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Document 2 - Annex 1









3M Comments 
August 20, 2018 
Executive Summary of 3M’s Comments 
 
The 3M Company (3M) appreciates the opportunity to review and comment on the “Draft 
Toxicological Profile for Perfluoroalkyls”.  As authors or a sponsor of many of the human 
epidemiology and toxicology studies discussed in the draft documents, we offer these detailed 
comments for Health Effects in assisting with that effort.  Given the magnitude of scientific 
literature that have become available since the last Draft was released in 2015, the following 
important scientific comments should be considered by ATSDR with the overall data integration. 
 
A.  The Public Comment Period was Too Short.  The Draft Toxicological Profile is 852 pages 
long.  Its support document is nearly 300 pages long. The 60-days provided to the public for 
review and comment was not adequate for detail review and comment on every aspect of the 
draft Toxicological Profile.  Accordingly, the lack of comment on any particular detail or 
section within this ATSDR document does not necessarily imply agreement with that 
content. 
 
B.  MRL Meaning and Limitations Not Prominently Presented.  ATSDR should be aware 
that for the public and regulators the Minimum Risk Levels (MRLs) will be an important 
component of the draft Toxicological Profile. Yet, ATSDR defers any explanation of what 
the MRLs mean and the limits on their use until deep in the technical appendices of this 
document (e.g., page 713 in Appendix A and page in Appendix C).  Accordingly, it is very 
important that ATSDR features this information in Chapter 1, where ATSDR presents the 
MRL values.  ATSDR should recognize that most readers will not go any further than this 
opening chapter. Media accounts show there is already great confusion among the general 
public, Congress, the media and NGOs as to what MRLs values mean and how they should 
or should not be used.  There is a clear misperception that MRLs represent a line between 
safe and unsafe exposure to a chemical, which is incorrect.   
ATSDR should include the following statements from the technical appendices in Chapter 1.  
From Appendix A (page A-1, page 713 of the profile), ATSDR should include: 
x  An MRL is an estimate of the daily human exposure to a hazardous substance that is 
likely to be without appreciable risk of adverse noncancer health effects over a 
specified route and duration of exposure. These substance-specific estimates, which 
are intended to serve as screening levels, are used by ATSDR health assessors to 
identify contaminants and potential health effects that may be of concern at 
hazardous waste sites. It is important to note that MRLs are not intended to define 
clean-up or action levels

x  They are below levels that might cause adverse health effects in the people most 
sensitive to such chemical-induced effects. 
x  MRLs are generally based on the most sensitive substance-induced endpoint 
considered to be of relevance to humans. Serious health effects (such as irreparable 
damage to the liver or kidneys, or birth defects) are not used as a basis for 
establishing MRLs. Exposure to a level above the MRL does not mean that adverse 
health effects will occur
.  


 

3M Comments 
August 20, 2018 
x  MRLs are intended only to serve as a screening tool to help public health 
professionals decide where to look more closely. 
x  In the absence of evidence to the contrary, ATSDR assumes that humans are more 
sensitive to the effects of hazardous substance than animals and that certain persons 
may be particularly sensitive. Thus, the resulting MRL may be as much as 100-fold 
below levels that have been shown to be nontoxic
 in laboratory animals 

From Appendix C (page C-1, page 835 of the profile), ATSDR should include: 
x  These MRLs are not meant to support regulatory action, but to acquaint health 
professionals with exposure levels at which adverse health effects are not expected 
to occur 
in humans.  

x  MRLs should help physicians and public health officials determine the safety of a 
community living near a hazardous substance emission, given the concentration of a 
contaminant in air or the estimated daily dose in water. MRLs are based largely on 
toxicological studies in animals and on reports of human occupational exposure. 

Finally, ATSDR’s website includes a description of MRLs for the general public, which 
should also be included to help the lay public: 
x  An MRL is an estimate of the amount of a chemical a person can eat, drink, or 
breathe each day without a detectable risk to health. MRLs are developed for health 
effects other than cancer.  If someone is exposed to an amount above the MRLs, it 
does not mean that health problems will happen
. When health assessors find 
exposures higher than the MRLs, it means that they may want to look more closely at 
a site.
 
 
C.  The PFOA, PFOS, and PFHxS MRLs are Critically Flawed, Lower than Appropriate 
or Necessary, Unsupported by the Science, and should be Withdrawn or Revised.  Due 
to time limitations, 3M’s review focused on the provisional Minimum Risk Levels (MRLs) 
for three perfluoroalkyls (PFOA, PFOS, and PFHxS).  The selection of the critical 
toxicological endpoints and the derivation process in establishing these provisional MRLs 
lacked scientific rigor and that the best available science was not applied. The improper uses 
of studies and overly conservative assumptions used by ATSDR resulted in MRL values that 
are significantly lower than supported by the science.  Key concerns with ATSDR’s MRL 
development are presented below: 
 
1)  Toxicological endpoints and human relevance 
 
Among the toxicological endpoints chosen by ATSDR for MRL calculations, they have 
not been observed in humans.  ATSDR should explain the relevance of these effects, if 
any, to human health to avoid undue public misperception.  Specifically, published mode 
of action data on xenosensor nuclear receptors have suggested that rodents may not be the 
most appropriate species for the hazard assessment of perfluoroalkyls on developmental 
toxicity in humans.  In addition, rodent hepatocytes appeared to be more sensitive to 
xenosensor nuclear receptor activations than human hepatocytes.  Therefore, ATSDR 

 

3M Comments 
August 20, 2018 
should take this into consideration when performing human risk assessment using rodent 
data. 
 
2)  Best available science not applied 
 
There are many technical uncertainties associated with the current MRL derivations for 
PFOA, PFOS, and PFHxS (all based on rodent studies), and ATSDR did not appear to 
apply the best available science.  Specifically: 
 
o  For PFOA, the two studies selected by ATSDR lacked fundamental scientific rigor 
(e.g., a single dose study without any dose-response, small sample size with only 6 
pregnant dams; no details on the reproductive nor the developmental hallmarks, litter 
bias, non-standard testing methods, no internal serum PFOA dosimetry data…etc.).  
The corresponding study results should not be used in any meaningful risk assessment 
for humans.  ATSDR is encouraged to consider evaluating a published phase 1 
clinical trial data with PFOA in 49 human subjects for its assessment (Convertino et 
al. 2018). 
 
o  For PFOS, ATSDR should take maternal toxicity influence as well as human 
relevance under consideration.  ATSDR is encouraged to consider evaluating a 
published clinical chemistry study with monkeys with PFOS for its risk assessment, 
given these non-human primates have much similar physiological resemblance to 
humans than those of rodents, and the effects of PFOS on 27 clinical chemistry 
parameters as well as the corresponding serum PFOS levels were followed for more 
than 400 days (Chang et al. 2017). 
 
o  For PFHxS, the thyroid histology finding in rats cannot be replicated in another 
rodent species (mice) under similar study conditions hence there is no conclusive 
evidence to suggest that PFHxS impacts thyroid homeostasis in rodents.  ATSDR is 
encouraged to consider evaluating a published reproductive and developmental study 
in mice with PFHxS for its assessment (Chang et al. 2018).  In addition, ATSDR 
should recognize that there are distinct differences in thyroid hormone regulations 
between rodents and humans; and similar to PPARα- or CAR/PXR-mediated 
hepatocellular hypertrophy noted in rats, thyroid findings in rodents are usually 
rodent-specific, usually not applicable to humans, and it requires careful (weight-of-
evidence) interpretation when extrapolating to human risk assessment. 
 
3)  Excessive and unnecessary adjustment factors applied for point of departure (POD) 
 
It is scientifically unjustified for ATSDR to apply a combined adjustment factor of 300 
for PFOA, PFOS, and PFHxS MRLs in addition to the (large) dosimetric TK adjustments 
that had already been incorporated.  The (very) large dosimetric adjustment factors 
(10,000, 14,400, and 15,500 for PFOA, PFOS, and PFHxS, respectively) more than 
adequately compensate for the difference between rodents and humans.  The additional 
combined factor of 300 reflected an overall adjustment factor of 3,000,000 for PFOA, 
4,320,000 for PFOS, and 4,650,000 for PFHxS from the point of departure (POD).  The 

 

3M Comments 
August 20, 2018 
extent of these adjustments, on the order of 10E6, is not made transparent by ATSDR and 
is excessive.   
 
Specific uncertainty factors that are not scientifically justified include: (a) factor of 10 for 
immunotoxicity (PFOS, PFHxS); and (b) factor of 10 for use of LOAEL (PFOA) 
 
4)  Toxicokinetics and half-lives in humans 
 
In their MRL calculations, ATSDR chose to use the arithmetic mean serum elimination 
half-life estimates for PFOA, PFOS, and PFHxS from Olsen et al. (2007) because the 
study of these retirees had a longer follow-up time.  These retirees averaged 66 years of 
age at the end of the study.  ATSDR was concerned that, based on a study by Seals et al. 
(2011), slower kinetics is likely to constitute a larger contribution to the terminal half-
life.  Olsen et al. had reservations of using arithmetic means to describe their data 
because of its right skewness; ATSDR chose to not acknowledge this limitation.  In 
addition, ATSDR chose not to consider serum elimination half-lives that are dependent 
on other factors such as age of the study subjects, and not just follow-up time, because 
age is associated with the glomerular filtration rate (GFR). Renal clearance of 
perfluoroalkyls is largely a sum of three processes involving glomerular filtration, renal 
tubular secretion, and renal tubular reabsorption. Because PFOA and other 
perfluoroalkyls vary in their affinities to bind plasma proteins, glomerular filtration of 
perfluoroalkyls is a product of the unbound fraction of the perfluoroalkyls and GFR.  
Thus, the lower estimates of serum elimination half-lives based on the younger ages in 
the other study populations (Bartell et al. 2010; Li et al. 2018) may be due to the higher 
GFR of these younger study subjects.  ATSDR also did not recognize that the proportion 
of the general population age ≥ 65 years old is approximately 15%.  Therefore, other 
serum elimination half-lives should be considered in ATSDR’s MRL calculations to 
reflect the overall general population and its greater GFR.  At a minimum, ATSDR 
should present sensitivity analyses using these collective data (see below).   
 
5)  Underestimation of HEDs and MRLs by ATSDR using slower half-life 
 
For PFOA, PFOS, and PFHxS, the corresponding HEDs (and subsequent MRLs) were 
likely to have been underestimated because ATSDR used the most conservative half-lives 
reported.  These half-lives were based on a cohort of retired fluorochemical workers 
whose exposure source was occupational and the elimination profile was dependent upon 
a GFR reflective of older adults.  ATSDR should use half-lives more closely matching 
the general population demographics and their GFR.  This will correspond to increases in 
MRLs ranging between 9 - 40% higher for PFOA; 12 – 38% higher for PFOS, and 14-
38% higher for PFHxS.   
 
6)  Chronic toxicology studies are available for PFOA and PFOS 
 
Scientifically pertinent data such as 2-year chronic studies with PFOS (Butenhoff et al. 
2012a) and PFOA (Butenhoff et al. 2012c) should be included by ATSDR for the weight-
of-evidence consideration.  In addition (to rodent data), in considering selection of 

 

 
 



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3M Comments 
August 20, 2018 
antibody response to another vaccine type, the ATSDR should consider immune 
responses to individual vaccines as distinct health outcomes. Mostly null findings were 
reported across all studies for PFOA, PFOS, PFHxS, and PFDeA. Furthermore, most 
studies have found no association between PFAS levels and increased incidence of 
infectious disease (or lower ability to resist or respond to infectious disease).  As such, 
the absence of clinical immunosuppression along with inconsistent findings both within 
and across studies, do not support the ATSDR conclusion “suggestive of a link between 
serum PFOA, PFOS, PFHxS, and PFDeA levels and decreased antibody responses to 
vaccines”. 
 
 
6)  Epidemiological association:  Increased risk of asthma diagnosis 
 
Prospective cohort studies have consistently reported no association between PFOA and 
asthma. Conversely, cross-sectional and case-cohort studies have reported inconsistent 
findings and were limited by temporal ambiguity, and unvalidated, self-reported asthma 
diagnosis.  NTP (2016) recognized these limitations and concluded that “there is low 
confidence that exposure to PFOA during childhood is associated with increased 
hypersensitivity responses based on the available studies
”. The rationale for this 
conclusion was “primarily due to the cross-sectional nature of the studies and 
uncertainty as to whether exposure levels reflect exposure prior to the development of 
hypersensitivity
.” Therefore, collectively, the existing epidemiologic evidence does not 
support an association between PFOA exposure and asthma risk. 
 
7)  Epidemiological association:  Increased risk of decreased fertility 
 
ATSDR incorrectly concluded an association exists between increased perfluoroalkyls 
(PFOA, PFOS) and decreased fertility based on epidemiologic studies.   In its 2018 draft 
Toxicological Profile, ATSDR failed to discuss methodological issues that have been 
repeatedly discussed in the published epidemiology literature, in particular, those 
surrounding the metric of time-to-pregnancy and the amount of interpregnancy time for 
reaccumulation of PFOA or PFOS.  Women with longer interpregnancy intervals would 
have longer time for reaccumulation; thus the potential for reverse causation to be 
observed in parous women with time to pregnancy.  As reviewed in their systematic 
review of the reproductive epidemiology literature regarding perfluoroalkyls, Bach et al. 
(2016) reported of the 8 epidemiologic studies reviewed related to time to pregnancy,  
only one study found an association when restricted to nulliparous women; 4 studies 
reported an association with parous women that Bach et al. (2016) concluded was not 
causal but likely the result of reverse causation and unmeasured confounding related to 
prior pregnancies and childbirths that could influence the measurement of PFAS.   
 
8)  Epidemiological association:  Small decreases in birthweight 
 
ATSDR incorrectly concluded that an association exists between lower birthweight (< 20 
gm) and PFOA.  ATSDR very briefly discussed two meta-analyses published by Johnson 
et al. (2014) and Verner et al. (2015).   Unfortunately, several important issues were not 
discussed via the historical context of these two meta-analyses, including understanding 

 

3M Comments 
August 20, 2018 
the relationship between maternal glomerular filtration and fetal growth.  In addition, 
ATSDR was not aware of two more recent meta-analyses (Negri et al. 2017; Steenland et 
al. 2018).  Negri et al. questioned the lack of a quantitative toxicological evidence to 
support the biological plausibility of a causal association in humans.   The study abstract 
from Steenland et al. was recently published on-line in the journal Epidemiology.  Based 
on their meta-analysis of 25 studies (that included one previously excluded large study), 
Steenland et al. reported an association of -1.0 grams (95% CI -2.4, 0.4) per ng/mL 
PFOA.  Restricting the studies to where blood samples for PFOA measurement were 
collected in early pregnancy (or even shortly before conception), the time period 
identified by Verner et al. in their PBPK simulations where confounding by maternal 
glomerular filtration rate would be of least concern, Steenland et al. reported a meta-
analysis nonsignificant estimate of -3.3 gm (95% CI -9.6, 3.0) per ng/mL PFOA; thus 
further indicating a lack of an association between lower birthweight and PFOA. 
 
 
 

 

3M Comments 
August 20, 2018 
Detailed Comments on PFOA MRL 
 
ATSDR position (page A-16) 
 

MRL Summary: A provisional intermediate-duration oral MRL of 3x10-6 mg/kg/day was 
derived for PFOA based on altered activity at 5–8 weeks of age and skeletal alterations at 13 
and 17 months of age in the offspring of mice fed a diet containing PFOA on GD 1 through 
GD 21 (Koskela et al. 2016; Onishchenko et al. 2011). The MRL is based on a HED LOAEL 
of 0.000821 mg/kg/day and a total uncertainty factor of 300 (10 for use of a LOAEL, 3 for 
extrapolation from animals to humans with dosimetric adjustments, and 10 for human 
variability).  
 
Selection of the Critical Effect: Intermediate-duration oral studies of PFOA in animals 
indicate that the liver, immune system, reproductive system, and the developing organism are 
the primary targets of toxicity because adverse outcomes were observed at lower doses than 
other effects and have been consistently observed across studies. 

 
3M Conclusion  
 
A.  Studies by Onishchenko et al. (2011) and Koskela et al. (2016) should not be used to 
derive the PFOA MRL 
B.  The critical effects cited by ATSDR for the PFOA MRL derivation (altered activity and 
skeletal alterations in offspring in mice) were not supported by the available animal data, 
and they contradicted ATSDR’s own evaluation of epidemiological data 
C.  PFOA does not affect the reproductive system in laboratory animals  
D.  The developmental effects reported in laboratory animals for PFOA were primarily 
mediated by maternal effects   
E.  Liver findings in rodents are not relevant for human risk assessment 
F.  Immune findings in rodents are not consistent; they lack concordance with 
epidemiological observation data 
G.  A study with one single dose group is not adequate in estimating point-of-departure 
H.  Serum PFOA concentrations in pups should be considered for POD instead of dams 
because critical effects chosen by ATSDR were based on (developing) pups 
I.  HED cannot be reliably estimated in the absence of serum concentration data  
J.  HED for PFOA will be higher when considering faster half-life 
K.  Wambaugh benchmark dose model used by ATSDR was not optimized 
L.  Uncertainty factors by ATSDR were conservative and not supported by scientific data 
1.  Incorrect use of “10” for a LOAEL.   
2.  Use of “3” for animal-to-human, in addition to large dosimetric TK adjustment, is 
conservative because humans are less sensitive than rodents with exposure to PFOA   
 
ATSDR’s overall interpretation on both toxicology and epidemiology data are inconsistent with 
the most current knowledge.  Its application of uncertainty factors is not scientifically justified 
and the proposed PFOA MRL is not supported by the scientific data.  The PFOA MRL derived 
for the human-health risk assessment is therefore inappropriate and not justified by an adequate 
scientific foundation. 
 9 
 
 

3M Comments 
August 20, 2018 
 
 
3M Comments (Details): 
 
A.  Studies by Onishchenko et al. (2011) and Koskela et al. (2016) should not be used to derive 
PFOA MRL.  The toxicology database for PFOA is quite comprehensive.  Many of these 
studies included detailed information on the reproductive and developmental toxicity with 
these compounds across different PFOA dose levels as well as valuable insights on the role 
of maternal effects and its attribution to the developmental outcomes in laboratory animals.  
Comprehensive review on the potential developmental toxicity of PFOA in laboratory 
animals was reported in 2004 (Kennedy et al. 2004; Lau et al. 2004) and updated 
subsequently (Abbott 2015; Andersen et al. 2008; Lau 2012; Lau et al. 2007).  Despite the 
wealth of data available, ATSDR chose mouse developmental studies reported by 
Onishchenko et al. (2011) and Koskela et al. (2016) as reference studies for its derivation of 
PFOA MRL (based on altered activity and skeletal alterations seen in offspring in mice).   
 
ATSDR’s assessments on these studies (and the corresponding reported critical effects) 
failed to make clear to the public that the proposed MRL did not reflect the absence of an 
association between PFOA exposure and musculoskeletal outcomes or neurological 
outcomes in humans (cf. pages 141 – 145; pages 293-296).  Furthermore, there are major 
technical concerns associated with these studies that preclude the results (from these studies) 
to be meaningful in any human risk assessment.  They include: 
 
1.  They are the same study.  Albeit published five years apart, these two publications 
actually originated from one single study.  From the same pregnant dams treated with 
dietary PFOA during gestation, the pups evaluated by Onishchenko et al. (2011) were 
litter-mates of the pups evaluated by Koskela et al. (2016).  As such, it was really one 
study (in essence) and the corresponding outcomes (from both studies) should be 
consolidated when discussed.   
  
2.  A single dose experiment cannot address (any) dose-response relationship.  There was 
only one PFOA dose group used in these two studies and as such, it is impossible to 
interpret the experimental data reported by these authors in terms of any dose-response.  
Considering the inherent variations in biological responses in any animal study, the 
nature of a single-dose study simply does not allow any specific evaluation of any dose-
and-effect responses or biological plausibility inference.   
 
Using a study that evaluated a single PFOA dose group was in absolute contradiction of 
what ATSDR stated in its MRL approach.  On page A-6 of the draft profile, ATSDR 
explicitly stated that one of the MRL approach was to “Identify laboratory animal studies 
that have evaluated dose-response relationship for toxicity targets identified in 
epidemiology studies
”. 
 
Hence for PFOA, not only did ATSDR not identify musculoskeletal or neurological 
outcomes as sensitive endpoints in humans; it did not select a laboratory animal study 
that appropriately addressed or evaluated dose-response relationship. 
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August 20, 2018 
 
3.  The study design was flawed and insufficient to support a NOAEL or LOAEL.  Again, 
given that there was only PFOA dose group used, the study design did not follow the 
fundamental practice of toxicology testing such as evaluation of a dose response 
relationship.  Hence, given the lack of any dose-response, it is scientifically impossible to 
establish a realistic NOAEL and/or LOAEL for the data reported. 
 
4.  Limited sample size.  There were only 6 dams that received PFOA diet to produce the 
pup cohort, and there was a total of 10 dams that received control diet; however, the 
control animals spanned from two (separate) blocks of individual experiments.  The 
sample size for the study was quite small and given that only a single PFOA dose group 
was used, it is impossible to properly address biological plausibility (if any) and 
background variability.   
 
For example, regardless of sex, Onishchenko et al. (2011) reported a statistically 
significant difference between control and PFOA pups for the number of inactive periods 
(Figure 3b).  However, on the accompanying graph (Figure 3a), they also reported a 
statistically significant difference between control and female pups from PFOS dose 
group for the number of inactive periods.  Without looking at the treatment groups and 
just comparing the sex-matched control responses alone between Figure 3a and Figure 3b 
(see illustration below), it became very apparent the large variations exist even in the sex-
matched control animals.  This large variation (on the background control alone) most 
likely attributed to the statistical significance when compared to the treatment groups 
(either PFOS or PFOA).  
 
                   
  
 
 
 
Another similar example is on the body weight.  The absence of statistical power to 
address inherent biological variations due to the limited study design did not allow for a 
valid comparison of biological responses between control and treatment.  While Koskela 
et al. (2016) reported an increase in the body weight in the female pups from PFOA-
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3M Comments 
August 20, 2018 
basis of higher vapor pressure, lower boiling point, and less hydrogen bonds (Innocenzi 
et al. 2008).  When ethanol is mixed with water, more hydrogen bonds are created; and 
when ethanol-in-water mixture is further mixed with PFOA as well as applied onto the 
surface of food chow (such as this study), the additional intramolecular forces (between 
ethanol and water, ethanol-in-water and PFOA, and, ethanol-in-water and PFOA and 
food chow ingredients) would have reduced the overall volatility of ethanol.  The authors 
should have obtained a quantitative measurement of the PFOA/chow mixture to 
demonstrate the absence of ethanol after 2-hour evaporation.  
 
This verification step was critical for this study because the authors evaluated and 
reported neurobehavior endpoints as findings.  Albeit the control animals also received 
food chow diet that had been applied with 95% ethanol followed by evaporation, 
however, the intramolecular force between ethanol, water and food chow (i.e., control 
food chow) would be different than the intramolecular force between ethanol, water, 
PFOA, and food chow (i.e., PFOA food chow).  Given that ethanol is well-known for its 
effects on the central nervous system (Boschen and Klintsova 2017; Harrison et al. 2017) 
and 95% ethanol was used in the study, any ethanol that had not evaporated and remained 
on the food chow could have confounded the study results, especially on the 
neurobehavior parameters. 
 
10. There were no serum PFOA data reported in these studies.  ATSDR has determined that, 
rather than relying on external dose, serum PFOA concentration (internal dosimetry) is 
the appropriate exposure matrix when determining a point-of-departure (POD) for the 
MRL derivation with PFOA (cf. page A-16 and Table A-7 on page A-24 of the draft 
profile).  Neither Onishchenko et al. (2011) or Koskela et al. (2016) reported any 
information on the serum PFOA concentrations; and this was a major deficiency of the 
study.  Even though ATSDR “estimated” the time-weighted-average serum PFOA 
concentration based on its PBPK model, the absence of serum PFOA data preluded the 
verification of the ATSDR PBPK model, in addition to the other unknowns associated 
with the study (i.e., no dose-response and no dose verification).   
 
It is also worth noting that the study authors had the technical capability to perform 
PFOA analysis because Onishchenko et al. (2011) reported PFOA concentrations in a 
subset of pup brain and liver samples.   
 
11. Timing of behavior assessments in pups were not appropriate.  In the study data reported 
by Onishchenko et al. (2011), numerous neurobehavior endpoints were evaluated by the 
study authors.  Given that the study was done under non-GLP protocols and by a 
university research lab(s), most of the timings and behavior assessment procedures (as 
described by the study authors) did not appear to follow the conventional 
recommendations and methodology.   As a result, it is difficult to determine the quality of 
the data that had been reported.  For instance, compared to the OECD 426 test guideline 
(TG) for developmental neurotoxicity study (OECD 2007), these authors did not follow 
standardized timeline recommended to FOB evaluations for the developing pups.  The 
table below is a side-by-side comparison between the OECD 426 TG recommendation 
timeline vs. what Onishchenko et al. did.  It was apparent that Onishchenko et al. had 
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3M Comments 
August 20, 2018 
missed critical windows for the assessments on many key parameters (i.e., no behavior 
assessments were done prior to weaning) and there were no specific references or 
rationales to explain or justify their study design. 
 
OECD 426 TG Recommendation for 
Study by 
 
developmental neurotoxicity study 
Onishchenko et al. 2011 
Dosage  
Control + 3 dose levels 
Control + 1 dose level 
Animal number 
20 litters / group 
6 litters / group 
Detailed clinical observation 
20 pups /sex (1 / sex/ litter) 
6 – 10 pups / sex 
Brain weight PND 11-22 
10 pups / sex (1 / litter) 
No data reported 
Brain weight PND 70 
10 pups / sex (1 / litter) 
No data reported 
Neuropathology PND 11-22 
10 pups / sex (1 / litter) 
No data reported 
Neuropathology PND 70 
10 pups / sex (1 / litter) 
No data reported 
Sexual maturation  
20 pups /sex (1 / sex/ litter) 
No data reported 
Behavioral ontogeny  
2X prior to weaning at PND 21 
No data reported 
(e.g., righting and reflex) 
Motor activity 
1-3X prior to weaning at PND 21;  
None prior to weaning; 
 
1X during PND 60-70 
1X during PND 35 – 56; 
Motor and sensory function 
1X during PND 23-27;  
None prior to weaning;  
 
1X during PND 60-70 
1X during PND 90 - 120 
Learning and memory 
1X during PND 23-27;  
None prior to weaning;  
(~ PND 23-27 and 60-70) 
1X during PND 60-70 
1X during PND 35 – 56; 
 
12. Non-standard behavior assessment procedures used in pups.  Among the behavior 
endpoints evaluated by Onishchenko et al., given that the study was done under non-GLP 
by university research lab(s) and it did appear that the tests were done on a single day 
without further repeat(s) later, it raised the question as to the overall reliability and 
reproducibility of the instruments and the corresponding data generated.   
 
For instance, to measure and record circadian activity in the home cage, the 
TrafficCageTM used by Onishchenko et al. is shown in the picture below (obtained from 
manufacturer’s website).  Compared to the conventional 3-D photo beam boxes where 
movements were recorded in vertical, horizontal, and lateral directions, the 
TrafficCageTM system lacks the ability to measure any vertical movements.  In addition, 
the TrafficCageTM system has several “dead spots” without any sensors.   The validity of 
the instrument and the corresponding results generated (circadian activity) are 
questionable.      
 
 
 
 
 
 
 
 
 
 
 
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August 20, 2018 
              
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Illustration of TrafficCageTM 
 
(Source: https://www.tse-systems.com/product-details/phenoworld/trafficage?open=3806#trafficage-3806) 
 
 
13. No information on background data for bone morphology and bone density.  Koskela et 
al. (2016) reported that female offspring from PFOA-treated dams had increased femoral 
periosteal area and decreased mineral density of tibias, hence ATSDR concluded that 
“skeletal alterations in offspring” was a critical effect with PFOA exposure in mice. 
 
Bone morphology is a collective description on the shapes (geometry) of the bones, such 
as long bones (e.g., femur and tibia), short bones (e.g., bones of the feet and hands), or 
flat bones (e.g., calvaria or breast bones).  There are many factors contributing to the 
morphological sizes of the bones.  The morphology of bone is not a “fixed” static 
structure, rather, it is a composite structure that will continue to evolve like other organs 
in the body.  While the components of the bones are maintained in a balanced manner, 
there are also inherent biological variability within each component that needs to be taken 
into account when determining the overall homeostatic status of the bones (Boskey and 
Coleman 2010; Jepsen 2009).   
 
It is well-known that age and body weight are two factors in establishing the size, mass, 
and strength of the bones (Iwaniec and Turner 2016).  In the data reported by Koskela et 
al., there was a pre-existing difference in body weight in female pups at birth where 
higher body weight was consistently observed in these female pups from PFOA-treated 
groups; and that difference reached statistical significance at 13 months and 17 months 
(vide supra).  Therefore, it should not be a surprise that increased bone sizes in offspring 
with higher body weight (e.g., offspring from PFOA-treated dams) had increased 
periosteal and medullary areas in both femurs and tibias.  On the other hand, given the 
small sample size of the animals used in this study, the inherent background variation 
cannot be ruled out.  For example, compared to control, the study authors also reported a 
decrease in mineral density in tibias in offspring born from PFOA-treated dams.  The 
extent of decrease was very minor (only 2.5%) and it was only observed in tibias, not in 
femurs.  Because the study authors did not have any additional information on the 
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3M Comments 
August 20, 2018 
background data with regards to these parameters, this minor difference may be well 
within the normal biological variations (again, especially with such small sample size).  
 
14. Mechanical determinants of bone functions were not affected in pups from PFOA-treated 
dams.  Based on study data reported by Koskela et al. (2016), ATSDR concluded that 
there were skeletal alterations in offspring from PFOA-treated dams and deemed it to be 
a critical health effect.  However, in the same cohort of pups, Onishchenko et al. (2011) 
reported motor and sensory function assessments (muscle grip strength and rotarod test) 
and found no differences in the outcomes between control and PFOA-treated groups.  
Given that muscle force is a strong determinant of bone integrity, the slight 
morphological difference noted by ATSDR possibly reflected the normal background 
variations in this strain of mice and not likely due to PFOA. 
 
15. Lack of supporting evidence on the effect of PFOA and bone development.  If PFOA 
exposure does have a direct (causal) effect on the bone development, then one would 
expect such effect to be even more pronounced under longer (repeated) dose conditions.  
This was not the case, as long-term toxicology studies in rodents and non-human 
primates have not identified bone as a target tissue with exposure to PFOA (Biegel et al. 
2001; Butenhoff et al. 2002; Butenhoff et al. 2012b). 
 
16. Other technical comments about the study data by Koskela et al. (2016).   
 
x  In addition to the likely litter-bias that has been discussed earlier, it is unclear why 
Koskela et al. only included female offspring in their evaluation but not male 
offspring. 
 
x  PFOA has a high affinity to binding with serum albumins and given that bone 
marrow is the hemopoietic origin of blood, one should not be surprised to find 
trace level of PFOA in the bone.  Albeit Koskela et al. claimed that bone marrow 
had been flushed out and only the hard bones were powdered and analyzed for 
PFOA content, it is important to recognize that the bone consists of “live” 
mesenchymal cells with lots of protein components (chondrocytes, osteoblasts, 
and osteocytes), not just marrow (Boskey and Coleman 2010; Iwaniec and Turner 
2016; Jepsen 2009). 
 
x  The study authors only evaluated long bone morphology but not others.  If bone is 
indeed a target tissue with exposures to PFOA, other bones (in addition to femur 
and tibia) also need to be included in the evaluation. 
 
x  It is well-known that there are large inter-species differences in bone composition, 
density, quality, as well as genetic variability within the same species (Aerssens et 
al. 1998).  Again, if bone is indeed a target tissue with exposures to PFOA, such 
cause-and-effect needs to be demonstrated in a dose-response fashion within the 
same animal model as well as other species.   
 
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3M Comments 
August 20, 2018 
x  Other factors that can affect bone morphology and density should also be 
comprehensively evaluated before drawing a conclusion.  For example, endocrine 
effects such as estrogen and IGF-1, essential nutrient status such as calcium and 
vitamin D3.  
 
x  The use of imaging devices in the assessment of bone morphology is not a new 
concept, and CT images have been used in both clinical settings as well as 
research settings.  However, similar to the comments provided above on the 
behavior assessments provided above, Koskela et al. should have demonstrated 
that the validity of the micro-CT scanning technique used in their facility as well 
as their competency in using the instrument.  Given the fact that a very small 
magnitude of surface area was being reported as a “statistically significant” 
change (in the range of 0.2 – 0.3 mm2), it is important to validate the sources of 
these measurements.  For example, was the instrument calibrated?  Were the 
operator(s) trained in using the equipment?  Were the acquired images analyzed 
by qualified radiologists who are trained in doing image interpretation?   
 
x  For any imaging-based scanning, it is absolutely critical that the object (or 
subject) remained steady for the duration of the scanning acquisition.  Any 
movement during the scanning process will deviate the result.  The study authors 
described that the bone was “wrapped in a PBS-moistened tissue paper and 
inserted into a plastic tube, with the proximal end pointing upwards.  The 
container was then placed into the chamber of the microCT device
”.  The 
description did not address attempts to prevent any movement of the bone (inside 
the plastic tube) during the scanning process.  Given the asymmetrical shape of 
femurs and tibias, it is important to immobilize the bone inside the tube and any 
slight shift will artificially affect the image data during scanning. 
 
Overall, the studies by Onishchenko et al. (2011) and Koskela et al. (2016) lacked scientific 
rigors to properly address the selected developmental endpoints and they should not be used 
for any human risk assessment.   
 
B.  The critical effects cited by ATSDR for PFOA MRL derivation (altered activity and skeletal 
alterations in offspring in mice) were not supported by available animal data and contradicted 
ATSDR’s own evaluation of epidemiological data.  There is insufficient evidence for an 
association between PFOA exposure and musculoskeletal outcomes or neurological 
outcomes in humans (cf. pages 141 – 145; pages 293-296).  ATSDR should offer a plausible 
explanation as to why it believes these effects are relevant to human risk assessment. 
 
C.  PFOA does not affect the reproductive system in laboratory animals.  It is incorrect for 
ATSDR to conclude that the reproductive system is one of the primary targets of toxicity 
with exposure to PFOA (cf. page A-16).   
 
On the contrary, PFOA did not affect the functional aspects of male or female reproduction 
in laboratory animals.  These included estrous cycles, sperm parameters, mating index, 
fertility index, and reproductive organ morphology.  A number of studies on the reproductive 
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3M Comments 
August 20, 2018 
and developmental effects of PFOA in laboratory animals have been published (Abbott et al. 
2007; Albrecht et al. 2013; Butenhoff et al. 2004; Gortner 1981, 1982; Lau et al. 2006; 
Staples et al. 1984; Yahia et al. 2010).  Many of these studies included detailed information 
on the reproductive and developmental toxicity with these compounds across different PFOA 
dose levels as well as valuable insights on the role of maternal effects and its attribution to 
the developmental outcomes in laboratory animals.  
 
The potential of PFOA to influence reproductive performance has been evaluated in mice, 
rats, and rabbits.  Gestational exposure to ammonium PFOA did not affect the number of 
uterine implantation sites in various strains of mice such as CD-1, Sv129, PPARD knockout, 
and humanized PPARD (Abbott et al. 2007; Albrecht et al. 2013; Lau et al. 2006; White et al. 
2007).  At inhalation dose up to 25 mg/m3/day of ammonium PFOA or oral doses up to 100 
mg/kg/day given during gestation to rats did not affect mating, pregnancy, and implantation 
(Staples et al. 1984).  Oral administration of ammonium PFOA up to 150 mg/kg/day in rats 
or 50 mg/kg/day in rabbits during GD 6 – 15 (period of organogenesis) also caused reduced 
body-weight gain, however, they did not affect the ovaries or the reproductive contents of the 
dams (Gortner 1981, 1982).  In a two-generation reproduction/developmental study in rats 
(Butenhoff et al. 2004), the reproductive outcome was not affected with daily oral 
ammonium PFOA administrations up to 30 mg/kg/day (the highest dose used in the study).  
There were no effects on the mating or fertility indices in either male or female rats.  Male 
rats had normal sperm parameters (count, motility, morphology) and female rats had regular 
estrous cycling with normal gestation lengths, and microscopic examination did not reveal 
any abnormalities in sex organs.  Furthermore, effects of PFOA on reproductive organ 
morphologies in male non-human primates were evaluated from a six-month oral study and 
results indicated no abnormalities (Butenhoff et al. 2002).  
 
D.  The developmental effects reported in laboratory animals for PFOA were primarily mediated 
by maternal effects.  While ATSDR concluded that developing organisms are primary targets 
of toxicity with exposure to PFOA (cf. page A-16), there are strong experimental evidences 
demonstrating that developmental effects associated with PFOA exposures in offspring are 
observed only where there were significant effects in the maternal animals.  Because neither 
Onishchenko et al. (2011) nor Koskela et al. (2016) reported detailed maternal-related 
endpoints with regards to reproduction, no maternal influence discussion is possible.  
However, observations involving maternal effects in the outcome of the developmental 
toxicity, as seen in the disruption of maternal homeostasis, include the following examples: 
 
Using the mouse developmental study data reported by Lau et al. (2006), which was the 
critical study chosen by U.S. EPA Office of Water for the derivation of the Lifetime Water 
Health Advisory for PFOA issued in 2016, there were statistically significant (p < 0.05), 
dose-related increases in maternal liver weight observed at doses 1 mg/kg/day ammonium 
PFOA or higher (the corresponding serum PFOA concentration was 21,900 ng/mL at the end 
of gestation).  Various developmental effects were reported (e.g., decreased postnatal 
survival, decreased body weight at birth and body-weight gain thereafter, and delays in eye 
openings) and they were only for litters from dams receiving 3 mg/kg/day or higher.  
Maternal responses clearly were present at doses that affected the fetus/neonate.  In addition, 
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3M Comments 
August 20, 2018 
(Braissant et al. 1996; Lee et al. 1995), it calls into question the relevance of nuclear 
receptor-mediated effects in rodents and their biological significance to humans.  Therefore, 
the developmental effects reported in the laboratory animals for PFOA were primarily 
mediated by maternal effects and based on the recent mode of action data, rodents may not 
be the most appropriate species for the hazard assessment of PFOA on developmental 
toxicity in humans.   
 
E.  Liver findings in rodents are not relevant for human risk assessment.  While it is commonly 
acknowledged that liver is a primary target organ with exposure to PFOA, it is important to 
recognize that the liver effects observed in laboratory animals were adaptive in nature and 
there was no conclusive evidence to support that liver findings observed in laboratory 
animals with exposure to PFOA are relevant for human risk assessment.  Given the known 
knowledge on the nuclear receptor activation and species relevance discussed earlier (vide 
supra
), liver findings cited by ATSDR should not be deemed relevant for human risk 
assessment.  For instance, in the study by Butenhoff et al. (2004), increased liver weights 
were reported in male rats of both the P and F1 generations at all dose levels.   
 
The corresponding increases in liver weight in laboratory animals with exposure to 
perfluoroalkyls reflected the adaptive nature of liver, which is a natural phenomenon due to 
cytochrome P450 enzyme inductions in the liver.  Given that PFOA is a known activator for 
several xenosensor nuclear receptors (as discussed above), microscopic changes in the liver 
of some PFOA-treated male rats such as hepatocellular hypertrophy and focal to multifocal 
necrosis were consistent with activation of these receptors and as discussed earlier, it is well-
known that human liver is less responsive than rodents to the pleiotrophic effects of 
activation of these receptors (Gonzalez and Shah 2008; Klaunig et al. 2003; Klaunig et al. 
2012; Lake 2009; Ross et al. 2010).  Thus, with respect to PPARα and CAR-mediated effects 
in the liver and related metabolism, the human response is either attenuated or absent as 
compared to that of the rodents.  Another federal agency, USEPA (in its assessments of 
PFOA in 2009 and again in 2016), as well as other international regulatory authorities such 
as European Chemical Agency Risk Assessment Committee (2015), European Food and 
Safety Authority (2018), and Australian Expert Health Panel (2018) also considered the liver 
weight findings in laboratory animal studies with PFOA (or other perfluoroalkyls) to be 
irrelevant for human risk assessments. 
 
It should be noted that, acetylsalicylic acid (commonly known as aspirin) and alcohol can 
also elicit increased liver weight in laboratory animals similar to the observations reported 
with perfluoroalkyls in rodents (EMEA 1999b). 
 
F.  Mammary gland development findings in mice are inconsistent: Despite that the availability 
of several studies that have investigated the potential effects of PFOA on the developing 
mammary glands in mice as a consequence of exposure during either the in utero or 
postnatal/peripubertal (Albrecht et al. 2013, Tucker et al. 2014, White et al. 2007, White et 
al. 2009, White et al. 2011, Yang et al. 2009, Zhao et al. 2010), ATSDR is correct that this 
endpoint cannot be consistently described and quantified in mouse models.  Given that 1) to 
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3M Comments 
August 20, 2018 
date, there is no standardized method or guideline of evaluating rodent mammary gland; and 
2) there is a lack of concordance among all the available data on mammary gland 
development in mice as well as an absence of such findings in human epidemiological 
studies calls for question on the biological significance of this phenotype and its relevance to 
human health.  This conclusion is consistent with the assessments from another federal 
agency, USEPA (in its assessments of PFOA in 2009 and again in 2016), as well as other 
international regulatory authorities such as European Chemical Agency Risk Assessment 
Committee (ECHA 2015), European Food and Safety Authority (EFSA 2018), and 
Australian PFAS Expert Health Panel (2018).  
 
It should be noted that there are three epidemiologic studies that have examined the potential 
association between maternal PFAS exposure and shorter duration of breastfeeding or greater 
risk of stopping breastfeeding (Fei et al. 2010b; Romano et al. 2016; Timmermann et al. 
2016). Fei et al (2010) measured PFOA and PFOS concentrations of 1400 women during 
early pregnancy. Self-reported data on the duration of breastfeeding (any and exclusive) were 
collected around 6 and 18 months after birth. While the study reported significant 
associations between PFOA concentrations and shorter duration of breastfeeding (before 3 
and 6 months) among multiparous women, no significant associations were observed among 
primiparous women. The authors note that multiparous women who breastfed during prior 
pregnancies or breastfed longer may have had lower serum PFOA levels through excretion 
via breast milk. Consequently, reverse causation could not be excluded.   The second study 
(Romana et al. 2016), observed a significant association between PFOA exposure and ending 
“any” breastfeeding by 3 and 6 months; however, no association was observed between 
PFOA exposure and ending “exclusive” breastfeeding by 3 and 6 months. More importantly, 
when stratified by parity, associations between PFOA and ending “any” breastfeeding at 3 
and 6 months were largely attenuated for nulliparous women. Like Fei et al (2010), the 
significant associations observed among multiparous women were likely attributed to reverse 
causation. The third study (Timmerman et al. 2016), examined the potential association 
between PFOA exposure and duration of breastfeeding (both total and exclusive) among 
1092 Faroese women with general population PFOA levels (median = 2.40 ng/mL). The 
authors reported that a doubling of maternal serum PFOA was significantly associated with a 
reduction in exclusive breastfeeding of 0.5 months. This association was observed among 
both primiparous and multiparous women (excluding the role of reverse causation). One 
important limitation of this study, worth noting, is that self-reported breastfeeding duration 
was collected 5 years after birth and was likely prone to misclassification error.   
 
Finally, it is important to recognize that reduced breastfeeding duration in humans is not 
equivalent to “delayed mammary gland development” in rodents. In humans, numerous 
factors can influence breastfeeding duration other than diminished milk production (e.g., lack 
of prenatal education, inadequate lactation support from healthcare providers after delivery, 
medications incompatible with breastfeeding, lack of spousal/family support, short maternity 
leave, sore nipples/breasts, infant intolerance to breast milk, and individual choice). These 
factors were not considered in the epidemiology studies, and may have influenced the 
observed associations.     
 21 
 
 

3M Comments 
August 20, 2018 
 
G.  Immune findings in rodents are not consistent; and they lack concordance with 
epidemiological observation data.  With exposure to PFOA, ATSDR also concluded that 
immunotoxicity is a primary target of toxicity based on decreased antigen-specific antibody 
responses in mice reported by DeWitt et al. (DeWitt et al. 2008; DeWitt et al. 2016) where 
PFOA suppressed T cell-dependent IgM antibody response (TDAR) but not the secondary 
IgG response.  While ATSDR concluded that such findings were consistent with human 
epidemiology studies with regards to vaccine responses (see epidemiology discussion 
below), it is important to recognize that the humoral immune response to vaccinations, as 
measured in the human epidemiology studies, is mainly a secondary IgG memory response.   
 
While suppression of the IgM response by PFOA was demonstrated in several studies where 
administered doses also induced signs of overt toxicity (i.e., reductions in body and lymphoid 
organ weight), the levels of IgG were not suppressed (either unchanged or enhanced).  It is 
difficult to interpret why the primary IgM response was suppressed in mice by PFOA and yet 
the secondary IgG response was either not affected or enhanced.  Collectively, human and 
animal bodies of evidence for antibody response are divergent.  Mouse studies showed 
suppression of the IgM response with no impairment of the secondary antigen specific IgG 
response, which is in contrast to the epidemiological associations which suggested 
suppression by PFOA of IgG-mediated antibody titers to vaccinations in some studies for 
certain vaccines.  Therefore, the weight of evidence and the lack of concordance between 
animal and human epidemiological data do not support the claim that PFOA induces 
immunotoxicity or caused decreased antibody response to certain vaccines.  Finally, as noted 
above, the fact that the epidemiological data does not reveal a consistent association between 
exposure and response across all vaccines is further evidence that the animal and human data 
are not consistent.  
 
Contrary to what ATSDR stated “the potential immunotoxicity of PFOA has not been 
investigated in chronic-duration studies” (cf. page A-30), it should be noted that the primary 
immune organs were evaluated microscopically in rats after 2 years of dietary treatment 
containing ammonium PFOA (Butenhoff et al. 2012c).  In this study, representative primary 
immune organs were collected (mesenteric lymph node, spinal cord, bone marrow, and 
spleen) and evaluated microscopically by a board-certified veterinary pathologist at the end 
of a 2-year period.  There were no neoplastic or non-neoplastic lesions observed in these 
immune organs.  This is important because it demonstrated the absence of a direct effect on 
primary immune organs with chronic PFOA exposures in the rats.  In addition, PFOA-treated 
rats had similar or higher percent survival compared to controls, which is contrary to chronic 
immunosuppression-mediated toxicity such as cyclosporin (a known immunosuppressant) 
that ultimately resulted in increased mortality in rats (Ryffel and Mihatsch 1986).     
 
H.  A study with one dose group is not adequate in estimating point-of-departure.  ATSDR 
selected two mouse studies with developmental endpoints (Onishchenko et al 2011 and 
Koskela et al 2016) for the point-of-departure (POD) to derive the MRL value for PFOA 
(endpoints were altered activity and skeletal alterations in offspring of C57Bl/6 mice).   
These studies tested only a control group and one dose of 0.3 mg/kg, which was chosen as 
the LOAEL.  As only one dose was tested, a dose-relationship cannot be evaluated.  
 22 
 
 

3M Comments 
August 20, 2018 
Selection of studies with no information on dose-response for effects is not acceptable to 
establish a point-of-departure.  ATSDR should follow its own guidance (as stated in pages A-
6).  
 
I.  Serum PFOA concentrations in pups should be considered for POD instead of dams because 
critical effects chosen by ATSDR were based on (developing) pups.  The studies chosen by 
ATSDR examined developmental endpoints that were measured in offspring, which are used 
as the basis for the MRL.  In order to estimate steady-state plasma concentrations of PFOA, 
ATSDR used the Wambaugh model for PFOA that is parameterized for adult animals and 
cannot be used to predict concentrations in fetuses or pups.  This model also does not account 
for life stage differences in physiology or pharmacokinetics, and can potentially over-predict 
as well as under-predict the area-under-the-curve (AUC).  In addition, AUC and steady-state 
concentration are probably different in the offspring than in the dam.  Overall internal 
exposure (as estimated by calculation of the AUC) may change with growth, and there could 
be a period of peak exposure. Use of the Wambaugh model (and thus use of the maternal 
plasma concentration as a surrogate for the offspring) introduces uncertainty in the MRL 
derivation as the offspring plasma concentration may be different that than of the maternal 
animals.  Use of a physiologically-based model that incorporates fetal and pup compartments 
would provide an estimate of fetal and pup internal exposure (rather than use of the maternal 
concentration as a surrogate), which would reduce the uncertainty in the MRL value.   
 
J.  HED cannot be reliably estimated in the absence of serum concentration data.  As discussed 
above, studies by Onishchenko et al. (2011) and Koskela et al. (2016) did not have any 
analytical verification on either the dietary PFOA level or the resulting serum PFOA 
concentrations in the mice.  With the questionable reliability of the study design as well as 
the data gathered, there were a great number of inherent uncertainties associated with 
attempting to predict the mean serum concentrations using modeling approach.   
 
Confirming that it is inappropriate to derive an MRL where there is an absence of serum 
concentration data, in its current draft profile for other perfluoroalkyls, ATSDR stated in 
several places that “…. Database was considered inadequate for derivation of an MRL  … 
because … study did not measure serum [perfluoroalkyl] levels, which are needed to 
calculate / estimate HEDs” (cf. pages A-14, A-56, A-65, A-72, A-109).   
 
K.  HED for PFOA will be higher when considering faster half-life.  In the MRL calculations, 
ATSDR chose to use the arithmetic mean serum elimination half-life estimate for PFOA 
from Olsen et al. (2007) over other studies because Olsen et al. had a longer follow up time 
and ATSDR was concerned that based on a study by Seals et al. (2011), slower kinetics is 
likely to constitute a larger contribution to the terminal half-life.  For example, whereas 
Olsen et al. had an average follow-up of 5 years, Bartell et al. had a follow-up of a year and 
Li et al. had a follow-up of 2.3 years among those studies that followed individuals and were 
not cross-sectional analyses of populations.   However, this line of reasoning by ATSDR for 
selection of the arithmetic mean from the Olsen et al. study fails to take into account several 
factors that likely biased upwards the ATSDR MRL estimates.  These include the following 
points. 
 
 23 
 
 

3M Comments 
August 20, 2018 
1.  The ATSDR chose not to use the geometric mean estimate that was discussed in the 
Olsen et al. paper.  Given the right skewness of their data, Olsen et al. were more 
favorable to use the geometric mean for a measure of central tendency.  ATSDR provided 
no explanation as to why they chose the arithmetic mean vs. the geometric mean in this 
study.  This decision is interesting (and curious) because ATSDR chose to report median 
initial and final concentrations in Table A2 rather than the arithmetic mean initial and 
final concentrations in Table A2.  A median concentration would be better represented by 
a half-life estimate based on the geometric mean.   
 
2.  The Olsen et al.  2007 study comprised 26 retirees (end of study average age = 66 years) 
who likely would have had an average glomerular filtration rate lower than those 
calculated from younger ages as reported in Bartell et al. (average age 55) and Li et al. 
(age range 15 – 55).  The average estimated glomerular filtration rate declines with age as 
shown in the table below. 
 
Estimated GFR 
Age range 
Source: 
(ml/min/1.73 m2) 
1-6 months 
77 
6-12 months 
103 
Heilbron et al. 1991 Pediatr Nephrol. Jan; 5(1):5-11. 
12-19 months 
127 
2-12 years 
127 
20–29 
116 
30–39 
107 
40–49 
99 
https://www.kidney.org/sites/default/files/docs/11-10-
50–59 
93 
1813_abe_patbro_gfr_b.pdf 
60–69 
85 
70+ 
75 
 
 
 
 
Renal clearance of perfluorocarboxylates (and perfluorosulfonates) is largely a sum of 
three processes involving glomerular filtration, renal tubular secretion, and renal tubular 
reabsorption (Han et al. 2012). Because PFOA and other perfluorocarboxylates vary in 
their affinities to bind plasma proteins, glomerular filtration of perfluorocarboxylates 
(and perfluorosulfonates) is a product of the unbound fraction of the perfluorocarboxylate 
and the glomerular filtration rate (GFR).  Thus, the higher estimates of GFR based on the 
younger ages in the other study populations, especially the younger Li et al. study which 
had approximately 50% of the follow-up time of Olsen et al., may be due to the age 
differences of the subjects, and not necessarily the shorter follow-up period considered in 
these studies.  Thus, the serum elimination half-lives of other studies are likely equally 
valid for consideration in MRL calculations. 
 
3.  The Olsen et al. study had to consider, during the course of their follow-up, the 
possibility of retirees reentering the 3M Decatur and Cottage Grove manufacturing 
plants.  Indeed, this resulted in Olsen et al. eliminating 1 study subject entirely, and 
truncating follow-up times for two retirees.  This would have biased estimates upwards 
for the serum elimination half-lives due to the increased exposure.  It is not likely that 
 24 
 
 

3M Comments 
August 20, 2018 
ambient general population level concentrations would have biased these retiree’s 
estimates substantially as discussed by Bartell et al. 2012.  On the other hand, although 
Bartell et al. and Li et al. had shorter follow-up times, the primary exposure in these 
populations was through drinking water.  Installation of GAC filters in these populations’ 
affected municipal water supply would have immediately ceased their primary exposure 
to PFOA, PFOS, and PFHxS. 
 
4.  ATSDR suggests the Seals et al study indicates a lower clearance rate may occur as 
subjects are followed long-term post exposure; thus, the decision by ATSDR to use the 
study that had the longest follow-up time (Olsen et al. 2007).  However, ATSDR did not 
mention the main limitations of the Seals et al. study: 1) the cross-sectional nature of the 
analysis.  Individual subjects were not followed.   Model-based estimates were instead 
calculated based on the initial concentrations; 2) there was the added assumption that 
there was uniform exposure based on the concentration of PFOA measured in each water 
district; and 3) subjects with initial PFOA concentrations < 15 ng/mL were excluded 
which maximized the probability of analyzing individuals with sufficiently high baseline 
PFOA concentrations that would not be at ambient levels. Seals et al. surmised their 
findings indicated the half-life for PFOA was between 2.3 and 3.8 years, not at the end of 
this range, as chosen by ATSDR via the arithmetic mean estimate from Olsen et al. Seals 
et al. did show their modeled estimates in clearance rates between low- and high-
exposure water districts could suggest a possible concentration-dependent or time-
dependent clearance process but could not rule out inadequate adjustment for background 
exposures. 
 
5.  Given the above additional considerations (beyond that of ATSDR’s consideration about 
the length of follow-up), the MRLs, assuming same PODs from the same studies, are 
recalculated in the table below using the different serum elimination half-life values for 
PFOA, PFOS, and PFHxS that are reported in Olsen et al., Bartell et al., Li et al., and 
Seals et al.  Accordingly, the percent of the MRL that might be overestimated by the 
ATSDR using in their most conservative serum elimination value (arithmetic means from 
Olsen et al. 2007) would then result in a range of overestimations of the MRL for PFOA 
between 9 and 40 percent.  This type of sensitivity analysis is definitely needed in 
Appendix A for the MRL calculations to take into account the variation of serum 
elimination half-life estimates that have been reported in the literature that will be, in 
part, a function of the GFRs from the population studied.  Given the fact that ATSDR has 
used developmental studies to calculate the PODs for their MRLs, it is therefore not 
justified to use the arithmetic mean half-life estimate based solely on retirees, in part, 
because the GFRs of older adults are markedly lower than adults of much younger age 
and people 65 years of age or older represent only approximately 15% of the general 
population   Therefore the estimated half-lives should reflect the entire population, not 
just the upper tail, which can be a reflection of lower GFRs that occur with age.  Thus, 
calculation of serum elimination half-lives may be age, sex, and concentration-dependent.  
MRLs, based in part on half-lives, should reflect this diversity of inputs in their 
calculations as shown in the table below. 
 
 
 
 25 
 
 

 
 
 
 28
 
 
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3M Comments

 
 
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and their re
abora
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DR was not optimiz
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ratory animals for PF
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tered PFOS via gavag
it
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r human risk assessment
effects 
ere
pidemio
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sensitive than rodents bas
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for
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ystem in l
w
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29
ents on PFOS 
ening 
xtrapolation from animals to hu
onger term epidemiology studies.
nt fo
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d e
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 be a 
y ATSDR with 
nt
 
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The most sensitive
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r w
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on delaye
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ff
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tive b
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y matern
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and dela
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inding
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tric adjustments and 10 for human v
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PF
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Inconclusive immune f
conclusions 
Serum PF
because 
W
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 HED for PFOS will be hig
 
 
MRL Summar
derived for PFOS based 
during lactation in the of
study (
and a total unce
dosime
concern that immunotoxi
 
Selec
animals are similar to th
include liver damage and
and small decreases in bi
neurological effects to be
A.
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3M Conclusion
 
 
ATSDR’s ove
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n et 
tions 
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(Abbott 
ctive and 
t al. 
st 20,
y with 
 discussion 
fe
or PF
OS 
d in mice
gnan
2008;  
f e
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their 
ype 
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 et al. 
3M Co
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hese ef
al data alone.   
enosensor 
ombe et al. 
 to influence 
et al. 2001).  
pup bod
miology
with PF
ary to the cur
ny metabolic 
and pre
of tox
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ductive func
s t
mans
d pup bod
y discussion 
y improve
incor
2003; 
ator
luoroa
s, mating
S
fails to make clea
ects and 
O
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eter
ieve
contr
It is 
ghts on the r
repro
eased 
et al. 
m
e epide
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crease
alez and Shah 
ctuall
.  
bbott 2015; Anderse
cr
y in rats 
(CAR), 
y targets 
au 
ara
 (se
rivation 
demiolog
ed on anim
L
y (A
 (de
y it bel
α or CAR/PXR activation 
abbits (Case 
levanc
ace 2009
y of the p
g and de
 de
l studies on the re
ntl
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e activation of x
ceptor 
all
as shown that ma
lopmental eff
y animals
ica
icit
otential of PF
posure
enin
even bas
y th
ator
, and r
d MR
h h
ect 
(Abbott et al. 2009; Butenhof
. 2006).  Given that humans are
ent deve
eonatal survival a
icolog
ycles, sperm p
.  The p
OS ex
tion as to wh
and their re
ye op
umans (see epi
rr
o rodents and often 
 et al. 2014; Gonz
ne of the primar
ty et al. 2005; 
included detailed inform
005a)
esearc
009;  Ross et al. 2010), the qualitative 
OS when compared to the wildt
ed subseque
gy
 (Abbott et al. 2009; Thibodeaux
plained b
jork and W
fects of PPAR
od
 tox
B
al. 2
 
plana
propose
ayed e
tion reproduction stud
n in h
cific t
ex
el et al
ake 2
aspects of male or female 
et 
30
effects 
ra
uv
L
estrous c
er 
en not shown in humans
 del
cts is inco
xample, n
ystem in labor
hanistic r
nce of r
ystem is o
en published 
cific 
re
gene
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re spe
or e
posed to PF
 be
ctional 
uebk
 
en show
eleva
 
al. 1980; Gras
gan morpholo
L
-spe
nden He
ctive s
re ex
un
aluated in mice
y ATSDR with PF
α, constitutive androstane re
a plausible ex
nt
jork et al. 2011; 
 et al. 2012;  
the f
s ev
er 
B
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produ
OS have
hile the text of the 
productive s
ct 
ctive or
ded b
e A-36).  
 in rats) has be
off
sessment.
e rode
by ATSDR a
lts from a 2-
ome of the e
by ATSDR a
instance, mec
s in rodents can be 
 PPAR
12b; Va
e to the pleiotrophic ef
unig
 humans.  F
e re
re
al animal (mammalian)
PF
ith these compounds as well as valuable insi
ttribution to the developmental outcomes in labor
n the potential developmental tox
.     
  These included 
e wa
lu
W
fects has be

au et al. 2004) and updat
du
t al. 2009; 
).  
or 
 et al. 2003).  These studies 
y w
L
pro
ening
isk as
gniz
ce to
ew o
co
posure
t al. 20
fect th
cts o
fe
icit
ormanc
etails): 
ents (Corton et al. 2014; Elcombe
ect conc
OS (cf. pag
periment
y animals.
ff
” included 
ature.  F
erf
eye op
et al. 2004)
, and re
utenhoff e
SDR should 
OS ex
gnifican
α knockout mice
 ex
ects and its a
B
T
cts
y less sensitiv
calls into question the r
OS did not affe
ator
ceptors such as
ff
au 
yed 
ased on the resu
et al. 2005a
fe
bl
L
re
 et al. 2003;  Kla
l si
 to PF
l e
rted in 2004 (
ts (
nt to human r

r (PXR) in the liver (
nces 
ica
po
ll, PF
y index
mments (D
ritical effect chosen 
ht, b
y “ef
n PPAR
OS does not af
ra
leva
ig
uebker 
an
ects to PF
posure
s re
rtilit
productive p
 The critical e
and dela
above).  A
re
ATSDR should re
the c
we
(L
that none of the listed ef
above), the inclusion of s
M
published liter
eff
nuclea
recepto
2012a; Elcombe e
considera
compared to rod
Klaunig
differe
biolog
whe
2009; Abbott et al. 2009).   
 PF
ATSDR to conclude that 
ex
 
A number of
developmental ef
2009b; Case et al. 2001; Gortner et 
al. 2005a; Thibodeaux
developmental tox
materna
Comprehensive revi
wa
al. 2008; 
 
Ove
in the labor
fe
re
2003), ra
 
 
3M Co
 
A.
 
B.
 
C.
 

 
 
8
 
1

ce 
ic 
ents
0
OS 

), 
m
 2
gain 
up to 
nd 
In 
ys of 

rgets 


ved 
m
y-
 
cies 
 ar
first 
.  
icit
alth or 
y ta
bbits, 
etal 

rious 
st 20,
ight 
– 20 and 
nan
ra
r.  N
< 0.05
in
gu
gestation 
rom 
y mediated 
s in 
he
3M Co
posed 

eg
 the 
-month ora
evidenc
spring
In 
s obser
Au
y-we
 lutea, 
y f
nal he
effects of 
perimental 
hts.  Eviden
n to male a
 primar
ig
nsecutive da
ic 
lantation sites in 
009; Thibodeaux
bod
reduced bod
ntents of the dams 
. 2005), 
roug
in male or
 of pr
uring
ora
l and potassium 
 neurotox
ater
imaril
re
ntal 
 Ex
posure
ludes the 
at “The f
cant (p 
cies.  
om GD 6 
or hig
h wa
resent at nontox
eated dur
003).  Va
t al

g/da
give
 p
gan histology
s in off
growth deficits) but 
/k
e pr
y we
fr
eter
 corp
≥6 co
rom a six
y inc
gnifi
e tr
rpholog
perime
OS ex
y spe
group 
creased 
al administration of PF
caused 
tive co
g-d 
m
atings d
posure
icit
y si
 et al. 2
tor
given 
yonic imp
g/k
emales, th
ara
g, number
 m
ctive or
elopmental
 
ganisms a
g ex
ra

ight, whic
ges were
bbott et al. 2
uebker e
 f
OS wer
oncluded th
ts, or
lso 
roduc
(L
y p
ts with 
he mo
aluated f
).
 or
nal animals. 
ams wer
mbr
for
etween contro
re noted on m
g dose 
abbits either when ex
lbeit de
yclin
verages for
OS ex
a dev
y wa
/k
y we
rs c
In ra
rtilit
produ
es, ra
ed such as bod
l labo
 of e
In 
s we
re ev
loping
ct
h as 3.2 m
 and, 
fe
ycl
e is stron
g/da
y in rats 
ences b
ect
fe
/k
tal bod
y autho
s a statisticall
cted in r
 or 
er
 af
OS (Thibodeaux
umber
nockout) (A
genesis) a
2001).  
ating
estrous c
ate, number of
us c
riod.  
FOS doses up to 1 mg
 eff
at et al. 2002
nimals for PF
, ther
ed with PF
re
evelopmental tox
n severa
mg
d fe
d no fetal chan
en pregnant d
 postnatal survival and 
D k
ries or the rep
re wa
ation, litter a
yos, and re
stro
 Furthermore, t
y a
-36)
ects in the mater
ects associated with PF
erved at 1 mg
ased
 
gano
f organogenesis) a
gh m
ant diff
f e
(Seac
y.  Stud
ls an
ator
ff
– 3.75 
crease
31
ct the n
 not affe
e et al. 
 doses as hig
ect mating
 o
-related
an primates we
aluated i
ecr
fe
hrou
ff
s obs
cy indices, 
nific
aluation pe
eight wh
(Cas
ect the ova
lopmental stud
, t
cant e
 w
.g., d

ff
ly a
ys to insemin
nan
l animals we
In mice, the
-viable embr
y sig
y ev
ats received P
atment
t al. 2009). 
-hum
fects associat
nifi
en ev
om 0.1 
xcept de
groups onl
g potassium PF
rve
rse
reg
 fr

ic dose leve
/k
ed (e
– 15 (period o
 of da
lopmental eff
OS (cf. page A
l liver
re sig
ymal sperm matur
ported in labor
ight gain wa
y tox
port
OS did not af
– 20 (period of or
 obse
 did not a
y has be
nging
 noted e
y dos
erna
D-1, Sv129, or PPAR
 and p
yos, non
utenhoff e
mplantations were

ere
duction/deve
rior to mating
not adve
umber
did
statisticall
the mean number
d no abnormalities 
s re
opmental ef
at deve
hen materna
s in the outcome of the d
icit
re
 as 1 mg
g GD 6 
as potassium salt)
g the 28-da
B
rgans in non
re we
mat
mbr
nant female r
y-we
g/da
et al. 2001).   
ere re
 to PF
y, i
r, they
epro
s, n
 no 
 the
 
/k
g GD 
iven 
evel
eeks p
effect
  While ATSDR concluded that deve
ed w
posure to PF
l bod
 
OS did 
g fertility
ere
l effect
cts w
 w
males in 
comes (
fects we
at maternall
(Case 
fe
posure
tion r
).  
tation.  No PFOS tre
ects.
OS (g
re
fe
OS, preg
ff
 that d
erna
ed 
/kg-d durin
y where
e observ
amples. 
al ef
rr
a dose as low
ains of mice (C
g-d durin
esults indicate
l e
lopmental tox
, the
emonstrates th
 materna
 ex
ed increase in 
/k
genera
ats for 6 w
cohabitation, epi
y with ex
d onl
e d
g ar
l doses” 
l str
gain, howeve
tation.  PF
OS administration ra
lat
ht 
icit
stational ex
ig
y with PF
y and r
ortner 1980
a two-
male r
males, includin
ek of 
OS-treated 
productive out
OS on reproductive o
sprin
OS deve
l PF
ects occu
Ge
severa
et al. 2003).  Similarl
3.75 mg
and food consumption w
up to 10 mg
we
(G
 
In 
potassium PF
fe
and lac
fe
per number of mating
we
implantations, viable e
particular
PF
diestrus or estrous durin
stud
gestation to lac
re
PF
stud
 The developmental 
by materna
of tox
demonstrating
observe
evidenc
off
involving
following
 
PF
ora
decreased mat
abnormal fet
with 2.5 and 3.75 mg
eff
materna
dose-re
gestation at 
develpmental ef
 
D.
 

 
 
8
1

α 
ents
0
nal 

nd 
m
 2
et al. 

fect 
genic 
m
au 
ater
her 
uebke

om 
g et al.  
fter 
ns
posed 
st 20,
erna
al ef
(L
ent mode 
r on 
ects 
s also 
moval of 
ceptors 
gu
aluated in 
y L
ator
ll 
α and 
3M Co
rtrophic a
Au
her 
ht and bod
ssessment of 
arlie
we
.CETP mouse 
-in tra
hen ex
y re
duced m
ts b
ased postnatal 
y mat
L
nscriptional 
hig
OS.  As 
een ev
re
 ra
eig
 labor
n the rec
omments to 
y animal studies 
iver eff
PPAR
ype
strated to be 
and Chan
ra
criptional 
ent liver fr
ock
.  W
group or hig
ecre
g/da
E3
etal liver a
has become 
ents and humans 
 as a critic
ed b
y in
y w
al hallmarks similar 
/k
azard a
ator
 to PF
en the rodent and 
ytes
rms of the re
OS or 
aused 
ht, d
r use
In the 
(Corton et al. 2014; 
l dose 
.  The c
en rod
ceptors 
ed bod
eig
ed in the
en demon
XR activation wa
(2009b) 
sulted in t
atoc
ame trans
etwe
ceptor kn
y modifi
rna
eceptors, l
P
nal gavage in the 
-1 mouse f
re
y w
ctivation of 
posure
educ
velopment
om 1.6 mg
t al. 
es for the h
ar r
r a
y be
ed re
y hep
De
ge’ in labor
opriate fo
arl
d the s
ences b
lopmental stud
ffects and based o
e fo
onsistent with activation of PPAR
α/CAR/
 c
er
g-d mate
tal bod
ects report
ama
 geneticall
tural human fo
y potassium PF
y of PFOS has also b
l e
/k
her.  
action betwe
dult males re
 has cle
utenhoff e
α and CAR/PXR 
g/da
icit
n to pregnant rats c
mg
 reported r
tal eff
erna
priate speci
ver d
nsideration.  Given that it is 
ensor nucle
nd inappr
response to ex
α/CAR/PXR activation as a mode of 
 PPAR
osen et al. 2010).  
f a
 observe
ponses of human and rod
al diff
 activate these 
d humaniz
man primar
 the na
eased fe
 a
t al. 2012b) point out, the h
posed via mater
y B
 o
e been
g/k
ction/deve
ilar to the comments provided e
thors
g or hig
rved in pups fr
 
enos
tic 
for
e (R
ment
 
y mat
ppro
posure
α/CAR/PXR in CD
 
au
r human risk assessment
ful co
-out an
32
gestatio
g/k
, decr
in mode-of-
y x
posure
ents that
y of hu
 10 m
gain at 2 
produ
 obse
ation of “li
en the res
funda
, the 
i.e.
ere
evelopmen
ated b
nt fo
OS.  Sim
nce 
perimental evidenc
nt hepa
OS ex
at pups ex
eported b
ype mic
ight 
cement with
rs (
ex
y r
-t
OS ex
etwe
 the 
 to ag
eiving
velopmental tox
y unjustified
e (mRNA) 
 gestation.
ailabilit
ation re
ys) w
pla
e the most a
eleva
 to PF
ges in lipid parameters
ctivation of PPAR
OS during 
y-we
y medi
tion at 0.4 m
y in humans.  
y PF
y othe
y of 
fore, the d
natur
y stud
posure
ceptor knock
icit
 not r
nd re
 
ences b
ase a
re
onists, mice that hav
t liver to PF
er
 ex
ased av
dams rec
 of PF
al bod
o-gener
 detail above
here
rimaril
tox
are
DR’s identific
odents warrant care
istinct differe
anges mediated b
dietar
011).  Rosen et al. (2009)
ff
e basis for
genera
ted b
ntal dela
ay not b
cientificall
ra
and chan
 p
xposure
ia used to establish PPAR
 s
nt. 
ctor in the rode
e et al. 2012a; Elcombe e
icolog
om
R ag
ors a
ter
fr
epor
ents 
e of 
ri
iles 
In a tw
ntal 
nts m
gs in r
e is d
iver ch
rom PND 21 male r
t al. 2
 to PFOS during
ecept
cribed in
re
y r
gher.  T
criptional sig
velopme
s f
elopment of 
OS were
rode
lopmental 
get with e
ents are
established bod
mental di
nts that incre
indin
spons
sponse 
r litters from 
gain and fet
s in rod
viousl
elated to ATS
ell-
ell as in adult male wild
ijland e
posure
 r
t al. (Elcomb
ssion prof
 funda
t al. 2014).  Th
y fo
In addition to mice, the de
l administration
ight 
 to age
ith dev
gain at pa
re
ed that ther
α and CAR/PX
inding
 comes to l
d in rod
d in liver
pre
e consistent with activation of PPAR
 is a w
nal ex
 are
tural mouse r
y-we
ht-
ction data, 
r f
gniz
rplastic re
rer w
ts.  Ora
au et al. 2003).  
ig
OS on deve
 human risk assessme
natur
ive
OA, liver f
co
posure
primaril
2003).   
ra
bod
(L
et al. (2005), des
we
to those pre
survival, and de
dose groups or hi
animals for PF
of a
PF
L
follow a
as sensitive tar
PF
re
when it
observe
for
 
There
CAR/PXR as a major fa
Elcombe e
hype
consistent with the c
action.  The trans
observe
developmental neurotox
(2009 ) as w
transgenic mouse model, 
gene ex
and PXR (B
sig
mater
 
There
ex
Elcombe e
human liver re
clea
mouse models and the incre
to PPAR
the na
 
 
E.
 

 
 
 
8
1

.  
 
ar 
 

ents
0
 

ell 
 
r a
ety 
ight 
m
 2
epatic 
ore
nt 
ant 
m
 et al. 
OA in 
y the
risti
ytes.   
esoid X 
lev
st 20,
e subtle 
egulation 
gu
acte
nscripts.  
toc

3M Co
ytes as w
urtherm
Au
sponse, o
OS in culture
ymes 
l other h
ra
or positive 
perimental data 
not 
ood and Saf
z and Shah 2008
especiall
 in tra
In 
that, “while there
a re
999; Hirose
 CYP4A11 
te metabolism to 
 is 
y than rodent 
he char
patoc
vera
humans, 
tabolic r
ussion above).  
ex
 use of rode
to be irre
nces between 
at hepa
s.  
e metabolic 
cells wer
AR3 isoform and 
c effects in rodents 
n F
red the liver we
α and CAR 
 to PF
ease
tors,
ydra
OS
ities such as 
yls) 
cytes, 
entl
 in t
α), and the farn
yte
y either human nucle
er
an he
isomal enz
ra
at and 
ert me
ctl
ent liver.  F
gy disc
lk
ests that
esult
XR
atoc
roa
e (Gonzale
pato
posure
tion of se
y human 
(Ehresman et al. 2014).  
yp4A1 in r
L
y concluded 
gg
een r
ypertrophi
y author
 perox
y no incr

μ
f mechanistic 
rfluo
t and hum
ctiva
articipate in th
ly su
ulator
ype mic
gonists diff
ted major differe
r than an ov
y o
 (2015), Europea
-t
posed to PPAR
y ra
isome prolife
R1H3 or 
ys betw
α a
 appear to r
the
tivation of human C
tivation (much less than f
y at 100 
α (N
n to activate dire
 wild
 and human he
orton et al. 2014; Gonzalez and Shah 
response to ex
ulation.  The
ytes ex
 
onstra
 mRNA for
ed essentiall
perox
rized the a

athwa
anges in primar
e ra
w
orts the liver h
ce also shows the lack of 
s compared to rod
s (see epidemiolo
OS strong
as USEPA (in its assessments of PF
onal reg
mmittee
nel (2018) also conside
or other pe
be et al. 1996; Goll et al. 1
(C
ntial shift from carboh
ht ac
ti
Pa
her 
acte
ch
g onl
y rat and human hep
cum
ch 
in
nificant bod
alth risk assessment of PF
 
ed in
α does not
spons
ells a
rna
OA (
 with primar
ytes in 
cepto
lear receptors p
 to PF
y su
33
mice 
 human
-he
en rodent
ure, dem
e ac
control in
ytes show
 in human as well as C
char
 re
a sig
and 
patoc
action supp
genc
etwe
orking
tiple nuc
g in a substa
M, with slig
posure
μ
l a
pert Health 
tions with ot
posure
(2011) 
glycerid
sponses; the 
-of-
OS in primar
re
 this, the potential ac
perimental eviden
sponse observ
one et al. 1998).  
ytes respond to PPAR
ease over 
sultin
cts noted in
s well as 
 the human
dera
ences b
d in rats 
ffe
 fe
er
ell line in cult
OS ex
y PF
, re
y Risk Assessment Co
 
ff
patic tri
1; Perr
epatoc
e (2009), w
ulated 
aptive metabolic re
died.  PFOS was not sho
se, in human liver c
 data a
ther
as well as other inte
stralian Ex
mal studies with PF
astic re
on of human PPAR
serve
and human he
ge incr
y PF
jork et al. 
CAR, the liver X
R) b
activation of metabolic p
s up to 33 
hed mode
sponse to ex
oint for
nts.
y di
esponse in human hepatoc
genc
e ob
allac
, the human hepatoc
α, B
FX
posure
α reg
an ad
f CAR3 and PXR occurr
OS.  The ex
e liver e
an liver c
ytes 
emonstrated mul
espon
nd Au
ry ani
yperpl
activati
ased b
stablis
al A
to
y d
y in the 
es) o
an endp
), a
e also been demonstrated (Elcom
atoc
ents.”  Supporting
ll et al. 199
spons
and W
OS ex
eflect 
centration
 to PF
ced r
advers
 the h
idation and he
du
tional human
s as 
yperplastic r
t hep
y justified.  O
ison to the lar
onsistent with observa
s incre
y r
y, the e
 no 
gain in 2016), 
 h
jork 
ceptors (PXR, 
NR1H4 or 
ly in PPAR
t con
ytes, and 
r, c
y re
y (2018
y ra
ot1 and Acox
re

r (
ytes, the
r a
posure
s in labora
rplastic re
ved in rod
inding
k of a
compar
y acid ox
cepto
sponse to PF
tt
cepto
om ex
 human risk assessme
do not have
Ross et al. 2010).  Ke
lac
activators, hav
2009; Parzefa
 
As noted above, human h
hepatoc
hype
2008).  B
as the HepG2 hum
primar
In 
Cte/Ac
Howeve
mRNA wa
 
In addition to PPAR
nuclea
re
hepatoc
re
fa
is some similarit
particular
and possibl
obser
human PXR has been stu
re
control substanc
 
Collectivel
fr
markedl
there were
The observa
that relates to the liver re
liver f
scientificall
2009 and a
European Chemic
Authorit
finding
for
 
 

 
 
8


1
r)

ents
0
ica
m
 2
in 
ys, 
OS 
entile 

m
et al., 
rum 
 

as 
ected 
potential 
 to 
 to 
st 20,
ght 
eight 
gnane X 
r se
l dose 
e for 
tin
gu
).  PF
xicolog
t al. 2011; 
y h
eiden.CETP 
lthough not 
sure
3M Co
s been 
eacat 
enosensor 
L
(mediated b
Au
 x
 
nd pre
y a sli
posure
po
obora
liver w
 of
nce 
nl
on), a
d fifth perc
hen more 
 one of the most 
g et al. 2017; 
l. 2002
eduction in serum 
2a; S
E*3.
E*3 model pape
 in lowe
OS also aff
rmed the 
serum lipid.
h ex
materna
f evidenc
dies mentioned 
yls in rodents 
α) a
ijland e
B
g lipoprotein and 
F
duction of 
fi
w
eara
 corr
riod of more than 1 
cti
abituation” wa
alk
anistic stud
. P
ra
-boun
and female monke
g-d 
It is incorrect for 
et associated with 
at et a
g Apo
g/ml, o
/k
er stu
y animals ha
other
aspirin),
.  
gets with ex
activation
sin
rease in 
e lack o

 with PFOS in to
ve targ
; Seac
-containin
OS resulted
ll as 
lpha (PPAR
ynthesis (
creased h
ype diet (Apo
y 165 u
g lower
y animals wit
al endpoint 
ll as oth
r a
f PF
glyceride cl
al. (2017) con
an inc
we
we
y animals
ApoB
rn-t
esulted in the re
/ml for male 
ator
om 1.0 mg
 et al. 2012a; Chan
y lipoprotein f

y r
 et 
imatel
uses 
y as 
y known a
polipoprotein B
hanistic studies and r
urs via the 
cepto
y and de
esponses.   U
este
espondin
account for th
y (a
 can also elicit increased 
rted with perfluoro
OS in laborator
(2009b), this is incorrect.   
d re
et al. 2012b).  Mech
 doses o
 of a
Chang
prox
 76 ug
n labor
l. 
 pups fr
e stud
monl
 serum lipid over a pe
po
enhoff
cat et al. 2003
related to dosing
ic r
matel
 to 
tud
enhanced tri
gh-densit
em is a sensitive tar
activit
ed
th
 re
 to PF
ut
in mec
ct 
FOS occ
learance of 
etary
tion
the corr
et a
 
com
(B
fe
idation and lipid s
hi
gan i
tor 
vation as a critic
ctivate
ges in
yst
d in 
34
et al., 2011; Elcombe et al., 201
h di
ed at ap
tions
roduc
imates, 
and 
posure
y ef
y of P
β-ox
han
ere 74 and
rve
tor-a
ated c
y the 
ypolipidem
 p
hiev
est that PFOS ca
c acid (
land 
ij
ra
) w
rvous s
utenhoff 
d
gg
vation in male
yli
rum lipid in laborator
y, ex
ctivit
y target or
t al. 2012b; Sea
y acid 
 attenu
eased
L1s
y B
rt of the same s
ases in serum lipid” is a sensiti
OS ac
att
ted that hig
-human pr
OS and c
cts obse
ansient obser
ates (B
 production with 
ynthesis which ulti
L
MC
imar
s pa
ylsalic
ugs used in the world,
ase in se
ase serum lipids 
D
le, tr
cet
r dr
re
“incre
cre
combe e
hypolipidemic agent 
L
ests that ne
wn to be an earl
ence f
l having
onstra
l as decr
 A1 s
th non
rum PF
t, was observed 
s (B
dence to su
t a pr
sient obser
ND) 17.  ATSDR fail
isome prolife
be et al. 2012a; Elcombe 
sterol (primaril
eported b
), the “increased mo
P
em
g V
erum PF
gical effe
ailable a
at, a
y (
s wel
y wi
counte
ypolipidemic a
ration
use inc
cin
an influ
hest se
gnifican
ations r
le, tran
re av
 
ed mode
du
.  
al da
OS.  To the contrar
 is no evi
y re
y si
re
ystem is no
ll
 et al. (2009
a sing
ata a
y shown to de
ablished as a 
t al. 2012a; El
ecent stud
y.  
ff
y animals similar to the observa
 to PF
ceptors perox
which c
 human-like lipoprotein metabolism on a W
 apolipoprotein
g HDL
ica
, the
re
t al. (2011) d
re

r, 
d as 
es with rodents and prim
ate of
fo
utenho
OS does not ca
posure
cepto
icolog
jork et al. 2011; Elcom
hibiting
ijland e
a more r
duction in serum chole
spectivel
OS.  ATSDR also sugg
OS per observ
nificant d
It should be noted th
common over-the-
laborator
(EMEA, 1999).
 
PF
ATSDR to conclude that 
ex
consistentl
Elcombe e
has been est
cholesterol has been sho
studi
2002, 2003).  The h
nuclea
re
B
elucidated how PFOS modulates the h
mice, a humaniz
ex
B
cholesterol b
lipoprotein lipase) a
the r
circulatin
 
In 
associations between s
year.  With the hig
re
tox
benchmark concent
re
 
There
PF
PF
 
In B
observe
group on postnat
developmental neurolo
studies. The use of this sing
sig
 
 The nervous s
F.
 
G.
 

 
 
8
 
1


ents
0
ta 
and 
 o
-
re 
ze 
m
 2
 
gm 
ye 
e; 
 
With
ry 
m
r da
g) 
di
meters 
y overt 
with the 


et al. 
 a T
for
g on 
y.  
 
st 20,
h the 
e fo
y recorde
xample, in 
re
gu
 in hand; 
g.  None
au 
icit
ms et al. 
3M Co
ment should 
tension; 
L
om dams 
innin
ffects of 
Au
ormed 
y respons
or e
htin
 tested 
 whe
uidanc
USEPA 
judg
 of learnin
sted using
ociated with 
dpoints evaluated 
t throug
d it included 
ts of 
ic tox
n-Ada
on
m
ial test para
erf
ere
s in mice whe
nfounded b
 tr
tudied para
 the man
r; palpebra
mb ex
 rig
avoid / minimi
ported 
s p
ir
sul
n te
gm beg
y. No e
ass
esponses, but no 
pert 
l en
upillar
at pups fr
di
a water-filled M-maze 
creased antibod
e co
C r
ex
wa
ystem
ica
iel maze swimming
lopmen

e re
ara
indings.  F
B
on the s
B
se of handling
 whe
y s
esponse
y is to 
s ar
as de
and 
O
nce of fu
y th
e p
y r
 
tion pups w
icolog
cation; p
y (
f the 
OS 
ara
gait; and a
ra
ed b
DAR) but not the seconda
y stud
IgM PF
ach 
 primitive for
ations among
y (F
imilar to the discussion with 
rv
 
g, and memor
xicit
rancis et al. 1990; 
OS.  
OS on deve
emoval; ea
-gene
 evaluated in 
gh dose phenomen
(F
 PF
OS.
et al., PND 22 r
l
re
ts.  S
ge et al. 2009; Pede
OS has also been 
iel maze swimming
ect of PF
rnin
n batter
e r
sponse; 
au 
r from controls
we
sponse (T
lopment is at odds with g
ies 
nce appro
tal neurotox
ituation (a
ee phases o
c B
her obse
sits; mucous membranes/skin color; e
ination/defe
fe
atio
11, 21, 35, 45, and 60; an
cag
th PF
be a hi

nvulsions/tremors; hindli
y L
t al., F
assive avoidanc
0, 
y, lea
mmunoto
d immune finding
ortant to note that the re
etation of immune f
 to PF
 decrease in 
eve
ase for
hab
an eff
ect of PF
-specific antibod
y re
ff
y b
 were confound
immunotoxicit
 
pr
ent
d to 
 
l d
y stud
evide
er e
-phasi
 no ot
se o
or; ur
l e
Ds 4, 
y depo
ry is also supported b
 abilit
ich
gen
educe
35
icit
hile 
eveal 
y in a p
posure
It is imp
gica
elopmen
: ea
havi
y PND 7
al. 2009; Guru
ht of 
ated in thr
e tri
ica
crust
e stud
uebk
anti
antibod
robust 
otox
e were
gth; tail pinch re
ht loss.  
-depend
y L
 et 
 a 
y dev
tional observ
y treatment wi
icolog
In th
IgM 
eig
ypic be
y b
imatel
eased 
dose
 noted.  
re evalu
roup on PN
cr
FOS appeare
h 28.  Th
y did not r
er; red, 
g and memo
estation did not dif
; Dong
y w
ct
y; muscle tone; co
rip stren
ected b
s in rodents wh
y ATSDR for r
y, a 
y we
hea; salivation; piloerection; appe
tereot
 bod
s to P
normal neurolo
mental neur
ate that a weig
 this has not been the c
one of man
or
memor
roups).  Ther
 neurotox
od.  A func
ex per g
ment permitting
hara
e/s
 (2005a).  
ghout g
tion, and memor
 on approx
 
one of the most sensitive targe
n the de
n conducting
 (2009; 2011), ex
ctivit
ion were
re

yorr
mobilit
as aff
In the stud
d.
-dependent 
al. 2011
te/c
arr
ten
rdination, swimming
ss
et al.
re
ell
ell a
posu
evelop
oo
rve
y wa
enhoff et al. (2009).  W
g and 
evelop
g et 
g et al.
ut
y ra
ased o
 / dose g
tion peri
ats per s

al; biz
fect on learnin
nation.  
ginning
ar c
 b
y, including
 suppre
g and mem
omodacr
ator
ye color; 
g/d throu
 obse
OS, ATSDR also concluded that i
(Don
guidelines st
y B
are
ssed T c
l studies cited b
activit
ggestive of a
es of d
an ef
uebker 
g/k
re
y principle i
icit
y Don
IgG
y b
e; e
 endpoints w
L
ica
It is evident that
 su
g; arous
B
nd 
 to PF
etation for d
earnin
e in 
luate learnin
re
g; forelimb/hindlimb g
O
k of 
g, short-ter
sponse 
y and should not be included in the inter
ssion of NK c
ssions with ex
 
her l
rimation/chr
 
rnin
 neuromuscul
 re
icolog
icit
ocomotor 
posure
sponses to vaccines) is 
OA, these 
OS suppre
below) that demonstrate 
interpr
1998)These 
be used. 
L
in the stud
hig
assessment on PNDs 22 throug
to eva
in pups (20 / sex
that we
PND 66 observa
same sets of 20 r
various stag
lac
closure; respir
prominenc
groomin
backin
these F
The lac
(2003) a
given 3.0 m
maze with alter
lea
PND 24, and, be
for
treatment we
 Inconsistent immune finding
ex
re
PF
PF
IgG
2008).  A ke
systemic tox
 
Tox
tox
the studies b
suppre
evidenc
suppre
 
H.
 

 
 
 
8
 

1
to 



G
 
ents
0

y) 
 Ig
m
 2
nd 
ll 
OS 
 
antl
ged 
ch is 
CR 
ow.  
m

Æ
ra
sponses.  
roup 
y IgM 
ymus, 
st 20,
well as 
rs should 
y b
nific
roup (3.10
antibod

esponse.  
t IgG in 
gu
IgM 
hallen
3M Co
 paper, there

y (memor
G, whi
IgM PF
d a
Au
mete
ht as 
two lower 
not measure

response a
ol g
tment g
re sig
primar
ar
y response a
 other 
tibod
er c
Ig

authors should 
n and th
ed the ove
eig
ors.  The data 
sion that PF
para
ry Ig
an
th
g the stud
ing
al values for
g et al.
 looke
y w
as the 
ased o
onclu
e contr
ch trea
 memor
ction of
y immune r
y.  The 
ea
conda
gression of 
en fur
rum. 
g immune 
ssion of 
ssive fact
y affect immune re
te that the responses are
ed in the first 
 to produce 
 
ced bod
y immune 
gain, usin
yin
gre
.  
ect
-sided critic
y IgG response 
educed b
du
l ke
etween th
ata for 
 
 and se
ess the follow
 1
bona fide
g et al. in splee
re
s r
ra
es.  A
y d
-based pro
ctivated wh
y titer
al. should have
y immune organ: bone marr
y indirectl
nge b
g treatment group we
ymus
 ke
sent.  This confound
 time
y to support the c
y addr
ole in stud
s not aff
 Table 1 in the Don
mmar
mputing
g/k
ccinations are se
s well as others) w
t the status of the second
 secondar
elicit a 
valuate the produ
normal pro
ells first as primar
ss switching
ibod
nse wa
n spleen cells onl
els to illustra
g et 
by Don
likel
 at
< 0.10).  
come a
nt
 
 because 
 immunosuppre
dit
een seve
ty studi
al r
 the
 c
be
y cla
f a
es
ici
operl
espo
eight cha
y co
< p 
as the
ed to 
y. 
y B
els in th
eight wa
 the su
s to va
y r
IgM lev
eported 
 
) were pre
e betw
a critic
y w
g et al. (a
flect wha
y w
and 
aluated i
 r
36
 known
tion.  The 
y studi
te 
re
nc
unotox
ys 
eight will 
y w
tion b
antibod
IgG lev
y authors.
entific vali
y titer
y induc
), in looking
y ev
y taking
ntibod
hts in the 0.5 m
y Don
era
duction
y did not pr
y w
tt’s t tests b
0.10 (0.05 
e in the stud
g et al. did not e
y did not take
ssessment o
re
ls we
ht pla
eig
α=
ntibod
ads to 
s onl
ht 
eig
g TAD
y w
y prolif
y le
 the a
y the stud
y wa
eig
e that, not onl
IgM produc
y w
ence bod
med that bod
g/k
(2.58).  B
od
eported b
iz
nly onc
 and the
ntl
 for
us and serum for 
le listed in point #3, Don
ample, the
nd Dunne
ove, Don
 into considera
vit
on b
y w
a r
y, which did not re
 serum leve
also lacked sci
nses.  Concorda
ted in these imm
ex
erence in mean bod
ym
ell as evaluated 
s not appropriatel
ged o
ypes
aimed that the a
tiona
n influ
al. clai
ff
rol group at 
y dat
 
ement
rone
 di
g group 
ont
s.
FCR acti
g et al. 
as an 
g et 
/k
allen
y illustra
ANOVA a
ell known that the a
y wa
which, ultimatel
 et al. cl
esponse onl
s ch
ass switching
l measur
IgM, as w
ects (i.e., bod
rs that ca
lobulin isot
f similar ra
h Don
tension from ab
IgM P
ff
y Don
wa
s a major omissi
aticall
ll known that bod
cto
ed to be a
tt’s test, the final b
y r
g et al, it wa
y cl
gen, 
y o
en 
 cells will subseque
linica
ed corticoste
sses immune respo
 antibod
y fa
ype.  The stud
plicate the 
hile Dong
hile the immune cell populations were
y did not look at these cell populations in another
y interpretation in the immunotoxicit
 et al. (2009) 
y wa
sented b
ystem
It is we
an
Althoug
dose groups (0.5 and 5 m
appear
and the 0.5 mg
re
Dunne
lower than the c
 
It is also w
isot
antibod
IgG
It is important to emphas
by Don
antig
As an ex
immunog
antibod
development involves the 
The B
by anti
the c
W
data; the 
have also looked at th
consistent. 
B
addition to 
W
the
That wa
 
 
 
 
 
 
 
systemic e
stud
increas
pre
suppre
be s
Dong
 
1.
2.
3.
4.
5.
6.
7.
 
 
 
 
 
 

 
 
8
1
-
 
 
ents
0
ge.  
 
m
 2
y.  
tion 
C) 
nt 

rum
rall 
m
DH 
L
ra
 to 
re
 agent, 
st 20,
DH 
 
 and non
e this.
 agent, 
r ove
gu
L
y an 
ssing
3M Co
ard CB
 
Au
y did not 
he 
. did not 
le mice
ssing
y data.  
cific assa
ell (SRB
gniz
upon challen
 not a 
ailable for use
y concur
ma
us, and se
nt control with 
-spe
yte prolife
y is
an
id not use the 
ery crude
eco
fe
ym
ood, and bone 
l. data as the basis 
re
D) did not 
y and t
ctivit
g et al
 v
cant lowe
rating” 
at all.  The standard 
d blood c
are
gens av
f the stand
s provided.
us, bl
g et a
concur
nifi
ctivit
ell a
ymphoc
ell’s mitochondrial 
y, which was not
re
 
g/ TA

ge 
rt o
g et al. d
 wa
ym
a sig
/k
r the spleen, the
K c
rolife
If PFOS was trul
Don
ell a
assa
.  
s N
sponses 
d not provide 
y fo
M
y and it is a non
y, which Don
 challen
 et al. failed to r
Ig
ly on 
ted a
 not “p
rDU 
C
IgG in spleen, th
us.  As an immunosuppre
 period, 
ess NK c
re
egrit
indicator of c
ative re
e B
al. was shee
B
Dong
rovided (pa
ne marrow
y but di
ytometr
d the splenic l
data is that MTT assa
R
ym
 lik
-cell dependent anti
nd 
s p
ype, not 
lar suppressive immune responses to be 
M and 
onl
th
ne cells and Don
 
ells were
y an 
g et 
serum.  As an immunosuppre
ne is to re
up mice (0.5 mg
y T
Ig
en 
y dosing
y in their stud
flow c
ece of 
thing
mu
gro
 
y prolifer
en, or bo
y should have also looked at 
If o
-da
y Don
es from S
en and 
y, when compared to the 
37
 man
ctivit
y used to ass
y is 
counts wa
IgG isot
ported.  
albumin) a
 sple
pect simi
creased 
ymus or 
re
ssa
ll membrane int
It is simpl
flect an
spons
 are
yte 
us,
ell populations in spleen, th
rence in the immune response.
s th
t sple
y wh
effect of PFOS an
IgM in sple
ration in im
g over 60
y, re
ym
esponses.  
ell activit
tion.  
 th
ch as de
 justif
h (i.e., ov
esponse is 
d with ce
g that the immune c
ifera
es not re
bstance used b
ymphoc
for
g et al. should not be interp
egative 
oblem with this pi

on.  There
arc
ed male mice; the
cific diffe
y r
ns such a
y looked a
l responses 
 
ate
 in the lowest dose 
r NK c
ce 
t, one would ex
 evaluated 
rga
sed immune c
nl
sed prolife
ate these r
 g
ica
eported NK cell a
ration would be some
ge su
ese
rgans su
y need to
gain of 3. 1 
us.  
fic pr
 r
lu
y Don
y fo
 
r-spe
gen
cell prol
nd it do
g et al
).
antibod
rea
rea
 a
y o
ey o
ht 
ym
rted a n
monstratin
allen
ell activati
l eviden
y evaluat
g et al.
eig
 et al. r
ay is not a standard a
ed b
assa
g et al. o
f de
y Don
ica
y gende
ssing
Don
pect dec
pect dec
y w
ment is associ
 
r, the speci
ment of 
 cell prolife
y.  
Don
-gain of 2.58
ne the th
DH ass
y o
aluation, the
ht
L
sure
 et al. repo
 et al. onl
orm.
sure
y for
d in major ke
 and 
ll bod
hile Dong
ami
eig
spiration state a
W
ex
The 
values report
mea
The standard 
perf
as a wa
Howeve
mea
re
assa
evaluated b
and in the field of immunolog
specific to T c
in the immunology
panel parameters
rule out an
ect methods to eva
y w
 
 
 Dong
 The antigen ch
 No information on blood l
 No histolog
 Dong
 their ev
8.
9.
10.
11.
12.
13.
14.
As discussed above, 
immunosuppre
observe
concurrentl
IgM status in other k
one would ex
marrow
one would ex
corr
for
an overa
bod
confound the immunolog
 
 
 
 
 
 
 
 
 
 

 
 
8
1

ents
0
but 
ed 
 in 
 
cic, 
all
yet 
m
 2

ere
ards 
m
IgM 
OS was 
control 

d doses 
ects 
s bas
laim 
-treated 
e that 
creased 
ff
st 20,
 no 
ssant) 
y animals 
effect of 
posure
 
gans in 
S
ight), it is 
gu
n in male 
oscopic
ere
O
OS and 
y in
3M Co
gans w
y to chronic 
gniz
ator
sses immune 
Au
 to PF
 an 
l ex
 w
co
n we
-generation 
s see
 potassium 
spective 
ssion of the 
ession of 
ora
y PF
 which wa
ing
rga
alue for PFOS 
1N1) after 
cervical, thora
re
y to what ATSDR 
ans were
ing
ne or
here
mune or
 re
ontrar
1986).     
dies with reg
 b
epidemiolog
labor
nd decreased 
e critical e
 v
y wa
posure
 rat 2
tion 
ated micr
y, the 
ggested b
L
sured in other ke
 
y stu
y in 
OS suppre
y.  
a direct effect on 
addition, PF
vel
ights a
ecaus
ctivit
y immu
rted suppr
contrar
-dura
al cord (
In 
y as su
we
 demonstrat
), 
ic
ymphoid o
ell a
rtalit
L
or these im
ts.  
as
imar
 and evalu
ce of 
  While ATSDR concluded 
essed in mice
ell activit
icit
gan 
 POD b
as not mea
y immune org
ported that ex
ctious disease,
 
y mo
year period.  T
l and Mihatsch 
.  
 chron
n compared with
ata.
pidemiolog
d in the human 
IgM.  While supp
y and l
y w
 also repo
eted 
OS MR
 absen
l d
ed.  Collecti
d for
y treatment contain
ymus)
a 2-
yffe
s suppr
a virus A/PR/8/34 (H
s in the ra
(R
ica
sure
, not 
phoid or
  ATSDR selected a
 They
2009) re
l animal studies where administere
y overt tox
m
ond to infe
unded b
t scientific evidence to support the c
ed the
se
dietar
esentative pr
 above), it is important to re
ture to derive the MR
(mesenteric), spin
log
ps.
end of 
ure
s in bod
n-neoplastic) f
ed to controls, which is c
ats 
human e
mea
e wa
s immune c
ar
ymphatic NK c
ll activit
pr
, and th
yclosporin (a known immunosuppre
era
al. (
sp
ly interpr

pos
pu
 c
spon
 
erum. 
 influenz
ssion in mice
ile (for PF
s o
the 
 
y, re
row
OS in diet whe
onstrat
as
y in r
f-dep
38
espons
y and ly
NK ce
ge et 
as confo
ted that the primar
pidemio
udies do not support that PF
clusive
y.  
amined following
year
ry re
eduction
ected or enhanc
-o
ist at 
al compar
creased l
ru
y w
l Prof
on
astic or no
y discussion
icit
eloping) 
ica
r 2 
ymph node 
y such 
cinations, as 
nimals to re
e is no robus
, l
opl
e it dem
y IgM r
ymus, or s
y Gu
1 mice to
ther
s not ex
afte
icit
In this stud
y (i.e., r
aus
ed mortalit
 consistent with 
eased bod
animal st
y b
atholog
re
e mediated in part b
y of a
icolog
 p
s (ne
ent surviv
icit
or the point
eported in
n, th
6C3F
d potassium PF
s in human e
we
demiolog
y IgG memo
est that PFOS impair
y b
s either not aff
8) r
plee
e stud
ver, the stud
abilit
s cannot be c
t Tox
”, it should be no
y in rats 
012a).  
ne marrow
num with bone mar
nding
 fe
with chronic PFOS ex
 perc
ding
 epi
dar
ma
els, decr
y.  The 
5a) f
emales; however, 
ale B
n increas
tions and 
with immune suppre
ction wa
ll
ts
ents 
sponse to vac
y the primar
wa
ra
ee

ations in pups should be considere
e based on (dev
ced 
em
ans 
gher
f overt tox
f f
ant fi
absence of overt tox
al. (200
ch as s
 hi
entr
IgG.  Th
du
copica
 et al. 2
ed veterinary
sulted i
et wh
ellularit
e o
male 
s in rod
OS.  Howe
ff
y a secon
y PFOS was demonstrated in sev
ns o
spons
erum lev
et al. 200
hese studie
ur with bo
nific
 fe
ssion-mediated tox
y re
ms et 
ans su
m
y, t
-44 of the draf
Immune fun
; spleen; ster
fe
certifi
ry re
y in the 
 to PF
y animal studies
utenho
y sig
gh doses which 
OS conc
y ATSDR wer
1 mice but not f
esistanc
OS is associated 
e A
ard-
ts. This is important bec
uebker 
ra
y immune org
cine responses (s
sponse b
entioned studies sugg
L
re
y hi
em
y (
6C3F
posure
OS on immune func
OS (B
ts had similar or
Peden-Ada
B
immune org
did not evaluate 
associated with re
on the r
ex
 
Collectivel
PF
that PF
 
On pag
stated that “
laborator
evaluated micros
PF
collected (
and lumbar)
by a bo
statisticall
either male or
group 
primar
ra
immunosuppre
that ultimatel
 
Inconclusive immune fin
that such finding
to vac
the humoral immune re
studies, is mainl
IgM 
also induced sig
difficult to interpr
the seconda
afor
at ver
corticosterone s
lymphoid tissue c
cell activit
Serum PF
chosen b
stud
 
 
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e more 
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 those 
n initial and 
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ertaint
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etric 
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al. wer
cy.  A
erage a
te declin
amined developmental 
s discuss
ed to
and 
posure
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pora
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am.  Over
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l ex
te lower than
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enin
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.  F
l tenden
e (A
ge with growt
ntroduces unc
ra
-life
ails to take into account sev
tes.  Th
iltrati
n vs. the 
tion ra
ye op
as the basis fo
y be dif
-life
et al. (2011), slo
y f
ent
curv
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nd of stud
pup interna
estimate that wa
ir data, Olsen et 
cause ATSDR chos
 
 filtra
yed e
 used 
OS, ATSDR used the 
ell et al. had a 
 estima
e of c
r than the arithmetic mea
entration would be bette
ell et al. (ave
la
are
PF
g than in the d
h would reduce the unc
imination half-life
art
ever, this line of r
L
ees (e
als and cannot be us
er-the-
gh model i
 model that incor
and 
aster half
e Olsen et al. had 
minal half
B
 studies that followed individu
 al. stud
ean 
asur
art
ch 
hic
y by Seals 
w
athe
conc
erular
B
glomerular f
sprin
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entration ma
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lsen et
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all
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y AT
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eported in 
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en b
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hen 
rom the O
y chose the arithmetic mea
sting
ysiolog
n estimate of fetal 
years 
n f
rds the ATSDR MR
y comp
d in offsprin
. Use of th
r w
ontribution to the ter
 use the ge
 the rig
follow-up of 5 
y the
ations in Table 
 on the ge
ud
ad an av
ages as r

y chos
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ure
lasma concent
or pups.  This model also does not account fo
y differe
he
vide a
arithmetic mea
ed that based on a stud

upwa
e h
ger 
bl
y calculation of the AUC) may
f a
ration as a surr
over other studies becaus
of 2.3 
iven
yses of populations.   Ho
geometric mean fo
ased pup bod
as
rameterized for
posure

rag
al
).  The average estimated 
re
cern
 me
tuses 
rmacokinetics.  The
roba
ex
ent
ave
r.  G
ision is intere
tions in Table A2.  A median 
youn
y-state p
 p
ak 
ra
– 55
e dec
r pha
y biased 
inal concentr
om 
OA, the stud
tion as to wh
fr
y o
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al conc
 
ent
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y would hav
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ation as the offspring
e to use the 
bl
ations in fe
ation are
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ad a follow-up 
ange 15 
l animals.  Use o
plana
y.  This dec
OS, which is pa
tments would pro
e r
ysiolog
 deriv
 value.  
vora
L
L
y to constitute a larger c
tion of the arithmetic mea
The ATSDR chose not to
Olsen et al. pape
fa
no ex
stud
initial and f
final conc
a half-life
 
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who likel
calculated 
(ag
shown in the table below
ndpoints wer
 PF
posure
om Olsen et al. (2007
i et al. h
ctors that likel
 
 
(e
Similar to PF
endpoints that were
to estimate stead
for
concentr
in ph
concentr
ex
be a period o
MR
materna
compar
of the matern
MR
 HED for PFOS will be hig
ATSDR chose to use the 
fr
and ATSDR was con
likel
Olsen et al. had an 
L
not cross-sectional an
selec
fa
points. 
 
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SDR did not 
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onsidera
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e populations’ 
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nd, althoug
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mption that 

car
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posure to P
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ere ex
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estimates 
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It is not 
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r f
y ex
rove
estimates were
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all
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stimates of 
youn
e G
posure
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cross
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ave biase
lear
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as the add
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action of the p
y ceas
her e
y equ
y the 
-up period consid
 1 stud
 w
 other perf
filtration of perf
nal tubular secr
nd fr
e hig
iall
ow
course
would have biased 
reased ex
l. 2012.  On the other ha
on of GAC filters in thes
 al. 2007).  How
dy: 1) the 
Model
here
ation of PF
re
would h
and
 Olsen et al., ma
oll
tr
ntrations < 15 ng
ilbron et al. 1991 Pedi
perfluorosulfona
; thus, the decision b
stu
d.   
en
unbou
This 
s a lower c
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OA 
g the 
catur and Cottag
-up times, the primar
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we
 
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-lives are likel
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artell et a
.  
posure
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iltration, 
).  Thus, th

-up time of
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ollow
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etire
ater
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ecause
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te (
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103 
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127 
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75 
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oroc
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s, and not the shorter f
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ted in Olsen et al. eliminating
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had shorter f
drinking
suppl
g-te
 follow-up time (Olsen et
ons of the Seals et al. 
lu
) is a product of the 
er stud
of the follow
entering

nitial concentrations; 2) t
er 
Estimated GF
sul
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re
y as
Seals et al stud
gest
posure
filtration ra
y ha
es 
 
y 50% 
i et al. 
L
S.
 
 
an et al. 2
e subject
ations.
elimination half
ral population leve
ests the 
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nge
ears
followed lon
ased on the i
rance of perf
es in the oth
imatel
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–29 
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cesses involving 
 follow-up times for two r
Individual subjects wer
fluorosulfonates
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40
50
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inities to bind plasma proteins, g
glomerular 
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Ind
Age
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ger ag
6-12 months 
2-12 y
12-19 months 
ell et al. and 
cted municipal wat
y that had the lon
ysis.  
absorption (H
nd per
 the serum 
art
OS, and PFHx
Renal clea
three pro
re
their aff
(a
and the 
youn
had approx
differe
studies.  Thus, the serum elimination half
in MR
 
The Olsen et al. stud
possibilit
plants.  
truncating
for
ambient gene
estimates substantiall
B
populations was throug
affe
PF
subjects are 
stud
mention the main limitati
anal
calculated b
there wa
district; and 3) subjects with initial PF
 
 
  
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ations in 
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her th
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h baseline 
tion about 
tween 12 
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te used, 
entrations 

er 
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L
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3M Co
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ls et al.  
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he GF
here
s, bas
 
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Au
udies, are
ction of the 
e 65 
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icient
y hig
TSDR using
lsen et al. 
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pendix
-life
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rum 
% MR
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nce ra
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 concentr
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mount of 
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rom O
r PF
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erum conc
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al., and Sea
ent.  MRL
ns f
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L
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ed.
e and peopl
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06 
06 
, but on the other
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eds to a
i et 
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rmacokin
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nal plasma
 
y n
al population 
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stimated b
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could be 12 to 38%
ls. 
fore not justified to use the 
es, in part, because t
M
rivation
ased pha
tire
youn
 
 de
y animals and s
he gener
Thus, calculation of se
fe 
 
 
 
 and 
 
L
y b
d that of ATSDR’s considera
e PODs from the same st

 serum elimination half
tell et al., 
e overe
s definitel
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 that will be, in part, a fun
re
ation, not just the upper tail, which can 
nputs in their calculations.
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ll
tor
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ge.  
centration
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g individuals with suff
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yzin
restimations of the MR
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ated
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m
 
 
 
y ATSDR.
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41
rted in Bar
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ysiolo
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).  This state
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nsitivit
ents and huma
rox
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utenhoff
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PK model 
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ages, sex
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 rod
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ported in the literature
Rs that occu
 be 
flect this 
ean
L
obabilit
t would not be at ambient leve
the MR
below using
S that are
erum elimination 
re
n studied.  Given the fact that ATSDR has used developmental 
ODs for
 estimate based solel
y lower than adults of muc
y app
ld reflect the 
OS can differ substantially
GF
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etic Mean 
F
ft profile
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ype of se

cause HED 
en 
dl
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er 
etric m
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ose model used b
that “Althoug
ped for
 administere
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th the PB
datasets 
tive s
-life
tud
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esult in a r
arithm
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gh model wa
additional considera
arke
sent onl
e S
eom
L
evelo
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n half
 m
ate. (
bove, be

follow-up), 
epre
renc
etween
ge 5 of
ated wi
fe
m
y stated 
et al. 20
imi
entrations tha
bove 
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chmark d
OS, and PFHx
alculations to take
Re
. pa
 Esti
elopmental 
th of 
gly, the percent of the MR
 c
cf
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om the populatio
R
D
lsen et al. 2007) 
h ben
PK model to pre
plicitl
y associ
culated in the table 
S
 O
sulting
T
m
urrent provisional MR
h the Wambau
uebker 
OA conc
lsen et al. 2007 (g
L
cal
OA, PF
cordin
Rs fr
i et al. 2018 
*A
fro
O
L
which max
PF
Given the a
the leng
re
PF
Ac
their most conserva
2007) would then r
and 38 percent.  This t
the MR
estimates that have be
GF
studies to calculate the P
arithmetic mea
older adults are
age or older r
estimated half-lives shou
be a reflection of low
elimination half-lives may
part on half-lives, should
As illustrated a
the re
the c
 
ambaug
 comparisons b
ct in its summary
ts from dev
 
5.
 
W
animal PB
has also ex
models have been d
for
in humans” (
uncertaint
fa
 
Althoug
ra
2005a; 
 
  
 
L.
 

 
 
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ents
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for
for
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y be 
m
 2

m
g this 
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g on this 
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ge et al. 
 studies:  
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 dosimetric 
OS MR
gu
lyin
ctor of 3 
3M Co
us monke
s not 
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icokinetic 
ctor of 3 
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ate; 3M does 
ulation (see 
based on 
derive human 
ing
uman 
rge
fa
ustment for 
e developed 
umans (rathe
 potentiall
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ment, is not 
itative 
ects with 
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lowing
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or PF
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ce or rats.  As 
en re
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ol
al. 2015 (Wistar 
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emale c
), Wang
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FOS
 that an additional factor o
lopmental e
actor of 14,400 
SDR could hav
 f
y animal
 based on th
alez and Shah, 2008; Klaunig
d in the larg
T
 to the uncertainty
 
nd f
t al. 2008 (
that adjusting
tor
L
y less sensitive to the pleiotrophic 
y conser
1 mice
 
y ATSDR for
α, CAR/PXR activation compared 
hia e
bedde
y. If A
e b
bl
ment of 43,000 whe
AR
umans.  Thus, the ver
m
fe stage diff
li
mice.  ATSDR states that they
tive and not supported
ge dosimetri
ance of P
o account fo
ified and unnec
ra
P
14; Gonz
oss et al., 2010), the qual
rodent deve
ensates for th
overl
lit
r human variabil

 and 2011 (C57BL
6C3F
 pharmacokinetics 
e studies the
TSDR 
g labora
y e
fo
ntributing
dpoint.   
or male a
d in strains that the model wa
y could not model the f
B
 values.
rva
 chos
presented a
for 
in
y is 
d f
and Ya
L
y just
ariabi
), 
or of 3 t
ch as P
t al., 20
nce of 
y comp
 
 conside
nces in
 with A
rum clear
-life
this re
ance to h
42
y conse
y in us
y is alread
 factor co
emale CD
e conducte
ere
ctor of 10 
al. 2008 (
y in MR
rl
rees
sents an adjust
ntificall
ake, 2009;  R
ameterize
g et al 2009
/6 mice
L
gnific
elopmental en
on
 ove
rtaint
ional fact
dequatel
at accounted 
ey state that the
epre
Elcombe e
l si
ms et 
ins, this limits th
rtaint
eceptors su
 dev
), D
ica
ct, r
not scie
 human variabilit
r a
y, th
, 3M does not agree with ATSDR
 has derived its proposed MR
 
-Ada
human, in addition to lar
elimination half
above).  While 
e is 
R
lear r
2014; 
l., 2012;  
is uncertaint
 for
model th
odel), this fa
 fo
While 3M ag
an and rodent se
f an addit
ecause humans are
uestion the releva
nts and humans.  ATSDR should not appl
hich is another
 and male and f
he studies wer
ficall
den
2011 (C57BL
ex or strain diff
SDR were
ertain stra
rther unce
T
-to-
ation
B
 et a
erum 
renc
rode
ence.  
“10”
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nt m
y c
y A
fe
e), Pe
et al. 
es fu
 
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y, ATSD
gs into q
rode
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FOS model was par
.  Speci
 animal
L
ls.  This, in fa
OS and biolog
ate PBPK 
call
h P
y justified.  
etween hum
enosensor nuc
etween 
ale SD rats,
1 mic
ed to account for unce
actors b
g on 
 
m
3” for
 to PF
y f
’s MR
y include:
nce b
ynamic dif
ree with the s
 
nces brin
nce b
al. 2013 (C57BL/6 mice
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elyin
ambaug
6C3F
icokinetic discussion 
is need
cts of x
posure leve
o account. The use o
icod
posure
 
 
duced.  
meterized for
meterized for
g et 
ertaint
Use of “
scientificall
differe
not ag
tox
ATSDR
“3” 
ex
int
tox
More
developmental data.  
effe
to rodents (Corton et al., 
et al., 2003;  Klaunig
differe
ex
adjustment of 14,400 more than a
differe
animal to human when th
the dosimetric differ
Additional factor of 
ATSDR included a
more appropri
than r
re
on
ts), Onishchenko 
 
 
para
model to estimate an MRL
 
The W
male and fe
model some data sets as t
para
L
2009 (B
ra
provides no evidence of s
ATSDR modeled onl
model and introduc
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data.  The
1.
2.
 
M.
 
 

 
 
8
1
ell 
  
ents
0
gh 


m
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act, 
en 

 
m
y hi
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stud
and 
ated. 
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st 20,
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t of 
gu
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3M Co
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Au
discussed 
ffect
atter of
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hoff et al. 
gher than the 
mental 
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y a
sse
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ealth Advisor
y.  As 
ctivities at ver
uten
re
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evelop
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y is incl
related to MOA 
xicit
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e critical st
gans.  As a m
OS suppre
time Water H
ffects indirectl
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et or
y factor of “10
 
ed the potential impac
ies exist 
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ife
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int
L
es immune c
doses
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ertaint
ells as
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onic stud
eproductive and d
W
ns on immunoto
ystemic e
ud
g the targ
y ATSDR.
 of the 
cer
e s
tion r
y in PFOS
an uncerta
er, unc
 al. 2005) was the sam
tion
 support the association between PFOS 
 
 con
OS influenc
year chr
do not support that PF
43
moved b
for
ystem bein
y and 
genera
er et
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icit
ming of exposure that are not yet clearly d
10” 
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uebk
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rm subchronic st
chronic stud
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ystem; howev
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esponded at a lower dose than the females. Be
posure
and as such, thes
) as well
OS (
use of “
ex
als 
e immune s
-year 
animal studies 
ater for
f overt tox
d should be re
ed that the 2-
W
.  EPA’s conclusion on the immunotoxicit
on, and/or
y th
an
 to PF
y anim
al. 2002
ence o
tent that 
fice of 
ex
tor
addition, long-te
posure
y unjustified 
In 
y justified 
It should be not
Both human and animal studies have demonstrat
y in the abs
OS issued in 2016

PFOS on the immune
the level, durati
The animal immunotoxicity studies
effects on the response to
natural killer cell populations; however, the 
across studies for comparable endpoints. 
evaluated, the males r
uncertainties, EPA did not quantitatively assess this endpoint.
sponses.  
 PF
Scientificall
earlier, to the 
doses in labora
re
al. 2017; Seacat et 
2012a) did not identif
the survival rates in the 2
concurrent control.  The 
activit
scientificall
[NOTE:  
in rats with ex
by U.S. EPA Of
for
 
 
 
3.
 
 
 
 

 
 
 
 


ork 
ed 

eeks 
hus, 
rived 
es of 
ell 
reas
 
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ts 
–6 w
nt. T
ust 20, 2018
rtainty 
y scientifi
ment, is 
y justified 
3M Comments
. Inc
 b
Aug
 
llicular c
in vitro
S MRL
equate 
rman and Y
nce to humans 
s. 
ale rats 
er effec
eases in live
ssessme
ratory animals 
ved in the males at 
diet for 4
day for thyroid 
 inconsistent with 
Hx
ed 
y ad
ed on 
are
PF
 b
ork 2003)
yroid fo
c TK adjust

MRL 
ion 2.9 for a discussion of 
 (th
se limitations, especiall
ata 
ct
y d
vels, and incr
f-life 
yroid homeostasis in rodents
databa
 in adult male rats administered 
see Se
xposure
th
ge dosimetri
S e
ects and their releva
ster hal
tive and not supported
tific data.  Th
oberman and Y
eride le
ant for human risk a
ns on 
Hx
eff
rva
y factors is not scientificall
g fa
DR was not optimiz
cer
epidemiolog
ion oral MRL of 2x10-5 mg/kg/day was 
 damage
enhoff et al. 2009a; Hobe
umans with dosimetric adjustments and 10 
ia were observed in F0 m
tal toxicity study, increased incidenc
a; H
rtrophy were also obser
effects were reported. Liv
mg/kg/day PFHxS in the 
criteria (
relev
 
tive and not supported

S impacts 
cell
 triglyc

yroid 
 con
ertaint
(But
en
rplas
tal 
Hx
y ATS
y conse
ensitive than rodents bas

y and 
y the scien
erva
 to 6 
duration studies was 3 mg/kg/
 
rl
for
44 
ents on PFHxS 
2012
onsiderin
icit
cific th
ons
 ove
 less s
ace 2009)
10” 
evelopm
llular hype
n c
icolog
elopmen
y c
all
l tox
 exposed
-spe
y ATSDR with PF
est that PF
nt
whe
overl
her 
human, in addition to lar
mans are
nd W
use of “
genera
t: Two intermediate-duration studies in labo
ere not considere
ded b
o sugg
SDR were
e rode
ose model used b
T
-to-
application of unc
 
(Butenhoff et al. 2009
own in humans
hig
lu
 is not supported b
ional intermediate-durat
 on thyroid follicular 
olation from animals to h
d a modifying factor of 10 for database limitation
ng the Hall et al. (
jork a
ects w
ied in intermediate-
ce t
y A
Its 
B
y and 
L
ed
ved in mice
gniz
A-49)
 an
co
 animal
ecause hu
xicit
ge.  
 MR
 assessment 
). Usi
ata (
ect conc
S will be 
chmark d
y unjustified 
S
Detailed Comm
actors b
 
e liver eff
3” for
tive b
yte d
3 for extrap
≥3 mg/kg/day 
 
as been not sh
h ben
y f
 
ll interpretation on both tox
ealth risk
 PFHxS for a minimum of 42 days 
MRL is based on a HED NOAEL of 0.0047 mg/kg/day and a total unce
ariability)
, th
OAEL identif
ra
es in serum lipids, increases in hepatic
ge) h
onclusive eviden
ent knowled
osition (page 
en identified for PFHxS. In a d
 were also obser
ertaint
 
Use of “
conserva
hepatoc
Scientificall
on immunoto
. The 
 
tion of the Critical Effec
nistered 
riteria)
ambaug
 
 
ects.
 The critical eff
dama
No c
ATSDR should re
W
Unc
data
1.
2.
 
 
 HED for PFHx
 
 
MRL Summary: A provis
derived for PFHxS bas
via gavage
2003)
factor of 30 (
for human v
 
Selec
have be
thyroid follicular cells hypertrophy, and hype
admi
liver weight and centrilobular hepatoce
≥3 mg/kg/day. No reproductive or dev
(decreas
weight)
(Bijland et al. 2011
the c
the lowest L
eff
A.
B.
C.
D.
E.
F.
 the human-h
 
ATSDR P
 
 
3M Conclusion
 
 
ATSDR’s ove
the most curr
and the proposed PFHx
for
scientific foundation.
 
 

 
 


   
 
 
y, 
gs 
 at 
ed 
S
ys o
Hx
gist.





 
  
.  
10
10
ion, 
yroid 
ce 
it is 
y) 
pre
tion as to 
f the
” bas
FHx
ddit
ust 20, 2018
 P
 42 da
 
 
y o
 cell 
ge findin
S MRL
ased 
n “th
fferen
ons in the 




3M Comments
3.0
10
In a
plana
y, both 
y patholo
g/kg/da
ects based on 
Aug
in rats 
Hx
pithelium 
m
d in that stud
y.  
 in an
s (
eff
licular
e ex
xS 
dama
PF
“incre
tassium
iated with PF
functi
ar e
ats after
tinct di
ell number), 
stud
stud
ure
nt
H
ll damage
se
 
 
icult to inter
ce
ve 




es not mea
1.0
10
ginal 
ertai
lated 
xS Do
re
 
riptor 
ri
yroid fol
 plausibl
” do
es of po
H
F

 
 
roducti
ere is a dis
reases in c
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e not meas
g or fertility
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er a
y with PF
m
0.3
10
yroid-
follicular cell 
y dos
group male r
y the o
ional unc
The desc
rplasia
yroid follicul
ail

y, th
he rep
yroid homeostasis in rodents.
yperplasia assoc
 its derivation of 
at the time of the 
y b
 
posure
yroid 
yroid follicular 
otassiu
ct t
e of th
y dos
gor
P
 
y/hype

10




yroid h
ctice 
cts on matin
 risk assessment.
s “th
(control)
o support th
OA ex
he th
asis for
ph
eceived d
g/da
yperplasia (inc
th
ra
fe
e cate
nes levels wer
hormone status was diff
ly affe
elopmental stud
 wa
/k
al. (2009a).  
cidenc
al
S impacts th
. h
 the b
tual 
 
 
ed ef
nce t
 et 
rats r
orphometricall
ard p
al 
 
yroid 
ation added addit
enti
45 
Hx
as
ff
hypertro
nce
lat
ere 
om
e) vs
as ac
m
tal 
 
-re
nt to human
and dev
 w
 stand
rted as on
Mild
oderate
To
all th
goriz
g evide
 
Mini
M
Incide
yroid hormo
utenho
y wh
e hist
re
po
uated
 th
cate
eleva
lude that there
ud
y, increased in
 the
e re
y ATSDR with PF
est that PF
ation.
y B
pithelium 
s eval
ia 
ical 
on could pot
et
g/da
es in cell siz
ther
rat
s no stron
sugg
productive 
/k
s noted in the 10 mg
as
og

 no treatment
ded b
own in humans.  ATSDR needs to off

 re
ATSDR concluded that t
ect and used that 
erpr
In that st
w).  Becaus
cre
use, following
asia wer
ale 
hors, the over
perplas
stol
lu
ects are r
R to conc
ported b
mg
a wa
 m
um
ysfuncti
ere
e wa
ce t
a), 
om a
/hy
f F0
pic  
heli
it
y aut
 w
fr
ect int
TSD
gs re
ge”.  
y (in
mine whe
 o
 
emic circulating
ned hi

ts beca
yperpl
land d
ber
ats, ther
ect conc
orr
r A
yroid follicular e
yst
lar ep
es these eff
e table belo
m
Microsco
pertrophy
yet there
as been not sh
ct fo
Nu
finding
 et al. 2009
y findin
ell dama
y/hyperplasi
y and h
ff
ypertroph
ollicu
y the stud
e combi
yroid g
 in the ra
(f
-treated r
y.   
ge) h
ent (se
hyroid hy
S
mments (Details): 
onclusive eviden
rtroph
rtroph
y it believ
 
T
ased on 
utenho
posure
Hx
 The critical eff
dama
wh
 
No c
B
(B
in rats was the critical eff
This is not the c
 
It is incorre
on the stud
incidence of th
follicular c
either 0, 0.3, 1, 3, or 10 
hype
treatm
between h
impossible to deter
ex
hype
 
 
 
 
 
 
 
 
 
 
 
Given that the s
as stated b
because th
because th
animals, but 
PF
this stud
 
 
 
 
 
 
3M Co
 
A.
B.
 

 
 
-
-

 
 
lf
-

DP
TSH 
In 
yroid 
tion is 
.  
ed in 
 
It has 
ll will
al. (2018) 
d at 
ts 
een 
er 
ust 20, 2018
yroid 
sed on 
ect on 
at
y not
ypertroph
era
g-d 
llular
t al. 2011; 
 et 
ect of 
 protein is 
3M Comments
ate of th
observa
ase in mild to 
/k
mpac
ng
Aug
on to see 
ocumented in 
S (ba
S i
y betw
hyroid hormon
tation when 
hy) ov
sed hepatic U
er r
m
this 
ailed discussion 
ncre
 mg
pen 1997).  
ijland e
re
Hx
s no eff
id hormones are
m albumin, which 
e in plasma half
o a gre
ellular h
ll-d
abolism is capable 
d i
epatoce
y Chang
re no eff
nce to humans
yroid hormone ha
yperplastic lesions 
ypertroph
 h
 (B
yro
y bindi
eru
nc
 h
y increased th
rtrop
S
 we
ysiolog
a th
re
r met
r turnov
gain, 
erve
A
g th
init
ys) (Ca
nd h
ences in t
epatoc
ype
ith increa
Hx
icokinetics between 
ere
ghe
ce it is com
ce) interp
y.  
ted the activation of 
 
ported b
e ph
 diffe
ellular
 (w
re
y, there wa
y, th
est that PFHx
h-aff
ely on s

posed to PF
gg
– 9 da
ased h
, the obs
y r
eased live
y hen
re
centrilobular
oteins attribute t
rtrophic a
fo
hepatoc
yte mass (h
currentl
yperplasia in the 10
y wa
in, it reflec
posed to PF
ype
-of-eviden
not in humans (see det
ects and their releva
nd this hig
iers.  The plasm
ier pr
 h
ht
en accompanied b
ase in 
In that stud
en 1997).  This is a we
patoc
The incr
sate for the hi
d activit
There
t importantl
humans, these
lar to 
apid turnover
hy con
ut 
n ex
 et al. 2018).  
2 stud
dence to su
eff
hyroid hormon
rimates, circulatin
) a
ents mainl
 humans (5 
carr
are distinct differ
eig
.  
 r
y and h
.  Aga
ed.  
 pups when serum TSH was measure
G
e carr
is oft
glan
S
1
loping
(Cap
d he
for

roph
Hx
y to 
difference in serum tox
yroid 
ist in t
46 
in rodents, incre
lism
; Chang
e status in mice ex
).  Rod
nts and 
eful (w
yroi
ypertrop
 is no evi
) than in
init
 
).
crease
ypert
 in rats whe
re
es ex
car
rode
e that 
rplasia 
y, to compen
 to PF
te OECD 42
s not alter
 aff
e that there 
receptors 
cific th
nc

e in th
eGroot 1991).  
ara
wa
, the
 globulin (TB
yroid hormon
en 
gniz
yroid h
non in rodents b
ell as the 
t al. 1995
gniz
y) 
re
-spe
ere
nd non-human p
co
y/hype
posure
allace 2009
 mice or in the F
fo
nt
s th
– 24 hours
co
ll liver metabo
yroid hormone 
pithelial h
yroid hormon
0
y as w
, a sep
12 
Groot 1991
troph
 due to the in
g th
Consequentl
n increas
an and D
ar e
nt
ice
at th
d binding
heimer e
G, a
hat, betwe
 De
sk assessment. 
atic nuclea
vera
hy and th
phenome
as consistent with the incre
dult F
There
e rode
ficant diff
human a
B
er (
t not humans) in deve
odents require 
en
es and binding
yper
).  
ceptor activation
ni
In 
and
se
ertai
 their development; and, mos
y.  
 
gniz
yroi
ated with ex
re
jork and W
an T
s in r

ated t
an 
irculatin
B
will be a
co
y short
nts (bu
ypertrop
-known 
e sig
lea
y th
 ar
y to th
ansfera
ell
n 1997; Curr
 this unc
yroid histopatholog
init
rode
 to human ri
pithelial h
yroid follicul
y associ
tivation of hep
g the c
y w
yl tr
llular h
group males w
ing
yroid hormon
ry, ATSDR should re
ats and female m
ll demonstr
y of 
niz
y demonstrated th
S on TSH in the a
yroid finding
nts and it is primarily
rtroph
nts and humans.  
addition, ATSDR should re
 is considerabl
sult in an increase in o
ulations between rodents and humans; and simi
jork et al. 2011; 
male r
Hx
yroid histopatholog
yroid homeostasis.
ts, th
trapolating
 
 
In 
due to ac
follicular e
rode
re
of directin
glucuron
hormones, there 
hepatoce
particularl
below) (Cape
moderate th
treatment 
hype
xenosensor nuc
B
 
Recog
fe
and the
levels and th
PF
multiple times during
th
th
 
ATSDR should re
addition, there
rode
bound primaril
absent in rodents (Opp
has lower aff
life
been we
lives of th
sensitivit
(Capen 1997; Curr
 
In summa
reg
ra
ex
 
C.
 
 


11
-10-
 
 
 

re

 
nd 
era
ge as 
ylate 
y in 
OA 
and 
years) 
an;5(1):5-
reas 
year a
ollowing
n in this 
sented b
i et al. 
pdf 
var
ylates 
arbox
ust 20, 2018
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L
pre
= 66 
3M Comments
_b.
y ATSDR for 
ed in the 
SDR provided 
mea
eport median 
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es with a
ly a sum of 
enal tubular 
box
roc
Aug
 calculations, 
r kinetics is 
e more 
ge 
and 
L
ollow up time 
T
n initial 
r re
gfr
ge
ylates 
luo
R
we
car
-up of a 
g b
de the f
e to r
e: 
ger f
etric 
erf
e M
xample, whe
rage a
atr Nephrol. J
s discuss
al. wer
cy.  A
te declin
ites/default/files/docs/11
arbox
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a lon
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Sourc
etion, and r
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tes) is lar
te lower than
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rag
luo
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l tenden
y.or
ails to take into account sev
ra
f-life
iltration ra
et al. (2011), slo
-life
n vs. the 
tion ra
action of the p

y f
ent
1813_abe_patbro_
nd of stud
ell et al. had a 
estimate that wa
ir data, Olsen et 
cause ATSDR chos
 
 filtra
 other perf
filtration of perf
nd fr
ster hal
 estimates.  Th
e of c
r than the arithmetic mea
entration would be bette
ell et al. (ave
nal tubular secr
imination half-life
re
e Olsen et al. had 
art
 studies that followed individuals and we
ever, this line of r
 al. stud
L
ean 
ees (e
art
and
ilbron et al. 1991 Pedi
perfluorosulfona
g fa
y by Seal
minal half
B
w
asur
the
conc
erular
B
glomerular f
unbou
ss of the
rious) be
 ra
He
OA 
rum el
 me
https://www.kidne
lsen et
 PF
lomerular 
47 
years, 
g those
wne
r a
glom
iltration, 
n se
nd cu

onsiderin
ometric m
2
 (a
ometric mean.  
rised 26 retir

ylates (and 
eported in 
n c
amon
ht ske
erage 
ecause
rom the O
arbox
whe
sting
years 
y chose the arithmetic mea
n f
rds the ATSDR MR
y comp
77 
103 
127 
127 
116 
107 
99 
93 
85 
75 
lomerular f
 the rig
012). B
her 
ontribution to the ter
 use the ge
follow-up of 5 
oroc
y the
ations in Table A2
 on the ge
ud
ad an av
ages as r

lu
) is a product of the 
hig
arithmetic mea
over other studies becaus
ed that based on a stud

of 2.3 
upwa
iven
e h
ger 
low
Estimated GF
tes

(ml/min/1.73 m
rag
yses of populations.   Ho
geometric mean fo
cern
).  The average estimated 
 larger c
al
ave
r.  G
ision is intere
tions in Table A2.  A median 
youn
 
 
an et al. 2
ra
– 55
S will be 
y biased 
om 
tion as to wh
inal concentr
nge
ent
 estimate based
fr
ears
rance of perf
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cesses involving g
 
inities to bind plasma proteins, g
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30
40
50
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tion of the arithmetic mea
vora
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nd per
The ATSDR chose not to
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initial and f
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shown in the table be
 
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ATSDR chose to use the 
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likel
Olsen et al. had an 
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points. 
 
1.
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tion 
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ater 
 
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y that 
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years o
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ust 20, 2018
upwa
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cluded 
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tion about 
ly, and 
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ls et al.  
3M Comments
 stud
onsidera
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likel
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artell et a
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n studied.  Given the fact that ATSDR has used developmental 
ODs for
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nitial concentrations; 2) t
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additional considera
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Individual subjects wer
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glomerular 
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gly, the percent of the MR
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culated in the table 
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cted municipal wat
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Rs fr
art
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OA conc
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OA, PF
cordin
and the 
youn
had approx
differe
studies.  Thus, the serum elimination half
in MR
 
The Olsen et al. stud
possibilit
plants.  
truncating
for
ambient gene
estimates substantiall
B
populations was throug
affe
PF
subjects are 
stud
mention the main limitati
anal
calculated b
there wa
district; and 3) subjects with initial
which max
PF
Given the a
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PF
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and 38 percent.  This t
the MR
estimates that have be
GF
studies to calculate the P
arithmetic mea
older adults are
age or older r
estimated half-lives shou
 
 
3.
 
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5.
 

 
 

 
 
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s, based in 
 
A
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call
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tration-depend
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and 
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flect this 
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nami
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lear r
. 2012;  
iolog
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human, in addition to lar
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uestion the releva
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B
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call
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plicitl
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h ben
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nces brin
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sulting
urrent provisional MR
sented a
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m
cts of x
lsen et al. 2007 (g
i e al. 2018 
icokinetic differe
pre
posure
be a reflection of low
elimination half-lives may
part on half-lives, should
 
 
*A
fro
O
L
 
As illustrated a
the re
the c
ertaint
ambaug
Use of “
scientificall
tox
re
additional factor of 
data to derive human 
when takin
rodent-to-human tox
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developmental data.  
effe
to rodents (Corton et al. 
et al. 2003;  Klaunig
differe
ex
ther than on suppo
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ct in its summary
 
 
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comments provided a
ra
animal PB
has also ex
models have been d
for
in humans” (
uncertaint
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data.  The
1.
 
 
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F.
 
 

 
 
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nce 

edded 
 
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y on 
y.  This 
rmation 
nd 
vailable 
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nces in 
icit
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ust 20, 2018
icology
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ts or mice 
3M Comments
additional 
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of lactation, 
rimar
These data 
y justified 
Aug
ady emb
uld have
l tox
oscopic a
re
or the PF
(2009a) a
e p
r the 
OA, the a
acr
ow.  
age differe
a; Chang
oxicit
t al. 
rr
s the conclusion b
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genera
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al t
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t al. 2009
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utenhoff e
trapolation.  ATSDR should not 
icit
y conser
y B
gestation to the end 
y comp
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ctor of 10 
r than PFOS or PF
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S to either
 the histolog
10” is not scientificall
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atel
n this uncertaint
ed that ther
ey tox
man
overl
nodes, or bone
of “
nce.  
variabilit
ccounted for life
munotoxicit
we
utenhoff e
re limited “
FHx
) or
unction, which wa
ns on databa
stat
fe
y k
B
 f
e a
y, ATSDR
dequ
y is 
at a
cer
ginning
ymph 
une
 
actor 
human 
S is 
xicit
elative
y f
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Hx
ed man
r r
50 
ents and hu
for
egards to im
ss
file).  
t al. 2011; 
 that ther
 the be
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ent model), this fa
y.  ATSDR 
eatments of P
ertaint
 
10” 
om
cts on imm
r of
icit
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cto
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ijland e
 on rod
l tox
ymus, spleen, l
between rod
for
r the dosimetric differe
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hts (absolute o
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a fa
riate PBPK model th
ced.  
use of “
ra
lications on PF
S have addre
d dose conditions following
ect in stating
s to the immunoto
ated or
t dams fr
ce of e
 the draft pro
abase unc
y ATSDR.
f 3 
rop
lying
du

Hx
nan
ence 
“10”
re
gene
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epe
peate
S, especiall
reg
cluding
absen
ult dat
e app
re
y be 
 on PF
efa
moved b
 differ
actor o
r than re
y and 
FHx
xaminations (B
djustment of 15,500 more than a
, with regard
for
 mor
the
y unjustifie
ans, in
xicit
ct. 
 
re
 studies to human risk assessment.  Studies b
ge adjustment fo
re
al. (2018), r
, the d
opic e
ys, and, p
re
se on P
 
HxS.
 et 
fo
y another f
, ATSDR included 
y support an 
 
L
 
xisting
rl
ctor of 3 
 42 da
dosimetric a
fa
appl
in the lar
Additional factor of 
MR
developed a
humans (ra
could potentiall
Scientificall
immunoto
databa
is not cor
Albeit the number of
studies (to date)
cholesterol under 
microsc
2018).  ATSDR is incorr
on PF
 
Furthermo
of e
Chang
for
had no effects on the weig
immune org
clea
ATSDR (on Table 2-5 of
 
There
and should be re
 
 
 
2.
3.
 

 
 
 
ed 
.” 



 
 
ghl

t al. 
In 
ampsia 
 
mation 
r more 
 
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OS 
ed 
y would 
ns of 
y). 
. (2009) 
nanc
ust 20, 2018
ow e
 fa
. The 
nd observ
3M Comments
2010; Savitz
ed on 3 
e-ecl
 of 
l infor
is a
 sig
of 
gnostic criteria 
9; Savitz et al. 
elow.  
is was a major 
ositive 
 preg
) a
Aug
nsion / 
arr
actors (which 
posure
 Stud
preced
model wa
eling
te
A and PF
emporalit
et al. 
s bas
eeclampsia in 
rt (D
ension and pre-
g dia
O
eled
wa
tant f
ealth
., t
w onset
a and/or
ans and 
gn, ex
cussed b
 (Stuart et al. 2013).  
which 
i.e
amined
. The 
mod
olan 
 
ypert
 (
 dis
rds
es, historica
estimates undoubtedl
 hyper
 
y ne
ertension/pre-eclampsia
ension and pr
reeclampsia 
y desi
ctional studies of a
ed h
aluated pr
l impor
stionnaire. Th
nd, ex
posure
bstetrici
are
ion (C8 H
addition, Stein et al
-2006, 
years
ypert
y, p
era
 stud
tatus (i.e. PF
In 
edicted (mod
fined b
y proteinuri
y ev
OS (Stein et al. 200
ampsia has a low p
 s
y 5 
OS, evidence 
 et al. 2014).
nanc
rs with differin
OA ex
y-induc
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y sev
ences 
 cross-se
y reg
ecl
rmacokinetic 
, PFOS)
-sectional (N
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er
en pr
gical evidence for an association 
uced h
lle
pre
een 2000
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ere
A
nduced hyp
ss
 PF
zed b
preg
orde
lege
ientific justification for combining
ff
ecificall
or PF
ned via que
posure
w
imatel
we
ated that “our 
y-i
nanc
For
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ffered b
) including
a) w
ex
ecall bias. 
rox
f r
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cy-ind
ek of 
aracteri
ported 
es bet
. Further, the American College 
y 3 sp
-Ohio Va
s obtai
nan
es preg
l o
0.67 bet
 we
rican Col
 
-re
y app
51 
th
me
ft profile
. (2012
 of their 
tcom
(2012a), on the other ha
-2006 and st
regnancy
ystem
gniz
psia (PFO
ften ch
et al. 2013; Starling
co
ypertensive
 (A
alidated against medical reco
ls of PFOA and/
 et al
m
n 6 studies: 4 cro
 et al. 2014).  
y o
an s
comes.   
ampsia wa
ments b
ents in 2005, residential histori
 et al. 
ow 
hile both diseases are
gies
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m
elation of 
suggestive epidemiolo
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hen v
nanc
ists re
y ATSDR, onl
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ecl
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d in 2005
tarling
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iven that self
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is “
d PFOS and pregnanc
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reg
her org
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strate
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nc
4).   These studies di
 ATSDR dra
psia assessment. These di
s g
%
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mea
 Savitz
easure
ure
ents on P

ps after the 20
ulation in the Mid
onmental distribution and pha
as based o
oduced some leve
reeclampsia ou
rall corr
psia
na
posure
m
pre-ecla
 et al. 2012b; Stein et al.
ynecolog
renced b
ported pre
envir
m
OA an
ce w
y intr
cohort (
ement 
l ex
y pop
clam
tion of p
y to anot
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ag
els meas
 et al. 201
(~50-60
articipant
Co
ssed in the
eported p
viden
ase-
hy ATSDR combined preg
re
ed an ove
f these studie
lue 
y p
om 1990 to 2004 in relation to modeled PF
leases, 
 
le health outcome. W
A, e
ar w
gists 2013).  Th
y o
hich likel
OA lev
O
l patholog
rtension that develo
 not add
OA re
osition
ls), w
 the 6 studies refe
re
dictive va
OA, and PFOS serum 
Detailed 
ynecolo
lation to materna
oth Stein et al. (2009) and Savitz
posed communit
ATSDR concluded ther
between serum PF
For PF
et al. 2012a; Savitz
2013) and 1 c
studies (Stein et al. 2009; Da
mments on Pree
It is uncle
into a sing
hype
serious complica
clinica
Obstetricians and G
eclampsia as two distinct
and disease man
G
these two distinct preg
 
Of
re
2012a; Starling
we
assessment and pr
 
B
ex
both studies, self-re
deficienc
pre
Further, stud
leve
obtained self-r
PF
be difficult to establish). 
outcomes fr
based on serum PFOA m
on PF
authors report
serum PF
 
ATSDR P
 
 
3M Co
 
 

 
 
f-

 

S
ft 
 
 
en 
 et 
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rous 
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re
 
ft 
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eported 
els 
posure
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ust 20, 2018
I: 1.1
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ll
y r
 ex
3M Comments
ed a 
n the log
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rof
led in the 
asma PFOA 
ud
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e is 
d PFOS 
ls: 2 cross
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Aug
sion of pa
er, no 
ations we
%C
r levels below 
 to the 75
) and Savitz
dica
ulliparous 
liparous 
clines in 
OA and PF
note that while 
O
nd the null 
 ATSDR dra
erv
s in the dra
th
ft p
l pl
F
lle
er
an
ssociation 
xclu
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ectiv
amined a hi
centr
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e studies and 
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y obs
as, however, 
en enrol
(2009
and PF
); howev
association
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 mate
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R = 1.3, 95
), but not fo
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re
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OA 
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OA con
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s. W
amined the a
e studies
ion. A
 et al. 2014), th
gths) of thes
nificant 
ease 
y stud
It is important to 
-Ohio River Va
eclampsia w
y Stein et al. 
clampsia, the e
 et al. 2014).  This st
l population lev
y ex
OA and PFOS leve
y reg
I: 1.01
I: 1.2
y of 976 wom
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ee
psia and mea
 stren
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lle
mpsia whe
 Pre
tud
psia and PF
%C
er interquartile increase i
no sig
he median (O
%C
the onl
r pr
m
riable. 
he Mid
S
eeclampsia 
012b) and one prosp
 p
ls.
amine the potential association betwe
dies b

non
 not affected b
genera
reover, the inclusion of nul
and PF
 va
y (
id not cite these null finding
 ex
y stud
ere
en pr
 specificall
IH) 
ons (or
 et al. 2012a). This stud
e) or
 2013).
eported 
above t
preecla
reeclam
(P
 et al. 2
-Ohio Va
amined per incr
-cohort s
nd 510 
y. Mo
esented 
52 
en estimated
R = 1.6: 95
ed to cite these findin
ctation (Starling
pr
y equal to t
en p
gest stud
betwe
rtension 
 et al.
R = 1.08, 95
spons
il
case
d PFOA leve
(O
continuous
pe
al. 2014) to
as the onl
ermore, it wa
e stud
y re
ension 
ow
AS levels w
y 3 studies
e (O
d wh
OS levels 
imatel
 hy
arr
tion” (Savitz
sure
 et 
 
y stron
entile 
OS was ex
d PF
all
ed
ypert
y. Furth
th of th
   
ic
association 
sifica
iation for risk of preecla
 increas
 observe
., no dose-re
ein et al. (2009) r
d mea
 perc
 ATSDR fa
tarling
evels was a 
 (2014) w
nc
ases (466 cases a
n important risk factor fo
eng
sure
nancies and la
s between risk of 
es and as a 
approx
009).  
ciation betwe
ic studies with inconsistent finding
2 studies (Stein et al. 2009; Savitz et al. 2012a), a
og
udies, onl
ced h
et al. 2010; Savitz
lysis (D
ulation in the Mid
edge notable limitati
L
Note: The ATSDR d
with PF
an 
induc
th
Child Cohort. Unlike stu
sia
p

ssoc
ere
y-
gain,
y (S
AS l
nd 
reg
g/m
y, St
e 90
egna
g et al.
y is a
e of 
y pop
gs w
ciated 
r a
able str
at mea
 an asso
cy-indu
cknowl
ote: A
 parit
d th
association
ation was 
egnanc
estimates. (
clampsia an
reeclam
ctional ana
entile or when PF
 mid pr
er 100 n
cent stud
 p
dditionall
ee
y asso
(N
eeclampsia c
s a not
yzed in quartil
entr
y Stein et al (2
reeclampsia st
egnan
ed to a
ed some misclas
il
med 
ls above th
.  
 perc
ian Mothe
 on
s of the methodol
th
ampsia and PF
n due to prior p
nificant 
entile.  
sion
nificant positive a
yzed p
nificant findin
ile). A
weg
ls during
n anal
ents on pr
ile fa
ported pr
nificantl
ecl
OA and PFOS levels in this stud
OS conc
ported b
posure
m
ike the p
posed communit
introduc
sig
anal
sig
evaluated in quintiles (i.e
transfor
prof
re
sig
and leve
the 90
perc
 
The most re
pre
Nor
al. (2012a), Starlin
leve
validated pr
women. Since
women wa
women ensure
burde
no sig
whe
PF
PF
re
The evidence for
limited to 3 epidemiolog
important limitations of 
finding
insufficient evidenc
ex
 
L
between pr
sectional studies (Nolan 
some cross-se
ex
prof
 Com
 
3M Conclu
 
3M
 
 

 
 
 
 

-

ater
y, 
en 
ly 

A, 
 w
hile 
OA 
ed 
OS 
 
I: 0.7
l risk 
twe
O
g first 
low 
lyses 
viousl
lysis 
ase. More
rtile 
ust 20, 2018
y with no 
ll finding
A). W
nd PF
y amon
s severe
 and still 
-2006 ma
tation. 
or PF
OA 
3M Comments
W
ervice 
serum PF
t ana
rs reported 
wth” and in 
A a
05
 F
ons were
nificant 
y and no 
ed that 
Aug
 drinking
H
wa
ersus 
 95% C
materna
oth ana
y introduc
on birth 
ced 
ecords be
ciall
 the first 
uintiles (with 
L
gro
O
 lac
esponse). No 
ater s
preceded PFOA 
etric amon
clud
gh v
k of 
posure
espe
ase and per 
and PF
as q
r interqua
IH, it 
autho
l PF
y for
 hi
y-indu
d in 20
sidential
yses. B
IH 
In the firs
associati
cies and
atel
OA m
mation was not cited in 
ciation (
erna
ement, sig
r quintile 3 onl
y for
ased ris
nal
OA ex
s of fetal 
nanc
ant dose-r
ation. As stated pre
re linked with lifetime 
y 1, the 
nan
een P
ed as pe
y PF
ase and 
within the stud
and re
egnant women.
ases of P
ate a
r unit incre
r interquartile incre
est
ch “undoubtedl
we
d mat
eg
nific
 an
nificant 

IH 
y limitations and overa
ater Asso
ained from birth r
ments. Rather, w
In Stud
sure
 nonpr
d betw
s measur
en P
cords 
-up (2008-2011), 
d for
stud
 W
approa
re
mea
ong
Note: this infor
serum measur
ted. The authors con
we
alidated c
sure
wo separ
w
erve
 wa
riables and fo
cant unadjusted OR = 1.2,
 with an incre
onship between modeled 
z et al. 2012a). 
residential address listed 

ata. 
n estimated PF
elated to preg
ascert
riables (pe
births and separ
yzed as pe
erve
r in unit incre
e observe
erved as a prox
birth, or indice
r, that 25% of the births 
multiple pr
cking
y v
ey d
ee
 PFAS levels measure
 va
 all 
OS
epor
such, 
after 
all
 mea
nifi
tw
rm 
anal
ysis of 
 follo
re obs
 obs
ment. (
g all births, sig
as pe

al relati
at 4 months of g
 (Savit
te
=106) 
re
n PF
lts wer
cords in t
ment am
y on the 
re
y 2), birt
A was unr
re
uintiles (with a sig
53 
ittle Ho
posure
HWA) s
anal
en due to 
A was 
ceive
L
L
a nonsig
this modeling 
posure
rted surv
O
 
easu
lyzed 
continuous
as q
O
esults. As 
elationship bet
e of medic
(Stud
po
ctive 
urthermore,
OS, amon
tent resu
OA ex
as not associated
clusivel
e in risk was r
d that 
-re
IH cases (n
y burd
n PF
y us
ysis 
rtension, pre
OS ana
cies con
 both continuous va
eported 
om birth re
OA ex
n association be
rum measu
ype
nd P
yzed as 
ase and 
 serum m
or PF
w.   
ls from the 
ed b
ual PF
OA w
ersus partial 
dy r
). 
ed fr
ledge
ased ex
 anal
on self
 h
rted that “PF
a prospe
) a
ant associations we
cre
ed whe
ter
nse), but not whe
gnan
ed for
, inconsis
increas
amined the potenti
of PF
 b
of a

rements. F
nd as quintiles among
). F
 anal
and PF
ll
ation of the r
amined the r
y v
cant associations we
at PF
ced
epo
 et al. 2012b).  
wa
), a
spo
et
ex
ere
nific
IH 
A leve
ased 
FAS levels at the time of
ngthen
acknow
ed PFAS bod
nifi
-re
. The stu
It is important to note, howeve
eived af
IH obtain
y b
ease
y-indu
eived after se
e observ
ft profile
e observ
een P
g first pre
as stre
 monotonic 
HWA onl
In the second
” (Savitz
end. Overa
e authors r
ls (2005-2006
f a
y discussed belo
nanc
y, no sig
es conc
y w
y lack of individ
posure
Nolan et al. 2009
as per in unit in
y authors 
et al. (2009) 
 reflected P
rtile incr
y conc
efl
y (L
d betw
e o
 et al. (2012b) ex
ates. 
OS serum measu
e. Amon
y 1), models w
 all births, sig
nificant dose
y 2, th
rtension
ow 
 bri
gor
nanc
yzed 
nanci
OA ex
ctors (
sidential histor
rr
OA and PFOS were
nificant tr
provided no interpr
are
 
Nolan et al. (2009) 
with elevated PFO
this stud
limited b
cate
PF
2.0 and concluded th
fa
 
Savitz
estimates and P
used modeled serum PFOA of the mother 
the stud
some misclassification” 
(Stud
certific
re
“no consistent evidence 
birth, preg
Stud
hype
 
Da
serum leve
2005 and 2010). 
and PF
not have
women with reduc
PF
interqua
preg
among
anal
associations wer
importantl
preg
the ATSDR dra
observe
no sig
increas
associations wer
sig
evidenc
 

 
 
ge 
nd 
et al. 
rted 
po

IH a
ow 
rr
ust 20, 2018

3M Comments
 and re
serum 
cknowled
cant positive 
id not.  Given 
ss all 3 
side the 
f a
ence of a
Aug
e o
at Da
gnifi
cro
s out
posure
asured 
posure and P
d si
videnc
given th
” but also a
y and a
OS ex
icient evid
 et al. 2012b) d
the e
urther, 
 
ists, 
”. 
e is insuff
tions between me
 hypertension
l. (2013) observe
ther
anted
09; Savitz
mited.  F
ced
   
et al. (2013) stud
 et a
rmation of these finding
 
y region ex
 is li
sion
ow 
IH in relation to PF
.  
 associa
n
rrow
rr
lle
confi
, therefore 
54 
erte
ssociation between PFOA ex
posure
posure
h Da
nd
egnancy-indu
 Hyp
ndent 
-Ohio Va
amined P
OA ex
ant tre
OS ex
ced
 classification is warr
u
d

s within the Da
dence of positive
me
gnific
examined the a
lts. Althoug
o studies (Nolan et al. 20
no indepe
and PF
and PF
evi
su
cy-in
IH 
y to have ex
IH 
n
na

ed re
ct that 
en P
en P
ompounds and pr
y in finding
y stud
reg
s with no si
y population in the Mid
 on P
rted mix
po
more refined outco
y three studies have 
ed finding
results provide some 
perfluorinated c
that “
 
Onl
have re
associations, the other tw
the inconsistenc
studies, and the fa
communit
association betwe
(2013) is the onl
mix
association betwe
 
3M Conclusion
  
 

 
 


 
ra
re
ges 


FOS, 
est 
ased on 
rase 
els 
ls.”  
  Noted 
rum 
e of 
gg
et al. 
-149 is 
-156 is a 
ft 
with 
-sectional 
or P
in 
ust 20, 2018
T, 
ases in 
S).”
itudinal 
e lev
L
y su
L
3M Comments
ies have 
th effects, 
 available 
by se
videnc
transfe
um bilirubin 
equate fo
ng
e dra
ross
d hepatic 
m
embers.  The 
bin levels.  
A
Aug
tion.  B
e and seve
cre
ed 
an
d with 
he available 
entl
GT leve
 
ad
ges 148
ages 150
y on page 186 
els and increases 
e levels wer
ted 
T
G
et al. (
y in
y m
ym
ciation.” F
es 
y stud
e heal
posur
y studies did not find 
in 
estive e
e is 
nd 3 lo
rum enzy
L
 
eleva
yl ex
ced b
FOS, PFHx
gg
ases in ser
ed on pa
associate
es) a
e, in fact, c
r disease 
OA lev
zym
re
emiolog
 advers
alanine amino
general population studies.  
 no asso
T, AST, or 
ross studies, the
y ar
ive
OA, P
OS.  As assess
renc
 L
isk of se
L
 studies have not found 
cited the 
 epid
rum PF
s ac
ST), 
fe
luoroalk
es and bilirubin is found on pa
, as eviden
 PF
-172 with summar
 the risk of 
 ATSDR wrote, “
 and communit
s cohort studies in th
posed communit
y and/or 
ls.” Present
te re
d the r
ym
re
s in the risk of liver disease or biliar
ber of
ds to induce
A or
when the
dies provide su
ase (A
vels and dec
nit
tudies, the evidenc
ease in humans.  On p
ica
 Mundt et al. 2007; Olsen et al. 2000, 
cohort).]
decreases in serum biliru
und, and serum enz
dies finding
se
xposure
and do not establish causa
inding
en perf
O
 and bilirubin levels in humans.  The
 leve
es 170
ed for
whe
Hepatic En

n levels (PF
posure
) le
ghly ex
re ATSDR 
T
T
 between se
y fo
amine
 stu
lation studies do not consist
nsferase, ALT)
 num
poun
twe
y stu
L
 dupl
sig
l and 
cy of f
ransfer
G
ymes
 A
does not appear to be 
ls and 
e mix
erum enz
d increases in A
mislabeled a
or hi
tentl
ge 196 
y across s
enz

al Studies 
ations
c s
55 
otra
yl com
se (G
ic
A on pag
OA 
ers 
 leve
al popu
 and increa
aminot
y for
O
e 197 we
ents on 
in
gh a large
ry of liver dis
onsisten
epati
 on pa
ciations be
ciated with PF
era
yme
r studies ex
sults wer
m
m
n consis
ccupational ex
upational, commu
ariabilit
nd Mandel 1996;
 to PF
ou
re
posure
m
luoroalk
O
OS levels an
-sectional in de
 the c
ased risk and two
yl transf
Co
est asso
S is on pag
e, “Althou
, this includes “liver damage
ross
ding
both cross-sectiona
gg
n aspartate 
 in occ
hese studies ar
e found associ
R
ease asso
els, the epidemiolog
m
S, particularl
ys a summa
tudies (not counting
r Epidemiolog
liland a
sease in work
il
ussed for PF
xposure
 GGT enz
e not bee
ange. F
ge; the 
ncre
udies or gener
FOS ex
Hx
 c
reases in serum bilirubi
E
 di
 st
erum PF
F
gluta
(alanine a
 
TSD
eases i
een P
eported
e disc
 and i
and dec
ations in serum hepatic 
ctional s
Incr
ument fo
sults hav
posure
A small number of occupational e
Detailed 
en r
e is considerable v
lter
gs ar
 
y studies su
gamma-
y studies hav
T, AST, and
rs.  
.  
f a
 Doc
L
g to the A
ymes 
nd bilirubin lev
ge.  
OS, and PFHx
Note: Some of t
e 5, ATSDR wrot
cross-se
ed risk of liver dis
ma
h ther
y o
ed risks of liver
r, the re
y within normal r
y mention of P
), and 
 ATSDR wrote, “
ll
eas
T
ls have be
 13 
re
eas
188 with the ATSDR summary
amined the potential of perf
cordin
yme a
OA, PF
re
yme findin
 
On pag
ex
most of the studies are
a number of factors inclu
epidemiolog
health outcomes.”   
 
Ac
serum enz
on page 147, ATSDR wrote, “
incr
enz
liver da
(AL
leve
Althoug
PF
Table 2-10, which displa
summar
we
studies.  [
Supporting
studies.  See Table 7 (G
2003; Olsen et al. 1999) (
enz
whe
incr
epidemiolog
in serum A
Howeve
typica
outside of the normal ran
two studies finding
the discussion of liver disease and h
187-
occupational ex
an association betw
tract disorde
associations between s
The onl
 
ATSDR position
 

 
 



 its 
 
 et al. 

ant 
It 
ile as 
yses of 
ls with 
ased due 
row
nal
ust 20, 2018
OA and
pected 
s therefor
l Prof
ar
3M Comments
leve
 PF
should be 
ex
xt i
gnific
 studies 
 with 
that 
al trial in 
the C8 Scienc
sectional and 
onvertino et 
ove 2 to 4- 
or is there an
Aug
e incre
o four-fold in 
cadian 
nal 
onium salt).  
al cohort 
y.  As defined 
ations over time 
ica
lsen et al. 2012; 
entrations of 
and
y si
el (D
e statisticall
ations of liver
om 
ross-
 (C
e ab
 

y b
efold 
mm
y b
L
(a
 fr
 c
(se
T).  N
f two- t
centr
xicolog
cupatio
 mod
l trial
L
 and GGT 
y authorities, (EMEA 
ere
rum conc
A
T
-within the 
y 47 hours
nificant cir
ase 1 clinic
OA 
ge” 
epidemiologic a
L
patic injur
-to thre
ll
ross-sectional
e and ma
IU 
y and Cullen, 2013).  
ed to mention this when 
ed oc
OA ma
il
OA con
-year)
L
g se
 
eases o
lates to A
ater w
ym
te he
ge’ in this conte
egulator
imatel
cern
 PF
 w
/m
et al. 2014).  
Incr
ma
 two c
asin
y of two
y, it should be noted 
itudinal studies (O

yzed.
emain we
e of the population studied that was 
e” enz
‘da
y con
y PFOA is minimal, at best, and the 
a as it re
uding
013).  
tivit

serum PF
based on a ph
the other two were
ns indica
ons of r
l phase 1 clinica
st “liver dama
LT r
s approx
 siz
ud
rinking
um (ng
o long
ase of 1 to 3 
a. 2016) or in occupation
y anal
y basis with sig
  Finall
ficients for
T ac
age.’  As will be discussed below, those 
levant (Cattle
T i
the
nd 
ia d
and 
 incl
nta
with incre
cre
 et 
al dat
leakag
L
-da
on in this ATSDR To
ciations between A
ic
huma
mated 
g the ter
y re
ll
of ALT b
f AL
 common cause of mild elev
e: 1) 
ative ser
and tw
ased liver disease in 
rrow
 o
y-to
 esti
ported.
aluati
perime
y an in
56 
T is a “
ation of A
ica
imum tolerated dose of PF
Da
L
ecommendati
ater, 2) the st
all
A
y and Cullen 2
ases in A
associated 
ression coef
cellular dam
T. Usin
perimental a
 to PFOA v
an ex
plained 
oskie 2012); (Raleig
L
 w
eful ev


reg
om incre
OA (
pidemiolog
amining
L
T value re
t al. 2007a) 
ge”.  
d A
car
as ex
y fr
posure
allo et al. 2012), 
y wa
y A
the e
 (Cattle
– 30% on a da
 to PF
y w
occupational studies
y did not find asso
ama
man primates, and 
sed on the r
002) incre
f ’hepato
 not toxicolog

1999; Kim et al. 2008).  ATSDR fa
ted ex
isease is the most
2005).   
y of 
 drinking
l (G
estimated cumul
tud
tudies’ 
rtalit
nd and W
gle AL
rtain the max
g ex
hese studies do not sugge
ariation ex
odest (gener
ere 
e s
rized 
epair
-hu
y, t
,”Ba
asured b
posure
at the
r r
et al. 
ery m
cte
y o
. It is also possible to have quite modest but statisticall
 conduc
y a sin
e worth
cernin
T that are
y liver d
el 2007; Sakr e
s me
ercent v
T v
eased mo
ed ex
ase “liver d
nge of measure
L
att
T and PFOA either becaus
OA via the
L
ariation of 1
L
ned to asce
ross-sectiona
ob
y and th
ls in the NHANES data set that the
iannini et al. 
Z
e) a
f incr
y-bas
 
d as indicated o
gic ra
our studies w
.  Collectivel
eas
e o
y studies (Steenla
S leve
rosis, injur
es in A
l studies ar
t al. 2007b).  On
nts, canines, non
all et al. 2012)
y misleading
n there is onl
itudinal based on an 
tion of A
Hx
H
lates to A
ysiolo
hl
eas
nificant v
ymes (G
posed to PF
lsen and 
OA.  Although some s
nificant, the p
2010) stud
PF
mments
 
ATSDR mischara
use of the phr
to nec
rode
by (
2010; FDA 2009; HED 2
considere
studies that have suggestion of an elev
ph
hig
incr
should be noted that the human half-life
sig
variation (Cordoba 
cohort studies are
whe
nonalcoholic f
enz
 
Severa
it re
ex
populations, or 3) the stud
humans desig
Three studies con
Panel (one c
long
2016).  F
(O
Sakr e
al. 2018)
fold incr
PF
sig
eleva
evidenc
communit
mortalit
 
 
 
 
3M Co
 

 
 
 


 
OA 
nc
β = 
t al. 
ed to 
 the 
OA; 
OA 
ctional 
ted 

t these 
PF
dels, 
0.2 
ated 

by 
) AL
e in 
fere
results 
cross 
ere up 
et al. 

nce 
w e
ression 
65 for 
s, 
c versus 
 including

iven
re
-<5.8 
 PF
llo 
ust 20, 2018
L
 w
rro
y, similar 
lysi
 is tha
2
med
associ
 
reg
3M Comments
een PFOA 
esides 
ee mo
A (g
 increas
ents a
g/m
ere
ectiona
Da
OA (2, 7, and 
Aug
ross-se
s don

.  
t c
ased to 
L
L
L
ents for PF
ctivel
en 0.1 and 
ansfor
ested the 
re
 A
 consistent with 
ici
 PF
year metri
etween R
as statisticall
 IU/
IU/
/L
gg
L-
 that wa
eff
1.3
OA.  Th
ctional ana
IU
y su
β coeffici
/m
nce b
as a substantive 
n (untr
y 45 
y were
s Quintile 1 (2.6
OA in the C8 Scie
ciles of PFO
s model 3 in Ga
s 23 
, the
/ml PF
β =0.012); and Model 3 (
icients in models wher
icient w
OA (+
7,092).  The ATSDR fail
wa
06 wa
ng
 These co
in addition to
e 0.170, 0.174, and 0.265, 
differe
 0.002 for these thr
FOA w
plained betwe
eff
modeling
y de
FOA that inc
e noted that the upper 
ximatel
ort stud
le 3 11.4-<26.7 n
ame a
es in these cross-s
ction and disease (
 provided the linear 
l 2 (
 and 0.235 respe
 of 0.170, 0.174, and 0.2
ir cross-se
ulative ng
oeff
ates (2, 7, and 11) b
co
ed a mea
 PF
lysis
T b
 P
L
ro
oh
end in the 
-20
y ex
L
L
 tr
 valu
fun
et al.
OA. 
raph)
eta c
OA (
ssion 
A
g/m
r c
2
posure of PF
 Mode
ariates 
 covari
h the 
e (N = 4
g/m
; Quinti
-3558.8 
re the s
ow 
rag
 on the C8 Health Projec
 a positive association betw
gression models, Gallo et al. repor
) b
hat is most important to note
 PF
gre
L
tes in the
L
est that P
al. show
hest decile 
It should b
T is app
 cov
 
ed
re
er of
 for
gg
e siz
et 
ctional ana
creasing
rtial R
2
thoug
y worke
g/m
 0.15, 0.232,
aria
 found
nt 
g/m
T as it onl
 at 30 n
OA in 2005
y on liver 
L
al
 values of 
L
e hig
OA.  
or AL
T per ln PF
ov
estimated cum
 or pa
L
β = 0.003);
above pa
57 
 numb
T, 
 in the re
 an in
L
y sampl 2
IU/
y) f
2
umulative ex
OA (n
 A
eported at 6 n
 the c
 r
-<11.4 n
/ml PF
tor
06.  They
on 3 differe
-PF
ent variable.  W
y does not su
e of ln A
f ln
 stud
ir fitting
iates), Gallo 
/L
f 22.2 
after.  Th
ng
ra
their cross-se
s communit
howing
 serum PF
 5.8
models, which we
vide R
ated c
worker stud
plement) of Darr
rmed A
odel 1 (
ame number of
models were
al. (see 
w was an 
allo et al. report
-20
 of these three models wer
emained 0.002, 0.001, and
IU
2
r, the partial R
T o
In 
el’
 PFOA; and Q5 81.5
 M
rro
 discussed below.
 
earl
e) s
ased 
ant ln
ve
L
L
stim
e sup
ansfo
re
re
2)
B
an increasing
 the s
we
OA) r
ance o
e of the
 low partial R
e covar
y 320 
y and 
-tr
y 20.9 
ued there
g on labo
e Pan
g/m
 these 3 
T.  
nific
 estimated
L
 PF
A in Da
ecaus
y an A
imatel
ysis of e
 for
O
y sig
y.  Ho
y.  This cl
OA; Quintile 2
riates in these 
2
dies (n = 
as the independ
f the vari
imatel
 
nal
imatel
ependin
et al. (2016).  
et al. did not pro
 PF
nitude to Gallo et 
h PF
T w
cluding
r a
ch model.  The R
) but platea
ow 
L
ow 
icients for ln
llo et al. (2012).  G
L
ent o
nificant b
llo et al.  Based on the
n values of th
pprox
T
rr
rr
yses.
 the 3 models we
ypes of studies a
ity stu
spectivel
spectivel
L
nge (d
/m
l t
un
Ga
data collected in 2005
and serum A
statisticall
lnA
three models had 
in ea
re
and ex
re
contributor to the increas
perc
sig
mention this very
Ga
mea
of a
approx
A
with approx
ra
 
Da
of the C8 Scienc
the Gallo et al. (abov
quintiles where
ng
Q4 26.7-<81.5 n
to 11 cova
Da
anal
 
In thei
Panel’s communit
2016), Table S1 (se
coeff
for
0.011) adjusted for
11).  The R
in mag
the same models adjusted for
althoug
mm
Severa
 
Co
 
 

 
 
 
 
 
OA 
 

 to 
” is 
-
%

zard 
partial 
al. 
 for
L
lowed 
y also 
ln 
T in 
tile) 
.6
 4
alue 
or the 
uintile 
ous as 
L
 PF
 
3.6%;
of 25 
al) for 
A
TSDR 
iated 
 et 
A

T v

ase 
y fol
amage
ust 20, 2018
A
% CI
L
y A
est that the 
e order of
OA 
A in this 
, the ha
liver 
3M Comments
row
), thus 
nce quin
 the 11 
 A
O
nce); Q
Aug
nt metric
-<311.3
T value 
ed b
ctivel
re
et al. stud
stimated 
L
ver dise
fere
efere
ase (95
end of norm
nge in thes
ll purposes, 
posure
est “liver d
 the Dar
ow 

y li
rr
-years PFO
ex
L
gg
nd inconsistent findings 
all shifts in 
 for
OA in this C8 Scienc
ad an A
ed 
ow did not show the 
/m
, adjusted for
 (uppe
orresponding
s a
rr
 the variance of ln 
L
nce h
/L
Da
 quintiles of e
U/
Quintile 5: 0.92 (0.58, 1.47).   
ination
despite a diffe
in the Da
%) to 0.002 (0.2%
Quintile 2 (191.2
4.1 ng
0%; and Quintile 5 (3997
, at least a 10X (on
IU
the c
y slight cha
uld be, for a
risk for an
is as related to PF
 Quintile 1 (re
or those prospe
(1.19 (0.75, 1.88); Quintile 3: 
et al.)  su
fere
her in cumulative PF
ed 
R to continue to sugg
al. (
OA 
estimated cumulative serum
rds
-year lagg
ence of sm
 (0.1
 should be emphasiz
tio f
and 
allo 
eterm
y little of
compared to the r
-<79
A) 4.
T wo
eas
ra
TSD
r disease in relation to PFOA 
 PF
nce); 
, the 
 (
O
cumulative PF
esulted in a 6% incre
een 45 
ariates, 
stimated cumulative serum PFOA 
cr
 cirrhos
 evid
 b
f e
agnosed liver disease there is no 
ard 
r A
or G
 for
rted
r increased
fere
y r
ases were
Science Panel (2012) stated the obvi
2
ve
y in
po
gnitude hig
) o
T pe
In other wo
Given the ver
 
L
-years PF
 ma
.  
y liver or
nce); Quintile 2 
 et al. (
h,
rtial R
plained ver
modeling
estimated 
L
tt
ver dise
studies of liver enzyme
posure.  It is uncertain if PFOA is the cause of 
58 
ficients of d
ange of 0.001
L
rc
he normal physiologic range, being assoc
r of
ant.  This point
y. Based on a 10
ere
ed risk of live
oef
y ex
/m
ohort stud
IU/
e in A
 report an
ef
rrow
t least 10X
act, the C8 
sea
 Table S1. 
ase in 
ample, if Quintile 1 re
of just 6% in an AL
 not
iver, fa
t stud
three li
ery similar to Gallo et 
y the pa
y low r
babl
ted, via 
-year) and re
:  Quintile 1 (re
%; Quintile 3 (311.3
6 ng
FOA 6%.  
re
ers c
 Quintile 5 would be 26.5 I
alue would ha
ted for the 11 cov
 orde
47.7 
gnific
 1 (r
e Da
In f
n re
e the c
 v
L
y inappropriate fo
d on our 
ere
 v
an
ge 
However, unlike Gallo et al., 
 pro
er in
/m
T
nge (a
hl
) 2.3
 inc
For ex
e for
L
djus
y insi
ohor
).  
y likel
tremel
A
y work
e ra
ll
r c
OA.  
eir ow
L
ecaus
hl
-years P
ould be 
or these 
L
gher)
T.  
nlarged l
-years)
OA wh
L
f e
I) f
re Quintile
gs from th
g/m
t al. pap
 percent chang
/m
T valu
L
If the A
a larg
clinica
row et al. did
ted th
y o
y worke
re
d (n
OA.  B
g/ml
ow e
et al. also estima
ation (ln ng

e A
 Quintile 1 a
ation) w
ations, a chan
Dar
gor
From our studies of patterns of di
evidence of any increas
exposure.  Base
in reported literature there is some
function, mainly within t
with increasing PFOA ex
 PF
-years PFO
sure
ow 
ollowing
L
nitude or hi
, th
for
 for
OA), it is hig
OA (n
rr
/m
L

 Quintile 5 (at least 
yme findin
y interp
2
mained in the ex
L
tios (95% C
mea
R
models 1, 2, and 3 are
PF
re
PF
the Darr
 
Da
concentr
the f
cumulative PF
ng
Quintile 4 (791.4-<3997.
205667.3 ng
mag
Panel’s communit
7.9%) in the A
IU/
covariates.  
A
for
concentr
values over 
concentr
considere
because 
subcate
communit
ra
2: 1.04 (0.82, 1.50); Quintile 3: 0.91 (0.64, 1.31); Quintile 4: 0.84 (0.59, 1.21); 
and quintile 5: 0.87 (0.61, 1.25). The haz
since 2006 we
1.02 (065, 1.61), Quintile 4 (0.94 (0.60, 1.48), 
 
Thus, it would be hig
enz
associated with PF
the
 
 

 
 


 
 
-
as 
 
st
e, 
OA 
 with 
ce of 
 
 

l R2 = 
β= 
71.  
A that 
for

5 (p
nt
he 1
le 
e to 
nt.  The 
cile 
lted in 
iden
O

f t
su
du
ust 20, 2018
ations 
ant (
ere
 deci
re
rol lowerin
e 3
n o th
ted 
3M Comments
ficient 
 
lysis tha
Aug
greement
ctive workers a
djusted (ag
OA 
 a
oduction are
gnific
 and PF
y differe
T
eleva
 
ble link” 
concentr
om 114 to 19
riates (mode
 at 3 diff
icient of 0.011
.”
 fr
ova
y si
 choleste
) in the first de
be 
rent ana
this is reflected in any 
sease.  Therefore, the 
vide strong ev
effect is biologically 
n of the 10
y be within the normal 
me
OA 
β = 0.031, p = 0.0
y of 506 mal
djusted mea
ression coef
gnificantl
and ln PF
 pro
greement and do not
nging
I -0.46, 1.54).
– 130

ysis of AL
y si
 decile.  An a
L
an also 
ce that 
nce Panel is in a
h stated,  
d on “proba
ns, working
ll
th
ent a
lysis of 1,025
t statisticall
not taking
ecame 
nal
he reg
% C
ed the a
ge 7 
.  A diffe
usted coeff
10
dj
LT c
hic
alth outco
ase
ana
rs 
 b
ammonium salt) pr
posed groups with more intermittent 
ations ra
T.  T
ctional stud
port
 (ran
eviden
the observed 
e A
), w
as no
ere
L
L
e 0.06)
 
onal 
 ex
ficient b
A
y re
e C8 Scie
 settlem
centr
ysis with 6 other c
T w
worke
amined ln A
e 24
s w
f a

g/m
PFOA (
gitudinal a
β= 0.54, 95
g medicatio
ex
-valu
y th
 o
esser
L
 cross-se
compared to the mea
r AL
 lon
sure
rin
e not statistica
d a probable link between exposure to PF
(pag
y those 
on coef
 60 n
there is no 
nce of diagnosed liver di
g b
nitude of the chance ma
 an adverse he
ross-secti
eciles, the
– 92,030) in the 
59 
ile 
t al. 2014)]
 c
ned in 
– 33) 
I resulted in an a
 onl
ressi
gnificant (
y d
ns wer
ysis that 
M
amined becaus
   
asonin
orks plant.    Median serum PF
egression anal
icient fo
I 25 
re
l Prof
e Panel finding
fined as part
land e
cted a
s assig
7 – 9,550).  
dian PFOA con
eff
e reg
onducted a
d their mea
y si
eported on a
sterol lowe
e mea
 anal
for B
discussion). 
rall incide
ica
e the mag
ar r
ations were
 
er
amining
an
) r
yzed b
OA of 0.0249 (p
el does not fin
aus
e de
ton W
ge 1
also c
range 3,710 
ssion
g chole
 (95% C
centr
atter was ex
icolog
) condu
an
(2007
L
 (r
s had me
ssion co
gre
e Pan
ashing
L
IU/
r ln PF
lycerides 
see below 
, this line of 
ant bec
ation (Steen
f the work
egre
obel 
– 38).  Thes
re
he C8 Scienc
ies (n = 4)
g/m
posure
s not statisticall
Z
s 29 
OA con
the association, but if so 
increase in ove
Scienc
and liver disease.”
“It should be noted that although the data may
an association, it does not imply that 
relev
limits or not indicative of
ons (n = 840), th
I 30 
ohol) re
t al. (2007a
 259 o
.  Based on a line
st ex
L
t al. (2007b) 
 C
ficient fo
s 494 n
I, alc
/m
OA wa
M
Furthermo
the ATSDR Tox
 
[NOTE:  T
assessments that wer
indicate caus
Sakr e
the DuPont W
among
wa
or pa
ng
0.276), the r
0.023, p = 0.124).  Ex
medicati
 
Sakr e
involved 231 workers 
PF
 
Olsen and 
workers, not takin
production sites.  Anal
decile wa
(95%
median PF
compared to 4,940 (
B
a coef
substituted trig
value 0.40).  The l
dyslipidemia (
cupational Stud
 
 
 
Oc
 
 
 

 
 




 
es 
lding
OSF) 
ym
FOA 
L
nge 
 
stent 
(P
oug

with 
single 
 
anged 
these 

ave 
zym
s.  
re 
r became 
 P
 done.  
L
g/m
L
y Sobus et 
) h
 en
r enz
ust 20, 2018

we

ect 
T cha
onvertino et 
y.  Forty-
unch
μM 
yzed 
HANES 
3M Comments
g/m
g/m
L
C
) on a 

ations that ar
Aug
worke
mistries,
rol consi
ments o
 data to 
re that 
 a 
OS 
 salt
wa
rs who 
yl fluoride 
re
conducted in
centr
-of-proj
l che

L
– 1530 
escribed b
ctional studie
ysis of N
ysis of live
or ultimatel
y conditions, 
-d
-awa
orke
nd
d tumors (
onium
ll
-se
sulfon
aseline clinica
n befo
OA or PF
clinica
OA con
y ATDSR anal
 anal
-year time period alth
nd the mean A
l trial was 
y at 870 
 (amm
octane
 of 
n the stud
at PF
ed b
 biomonitoring
eb et al. (2018), in their 
ysis of w
 a 2
nd-of-project was 5.3 n
FOS (median 4.2 n
m PF
LT a
A in soli
A
gor
pulation measure
S
nd Gleason et al. (2015
DR is well
er
me.  B
ere take
y similar e
ncentrations < 15 n
 P
ru
O
calation phase 1 stud
e and total bilirubin were
s been we
es to the anal
luor
at e
L
FO
ate
) a
-sectional data with liver
y D
rf
n A
e clinica
l po
eport
al limitation that has not been 
lat
ction of serum choleste
.  Give
ed P
A c
ic
al. with their
tion and removal of production bui
 pe
ed ov
g/m
rr
eline co
ease 
 on
ated dose that could be provided 
ammonium salt) f
O
du
ent
ents ha
gn, ATS
ments w
ile, re
period of ti
3 dose es
g NHANE
followed b
ases in se
genera
ese NHANES cross
shown b
OA (
+
 a re
e not altered 

in
gitudinal anal
at 

receiv
y desi
asure
y distribution functions, A
hest PF
ANES cross
, demoli
 th
ge in media
ere
 week.  Monitoring
   
in et al. (2010
al Prof
60 
 lon
imum toler
bilit
es wer
s of us
L
ic
yl me
ubjects 
) wh
 than th
l of the studies r
isk assessm
the hig
L
ect was evid
ym
cle NH
cted a
he production of
of r
ation work occu
alk
, which wa
modest incre
 
A 6-week phase
.  S
proba
 eff
vera
lenge
 both 
cy
 to its stud
ortant methodolog
t al. or Gleason et 
m lipids.  As 
gaged for
workers with bas
0.0001) and 0.7 n
rapeutic potential of PF
s a standard 3
200 mg
g/m
eater
termined in th

as no chan
GT, alkaline phosphatas
r enz
gr

ese 
 w
as 1
in e
condu
mmissioning
 en
luoro
at se
year 
L
emedi
rf
y wa
NES) studies
e chal
y imp
f 120 
FOS, their median incr
) (
cipated
ynamic
A
y form 
eco
 1) 
gh 
 P
L
= 0.53).
H
all
L
hemothe
 stud
FOS. Due
g/m
 (p 
al administration of PF
T, AST, G
ysis of the 
gnitude 
annot be de
g/m
/L
L
gorization with 
– ~632,000 n
 ma
In this regard,
n equ
y either 
 involved with t
IL
dy (n =
y or
g the c
 A
anal
rmacod
y c
ate
te into an
re
ations, there
OA.  This r
ments.  O
r, a

OA or P
ged in the d
y dose as hi
y c
ssed b
sure
0.0001).  Given th
s -0.7 
ekl
 an
yzed multiple 2-
ental stu
ased on 
OA
 
Olsen et al. (2012) 
enga
that we
and PF
not all workers were
chemistries and pe
involved with the project
mea
and < 50 n
(mean 44.2 n
(p<
concentr
wa
Convertino et al (2018).  
Scotland to determine the max
the weekl
evaluatin
al. 2018).  The
nine subjects parti
we
including
B
for
(~360,000 
with a pha
authors concluded live
5 orders of
PF
It should be noted th
NHANES data.  Th
incorpora
al. (2015).  
anal
and PF
temporalit
Howeve
addre
data, or this ATSDR Toxicolog
data in relation with seru
neral Population (N
 
Experim
 
 
Ge
 
 

 
 
 

d to 



ll as 
eak 
tion 
sex
ndard 

nts and 
ver 
yls, 
eported 
lzer e
we
y w
us 
ysica
2008).  
 
en 
y, and 
ght be 
gher 
er 
ard, with 
 

ht nee
ro
y sta
plana
ust 20, 2018
 wa
eme
(Me
 age, 
, ph
3M Comments
L
ased li
ee 
er ver
luding
ave been 
This small 
y an
e ex
 there is 
Aug
D
L
AST 
ht be a
with lipids (a
fluoroalk
ce/ethnicit
yls and liv
omen)
Kim et al. 
T h
as not been r
In this reg
abdominal 
 (
L
ge b
yls and live
(w
T and 
yls measur
, ra
et al. 2013) as 
 of 
anges.  
ma
.  Thus,
L
and incre
est this path (hi
en per
OA in the C8 Health 
T, including
y different 
l r
T
pids mig
oncentrations, mi
entrations (s
nt.  Thus, nume
ated)
sure
L
e, sex
associated 
el
yls) 
luoroalk
 there h
lucose 
rr
ges in A
gica
ver da
A

luoroalk
luoroalk
 to PF
an
r ag
to sugg
th of serum lipids mig
e in NHANES data 
 (Fisher 
ver disease.  
s of AL
 mea
 co
 is an association betwe
l. reported that 
vated A
rf
then li
erf
y be 
t low c
oalk
yl conc
ue betwe
er, is
yls in populations whose serum 
differe
hol, g
te li
re
ce 
as
ysiolo
g fo
en perf
y li
alk
lyse
and liver disease inc
ge ch
 across vastl
n ele
luor
posure
ymes 
een p
att
 it is inappropriate to inf
OS 
s Survey
e,
 be ruled out as a possibl
luoro
nitude 
atio as a
centa
t indica
an influenc
   
.  Deb et a
justin
 enz
FOA ma
rol, alco
e, lipids, a
 (perf
re
 PF
rfluoroalk
erf
 negatively
T.
-2012 the
ed in ana
re
annot
L
on betw
est P
d liver dise
d p
f mag
A or
gy studies
 c
gg
ciation betwe
hts into this iss
rte
-to-hip r
O
does no
rs that c
xposure
rs o
mall per
61 
e in odds of a
ciation between pe
gher pe
po
sure
ist
 two a
S
y su
onsider
cto
om 1999
asso
sent, 
eas
ssociati
hat is certain, howev
alth Measu
y hi
e within normal ph
y wa
y fa
a fr
and lipid levels
y asso
sider at least ad
iated with liver
e ma
ons).  Therefor
en the e
vel
Thus, the intermediate pa
d no insig
.  W
 self-re
n He
liver disease with ex
. 2016), including f
 be orde
e latter
either PF
risk for liver diseas
and mea
rabl
el, total choleste
r hand, there is less eviden
ying the 
t al

en 
irrhosis.  
, but ar
efe
g (th
y in epidemiolo
ymes 
fold incr
 assoc
ying the a
etwe
L
entrati
nzymes
alidated 
ow e
 (pr
 or c
ions
t is even pre
ine.  Confounding
o the man
enz
ever, som
an association with A
ations can
at
HANES dat
conc
ased risk of
y v
ed in stud
ll
y increased 
g factors must be c
glyceride lev
f N
ts at substanti
y (Darr
entr
y liver,
centr
ge, if i
d liver 
ments.  Thus, an
ymes should con
OA 
is
ausal path b
an
ciation betwe
att
nz
If lipids are
n incre
y), tri
y, and smokin
chan
e of medic
ysis o
sure
sure
ymes.  How
ymes. On the othe
ymes. ATSDR offere
k of 
yl con
AS conc
y mass index
ctic
 
albeit inconsistentl
anal
mea
associated with a 2-
mea
liver e
lipids.  
confounder in stud
enz
lower PF
on the c
enz
lipids) ex
Convertino et al. 2018).  
be consider
enz
lipids, and liver e
to be a
al. 2010), in the Canadia
with medica
Panel stud
a lac
associations with A
PF
confoundin
bod
obesit
activit
 is no asso
ed liver, f
l pra
luoroalk
nitude of 
ported, 
 this observation due t
 
 
There
enlarg
re
perf
mag
clinica
for
insufficient evidence of 
3M Conclusion 
  
 

 
 
-

In 

ls 

ra
y of 
-

ased on 
y not 
ge 
ailable 
es with 
OA, 
nge in 
cPherson 
-
L
an
ust 20, 2018
ted 
y found.  
 
posed to 
D
s a dose 
tion and its 
3M Comments
th effects, 
 available 
(PF
a summar
t cha
risk relative to 
ages 172, 177
lesterol per 
terol levels 
he dose
also been 
 ex
ists, such a
 Ma
SDR is 
ica
Aug
tion.  B
e and seve
leva
HDL
mans ma
e 1 clinica
wa
OA (r
 all dose leve
d to lipids (a
F
re that the 
 been av
gy studies have 
ph of percent 
contrast to the 
rum lipids, 
t (p
gon
ct by
 P
late
e heal
es e
posur
gra
ercen
In 
 choles
h hu
 phas
re
consistentl
α a
 adjusted 
ge in cho

ed “
ctions in L
curred at
yl ex
cholesterol 
evels and t
OA and 
-9 is a 
L
edu
ase 1 trial 
pidemiolo
 advers

ph of p
D
han
gniz
y in humans
ects, similar to those 
R
ross studies, the
L
 2
L
D
-10 provid
OA l
ect oc
Toxicological Scienc
FOA as 
ssociations have 
co
esults of a
 P
olesterol 
 of e
L
ure
rum PF
 r
s ac
e 2
ted 
luoroalk
increases in se
ig
 the c
es in serum
OA, althoug
ur
f PF
 to other PPAR
Ch
ig
e o
en se
 this phase 1 trial have
number
ds to induce
 2-11 is a gra
ed in the ATSDR tex
increas
ositive a
we
ipidemic eff
d to PF
act stated “
inistered at 1200 mg
vertino et al. 2018).   AT
vertino et al. (2018) publ
and do not establish causa
inding
en perf
ang
liminary
d in 2010 as an abstra
rved.”  The ph
her this eff
m
6, 2018 in 
eview for
els; F
amining
ons have not bee
ATSDR re
ct.   ATSDR was not awa
perimental stud
rge 
poun

ter 
twe
xposure
pose
y 1
 
sig
 abstr
cy of f
y lipoprotein (
Figure
rovides eleva
wer r
 ex
hypol
e pre
 obse
bstra
ar
, (Con
). 
grea
an
nsit
-169 is Table 2-12, which provides 
OA lev
associati
e a
 found bet
ain whet
ebru
r the Con
62 
ents on 
gh a la
age 187, 
y dose adm
 
yl com
OA; 
-12 p

 were
evidence r
-de
 2
“studies ex
re
 
gy.  The
essment fro
onsisten
found 
elationship. P
ciations be
or various studies: F
eekl
es 156
ure
ls at the lo
rol
ffect
ht of 
Althou
ig
 studies, 
and human e
y ass
luoroalk
y 2018 issue
 to ATSDR, this included “
e 186), 
ls.” On p
y conside
-sectional in de
 the c
es and studies present
es 181, 187) th
hest w
yroid hormones
lative to PF
 
l Oncolo
full
 cholesterol
est asso
ross
ding
gg
ding
rol and low
re
vels; F
gur
(pag
evels have 
a biphasic r
terol, althoug
e leve
miology
. 2011) 
2009), suggest that 
h a PD e
hig
hemistr
y occur in humans ex
(pag
ica
DR was not cert
not present in th
published on F
he Ma
are
R’s weig
d th
 c
”  On pag
rol relative to PF
es

l c
ccor
e fi
t al
an 
ents.”
ed 
SD
eA).
A le
OA l
ests 
 Clin
es an
D
O
gg
 chol
L
glycerid
gniz
s rod
A and Choleste
ym
Detailed Comm
FOA and
 su
D
ents, ma
O
co
ammonium salt) that was publishe
y with the 
g).  ATS
nz
y studies su
rum PF
L

consistent associations we
y and Pah
in the J
fication wa
e Access and 
couraged to c
ly total choleste
NA, PF
urve
OA (
lari
e 5, the ATSDR wrote, “
PF
lative to PF
d fo
y publication in t
l, no 
d in rod
ly en
ge in total choleste
 re
ge in se
 – 1200 m
op
amined the potential of perf
alth outcomes.”  A
OS, 
L
ll as liver e
D
OA.  Based on thes
sponse c
sults observed in epide
OA (MacPherson e
sults from the clinica
mification(s) in AT
 
On pag
ex
most of the studies are
a number of factors inclu
epidemiolog
he
particular
PF
serum lipid outcomes in humans.  F
chan
cholesterol adjusted risk 
L
PF
182), ATSDR concluded 
chan
associated with serum PFOA leve
re
observe
genera
cholesterol or tri
re
PF
fibrates (Ro
observe
be as sensitive a
mments on PF
 
The ATSDR re
trial of PF
et al. (2011) 
cholesterol consistent wit
escalation stud
50mg
as such c
re
via Advanc
hardc
strong
ra
we
 
ATSDR position on P
 
3M Co
 

 
 

ed 

et 
 


ger 

w
he 

t al.  
L
ur in 
ction 
y the 
ekl
s to 
 
ction 
sho
L

finit
/m
 49 
sure
nland 
/m
should 
enosensor 
 likel
 af
uch lar
ust 20, 2018
re
y wa
ge 181); 
nitude lowe
3M Comments
 
 we
ved we
 subject 
ated dose wa
e based on 
o mea
yroid) 
nsition in 
0 ng
ed to occ
. 2010), 
n with 
 cholesterol at 
SDR 
lesterol, 
h a x
 
ive 
ing
iven the 
y Stee
utenhoff e
odes of a
 low ng
Aug
baseline 
OA 
otal cholesterol 
o et al. in t
 in m
 equations a 
F
model. 
s are
r associations 
nic kidne
1).  Convertino 
B
y assessed the 
cei
e s
er th
ted
ar tra
f mag
et al
eport
 posit
ated
ic m
f this stud
ed at 
ting
ations of PFOA 
chro
e bind
rted b
rted at
y dos
d, was considere
r o
ge 18
ynamic 
– 230,00
eleva
ested the
anism g
ATSDR (pa
plic
po
y that re
entration
re than one
imum toler
orm
ee und
rde
centr
gg
  These would include the 
y shar
ap
erf
y Convertin
al population. 
cpherson 
ith total cho
onc
amined as 
alation stud
m salt).  There
 p
– s
ny possible modes of a
y the 
ed estima
 a decrease in t
ght and 
y an o
ner
s consistent wit
en su
(Ma
h con
A c
tions.
gic mech
y ex
-esc
y purpose o
liz
rted b
lear w
hl
rd ther
O
ee T4 
y 175,000 
y th
 that ma
ver, no mo
, and is consistent with the 
epo
her than those r
enera
L
imatel
SDR 
l studies showing
r PF
plana
y ATSDR on pa
r birthwei
1 dose
tanda
primar
we
evel so a max
commended phase 2 dos
D
d the ge
T
sic response in the huma
hysiolo
cts took the weekl
ot dose administere
 g
and fr
entrations with a cle
imatel
er, r
e hig
ncentrations and 
ertino et al. did.  The AT
 tract
nd cholesterol repo
At the hig
we
ex
d b
horoug
esponse wa
gica
te which confounds othe
we
ate (ammoniu
rements were
functions for
al 
g p
y, an
 co
did not offer a
 1) and should be re
ation of plausible biolog
iled s
su
y, n
cokinetic/pharmacod
conc
approx
e to A
y lo
ic
 lo
also mentioned b
een t
 phase 
A.  Ho
pprox
, not H
a bipha
FOA a
tano
fa
at 
ntione
O
y dose l
as the re
gnitud
 b
included
stribution functions at various P
ma
ease became c

OA 
L
onse.  
D

reas Conv
cr
kedl
ration ra
e (n =
amin
63 
eeks.  The 
rooc
y mea
ot all subje
L
y of 
y di
OA (a
ilt
 underlin
een P
y at an
her PFOA
al biolog
rolemia positive association re
luo
whe
y of PF
l dosimetr
lyses 
ations, howev
gastrointestinal
y dose w
mistr
rum PF
ers of ma
ypolipidemic r
ged ex
tients who 
or 6 w
icit
abilit
y distribution 
r, the ATSDR 
e the de
y not have
) f
icit
fter.  N
tment phar
OA including
, total cholesterol (
μM PF
inia communit
tional epidemiolo
 tox
eekl
l che
ea
nts observe
l ord
d n betw
holeste
 tox
 prob
oncentr
esponse 
 noncaus
lomerular f
(2010) that wa
 et al. (2018), this
al of perf
 c
ncer pa
0 mg
ting
g w
tistical ana
ng
eased se
 565 
ct that was availabl
 the possibilit
 g
ers in the 
 low sample siz
compar
 et al.
obabilit
rved involved 
 rode
A
vera
orted at hig
Howeve
ed wher
lesterol and mar
ore
with PF
erve
al. 
atter ma
al. also ur
clinica
y ther
ation, interna
O
est Virg
α-mediated mode of action.  The
yperc
cho
– 120
rd 
ekl
re se
asur
rted 
e et 
nsport
centr
ce.  Sta
ysis usi
f the pr
y abstra
tions for a biphasic resp
e or m
y in the
ra
OA; saturation of an
tremely
(50 
evels.  
 biphasic r
PPAR
po
 dose limi
ng to lipoproteins (also me
hoi
y 420 and
ex
nal
effect obse
posed W
ulated about
 with the observa
Frisbe
peutic potenti
end with incr
ange o
l evidence in
e stud
xplana
e of on
abilit
en re
ssociation obs
g to Convertino
y.  Standa
OA con
cholesterol rep
ceptor 
ganic t
y solid-tumor ca
ed.  The 1000 m
ations, and a 2-
g to Convertino
imatel
ica
ation.  The PF
an ex
y lower l
r e
tion for a
ered and me
r re
OA bindi
mine the dose limiting
bilit
bilistic a
nist
cordin
gative tr
amination and we
cordin
OA).  The 
icolog
ased on th
plana
er thei
Ac
chemothera
primaril
doses of PFOA 
deter
demonstrated a
not reach
tolera
ex
serum PF
the metric of c
proba
concentr
Ac
a ne
shape and r
at approx
PF
tox
concentr
phase 1 clinal trial a
workers, 
 
B
ATSDR spec
decreased 
markedl
ex
off
admi
Convertino et al. suggested this h
nuclea
inconsistency
associations between 
consequenc
inherent vari
that have be
disease; or
with lipids and PF
nonlinear a
al. (2009) and 
and PF
et al. cautioned that the l
(2012d) had an 
numbers.  Convertino et 
that could support the h
 

 
 

ate 
ger 
  
 
yl 
oth 
d in 
g the 
fects.”  
-be 


ccur

spons

OS, 
 ef
oalk
 the 
ica
R.  B
atin
ly total 
ust 20, 2018
-re
n no lon
y wrote on 
-sectional 
e ina
3M Comments
ing
ss
luor
ased on the 
yet-to
  
l population 
olog
e mode of 
hat has 
e) but other
onvertino et 
h altere
should 
for
Aug
dose
in man
– cre
esterol and 
OA, PF
gh 2-12 
g to an
ffect the 
fects observe
en the
   
amining
ed 
ying, 
y C
y a
OA 
ary associations, but 
her cholesterol that 
ypolipidemia. 
e ef
e of cro
icologists and 
genera
rl
OA bi
 to PF
, particular
h conflict
ata.”
ghtenin
erum perf

escribe th
-9 throu
 d
ciated wit
It is there
nli
l evidence t
, “Th
s 2
lianc
re
gest that the 
her s
 in humans b
to d
can both affect GF
posure
rted contr
ica
esults in h
tions (see abov
decreased chol
OA.  
po
gure
xposure
y (both tox
ase 
amount of PF
, ex
nt to humans.  This ca
y to be e
y the 
n stated
ection of unde
bove, 
OA r
plana
ects (
istence of suc
commendation wh
fl
icolog
 to PF
ample, not stated b
y dise
her 
 
ex
lication of Convertino et al. (2018).
 re
echanistic studies ex
erum lipid level would also provide 
ated a
 also been asso
 eff
 have re
eleva
ack of e
studies that could be used to establish 
a re
noncausal lipid/PF
f PF
al ex
ex
hig
ertino et al., the ATSDR 
humans
ited in Fi
nlikel
m lipids sug
ns out at hig
mmunit
sponse curve
(Convertino et al. 2018). 
at the much lowe
ne
34 whe
n serum lipid levels
g r
y u
re
r the associations observ
aus
mic
posure
In 
s i
e pub
 this
For 
 and s
y be 
 the association with hig
yslipidemia. All three ma
ge 6
pers c
th
ghl
elf, has
y studies.
yna
h ex
 hi
ta is limited b
hethe
sult in a 
64 
es with
y, and the l
re
posure
ientific co
in humans 
 desire, so st
sults in
and human tox
entrations o
ation.  
chronic kid
acod
tion of Conv
tional studies
given 
ss-sectional) 
y actuall
y maintain a 
rm
usalit
“Studies of seru
ations and flatte
estig
yl ex
ro
nimal 
conc
d in humans.  
y done 
y c

l possible nonc
R ma
pidemiolog
f pha
esses that 
y does not support the 
OA ma
yslipidemia, its
y hig
y of inv
y o
se observa
ps would be valuable.  M
nc
observe
e authors of the pa
nimal data as not bein
onal studies are
ge 635, 
concentr
d et al. 2010), additional 
tl
fluoroalk
DR and the sc
rimaril
r PF
 doses that re
ith the a
severa
d disease and 
so associated with d
ome e
ecent publica
d humans with hig
SDR provided on pa
ar to result in increase
y a
g.  ATSDR agre
er 
ged to reassess the dose 
should consider w
l proc

te.  D
ered GF
T
cien
e in the literature 
els fo
gica
e low
yroi
d in s
appe
 
y of th
t low
en per
re ur

rote, “the
ontrar
lationshi
perimental stud
rstood biolog
ross-secti
om those 
erpretation of the human da
 also worth
efore, ATS
y lev
t suffi
fr
y w
e c
e re
ysiolo
Int
per a
ons (Steenlan
ists) a
y ex
ic studies (p
y at thes
iltration ra
efore, a low
er 
ry, given the r
ge the consiste
y unde
which do not establish ca
ati
spons
ly inconsistent w
 written what A
cepted practic
y, mor
rl
 is stee
ht.” Ther
) in both animals an
nts diff
OA.  The
entl
R.  Ther
L
D
NA, and PFDe
PF
curr
And, in fact, man
discounted the c
be ac
Clea
scientific understandin
page 635, “
studies, 
 
ATSDR also wrote on pa
curve
concentr
dose-re
association betwe
insig
epidemiolog
one and onl
 
In this regard, ATSDR 
epidemiolog
and communit
identified, ph
associations.  This includes ATSDR’s
action likel
is entire
demonstrated a
Convertino et al. offere
possibilities are
al., is the fact that th
of these conditions are al
glomerular f
GF
association observe
 
In summa
acknowled
L
to have
rode
PF
cholesterol levels.”  
 
 
 
 
 

 
 
 

es 
ay 
nce 


 
ur
en 
 

-13, 
ewer 
ria

gniz
 
-189) 
rianc
co
ction is 
r serum 
ported in 
sented 
e 2
 f
OS m
ust 20, 2018
y as 
 are
 pre
e 188
-194).  
an primate 
y.  This 
3M Comments
HDL
of a
contrar
derstood as to 
igur
lesterol 
re
ed betwe
93
tud
gh PF
hat althoug
aller studies), 
 the va
uld re
m
primates.  The
Aug
ovascular
  Not discussed 
br
α, which is 

6, with fig
 a
y had hig
r)
gender, and 
sho
re
, not 
 cho
port
ud
r model of 
ctivel
L
ations, as re
-19
L
A, there
te
y (pag
erol.
ge, 
 
as 74,000 and 
D
als that lowe
D
 a
) was reported with 
spe
e, ce
 PPAR
y.   Th
L
 wa
 L
re
L
re
mil
centr
yet to be un
es 188
t al. 2009 s
holest
g a non-hu
D
), 
fa
OS level in F
ls (our st
ge portion of
us
cupational studies nor the 
rs we
ardin
y H
rmaceutic
-14, and 
ssociations re
ators that althou
nland e
y of non-human 
entration w
ery diseas
 2
It should be noted t
eceptor 
OS and c
OS was < 0.01.   
ynomolg
y art
r r
ure
-14. Unlike PFO
plain a lar
o serum PF
compared with prior sm
ar
centrations of PFOA will 
terol involving
ate pha
er the oc
sitive a
as Stee
 investig
n et al. stated for thei
d above, the ATSDR 
l (primaril
ceptors, including
dies, remains 
opulation studies (page 1
 
lesterol on pag
e 2
rote, “
 of lipid leve
 PF
ark conc
ith
OS in the drinking
ll 
en PF
FOS did contribute much to the va
(2017) reg
ys (c
con
re
 po
l p

Fibr
ith low PFOA con
y.  
ho
igur
age 188) and communit
we
nces 
 for
-month stud
coron

w
y stu
etwe
ls, P
 Olse 2
elative t
  Ne
ere
l (p
y both
t al. w
a 6
nchm
edictors
ere
discusse
ame nuclea
genera
y as 
OS. 
g et al. 
holestero
65 
ry hig
FOS.
rtial R
  
 nuclea
ssed b
ale monke
 humans.  
 
OS and c
OS levels in Fig
posed to PF

ported b
nland e
l trial 
entile be
m
erum total choles
nge (%) r
OS level in F
xpre
es for P
ed in the 
en PFOA and 
d s
gnificant pr
 perc
re
enosensor
lesterol
ur
s not ex
s from Chan
th
 mix
lestero
y si
n x
, including
o bind to this s
lesterol associated 
ational epidemiolog
oncausal) plausibilit
rol with PF
rum PF
 wa
SDR wrote there w
th the occupationa
y significant diff
ociations re
unds themselves did not ex
um levels of PF
 = 0.06, the pa
se 1 clinica
ding
ction in serum c
nd 5
male and fe
ypertension.  Ve
xample, Stee
ghl
2
g o
cies
cho
esterol cha
este

hich
AT
e hi
OS (potassium salt) in 
A and cholesterol 
nd h
ctin
her 
 and Cho
er bou
S
cant predictors of lipid leve
For e
 the R
OA pha
 thes
O
ciation betwe
sult in lowe
perimental studies in both animals and humans.  The mode 
y spe
y (w
esults were
, not ser
ght redu
F
FOS and cho
O
ed compo
e), a
A a
y re
s.  The 
nifi
ct statisticall
g low
 for
ll
sented information on PF
 positive ass
or total cholesterol, the most important predicto
 a sli
L
) relative to se
holesterol wi
y stud
ure
tion of PF
 on P
ical (causal or n
diction.  
/m
bnormal chol
%
 on PF
e for
luorinat
 is no asso
l but not all observ
rf
y via PFO
ge (
r to dete
sented on total chol
y where
OS and c
OA and PFOS ar
y mass index
espondin
hich it has not) the fin
 
There
disease (strok
unequivoca
cholesterol in ex
likel
common to man
cholesterol in humans als
association of hig
severa
its biolog
 
ATSDR pre
pre
risk of a
chan
studies presented in these fig
communit
in these fig
PF
studies but the r
mments
 
ATSDR cited the Olsen et al. 2003a stud
evidenc
by the ATSDR was the concern e
have been sig
of the pre
PF
powe
the pe
in lipids.”  F
bod
cholesterol where
 
Similar to the PF
(w
stud
administra
corr
86,000 ng
3M Conclusion
 
ATSDR position on P
 
3M Co
 

 
 
ust 20, 2018
 and lipids 
 to result in 
S
3M Comments
O
Aug
OS is likely
ists between PF
n humans. 
centrations, PF
tions i
ra
ciation ex
asso
gh con

concent
y hi
66 
 
clude a
icientl
 
at at suff
erum cholesterol 
ence to con
) s
est th
L
D
y literature.  
gg
L
S and cholesterol
ent evid
O
F

ici
, not 
L
 on P
 would su
HD
 is insuff
finding
lower (
 
There
in the epidemiolog
 
3M Conclusion
  
 

 
 


ra
ase 

ferred 
ased on 
OS, 18 
yroid 
 
e T3 
ted TSH.  
ust 20, 2018
or PF
Further, 
ding
OA and 
3M Comments
y studies hav
th effects, 
 available 
yroid dise
 F
iscussed 
ided that an 
disease.  This 
f scientific 

opin (TSH) 
and fre
 in Graves
 cause of 
et al. (2015).  
.”  
, trends in 
Aug
tion.  B
e and seve
ATSDR 
ader is re
rs that of the 21 
ents in the 
scientific 
eleva
risk for th
y-based and 
re
gn 
y d
k o

e heal
erstan
posur
es in humans.  This 
yroid 
yrotr
evels
erum PF
ewis 
the results are not 
ge 25.  
cohort. 
 L
rt component. ATSDR 
e of a
 free T4 
yl ex
y desi
y a 
ry statem
 a common
lysis basis
 Disease 
 epidemiolog
 advers
erum th
ated
s do not suggest an 
ross studies, the
 —
ation), it appea
plain how it dec
esented in the 
lev
cept for
eported, 
er of
a coho
gh s
ation.  Subclinica
s ac
ed risk of th
luoroalk
yroid outcom
r the stud
tionale of und
 ex
e pr
 indicate the lac
 
posure
 fo
 ra
 no summa
ons between s
yroid hormone l
 inform
y had 
y a hi
yroiditis
e numb
ds to induce
s provided on pa
y of th
id hormones as well as th
ng
ud
id not
increas
SDR
 b
concentr
-TSH-receptor antibodies
ciati
al ex
population ana
and do not establish causa
inding
en perf
ccupational, communit
T
cti
ng
e are
 d
videnc
ed
s th
gnosis. 
ave been r
 wa
yro
-sectional studies as the
on studies ex
poun

al Ft4 in the presenc
twe
re
s but no
nd
y A
s.  
iz
sig
cy of f
or
ctional with one stud
 b
TSH level and e
as anti
tions in th
gh a larg
(c
and 1 st
ine fT4 
a summar
ted) in o
 
inding
ent
make
aracter
shimoto'
 “no asso
ccupation
67 
yl com
Thus, on a 
re not listed in these tables and the 
OA 
e of cross
OS.
yrox
Ha
ere
ents on Thyroid
alida
ross-se
nconsistent e
as a norm
eased 
al populati
Althou
onsisten
ciations be
anc
y ch
cr
the o
).”  
y v
r in the supporti
 c
ectional 
A/PFOS and an 
e i
e w
-237) as 
gns a
or PF
ture of f
O
y statem
ner
h TSH, T3 or T4 h
ote, “
luoroalk
 to the ATSDR, this includes “increased 
y th
OA and altera
e 222
-sectional in de
 the c
ponder
OA or PF
s a de
idase in 
wr
est asso
.  Similar statement
y desi
yroid is disjointed a
y defined 
pag

ross
ding
erum free th
gg
rding
)”
medicall
tion.  F
re cross-s
pre
nlike other sections, ther
PF
een PF
art, b
summar
is clinicall
all
c antibodies, such 
erox
238), ther
n the ge
so wrote, “
m PF
thoug
 c
al
cco
e th

y also contribute to the dia
(pages 223
.  U
cifi
ener
at 
ATSD
clusion that ATSDR 
 ma
A, PFOS
 informa
yroid p
ists betw
ack of 
on
yroidism 
g spe
 —
as well as 
ex
y studies su
FO
 text presents a mix
nti-th
Detailed Comm
 
y ATSDR
ction for either 
ypoth
e 5 and 6, 
  
ation and a low s
yroidism is defined a
eported 
l populations.  Stud
y h
yroidism is g
yroidism
ge 222, ATSDR al
iation between seru
R conceded th
ature.  The l
ls. Measurin
D
amined the potential of perf
lf-r
yroid. The
yroid se
yperth
n pa
On pag
ex
most of the studies are
a number of factors inclu
epidemiolog
health outcomes.”   A
disorders.  (P
provides Table 2-15 
table contains both studies that reported both th
(se
genera
to the supporting
misidentification discussed earlie
studies listed in Table 2-15, 20 are
studies in Table 2-15 we
did not comment on this 
th
provided b
th
mments
 
ATSDR’s review of th
“association” 
confusion is caused, in p
liter
support for the c
 
Primar
concentr
hypoth
H
leve
disease, or a
hypoth
 
As ATSDR wrote (page 
TSH or T4 levels found i
O
assoc
ATS
consistent across studies (
 
ATSDR position
 
 
3M Co
 

 
 
 


 
es 

mal
r, the
iven 

tor to 
s 870 


d to b
ts where
y of 
 
  
ctional 

ust 20, 2018
wa
 
nland 
OS
).
3M Comments
ndica
 tests done for 
peare
 population 
nvertino et al. 
eiss et al. 
ism).  G
ajorit
tee
n tables (see 
 statisticall
Aug
PF
onvertino et al. 
ge in TSH 
ine without
orted b
irect conflict 
C
ange 
ons for fe
yroid
e ap
”.  Howeve
e in the lipids 
chan
y wrote: 
alysis, an 
ported for
FOS in ra
yrox
yroid
(in retrospective 
 P
 valley
 and S

gnostic i
OA or 
gory r
e to displacement of 
ed the m
s no 
not supp
ate
. Ther
 for
ree th
yperth

re the
tive analyses
tive an
 informatio
eported no
l dia
A
ested to Co
sum
inquist
 to PF
 wa
O
rted
 wa
ribed abov
y be du
ases f
pre
W
ghest c
) PF
po
ported associati
-Ohio river
 and hypothyroidism among 
ong wome
prospec
 clinica
mmonium salt) (
L
view of Winquist and Steenland 
posure
OA.  
re
(This would be in d
d (hi
/m
 et al. 2007,20008; W
(in 
ct is re
y incre
yroidism, h

nland 2014) r
mary
it can be 
r, in prospec
th ex
OA (a
y is desc
ng
sition point than re
on TSH sugg
fe
tl
th
his finding
 the mid
on section whe
hypothyroidism was found in me
F
e T4, the usual two th
ant but ma
2010) re
ed PF
ve
yses. 
asure
an
ect 
Stee
e pri
g wi
re
n ef
hypo
between PFOA exposure and fun
ATSDR 
No associations between cumulative 
gnific
anal
ransien
t al. (
ysis of
hyroidism were found in retrospective 
kin
nd f
ion functions, there
er (
perthyroidism
FOA tr
yroid.  T
rent eff
y si
er e
y the 
).  Howe
68 
l trial of P
e 238, 
 – ~632,000 
ll
eenland 2014 supporting
yroidism in women in either their retrospective, 
ctive 
L
 
), is lac
 TSH a
ypoth
inquist and 
/m
gher P
ter that contain
y their Discussi
 
rospe
y distribut
FOA.  Such a
 proteins t
e h
act:
y for hyperthyroidism am
ypoth
an association 
yroidism among me
 serum PFOA and 
.”
 p
t a hi
y P
yroid disord
yroidism in females, 
 wa
or h
in particular TSH (th
hyroidism
hase 1 clinica
amined for
nt.  The phase 1 trial stud
4) a
e with no appa
ne b
ormone homeostasis (Chang
ses wer
y Abstr
ot supported b
eenland 2014b
ulative
2014b)
inquist and St
05) f
centrations of PFOA me
T
ypoth
R wrote on pag
(f
 “current thyroid disease with thyroid medication
e ca
erthyroidism or hypot
eTable 6 in W
evels, 
ypert
ying year, or
yroid h
y type of th
nland (2014) in their anal
evidence of 
nland 
gh 
cians ex
ce of h
ver, is n
assessme
μM (~360,000 ng
ine from binding
aving
tee
 
) and for hypoth
alif
ysi
ghest con
ase in fT4 was not clinica
all th
posed to drinking
n.”
 the ATSD
ends (P < 0.
μM (
yrox
ysis of NHANES data, Melz
e found 
re
inquist and St
ysis of the W
hypo-or h
yroid 
ased on the probabilit
er
evalen
al
ase in free T4 
nal
valent femal
e ex
r, this was not supported b
W
he
abovementioned p
l th
 ov
r a
h pr
“Associations were observed for hy
wome
 

thyroid disease, especiall
analyses
nose 
1530 
yroid bound hormo

aced th
gorized as h
Table 1 throu
yroid hormone l
inquist and S
inquist and Stee
nificant tr
trospective qu
th
diag
   
In the 
2018), the ph
clinica
section.  B
even at the hi
μM 
an incre
cholesterol.  This increas
that the incre
the th
displ
altering
2009).  
 
In thei
cate
did not delineate b
the hig
these pre
W
who wer
(2014) wrote in their stud
 
 
Howeve
 
This quote, howe
(2014) w
serum PFOA and hyp
analysis (W
association between cum
(W
 
Indeed, an
the e
sig
re
 

 
 
 
re
t al. 
s and 
e trend 
trend test 
yroid 
 males, 
ust 20, 2018
yses 
 
yroid 
 th
y ATSDR, is 
ts as related 
3M Comments
nal
For 
.1 and < 0.2; 
ests with a p- 
d tests with a 
ong
sease in male 
nd et al. 
p valu
“th
 b
for
87, and 0.23; p 
Aug
.05; 1 
 for
dism“  whe
xis
es.  
nla
 
test a
>= 0
end t
yroi
yroid hormone
 tabl
yroid di
t al. or
end 
 4 tr
ypoth
e, 0.79, 0.
ciation e
-values < 0
etween 
ere
< 0.1; 4 tren
 12 tr
 w
e h
enland e
renc
fact, what Stee
fe
n asso
yroidism but none
ciations of th
tions do not support an association 
In 
e, 1.64, 1.13, 2.16 (
this information as 
y Ste
nificant) in women 
 
nc
 published in 2015, Steenland e
ed 
 1.0 re
there were
erva
n.  
men, there
>= 0.05 and 
ith a p-value >= 0.2.  Am
y,”  
nd for mal
sed b
ot sig
g asso
r, 
 hypoth
re
efere
ent
onclude a
) in these supporting
g women with p
 with a p-value b
 wo
een 
ts w
for
OA and the risk of th
gethe
ese obs
tw
end (n
g wome
tr
ce to c
lative were
regardin
 
-values
 0.05 
orks facilit
nificant t
e 1.00 r
ve 
69 
at in a study
rum PF
r table pres
-sig
 
ature 
.).  Alto
ton W
isk wer
ype.  Not discus
egati
t al
nds in re
nd test p
end tests amon
yroidism among
y n
ver, thei
icient eviden
 
er e
ge 222) th
 tre
 0 tr
 
yroidism amon
ashing
OS.
elz
del tre
ere
nd < 0.1; 3 trend tests
-value >= 0.2.  Th
th
elative r
equall
 in the liter
yperth
s with a p-value be
< 0.2; and 2 trend tes
ee pa
on between se
W
positive non
howe
ed to the t
r lag
es p = 0.13). 
PF
 h
an 
r mo
ypo
s a 
-yea
for
e is insuff
 
wa
ntiat
gori
nds in r
OA or 
s from M
s at the 
e was 
oid disease
cate
g linea
end tests with a p-value <
 tre
een 0.1 and 
ker
her
 the 10
se, ther
tw
 4 tr
es p = 0.06), 
 to PF
wor
“there 
hat t
 on thyr
yroidism, there w
 0.05; 2 trend test
yroidism.  
year lag
gori
rth
posure
emale 
ate
yroid disea
with the finding
conducted (lo
hypoth
with a p-value >= 0.05 a
and 8 trend tests with a p
between PFOA and h
 
On the other hand, 
value <
p-value be
there were
hype
 
ATSDR also reported (s
“did not find an associati
or f
wrote, was 
the 10 
via c
disease” not differe
the fact t
disease where
value trend via 
 
Given the inconsistencies
th
to ex
3M Conclusion
 
 
 
 

 
 
es 
-
t al. 
gate 
-
AS 
ensen 
cines 
gen. 
rious 
 
ross
er e
nasal, 
es 
tween 
 
h va
er 
ges in 
ust 20, 2018
re
ook
H. 
sponse 
vaccine
3M Comments
 we
ther PF
red. The 
 et al., 2014) 
studies, 
 studi
  (L
b), 
tinct vac
mumps and 
oug
onse, 
y diff
e re
se is 
(2013), a
stent with 
Aug
ink be
esponses to 
012; Mog
er
”). 
cine anti
.g., intra
ll vaccines 
d chan
ic 
easles studies 
sp
easu
ook
(killed), conju
y, a
ve
se to Vaccin
 m
L
e vac
y re
ic studies (4 c
tion (e
as consi
 
ccinations
ra
emiolog
) were
cine with 5
ean et al. 2
e which ma
ted 
eA)
pid
a B
ndj
different vaccines may 
ature of th
he antibod
efore, obser
 Respon
OA, PFOS and o
a A/H1N1 (
e inactivated 
mune response thr
accin
rences in immun
 the e
esponses to vaccines
, PFD
y titers to va
prove t
 the v
”. Ther
nce is suggestive of a l
theria, tetanus, mumps, measles, 
17), two rubella and m
fluenz
 responses to these 8 dis
y r
cines whereas measles, 
ystem. Additionall
m, which can explain the 
om 8 epidemiolog
erum PF
 influenz
he tetanus vac
num et al. 2013; Kielsen et al. 2016; 
nfluenza A/H3N2 studies
hod of administ
s an im
m
ng
the diffe
ot be interpre
xS
and decreased antibody r
g on the n
ccines ar
luded that “
 and
a studies (Gra
va
cit
evide
antibod
” (NTP 2016).  Granum et al 
 and in
antibod

ter 2007).   
ated/effective antibody respon
edged 
conc
xposure
 levels 
was to t
et al. 20
xoid vac
and met
deliveri
une syste
A
ependin
ax
ments of s
s (i.e., diph
2017; Gra

a B
et antibody
 to

B
elev
lso 
70 
, PFH
in 
S
esponses to mumps (Stein et al., 2016
eased 
e type eli
e (
knowl
ne should n
sure
a A/H3N2
fer d
Influenz
 adjuvants to i
le, a
et al. 
y r
y.   
ecr
s of the immune s
cci
creased Antibody
response 

y 4 diphtheri
ud
accin
ccin
The strength of an antibody response in terms of 
 PFO
d b
ram ac
xample, are
ft profi
ffect of PFAS e
A,
S, and PFDe
inct vaccine
ndjea
 on the stra
y 1 st
Hx
 this conclusion comes fr
ortive animal studies.  Among
ist
vaccine 
ra
llowe
2016; Grandjea
. Antibod
2013), influenz
SDR to interpr
e (i.e., “d
vaccines dif
d that “
for e
ing
y, each v
echanism
n the va
y Prog
 of time that an 
R dra
the e
rticular va
FO
F
fo
T
ed vaccines. 
cument concluded that 
ctive cohort) in which 
ed 
t al. 
g o
r A
ers, and vehicles fo
epend
es in 
ents on De
(P
do
cipients including
ft 
icolog
a A/H1N1, influenz
ned in onl
and state
m
y studi
num et al., 
cellular m
m
al. 2013; Stein et al. 2016b) and two i
ra
ami
riate fo
y available 
el and length
 
esponses to 8 d
ex
y dependin
e live attenuat
esponse to a pa
Co
”.  Evidence for
 (G
y r
an et al. 2012; G
en et al. 2015) 
le health outcom
atives, stabiliz
tional Tox
y r
 commonl
ndje
ens
num et 
each 
osition
ls, coupled with supp
bod
lla, influenz
lla ar
y cited in the ATSD
ra
ra
ectable). Consequentl
serv
The ATSDR dra
serum PFOA, PFOS, P
vaccines
sectional and 4 prospe
quantified in combination with mea
leve
anti
rube
most
(G
Mog
et al. 2015; Kielsen e
(G
2014; Stein et al. 2016a))
influenza
were 
mments 
It is inapprop
as a sing
Commerciall
Tetanus and diphtheria, 
rube
or live attenuated d
inj
molecular and 
contain various ex
pre
substantiall
 
The Na
across vaccines, 
antibody lev
maintained is known to differ across vaccines
stud
stimulate different components of the imm
dependent differenc
antibod
Detailed 
 
 
 
ATSDR P
 
 
3M Co
 
 


 
 
 
te 
or 

 



ypes 
cant.  
S, 


eported 
d fo
nifi
ust 20, 2018
y illustra
Hx
FOA), 2-21 
rl
y r
rve
3M Comments
ocument 
P
y ATSDR. F
ud
studies, 
 cited in the 
ociation 
 vaccine t
f the 18 
y sig
Aug
gnificant 
ant) finding
t d
gs (i.e., the 
clea
r 4 
-19 (

 a si
y 5 o
FOS, PF
s 2
y one st
cant ass
gnific
y findin
gure
viewed b
 also obse
amined antibod
-si
e statisticall
gure
e fi
nifi
s across all
nt for P
ic stud
 
a sig
y non
xample, onl
ines as distinct health 
els wer
).  Thes
hile both studies are
sults were
The ATSDR draf
ls) in Fi
A
wo influenza studies with mostl
ion, finding
De
ported 
y lev
nd mostl
ne.  
l vacc
demiolog
 leve
studies that ex
et al., 2012). The othe
12, did not observe
al., 2017). 
ults from these two studies wer
heir omission.)  
re
dit
-19, for e
bod
re also appare
AS
(PF
an 
om t
 2
acci
ts epi
across the 8 studies re
rum PFOA levels, onl
n et 
at res
anti
ndje
consistent re
 In ad
ra
ypes a
esen
esults fr
ge th
Figure
71 
nd 2-27 
 and 
an et al., 20
 r
ge in 
consistent (a
y pr
OA, in
cine t
ll
els (G
chan
NA) a
relative to se
r PF
 the in
y lev
Grandje
els (Grandjea
all vac
lative to serum PF
e 2-19 are
d fo
raphica
y lev
esponse to another v
 g
y of 
ls re
ts both within
l. 2014; Stein et al. 2016b). W
elow), shows that of the 5 
accine 
tibod
gur
 and provide reasons for t
erve
A.  None of the 5 studies 
y levels and PFNA. 
OA and a 
sidering
y r
une responses to individua
file
), 2-25 (PF
sul
an
F
S
et a
De
re
bod
bod
y leve
-up stud
antibod
igure
ft pro
FHx
A. Con
y in 
sults obs
er imm
e 2-19 (b
ease in 
ooker 
eit
L
he anti
ATSDR should acknowled
S and PF
sid
ecr
  
s (
anus anti
gen
igur
 a follow
om the F
Hx
es.
ges in t
tero
om
ges in antibod
OS), 2-23 (P
 also inconsistent.   As presented in 
ample, F
nificant d
ote: Not included in Fi
ft profile, 
OS, PF
re
NA, and PFDe
chan
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have identified associations between 
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or a link be
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between PFAS levels an
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The strongest evidence f
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PFOS exposure on 
 

 
 

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3M Comments
ngst other 
ns reg
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ence of 
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nsistenc
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IVM, 2016):
 
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with variations
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more tenuous.”  
observed across studies, 
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characteristics. Moreov
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the association remains unclear
PF
 
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of dec
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ust 20, 2018
n et al. 
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74 
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f c
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port
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vailable studies
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the draft docum
epidemiolog
anum et al. 2013; Humblet et al. 2014; Smit et al. 2015; Stein et 
f se
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rted asthma wh
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TP, 2016)”.  The 
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sthma questionnaires 
low). This 
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and an increased risk of 
studies (2 prospective co
that ex
ATSDR provided no interpr
conclusion of a “possible
document is the following
of an association between serum PFOA and asth
although this find
allergic sensitization does not appear to be associated with serum PFOA 
mments 
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that exposure to PFOA d
responses based on the a
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which wa
to whether exposure levels reflect ex
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1993). Consequentl
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al. 2015); (
2013; Z
same population (456 Taiwanese childr
of Childhood Asthma (G
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odds of a
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posure
pants who self
ere
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w
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75 
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ficant asso
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Z
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nd included in the statistical ana
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tioned in the ATSDR 
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association between PF
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nosis was v
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end 
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years (OR for hi
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pre
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prof
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associations wer
associations wer
age 5 and 13 
evident b
prospe
 

 
 
AS 
n 2 and 
y its 
OA and 
ust 20, 2018
en PF
 
3M Comments
n PF
iation 
Aug
we
renatal 
ened b
ee
y temporal 
ngth
essment. 
gnosis in childre
 
ss
t an assoc
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y wa
nosis. 
sthma dia
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rt studies are
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This stud
 
xamined the a
asthma diag
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port
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y vali
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nifican
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lidated 
evidenc
76 
a diagnosis
ic 
s, and unv
lated outcomes.  
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blood and medica
thma re
essment and va
s have consistentl
s-sectional and ca
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ased risk
consistent finding
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Investigators found no sig
ly, cros
rom cord 
OA and as
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k of 
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y, the e
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years of
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Childhood Asthma (ECA) birth cohort which e
mea
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ex
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the 

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Fertility 
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clude 
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y studies hav
th effects, 
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es adjusted 
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and the stud
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yl ex
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agraph 3.  
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centrations a
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 studies that desc
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Pag
be effects on f
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 2-31.  This fig
fig
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and do not establish causa
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serum conc
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and
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FOS 
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FOS 
emiology
r PF
l issues 
luoro
ages 318-
-32. This 
with “incr
rf
gure
ilure
77 
yl com
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y sta
posure
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fi
es.  Thes
OS for 13 
e 2
rit
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onsisten
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OA and P
nc
e provides infertilit
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ge 333 is F
ig
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assessment of
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tion between an i
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rences.  This fig
Table 2-21 (p
parous or nulliparous. 
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fined PF
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atified b
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OS).
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most of the studies are
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page 327 is F
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conclusion that ther
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OA and a 
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ified ana
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by ATSDR.  
ment: An 
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g equal, those wome
y be an earli
longer interval between 
y parit
?  Epidemiology
man f
ations at their next birth 
spe
9: 
a cause of PFC conc
ditions of causal inference.  
conundrum of trying t
e long serum eli
r the reasonable assumption 
trates the c
e obtained copyright figure below)
en births (
entr
l (Fig 6)
y with women in the Danish National 
(se
 con
s the 
 between births and so may ha
y.  This would result in longer 
lit
data b
Commentary
 and hu
al per
heir pape
ausation
of the ori
ic
al. 200
e, unde
 but the direction of the causali
ises from not explicitly representin
 level ma
 betwe
(the first to do so) be
erti
 c
et al. 2009 wa
als
ight
All else bein
 time
tes the
 to absorb PFCs that could replace
inf
y their 
rse
mic
2012). 
eview 
icolog
ecundity and 
 highl
ge 228 of t
xt pregnanc
78 
ciation 
y a r
n who begin with comparable PFC conc
ote: Olsen 
yl che
e pa
me, it
entrations.  This illus
l and tox
hen the actual
ome
(Fei et al. 
tween births.  
e depicted in Fig. 6 
utcome of f
nge that viola
ial cycle that ar
wer after a pregnancy, a 
e different PFC conc
 with PFC levels,
  
h compounds that may hav
FOA.  For exampl
e for a woman
y did not stratif
luoroalk
al question of Fei et 
ic
cha
 hav
 longer intervals of
h clinica
. wrote (se
eported an asso
the
 link based on reve
Perf
ill be lo
y and an increase in 
as prompted b
al. 2009) (N
og
en wit
), 
l have
els prior to the ne
y: A
 ev
ncountered when a causal mode
en et 
 PFC level over ti
yclic chain.”
e 330
ysis w
years later (see 
ls
evel,
gnanc
ecundabilit
y (O
ic review wit
ion of
et al. 2009 see 
ted methodol
h a current PFC level, w
ferent l
 PFC levels w
asurements associated
pendent c
ei et al. (2009) r
 “Another troubling issu
is that parity is both an o
this induces a cyclic 
Although this is an artific
variat
wit
dif
lives such as PFOS or P
that
would result in more tim
incurred from the birth.  W
and equal parity may
on the time that passed be
longer TTP wil
higher PFC lev
me
be backwards: it would be the longer time
resulted in higher PFC conc
that could be e
de
lsen 
hile F
irth Cohort (pag
s published 3 
W
decrease in f
B
wa
and time to pre
This stratified anal
publication b
For O
epidemiolog
27:212-230).   Olsen et al
their suspec
 
 


 
 
 
-
er, 
n may
e is a 
ver 
n, an 
en 
ext 
rease
FC 
dity at 
 of the 
hitworth 
s of 
earli
OA and 
el
un
ust 20, 2018
ed ev
3M Comments
 (2009), 
us), the 
oned 
f their 2009 
Aug
y with their use 
hile W
 to PF
ro
ing the 
arlier, ther
ver, and 
ow
e more 
y o
g the timing
     
ct on subfec
ase.  W
posure
 be produc
ffe
y histor
y Olsen et al.
tab
hich levels can inc
y and infertilit
) da
y and ex
res to the toxicant vary o
nanc
ised b
A
us and nulliparous wome
ry.  As noted e
history and current lev
dity may
pregnancy, deli
hild and the start of the n
ring w
unds.  Based on the nulliparous 
dverse e
 ra
y (nulliparous, pa

un
y preg
ne.  Therefore, as menti
tion
compo
 b
cundabilit
y (MOB
y parit
men.  Whitworth et al. wrote the 
l. 2009) and regardin
en exposu
 It is possible that foll
icol 27:212-230. 
es
ud
ecundabilit
ese 
ysis
ata b
th
ase f
 
anal
sue on fe
re
arous wo
79 
y Olsen et a
g p
 for a longer time du
on.”
tation and qu
ncrease to baseli
low
pre
particularly wh
cokinetics of PFCs during pregnancy and lactatio
oncausal association between subfecundity and P
ised b
atified their d
en a woman’s pregnanc
d amon
:  
l al
sults we observed among paro
al. 2009.  Reprod Tox
al inter
xamined this is
 and Child Cohort St
ey str
erve
ion
stion ra
ic
n our populati
y factors related to pregnancy histo
ernal PFC levels observed during 
association with dec
empt wil
hen th
y obs
 to the pharma
evels i
s onl
on, the levels again i
n in our study, we found no evidence of an a
e of the que
rom Olsen et 
egian Mother
ver, w
.  Due
els.  Results from women with no previous pregnancies may b
th et al. (2012) e
 in their discuss
Fei et al. published their stratified 
    F
“The discrepant re
be explained b
complex relation betwe
environmental toxicants, 
time
apparent association between PFCs and subfec
when a causal association does not exist. 
decrease in mat
lactati
a long interval between the birth of the previous c
pregnancy att
potential resulting in a n
lev
informative regarding toxic effects of 
wome
the PFC l
caus
hitwor
OS; howe
Given this methodolog
W
of the Norw
et al.  also found an 
PF
association wa
following
 
 
In 2012, 
paper be
                        
 
 

 
 
 
 
re

 
 
A)
y, 
 
re 
ction 
F
ast 
O
and 
. “
nd the 
r parity 
 the 
 a 
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n may
iled to 
OA.
P
ay serve 
 to 
es
ust 20, 2018
 m
FCs)
y ORs we
d limited 
), but at the 
A/PFOS.  
inal sample 
3M Comments
Introdu
oduc
women we
ards the null 
on for
we
med further 
anish National 
rig
the pooled 
DR fa
and PF
, studies b
Aug
(P
tilit
iations.  
tnoate (
eal
causality is a 
esent and p
n with longer TTP 
e pr
elco
n the 
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atificati
rote “
e 328)
assoc
e in their 
.  Pr
hemicals 
 not measured at
whe
rticular D
uoroocta
s, 
creased infer
ted more tow
ysis of the o
ge 325), ATS
nal
 perfl
n pointed out by Olsen 
elationships among these 
 al 2012)
rol confounding.  However, a 
the measured PFO
gure
ach et al. w
ohort.  Reverse 
verage, wome
cundability.  Adjusting fo
OS were
in the available data, the 
C
 influenced by TTP for parous 
 of this pa
P to 
mained after str
 al. (2012) wrot
sks attenua
re associated with longer time
erfluorinated c
y Fei et.
 OR and in
 surmised their stud
updated a
PFOA and TTP in parous wome
sion (see pa
ATSDR notes (pag
S.  On a
hich would have been id
or their results and w
alyses
12)that reported no 
hence cont
hemicals.  Such influenc
ility
er old sample, but we did not corroborate 
g parous women with TTP 
) we
 past pregnancies and deliveries
(w
esenting the r
ved.  Thus, 
ab
ese ri
as an 
g, as 
ei et al.
ation f
 w
’s discus
amon
et al. 20
eption 
nd th
80 
) repr
(provided b
terminants, and those determinants confou
n, that arrow does not exist in a model that 
ecund
plan
 
y.]   F
 includin
 high maternal levels of
AG
 additional an
ompounds.  Fei et
he association, as has bee
(D
e DAG is that PFOA/PF
yed in their subsequent fi
re
Danish National Birth 
 to reaccumulate p
gure. 
mon de
t pathway and 
ad been achie
ulation of the c
h the arrow from TT
In ATDSR
 causation’ 
estergaard 
om
y h
creased f
Note: the association re
”  
els of PFOA and PFO
, de
 (2015).  There
arous women a
l. 2012 stud
ation as an ex
there we
rinated c
ditional 440 women included.  B
) in the 
012) wrote,
 
5) displa
en.  [
al.
on.
orthcoming
reverse
 f
nd (V
ylic graph 
rity
) were driven by the larg
luo
e 32
 that 
an ad
y towards an association for 
erf
(TTP
ei et a
e caus
ausati
xplanation for t
y pa
ach et 
nc
 
 had more time
ted ac
ous wom
:  
er, for nulliparous wome
evers
y B
, Fei et al. (2
n through reaccum
 r
re
undability share c
asurement of PFOA/PFOS can potentially be
this issue of ‘
et al. 2014) a
ment of p
gorized b
(both samples
 
“In 2008, we reported that
and perfluorooctane sulfonate (PFOS
pregnancy 
possible e
colleagues.  Even with age adjustment,
to lower stored lev
will have
 
“A direc
factors is shown in the Fi
fec
relationship between PFOA/PFOS and present fe
should serve to block tha
subtlety not capture by th
beginning of the attempt at conc
end, after a pregnanc
me
wome
cycle in the graph throug
Howev
adjusts for age.”
OS in the F
e for
ious finding of an association between high PFOS and longer TTP in the new 

ate
 nullipar
sure
ollowing
gniz
ensen 
irth Cohort b
org
mea
the f
 
Furthermo
 
As the ATSDR (pag
then c
more often found in the p
among
with PF
evidenc
studies.   
 
ATSDR was correct
B
n = 1161 as well as 
analyses 
our prev
sample.  The tende
be due to reverse c
reco
 
Additional studies were
(J
 

 
 
 
y, 
tion.  
lez 
an 
– 


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y is not 
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AS levels 
AS and 
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er time 
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rum 
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y found 
sult of 
amination of 
3M Comments
C
abilit
ong
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OA (not 
owe
atification 
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f se
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f pa
Subsequentl
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ociation with 
re
 and 
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 as the metric 
long
Aug
hich showed 
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easoned that 
n TTP and 
en PF
tud
of
mented or 
odolog
ATS
ex
y r
ee
y reported 
ass
gh 
yzed
.  A 
ouis et al. did show 
ying the potential 
yses o
eview of
y one s
nancies
e docu
rou
xt pregnanc
(2013) w
L
ed fecund
r Whitm
not cited
OS (odds
above.  
FOS.  This could 
– 1.17) am
y with PF
anal
irth Cohort.  
gued that i
y.  The
eg
e 2009.  
posure
uck 
elow the limit of de
eas
n stud
y) as the
h collider str
B
ar
ausal but a 
y ATSDR 
en anal
et al 
tio 0.94, 95% 
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ssed 
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ecr
I 0.71 
ertilit
ecundit
y whe
rhus 
.   
ar to hav
y, wh
OS ex
ouis 
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ystematic r
y not c
L
ak d
ouis 2013 o
rit
AS
– 1.17). B
OS) but this finding
L
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n association betw
stricted their 
-1.30) and PF
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rtilit
y and inf
 discussed sinc
85 
(95%
ity, infertilit
f PF
f PF
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ed a s
uck 
educed f
udies discussed above, h
or pa
ter
93
by ATSDR) 
e omission b
assessment.  These meth
t basis to conclude that there
S)”
 
the start of the ne
om the Aa
of a
urious association betwe
not appe
A or PF

on of PFOA or P
y Buck 
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ed
B
g re
I 0.
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adjusted odds ra
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rt
as r
er st
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tion issues addre
abilit
and 
y b
for
po
yses f
adjustment throug
ng related to prior pr
eas
as 0.91 
 w
en PFAS and TTP.  Onl
atter was likel
and th
ficien
cr
mulati
re
al
conduct
ement o
tensively
A, PFO
y re
y oth
over 
y havin
evidence 
cund
ex
O
 child 
81 
y amide o
ents 
-eviden
accu
er stud
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m
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ccumula
easur

gument in a let
s no 
confoundi
f-the
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re
y their an
eas
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vious
y for
tio 0.99 (95 C
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ar

atu
2018 document. 
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tio 1.10; 95% C
y ma
y ATSDR) 
ht
rtilit
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sure
e the m
ig
ssociation betwe
concluded the l
y liter
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dabilit
y, including
odds ra
A (the primar
S
the measure
orth (2016) onl
uartile distance w
ither of
TSDR 
5) concluded the
dy.  Unlike man
or stratif
cts (decr
ould introduce 
ned this 
TTP to 1,372 women
dds ra
ausalit
n due to rea
ed to nulliparous women; 4 studies reported an 
al. 
mea
on in the literature 
 we
ghts have been 
og
liparous women for PFO
of the pre
otential for re
O
fe
ach et al. (2015) b
rted there wa
ach et al. (2016) (not cite
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gical issues, ATSDR does 
ate
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% of 
hitw
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IREC stu
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cids and 
an fertilit
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B
essment as there
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cre
greater p
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OSA (interq
amined the a
n
en the birth 
OS (adjusted 
cause 90
 on parit
lez et al. 
yl a
et al. repo
ation and un
n appropri
nanc
produ
ls of PF
bove discussi
yses and insi
y criticiz
s of hum
 on i
et be
 re
I -0.95-1.29).  
 cited in the draft A
y, Vé
et al. (2016b) 
e caus
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n the
luoroalk
y, Bach 
sure
eased risk of d
tio with PF
re
OS) in the M
ach 
vers
consider its ass
ATSDR did not include the preplann
no association with fecun
1.10) or PF
an association with PF
interpr
Another stud
ra
primiparous women.   Ne
we
 
Finall
PF
et al. chose not to adjust 
adverse
conditioning
bias. Vélez et al. maintai
whe
perf
stud
serum leve
95% C
conditioned on, reve
and TTP in parous wome
B
mea
studies that ex
association whe
parous women.  
re
childbirths that could influenc
 
Given the a
these above methodolo
conducted a
issues, anal
re
“incr
this published epidemiol
 
There
time to preg
period betwe
will allow for a 
 
3M Conclusion
 

 
 
 
ust 20, 2018
3M Comments
Aug
en assessing
 
OS.
ous women wh
OA or PF
ed in par
cy with PF
nan
82 
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ausal associations observ
ic of time to
y the metr
sult in nonc
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cundit
potentiall
subfe
 

 
 


te 
ra
y of 
egri 
OS 
yses 
-2.72 
ysis 
ased on 
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ritical to 
levant 
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association 
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ly re
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tion.  B
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g chan
ar f
meta-anal
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meta-anal
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al
nd P
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ly birth
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ohnson et al. (2014) and 
t to these two studies.  
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centl
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papers 
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l g
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t al. 
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Althou
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L
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er e
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luoroalk
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luated birth outcome
-7.92 g
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or PF
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al Prof
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nt wa
t eva
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%.”  On page 381, ATS
ysis, the
r 1 ng
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g ch
ge (-181, -1.11
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SDR provided no historical contex
nt infor
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additional meta-anal
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FOA is likel
TSDR stated there
whe
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mportant issues were
t al. 2018).  The latter
ic
cco
es in birth weig
an
l i
icie
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ght pe
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I -21
y and
cusse
ff
ATSD
y studies have found 
eas
).   A
era
sults have been found 
nal PFOA or 
 estimated that taking
g ch
I -3.40, 
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icolog
crease in 
% C
nland e
espectivel
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rd blood.  F
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ic studies tha
ther
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L
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ht (95
at deliver
addition, two 
Detailed Comm
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t al. did at -5.00 
t al. (2015
 whe

g/m
es in mater
sults b

d in co
   
ge (95
Epidemiology
S).”
eas
ge in birth wei
sure
sure
an
ortunatel
ohnson et al. (2014) 
amined the potential of perf
O
posure
ohnson et al. (2014) for
rner e
rner e
ists.  I
e ATSDR Tox
 
On pag
ex
most of the studies are
a number of factors inclu
epidemiolog
health outcomes.”   A
per 1 n
PF
epidemiolog
states, “mix
Some epidemiolog
ex
incr
birth weig
these re
of J
Johnson et al. meta-anal
chan
the same number of
birth weig
simulations, they
would reduce this estima
mea
mea
Ve
attenuate to -1.46 
g ch
mments
 
ATSDR briefl
Ve
Unf
deciding
ex
et al. 2017; Stee
journal 
lower birth wei
(se
 
First, as a minor point, A
by J
 
ATSDR position
 
3M Co
 

 
 
 

gm 
rs 
nd 
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ic 
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as 
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hich 
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hl
ohnson et 
ase in 
In thei
fter 
 the
ust 20, 2018
ohnson et 
t al. pape
ht births 
sult, the 
R.  As with 
ause it w
ted wom
nanc
uence that 
 PFOA 
AS resulted 
3M Comments
by J
. (2015) meta 
ut hig
id J
d “limited a
their 
 The 
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a re
eliminated via 
ciation 
od. 
Mother Child 
n in Morken et 
aternal and 
ed a
here
PF
Aug
not include the 

11) papers b
(2015) (w
reg
e of the 
mall studies 
l GF
epidemiolog
ociation was 
et al
 these two 
rner e
 p
epidemiolog
g/mL

r weig
laps
rge b
 
AS 
asso
ian 
y foun
sult in an increase 
e siz
ery s
r n
Kim et al. (2011) were
s show
cy).  As 
f 953 selec
e the 
ected 
considere
ere la
ysis than d
en et al. 
al. (2014). 
as that the i
 PFOA.
nan
lationship bec
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cord blood 
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FR during
should also include the 
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t al. (2015
AS concentrations retained due 
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iltration ra
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ashino et al. (2009) an
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tal 
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gest published stud
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impre
papers a
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inconsistent data that we
fe
et al. (2014) pap
systematic r
included most of the auth
hypothesis (discussed b
plasma volume ex
in the materna
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systematic r
lar
published after their 
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infant birth wei
associations.  [
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that we
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al., Verner e
GF
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3M Comments
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SDR to conclude that there is 
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sample collection later in
 
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Johnson et al. (2014) included the publica
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transformed) 
birthweig
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associations from studies conducted in Asia 
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blood.  The latter
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timing
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confoundin
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ust 20, 2018
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Note: 
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posure
3M Comments
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aternal or 
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conception (5393 births),
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small and not likel
 
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ft 2015 
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3M Comments
escribed on 
he dra
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hould be 
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9, 2015, and 
luorooctanoic 
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FOS; 4) a
  
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and a peer 
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health effects 
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2007). More
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fig
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L
Abbott et al
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tion.
icol Sci 131 568
icol 84 787
jork et 
yl CoA ox
n et al. 2008; Koskela et 
plain wh
n mammary gland 
y b
y studies su
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ex
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s around 75 
n Chapter 1. Other
alit
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palmito
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cte
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us
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rc
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-99
ara
ta to 
al loss, reduced neonate weight an
e stud
mode
chie
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which followed a 
al. 2013 Tox
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eptors in its discussion, such as CAR/PXR.  
patic 
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mal 
en a
et 
ar rec
eacat et al
were
91 
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nt stud
-401), 
et al 2010 A
-489; Albrecht et al. 2013 Tox
centr
y burd
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ed to refl
 
nt ani
icokinetic into considera
icol 33 513
eleva
icol Sci 111 89
ys in S
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ng, vaginal
ng et al. 2013; Johansso
eiv
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sleadin
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ns provided on pa
are mi
ith differe
t final bod
king
prod Tox
by Elcombe 
09 Tox
ng
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m lipid profiles 
se in serum cholesterol o
ical Prof
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icol Sci 92 476
icol Sci 156 387
ea
e misperc
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Specific e
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r liver 
adin
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utenhoff e
uvel et al. 2006 Tox
listing
“associations” ma
re
 
– 9:
Figu
differe
the
re
Unde
2010 Arch Tox
B
 
ATSDR should also include other nuc
It should include studies 
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582; B
8-17. 
ATSDR is incorre
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al. manuscript).   
ATSDR should also cite another r
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out. 
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rtant aspects of 
In addition, 
developments 
010 Dru
012 
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y in rats (Perkins 
g during
olf et al. 2007; 
g data to illustra
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sed
spo
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W
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hite et al. 
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y meanin
enhoff
enhoff
al. 2014; Onishchenko 
009, 2011; 
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nal influen
et or
ut
ut
pellin
s medi
il et al. did not evaluate the 
ies which pr
ented b
y gland du
y W
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te such man
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ts (B
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tion in rats (
ys 
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IgG isot
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OS suppre
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r mater
esponses cannot b
ke
mice cited b
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ata pres
mmar
rted b
clusions re
011) had man
d as targ
n ra
stress such as r
et al. 2011, whe
mmune para
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that Ke
y immune pa
onstra
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lar suppressive immune responses to b
re compelling
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deficienc
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ys i
genera
posure
ch as
we
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ci 60 44
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and 
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Onishchenko 
acon et al. 2011;
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conclusions re
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OA ex
icted with the 
s not compr
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y with PF
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gn (
lso had numerous 
 et al. failed to dem
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y Onishch
icol 27 361
icit
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IgG titer, not 
riefl
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9 Reproduct Tox
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ox
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y desi
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y immune org
n risk assessment. 
ort the conclusion that PF
ance b
t, one would ex
gors necess
m have
iegel et al 2001 Tox
velopmental altera
008) wa
09) a
B
B
),
y Dong
y A
y w
rted
xplained non-PF
gen
yste
y.   
 a
icit
y b
r une
er huma
y to supp
concord
cited b
andardize
al. (2011) 
g Chem T
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ssing
g et al. 200
y poor stud
y stud
uentes et al.
eil et al. (2
is based on 
g et al. (20
ia et al. 2010)
yed mammary
l studies, including
icol 33 131-13
 298 1-13; 
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velopmental tox
ah
la
comes repo
ed scientific ri
ica
 
 
y (F
y K
ation 
xicit
2016; Lau et al. 2006; M
2011; Sobolewski et al. 2014; 
Y
maternal toxicity
s no st
s used)
y Don
and nervous s
te de
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e wa
y out
in 
y b
icolog
icology
icology
nanc
ra
and 14:
addition, the neurode
ported b
 
In the studies 
developmental tox
ther
and the de
and Macon et 
al. 2014, Yan
Chem Tox
 
Stud
data lack
assessment.   
 
B
tox
Tox
et al. 2004 Dru
Tox
244-257).
Similar to comments provided on PFOA, there were
illustra
In 
confounded b
dose wa
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re
immuniz
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Stud
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viousl
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gs. Of the 18 
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ur
re temp
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s and tables in Chapte
sure
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tox
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ported 
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are
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Perc
“clear”
ATSDR should identif
sectional. 
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some potential tar
established for
studies“
discussed.
Consolidate
page draft Supporting
provided the r
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cited are
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age
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10 
14 
18 
19 
31 
42 
43 
44 
46 
71 
84 
86 
87 
105 
106 
237 
239 
253 
posure
ust 20, 2018
3M Comments
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he Ex
the words 
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estimate’ or
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Simpson et al. 2015
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ssessment of this mischaracteriz
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ren
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these corrections must be
own a
Dr
whe
Column of the C8 Scienc
‘e
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
age
P

10 
14 
18 
19 
29 
31 
38 
39 
40 
42 
43 
46 
52 
53 
63 
69 
71 
76 
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83 
84 
86 
90 
98 
105 
140 
141 
142 
143 
152 
152 
168 
182 
225 
229 
237 
238 
251 
253 
253 
ust 20, 2018

3M Comments
Aug















 stud
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ross-sectional
ross-sectional
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103 
 
 
 
 
 
2014b
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
nland 2014a 
 
 
 
 
nland 2014a 
 
 
 
 
 
 
inquist 
 
 
 
 
oskie et al. 2012
oskie et al. 2012
tee
tee
 
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t al. 2015
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obel 2007  
obel 2007  
Z
t al.  2015
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t al. 2015
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ach 
ach 
undin et al. 2009. 
Study
Stee
Stee
Simpson et al. 2013
W
Olsen et al. 1998a.   
Stee
Gilliland and Mandel 1996 
Olsen et al. 2000 
Olsen and 
Stee
Da
W
Olsen et al. 1999
Olsen et al. 2003
Mundt et al. 2007      
L
Stee
Olsen et al. 1998a 
Olsen et al. 1998b 
Olsen and 
Stee
Stee
Olsen et al. 1998a 
Mundt et al. 2007 
Stee
Olsen et al. 1998b 
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Dhing
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Olsen et al. 1998a  
B
B
W
B
B
Stee
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L
Stee
Stee
 
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a o
luor
f r
 Pe
r o
iological Studies f
m
 Epide
r o
nt f
e
m
u
ting Doc
 Suppor
aft
Dr
 
 
 

 
 


au, 
rt 
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., 
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te 
-induce
enhoff
eptors 

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ch. 
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y. Repo
port
ust 20, 2018
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a, S., 
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w Solutions 
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OA)
isome 
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D) in the 
ects of 
the 
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stries
An upda
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esear
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Da
 Da
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5. 
n C
jork, J
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