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.
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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
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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
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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 “s
uggestive 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
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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.
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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.
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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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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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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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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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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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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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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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(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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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.
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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.
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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.
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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
duced.
re
be
y
potentiall
could
y
r human variabilit
fo
ctor of 10
odel), this fa
nt m
rode
on
g
in
y l e
than r
r
mans (rathe
u
ces in h
eren
fe stage diff
li
for
at accounted
model th
ate PBPK
more appropri
a
developed
e
TSDR could hav
f A
I . y
lit
i
riab
a
factor of 10 for human v
ATSDR included a
, L
OA MR
PF
r o
vative. F
conser
y
overl
is
y
human variabilit
for
“10”
Additional factor of
3.
ence.
r
dosimetric diffe
e
ge adjustment for th
lar
d in the
embedde
y
alread
is
y
n this uncertaint
trapolation whe
ex
animal to human
of 3 for
r factor
e
anoth
y
not appl
SDR should
T
n rodents and humans. A
twee
e
ce b
n
ere
or diff
f 3 f
ctor o
dditional fa
the a
for
ensates
comp
y
tel
a
dequ
000 more than a
djustment of 10,
large dosimetric a
y r
Thus, the ve
and humans.
between rodents
e
nc
releva
and human
ce
differen
litative
supported the qua
Abbott et al., 2007). This further
d out (
e
knock
s were
e n e
g
α
en PPAR
attenuated wh
re
e
OA w
posed to PF
n ex
mice whe
pe
y
d noted in wildt
serve
cts ob
fe
developmental ef
he
of t
y
ample, man
x
or e
. F
to humans
ance
nific
al sig
ic
g
OA and their biolo
PF
to
posure
ects with ex
opmental eff
l
nt deve
e
od
of r
e
nc
s into question the releva
bring
ences
ve differ
litati
2009; Ross et al. 2010), the qua
e k a L
2012;
et al.
et al. 2003; Klaunig
ust 20, 2018
Aug
3M Comments
8
1
).
ents
0
y
.
m
2
cines,
ed
m
y
st 20,
ms
deriv
gu
y
ment, is
3M Co
y justified
L
Au
y justified
-generation
pup bod
mans
s
ere primaril
icit
entific data
in vitro
F2 body weight
2
mans with
These effects
ntly found
ad of da
y
y sci
inconsistent with
mg/kg/day was
esponse to vac
OS
ed
OS MR
-6
elopmental toxicity
eased
OS w
ed on
are
e in a
0.000515 mg/kg/day
e to hu
xicit
cr
c TK adjust
PF
entificall
dev
to PF
ata
e
MRL
rease in
(de
ystemic tox
eloping) pup
levanc
do not support ATSDR
POD inste
y s
y d
y animals
ata
modifying factor of 10 for
y animals
posure
l d
d for
els.
posure
tor
half-life
ica
ge dosimetri
ns on immunoto
tific data. Th
and a
tive and not sci
endpoint than
ounded b
OS ex
not shown in humans
and their re
abora
with ex
log
ased on (dev
aster
DR was not optimiz
and not supported b
y factors is not scientificall
cer
epidemiolog
en
ratory animals for PF
g f
and transient dec
ive
targets of PFOS toxicity in laboratory
PF
gan
conf
tive
tered PFOS via gavag
it
con
ipids, decreased antibody r
r human risk assessment
effects
ere
pidemio
y ATS
ertaint
erva
sensitive than rodents bas
y and
for
conserva
ariability)
iology studies have not consiste
ystem in l
w
y the scien
re
29
ents on PFOS
ening
xtrapolation from animals to hu
onger term epidemiology studies.
nt fo
unc
cific
cons
less
10”
more sens
ats) has be
rum lipid in laborator
y target or
considerin
ace 2009)
icolog
efo
ye op
pidem
3 for e
eleva
all
in r
-spe
y ATSDR were b
hen
d e
MRL is based on a HED NOAEL of
be a
y ATSDR with
nt
imar
pups should be considere
s in human e
The most sensitive
ported in the labo
not r
s in rodents
r w
human, in addition to lar
mans are
nd W
use of “
:
productive s
ase in se
he
ded b
pening
SDR were
e rode
re
s re
are
re
t a pr
ding
ose model used b
T
-to-
application of
. The
hosen b
lu
fects
in
ional intermediate-duration oral MRL of 2x10
on delaye
fspring of rats adminis
city may
ations in
jork a
ose identified in l
increases in serum l
rth weight; e
associated with serum PFOS lev
ye o
the
Its
is not supported b
gniz
effect
al ef
ents
cts c
y A
B
L
A-36)
co
fect
use inc
entr
animal
ecause hu
ge.
assessment is ther
yed e
ffe
chmark d
ata (
y unjustified
Detailed Comm
ect conc
A provis
s in rod
ystem is no
actors b
et al. 2005a)
rtainty factor of 30 (
ff
3” for
tive b
y:
y matern
yte d
OS conc
h ben
y f
ker
and dela
critical e
ll interpretation on both tox
ealth risk
inding
ra
ht
r f
ent knowled
osition (page
ueb
L
tric adjustments and 10 for human v
ig
ertaint
Use of “
conserva
hepatoc
Scientificall
tion of the Critical Effect
OS does not af
ive
OS does not ca
ambaug
The critical e
we
ATSDR should re
PF
mediated b
L
PF
Inconclusive immune f
conclusions
Serum PF
because
W
1.
2.
The developmental
The nervous s
Inconsistent immune finding
Unc
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.
B.
C.
D.
E.
F.
G.
H.
I.
J.
K.
L.
M.
the human-h
ATSDR P
3M Conclusion
ATSDR’s ove
the most curr
and the proposed PFOS MR
for
8
1
ents
0
r
t
,
m
2
ht
are
OS,
rent
e X
n et
tions
m
eig
er e
cts
y
(Abbott
ctive and
t al.
st 20,
y with
discussion
fe
or PF
OS
d in mice
gnan
2008;
f e
index
yl acids
gu
y w
their
ype
icit
uebk
ole of
et al.
3M Co
rect for
L
lk
Au
. F
produ
y animals.
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
ation on the
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
; Elc
erf
eter
ieve
contr
It is
ghts on the r
repro
eased
et al.
m
e epide
e to hu
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
L
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
ffe
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
we
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
f
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
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
l
ce
ic
ents
0
OS
e
),
m
2
gain
up to
nd
In
ys of
y
rgets
e
o
ved
m
y-
cies
ar
first
.
icit
alth or
y ta
bbits,
etal
g
rious
st 20,
ight
– 20 and
nan
ra
r. N
< 0.05
in
gu
gestation
rom
y mediated
s in
he
3M Co
posed
h
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
s
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
s
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
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
e
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
7
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
r
α
ents
0
nal
y
nd
m
2
et al.
l
fect
genic
m
au
ater
her
uebke
y
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
c
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
t
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
M
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
r
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
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
l
,
1
r)
y
ents
0
ica
m
2
in
ys,
OS
entile
s
m
et al.,
rum
g
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
s
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
s
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
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
d
f
ents
0
ta
and
o
-
re
ze
m
2
gm
ye
e;
With
ry
m
r da
g)
di
meters
y overt
with the
y
l
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
f
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
s
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
m
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
y
d
s
G
ents
0
y
y)
Ig
m
2
nd
ll
OS
antl
ged
ch is
CR
ow.
m
y
Æ
ra
sponses.
roup
y IgM
ymus,
st 20,
well as
rs should
y b
nific
roup (3.10
antibod
y
esponse.
t IgG in
gu
IgM
hallen
3M Co
paper, there
G
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
n
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
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g et
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likel
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come a
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eported
) were pre
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a critic
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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
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entific vali
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y Don
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y did not pr
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tt’s t tests b
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e in the stud
g et al. did not e
y did not take
ssessment o
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ht
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ence bod
med that bod
g/k
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le listed in point #3, Don
ample, the
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into considera
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s not appropriatel
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y dat
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as an
g et
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ell known that the a
y wa
which, ultimatel
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ass switching
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ects (i.e., bod
rs that ca
lobulin isot
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h Don
tension from ab
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wa
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ll known that bod
cto
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g et al, it wa
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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
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lower than the c
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It is important to emphas
by Don
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As an ex
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have also looked at th
consistent.
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That wa
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1.
2.
3.
4.
5.
6.
7.
8
1
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ents
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m
2
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tion
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nt
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rum
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and non
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agent,
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gu
L
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ssing
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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
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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
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y, which was not
re
g/ TA
p
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rt o
g et al. d
wa
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a sig
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r the spleen, the
K c
rolife
If PFOS was trul
Don
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challen
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C
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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
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data is that MTT assa
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lik
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s p
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lar suppressive immune responses to be
M and
onl
th
ne cells and Don
ells were
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g et
serum. As an immunosuppre
ne is to re
up mice (0.5 mg
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en
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y in their stud
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thing
mu
gro
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en, or bo
y should have also looked at
If o
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es from S
en and
y, when compared to the
37
man
ctivit
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counts wa
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ported.
albumin) a
sple
pect simi
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ymus or
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It is simpl
flect an
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ell populations in spleen, th
rence in the immune response.
s th
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effect of PFOS an
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ration in im
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y, re
ym
esponses.
ell activit
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th
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esponse is
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ifera
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bstance used b
ymphoc
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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
).
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rea
rea
a
y o
ey o
ht
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rted a n
monstratin
allen
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g et al.
eig
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ay is not a standard a
ed b
assa
g et al. o
f de
y Don
ica
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pect dec
pect dec
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ment is associ
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ment of
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y.
Don
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ne the th
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spiration state a
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values report
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mea
re
assa
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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
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ents
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but
ed
in
cic,
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yet
m
2
y
ere
ards
m
IgM
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ects
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laim
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ff
st 20,
no
ssant)
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effect of
posure
gans in
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ight), it is
gu
n in male
oscopic
ere
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OS and
y in
3M Co
gans w
y to chronic
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to PF
an
l ex
w
co
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-generation
s see
potassium
spective
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ession of
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y PF
which wa
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rga
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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
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ctivit
y immu
rted suppr
contrar
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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)
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yffe
s suppr
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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
f
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
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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
e
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
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cine responses (s
sponse b
entioned studies sugg
L
re
y hi
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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
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that ultimatel
Inconclusive immune fin
that such finding
to vac
the humoral immune re
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IgM
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etric
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tes. Th
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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
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ell et al. had a
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entration would be bette
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g than in the d
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art
ever, this line of r
L
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als and cannot be us
er-the-
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model that incor
and
aster half
e Olsen et al. had
minal half
B
studies that followed individu
al. stud
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asur
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ch
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lsen et
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rds the ATSDR MR
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ations in Table
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)
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e dec
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inal concentr
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across studies for comparable endpoints.
evaluated, the males r
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sponses.
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h
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eru
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y increased th
rtrop
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ted the activation of
ported b
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re
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y wa
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ype
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ects and their releva
nd this hig
iers. The plasm
ier pr
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en accompanied b
ase in
In that stud
en 1997). This is a we
patoc
The incr
sate for the hi
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lar to
apid turnover
hy con
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et al. 2018).
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dence to su
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ents mainl
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y to
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yroid
ist in t
46
in rodents, incre
lism
; Chang
e status in mice ex
). Rod
nts and
eful (w
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crease
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rplasia
y, to compen
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te OECD 42
s not alter
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receptors
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nc
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e in th
eGroot 1991).
ara
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, the
globulin (TB
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en
gniz
yroid h
non in rodents b
ell as the
t al. 1995
gniz
y)
re
-spe
ere
nd non-human p
co
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posure
allace 2009
mice or in the F
fo
nt
s th
– 24 hours
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ll liver metabo
yroid hormone
pithelial h
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Groot 1991
troph
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ice
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atic nuclea
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e rode
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r
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nts (bu
ypertrop
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e sig
lea
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ar
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ansfera
ell
n 1997; Curr
this unc
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init
rode
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addition, ATSDR should re
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ulations between rodents and humans; and simi
jork et al. 2011;
male r
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yroid histopatholog
yroid homeostasis.
ts, th
trapolating
In
due to ac
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rode
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fe
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levels and th
PF
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th
th
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addition, there
rode
bound primaril
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has lower aff
life
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lives of th
sensitivit
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In summa
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ra
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.
11
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y
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l
nd
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and
years)
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or
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ls et al.
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stud
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on of GAC filters in thes
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Model
ation of PF
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tell et al.,
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course
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artell et a
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in MR
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possibilit
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truncating
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PF
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mention the main limitati
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district; and 3) subjects with initial
which max
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Given the a
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their most conserva
2007) would then r
and 38 percent. This t
the MR
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GF
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older adults are
age or older r
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s, based in
A
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nami
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urrent provisional MR
sented a
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m
cts of x
lsen et al. 2007 (g
i e al. 2018
icokinetic differe
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posure
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elimination half-lives may
part on half-lives, should
*A
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As illustrated a
the re
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Use of “
scientificall
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when takin
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effe
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et al. 2003; Klaunig
differe
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ra
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models have been d
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These data
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icit
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for
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t al. 2011;
that ther
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ent model), this fa
y. ATSDR
eatments of P
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for
hts (absolute o
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ced.
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ect in stating
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r than re
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, with regard
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re
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ge adjustment fo
re
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Albeit the number of
studies (to date)
cholesterol under
microsc
2018). ATSDR is incorr
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Furthermo
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for
had no effects on the weig
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clea
ATSDR (on Table 2-5 of
There
and should be re
2.
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ed
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y
y
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ghl
s
t al.
In
ampsia
mation
r more
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OS
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y would
ns of
y).
. (2009)
nanc
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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
of O
y sev
ences
cross-se
y reg
ecl
rmacokinetic
, PFOS)
-sectional (N
de
er
en pr
gical evidence for an association
uced h
lle
pre
een 2000
-induced
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
dis
ffered b
) including
a) w
ex
ecall bias.
rox
f r
2009) 1 prospective coho
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
aware
m
elation of
suggestive epidemiolo
rr
hen v
nanc
ists re
y ATSDR, onl
leve
ecl
sure
d in 2005
tarling
y out
iven that self
) w
is “
d PFOS and pregnanc
S
reg
her org
types of h
strate
e ATSDR provided no sc
nc
4). These studies di
ATSDR dra
psia assessment. These di
s g
%
s were
mea
Savitz
easure
ure
ents on P
e
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
eeclam
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-
)
y
S
ft
en
et
is
rous
O
-
re
ft
-1.7
th
bod
e
ghly
s
e).
y
eported
els
posure
th
ust 20, 2018
I: 1.1
il
ll
y r
ex
3M Comments
ed a
n the log
between sel
rof
led in the
asma PFOA
ud
y lev
S
e is
d PFOS
ls: 2 cross
e cohort, with
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
els, the median
ectiv
amined a hi
centr
rna
d P
e studies and
ex
y obs
as, however,
en enrol
(2009
and PF
); howev
association
sure
gain, the
mate
hen considering
modeled PFOA wa
R = 1.3, 95
), but not fo
om the 25
y to use me
y recent de
fr
re
nd include n
OA
and PFOA
n
OA con
-1.15
-2.3
gs in the dra
) a
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
-cases
ee
psia and mea
stren
serum PF
y to measu
tarling
All thre
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
s
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
s
-
y
ater
y,
en
ly
g
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
d
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
h
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
d
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
s
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
n
IH a
ow
rr
ust 20, 2018
n
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
y
l
ra
re
ges
r
e
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
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
e
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
e
e
y
its
et al.
y
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
T
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
h
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
m
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
s
T
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
0
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
T
e
OA
nc
β =
t al.
ed to
the
OA;
OA
ctional
ted
e
t these
PF
dels,
0.2
ated
y
by
) AL
e in
fere
results
cross
ere up
et al.
l
nce
w e
ression
65 for
s,
c versus
including
e
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
.
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
e
to
” is
-
%
T
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
e
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
r
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
d
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
T
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
t
g
-
as
st
e,
OA
with
ce of
5
l R2 =
β=
71.
A that
for
t
5 (p
nt
he 1
le
e to
nt. The
cile
lted in
iden
O
M
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
T
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
d
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
s
e
e
h
es
lding
OSF)
ym
FOA
L
nge
stent
(P
oug
)
with
single
anged
these
f
ave
zym
s.
re
r became
P
done.
L
g/m
L
y Sobus et
) h
en
r enz
ust 20, 2018
y
we
l
ect
T cha
onvertino et
y. Forty-
unch
μM
yzed
HANES
3M Comments
g/m
g/m
L
C
) on a
s
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
T
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
e
in
gitudinal anal
at
s
receiv
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al Prof
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m lipids. As
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0.0001) and 0.7 n
rapeutic potential of PF
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cipated
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enga
that we
and PF
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mea
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Convertino et al (2018).
Scotland to determine the max
the weekl
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al. 2018). The
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including
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for
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authors concluded live
5 orders of
PF
It should be noted th
NHANES data. Th
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anal
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att
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e,
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and lipid levels
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Thus, the intermediate pa
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self-re
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liver disease with ex
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ctic
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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
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a lac
associations with A
PF
confoundin
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l pra
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nitude of
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3M Conclusion
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cPherson
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ted
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posed to
D
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tion and its
3M Comments
th effects,
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ages 172, 177
lesterol per
terol levels
he dose
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ph of percent
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phas
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pidemiolo
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ects, similar to those
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ross studies, the
L
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Toxicological Scienc
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ig
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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
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en perf
ang
liminary
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m
6, 2018 in
eview for
els; F
amining
ons have not bee
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ct. ATSDR was not awa
perimental stud
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ter
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y lipoprotein (
Figure
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ciations be
or various studies: F
eekl
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rol
ffect
ht of
Althou
ig
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y ass
luoroalk
y 2018 issue
to ATSDR, this included “
e 186),
ls.” On p
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the c
es and studies present
es 181, 187) th
hest w
yroid hormones
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full
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est asso
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rol and low
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gur
(pag
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terol, althoug
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. 2011)
2009), suggest that
h a PD e
hig
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y occur in humans ex
(pag
ica
DR was not cert
not present in th
published on F
he Ma
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c
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rol relative to PF
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ed
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ests
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Detailed Comm
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ents, ma
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ammonium salt) that was publishe
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g). ATS
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rum PF
L
r
consistent associations we
y and Pah
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fication wa
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ly total choleste
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urve
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lari
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PF
lative to PF
d fo
y publication in t
l, no
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– 1200 m
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amined the potential of perf
alth outcomes.” A
OS,
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sponse c
sults observed in epide
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sults from the clinica
mification(s) in AT
On pag
ex
most of the studies are
a number of factors inclu
epidemiolog
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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
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50mg
as such c
re
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strong
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ATSDR position on P
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nitude lowe
3M Comments
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nsition in
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n with
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SDR
lesterol,
h a x
ive
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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
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er th
ted
ar tra
f mag
et al
eport
posit
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ed at
ting
ations of PFOA
chro
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rted at
y dos
d, was considere
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ge 18
ynamic
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ested the
anism g
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plic
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imum toler
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These would include the
y shar
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al population.
cpherson
ith total cho
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amined as
alation stud
m salt). There
p
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ny possible modes of a
y the
ed estima
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y an o
ner
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A c
tions.
gic mech
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y 175,000
y th
that ma
ver, no mo
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epo
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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
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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
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approx
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y lo
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lo
also mentioned b
een t
phase
A. Ho
pprox
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a bipha
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tano
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at
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O
y dose l
as the re
gnitud
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included
stribution functions at various P
ma
ease became c
s
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L
onse.
D
d
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cr
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amin
63
eeks. The
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y of
y di
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ilt
underlin
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y at an
her PFOA
al biolog
rolemia positive association re
luo
whe
y of PF
l dosimetr
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ations, howev
gastrointestinal
y dose w
mistr
rum PF
ers of ma
ypolipidemic r
ged ex
tients who
or 6 w
icit
abilit
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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
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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
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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
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ation, interna
O
est Virg
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yperc
cho
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rd
ekl
re se
asur
rted
e et
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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
e
ate
ger
yl
oth
d in
g the
fects.”
-be
l
d
ccur
y
spons
y
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
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l population
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hat has
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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
r
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
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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
h
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
d
te. D
ered GF
T
cien
e in the literature
els fo
gica
e low
yroi
d in s
appe
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t low
en per
re ur
A
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
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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
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which do not establish ca
ati
spons
ly inconsistent w
written what A
cepted practic
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rl
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ht.” Ther
) in both animals an
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entl
R. Ther
L
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NA, and PFDe
PF
curr
And, in fact, man
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scientific understandin
page 635, “
studies,
ATSDR also wrote on pa
curve
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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.”
e
es
ay
nce
h
e
ur
en
y
-13,
ewer
ria
h
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
e
6, with fig
a
y had hig
r)
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sho
re
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port
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ctivel
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ations, as re
-19
L
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te
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erol.
ge,
as 74,000 and
D
als that lowe
D
a
) was reported with
spe
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L
wa
L
re
L
re
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centr
yet to be un
es 188
t al. 2009 s
holest
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D
),
fa
OS level in F
ls (our st
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cupational studies nor the
rs we
ardin
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rmaceutic
-14, and
ssociations re
ators that althou
nland e
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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
r
Fibr
ith low PFOA con
y.
ho
igur
age 188) and communit
we
nces
for
-month stud
coron
h
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
l
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
e
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
n
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
e
l
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
l
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
n
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
n
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
R
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
a
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
e
y
es
y
mal
r, the
iven
n
tor to
s 870
y
.
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
n
gnostic i
OA or
gory r
e to displacement of
ed the m
s no
not supp
ate
. Ther
for
ree th
yperth
s
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
n
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
a
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
n
a B
et antibody
to
r
B
elev
lso
70
, PFH
in
S
esponses to mumps (Stein et al., 2016
eased
e type eli
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knowl
ne should n
sure
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fer d
Influenz
adjuvants to i
le, a
et al.
y r
y.
ecr
s of the immune s
cci
creased Antibody
response
n
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
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port
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D) in the
ects of
the
2.
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