Number of Birth Weight-Related Deaths         665.4    1,214.7      1,915.4        665.4    1,214.7      1,915.4
 Avoided..............................
Total Annualized Birth Weight Benefits       $95.73    $175.05      $276.44       $74.66    $136.97      $217.02
 (Million $2021) \2\..................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                               Table 48--National Birth Weight Benefits, Option 1b
                                         [PFOA and PFOS MCLs of 5.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Increase in Birth Weight (millions of          97.6      181.9        292.1         97.6      181.9        292.1
 grams)...............................
Number of Birth Weight-Related Deaths         578.9    1,069.5      1,707.3        578.9    1,069.5      1,707.3
 Avoided..............................
Total Annualized Birth Weight Benefits       $83.27    $154.13      $246.43       $64.94    $120.59      $193.47
 (Million $2021) \2\..................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                               Table 49--National Birth Weight Benefits, Option 1c
                                        [PFOA and PFOS MCLs of 10.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Increase in Birth Weight (millions of          51.0      109.2        195.3         51.0      109.2        195.3
 grams)...............................
Number of Birth Weight-Related Deaths         299.5      643.3      1,140.5        299.5      643.3      1,140.5
 Avoided..............................
Total Annualized Birth Weight Benefits       $43.22     $92.70      $164.19       $34.18     $72.51      $125.80
 (Million $2021) \2\..................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

2. Quantified Cardiovascular Effects
    CVD is one of the leading causes of premature mortality in the
United States (D'Agostino et al., 2008; Goff et al., 2014; Lloyd-Jones
et al., 2017). As discussed in EPA's Proposed Maximum Contaminant Level
Goals for PFOA and PFOS in Drinking Water, exposure to PFOA and PFOS
through drinking water contributes to increased serum PFOA and PFOS
concentrations and potentially elevated levels of total cholesterol and
elevated levels of systolic blood pressure (USEPA, 2023b; USEPA,
2023c). Changes in total cholesterol and blood pressure are associated
with changes in incidence of CVD events such as myocardial infarction
(i.e., heart attack), ischemic stroke, and cardiovascular mortality
occurring in populations without prior CVD event experience (D'Agostino
et al., 2008; Goff et al., 2014; Lloyd-Jones et al., 2017).
    EPA recognizes that the epidemiologic literature that provides
strong support for an effect of PFOA and PFOS on cholesterol and blood
pressure does not provide direct support for an effect of PFOA and PFOS
on the risk of CVD. Therefore, EPA uses the approach outlined below to
link changes in CVD risk biomarkers (i.e., cholesterol and blood
pressure) to changes in CVD risk.
    For each entry point, evaluation of the changes in CVD risk
involves the following key steps:
    1. Estimation of annual changes in total cholesterol and blood
pressure levels using exposure-response functions for the potential
effects of serum PFOA/PFOS on these biomarkers;
    2. Estimation of the annual incidence of fatal and non-fatal first
hard CVD events, defined as fatal and non-fatal myocardial infarction,
fatal and non-fatal ischemic stroke or other coronary heart disease
death occurring in populations without prior CVD event experience
(D'Agostino et al., 2008; Goff et al., 2014; Lloyd-Jones et al., 2017),
and post-acute CVD mortality corresponding to baseline and regulatory
alternative total cholesterol and blood pressure levels in all
populations alive during or born after the start of the evaluation
period; and
    3. Estimation of the economic value of reducing CVD mortality and
morbidity from baseline to regulatory alternative levels, using the
Value of a Statistical Life and cost of illness measures, respectively.
    Given the breadth of evidence linking PFOA and PFOS exposure to
effects on total cholesterol and blood pressure in general adult
populations, EPA quantified public health impacts of changes in these
well-established CVD risk biomarkers (D'Agostino et al., 2008; Goff et
al., 2014; Lloyd-Jones et al., 2017) by estimating changes in incidence
of several CVD events. Specifically, EPA assumed that PFOA/PFOS-related
changes in total cholesterol and blood pressure had the same effect on
the CVD risk as the changes unrelated to chemical exposure and used the
Pooled Cohort Atherosclerotic Cardiovascular Disease (ASCVD) model
(Goff et al., 2014) to evaluate their impacts on the incidence of
myocardial infarction, ischemic stroke, and cardiovascular mortality
occurring in populations without prior CVD event experience.
    The ASCVD model includes total cholesterol as a predictor of first
hard CVD events. EPA did not identify any readily available
relationships for PFOA or PFOS and total cholesterol that were
specifically relevant to the age group of interest (40-89 years, the
years for which the ASCVD model estimates the probability of a first
hard CVD event). Therefore, the Agency developed a meta-analysis of
studies reporting associations between serum PFOA or PFOS and total
cholesterol in general populations (e.g., populations that are not a
subset of workers or pregnant women). Statistical analyses that combine
the results of multiple studies, such as meta-analyses, are widely
applied to investigate the associations between contaminant levels and
associated health effects. Such analyses are suitable for economic
assessments because they can improve precision and statistical power
(Engels et al., 2000; Deeks, 2002; R[uuml]cker et al., 2009).
    EPA identified 14 studies from which to derive slope estimates for
PFOA and PFOS associations with serum total cholesterol levels.
Appendix A to USEPA (2023i) provides further detail on the studies
selection criteria, meta-data development, meta-analysis results, and
discussion of the uncertainty and limitations inherent in EPA's
exposure-response analysis.
    EPA developed exposure-response relationships between serum PFOA/
PFOS and total cholesterol for use in the CVD analysis using the meta-
analyses restricted to studies of adults in the general population
reporting similar models. When using studies reporting linear
associations between total cholesterol and serum PFOA or PFOS, EPA
estimated a positive increase in total cholesterol of 1.57 (95% CI:
0.02, 3.13) mg/dL per ng/mL serum PFOA (p-value=0.048), and of 0.08
(95% CI: -0.01, 0.16) mg/dL per ng/mL serum PFOS (p-value=0.064). Based
on the systematic review conducted by EPA to develop EPA's Proposed
Maximum Contaminant Level Goals for PFOA and PFOS in Drinking Water,
the available evidence supports a positive association between PFOS and
total cholesterol in the general population. For more information on
the systematic review and results, see USEPA, 2023b and USEPA, 2023c.
    PFOS exposure has been linked to other cardiovascular outcomes,
such as systolic blood pressure and hypertension (Liao et al., 2020;
USEPA,

2023c). Because systolic blood pressure is another predictor used by
the ASCVD model, EPA included the estimated changes in blood pressure
from reduced exposure to PFOS in the CVD analysis. EPA selected the
slope from the Liao et al. (2020) study--a high confidence study
conducted based on U.S. general population data from NHANES cycles
2003-2012. The evidence on the associations between PFOA and blood
pressure is not as consistent as for PFOS. Therefore, EPA is not
including effect estimates for the serum PFOA-blood pressure
associations in the CVD analysis.
    EPA relies on the life table-based approach to estimate CVD risk
reductions because (1) changes in serum PFOA/PFOS in response to
changes in drinking water PFOA/PFOS occur over multiple years, (2) CVD
risk, relying on the ASCVD model, can be modeled only for those older
than 40 years without prior CVD history, and (3) individuals who have
experienced non-fatal CVD events have elevated mortality implications
immediately and within at least five years of the first occurrence.
Recurrent life table calculations are used to estimate a PWS entry
point-specific annual time series of CVD event incidence for a
population cohort characterized by sex, race/ethnicity, birth year, age
at the start of the PFOA/PFOS evaluation period (i.e., 2023), and age-
and sex-specific time series of changes in total cholesterol and blood
pressure levels obtained by combining serum PFOA/PFOS concentration
time series with exposure-response information. Baseline and regulatory
alternatives are evaluated separately, with regulatory alternative
total cholesterol and blood pressure levels estimated using baseline
information on these biomarkers from external statistical data sources
and modeled changes in total cholesterol and blood pressure due to
conditions under the regulatory alternatives.
    EPA estimated the incidence of first hard CVD events based on total
cholesterol serum and blood pressure levels using the ASCVD model (Goff
et al., 2014), which predicts the 10-year probability of a hard CVD
event to be experienced by a person without a prior CVD history. EPA
adjusted the modeled population cohort to exclude individuals with pre-
existing conditions, as the ASCVD risk model does not apply to these
individuals. For blood pressure effects estimation, EPA further
restricts the modeled population to those not using antihypertensive
medications for consistency with the exposure-response relationship.
Modeled first hard CVD events include fatal and non-fatal myocardial
infarction, fatal and non-fatal ischemic stroke, and other coronary
heart disease mortality. EPA also has estimated the incidence of post-
acute CVD mortality among survivors of the first myocardial infarction
or ischemic stroke within 6 years of the initial event.
    The estimated CVD risk reduction resulting from reducing serum PFOA
and serum PFOS concentrations is the difference in annual incidence of
CVD events (i.e., mortality and morbidity associated with first-time
CVD events and post-acute CVD mortality) under the baseline and
regulatory alternatives. Appendix G to USEPA (2023i) provides detailed
information on all CVD model components, computations, and sources of
data used in modeling.
    EPA uses the Value of a Statistical Life to estimate the benefits
of reducing mortality associated with hard CVD events in the population
exposed to PFOA and PFOS in drinking water. EPA relies on cost of
illness-based valuation that represents the medical costs of treating
or mitigating non-fatal first hard CVD events (myocardial infarction,
ischemic stroke) during the three years following an event among those
without prior CVD history, adjusted for post-acute mortality.
    The annual medical expenditure estimates for myocardial infarction
and ischemic stroke are based on O'Sullivan et al. (2011). The
estimated expenditures do not include long-term institutional and home
health care. For non-fatal myocardial infarction, O'Sullivan et al.
(2011) estimated medical expenditures are $51,173 ($2021) for the
initial event and then $31,871, $14,065, $12,569 annually within 1, 2,
and 3 years after the initial event, respectively. For non-fatal
ischemic stroke, O'Sullivan et al. (2011) estimated medical
expenditures are $15,861 ($2021) for the initial event and then
$11,521, $748, $1,796 annually within 1, 2, and 3 years after the
initial event, respectively. Annual estimates within 1, 2, and 3 years
after the initial event include the incidence of secondary CVD events
among survivors of first myocardial infarction and ischemic stroke
events.
    To estimate the present discounted value of medical expenditures
within 3 years of the initial non-fatal myocardial infarction, EPA
combined O'Sullivan et al. (2011) myocardial infarction-specific
estimates with post-acute survival probabilities based on Thom et al.
(2001) (for myocardial infarction survivors aged 40-64) and Li et al.
(2019) (for myocardial infarction survivors aged 65+). To estimate the
present discounted value of medical expenditures within 3 years of the
initial non-fatal ischemic stroke, EPA combined O'Sullivan et al.
(2011) ischemic stroke-specific estimates with post-acute survival
probabilities based on Thom et al. (2001) (for ischemic stroke
survivors aged 40-64, assuming post-acute myocardial infarction
survival probabilities reasonably approximate post-acute ischemic
stroke survival probabilities) and Li et al. (2019) (for ischemic
stroke survivors aged 65+). EPA did not identify post-acute ischemic
stroke mortality information in this age group, but instead applied
post-acute myocardial infarction mortality estimates for ischemic
stroke valuation. Table 50 presents the resulting myocardial infarction
and ischemic stroke unit values.

               Table 50--Cost of Illness-Based Value of Non-Fatal First CVD Event Used in Modeling
----------------------------------------------------------------------------------------------------------------
                                                                                Present discounted value of 3-
                                                                                year medical expenditures
                                                                                ($2021) \1\ \2\, adjusted for
    Type of first non-fatal hard CVD event                  Age group                post-acute mortality \3\
                                                                                -------------------------------
                                                                                3% discount     7% discount
                                                                                rate            rate
----------------------------------------------------------------------------------------------------------------
Myocardial Infarction (MI)....................  40-65 years.....................        $105,419        $104,155
                                                66+ years.......................          92,658          91,881
Ischemic Stroke (IS)..........................  40-65 years.....................          29,154          29,017
                                                66+ years.......................          26,844          26,762
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ Estimates of annual medical expenditures are from O'Sullivan et al. (2011);

\2\ Original values from O'Sullivan et al. (2011) were inflated to $2021 using the medical care CPI (Bureau of
  Labor Statistics, 2021);
\3\ Post-acute myocardial infarction mortality data for those aged 40-64 years is from Thom et al. (2001);
  probabilities to survive 1 year, 2 years, and 3 years after the initial event are 0.93, 0.92, and 0.90,
  respectively. EPA applies these mortality values to derive the ischemic stroke value in this age group. Post-
  acute myocardial infarction mortality data and post-acute IS mortality data for persons aged 65 and older are
  from Li et al. (2019). For myocardial infarction, probabilities to survive 1 year, 2 years, and 3 years after
  the initial event are 0.68, 0.57, and 0.49, respectively. For ischemic stroke, probabilities to survive 1
  year, 2 years, and 3 years after the initial event are 0.67, 0.57, and 0.48, respectively.

    Table 51 to Table 54 provide the health effects avoided and
valuation associated with CVD. EPA estimated that, over the evaluation
period, the proposed option will result in an average annual benefit
from avoided CVD cases and deaths from $421 million ($2021, 7% discount
rate) to $533 million ($2021, 3% discount rate).

                                Table 51--National CVD Benefits, Proposed Option
                                  [PFOA and PFOS MCLs of 4.0 ppt and HI of 1.0]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal MI Cases Avoided..      1,251.5    6,081.0     11,738.7      1,251.5    6,081.0     11,738.7
Number of Non-Fatal IS Cases Avoided..      1,814.0    8,870.8     17,388.5      1,814.0    8,870.8     17,388.5
Number of CVD Deaths Avoided..........        753.6    3,584.6      7,030.9        753.6    3,584.6      7,030.9
Total Annualized CVD Benefits (Million      $111.78    $533.48    $1,051.00       $85.94    $421.10      $822.88
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 52--National CVD Benefits, Option 1a
                                         [PFOA and PFOS MCLs of 4.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal MI Cases Avoided..      1,248.7    5,983.8     11,614.9      1,248.7    5,983.8     11,614.9
Number of Non-Fatal IS Cases Avoided..      1,786.4    8,729.6     17,149.5      1,786.4    8,729.6     17,149.5
Number of CVD Deaths Avoided..........        744.6    3,527.8      6,951.5        744.6    3,527.8      6,951.5
Total Annualized CVD Benefits (Million      $110.45    $525.05    $1,035.36       $86.32    $414.45      $817.79
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 53--National CVD Benefits, Option 1b
                                         [PFOA and PFOS MCLs of 5.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal MI Cases Avoided..      1,105.9    5,220.7     10,215.4      1,105.9    5,220.7     10,215.4
Number of Non-Fatal IS Cases Avoided..      1,609.3    7,624.2     15,029.5      1,609.3    7,624.2     15,029.5
Number of CVD Deaths Avoided..........        645.9    3,084.6      6,102.2        645.9    3,084.6      6,102.2
Total Annualized CVD Benefits (Million       $99.73    $459.09      $908.82       $72.72    $362.42      $717.85
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 54--National CVD Benefits, Option 1c
                                        [PFOA and PFOS MCLs of 10.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal MI Cases Avoided..        619.0    3,032.5      6,320.7        619.0    3,032.5      6,320.7
Number of Non-Fatal IS Cases Avoided..        878.1    4,445.9      9,439.4        878.1    4,445.9      9,439.4
Number of CVD Deaths Avoided..........        343.8    1,806.7      3,835.8        343.8    1,806.7      3,835.8
Total Annualized CVD Benefits (Million       $51.00    $268.78      $571.32       $41.85    $212.18      $450.51
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

3. Quantified Kidney Cancer Effects
    Data on the association between PFOA exposure and kidney cancer
(i.e., RCC) are limited but suggest a positive association between
exposure and increased risk of RCC. Epidemiology studies indicated that
exposure to PFOA was associated with an increased risk of RCC
(California Environmental Protection Agency, 2021; USEPA, 2016e; ATSDR,
2021; USEPA, 2023b). In the PFOA HESD (USEPA, 2016e), EPA characterized
the evidence for PFOA effects on RCC as ``probable'' based on two
occupational population studies (Raleigh et al., 2014; Steenland and
Woskie, 2012) and two high-exposure community studies (Vieira et al.,
2013; Barry et al., 2013). A recent study of the relationship between
PFOA and RCC in U.S. general populations found strong evidence that
exposure to PFOA causes RCC in humans (Shearer et al., 2021). As such,
EPA selected RCC as a key outcome when assessing the health impacts of
reduced PFOA exposures.
    EPA quantified and valued the changes in RCC risk associated with
reductions in serum PFOA levels that are in turn associated with
reductions in drinking water PFOA concentrations under the regulatory
alternatives. PWS entry point-specific time series of the differences
between serum PFOA concentrations under baseline and regulatory
alternatives are inputs into this analysis. For each PWS entry point,
evaluation of the changes in RCC impacts involves the following key
steps:
    1. Estimating the changes in RCC risk based on modeled changes in
serum PFOA levels and the exposure-response function for the effect of
serum PFOA on RCC;
    2. Estimating the annual incidence of RCC cases and excess
mortality among those with RCC in all populations corresponding to
baseline and regulatory alternative RCC risk levels, as well as
estimating the regulatory alternative-specific reduction in cases
relative to the baseline, and
    3. Estimating the economic value of reducing RCC mortality from
baseline to regulatory alternative levels, using the Value of a
Statistical Life and cost of illness measures, respectively.
    To identify an exposure-response function, EPA reviewed three
studies highlighted in the HESD for PFOA (USEPA, 2016e) and a recent
study discussed in both the California Environmental Protection
Agency's Office of Environmental Health Hazard Assessment (OEHHA) PFOA
Public Health Goals report (California Environmental Protection Agency,
2021) and EPA's Proposed Maximum Contaminant Level Goal (MCLG) for PFOA
(USEPA, 2023b). Steenland et al. (2015) observed an increase in kidney
cancer deaths among workers with high exposures to PFOA. Vieira et al.
(2013) found that kidney cancer was positively associated with high and
very high PFOA exposures. Barry et al. (2013) found a slight trend in
cumulative PFOA serum exposures and kidney cancer among the C8 Health
Project population. In a large case-control general population study of
the relationship between PFOA and kidney cancer in 10 locations across
the U.S., Shearer et al. (2021) found strong evidence that exposure to
PFOA causes RCC, the most common form of kidney cancer, in humans.
    To evaluate changes between baseline and regulatory alternative RCC
risk resulting from reduced exposure to PFOA, EPA relied on the
estimated time series of changes in serum PFOA concentrations (Section
6.3) and the serum-RCC exposure-response function provided by Shearer
et al. (2021): 0.00178 (ng/mL)-1. The analysis from Shearer et al.
(2021) was designed as a case-control study with population controls
based on 10 sites within the U.S. population. Shearer et al. (2021)
included controls for age, sex, race, ethnicity, study center, year of
blood draw, smoking, and hypertension. Results showed a strong and
statistically significant association between PFOA and RCC. EPA
selected the exposure-response relationship from Shearer et al. (2021)
because it included exposure levels typical in the general population
and was found to have a low risk of bias based on EPA's Proposed
Maximum Contaminant Level Goal for PFOA (USEPA, 2023b).
    The linear slope factor based on Shearer et al. (2021) enables
estimation of the changes in lifetime RCC risk associated with reduced
lifetime serum PFOA levels. Because baseline RCC incidence statistics
are not readily available from the NCI public use data, EPA used kidney
cancer statistics in conjunction with an assumption that RCC comprises
90% of all kidney cancer cases to estimate baseline lifetime
probability of RCC (USEPA, 2023b). EPA estimated the baseline lifetime
RCC incidence for males at 1.89% and the baseline lifetime RCC
incidence for females at 1.05%. Details of these calculations are
provided in Appendix H to USEPA (2023i).
    Similar to its approach for estimating of CVD risk reductions, EPA
relies on the life table approach to estimate RCC risk reductions. The
outputs of the life table calculations are the PWS entry point-specific
estimates of the annual change in the number of RCC cases and the
annual change in excess RCC population mortality. For more detail on
EPA's application of the life table to cancer benefits analyses, please
see Appendix H to USEPA (2023j).
    Although the change in PFOA exposure likely affects the risk of
developing RCC beyond the end of the

analysis period (the majority of RCC cases manifest during the latter
half of the average individual lifespan; see Appendix H to USEPA
(2023j), EPA does not capture effects after the end of the period of
analysis, 2104. Individuals alive after the end of the period of
analysis likely benefit from lower lifetime exposure to PFOA. Lifetime
health risk model data sources include EPA SDWIS, age-, sex-, and race/
ethnicity-specific population estimates from the U.S. Census Bureau
(2020), the Surveillance, Epidemiology, and End Results (SEER) program
database (Surveillance Research Program--National Cancer Institute,
202a; 2020b), and the Centers for Disease Control and Prevention (CDC)
NCHS. Appendix H to USEPA (2023i) provides additional detail on the
data sources and information used in this analysis as well as baseline
kidney cancer statistics. Appendix B to USEPA (2023i) describes
estimation of the affected population.
    EPA uses the Value of a Statistical Life to estimate the benefits
of reducing mortality associated with RCC in the population exposed to
PFOA in drinking water. EPA uses the cost of illness-based valuation to
estimate the benefits of reducing morbidity associated with RCC.
    EPA used the medical cost information from a recent RCC cost-
effectiveness study by Ambavane et al. (2020) to develop cost of
illness estimates for RCC morbidity. Ambavane et al. (2020) used a
discrete event simulation model to estimate the lifetime treatment
costs of several RCC treatment sequences, which included first and
second line treatment medication costs, medication administration
costs, adverse effect management costs, and disease management costs
on- and off-treatment. To this end, the authors combined RCC cohort
data from CheckMate 214 clinical trial and recent US-based healthcare
cost information assembled from multiple sources (see supplementary
information from Ambavane et al. (2020)). Ambavane et al. (2020) found
that RCC treatment sequences using a combination of two immunotherapy
drugs as the first line medications were the most cost-effective.
    Table 55 summarizes RCC morbidity cost of illness estimates derived
by EPA using Ambavane et al. (2020)-reported disease management costs
on- and off-treatment along with medication, administration, and
adverse effect management costs for the first line treatment that
initiated the most cost-effective treatment sequences as identified by
Ambavane et al. (2020), i.e., the nivolumab/ipilimumab drug
combination. This is a forward-looking valuation approach in that it
assumes that the clinical practice would follow the treatment
recommendations in Ambavane et al. (2020) and other recent studies
cited therein. EPA notes that the second line treatment costs are not
reflected in EPA's cost of illness estimates, because Ambavane et al.
(2020) did not report information on the expected durations of the
treatment-free interval (between the first line treatment
discontinuation and the second line treatment initiation) and the
second line treatment phase, conditional on survival beyond
discontinuation of the second line treatment. As such, EPA valued RCC
morbidity at $251,007 ($2021) during year 1 of the diagnosis, $190,969
($2021) during year 2 of the diagnosis, and $1,596 ($2021) starting
from year 3 of the diagnosis. Additionally, EPA assumed that for
individuals with RCC who die during the specific year, the entire year-
specific cancer treatment regimen is applied prior to the death event.
This may overestimate benefits if a person does not survive the entire
year.

                                                            Table 55--RCC Morbidity Valuation
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                First line
                                                            First line      First line    adverse effect      Disease
                      Time interval                         medication    administration    management      management     Total ($2018)   Total ($2021)
                                                            ($2018) \1\     ($2018) \1\     ($2018) \1\     ($2018) \1\                         \4\
                                                                                \3\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Monthly cost, month 1-3 from diagnosis \1\ \5\..........          32,485             516              78              73          33,152          35,927
Monthly cost, month 4-24 from diagnosis \2\ \6\.........          13,887             647              78              73          14,685          15,914
Monthly cost, month 25+ from diagnosis \7\..............  ..............  ..............  ..............             123             123             133
Annual cost, year 1 from diagnosis......................         222,438           7,371             934             878         231,621         251,007
Annual cost, year 2 from diagnosis......................         166,644           7,764             934             878         176,220         190,969
Annual cost, year 3+ from diagnosis.....................  ..............  ..............  ..............           1,473           1,473           1,596
--------------------------------------------------------------------------------------------------------------------------------------------------------
Notes:
\1\ Ambavane et al. (2020) Table 1.
\2\ Ambavane et al. (2020) p. 41, a maximum treatment duration assumption of 2 years.
\3\ The adverse effect management costs of $1,868 in Ambavane et al. (2020) Table 1 were reported for the treatment duration. EPA used the treatment
  duration of 24 months (i.e., 2 years) to derive monthly costs of $77.83.
\4\ To adjust for inflation, EPA used U.S. BLS CPI for All Urban Consumers: Medical Care Services in U.S. (City Average).
\5\ First line treatment induction.
\6\ First line treatment maintenance.
\7\ Treatment-free interval.

    Tables 56 to 59 provide the health effects avoided and valuation
associated with RCC. EPA estimated that, over the evaluation period,
the proposed rule will result in an average annual benefit from avoided
RCC cases and deaths from $217 million ($2021, 7% discount rate) to
$301 million ($2021, 3% discount rate).

                                Table 56--National RCC Benefits, Proposed Option
                                  [PFOA and PFOS MCLs of 4.0 ppt and HI of 1.0]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal RCC Cases Avoided.      1,313.6    6,872.0     17,387.8      1,313.6    6,872.0     17,387.8
Number of RCC-Related Deaths Avoided..        308.7    1,927.8      5,049.3        308.7    1,927.8      5,049.3
Total Annualized RCC Benefits (Million       $54.23    $300.56      $758.03       $45.36    $217.37      $515.89
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 57--National RCC Benefits, Option 1a
                                         [PFOA and PFOS MCLs of 4.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal RCC Cases Avoided.      1,289.6    6,753.3     17,147.8      1,289.6    6,753.3     17,147.8
Number of RCC-Related Deaths Avoided..        300.5    1,895.2      4,960.4        300.5    1,895.2      4,960.4
Total Annualized RCC Benefits (Million       $52.92    $295.53      $744.64       $45.09    $213.78      $508.56
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 58--National RCC Benefits, Option 1b
                                         [PFOA and PFOS MCLs of 5.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal RCC Cases Avoided.      1,017.6    5,681.7     14,962.1      1,017.6    5,681.7     14,962.1
Number of RCC-Related Deaths Avoided..        235.9    1,602.1      4,317.6        235.9    1,602.1      4,317.6
Total Annualized RCC Benefits (Million       $42.28    $250.60      $643.71       $36.32    $182.24      $446.80
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

                                   Table 59--National RCC Benefits, Option 1c
                                        [PFOA and PFOS MCLs of 10.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal RCC Cases Avoided.        433.5    2,903.0      8,205.4        433.5    2,903.0      8,205.4
Number of RCC-Related Deaths Avoided..        101.1      831.8      2,406.2        101.1      831.8      2,406.2
Total Annualized RCC Benefits (Million       $18.58    $131.44      $367.38       $17.34     $97.30      $260.54
 $2021) \2\...........................
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.

\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized total annualized benefits in this table.

4. Key Limitations and Uncertainties in the Benefits Analysis
    The section below discusses the uncertainty information
incorporated in the quantitative benefits analysis. There are
additional sources of uncertainty and limitations that could not be
modeled quantitatively as part of the national benefits analysis. These
sources of uncertainty are characterized in detail in Section 6.8 of
USEPA (2023j). This summary includes uncertainties that are specific to
application of PK models for blood serum PFAS concentration estimation,
developmental effects (i.e., infant birth weight) modeling, CVD impacts
modeling, RCC impacts modeling, and modeling of bladder cancer impacts
from GAC treatment-related reductions in the sum of four
trihalomethanes (THM4). Table 60 below presents the key limitations and
uncertainties that apply to the benefits analysis for the proposed
rule. EPA notes that in most cases it is not possible to judge the
extent to which a particular limitation or uncertainty could affect the
magnitude of the estimated benefits. Therefore, in each table below,
EPA notes the potential direction of the impact on the quantified
benefits (e.g., a source of uncertainty that tends to underestimate
quantified benefits indicates expectation for larger quantified
benefits) but does not prioritize the entries with respect to the
impact magnitude.

  Table 60--Key Limitations and Uncertainties That Apply to Benefits Analyses Considered for the Proposed PFAS
                                                      Rule
----------------------------------------------------------------------------------------------------------------
                                              Effect on  benefits
         Uncertainty/assumption                     estimate                             Notes
----------------------------------------------------------------------------------------------------------------
EPA quantified benefits for three health  Underestimate..............  For various reasons, EPA has not
 endpoints for PFOA and PFOS.                                           quantified the benefit of removing PFOA
                                                                        and PFOS from drinking water for most of
                                                                        the health endpoints PFOA and PFOS are
                                                                        expected to impact. See discussion in
                                                                        section C for more information about
                                                                        these nonquantifiable benefits.
EPA has only quantified benefits for one  Underestimate..............  Treatment technologies installed to
 co-removed contaminant group (THM4).                                   remove PFAS can also removes numerous
                                                                        other contaminants, including other
                                                                        unregulated PFAS, additional regulated
                                                                        and unregulated DBPs, heavy metals,
                                                                        organic contaminants, pesticides, among
                                                                        others. These co-removal benefits may be
                                                                        significant, depending on co-occurrence,
                                                                        how many facilities install treatment
                                                                        and which treatment option they select.
EPA has not quantified benefits for any   Underestimate..............  PFHxS, PFNA, PFBS, and HFPO-DA each have
 health endpoint for PFHxS, PFNA, PFBS,                                 substantial health impacts on multiple
 and HFPO-DA.                                                           health endpoints. See discussion in
                                                                        section D for more information about
                                                                        these nonquantifiable benefits.
The analysis considers PFOA/PFOS          Overestimate...............  Some SDWIS population served estimates
 concentrations from NTNCWSs.                                           for NTNCWSs represent the both the
                                                                        population that has regular exposure to
                                                                        the NTNCWS' drinking water (e.g., the
                                                                        employees at a location) and the peak
                                                                        day transient population (e.g.,
                                                                        customers) who have infrequent exposure
                                                                        to the NTNCWS' drinking water.
                                                                        Estimating the demographic distribution
                                                                        and the share of daily drinking water
                                                                        consumption for these two types of
                                                                        NTNCWS populations would be difficult
                                                                        across many of the industries which
                                                                        operate NTNCWSs. The inclusion of NTNCWS
                                                                        results is an overestimate of benefits
                                                                        because daily drinking water consumption
                                                                        for these populations is also modeled at
                                                                        their residential CWS.
EPA assumes that the effects of PFOA and  Uncertain..................  The exposure-response functions used in
 PFOS exposures are independent.                                        benefits analyses assume that the
                                                                        effects of serum PFOA/PFOS on the health
                                                                        outcomes considered are independent and
                                                                        therefore additive. Due to limited
                                                                        evidence, EPA does not consider
                                                                        synergies or antagonisms in PFOA/PFOS
                                                                        exposure-response.
The derivation of PFOA/PFOS exposure-     Overestimate...............  The new data and EPA's proposed MCLGs
 response functions for the relationship                                indicate that the levels at which
 between PFOA/PFOS serum and associated                                 adverse health effects could occur are
 health outcomes assumes that there are                                 much lower than previously understood
 no threshold serum concentrations below                                when EPA issued the 2016 health
 which effects do not occur.                                            advisories for PFOA and PFOS (70 parts
                                                                        per trillion or ppt)--including near
                                                                        zero for certain health effects.
                                                                        Therefore, the exposure-response
                                                                        functions used in benefits analyses
                                                                        assume that there are no threshold serum
                                                                        concentrations below which effects do
                                                                        not occur. This could result in a slight
                                                                        overestimate of benefits for certain
                                                                        health endpoints.
The exposure-response functions used to   Overestimate...............  Analyses evaluating the evidence on the
 estimate risk assume causality.                                        associations between PFAS exposure and
                                                                        health outcomes are ongoing and EPA has
                                                                        not conclusively determined causality.
                                                                        As described in Section 6.2, EPA modeled
                                                                        health risks from PFOA/PFOS exposure for
                                                                        endpoints for which the evidence of
                                                                        association was found to be likely.
                                                                        These endpoints include birth weight,
                                                                        total cholesterol, and RCC. While the
                                                                        evidence supporting causality between
                                                                        DBP exposure and bladder cancer has
                                                                        increased since EPA's Stage 2 DBP Rule
                                                                        (NTP, 2021; Weisman et al., 2022),
                                                                        causality has not yet been conclusively
                                                                        determined (Regli et al., 2015).

The analysis assumes that quantified      Uncertain..................  EPA did not model birth weight, CVD, RCC,
 benefits categories are additive.                                      and bladder cancer benefits jointly, in
                                                                        a competing risk framework. Therefore,
                                                                        reductions in health risk in a specific
                                                                        benefits category do not influence
                                                                        health risk reductions in another
                                                                        benefits category. For example, lower
                                                                        risk of CVD and associated mortality
                                                                        implies a larger population that could
                                                                        benefit from cancer risk reductions,
                                                                        because cancer incidence grows
                                                                        considerably later in life.
The analysis does not take into account   Underestimate..............  The benefits analysis does not reflect
 population growth and other changes in                                 the effects of growing population that
 long-term trends.                                                      may benefit from reduction in PFOA/PFOS
                                                                        exposure. Furthermore, EPA uses present-
                                                                        day information on life expectancy,
                                                                        disease, environmental exposure, and
                                                                        other factors, which are likely to
                                                                        change in the future.
For PWSs with multiple entry points, the  Uncertain..................  Data on the populations served by each
 analysis assumes a uniform population                                  entry point are not available and EPA
 distribution across the entry points.                                  therefore uniformly distributes system
                                                                        population across entry points. Effects
                                                                        of the regulatory alternative may be
                                                                        greater or smaller than estimated,
                                                                        depending on actual populations served
                                                                        by affected entry points. For one large
                                                                        system serving more than one million
                                                                        customers EPA has sufficient data on
                                                                        entry point flow to proportionally
                                                                        assign effected populations.
EPA does not characterize uncertainty     Uncertain..................  EPA did not quantitatively characterize
 associated with the Value of                                           the uncertainty for the VSL reference
 Statistical Life (VSL) reference value                                 value and income elasticity. Because the
 or VSL elasticity.                                                     economic value of avoided premature
                                                                        mortality comprises the majority of the
                                                                        overall benefits estimate, not
                                                                        considering uncertainty surrounding the
                                                                        VSL is a limitation.
----------------------------------------------------------------------------------------------------------------

E. Nonquantifiable Benefits of PFOA and PFOS Exposure Reduction

    In this section EPA qualitatively discusses the potential health
benefits resulting from reduced exposure to PFOA and PFOS in drinking
water. These nonquantifiable benefits are expected to be realized as
avoided adverse health effects as a result of the proposed NPDWR, in
addition to the benefits that EPA has quantified. EPA anticipates
additional benefits associated with developmental, cardiovascular,
liver, immune, endocrine, metabolic, reproductive, musculoskeletal, and
carcinogenic effects beyond those benefits associated with decreased
PFOA and PFOS that EPA has quantified. The evidence for these adverse
health effects is briefly summarized below.
    EPA identified a wide range of potential health effects associated
with exposure to PFOA and PFOS using five comprehensive Federal
government documents that summarize the recent literature on PFAS
(mainly PFOA and PFOS) exposure and its health impacts: EPA's Health
Effects Support Documents for PFOA and PFOS, hereafter referred to as
EPA HESDs (USEPA, 2016e; USEPA, 2016f); EPA's Proposed Maximum
Contaminant Level Goals for PFOA and PFOS in Drinking Water (USEPA,
2023b; USEPA, 2023c); and the U.S. Department of Health and Human
Services Agency for Toxic Substances and Disease Registry's (ATSDR)
Toxicological Profile for Perfluoroalkyls (ATSDR, 2021). Each source
presents comprehensive literature reviews on adverse health effects
associated with PFOA and PFOS. EPA notes that the National Academies of
Science, Engineering, and Medicine also published a report which
includes a review of the adverse health effects for numerous PFAS
(NASEM 2022). That document is included in the docket for this proposed
rulemaking.
    The most recent literature reviews on PFAS exposures and health
impacts, which are included in EPA's Proposed Maximum Contaminant Level
Goal for PFOA and PFOS in Drinking Water (USEPA, 2023b; USEPA, 2023c),
discuss the weight of evidence supporting associations between PFOA or
PFOS exposure with health outcomes as indicative (likely), inadequate,
or suggestive. For the purposes of the reviews conducted to develop the
proposed MCLGs, an association is deemed indicative when findings are
consistent and supported by substantial evidence. The association is
inadequate if there is a lack of information or an inability to
interpret the available evidence (e.g., findings across studies). The
association is suggestive if findings are consistent but supported by a
limited number of studies or analyses, or only observed in certain
populations or species. Note that these determinations are based on
information available as of February 2022.
    Developmental effects: Exposure to PFOA and PFOS during
developmental life stages is linked to developmental effects including
but not limited to the infant birth weight effects that EPA quantified.
Other developmental effects include SGA, birth length, head
circumference at birth, and other effects (Verner et al., 2015; USEPA,
2016e; USEPA, 2016f; Negri et al., 2017; ATSDR, 2021; Waterfield et
al., 2020; USEPA, 2023b; USEPA, 2023c). SGA is a developmental health
outcome of interest when studying potential effects of PFOA/PFOS
exposure because SGA infants have increased health risks during
pregnancy and delivery as well as post-delivery (Osuchukwu and Reed,
2022). Epidemiology evidence related to PFOA/PFOS exposure was mixed;
some studies reported increased risk of SGA with PFOA/PFOS exposure,
while other studies observed null results (USEPA, 2023b; USEPA, 2023c).
For instance, some studies suggested a potentially positive association
between PFOA exposure and SGA (Govarts et al., 2018; Lauritzen et al.,
2017; Y. Wang et al., 2016; USEPA, 2023b). For PFOS, few patterns were
discernible, and overall confidence of an association between the two
factors was low (USEPA, 2023c). Similarly, ATSDR found no strong
associations between PFOA or PFOS exposure and increases in risk of SGA
infants (ATSDR, 2021). Toxicology studies on PFOS exposures in rodents
reported effects on multiple developmental toxicity endpoints
(including increased mortality, decreased BW and BW change, skeletal
and soft tissue effects, and delayed eye-opening) (USEPA, 2023c). For
additional details on developmental studies and their individual
outcomes, see Chapter 3.4.1 (Developmental) in USEPA (2023b) and USEPA
(2023c).

    Cardiovascular effects: In addition to the CVD effects that EPA
quantified associated with changes in total cholesterol and blood
pressure from exposure to PFOA or PFOS (see Section 6.2 of USEPA
(2023j)), available evidence suggests an association between exposure
to PFOA or PFOS and increased LDLC (ATSDR, 2021; USEPA, 2023b; USEPA,
2023c). High levels of LDLC lead to the buildup of cholesterol in the
arteries, which can raise the risk of heart disease and stroke.
Epidemiology studies showed a positive association between PFOA or PFOS
exposure and LDLC levels in children (USEPA, 2023b; USEPA, 2023c). In
particular, the evidence suggested positive associations between serum
PFOA and PFOS levels and LDLC levels in adolescents ages 12-18, while
positive associations between serum levels and LDLC levels in younger
children were observed only for PFOA (ATSDR, 2021). Studies conducted
on PFOS showed evidence of an association between exposure and LDLC
levels in adults. For instance, all five epidemiology studies evaluated
in EPA's Proposed MCLGs for PFOA and PFOS in Drinking Water reported
positive associations, although the association was only statistically
significant in obese women. Available evidence regarding the impact of
PFOA and PFOS exposure on pregnant women was too limited for EPA to
determine an association (ATSDR, 2021; USEPA, 2023b; USEPA, 2023c). For
additional details on LDLC studies and their individual outcomes, see
Chapter 3.4.4 (Cardiovascular) in USEPA (2023b) and USEPA (2023c).
    Liver effects: Several biomarkers can be used clinically to
diagnose liver diseases, including the ALT. High levels of serum ALT
may indicate liver damage. Epidemiology data provides consistent
evidence of a positive association between PFOS/PFOA exposure and ALT
levels in adults (ATSDR, 2021; USEPA, 2023b; USEPA, 2023c). Studies of
adults showed consistent evidence of a positive association between
PFOA exposure and elevated ALT levels at both high exposure levels and
exposure levels typical of the general population (USEPA, 2023b). There
is also consistent epidemiology evidence of associations between PFOS
and elevated ALT levels, although the associations observed were not
large in magnitude. Study results showed inconsistent evidence on
whether the observed changes led to changes in specific liver disease
(USEPA, 2023c).
    Associations between PFOS/PFOA exposure and ALT levels in children
were less consistent than in adults (USEPA, 2023b; USEPA, 2023c), and
PFOA toxicology studies showed increases in ALT and other liver enzymes
across multiple species, sexes, and exposure paradigms (USEPA, 2023b).
Toxicology studies on the impact of PFOS exposure on ALT in rodents
also reported increases in ALT and other liver enzyme levels in
rodents, though these increases were modest (USEPA, 2023c). For
additional details on the ALT studies and their individual outcomes,
see Section 3.4.2 (Hepatic) in USEPA (2023b) and USEPA (2023c).
    Immune effects: Proper antibody response helps maintain the immune
system by recognizing and responding to antigens. Some evidence
suggests a relationship between PFOA exposure and immunosuppression;
epidemiology studies showed suppression of at least one measure of the
antibody response for tetanus and diphtheria among people with higher
prenatal, childhood, and adult serum concentrations of PFOA (USEPA,
2023b). It is less clear whether PFOA exposure impacts antibody
response to vaccinations other than tetanus and diphtheria (ATSDR,
2021; USEPA, 2023b). Epidemiology evidence suggests that children with
preexisting immunological conditions are particularly susceptible to
immunosuppression associated with PFOA exposure (USEPA, 2023b).
Available studies supported an association between PFOS exposure and
immunosuppression in children, where increased PFOS serum levels were
associated with decreased antibody production (USEPA, 2023c). However,
the association between PFOS exposure and immunosuppression was not
apparent in adults (USEPA, 2023c).\8\ Other potential associations with
PFOS exposure with a high degree of uncertainty included asthma and
infectious diseases (e.g., the common cold, lower respiratory tract
infections, pneumonia, bronchitis, ear infections) (USEPA, 2023c).
Animal toxicology study evidence suggested that PFOA or PFOS exposure
results in effects similarly indicating immune suppression, such as
reduced response of immune cells (e.g., natural killer cell activity
and immunoglobulin production) (USEPA, 2023b; USEPA, 2023c). For
additional details on antibody studies and their individual outcomes,
see Section 3.4.3 (Immune) in USEPA (2023b) and USEPA (2023c).
---------------------------------------------------------------------------

    \8\ This may be due to the lack of high-quality data at present.
---------------------------------------------------------------------------

    Endocrine effects: Elevated thyroid hormone levels can accelerate
metabolism and cause irregular heartbeat; low levels of thyroid hormone
can cause neurodevelopmental effects, tiredness, weight gain, and
increased susceptibility to the common cold. There is suggestive
evidence of a positive association between PFOA/PFOS exposure and
thyroid hormone disruption (ATSDR, 2021; USEPA, 2023b; USEPA, 2023c).
Epidemiology studies reported inconsistent evidence regarding
associations between PFOA or PFOS exposure and general endocrine
outcomes, such as thyroid disease, hypothyroidism, and hypothyroxinemia
(USEPA, 2023b; USEPA, 2023c). However, studies reported suggestive
evidence of positive associations for thyroid stimulating hormone (TSH)
in adults, and the thyroid hormone thyroxine (T4) in children (USEPA,
2023b; USEPA, 2023c). Toxicology studies indicated that PFOA and PFOS
exposure leads to decreases in thyroid hormone levels \9\ and adverse
effects to the endocrine system (ATSDR, 2021; USEPA, 2023b; USEPA,
2023c). Despite uncertainty around the applicability of animal studies
in this area, changes in thyroid hormone levels in animals did indicate
adverse effects after PFOS and PFOA exposure that is relevant to humans
(USEPA, 2023b; USEPA, 2023c). For additional details on endocrine
effects studies and their individual outcomes, see Chapter C.2
(Endocrine) in USEPA (2023k) and USEPA (2023l).
---------------------------------------------------------------------------

    \9\ Decreased thyroid hormone levels are associated with effects
such as changes in thyroid and adrenal gland weight, hormone
fluctuations, and organ histopathology (ATSDR, 2021; USEPA, 2023b;
USEPA, 2023c).
---------------------------------------------------------------------------

    Metabolic effects: Leptin is a hormone that controls hunger, and
high leptin levels are associated with obesity, overeating, and
inflammation (e.g., of adipose tissue, the hypothalamus, blood vessels,
and other areas). Evidence suggests a direct association between PFOA
exposure and leptin levels in the general adult population (ATSDR,
2021; USEPA, 2023b). Based on a review of 69 human epidemiology
studies, evidence of associations between PFOS and metabolic outcomes
appears inconsistent, but in some studies, suggestive evidence was
observed between PFOS exposure and leptin levels (USEPA, 2023c).
Studies examining newborn leptin levels did not find associations with
maternal PFOA levels (ATSDR, 2021). Maternal PFOS levels were also not
associated with alterations in leptin levels (ATSDR, 2021). For
additional details on metabolic effect studies and their individual
outcomes, see Chapter C.3

(Metabolic/Systemic) in USEPA (2023k) and USEPA (2023l).
    Reproductive effects: Studies of the reproductive effects from
PFOA/PFOS exposure have focused on associations between exposure to
these pollutants and increased risk of gestational hypertension and
preeclampsia in pregnant women (ATSDR, 2021; USEPA, 2023b; USEPA,
2023c). Gestational hypertension (high blood pressure during pregnancy)
can lead to fetal health outcomes such as poor growth and stillbirth.
Preeclampsia--instances of gestational hypertension where the mother
also has increased levels of protein in her urine--can similarly lead
to fetal problems and maternal complications. The epidemiology evidence
yields mixed (positive and non-significant) associations, with some
suggestive evidence supporting positive associations between PFOA/PFOS
exposure and both preeclampsia and gestational hypertension (ATSDR,
2021; USEPA, 2023b; USEPA, 2023c). For additional details on
reproductive effects studies and their individual outcomes, see Chapter
C.1 (Reproductive) in USEPA (2023k) and USEPA (2023l).
    Musculoskeletal effects: Adverse musculoskeletal effects such as
osteoarthritis and decreased bone mineral density impact bone integrity
and cause bones to become brittle and more prone to fracture. There is
limited evidence from studies pointing to effects of PFOS on skeletal
size (height), lean body mass, and osteoarthritis (USEPA, 2023c).
Epidemiology evidence suggested that PFOA exposure may be linked to
decreased bone mineral density, bone mineral density relative to bone
area, height in adolescence, osteoporosis, and osteoarthritis (ATSDR,
2021; USEPA, 2023b). Evidence from four PFOS studies suggests that PFOS
exposure has a harmful effect on bone health, particularly measures of
bone mineral density, with greater statistically significance of
effects occurring among females (USEPA, 2023c). Some studies found that
PFOA/PFOS exposure was linked to osteoarthritis, in particular among
women under 50 years of age (ATSDR, 2021). However, other reviews
reported mixed findings on the effects of PFOS exposure including
decreased risk of osteoarthritis, increased risk for some demographic
subgroups, or no association (ATSDR, 2021). For additional details on
musculoskeletal effects studies and their individual outcomes, see
Chapter C.8 (Musculoskeletal) in USEPA (2023k) and USEPA (2023l).
    Cancer Effects: In EPA's Proposed Maximum Contaminant Level Goal
for PFOA in Drinking Water, the Agency evaluates the evidence for
carcinogenicity of PFOA that has been documented in both
epidemiological and animal toxicity studies (USEPA, 2023b). The
evidence in epidemiological studies is primarily based on the incidence
of kidney and testicular cancer, as well as some evidence of breast
cancer, which is most consistent in genetically susceptible
subpopulations. Other cancer types have been observed in humans,
although the evidence for these is generally limited to low confidence
studies. The evidence of carcinogenicity in animal models is provided
in three chronic oral animal bioassays in Sprague-Dawley rats which
identified neoplastic lesions of the liver, pancreas, and testes
(USEPA, 2023b). EPA determined that PFOA is Likely to Be Carcinogenic
to Humans, as ``the evidence is adequate to demonstrate carcinogenic
potential to humans but does not reach the weight of evidence for the
descriptor Carcinogenic to Humans.'' This determination is based on the
evidence of kidney and testicular cancer in humans and LCTs, PACTs, and
hepatocellular adenomas in rats (USEPA, 2023b). EPA's benefits analysis
for avoided RCC cases from reduced PFOA exposure is discussed in
Section XII.D of this preamble and in Section 6.6 of USEPA (2023j).
    In EPA's Proposed Maximum Contaminant Level Goal for PFOS in
Drinking Water, the Agency evaluates the evidence for carcinogenicity
of PFOS and concluded that several epidemiological studies and a single
chronic cancer bioassay comprise the evidence database for the
carcinogenicity of PFOS (USEPA, 2023c). The available epidemiology
studies report elevated risk of bladder, prostate, kidney, and breast
cancers after chronic PFOS exposure. However, in developing this
proposal, EPA did not identify information to quantify the benefits
that reducing PFOS would have on reducing various cancers in humans.
The sole animal chronic cancer bioassay study provide support for
multi-site tumorigenesis in male and female rats. EPA reviewed the
weight of the evidence and determined that PFOS is Likely to Be
Carcinogenic to Humans, as ``the evidence is adequate to demonstrate
carcinogenic potential to humans but does not reach the weight of
evidence for the descriptor Carcinogenic to Humans.''
    EPA anticipates there are additional nonquantifiable benefits
related to potential testicular, bladder, prostate, kidney, and breast
carcinogenic effects summarized above. For additional details on cancer
studies and their individual outcomes, see Chapter 3.5 (Cancer) in
USEPA (2023b) and USEPA (2023c).
    After assessing the available health and economic information, EPA
was unable to quantify the benefits of avoided health effects discussed
above. The Agency prioritized health endpoints with the strongest
weight of evidence conclusions for this assessment and readily
available data for monetization, namely cardiovascular effects,
developmental effects, and carcinogenic effects. Several other health
endpoints that had indicative evidence of associations with exposure to
PFOA or PFOS have not been selected for the Economic Analysis for the
reasons below.
     While immune effects had indicative evidence of
associations with exposure to PFOA or PFOS, EPA did not identify the
necessary information to connect the measured biomarker responses
(i.e., decrease in antibodies) to a clinical effect that could be
valued in the Economic Analysis;
     Evidence indicates associations between PFOA and PFOS
exposure and hepatic effects, such as increases in ALT. However, EPA is
not able to model this health endpoint because ALT is a non-specific
biomarker. Similar challenges with non-specificity of the biomarkers
representing metabolic effects (i.e., leptin) and musculoskeletal
effects (i.e., bone density) prevented economic analysis of these
endpoints;
     There is indicative evidence of association with exposure
to PFOA for testicular cancer; however, the available slope factor
implied small changes in the risk of this endpoint. Furthermore,
testicular cancer is rarely fatal which implies low expected economic
value of reducing this risk because Value of Statistical Life is the
driver of economic benefits evaluated in the Economic Analysis;
     Finally, other health endpoints, such as SGA and LDLC
effects, were not modeled in the Economic Analysis because they overlap
with effects that EPA did model. For example, infants that are
considered SGA are often born at low birth weight or receive similar
care to infants born at low birth weight. LDLC is a component of total
cholesterol and could not be modeled separately as EPA used total
cholesterol as an input to the ASCVD model to estimate CVD outcomes.

F. Nonquantifiable Benefits of Removal of PFAS Included in the Proposed
Regulation and Co-Removed PFAS

    EPA also qualitatively summarized the potential health benefits
resulting from reduced exposure to PFAS other than PFOA and PFOS in
drinking water. The proposed option and all regulatory alternatives are
expected to result in benefits that have not been quantified. Treatment
responses implemented to reduce PFOA and PFOS exposure under the
proposed option and Options 1a-c are likely to remove some amount of
additional PFAS contaminants where they co-occur. Co-occurrence among
PFAS compounds has been observed frequently as discussed in Section VII
of this preamble and USEPA (2023e). The proposed option will require
reduced exposure to PFHxS, HFPO-DA, PFNA, and PFBS to below their
respective HBWCs. EPA also expects that compliance actions taken under
the proposed rule will remove additional unregulated co-occurring PFAS
contaminants where present because the BATs have been demonstrated to
co-remove additional PFAS (see Section XI of this preamble for more
information). EPA identified a wide range of potential health effects
associated with exposure to PFAS compounds other than PFOA and PFOS
using documents that summarize the recent literature on exposure and
associated health impacts: ATSDR's Toxicology Profile for
Perfluoroalkyls (ATSDR, 2021); EPA's summary of HFPO-DA toxicity
(USEPA, 2021b); publicly available draft IRIS assessments for PFBA, and
PFHxA (USEPA, 2021k; USEPA, 2022h); a human health assessment for PFBS
(USEPA, 2021a); and the recent National Academies of Sciences,
Engineering, and Medicine Guidance on PFAS Exposure, Testing, and
Clinical Follow-up (NASEM, 2022). Note that the determinations of
associations between PFAS compounds and associated health effects are
based on information available as of May 2022, and that the
finalization of the IRIS assessments may result in slight changes to
the discussion of evidence. Additional discussion of the evidence from
epidemiology and toxicology studies for associations between different
categories of health effects and exposure to additional PFAS can be
found in Section 6.2 of USEPA (2023j).
    Developmental effects: Toxicology and/or epidemiology studies
observed evidence of associations with decreased birth weight and/or
other developmental effects and exposure to PFBA, perfluorodecanoic
acid (PFDA), PFHxS, HFPO-DA, PFNA, and PFBS. Specifically, data from
animal toxicological studies support this association for PFBS, PFBA,
and HFPO-DA while both animal toxicological and epidemiological studies
support this association for PFDA and PFNA (ATSDR 2021) although some
mixed results have been found for birth outcomes, particularly birth
weight. In general, epidemiological studies did not find associations
between perfluoroalkyl exposure and adverse pregnancy outcomes
(miscarriage, preterm birth, or gestational age) for PFHxS, PFNA, PFDA,
or perfluoroundecanoic acid (PFUnA) (ATSDR, 2021; NASEM, 2022).
    Cardiovascular effects: Epidemiology and toxicology studies
observed evidence of associations between PFNA or PFDA exposures and
total cholesterol, LDLC, and HDLC. Evidence for associations between
PFNA exposure and serum lipids levels in epidemiology studies was
mixed; associations have been observed between serum PFNA levels and
total cholesterol in general populations of adults but not in pregnant
women, and evidence in children is inconsistent (ATSDR, 2021). Most
epidemiology studies did not observe associations between PFNA and LDLC
or HDLC (ATSDR, 2021).
    Similarly inconsistent evidence was observed for PFDA (ATSDR,
2021). Other PFAS for which lipid outcomes were examined in toxicology
or epidemiology studies observed limited to no evidence of
associations. Studies have examined possible associations between
various PFAS and blood pressure in humans or heart histopathology in
animals. However, studies did not find suggestive or likely evidence
for any PFAS in this summary except for PFOS.
    Hepatic effects: Toxicology studies reported associations between
exposure to PFAS compounds (PFBA, PFDA, PFHxA, PFHxS, HFPO-DA, and
PFBS) and hepatotoxicity following inhalation, oral, and dermal
exposure in animals. The results of these studies provide strong
evidence that the liver is a sensitive target of PFHxS, PFNA, PFDA,
PFUnA, PFBS, PFBA, perfluorododecanoic acid (PFDoDA), and PFHxA
toxicity. Observed effects in rodents include increases in liver
weight, hepatocellular hypertrophy, hyperplasia, and necrosis (ATSDR,
2021; USEPA, 2021b; USEPA, 2022h). Increases in serum enzymes (such as
ALT) and decreases in serum bilirubin were observed in one
epidemiologic study of PFHxS, and mixed effects were observed for
epidemiologic studies for PFNA (ATSDR, 2021).
    Immune effects: Epidemiology studies have reported evidence of
associations between PFDA and PFHxS exposure and antibody response to
tetanus or diphtheria. There is also some limited evidence for
decreased antibody response for PFNA, PFUnA, and PFDoDA, although many
of the studies did not find associations for these compounds. There is
limited evidence for associations between PFHxS, PFNA, PFDA, PFBS, and
PFDoDA and increased risk of asthma due to the small number of studies
evaluating the outcome and/or conflicting study results. The small
number of studies investigating immunotoxicity in humans following
exposure to PFHpA and PFHxA did not find associations (ATSDR, 2021).
Toxicology studies have reported evidence of associations between HFPO-
DA and immune-related endpoints in animals (USEPA, 2021b). No
laboratory animal studies were identified for PFUnA, PFHpA, PFDoDA, or
perfluorooctane sulfonamide (FOSA). A small number of toxicology
studies evaluated the immunotoxicity of other perfluoroalkyls and most
did not evaluate immune function. No alterations in spleen or thymus
organ weights or morphology were observed in studies on PFHxS, PFBA,
and PFDA. A study on PFNA found decreases in spleen and thymus weights
and alterations in splenic lymphocyte phenotypes (ATSDR, 2021).
    Endocrine effects: Epidemiology studies have observed associations
between serum PFHxS, PFNA, PFDA, and PFUnA and TSH, triiodothyronine
(T3), or thyroxine (T4) levels or thyroid disease, however the results
are not consistent across studies and a large number of studies have
not found associations (ATSDR, 2021; NASEM, 2022). Toxicology studies
have reported associations with thyroid hormone disruption in animals
for PFBA, PFHxA, and PFBS (USEPA, 2021a; 2021k; USEPA, 2022h).
    Metabolic effects: Epidemiology and toxicology studies have
examined possible associations between various PFAS and metabolic
effects, including leptin, BW, or body fat in humans or animals (ATSDR,
2021). However, evidence of associations was not suggestive or likely
for any PFAS in this summary except for PFOA. Evidence did not include
changes such as BW gain, pup BW, or other developmentally focused
weight outcomes (ATSDR, 2021; NASEM, 2022).
    Renal effects: A small number of epidemiology studies with
inconsistent results evaluated possible associations between PFHxS,
PFNA, PFDA, PFBS, PFDoDA, or PFHxA and renal functions

(including estimated glomerular filtration rate and increases in uric
acid levels) (ATSDR, 2021; NASEM 2022). Toxicology studies have not
observed impaired renal function or morphological damage following
exposure to PFHxS, PFDA, PFUnA, PFBS, PFBA, PFDoDA, or PFHxA.
Associations with kidney weight in animals were observed for HFPO-DA
and PFBS (ATSDR, 2021; USEPA, 2021b; USEPA, 2021a).
    Reproductive effects: A small number of epidemiology studies with
inconsistent results evaluated possible associations between PFHxS,
PFNA, PFUnA, PFDoDA, or PFHxA exposure and reproductive hormone levels
(ATSDR, 2021). Some associations between PFAS (PFHxS, PFNA, or PFDA)
exposures and sperm parameters have been observed. While there is
suggestive evidence of an association between PFHxS or PFNA exposure
and an increased risk of early menopause, this may be due to reverse
causation since an earlier onset of menopause would result in a
decrease in the removal of PFAS via menstrual blood. Epidemiological
studies provide mixed evidence of impaired fertility (increased risks
of longer time to pregnancy and infertility), with some evidence for
PFHxS, PFNA, PFHpA, and PFBS but the results are inconsistent across
studies or were only based on one study (ATSDR, 2021). Toxicology
studies have evaluated the potential histological alterations in
reproductive tissues, alterations in reproductive hormones, and
impaired reproductive functions. No effect on fertility was observed
for PFBS, PFHxS or PFDoDA, and no histological alterations were
observed for PFBS, PFHxS and PFBA. One study found alterations in sperm
parameters and decreases in fertility in mice exposed to PFNA, and one
study for PFDoDA observed ultrastructural alterations in the testes
(ATSDR, 2021).
    Musculoskeletal effects: Epidemiology studies observed evidence of
associations between PFNA or PFHxS and musculoskeletal effects
including osteoarthritis and bone mineral density, but data are limited
to two studies (ATSDR, 2021). Epidemiology studies reported limited to
no evidence of associations between exposure to PFDA and
musculoskeletal effects. Toxicology studies reported no morphological
alterations in bone or skeletal muscle in animals exposed to PFBA,
PFHxA, PFHxS, or PFBS (ATSDR, 2021).
    Hematological effects: A single epidemiologic study reported on
blood counts in pregnant Chinese women exposed to PFHxA and observed no
correlations with any of the hematological parameters evaluated (total
white blood cell counts, red blood cell (RBC) counts, and hemoglobin)
(USEPA, 2022h). Epidemiological data were not identified for the other
PFAS (ATSDR, 2021). A limited number of toxicology studies observed
alterations in hematological indices following exposure to higher doses
of PFHxS, PFDA, PFUnA, PFBS, PFBA, PFDoDA, or PFHxA (ATSDR, 2021).
Toxicology studies observed evidence of association between HFPO-DA
exposure and hematological effects including decreases in RBC number,
hemoglobin, and percentage of RBCs in the blood (USEPA, 2021b).
    Other non-cancer effects: A limited number of epidemiology and
toxicology studies have examined possible associations between other
PFAS and dermal, ocular, and other non-cancer effects. However,
evidence of associations was not considered to be suggestive or likely
for any PFAS compound in this summary except for PFOA and PFOS (ATSDR,
2021; USEPA, 2021a; USEPA, 2021k; USEPA, 2022h).
    Cancer effects: A small number of epidemiology studies reported
limited associations between exposure to multiple PFAS (i.e., PFHxS,
PFDA, PFUnA, and FOSA) and cancer effects. No consistent associations
were observed for breast cancer risk for PFHxS, PFNA, PFHpA, or PFDoDA;
increased breast cancer risks were observed for PFDA and FOSA, but this
was based on a single study (Bonefeld-J[oslash]rgensen et al., 2014).
No associations between exposure to PFHxS, PFNA, PFDA, or PFUnA,
individually and prostate cancer risk were observed. However, among men
with a first-degree relative with prostate cancer, associations were
observed for PFHxS, PFDA, and PFUnA, but not for PFNA (ATSDR, 2021).
Epidemiological studies examining potential cancer effects were not
identified for PFBS, PFBA, or PFHxA (ATSDR, 2021). Aside from a study
that suggested an increased incidence of liver tumors in rats exposed
to high doses of HFPO-DA, toxicology studies reported no evidence of
associations between exposure to PFDA or PFHxA and risk of cancer
(ATSDR, 2021; USEPA, 2021b).
    Coronavirus Disease 2019 (COVID-19): A cross-sectional study in
Denmark (Grandjean et al., 2020) showed that PFBA exposure was
associated with increasing severity of COVID-19, with an OR of 1.77
[95% Confidence Interval (CI): 1.09, 2.87] after adjustment for age,
sex, sampling site, and interval between blood sampling and diagnosis.
However, the study design does not allow for causal determinations.
    A case-control study showed increased risk for COVID-19 infection
with high urinary PFAS (including PFOA, PFOS, PFHxA, PFHpA, PFHxS,
PFNA, PFBS, PFDA, PFUnA, PFDoDA, perfluorotridecanoic acid [PFTrDA],
and perfluorotetradecanoic acid [PFTeDA]) levels (Ji et al., 2021).
Adjusted odds ratios were 1.94 (95% CI: 1.39, 2.96) for PFOS, 2.73 (95%
CI: 1.71, 4.55) for PFOA, and 2.82 (95% CI: 1.97, 3.51) for sum PFAS,
while other PFAS were not significantly associated with COVID-19
susceptibility after adjusting for confounders.
    In a spatial ecological analysis, Catelan et al. (2021) showed
higher mortality risk for COVID-19 in a population heavily exposed to
PFAS (including PFOA, PFOS, PFHxS, PFBS, PFBA, perfluoropentanoic acid
[PFPeA], PFHxA, and PFHpA) via drinking water in Veneto, Italy.
Overall, results may indicate a general immunosuppressive effect of
PFAS and/or increased COVID-19 respiratory toxicity due to a
concentration of PFBA in the lungs, however the study design precludes
causal determinations.
    Although these studies provide a suggestion of possible
associations, the body of evidence does not permit any conclusions
about the relationship between COVID-19 infection, severity, or
mortality, and exposures to PFAS.

G. Benefits Resulting From Disinfection By-Product Co-Removal

    As part of its health risk reduction and cost analysis, EPA is
directed by SDWA to evaluate quantifiable and nonquantifiable health
risk reduction benefits for which there is a factual basis in the
rulemaking record to conclude that such benefits are likely to occur
from reductions in co-occurring contaminants that may be attributed
solely to compliance with the MCL (SDWA 1412(b)(3)(C)(II)). These co-
occurring contaminants are expected to include additional PFAS
contaminants not directly regulated by the proposed PFAS NPDWR, co-
occurring chemical contaminants such as SOCs, VOCs, and DBP precursors.
In this section, EPA presents a quantified estimate of the reductions
in DBP formation potential that are likely to occur as a result of
compliance with the proposed PFAS NPDWR. The methodology detailed below
and in Section 6.7.1 of USEPA (2023j) to estimate DBP reductions was
externally peer reviewed by three experts in GAC treatment for PFAS
removal and DBP formation potential (USEPA, 2023m). The external peer
reviewers supported EPA's approach

and edits based on their recommendations for clarity and completeness
are reflected in the following analysis and discussion. Some peer
reviewer comments suggested EPA provide additional baseline data
summaries for TOC and THM4 occurrence information. EPA intends to
evaluate and potentially include these additional summaries in the EA
for the final rule.
    DBPs are formed when disinfectants react with naturally occurring
materials in water. There is a substantial body of literature on DBP
precursor occurrence and THM4 formation mechanisms in drinking water
treatment. EPA regulates 11 individual DBPs from three subgroups: THM4,
five haloacetic acids (HAA5), and two inorganic compounds (bromate and
chlorite) under the Stage 2 Disinfectants and Disinfection Byproducts
Rule (USEPA, 2006a). The formation of THM4 in a particular drinking
water treatment plant is a function of several factors including
disinfectant type, disinfectant dose, bromide concentration, organic
material type and concentration, temperature, pH, and system residence
times. Epidemiology studies have shown that THM4 exposure, a surrogate
for chlorinated drinking water, is associated with an increased risk of
bladder cancer, among other diseases (Cantor et al., 1998; Cantor et
al., 2010; Costet et al., 2011; Beane Freeman et al., 2017; King and
Marrett, 1996; Regli et al., 2015; USEPA, 2019d; Villanueva et al.,
2004; Villanueva et al., 2006; Villanueva et al., 2007). These studies
considered THM4 as surrogate measures for DBPs formed from the use of
chlorination that may co-occur. The relationships between exposure to
DBPs, specifically THM4 and other halogenated compounds resulting from
water chlorination, and bladder cancer are further discussed in Section
6.7 of USEPA (2023j). Reductions in exposure to THM4 is expected to
yield public health benefits, including a decrease in bladder cancer
incidence (Regli et al., 2015). Among other things, Weisman et al.
(2022) found that there is even a stronger weight of evidence linking
DBPs and bladder cancer since the promulgation of the 2006 Stage 2 DBP
regulations and publication of Regli et al. (2015). While not the
regulated contaminant for this rulemaking, the expected reduction of
DBP precursors and subsequent DBPs that result from this rulemaking are
anticipated to reduce cancer risk in the U.S. population.
    GAC adsorption has been used to remove SOCs, taste and odor
compounds, and NOM during drinking water treatment (Chowdhury et al.,
2013). Recently, many water utilities have installed or are considering
installing GAC and/or other advanced technologies as a protective or
mitigation measure to remove various contaminants of emerging concern,
such as PFAS (Dickenson and Higgins, 2016). Because NOM often exists in
a much higher concentration (in mg/L) than trace organics (in [mu]g/L
or ppt) in water, NOM, often measured as TOC, can interfere with the
adsorption of trace organics by outcompeting the contaminants for
adsorption sites and by general fouling (blockage of adsorption pores)
of the GAC.
    NOM and inorganic matter are precursors for the formation of
trihalomethanes (THMs) and other DBPs when water is disinfected using
chlorine and other disinfectants to control microbial contaminants in
finished drinking water. Removal of DBP precursors through adsorption
onto GAC has been included as a treatment technology for compliance
with the existing DBP Rules and is a BAT for the Stage 2 DBP Rule. DOM
can be removed by GAC through adsorption and biodegradation (Crittenden
et al., 1993; Kim et al., 1997; Yapsakli et al., 2010). GAC is well-
established for removal of THM and haloacetic acid precursors (Cheng et
al., 2005; Dastgheib et al., 2004; Iriarte-Velasco et al., 2008;
Summers et al., 2013; Cuthbertson et al., 2019; L. Wang et al., 2019).
In addition to removal of organic DBPs, GAC also exhibits some capacity
for removal of inorganic DBPs such as bromate and chlorite (Kirisits et
al., 2000; Sorlini et al., 2005) and removal of preformed organic DBPs
via adsorption and biodegradation (Jiang, et al., 2017; Terry and
Summers, 2018). Further, GAC may offer limited removal of dissolved
organic nitrogen (Chili et al., 2012).
    Based on an extensive review of published literature in sampling
studies where both contaminant groups (PFAS and DBPs) were sampled,
there is limited information about PFAS removal and co-occurring
reductions in DBPs, specifically THMs. To help inform its Economic
Analysis, EPA relied on the DBP Information Collection Rule Treatment
Study Database and DBP formation studies to estimate reductions in THM4
([Delta]THM4) that may occur when GAC is used to remove PFAS.
Subsequently, these results were compared to THM4 data from PWSs that
have detected PFAS and have indicated use of GAC.
    The objective of EPA's co-removal benefits analysis was to
determine the reduction in bladder cancer cases associated with the
decrease of regulated THM4 in treatment plants due to the installation
of GAC for PFAS removal. Evaluation of the expected reductions in
bladder cancer risk resulting from treatment of PFAS in drinking water
involves five steps:
    1. Estimating the number of systems expected to install GAC
treatment in compliance with the proposed PFAS NPDWR and affected
population size;
    2. Estimating changes in THM4 levels that may occur when GAC is
installed for PFAS removal based on influent TOC levels;
    3. Estimating changes in the cumulative risk of bladder cancer
using an exposure-response function linking lifetime risk of bladder
cancer to THM4 concentrations in residential water supply (Regli et
al., 2015);
    4. Estimating annual changes in the number of bladder cancer cases
and excess mortality in the bladder cancer population corresponding to
changes in THM4 levels under the regulatory alternative in all
populations alive during or born after the start of the evaluation
period; and
    5. Estimating the economic value of reducing bladder cancer
mortality from baseline to regulatory alternative levels, using the
Value of a Statistical Life and cost of illness measures, respectively.
    EPA expects PWSs that exceed the PFAS MCLs to consider both
treatment and non-treatment options to achieve compliance with the
drinking water standard. EPA assumes that the populations served by
systems with entry points expected to install GAC based on the
compliance forecast detailed in Section 5.3 of USEPA (2023j) will
receive the DBP exposure reduction benefits. EPA notes that other
compliance actions included in the compliance forecast could result in
DBP exposure reductions, including installation of RO. However, these
compliance actions are not included in the DBP benefits analysis
because this DBP exposure reduction function is specific to GAC.
Switching water sources may or may not result in DBP exposure
reductions, therefore EPA assumed no additional DBP benefits for an
estimated percentage of systems that elect this compliance option.
Lastly, EPA assumed no change in DBP exposure at water systems that
install IX, as that treatment technology is not expected to remove a
substantial amount of DBP precursors. EPA also assumes that the PWSs in
this analysis use chlorine only for disinfection and have conventional
treatment in place prior to installation of GAC technology.
    EPA used the relationship between median raw water TOC levels and
changes in THM4 levels estimated in the 1998 DBP Information Collection

Rule to estimate changes in THM4 concentrations in the finished water
of PWSs fitted with GAC treatment. For more detail on the approach EPA
used to apply changes in THM4 levels to PWSs treating for PFAS under
the proposed rule, please see Section 6.7 of USEPA (2023j).
    EPA models a scenario where reduced exposures to THM4 begin in
2026. Therefore, EPA assumed that the population affected by reduced
THM4 levels resulting from implementation of GAC treatment is exposed
to baseline THM4 levels prior to actions to comply with the rule (i.e.,
prior to 2026) and to reduced THM4 levels from 2026 through 2104.
Rather than modeling individual locations, EPA evaluates changes in
bladder cancer cases among the aggregate population per treatment
scenario and source water type that is expected to install GAC
treatment to reduce PFAS levels. Because of this aggregate modeling
approach, EPA used national-level population estimates to distribute
the SDWIS populations based on single-year age and sex and to grow the
age- and sex-specific populations to future years. Appendix B to USEPA
(2023j) provides additional details on estimation of the affected
population.
    Regli et al. (2015) analyzed the potential lifetime bladder cancer
risks associated with increased bromide levels in surface source water
resulting in increased THM4 levels in finished water. To account for
variable levels of uncertainty across the range of THM4 exposures from
the pooled analysis of Villanueva et al. (2004), they derived a
weighted mean slope factor from the odds ratios reported in Villanueva
et al. (2004). They showed that, while the original analysis deviated
from linearity, particularly at low concentrations, the overall pooled
exposure-response relationship for THM4 could be well-approximated by a
linear slope factor that predicted an incremental lifetime cancer risk
of 1 in ten thousand exposed individuals (10-4) per 1 [micro]g/L
increase in THM4. The linear slope factor developed by Regli et al.
(2015) enables estimation of the changes in the lifetime bladder cancer
risk associated with lifetime exposures to reduced THM4 levels. Weisman
et al. (2022) applied the dose-response information from Regli et al.
(2015) and developed a robust, national-level risk assessment of DBP
impacts, where the authors estimated that approximately 8,000 of 79,000
annual U.S. bladder cancer cases are attributable to chlorination DBPs,
specifically associated with THM4 concentrations.
    EPA estimated changes in annual bladder cancer cases and annual
excess mortality in the bladder cancer population due to estimated
reductions in lifetime THM4 exposure using a life table-based approach.
This approach was used because (1) annual risk of new bladder cancer
should be quantified only among those not already experiencing this
chronic condition, and (2) bladder cancer has elevated mortality
implications.
    EPA used recurrent life table calculations to estimate a water
source type-specific time series of bladder cancer incidence for a
population cohort characterized by sex, birth year, and age at the
beginning of the PFOA/PFOS evaluation period under the baseline
scenario and the GAC regulatory alternative. The estimated risk
reduction from lower exposure to DBPs in drinking water is calculated
based on changes in THM4 levels used as inputs to the Regli et al.
(2015)-based health impact function, described in more detail in
Section 6.7 of USEPA (2023j). The life table analysis accounts for the
gradual changes in lifetime exposures to THM4 following implementation
of GAC treatment under the regulatory alternative compared to the
baseline. The outputs of the life table calculations are the water
source type-specific estimates of the annual change in the number of
bladder cancer cases and the annual change in excess bladder cancer
population mortality.
    EPA uses the Value of a Statistical Life to estimate the benefits
of reducing mortality associated with bladder cancer in the affected
population. EPA uses the cost of illness-based valuation to estimate
the benefits of reducing morbidity associated with bladder cancer.
Specifically, EPA used bladder cancer treatment-related medical care
and opportunity cost estimates from Greco et al. (2019). Table 61 shows
the original cost of illness estimates from Greco et al. (2019), along
with the values updated to $2021 used in this analysis.

                                  Table 61--Bladder Cancer Morbidity Valuation
----------------------------------------------------------------------------------------------------------------
                                                                      Cost in                         Cost in
                                                   Cost in first    subsequent     Cost in first    subsequent
  Bladder cancer subtype \1\      Type of cost     year ($2010)    years ($2010)   year ($2021)    years ($2021)
                                                        \2\             \2\             \c\             \3\
----------------------------------------------------------------------------------------------------------------
Non-invasive..................  Medical care....           9,133             916          12,350           1,239
                                Opportunity cost           4,572              24           5,921              31
                                                 ---------------------------------------------------------------
                                   Total cost...          13,705             941          18,272           1,270
----------------------------------------------------------------------------------------------------------------
Invasive......................  Medical care....          26,951           2,455          36,445           3,320
                                Opportunity cost          10,513              77          13,616             100
                                                 ---------------------------------------------------------------
                                   Total cost...          37,463           2,532          50,061           3,420
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ The estimates for non-invasive bladder cancer subtype were used to value local, regional, and unstaged
  bladder cancer morbidity reductions, while the estimates for the invasive bladder cancer subtype were used to
  value distant bladder cancer morbidity reductions.
\2\ The estimates come from Greco et al. (2019).
\3\ To adjust for inflation, EPA used U.S. BLS CPI for All Urban Consumers: Medical Care Services in U.S. (City
  Average).

    Table 62 to 65 presents the estimated changes in bladder cancer
cases and excess bladder cancer mortality from exposure to THM4 due to
implementation of GAC treatment by option. EPA estimated that, over the
evaluation period, the proposed rule will result in an average annual
benefit from avoided bladder cancer cases and deaths from $131 million
($2021, 7% discount rate) to $221 million ($2021, 3% discount rate).

                           Table 62--National Bladder Cancer Benefits, Proposed Option
                                  [PFOA and PFOS MCLs of 4.0 ppt and HI of 1.0]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal Bladder Cancer          4,079.1    5,238.6      6,475.3      4,079.1    5,238.6      6,475.3
 Cases Avoided........................
Number of Bladder Cancer-Related            1,436.0    1,844.4      2,280.0      1,436.0    1,844.4      2,280.0
 Deaths Avoided.......................
Total Annualized Bladder Cancer             $173.09    $221.30      $273.62      $102.08    $130.63      $161.56
 Benefits (Million $2021) \2\.........
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized annualized benefits in this table.

                              Table 63--National Bladder Cancer Benefits, Option 1a
                                         [PFOA and PFOS MCLs of 4.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal Bladder Cancer          4,066.1    5,219.4      6,488.8      4,066.1    5,219.4      6,488.8
 Cases Avoided........................
Number of Bladder Cancer-Related            1,431.5    1,837.6      2,284.9      1,431.5    1,837.6      2,284.9
 Deaths Avoided.......................
Total Annualized Bladder Cancer             $171.72    $220.48      $274.24      $101.34    $130.15      $161.56
 Benefits (Million $2021) \2\.........
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized annualized benefits in this table.

                              Table 64--National Bladder Cancer Benefits, Option 1b
                                         [PFOA and PFOS MCLs of 5.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal Bladder Cancer          3,342.7    4,334.3      5,382.5      3,342.7    4,334.3      5,482.5
 Cases Avoided........................
Number of Bladder Cancer-Related            1,176.8    1,526.0      1,895.3      1,176.8    1,526.0      1,895.3
 Deaths Avoided.......................
Total Annualized Bladder Cancer             $141.17    $183.10      $227.85       $83.31    $108.08      $135.37
 Benefits (Million $2021) \2\.........
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized annualized benefits in this table.

                              Table 65--National Bladder Cancer Benefits, Option 1c
                                        [PFOA and PFOS MCLs of 10.0 ppt]
                                                 [Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
           Benefits category                5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\       benefits      \1\          \1\       benefits      \1\
----------------------------------------------------------------------------------------------------------------
Number of Non-Fatal Bladder Cancer          1,615.9    2,175.5      2,807.4      1,615.9    2,175.5      2,807.4
 Cases Avoided........................
Number of Bladder Cancer-Related              568.9      766.0        988.6        568.9      766.0        988.6
 Deaths Avoided.......................
Total Annualized Bladder Cancer              $68.26     $91.90      $118.64       $40.29     $54.25       $70.10
 Benefits (Million $2021) \2\.........
----------------------------------------------------------------------------------------------------------------
Notes:
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 72. This range does not include the uncertainty described in Table 60.
\2\ See Table 70 for a list of the nonquantifiable benefits, and the potential direction of impact these
  benefits would have on the estimated monetized annualized benefits in this table.

H. Comparison of Costs and Benefits

    This section provides a comparison of the costs and benefits of the
proposed rule, as described in Chapter 7 of the Economic Analysis.
Included here are estimates of total quantified annualized costs and
benefits for the proposed option and regulatory alternatives
considered, as well as considerations for the nonquantifiable costs and
benefits. EPA notes that it cannot make determinations as to whether
the costs are justified by the benefits based on quantified costs and
benefits alone, as SDWA 1412(b)(3)(C)(I) and (II) mandates that the
Agency must consider nonquantifiable benefits.
    The incremental cost is the difference between quantified costs
that will be incurred if the proposed rule is enacted over and above
current baseline conditions. Incremental benefits reflect the avoided
future adverse health outcomes attributable to PFAS reductions and co-
removal of additional contaminants due to actions undertaken to comply
with the proposed rule.
    Table 66 provides the incremental quantified costs and benefits of
the proposed option at both a 3 percent and a 7 percent discount rate
in 2021 dollars. The top row shows total monetized annualized costs
including total PWS costs and primacy agency costs. The second row
shows total monetized annualized benefits including all endpoints that
could be quantified and valued. For both, the estimates are the
expected (mean) values and the 5th percentile and 95th percentile
estimates from the uncertainty distribution. These percentile estimates
come from the distributions of annualized costs and annualized benefits
generated by the 4,000 iterations of SafeWater MCBC. Therefore, these
distributions reflect the joint effect of the multiple sources of
variability and uncertainty for costs, benefits, and PFAS occurrence,
as detailed in Sections 5.1.2, 6.1.2, and Chapter 4 of the Economic
Analysis, respectively (USEPA, 2023j). For further discussion of the
quantified uncertainties in the Economic Analysis, see Section G of
this preamble below.
    The third row shows net benefits (benefits minus costs). At a 3
percent discount rate, the net annual incremental benefits are $461
million. The uncertainty range for net benefits is a negative $45
million to $1,141 million. At a 7 percent discount rate, the net annual
incremental quantified benefits are a negative $297 million. The
uncertainty range for net benefits is a negative $628 million to $141
million.

                  Table 66--Annualized Quantified National Costs and Benefits, Proposed Option
                          [PFOA and PFOS MCLs of 4.0 ppt and HI of 1.0; Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
                                            5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\        value        \1\          \1\        value        \1\
----------------------------------------------------------------------------------------------------------------
Total Annualized Rule Costs \2\ \3\         $704.53    $771.77      $850.40    $1,106.01  $1,204.61    $1,321.01
 \4\..................................
Total Annualized Rule Benefits \4\....       659.91   1,232.98     1,991.51       477.69     908.11     1,462.43
                                       -------------------------------------------------------------------------
    Total Net Benefits................       -44.62     461.21     1,141.11      -628.31    -296.50       141.42
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 71 and Table 72. This range does not include the uncertainty described in
  Table 41 for costs and Table 60 for benefits.
\2\ Total quantified national cost values do not include the incremental treatment costs associated with the
  cooccurrence of HFPO-DA, PFBS, and PFNA at systems required to treat for PFOA, PFOS, and PFHxS. The total
  quantified national cost values do not include treatment costs for systems that would be required to treat
  based on HI exceedances apart from systems required to treat because of PFHxS occurrence alone. See Appendix
  N, Section 3 of the Economic Analysis (USEPA, 2023i) for additional detail on co-occurrence incremental
  treatment costs and additional treatment costs at systems with HI exceedances.
\3\ PFAS-contaminated wastes are not considered hazardous wastes at this time and therefore total costs reported
  in this table do not include costs associated with hazardous waste disposal of spent filtration materials. To
  address stakeholder concerns about potential costs for disposing PFAS-contaminated wastes as hazardous should
  they be regulated as such in the future, EPA conducted a sensitivity analysis with an assumption of hazardous
  waste disposal for illustrative purposes only. See Appendix N, Section 2 of the Economic Analysis (USEPA,
  2023i) for additional detail.
\4\ See Table 70 for a list of the nonquantifiable benefits and costs, and the potential direction of impact
  these benefits and costs would have on the estimated monetized total annualized benefits and costs in this
  table.

    Tables 67 to 69 summarize the total annual costs and benefits for
Options 1a, 1b, and 1c, respectively.

                     Table 67--Annualized Quantified National Costs and Benefits, Option 1a
                                 [PFOA and PFOS MCLs of 4.0 ppt; Million $2021]
----------------------------------------------------------------------------------------------------------------
                                                  3% Discount rate                     7% Discount rate
                                       -------------------------------------------------------------------------
                                            5th                     95th         5th                     95th
                                         Percentile   Expected   Percentile   Percentile   Expected   Percentile
                                            \1\        value        \1\          \1\        value        \1\
----------------------------------------------------------------------------------------------------------------
Total Annualized Rule Costs \2\ \3\...      $688.09    $755.82      $833.48    $1,078.51  $1,177.31    $1,292.01
Total Annualized Rule Benefits \3\....       651.19   1,216.08     1,971.01       471.53     895.36     1,456.23
                                       -------------------------------------------------------------------------
    Total Net Benefits................       -36.90     460.26     1,137.53      -606.97    -281.95       164.22
----------------------------------------------------------------------------------------------------------------
Notes:
Detail may not add exactly to total due to independent rounding.
\1\ The 5th and 95th percentile range is based on modeled variability and uncertainty described in section
  XIII.I of this preamble and Table 71 and Table 72. This range does not include the uncertainty described in
  Table 41 for costs and Table 60 for benefits.

\2\ PFAS-contaminated wastes are not considered hazardous wastes at this time and therefore total costs reported
  in this table do not include costs associated with hazardous waste disposal of spent filtration materials. To
  address stakeholder concerns about potential costs for disposing PFAS-contaminated wastes as hazardous should
  they be regulated as such in the future, EPA conducted a sensitivity analysis with an assumption of hazardous
  waste disposal for illustrative purposes only. See Appendix N, Section 2 of the Economic Analysis (USEPA,
  2023i) for additional detail.
\3\ See Table 70 for a list of the nonquantifiable benefits and costs, and the potential direction of impact