pb may be facilitated by an increase in the plasma/blood Pb concentration 22 

### ratio during pregnancy. Maternal

- to

- fetal transfer of Pb appe ars to be related partly to the 23



### mobilization of Pb from the maternal skeleton. 24



### The dominant elimination phase of Pb kinetics in the blood, exhibited shortly after a 25 

### change in exposure occurs, has a half

- life of ~20

- 30 days. An abrupt change in Pb uptake 26 

### gives rise to a relatively rapid change in blood Pb, to a new quasi

- steady state, achieved 27



### in ~75

- 100 days ( i.e., 3

- 4 times the blood elimination half

- life). A slower phase of Pb 28 

### clearance from the blood may become evident with longer observation periods f ollowing 29 

### a decrease in exposure due to the gradual redistribution of Pb among bone and other 30


### compartments. 31



### 4.7.3 Lead Biomarkers

Overall, trends in blood Pb levels have been decreasing among U.S. children and adults 32 

### over the past 20 years (Section 4.4 ). The median blood Pb level for the entire U.S. 33 

### population is 1.2 μg/dL and the 95th percentile blood Pb level was 3.7 μg/dL, based on 34February 2012 4

- 122 Draft

– Do Not Cite or Quote 

### the 2007

- 2008 NHANES d ata ( NCHS, 2010 )

. Among children aged 1

- 5 years, the 1 

### median and 95th percentil es were slightly higher at 1.4 μg/dL and 4.1 μg/dL, 2 

### respectively. 3



### Blood Pb is dependent on both the recent exposure history of the individual, as well as 4 

### the long

- term exposure history that determines body burden and Pb in bone. The 5



### contribution of bone P b to blood Pb changes depending on the duration and intensity of 6 

### the exposure, age, and various other physiological stressors that may affect bone 7 

### remodeling ( e.g., nutritional status, pregnancy, menopause, extended bed rest, 8 

### hyperparathyro i dism) beyond th at which normally and continuously occurs . In children, 9 

### largely due to faster exchange of Pb to and from bone, blood Pb is both an index of recent 10 

### exposure and potentially an index of body burden. In adults and children, where exposure 11



### to Pb has effectivel y ceased or greatly decreased, a slow decline in blood Pb 12 

### concentrations over the period of years is most likely due to the gradual release of Pb 13 

### from bone. Bone Pb is an index of cumulative exposure and body burden. Even bone 14 

### compartments should be recogn ized as reflective of differing exposure periods with Pb in 15 

### trabecular bone exchanging more rapidly than Pb in cortical bone with the blood. This 16



### diffe rence in the compartments makes Pb in cortical bone a better marker of cumulative 17 

### exposure and Pb in trab ecular bone more likely to be correlated with blood Pb, even in 18



### adults. 19



### Sampling frequency is an important consideration when evaluating blood Pb and bone Pb 20 

### levels in epidemiologic studies, particularly when the exposure is not well characterized. 21



### It is difficult to determine what blood Pb is reflecting in cross

- sectional studies that 22 

### sample blood Pb once, whether recent exposure or movement of Pb from bone into blood 23 

### from historical exposures. In contrast, cross

- sectional studies of bone Pb and longitudi nal 24 

### samples of blood Pb concentrations over time provide more of an index of cumulative 25 

### exposure and are more reflective of average Pb body burdens over time. The degree to 26 

### which repeated sampling will reflect the actual long

- term time

- weighted average blo od 27 

### Pb concentration depends on the sampling frequency in relation to variability in 28 

### exposure. High variability in Pb exposures can produce episodic (or periodic) oscillations 29 

### in blood Pb concentration that may not be captured with low sampling frequencies. 30 

### Furthermore, similar blood Pb concentrations in two individuals (or populations), 31 

### regardless of their age, do not necessarily translate to similar body burdens or similar 32 

### exposure histories. 33



### The concentration of Pb in urine follows blood Pb concentration, in that it mainly reflects 34 

### the exposure history of the previous few months and therefore, is likely a relatively poor 35 

### index of Pb body burden. There is added complexity with Pb in urine because 36 

### concentration is also dependent upon urine flow rate, which r equires timed urine samples 37February 2012 4

- 123 Draft

– Do Not Cite or Quote 

### that is often not feasible in epidemiologic studies. Other biomarkers have been utilized to 1 

### a lesser extent ( e.g., Pb in teeth). 2



### 4.7.4 Air Lead

- Blood Lead Relationships

The 1986 Pb AQCD described epidemiological studies of relationshi ps between air Pb 3 

### and blood Pb. Much of the pertinent earlier literature described in the 1986 Pb AQCD 4



### was drawn from a meta

- analysis by Brunekreef ( 1984 )

. Based on the studies available at 5 

### that time that considered multiple air

- related Pb exposure pathways in the aggregate, the 6


### 19 86 Pb AQCD concluded that “the blood Pb versus air Pb slope β is much smaller at 7 

### high blood and air levels.” This is to say that the slope β was much smaller for 8 

### occupational exposures where high blood Pb levels (>40 μg/dL) and high air Pb levels 9 

### (much gre ater than 10 μg/m 3 

### ) prevailed relative to lower environmental exposures which 10 

### showed lower blood Pb and air Pb concentrations (<30 μg/dL and <3 μg/m 3 

### ). For those 11 

### environmental exposures, it was concluded that the relationship between blood Pb and air 12



### Pb “

... for direct inhalation appears to be approximately linear in the range of normal 13 

### ambient exposures (0.1

- 2.0 μg/m 3 

### ) ” (pp 1

- 98 of the 1986 Pb AQCD). In addition to the 14



### meta

- analysis of Brunekreef ( 1984 )

, more recent studies have provided data from which 15



### estimates of the blood Pb

- air P b slope can be derived for children ( Table 2

- 7 ). The ran ge 16



### of estimates from these s tudies is 2

- 9 μg/dL per μg/m 3 

### , which encompasses the estimate 17



### from the Brunekreef ( 1984 ) meta

- analysis of (3

- 6 μg/dL per μg/m 3 

### ). Most studies have 18



### described the blood Pb

- air Pb rel ationship as either log

- log ( Schnaas et al., 2004 ; Hayes 19 

### et al., 1994 ; Brunekreef, 1984 )

, which predicts an increase in the blood Pb

- air Pb slope 20 

### with decreasing air Pb concentration or linear ( Hi lts, 2003 ; Tripathi et al., 2001 ; Schwartz 21 

### and Pitcher, 1989 )

, which predicts a constant blood Pb

- air Pb slope across all air Pb 22 

### concentrations. These differences may simply reflect model selection by the 23 

### investigators; alternative models are not reported in these studies. The blood Pb

- air Pb 24 

### slope may also be af fected in some studies by the inclusion of parameters (e.g., soil Pb) 25 

### that may account for some of the variance in blood Pb attributable to air Pb. Other factors 26 

### that likely contribute to the derived blood Pb

- air Pb slope include differences in the 27 

### populat ions examined and Pb sources, which varied among individual studies. 28



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