0
 No LSL
 Rep
                                                                           0.82
 No LSL
 Rep
 Yes
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
Acronyms: CCT = corrosion control treatment; LSL = lead service line; POU = point-of-use.

Exhibit G.21: Summary of Geometric Mean Water Lead Concentration Changes Resulting from Rule Implementation, and Associated Number of People for Each Treatment Combination Change over 35-Year Analysis Period (Alternative First Liter Compliance Sampling Option, High Cost Scenario)
Beginning Condition
Ending Condition
Number of People (over 35 years)
LSL
CCT
Concentration ug/L
LSL
CCT
POU
Concentration ug/L
Baseline
Option
Incremental
 LSL
 None
                                                                          18.08
 No LSL
 None
 None
                                                                           0.82
                                                                          8,450
                                                                          6,483
                                                                         -1,967
 LSL
 None
                                                                          18.08
 LSL
 Rep
 None
                                                                           5.48
                                                                         31,482
                                                                         22,396
                                                                         -9,086
 LSL
 None
                                                                          18.08
 No LSL
 Rep
 None
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
 LSL
 None
                                                                          18.08
 LSL
 None
 Yes
                                                                           0.82
                                                                              0
                                                                         14,276
                                                                         14,276
 Partial
 None
                                                                           8.43
 No LSL
 Partial
 None
                                                                           0.82
                                                                              0
                                                                          1,770
                                                                          1,770
 Partial
 None
                                                                           8.43
 Partial
 Rep
 None
                                                                           2.64
                                                                              0
                                                                          5,599
                                                                          5,599
 Partial
 None
                                                                           8.43
 No LSL
 Rep
 None
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
 Partial
 None
                                                                           8.43
 Partial
 Partial
 Yes
                                                                           0.82
                                                                              0
                                                                          3,569
                                                                          3,569
 No LSL
 None
                                                                           0.82
 No LSL
 Rep
 None
                                                                           0.82
                                                                      4,250,688
                                                                      3,656,471
                                                                       -594,217
 No LSL
 None
                                                                           0.82
 No LSL
 None
 Yes
                                                                           0.82
                                                                              0
                                                                        500,659
                                                                        500,659
 LSL
 Partial
                                                                           9.92
 No LSL
 Partial
 No
                                                                           0.82
                                                                        132,648
                                                                        786,830
                                                                        654,183
 LSL
 Partial
                                                                           9.92
 LSL
 Rep
 None
                                                                           5.48
                                                                        610,584
                                                                      5,713,470
                                                                      5,102,886
 LSL
 Partial
                                                                           9.92
 No LSL
 Rep
 None
                                                                           0.82
                                                                              0
                                                                        150,261
                                                                        150,261
 LSL
 Partial
                                                                           9.92
 LSL
 Partial
 Yes
                                                                           0.82
                                                                              0
                                                                         76,197
                                                                         76,197
 Partial
 Partial
                                                                           4.72
 No LSL
 Partial
 No
                                                                           0.82
                                                                        219,833
                                                                        191,858
                                                                        -27,975
 Partial
 Partial
                                                                           4.72
 Partial
 Rep
 None
                                                                           2.64
                                                                        980,129
                                                                      1,420,079
                                                                        439,950
 Partial
 Partial
                                                                           4.72
 No LSL
 Rep
 None
                                                                           0.82
                                                                              0
                                                                         37,557
                                                                         37,557
 Partial
 Partial
                                                                           4.72
 Partial
 Partial
 Yes
                                                                           0.82
                                                                              0
                                                                         17,931
                                                                         17,931
 No LSL
 Partial
                                                                           0.82
 No LSL
 Rep
 None
                                                                           0.82
                                                                     16,034,874
                                                                     53,114,813
                                                                     37,079,938
 No LSL
 Partial
                                                                           0.82
 No LSL
 Partial
 Yes
                                                                           0.82
                                                                              0
                                                                         77,208
                                                                         77,208
 LSL
 Rep
                                                                           5.48
 No LSL
 Rep
 None
                                                                           0.82
                                                                              0
                                                                        230,119
                                                                        230,119
 LSL
 Rep
                                                                           5.48
 LSL
 Rep
 Yes
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
 Partial
 Rep
                                                                           2.64
 Partial
 Rep
 Yes
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
 No LSL
 Rep
                                                                           0.82
 No LSL
 Rep
 Yes
                                                                           0.82
                                                                              0
                                                                              0
                                                                              0
Acronyms: CCT = corrosion control treatment; LSL = lead service line; POU = point-of-use.

Exhibit G.22 and Exhibit G.23 display the estimated benefits results for the alternative first liter compliance sampling Option at a 3 and 7 percent discount rate, respectively. Using this alternative option using the first liter compliance sampling protocol in place of the sampling protocol of the final LCRR reduced benefits by 48 percent in the low cost option and 16 percent in the high cost option assuming a 3 percent discount rate, and decreases benefits by 49 percent in the low cost and 15 percent in the high cost option assuming a 7 percent discount rate.

Exhibit G.22: National Annual Benefits - All PWS Alternative First Liter Compliance Sampling Option at 3% Discount Rate (2016$)

Low Cost Estimate
High Cost Estimate

                                                                   Previous LCR
                                                             First Liter Option
                                                                    Incremental
                                                                   Previous LCR
                                                             First Liter Option
                                                                    Incremental
 Number of Children Impacted (over 35 years)
                                                                         29,000
                                                                        480,000
                                                                        452,000
                                                                        704,000
                                                                      2,812,000
                                                                      2,108,000
 Annual IQ Point Decrement Avoided (CCT Due to ALE)
                                                                            190
                                                                            718
                                                                            528
                                                                          5,228
                                                                         10,000
                                                                          4,997
 Annual Value of IQ Impacts Avoided (CCT Due to ALE)
                                                                     $3,344,000
                                                                    $12,119,000
                                                                     $8,776,000
                                                                    $96,449,000
                                                                   $186,130,000
                                                                    $89,680,000
 Annual IQ Point Decrement Avoided (CCT Due to TLE)
                                                                              0
                                                                          2,673
                                                                          2,673
                                                                              0
                                                                         15,000
                                                                         15,000
 Annual Value of IQ Impacts Avoided (CCT Due to TLE)
                                                                             $0
                                                                    $46,895,000
                                                                    $46,895,000
                                                                             $0
                                                                   $274,502,000
                                                                   $274,502,000
 Annual IQ Point Decrement Avoided (LSLR  -  Mandatory)
                                                                            128
                                                                            585
                                                                            457
                                                                          3,106
                                                                          4,851
                                                                          1,745
 Annual Value of IQ Impacts Avoided (LSLR-Mandatory)
                                                                     $2,375,000
                                                                    $10,252,000
                                                                     $7,877,000
                                                                    $61,497,000
                                                                    $93,337,000
                                                                    $31,840,000
 Annual IQ Point Decrement Avoided (LSLR  -  Goal Based)
                                                                              0
                                                                          1,257
                                                                          1,257
                                                                              0
                                                                          4,522
                                                                          4,522
 Annual Value of IQ Impacts Avoided (LSLR-Goal Based)
                                                                             $0
                                                                    $22,831,000
                                                                    $22,831,000
                                                                             $0
                                                                    $87,103,000
                                                                    $87,103,000
 Annual IQ Point Decrement Avoided (LSLR  -  Customer Requested)
                                                                              0
                                                                          1,637
                                                                          1,637
                                                                              0
                                                                          1,747
                                                                          1,747
 Annual Value of IQ Impacts Avoided (LSLR-Customer Requested)
                                                                             $0
                                                                    $28,668,000
                                                                    $28,668,000
                                                                             $0
                                                                    $30,461,000
                                                                    $30,461,000
 Annual IQ Point Decrement Avoided (POU)
                                                                              0
                                                                              1
                                                                              1
                                                                              0
                                                                          1,389
                                                                          1,389
 Annual Value of IQ Impacts Avoided (POU)
                                                                             $0
                                                                        $26,000
                                                                        $26,000
                                                                             $0
                                                                    $27,930,000
                                                                    $27,930,000
 Total Annual Benefits
                                                                     $5,719,000
                                                                   $120,792,000
                                                                   $115,074,000
                                                                   $157,946,000
                                                                   $699,463,000
                                                                   $541,517,000
 Note: Benefits were estimated using blood lead levels in Exhibit 6-24 and the concentration-response function from Crump et al. (2013) and IQ valuation from EPA's reanalysis of Salkever (1995). IQ points are rounded to the nearest 100. This IQ point rounding occasionally results in incremental results that do not equal the exact difference between the presented previous LCR results and the presented First Liter Option results. The benefits are calculated based on the alternative first liter compliance sampling protocol.
Acronyms: ALE = action level exceedance; CCT = corrosion control treatment; LSLR = lead service line replacement; POU = point-of-use; TLE = trigger level exceedance.

Exhibit G.23: National Annual Benefits - All PWS Alternative First Liter Compliance Sampling Option at 7% Discount Rate (2016$)

Low Cost Estimate
High Cost Estimate

                                                                   Previous LCR
                                                             First Liter Option
                                                                    Incremental
                                                                   Previous LCR
                                                             First Liter Option
                                                                    Incremental
 Number of Children Impacted (over 35 years)
                                                                         29,000
                                                                        480,000
                                                                        452,000
                                                                        704,000
                                                                      2,812,000
                                                                      2,108,000
 Annual IQ Point Decrement Avoided (CCT Due to ALE)
                                                                            190
                                                                            718
                                                                            528
                                                                          5,228
                                                                         10,000
                                                                          4,997
 Annual Value of IQ Impacts Avoided (CCT Due to ALE)
                                                                       $581,000
                                                                     $1,975,000
                                                                     $1,395,000
                                                                    $17,790,000
                                                                    $33,645,000
                                                                    $15,856,000
 Annual IQ Point Decrement Avoided (CCT Due to TLE)
                                                                              0
                                                                          2,673
                                                                          2,673
                                                                              0
                                                                         15,000
                                                                         15,000
 Annual Value of IQ Impacts Avoided (CCT Due to TLE)
                                                                             $0
                                                                     $8,111,000
                                                                     $8,111,000
                                                                             $0
                                                                    $50,532,000
                                                                    $50,532,000
 Annual IQ Point Decrement Avoided (LSLR  -  Mandatory)
                                                                            128
                                                                            585
                                                                            457
                                                                          3,106
                                                                          4,851
                                                                          1,745
 Annual Value of IQ Impacts Avoided (LSLR-Mandatory)
                                                                       $451,000
                                                                     $1,781,000
                                                                     $1,330,000
                                                                    $12,707,000
                                                                    $18,481,000
                                                                     $5,774,000
 Annual IQ Point Decrement Avoided (LSLR  -  Goal Based)
                                                                              0
                                                                          1,257
                                                                          1,257
                                                                              0
                                                                          4,522
                                                                          4,522
 Annual Value of IQ Impacts Avoided (LSLR-Goal Based)
                                                                             $0
                                                                     $4,195,000
                                                                     $4,195,000
                                                                             $0
                                                                    $17,314,000
                                                                    $17,314,000
 Annual IQ Point Decrement Avoided (LSLR  -  Customer Requested)
                                                                              0
                                                                          1,637
                                                                          1,637
                                                                              0
                                                                          1,747
                                                                          1,747
 Annual Value of IQ Impacts Avoided (LSLR-Customer Requested)
                                                                             $0
                                                                     $4,991,000
                                                                     $4,991,000
                                                                             $0
                                                                     $5,268,000
                                                                     $5,268,000
 Annual IQ Point Decrement Avoided (POU)
                                                                              0
                                                                              1
                                                                              1
                                                                              0
                                                                          1,389
                                                                          1,389
 Annual Value of IQ Impacts Avoided (POU)
                                                                             $0
                                                                         $4,899
                                                                         $4,899
                                                                             $0
                                                                     $5,915,000
                                                                     $5,915,000
 Total Annual Benefits
                                                                     $1,032,000
                                                                    $21,059,000
                                                                    $20,027,000
                                                                    $30,497,000
                                                                   $131,155,000
                                                                   $100,659,000
 Note: Benefits were estimated using blood lead levels in Exhibit 6-24 and the concentration-response function from Crump et al. (2013) and IQ valuation from EPA's reanalysis of Salkever (1995). IQ points are rounded to the nearest 100. This IQ point rounding occasionally results in incremental results that do not equal the exact difference between the presented previous LCR results and the presented First Liter Option results. The benefits are calculated based on the alternative first liter compliance sampling protocol.
Acronyms: ALE = action level exceedance; CCT = corrosion control treatment; LSLR = lead service line replacement; POU = point-of-use; TLE = trigger level exceedance.
References
CDC. 2017. National Vital Statistics Reports. Births: Final Data for 2015
Crump, K. S., Van Landingham, C., Bowers, T. S., Cahoy, D., & Chandalia, J. K. 2013. A statistical reevaluation of the data used in the Lanphear et al. ( 2005 ) pooled-analysis that related low levels of blood lead to intellectual deficits in children. Crit Rev Toxicol, 43(9), 785-799. doi:10.3109/10408444.2013.832726
Kirrane, E. F.., & Patel, M. M. 2014. Memorandum from EPA NCEA to ISA for Lead Docket: Identification and consideration of errors in Lanphear et al. (2005), "Low-Level Environmental Lead Exposure and Children's Intellectual Function: An International Pooled Analysis."
Lanphear, B. P., Hornung, R., Khoury, J., Yolton, K., Baghurst, P. A., Bellinger, D. C., . . . Roberts, R. 2005. Low-Level Environmental Lead Exposure and Children's Intellectual Function: An International Pooled Analysis. Environmental Health Perspectives, 113(7), 894-899. doi:10.1289/ehp.7688
Lin, D., Lutter, R., & Ruhm, C. J. 2018. Cognitive performance and labour market outcomes. Labour Economics, 51, 121-135.
Salkever, D. S. 1995. Updated Estimates of Earnings Benefits from Reduced Exposure of Children to Environmental Lead. Environmental Research, 70, 1-6. doi:0013-9351/95
U.S. EPA. 2007. Review of the National Ambient Air Quality Standards for Lead: Policy Assessment of Scientific and Technical Information.

: Alternative Approaches to Estimating Changes in Blood Lead Levels in Adults
In this section, EPA presents an assessment of alternative approaches to estimating the adult blood lead level (BLL) changes that could result from the final Lead and Copper Rule revisions (LCRR). The main approach for modeling BLLs in adults is described in Chapter 6. This approach uses BLLs from the National Health and Nutrition Examination Survey (NHANES) to approximate background exposures from sources other than water, the simulated drinking water concentrations summarized in Exhibit 6-12 and EPA's Adult Lead Methodology (ALM) to estimate adult BLLs under different drinking water treatment scenarios. Section H.1 describes alternative estimates of blood lead values in adults based on the use of an alternative exposure estimation model coupled with the ALM and the use of the All Ages Lead Model (AALM) to estimate BLL impacts.
In Appendix J, EPA provides a description of studies that inform its understanding about the concentration-response functions for one cardiovascular disease (CVD) endpoint  -  mortality  -  in adults. EPA acknowledges remaining uncertainty about the best quantitative relationship to describe the impacts of small changes in current adult BLLs on the risk of CVD mortality.
Blood Lead in Adults
In the main analysis described in Chapter 6, EPA estimated BLLs using the adult lead methodology with geometric mean inputs for background BLLs, drinking water lead concentrations, and drinking water consumption (as described in Section 6.5).
ALM Based Blood Lead
There are uncertainties in the best blood lead metric to use for estimating adult benefits, and this metric may depend on the health endpoint under consideration. The ALM model can generate yearly blood leads, which in turn can be averaged over various time periods of the adult's life.
ALM Based on Estimates of Daily Lead Intake from SHEDS Only
EPA also estimated blood lead using the ALM and estimates of daily lead intake from The Stochastic Human Exposure and Dose Simulation (SHEDS) only. That is, instead of using the background BLLs from NHANES as inputs into the ALM as was done in Chapter 6, EPA instead used geometric mean estimates of daily lead intake (ug/day) from SHEDS for soil, dust, and diet in addition to those for water. This avoids the potential double counting issue for drinking water lead discussed in Section 6.5.1. Exhibit H-1 shows blood lead estimates in adults using this method. For the SHEDS-ALM modeling, EPA continued using the model parameters summarized in Exhibit 6-30.
Exhibit H-1: ALM Estimates of Blood Lead Levels in Adults Based on Estimates of Daily Lead Intake from SHEDS
Lead Service Line Status
Corrosion Control Treatment Status
Blood Lead Level (ug/dL) for Specified Age Group in Years

20-29
30-39
40-49
50-59
60-69
70-80
                                      LSL
                                     None
                                     2.26
                                     2.88
                                     3.23
                                     3.42
                                     3.23
                                     3.13
                                    Partial
                                     None
                                     1.31
                                     1.60
                                     1.71
                                     1.84
                                     1.77
                                     1.68
                                    No LSL
                                     None
                                     0.54
                                     0.58
                                     0.60
                                     0.59
                                     0.56
                                     0.54
                                      LSL
                                    Partial
                                     1.44
                                     1.77
                                     1.93
                                     2.10
                                     2.02
                                     1.88
                                    Partial
                                    Partial
                                     0.73
                                     0.82
                                     0.87
                                     0.88
                                     0.86
                                     0.81
                                    No LSL
                                    Partial
                                     0.54
                                     0.58
                                     0.60
                                     0.59
                                     0.56
                                     0.54
                                      LSL
                                Representative
                                     1.01
                                     1.19
                                     1.27
                                     1.33
                                     1.30
                                     1.22
                                    Partial
                                Representative
                                     0.93
                                     1.08
                                     1.16
                                     1.21
                                     1.18
                                     1.09
                                    No LSL
                                Representative
                                     0.54
                                     0.58
                                     0.60
                                     0.59
                                     0.56
                                     0.54
                                      POU
                                     0.54
                                     0.58
                                     0.60
                                     0.59
                                     0.56
                                     0.54
Acronyms: LSL = lead service line; POU = point-of-use.
The SHEDS model does not output exposure estimates separately for males and females, so the values in Exhibit H-1 represent an average of both sexes. To facilitate comparison, the ALM-generated BLLs using NHANES as background (from Chapter 6, Exhibit 6-31) are averaged for males and females and displayed in Exhibit H-2.
Exhibit H-2: Average of Male and Female Blood Lead Levels from Exhibit 6-31
Lead Service Line Status
Corrosion Control Treatment Status
GM Blood Lead Level (ug/dL) for Specified Age Group in Years from the ALM at the 5[th] liter

20-29
30-39
40-49
50-59
60-69
70-80
                                      LSL
                                     None
                                     1.72
                                     1.86
                                     2.06
                                     2.32
                                     2.49
                                     2.70
                                    Partial
                                     None
                                     1.16
                                     1.28
                                     1.48
                                     1.74
                                     1.89
                                     2.07
                                    No LSL
                                     None
                                     0.72
                                     0.82
                                     1.02
                                     1.29
                                     1.41
                                     1.57
                                      LSL
                                    Partial
                                     1.25
                                     1.37
                                     1.57
                                     1.83
                                     1.98
                                     2.17
                                    Partial
                                    Partial
                                     0.94
                                     1.06
                                     1.26
                                     1.52
                                     1.66
                                     1.82
                                    No LSL
                                    Partial
                                     0.72
                                     0.82
                                     1.02
                                     1.29
                                     1.41
                                     1.57
                                      LSL
                                Representative
                                     0.99
                                     1.10
                                     1.30
                                     1.57
                                     1.70
                                     1.87
                                    Partial
                                Representative
                                     0.82
                                     0.93
                                     1.13
                                     1.40
                                     1.53
                                     1.69
                                    No LSL
                                Representative
                                     0.72
                                     0.82
                                     1.02
                                     1.29
                                     1.41
                                     1.57
                                      POU
                                     0.72
                                     0.82
                                     1.02
                                     1.29
                                     1.41
                                     1.57
Acronyms: ALM = Adult Lead Methodology; GM = geometric mean; LSL = lead service line; POU = point-of-use.

ALM Based Percentiles
As an additional sensitivity analysis of estimates of changes in adult BLLs, EPA calculated BLLs using inputs for background BLLs from NHANES, drinking water ingestion rates, and drinking water concentrations at the 25[th] and 75[th] percentiles. Exhibit H-3 shows the resulting BLLs for the 25[th] percentile and Exhibit H-4, for the 75[th] percentiles. This sensitivity analysis exemplifies the combined contribution that exposure factor assumptions, such as background lead, drinking water ingestion rate, and drinking water lead concentration have on the resulting BLLs. These blood lead estimates can be thought of as reasonable "high" and "low" estimates of BLLs, given the combination of high exposure factors versus low exposure factors.
Exhibit H-3: Estimates of Blood Lead Levels in Adults Associated with Background and Drinking Water Lead Exposures at the 25th Percentile using the Adult Lead Methodology
Lead Service Line Status
Corrosion Control Treatment Status
Sex
Blood Lead Level (ug/dL) for Specified Age Group in Years

20-29
30-39
40-49
50-59
60-69
70-80
25th Percentile
                                      LSL
                                     None
                                     Males
                                     0.81
                                     0.88
                                     1.04
                                     1.18
                                     1.30
                                     1.45

                                    Females
                                     0.65
                                     0.71
                                     0.84
                                     1.08
                                     1.17
                                     1.28
                                    Partial
                                     None
                                     Males
                                     0.66
                                     0.73
                                     0.88
                                     1.03
                                     1.13
                                     1.26

                                    Females
                                     0.50
                                     0.55
                                     0.69
                                     0.93
                                     1.00
                                     1.09
                                    No LSL
                                     None
                                     Males
                                     0.54
                                     0.61
                                     0.76
                                     0.91
                                     1.00
                                     1.11

                                    Females
                                     0.38
                                     0.43
                                     0.56
                                     0.81
                                     0.87
                                     0.94
                                      LSL
                                    Partial
                                     Males
                                     0.69
                                     0.76
                                     0.91
                                     1.05
                                     1.16
                                     1.29

                                    Females
                                     0.52
                                     0.58
                                     0.71
                                     0.95
                                     1.03
                                     1.12
                                    Partial
                                    Partial
                                     Males
                                     0.61
                                     0.67
                                     0.82
                                     0.97
                                     1.07
                                     1.19

                                    Females
                                     0.44
                                     0.49
                                     0.63
                                     0.87
                                     0.94
                                     1.02
                                    No LSL
                                    Partial
                                     Males
                                     0.54
                                     0.61
                                     0.76
                                     0.91
                                     1.00
                                     1.11

                                    Females
                                     0.38
                                     0.43
                                     0.56
                                     0.81
                                     0.87
                                     0.94
                                      LSL
                                Representative
                                     Males
                                     0.62
                                     0.68
                                     0.84
                                     0.98
                                     1.08
                                     1.20

                                    Females
                                     0.45
                                     0.51
                                     0.64
                                     0.88
                                     0.95
                                     1.04
                                    Partial
                                Representative
                                     Males
                                     0.57
                                     0.64
                                     0.79
                                     0.94
                                     1.03
                                     1.15

                                    Females
                                     0.41
                                     0.46
                                     0.59
                                     0.83
                                     0.90
                                     0.98
                                    No LSL
                                Representative
                                     Males
                                     0.54
                                     0.61
                                     0.76
                                     0.91
                                     1.00
                                     1.11

                                    Females
                                     0.38
                                     0.43
                                     0.56
                                     0.81
                                     0.87
                                     0.94
                                      POU
                                     Males
                                     0.54
                                     0.61
                                     0.76
                                     0.91
                                     1.00
                                     1.11

                                    Females
                                     0.38
                                     0.43
                                     0.56
                                     0.81
                                     0.87
                                     0.94
Acronyms: LSL = lead service line; POU = point-of-use.

Exhibit H-4: Estimates of Blood Lead Levels in Adults Associated with Background and Drinking Water Lead Exposures at the 75th Percentile using the Adult Lead Methodology
Lead Service Line Status
Corrosion Control Treatment Status
Sex
Blood Lead Level (ug/dL) for Specified Age Group in Years

20-29
30-39
40-49
50-59
60-69
70-80
75th Percentile
                                      LSL
                                     None
                                     Males
                                     5.79
                                     6.01
                                     6.29
                                     6.68
                                     6.69
                                     6.60

                                    Females
                                     5.29
                                     5.52
                                     5.76
                                     6.27
                                     6.18
                                     6.13
                                    Partial
                                     None
                                     Males
                                     3.34
                                     3.51
                                     3.80
                                     4.19
                                     4.28
                                     4.33

                                    Females
                                     2.84
                                     3.03
                                     3.26
                                     3.77
                                     3.78
                                     3.86
                                    No LSL
                                     None
                                     Males
                                     1.42
                                     1.57
                                     1.85
                                     2.24
                                     2.41
                                     2.56

                                    Females
                                     0.93
                                     1.09
                                     1.32
                                     1.83
                                     1.91
                                     2.09
                                      LSL
                                    Partial
                                     Males
                                     3.72
                                     3.91
                                     4.19
                                     4.58
                                     4.66
                                     4.69

                                    Females
                                     3.23
                                     3.42
                                     3.66
                                     4.17
                                     4.16
                                     4.22
                                    Partial
                                    Partial
                                     Males
                                     2.39
                                     2.55
                                     2.84
                                     3.23
                                     3.36
                                     3.45

                                    Females
                                     1.90
                                     2.07
                                     2.30
                                     2.81
                                     2.85
                                     2.99
                                    No LSL
                                    Partial
                                     Males
                                     1.42
                                     1.57
                                     1.85
                                     2.24
                                     2.41
                                     2.56

                                    Females
                                     0.93
                                     1.09
                                     1.32
                                     1.83
                                     1.91
                                     2.09
                                      LSL
                                Representative
                                     Males
                                     2.60
                                     2.76
                                     3.05
                                     3.44
                                     3.56
                                     3.65

                                    Females
                                     2.10
                                     2.28
                                     2.52
                                     3.03
                                     3.06
                                     3.18
                                    Partial
                                Representative
                                     Males
                                     1.87
                                     2.03
                                     2.31
                                     2.70
                                     2.85
                                     2.98

                                    Females
                                     1.38
                                     1.54
                                     1.78
                                     2.29
                                     2.35
                                     2.51
                                    No LSL
                                Representative
                                     Males
                                     1.42
                                     1.57
                                     1.85
                                     2.24
                                     2.41
                                     2.56

                                    Females
                                     0.93
                                     1.09
                                     1.32
                                     1.83
                                     1.91
                                     2.09
                                      POU
                                     Males
                                     1.42
                                     1.57
                                     1.85
                                     2.24
                                     2.41
                                     2.56

                                    Females
                                     0.93
                                     1.09
                                     1.32
                                     1.83
                                     1.91
                                     2.09
Acronyms: LSL = lead service line; POU = point-of-use.
Blood Lead Estimates from the All Ages Lead Model
EPA additionally used the All Ages Lead Model (AALM), version 2.0 released in 2019 as an alternative approach to estimate BLLs in adults. The results from AALM were compared with those of the ALM. The AALM is a model that "has the capability of simulating Pb levels in body tissues (e.g., blood, bone, brain) and excreta at resulting from acute or chronic exposures to inorganic Pb that occur from birth through adulthood" (U.S. EPA, 2019, p. 4). It is a conceptual extension of the EPA IEUBK model and incorporates concepts from other blood lead models including the Leggett (Leggett, 1993) and O'Flaherty (O'Flaherty, 1998) models.  Users may modify inputs for lead concentrations in environmental media, ingestion rates, and other biokinetic parameters such as relative bioavailability.
Exposure estimates from SHEDS were used as inputs to the AALM to estimate BLLs in adults age 20-80. Exposure estimates from SHEDS include exposures to lead from air, dust, and food, in addition to water. Age and corresponding exposure levels via air, dust, water, and food from SHEDS were used in place of the AALM default exposure levels in the model. The gastrointestinal (GI) absorption fraction for each age in the AALM model was determined based on the formula within the model (U.S. EPA, 2019, Equation 2.3-28, p. 24). The methods used to run the AALM model using the SHEDS output are further detailed in Appendix G.1.3. AALM estimated BLLs using both arithmetic mean lead exposure and geometric mean lead exposure from SHEDS are presented in Exhibit H-5 and Exhibit H-6, respectively.
Exhibit H-5: AALM Estimated Blood Lead Levels (ug/dL) in Adults (20-80) Using 5[th] Liter SHEDS Arithmetic Mean Exposure Estimates
Lead Service Line Status
Corrosion Control Treatment Status
Sex
20-29
30-39

40-49
50-59

60-69

70-80
                                      LSL
                                     None
                                     Males
                                     5.41
                                     5.50
                                     5.74
                                     5.85
                                     5.54
                                     5.18

                                    Females
                                     7.00
                                     7.14
                                     7.44
                                     7.57
                                     7.17
                                     6.70
                                      LSL
                                Representative
                                     Males
                                     2.35
                                     2.24
                                     2.21
                                     2.21
                                     2.12
                                     1.98

                                    Females
                                     3.04
                                     2.91
                                     2.86
                                     2.86
                                     2.75
                                     2.56
                                    No LSL
                                     None
                                     Males
                                     1.26
                                     1.07
                                     0.99
                                     0.96
                                     0.90
                                     0.86

                                    Females
                                     1.63
                                     1.39
                                     1.29
                                     1.25
                                     1.17
                                     1.11
                                      LSL
                                    Partial
                                     Males
                                     3.38
                                     3.40
                                     3.32
                                     3.56
                                     3.37
                                     3.09

                                    Females
                                     4.37
                                     4.42
                                     4.30
                                     4.61
                                     4.35
                                     4.00
                                    Partial
                                    Partial
                                     Males
                                     2.17
                                     2.00
                                     1.99
                                     1.98
                                     1.95
                                     1.78

                                    Females
                                     2.80
                                     2.60
                                     2.58
                                     2.57
                                     2.52
                                     2.30
                                    No LSL
                                    Partial
                                     Males
                                     1.26
                                     1.07
                                     0.99
                                     0.96
                                     0.90
                                     0.86

                                    Females
                                     1.63
                                     1.39
                                     1.29
                                     1.25
                                     1.17
                                     1.11
                                    Partial
                                     None
                                     Males
                                     3.06
                                     3.00
                                     2.98
                                     3.08
                                     2.97
                                     2.75

                                    Females
                                     3.96
                                     3.89
                                     3.86
                                     3.99
                                     3.84
                                     3.56
                                    Partial
                                Representative
                                     Males
                                     1.67
                                     1.52
                                     1.47
                                     1.45
                                     1.40
                                     1.29

                                    Females
                                     2.16
                                     1.97
                                     1.90
                                     1.88
                                     1.81
                                     1.66
                                    No LSL
                                Representative
                                     Males
                                     1.26
                                     1.07
                                     0.99
                                     0.96
                                     0.90
                                     0.86

                                    Females
                                     1.63
                                     1.39
                                     1.29
                                     1.25
                                     1.17
                                     1.11
                                      POU
                                     Males
                                     1.26
                                     1.07
                                     0.99
                                     0.96
                                     0.90
                                     0.86

                                    Females
                                     1.63
                                     1.39
                                     1.29
                                     1.25
                                     1.17
                                     1.11
Acronyms: LSL = lead service line; POU = point-of-use.

Blood lead levels estimated using version 2.0 of the AALM differed than those used in the main analysis, which were estimated using the ALM (see Chapter 6, Section <IP_ADDRESS>). For scenarios with higher water concentrations, AALM generally predicted higher blood leads than ALM, and this is more pronounced when the arithmetic mean SHEDS inputs are used, which is consistent with the higher arithmetic mean than geometric mean in the drinking water data. Since the lead intake for men and women was the same, it was observed and expected that blood lead levels in women would be higher than blood lead levels in men due to differences in biokinetic parameters for each sex.
Exhibit H-6: AALM Estimated Blood Lead Levels (ug/dL) in Adults (20-80) Using 5[th] Liter SHEDS Geometric Mean Exposure Estimates
Lead Service Line Status
Corrosion Control Treatment Status
Sex
20-29
30-39
40-49
50-59
60-69
70-80

                                      LSL
                                     None
                                     Males
                                     3.04
                                     3.24
                                     3.38
                                     3.55
                                     3.44
                                     3.36

                                    Females
                                     3.93
                                     4.20
                                     4.38
                                     4.60
                                     4.45
                                     4.34
                                    Partial
                                     None
                                     Males
                                     1.55
                                     1.47
                                     1.44
                                     1.47
                                     1.45
                                     1.38

                                    Females
                                     2.00
                                     1.90
                                     1.87
                                     1.91
                                     1.88
                                     1.79
                                    No LSL
                                     None
                                     Males
                                     1.00
                                     0.83
                                     0.77
                                     0.74
                                     0.70
                                     0.67

                                    Females
                                     1.29
                                     1.08
                                     0.99
                                     0.96
                                     0.91
                                     0.87
                                      LSL
                                    Partial
                                     Males
                                     2.07
                                     2.08
                                     2.10
                                     2.23
                                     2.18
                                     2.08

                                    Females
                                     2.67
                                     2.69
                                     2.72
                                     2.89
                                     2.83
                                     2.69
                                    Partial
                                    Partial
                                     Males
                                     1.46
                                     1.35
                                     1.33
                                     1.36
                                     1.33
                                     1.25

                                    Females
                                     1.88
                                     1.76
                                     1.72
                                     1.76
                                     1.72
                                     1.62
                                    No LSL
                                    Partial
                                     Males
                                     1.00
                                     0.83
                                     0.77
                                     0.74
                                     0.70
                                     0.67

                                    Females
                                     1.29
                                     1.08
                                     0.99
                                     0.96
                                     0.91
                                     0.87
                                      LSL
                                Representative
                                     Males
                                     1.91
                                     1.90
                                     1.88
                                     1.97
                                     1.93
                                     1.86

                                    Females
                                     2.47
                                     2.46
                                     2.44
                                     2.56
                                     2.50
                                     2.40
                                    Partial
                                Representative
                                     Males
                                     1.21
                                     1.08
                                     1.03
                                     1.03
                                     1.00
                                     0.96

                                    Females
                                     1.57
                                     1.40
                                     1.34
                                     1.33
                                     1.29
                                     1.24
                                    No LSL
                                Representative
                                     Males
                                     1.00
                                     0.83
                                     0.77
                                     0.74
                                     0.70
                                     0.67

                                    Females
                                     1.29
                                     1.08
                                     0.99
                                     0.96
                                     0.91
                                     0.87
                                      POU
                                     Males
                                     1.00
                                     0.83
                                     0.77
                                     0.74
                                     0.70
                                     0.67

                                    Females
                                     1.29
                                     1.08
                                     0.99
                                     0.96
                                     0.91
                                     0.87
Acronyms: LSL = lead service line; POU = point-of-use.

References
Leggett, R. W. 1993. An Age-Specific Kinetic Model of Lead Metabolism in Humans. Environmental Health Perspectives, 101: 598-616.
O'Flaherty, E.J. 1998. A physiologically based kinetic model for lead in children and adults. Environmental Health Perspectives, 106, Supplement 6: 1495-1503. https://ehp.niehs.nih.gov/doi/pdf/10.1289/ehp.98106s61495.
United States Environmental Protection Agency (U.S. EPA). 2019. Technical Support Document for the All Ages Lead Model (AALM)  -  Parameters, Equations and Evaluations. EPA600/R-19/011. Office of Research and Develop. Washington, D.C.

: Discussion of Additional Potentially Reduced Adverse Health Endpoints in Children
In this Appendix, EPA presents methods by which one may consider quantifying two additional endpoints in children: decreases in attention-deficit/hyperactivity disorder (ADHD) (Section I.1) and reductions in birth weight (Section I.2) and present potential methods for estimating necessary blood lead levels. Once more detailed methods have been developed, EPA will subject them to external peer review. However, as an external peer review has not yet been conducted on the quantification of these endpoints in regulatory analysis, these endpoints do not appear in the quantified benefits estimates for the Final LCRR.
Attention-Deficit/Hyperactivity Disorder
Attention-deficit/hyperactivity disorder (ADHD) is a disorder that is characterized by persistent symptoms of hyperactivity, impulsivity, and/or inattention. Inattentive symptoms include difficulty in sustaining concentration, keeping organized, and completing tasks. Hyperactivity and impulsivity refer to symptoms such as restlessness, excessive talking, and interrupting others. ADHD is linked to decreased academic achievement and performance and increased likelihood of criminal behavior (Doshi et al., 2012). It is thus associated with large economic costs to society as a result of its impact on health care, education, the criminal justice system, and income and productivity losses (Doshi et al., 2012).
EPA (2013) and the National Toxicology Program (2012) have both assigned the highest weight of evidence (causal determination and sufficient determination, respectively) to the association between symptoms of ADHD and lead exposure. The causal relationship cited in the EPA ISA relies on data from both cross-sectional studies and prospective cohort studies. The research collectively looked at lead exposures at various points in time including prenatal blood lead, blood lead measured 9-11 years before attention was measured, lifetime average blood lead, or tooth lead level. For example, Bellinger et al. (1994) measured tooth lead (dentin) in participants in 1[st]-2[nd] grade and found an association with several measures of attention assessed over a decade later, at ages 19-20 years old. Overall, most studies of children with mean blood lead levels from 1 to 13 μg/dL found an association with attention decrements, though evidence is more variable for blood lead levels from 1 to 6.5 μg/dL.
Although the EPA ISA did not assign a rating to the relationship between lead exposures and ADHD diagnosis specifically, the report does examine studies on this association separately within the discussion on attention, impulsivity, and hyperactivity. The main limitation of the body of research investigating ADHD as an outcome was that all identified studies were cross-sectional, which means that temporality between lead exposures and ADHD incidence cannot be determined by these studies alone. In addition, the diagnostic criteria for ADHD include a range of behaviors; there may be differences in subjects regarding which specific behaviors led to the ADHD diagnosis. Because of this, the studies specifically looking at ADHD as an outcome are characterized in the ISA as weak relative to those investigating the effects of lead on the broader category of attention, impulsivity, and hyperactivity. However, numerous studies have shown associations between lead exposures and ADHD incidence in diverse populations. For example, Wang et al. (2008) found a positive association in Chinese children recruited from pediatric clinics. Braun et al. (2006) analyzed data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) and found that children aged 4-15 years old who had blood lead levels above 2 ug/dL had a 4.1 times greater risk of ADHD than children with blood lead below 0.8 ug/dL. Additionally, studies using ADHD diagnosis as the endpoint, rather than symptoms related to ADHD, are more amenable to benefits analysis. This is because diagnoses may be more easily monetized than behaviors. For these reasons, along with the evidence from the ISA on the broader category of attention, impulsivity, and hyperactivity, EPA tasked Abt Associates to review studies of childhood lead exposure and ADHD and to derive a concentration-response function to link changes in lead exposures to changes in ADHD prevalence in children. In the following sections, we discuss methods for estimating blood lead levels in this population (I.1.1) and describe the concentration-response function derived by Abt Associates (I.1.2), using the findings of Froehlich et al. (2009), a study of lead exposure and ADHD in children aged 8 to 15 years.
 Estimates of Blood Lead in Children Aged 8-15
To estimate changes in attention-deficit/hyperactivity disorder (ADHD) as a result of the rule, estimates of changes in blood lead levels in children aged 8 to 15 years old will be needed. However, there is currently no established model for estimating blood lead levels in children over the age of seven. The All Ages Lead Model (AALM) has the capability to estimate blood lead in this population, but it is currently still in the process of peer review. For this discussion, EPA used two methods for estimating blood lead in this population: estimates based on scaling of changes in blood lead levels in children aged 6-7 from the SHEDS-IEUBK coupling, and those based on the beta version of the AALM.
To scale blood lead estimates for 6- to 7-year-olds to those of 8- to 15-year-olds, EPA compared blood lead levels reported in the concentration-response function study by Froehlich et al. (2009) to those for 6- to 7-year-olds in the same 2001-2004 NHANES cohort. Blood lead levels in the 8- to 15-year-olds studied by Froehlich et al. (2009) were 0.8 times the BLLs in 6- to 7-year-olds. Thus, EPA multiplied the SHEDS-IEUBK coupling estimates by 0.8 to estimate blood lead levels in 8- to 15-year-olds. Exhibit I-1 shows the blood lead levels from SHEDS-IEUBK used to estimate changes in ADHD.
Exhibit I.1 Geometric Mean Blood Lead in 8- to 15-Year-Olds Based on SHEDS-IEUBK Coupling
Lead Service Line Status
                          Corrosion Control Treatment
                   Geometric Mean Blood Lead Level (ug/dL)
LSL
None
                                     1.87
Partial
None
                                     1.32
No LSL
None
                                     0.79
LSL
Partial
                                     1.41
Partial
Partial
                                     1.10
No LSL
Partial
                                     0.79
LSL
Representative
                                     1.15
Partial
Representative
                                     0.96
No LSL
Representative
                                     0.79
                                      POU
                                     0.79

Blood lead estimates were additionally estimated using the beta version of the AALM assuming drinking water concentrations for the various LCR scenarios. Exposure estimates from SHEDS were used as inputs to the AALM to estimate blood lead levels in 8- to 15-year-olds. Exposure estimates from SHEDS include exposures to lead from air, dust, and food, in addition to water.
Age and corresponding lead exposure levels via air, dust, water and food from SHEDS were used in place of the AALM default exposure levels. The GI absorption fraction for each age in the AALM model was determined based on the formulas built within the model. The methods used to run the AALM model using the SHEDS output are further detailed in Appendix G.1.3. AALM estimated blood lead levels using both arithmetic mean lead exposure and geometric mean lead exposure from SHEDS are presented in Exhbit I.2 and Exhibit I.3, respectively. Since the AALM uses different assumptions for biological parameters in each sex, results for males and females are presented separately.
Exhibit I.2: AALM Estimated Blood Lead Levels in 8- to 15-Year-Olds from 5[th] Liter SHEDS Arithmetic Mean Exposure Estimates
                           Lead Service Line Status
                      Corrosion Control Treatment Status
                                     Males
                                    Females
                            Average for Both Sexes

                                      LSL
                                     None
                                     4.08
                                     4.09
                                     4.08
                                    Partial
                                     None
                                     2.78
                                     2.79
                                     2.78
                                    No LSL
                                     None
                                     1.77
                                     1.78
                                     1.78
                                      LSL
                                    Partial
                                     2.98
                                     3.00
                                     2.99
                                    Partial
                                    Partial
                                     2.30
                                     2.31
                                     2.30
                                    No LSL
                                    Partial
                                     1.77
                                     1.78
                                     1.78
                                      LSL
                                Representative
                                     2.38
                                     2.39
                                     2.39
                                    Partial
                                Representative
                                     2.01
                                     2.02
                                     2.01
                                    No LSL
                                Representative
                                     1.77
                                     1.78
                                     1.78
                                      POU
                                     1.77
                                     1.78
                                     1.78

Exhibit I.3: AALM Estimated Blood Lead Levels in 8- to 15-Year-Olds from 5[th] Liter SHEDS Geometric Mean Exposure Estimates
                           Lead Service Line Status
                      Corrosion Control Treatment Status
                                     Males
                                    Females
                            Average for Both Sexes

                                      LSL
                                     None
                                     3.05
                                     3.12
                                     3.09
                                    Partial
                                     None
                                     2.21
                                     2.26
                                     2.23
                                    No LSL
                                     None
                                     1.56
                                     1.58
                                     1.57
                                      LSL
                                    Partial
                                     2.34
                                     2.39
                                     2.37
                                    Partial
                                    Partial
                                     1.89
                                     1.93
                                     1.91
                                    No LSL
                                    Partial
                                     1.56
                                     1.58
                                     1.57
                                      LSL
                                Representative
                                     1.95
                                     1.99
                                     1.97
                                    Partial
                                Representative
                                     1.71
                                     1.74
                                     1.72
                                    No LSL
                                Representative
                                     1.56
                                     1.58
                                     1.57
                                      POU
                                     1.56
                                     1.58
                                     1.57

Estimates of blood lead associated with each LSL and CCT combination are lower using the SHEDS-IEUBK scaling method. However, the changes in blood lead levels are smaller when using the SHEDS-IEUBK estimates than the AALM estimates.
Concentration-Response Function for Lead and ADHD
EPA is exploring the use of a paper by Froehlich et al. (2009), "Association of Tobacco and Lead Exposures with Attention-Deficit/Hyperactivity Disorder," to develop a concentration-response function. Froehlich et al. (2009) analyzed 2001-2004 NHANES data on the association between ADHD diagnosis and blood lead levels in 8 to 15 year olds while controlling for several confounders. In the sample of 2,588 children, 8.7% met the criteria for DSM diagnosis for ADHD. There was a significant association between blood lead levels and ADHD: children in the highest tertile of lead exposure (>1.3 ug/dL) were 2.3 times (95% CI, 1.5-3.8) as likely to have ADHD as those in the lowest tertile (0.2-0.8 ug/dL). When BLLs were log-transformed, the adjusted OR for ADHD diagnosis was 1.8 (95% CI, 1.2-2.8). This study can be used to inform a health impact function to estimate changes in the rate of ADHD as a result of reductions in blood lead that result from the implementation of CCT and LSL replacement under the final changes to the LCR.
In this appendix, EPA presented two methods of estimating blood leads in 8- to 15-year-olds which could be used in conjunction with a concentration-response function from a study Froehlich et al. (2009) to estimate reductions in ADHD due to reductions in lead exposures.  To scale blood lead estimates for 6- to 7-year-olds to those of 8- to 15-year-olds, EPA compared blood lead levels reported in the study by Froehlich et al. (2009) to those for 6- to 7-year-olds in the same 2001-2004 NHANES cohort. Blood lead levels in the 8- to 15-year-olds studied by Froehlich et al. (2009) were 0.8 times the BLLs in 6- to 7-year-olds. Thus, EPA multiplied the SHEDS-IEUBK coupling estimates by 0.8 to estimate blood lead levels in 8- to 15-year-olds.
Reductions in Birth Weight
Reductions in birth weight can increase the risk of medical complications in infants (Goldenberg & Culhane, 2007). In the long-term, low birth weight can increase the risk of diseases such as heart disease and diabetes in adulthood (Goldenberg & Culhane, 2007). In the 2013 Integrated Science Assessment for Lead, EPA concluded that the scientific literature is suggestive of an association between lead exposure and reduced birth weight. Specifically, the EPA ISA stated:
   "Associations were observed between Pb and low birth weight in epidemiologic studies of maternal bone Pb and studies of air exposures and birth weight. The associations were less consistent when using maternal blood Pb or umbilical cord and placenta Pb as the exposure measurement although some studies did report an association" (U.S. EPA, 2013), p. 4-655.
The NTP Monograph found "sufficient evidence that maternal blood Pb levels <5 ug/dL are associated with reduced fetal growth and lower birth weight" (National Toxicology Program, 2012, p. 139). NTP makes this conclusion while acknowledging that the results are not entirely consistent across studies but states that "multiple prospective, retrospective, and cross-sectional studies provide sufficient evidence that maternal blood Pb levels <10 ug/dL are associated with reduced fetal growth and lower birth weight" (National Toxicology Program, 2012, p. 140). NTP also stated that the findings between bone lead and birth weight were consistent, but the evidence was limited because all the studies that use bone as the biomarker for maternal lead exposure are based on a single cohort in Mexico City.
Given the sufficient evidence determination by NTP and the fact that EPA noted that associations between lead and lower birth weight were observed in well-conducted epidemiologic studies, EPA tasked Abt Associates to review the literature to select a concentration-response function for the association between maternal blood lead levels and reductions in birth weight. Section I.2.1 describes an approach to estimate blood lead levels in pregnant women for use in a concentration-response function, which is described in Section I.2.2.
Estimates of Blood Lead Levels in Pregnant Women
To estimate blood lead levels in pregnant women, EPA used the ALM to generate estimates of blood lead in women of childbearing age, who are defined as women between 17 and 45 years old. The geometric mean blood lead level from NHANES 2009-2014 for women aged 17 to 45 years old was used as the baseline blood lead in the ALM model. For drinking water inputs, geometric mean drinking water ingestion for adults was used along with the drinking water lead concentrations for each scenario under the Final LCRR. Exhibit I.3 shows the estimated pre- and post-rule blood lead levels in pregnant women.

Exhibit I.4: Geometric Mean Estimates of Blood Lead in Pregnant Women
                                  LSL Status
                                  CCT Status
                         Blood Lead Estimate (ug/dL)
                                      LSL
                                     None
                                     1.72
                                    Partial
                                     None
                                     1.14
                                    No LSL
                                     None
                                     0.69
                                      LSL
                                    Partial
                                     1.23
                                    Partial
                                    Partial
                                     0.92
                                    No LSL
                                    Partial
                                     0.69
                                      LSL
                                Representative
                                     0.97
                                    Partial
                                Representative
                                     0.80
                                    No LSL
                                Representative
                                     0.69
                                      POU
                                     0.69
Concentration-Response Function for Maternal Blood Lead and Reduced Birth Weight
EPA commissioned an updated review of the literature on the association between maternal blood lead levels and low birth weight; after EPA conducts additional analysis the intent is to have the report externally peer reviewed. Out of the 11 studies reviewed, nine found a significant negative association between maternal blood lead and reduced birth weight in offspring. Below we consider one of the studies with the most robust data for use in developing a dose-response function.  Zhu et al. (2010) was well-designed and had a very large sample size (approximately 43,000). In the National Toxicology Program's 2012 Monograph on the Health Effects of Low-Level Lead, the study by Zhu et al. (2010) was cited as the main reason for the "sufficient" weight-of-evidence determination for low birth weight and lead exposures. The beta estimate from Zhu et al. (2010) can be applied to a health impact function that could be used to estimate the changes in birth weight from changes in maternal blood lead resulting from the implementation of CCT and LSL replacement under the final changes to the LCR.
References
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Biederman, J., & Faraone, S. V. (2006). The effects of attention-deficit/ hyperactivity disorder on employment and household income. Med Gen Med, 8(12).
Braun, J. M., Kahn, R. S., Froehlich, T., Auinger, P., & Lanphear, B. P. (2006). Exposures to Environmental Toxicants and Attention Deficit Hyperactivity Disorder in U.S. Children. Environmental Health Perspectives, 114(12), 1904-1909. doi:10.1289/ehp.9478
Doshi, J. A., Hodgkins, P., Kahle, J., Sikirica, V., Cangelosi, M. J., Setyawan, J., & Neumann, P. J. (2012). Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. Journal of the American Academy of Child & Adolescent Psychiatry, 51(10), 990-1002.
Fischer, M., & Barkley, R. (2006). Young adult outcomes of children with hyperactivity: leisure, financial, and social activities. Int J Disabil Dev Educ, 53, 229-245.
Fletcher, J., & Wolfe, B. (2009). Long-term consequences of childhood ADHD on criminal activities. J Ment Health Policy Econ., 12(3), 119-138.
Froehlich, T. E., Lanphear, B. P., Auinger, P., Hornung, R., Epstein, J. N., Braun, J., & Kahn, R. S. (2009). Association of Tobacco and Lead Exposures With Attention-Deficit/Hyperactivity Disorder. Pediatrics, 124(6), 1054-1063. doi:10.1542/peds.2009-0738
Goldenberg, R. K., & Culhane, J. F. (2007). Low birth weight in the United States. The American Journal of Clinical Nutrition, 85(2), 584S-590S.
Guevara, J., Lozano, P., Wickizer, T., Mell, L., & Gephart, H. (2001). Utilization and cost of health care services for children with attentiondeficit/hyperactivity disorder. Pediatrics, 108, 71-78.
Hodgkins, P., Montejano, L., Sasane, R., & Huse, D. (2011). Cost of illness and comorbidities in adults diagnosed with attention-deficit/ hyperactivity disorder: a retrospective analysis Prim Care Companion CNS Disord, 13.
Jones, D. E., & Foster, E. M. (2009). Service use patterns for adolescents with ADHD and comorbid conduct disorder. J Behav Health Serv Res, 36, 436-449.
Kessler, R. C., Lane, M., Stang, P. E., & Van Brundt, D. L. (2009). The prevalence and workplace costs of adult attention deficit hyperactivity disorder in a large manufacturing firm. Psychol Med, 39, 137-147.
Marks, D. J., Mlodnicka, A., Bernstein, M., Chacko, A., Rose, S., & Halperin, J. M. (2009). Profiles of service utilization and the resultant economic impact in preschoolers with attention deficit/hyperactivity disorder. J Pediatr Psychol, 34, 681-689.
National Toxicology Program. (2012). NTP Monograph on Health Effects of Low-Level Lead.
Robb, J. A., Sibley, M. H., Pelham Jr., W. E., Foster, E. M., Molina, B. S., Gnagy, E. M., & Kuriyan, A. B. (2011). The estimated annual cost of ADHD to the US education system. School Mental Health, 3(3), 169-177.
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Wang, H. L., Chen, X. T., Yang, B., Ma, F. L., Wang, S., Tang, M. L., . . . Ruan, D. Y. (2008). Case - Control Study of Blood Lead Levels and Attention Deficit Hyperactivity Disorder in Chinese Children. Environmental Health Perspectives, 116(10), 1401-1406. doi:10.1289/ehp.11400
Zhu, M., Fitzgerald, E. F., Gelberg, K. H., Lin, S., & Druschel, C. M. (2010). Maternal low-level lead exposure and fetal growth. Environmental Health Perspectives, 118(10), 1471-1475. doi:10.1289/ehp.0901561

: Detailed Summaries of Studies That May Potentially Inform Concentration-Response Functions
This appendix contains longer summaries of studies that EPA used for estimating IQ loss, and may consider using to develop concentration-response functions for additional benefits. It contains the summaries for the endpoints of IQ, ADHD, low birth weight and cardiovascular mortality.
Decreases in Intelligence Quotient
Lanphear et al. (2005)
Lanphear et al. (2005) examined the quantitative relationship between IQ test performance and measures of blood lead levels in children followed prospectively from infancy to age 5 - 10. The authors also explored the concentration-response functions (CRFs) between lead and IQ above and below two blood lead cutoff points (7.5 ug/dL and 10 ug/dL) chosen a priori, hypothesizing that a given increase in lead exposures would be associated with greater IQ deficits in children with blood lead levels below the cutoff points than in those with higher blood lead levels. To examine the CRF, Lanphear et al. (2005) conducted a pooled analysis of seven international cohort studies that investigated the relationship between children's blood lead levels and full-scale IQ (composite of verbal and performance test) scores. Children in all cohorts completed a version of the Wechsler Intelligence Scale for Children to measure full-scale IQ scores. Four different measures of blood lead levels in children were studied: concurrent (measurement obtained closest to the IQ test), maximum (peak value at any time prior to IQ test), early (mean blood lead from 6 to 24 months of age), and lifetime (mean from 6 months to concurrent). In six of seven cohorts, IQ tests were administered between the ages of 4 years 10 months and 7 years old; in the final cohort (Boston), IQ test scores were only available at age 10, with the nearest concurrent blood lead measurements at age 5.
Lanphear et al. (2005) assessed the relationship between blood lead levels and IQ by constructing an adjusted log-linear model for each blood lead measurement type. Lanphear et al. (2005) then examined the R[2] values of each regression model and found that all blood lead measures were highly correlated with IQ (r = 0.74-0.96). The measure with the strongest relationship to IQ, as indicated by the highest R[2] value, was concurrent blood lead, which was thus selected as the primary lead exposure index for further analyses. Based on the R[2] values, Lanphear et al. (2005) also recommended use of lifetime average blood lead levels over maximum and early childhood blood lead levels. The preferred final model chosen by Lanphear et al. (2005) used five factors to predict IQ loss in children: log of concurrent blood lead, site, maternal IQ, HOME Inventory score, birth weight, and maternal education.
Lanphear et al. (2005) found a significant association between intellectual deficits and all four measures of childhood blood lead levels, as shown in Exhibit J.1. The curve of the final log-linear regression model indicated that the steepest declines in IQ occur at lower levels of lead exposures (concurrent blood lead < 10 μg/dL). The estimated decreases in IQ from increases in blood lead levels of 2.4 to 10 μg/dL, 10 to 20 μg/dL, and 20 to 30 μg/dL were 3.9, 1.9 and 1.1 points respectively (Lanphear et al. 2005). Lanphear et al. (2005) also divided the dataset and created two linear models using the aforementioned a priori cutoff points. Concurrent blood lead coefficients were significantly different using the 7.5 μg/dL cutoff point: for any given increase in blood lead, the estimated loss in IQ points was significantly greater in children with maximal blood lead levels < 7.5 μg/dL than in those with blood lead levels >= 7.5 μg/dL (β = -2.94 vs. -0.16, p = 0.015). Although the same trend was observed for a cutoff point of 10 μg/dL, the difference in coefficients failed to reach statistical significance. In summary, the Lanphear et al. (2005) analysis resulted in two main conclusions: IQ loss is most strongly predicted by concurrent and lifetime average blood lead levels; and given the same unit increase in blood lead, IQ loss is greater for children with lower levels of lead exposures versus higher levels.
Exhibit J.1: Mean Unadjusted and Adjusted* Changes in Full-Scale IQ Score Associated with an Increase in Blood Lead Concentration (Log Scale), from the 5th to 95th Percentile of the Concurrent Blood Lead at the Time of IQ Testing
Blood Lead Variable
Unadjusted IQ Estimates
[β (95% CI)]
Adjusted IQ Estimates
[β (95% CI)]
Blood Lead
(5[th] to 95[th] percentile, ug/dL)
IQ Deficits [5[th] to 95[th] percentile (95% CI)]
Early Childhood
                                     -3.57
                               (-4.86 to -2.28)
                                     -2.04
                               (-3.27 to -0.81)
                                 4.1  -  34.8
                               4.4 (1.7  -  7.0)
Peak
                                     -4.85
                               (-5.16 to -3.54)
                                     -2.85
                               (-4.10 to -1.60)
                                 4.0  -  34.5
                               6.1 (3.4  -  8.8)
Lifetime Average
                                     -5.36
                               (-6.69 to -4.03)
                                     -3.04
                               (-4.33 to -1.75)
                                 6.1  -  47.0
                               6.2 (3.6  -  8.8)
Concurrent
                                     -4.66
                               (-5.72 to -3.60)
                                     -2.70
                               (-3.74 to -1.66)
                                 2.4  -  33.1
                               7.1 (4.4  -  9.8)
Source: Lanphear et al. (2005).
*Adjusted for site, HOME Inventory score, birth weight, maternal IQ, and maternal education.

Crump et al. (2013)
In 2013, Crump et al. published a statistical reevaluation of the data used in the Lanphear et al. (2005) pooled-analysis that related low levels of blood lead to intellectual deficits in children. In this work Crump et al. had two main goals: (1) to reproduce the results of Lanphear et al. (2005) and correct any errors, and (2) perform an independent analysis of the Lanphear et al. (2005) database. Given that one of Crump et al.'s (2013) aims was to reproduce the Lanphear et al. (2005) analysis, EPA refers to the summary of Lanphear et al. (2005) above for the majority of the methods. In this section, EPA describes minor errors in the original analysis that Crump et al. (2013) identified and corrected. EPA then summarizes the independent analysis.
Crump et al. (2013) obtained data from all seven cohorts by Freedom of Information Act (FOIA) request. In attempting to recreate the results of Lanphear et al. (2005), Crump et al. (2013) identified and corrected two minor errors in the original analysis:
 Data from the Boston cohort had been transformed by ln(BLL+1); in untransforming these values, Lanphear et al. (2005) mistakenly added one to the antilog instead of subtracting it. Therefore, Crump et al. (2013) used corrected BLL measurements for the Boston cohort.
 Although Lanphear et al. (2005) stated that full-scale IQ was used in the Boston cohort, according to Crump et al. (2013), performance IQ was accidentally used instead. Therefore, in the corrections to the Lanphear analysis, Crump et al. (2013) replaced performance IQ with full-scale IQ.
Correcting these minor errors in the Lanphear et al. (2005) analysis resulted in slightly different β coefficients for the relationship between ln(BLL) and IQ, as displayed in Exhibit J.2. It is apparent from Exhibit J.2 that the minor corrections conducted by Crump et al. (2013) resulted in fairly insignificant changes to the β coefficients for the relationship between ln(BLL) and IQ.
Exhibit J.2: Comparison of Adjusted[a] Coefficients from Lanphear et al. (2005) to Those Obtained in the Crump et al. (2013) Reanalysis and Independent Analysis
BLL Variable
Lanphear et al. (2005)
Crump et al. (2013) Reanalysis ln(PbB)
Crump et al. (2013) Independent Analysis ln(PbB+1)

β (95% CI)
R[2 b]
β (95% CI)
R[2]
β (95% CI)
R[2]
Early
-2.04 (-3.27, -0.81)
0.626
-2.21 (-3.38, -1.03)
0.643
-2.46 (-3.81, -1.10)
0.659
Peak
-2.85 (-4.10, -1.60)
0.624
-2.86 (-4.10, -1.61)
0.640
-2.48 (-3.83, -1.14)
0.656
Lifetime
-3.04 (-4.33, -1.75)
0.624
-3.19 (-4.45, -1.94)
0.641
-3.25 (-4.66, -1.83)
0.659
Concurrent
-2.70 (-3.74, -1.66)
0.626
-2.65 (-3.69, -1.61)
0.641
-3.32 (-4.55, -2.08)
0.658
a Coefficients were adjusted for site, birth weight, mother's education, mother's IQ, & HOME inventory score.
b R[2] not reported in Lanphear et al. (2005) and was calculated using their data.
Source: Table 2 and Table 5, Crump et al. (2013).

Although Lanphear et al. (2005) stated that the best measure of BLL to describe the relationship to IQ (i.e., concurrent) was chosen based on the highest observed R[2] value, the authors did not present the R[2] values in their paper. Based on the R[2] values presented by Crump et al. (2013), the difference in the models seems negligible: concurrent and early BLL have the same R[2] value in the reanalysis conducted by Crump et al. (2013), while early BLL has the highest R2 value in their independent analysis. Interestingly, Lanphear et al. (2005) state that the range of r values is 0.74 - 0.96, whereas the r values calculated from the Crump et al. (2013) reanalysis only range from 0.78 to 0.79.
For their independent analysis of the Lanphear et al. (2005) database, Crump et al. (2013) took a different approach to defining BLL variables and selecting IQ measurements. Specifically, they set up site-specific a priori definitions for each BLL measurement. In contrast, Lanphear et al. (2005) used general overarching definitions for concurrent, lifetime, early, and peak BLL levels. Because each study had 24-month BLL data available, Crump et al. (2013) also explored this BLL measure as it relates to IQ. For the average BLL measurements (lifetime and early childhood), Crump et al. (2013) weighted the averages using "the trapezoid rule for approximating an integral when the subintervals are of unequal length" (p. 786). Additionally, they used the correct blood lead values for the Boston cohort, as described above.
Crump et al. (2013) used the same scores as Lanphear et al. (2005) for IQ, except for the Boston cohort. In this cohort, Crump et al. (2013) elected to use IQ measurements from 57 months, as opposed to 120 months as in the original Lanphear et al. (2005) analysis. In Crump et al. (2013), the authors' rationale for this change was to make the timing of IQ test scores align more closely with BLL measurements, which were also taken at 57 months. It should be noted, however, that the 57-month IQ measurements were assessed with the McCarthy General Cognitive Index, whereas all other IQ measurements used were based on some form of the Wechsler Intelligence Scale for Children. Use of the 57-month IQ scores reduced the standard deviation of age at IQ measurement from 20 months to 12 months.
To assess the potential effects of confounding variables, Crump et al. (2013) examined the same covariates as in Lanphear et al. (2005) and additionally included gestational age. Since several of the confounding variables were measured differently in different cohorts (e.g., maternal alcohol and smoking), Crump et al. (2013) defined them as site-specific. The final model included eight confounding variables: site, HOME score, maternal education, maternal IQ, birth weight, maternal alcohol use, maternal smoking, and birth order. Crump et al. (2013) performed statistical analyses to determine which BLL measure was most significantly associated with IQ, and whether a linear or log-transformed model provided a better fit for the data.
In support of the conclusions of Lanphear et al. (2005), the independent analysis by Crump et al. (2013) indicated that concurrent and lifetime blood lead measures are the best predictors of IQ. In addition, the log-transformed BLL model (i.e., ln(BLL + 1)) provided a better fit than the linear model. EPA used the lifetime function based on this transformation in the main benefits analysis. Thus, the Crump et al. (2013) reanalysis, as well as the independent analysis, validated the main conclusions made by Lanphear et al. (2005). Crump et al. (2013) stated that "even though our reanalysis of results in Lanphear et al. (2005) found some problems with their analyses, our independent analysis found results that mirrored the conclusions of Lanphear et al., namely that the relationship between BLL and IQ is non-linear, that concurrent BLL provided the best statistical description of the exposure-response, and that there is a statistical evidence for an association of BLL with IQ at peak BLL exposure below 7 ug/dL" (p.797). Exhibit J.2 displays the differences in betas between the Lanphear et al. (2005) and Crump et al. (2013) analyses.
Kirrane and Patel (2014)
Kirrane and Patel (2014) published a memorandum to identify errors in the Lanphear et al. (2005) analysis and to determine whether these errors would affect any conclusions in EPA's 2013 Lead ISA regarding the effects of lead exposure on IQ. Exhibit J.3 provides a comparison of the findings from Lanphear et al. (2005) and the recalculations by EPA from Kirrane and Patel (2014).
Exhibit J.3: Statistics Associated with Lanphear et al. (2005) that were Recalculated by EPA Kirrane and Patel (2014)
Finding from Lanphear et al. (2005)
Corrected Information
(Kirrane & Patel, 2014)
Previously Reported Information
(Lanphear et al. 2005)
Log-linear model coefficient for blood lead metrics and IQ, adjusted for site, HOME score, birth weight, maternal IQ, and maternal education (Table 4)
Early childhood:
-2.21 (-3.38, -1.04)
Peak:
-2.86 (-4.10, -1.61)
Lifetime average:
-3.14 (-4.39, -1.88)
Concurrent:
-2.65 (-3.69, -1.61)
Early childhood:
-2.04 (-3.27, -0.81)
Peak:
-2.85 (-4.10, -1.60)
Lifetime average:
-3.04 (-4.33, -1.75)
Concurrent:
-2.70 (-3.74, -1.66)
IQ decrement over different concurrent blood lead ranges based on the log-linear model
2.4 to 30 ug/dL:
6.7 IQ points (4.1-9.3)
2.4 to 10 ug/dL:
3.8 IQ points (2.3-5.3)
10 to 20 ug/dL:
1.8 IQ points (1.1-2.6)
20 to 30 ug/dL:
1.1 IQ points (0.7-1.5)
2.4 to 30 ug/dL:
6.9 IQ points (4.2-9.4)
2.4 to 10 ug/dL:
3.9 IQ points (2.4-5.3)
10 to 20 ug/dL:
1.9 IQ points (1.2-2.6)
20 to 30 ug/dL:
1.1 IQ points (0.7-1.5)
Linear coefficient, sample size (N), and concurrent blood lead measurements (mean, minimum, 5[th] and 95[th] percentiles, and maximum) for subset with peak BLLs < 7.5 ug/dL
-2.53 (-4.48, -0.58)
N = 118
(3.3, 0.9, 1.1, 6.7, 7.4 ug/dL)
-2.94 (-5.16, -0.71)
N = 103
(3.24, 0.9, 1.3, 6.0, 7.4 ug/dL)*
Linear coefficient, sample size (N), and concurrent blood lead measurements (mean, minimum, 5[th] and 95[th] percentiles, and maximum) for subset with peak blood lead levels >= 7.5 ug/dL
-0.15 (-0.19, -0.11)
N = 1215
(13.0, 0.1, 3.7, 34.2, 71.7 ug/dL)
-0.16 (-0.24, -0.08)
N = 1230
(12.9, 0.1, 3.5, 34.0, 71.7 ug/dL)*
Linear coefficient, sample size (N), and concurrent blood lead measurements (mean, minimum, 5[th] and 95[th] percentiles, and maximum) for subset with peak blood lead levels < 10 ug/dL
-0.77 (-1.65, 0.12)
N = 258
(4.4, 0.1, 1.4, 8.0, 9.8 ug/dL)
-0.80 (-1.74, 0.14)
N = 244
(4.3, 0.1, 1.4, 8.0, 9.8 ug/dL)*
Linear coefficient, sample size (N), and concurrent blood lead measurements (mean, minimum, 5[th] and 95[th] percentiles, and maximum) for subset with peak blood lead levels >= 10 ug/dL
-0.13 (-0.22, -0.04)
N = 1,075
(14.0, 0.1, 4.4, 35.5, 71.7 ug/dL)
-0.13 (-0.23, -0.03)
N = 1,089
(13.9, 0.1, 4.3, 35.4, 71.7 ug/dL)*
Sensitivity of concurrent blood lead - IQ association to omitting one cohort
Slopes range from -2.36 to -2.94
Slopes range from -2.31 to -2.94
Number of children from Boston cohort with peak blood lead levels < 7.5 ug/dL
Boston = 28
Boston = 13
*Findings were not published in Lanphear et al. (2005), but were obtained from Richard Horning via email correspondence with EPA (see 2006 Pb AQCD, p. 6-70 and docket document number EPA-HQ-OAR-2006-0735-5512, available at www.regulations.gov).
Source: Table 1, Kirrane and Patel (2014)

Kirrane and Patel (2014) concluded that none of the identified errors would materially affect any conclusions on the relationship between lead exposure and IQ. The lifetime beta estimate from Kirrane and Patel is used in the Final LCRR sensitivity runs.
Budtz-Jørgensen et al. (2013)
Budtz-Jørgensen et al. (2013) reanalyzed the Lanphear et al. (2005) data using additional statistical methods and a benchmark dose approach. The benchmark dose (BMD) is the dose that leads to a specified benchmark response (BMR).  Budtz-Jørgensen et al. (2013) chose a BMR of 1 IQ point and performed benchmark analyses using log-linear, linear and piecewise linear regressions (with cut points of 7.5 and 10 ug/dL). They found a similar BMD using both the lifetime and concurrent measures of blood lead. Consistent with the results of the original Lanphear et al. (2005) analysis, Budtz-Jørgensen et al. (2013) concluded that the log-linear model provided the best fit for the data. Budtz-Jørgensen et al. (2013) also confirmed the conclusions of Lanphear et al. (2005) regarding robustness of the model (i.e., model results did not change when each study site was excluded from the analysis in turn) and choice of concurrent BLL as the measurement showing an association to IQ loss. The authors compared logarithmic models of concurrent blood lead and lifetime blood lead and identified that the BMD's associated with a loss of 1 IQ point were 0.354 and 0.355 ug/dL, respectively.
Jusko et al. (2008) and Min et al. (2009)
EPA reviewed two additional studies, Jusko et al (2008) and Min et al (2009), which use more recent blood lead levels than those used in the Crump and Lanphear analyses, both identified deficits in IQ at a lower BLL than Crump et al (2013), who used the data published by Lanphear et al in 2005. Min et al (2009) only examines concurrent exposure, and the authors identify that at age 4 there is a decrease of 0.77 IQ points for every 1 ug/dL increase in blood lead level. In Min et al (2009), the dose-response relationship between concurrent BLL and Performance IQ at 4 years showed a steep slope at lower levels (up to 7 ug/dL) but did not reach significance. Jusko et al (2008) concluded that lifetime average of blood lead levels between 5-9.9 ug/dL caused a decrease of 4.9 IQ points whereas the concurrent exposure correlated with a decrease of 3.7 points for levels between 5-9.9 ug/dL. Additionally, the authors demonstrated that the slope of the blood-lead IQ relationship was steeper at lower levels of lead exposure where IQ decreased by 1.2, 0.32, and 0.15 points per 1-μg/dL increase in peak blood lead over the range of 2.1 - 10 μg/dL, 10 - 20 μg/dL, and 20 - 30 μg/dL, respectively. In both the studies, the steeper slopes at lower BLL without log transformation showed increased deficits; this reinforces the fact that reducing lead levels in lower ranges of average BLL has a significant impact on preventing IQ loss.
Lanphear et al. (2019) Erratum
Lanphear et al. published an Erratum (2019) that corrected previous minor mistakes in their 2005 analysis. In the original analysis, performance IQ data were used for the Boston cohort instead of the appropriate full-scale IQ data (Lanphear et al. 2019 Erratum). Additionally, in the log-transformation of the children's blood lead level measurements within the Boston cohort (at 6-, 18-, and 24-months), the value of 1 was added instead of subtracted (Lanphear et al. 2019 Erratum). These errors resulted in an incorrect analysis of the Boston cohort, as well as an incorrect pooled analysis of blood lead levels and IQ data for the broader study group (Lanphear et al. 2019 Erratum). The 2019 Erratum corrected these analytic mistakes; β's from the reanalsysis are presented below. The findings were largely the same with the corrected dataset and reaffirmed the original conclusions.
Exhibit J.4: Statistics from Lanphear et al (2019) Erratum as the corrected analysis of 2005 data
BLL Variable
Lanphear et al. (2019) erratum

β (95% CI)
R2 [a]
                                     Early
                             -2.21 (-3.38, -1.04)
                                      n/a
                                     Peak
                             -2.86 (-4.10, -1.61)
                                      n/a
                                   Lifetime
                             -3.25 (-4.51, -1.99)
                                      n/a
                                  Concurrent
                             -2.65 (-3.69, -1.61)
                              reported as highest
[a]R[2] not reported in Lanphear et al. (2019)

Increases in Attention-Deficit/Hyperactivity Disorder
Froehlich et al. (2009)
In their 2009 paper "Association of Tobacco and Lead Exposures with Attention-Deficit/Hyperactivity Disorder", Froehlich et al. aimed to investigate the associations between ADHD and childhood lead exposures, both independently and in combination with prenatal tobacco exposures. The authors analyzed data from 2001-2004 NHANES on 2,588 children aged 8 to 15 years old with complete information on ADHD diagnosis, lead and tobacco exposures, and additional covariates. Children with high serum cotinine levels (>10 ng/mL), which are indicative of active smoking, were excluded from the study to prevent confounding of the effects of secondhand tobacco exposure. In the main analyses, ADHD diagnosis in NHANES was based on completion of the Diagnostic Interview Schedule for Children (DISC) by caregivers. The DISC is a structured interview that contains questions on ADHD symptoms, onset, pervasiveness, and severity in the last 12 months and uses DSM-IV criteria to diagnose ADHD. As a secondary outcome, the definition of ADHD diagnosis was expanded to capture children with ADHD who did not meet full DSM-IV criteria due to appropriate medication treatment. In these secondary analyses, children with caregiver report of both history of ADHD diagnosis and ADHD medication use in the past year were additionally included in the analyses. The authors investigated variables that had previously been shown to be associated with ADHD as potential confounders. In the secondary analyses, health insurance status was also examined as a covariate. Logistic regression analyses were used to examine associations between lead exposures and ADHD, adjusted for confounders that were confirmed to be significantly associated with ADHD (χ[2] test, p < 0.2). The final logistic regression model was adjusted for sex, age, race/ethnicity, preschool attendance, birth weight, income/poverty ratio, maternal age at child's birth, and both current secondhand and prenatal tobacco exposures (operationalized by serum cotinine levels and via maternal report, respectively). Additional analyses were performed restricting the sample to children with blood lead < 5 ug/dL. Joint toxicant (i.e., both lead and tobacco exposure) effects were assessed by examining ADHD incidence at varying levels of co-exposures.
Froehlich et al. (2009) found that 8.7% of children studied met DSM criteria for ADHD diagnosis. Children in the highest tertile of lead exposure (>1.3 ug/dL) were 2.3 times more likely to be diagnosed with ADHD (95% CI, 1.5-3.8) than children in the lowest tertile (0.2 to 0.8 ug/dL). The same adjusted OR was observed when restricting the sample to children with blood lead < 5 ug/dL. When blood lead was logarithmically transformed and analyzed as a continuous variable, the adjusted OR for ADHD diagnosis was 1.8 (95% CI, 1.2-2.8) given a one-unit increase in natural log blood lead. The significant association between lead exposures and ADHD remained when the definition of ADHD diagnosis was expanded in the secondary analyses: the adjusted OR was 2.0 (95% CI, 1.3-3.0). Childhood lead exposures and prenatal tobacco exposures combined had a multiplicative effect on the risk of ADHD. Froehlich et al. (2009) estimated that 25% of ADHD cases among U.S. children with blood lead > 1.3 ug/dL are attributable to lead exposures, corresponding to approximately 598,000 cases. Results of Froehlich et al. (2009) were consistent with prior studies that found a relationship between childhood lead exposures and DSM-IV ADHD diagnosis.
Increases in Cardiovascular Mortality
Cardiovascular Mortality Study Summaries
Lead has been associated with adverse impacts to the cardiovascular system in numerous studies. In the Integrated Science Assessment for Lead, EPA deemed the association between lead exposure and coronary heart disease (including cardiovascular disease (CVD) mortality) to be causal. Specifically, EPA stated, "despite the differences in design and methods across studies, with few exceptions, associations between higher levels of Pb biomarkers and higher risk of [coronary heart disease]-related mortality were consistently observed" (U.S. EPA, 2013a, pp. 4-412). A recent meta-analysis supports these findings. Chowdhury et al., (2018) looked at 37 studies examining the relationship between metals and cardiovascular disease in a systematic review. In order to standardize the analysis, they compared top versus bottom thirds of baseline levels, pooled relative risks and found a RR (95 percent confidence interval) for lead of 1.43 (1.16 to 1.76) for cardiovascular disease, 1.85 (1.27 to 2.69) for coronary heart disease, 1.63 (1.14 to 2.34) for stroke.

Both short-term and longer-term exposure may be important for the role of lead and adverse cardiovascular outcomes. These include indirect impacts (e.g., increasing oxidative stress, disturbing hormone homeostasis, disrupting calcium signaling) for which the cascading impacts can adversely impact cardiovascular health. There is also evidence that lead can directly impact cardiovascular health through mechanisms such as damaging the endothelial lining, causing dose-dependent increases in vasoconstriction and directly impacting heart performance. This evidence is discussed in greater detail in Appendix D.
Building upon the findings of the EPA 2013 ISA and the NTP Monograph, EPA conducted a review of the literature on the association between lead exposures and CVD mortality. This section summarizes four studies that estimated concentration-response functions for the association between adult blood lead and cardiovascular mortality. These four studies were selected from the literature because they are the only studies that met the following criteria:
 The study is representative of the general U.S. population, as characterized by:
          Mean blood Pb level below 5 ug/dL,
          Relatively large sample size
 The study included an analysis of CVD mortality with blood Pb as a continuous, rather than categorical, variable.