PFOA exposure and health
A review of scientific literature

RIVM Report 2017-0086
K.J. Rijs | R.P. Bogers

PFOA exposure and health
A review of scientific literature

RIVM Report 2017-0086

RIVM Report 2017-0086

Colophon

© RIVM 2017
Parts of this publication may be reproduced, provided acknowledgement
is given to: National Institute for Public Health and the Environment,
along with the title and year of publication.
DOI 10.21945/RIVM-2017-0086

K.J. Rijs (author), RIVM
R.P. Bogers (author), RIVM
Contact:
R.P. Bogers
DMG
rik.bogers@rivm.nl
This investigation has been performed by order and for the account of
Ministerie van Infrastructuur en Milieu, within the framework of
continued research on PFOA ('Vervolgonderzoek PFOA').

This is a publication of:
National Institute for Public Health
and the Environment
P.O. Box 1 | 3720 BA Bilthoven
The Netherlands
www.rivm.nl/en
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Publiekssamenvatting

PFOA en mogelijke gezondheidseffecten
Een overzicht van wetenschappelijke literatuur
Er zijn enkele verbanden gevonden tussen concentraties PFOA in het
bloed van mensen met mogelijke gezondheidseffecten en de werking
van het lichaam. Dit blijkt uit een literatuuronderzoek door het RIVM van
de wetenschappelijke literatuur over onderzoek in mensen. Het is niet
zeker dat PFOA in het bloed daadwerkelijk de oorzaak is of dat er andere
verklaringen zijn voor de gevonden verbanden.
Aanleiding voor het onderzoek zijn vragen van omwonenden van de
Dupont/Chemours-fabriek in Dordrecht over mogelijke
gezondheidseffecten als gevolg van de emissie van PFOA door de
fabriek. Het rapport geeft meer inzicht in wat uit de literatuur bekend is
over welke mogelijke effecten samenhangen met blootstelling aan PFOA
bij de mens, de concentraties PFOA in het bloed waarbij deze mogelijke
effecten worden gevonden en de omvang van deze effecten.
Concentraties PFOA in het bloed geven aan in welke mate mensen zijn
blootgesteld aan deze stof.
Het wetenschappelijke bewijs verschilt tussen de gevonden effecten. De
meest duidelijke aanwijzingen zijn er voor een verband tussen de
blootstelling aan PFOA met hogere zogeheten totaal-cholesterolgehalten
in bloed, hogere concentraties van het leverenzym ALT in het bloed en
een lager geboortegewicht. Voor alle andere mogelijke effecten zijn de
aanwijzingen minder duidelijk. Er zijn aanwijzingen voor een verband
met hogere concentraties in het bloed van andere leverenzymen, LDLcholesterol en urinezuur. Ook zijn aanwijzingen gevonden voor een
grotere kans op chronische darmontsteking (colitis ulcerosa), zaadbalen nierkanker, hoge bloeddruk tijdens de zwangerschap en
zwangerschapsvergiftiging. Verder zijn er aanwijzingen voor een
verband tussen de blootstelling en een verminderde toename van
antilichamen in het bloed na vaccinaties, hogere of lagere concentraties
in het bloed van schildklierhormonen en schildklierziekten.
Kernwoorden: PFOA, C8, perfluoroctaanzuur, epidemiologie, review

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Synopsis

PFOA and possible health effects
A review of scientific literature
Associations were found between blood concentrations of PFOA in
humans and possible health effects and functioning of the body. This is
the result of a review of previously performed reviews of the scientific
literature on studies conducted among humans by the National Institute
for Public Health and the Environment. It is not certain whether PFOA is
the true cause or whether there are other explanations for the observed
associations.
This study was performed because of questions raised by residents who
live in the vicinity of the Dupont/Chemours factory in Dordrecht
concerning possible health effects due to the emission of PFOA by the
factory. The objective of this review was to address the question what
biological and physiological parameters and diseases are associated with
blood PFOA concentrations in humans, to determine in what ranges of
blood concentrations the associations are observed and to provide an
indication of the magnitude of the associations. Concentrations of PFOA
in blood are an indication of the level of exposure to this chemical.
The strength of evidence for the existence of a possible association
differs between the observed effects. The clearest evidence has been
found for a relationship between exposure to PFOA and higher total
cholesterol concentrations in blood, higher concentrations of the liver
enzyme ALT in blood and a lower birth weight. For all other examined
associations, the evidence is less clear. There are indications of an
association with higher blood concentrations of other liver enzymes,
LDL-cholesterol and uric acid. Indications have also been found for a
higher risk of chronic inflammation of the bowel (ulcerative colitis),
testis and kidney cancer, as well as pregnancy-induced hypertension
and preeclampsia. Furthermore, associations have been found between
exposure to PFOA and a decreased vaccination response, changes in
concentrations of thyroid hormones in blood and thyroid disease.
Keywords: PFOA, C8, perfluorooctanoic acid, epidemiology, review

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Contents

Summary — 9
1
1.1
1.2
1.3
1.4
1.5
1.5.1
1.5.2
1.5.3

Introduction — 11
Background — 11
Objectives — 12
Organization of this report — 12
PFOA in blood as a biomarker of exposure — 12
Blood PFOA concentrations in different populations — 13
General population — 13
High-exposure communities — 14
Occupationally exposed populations — 14

2
2.1
2.1.1
2.2
2.3
2.4
2.5
2.6

Methods — 15
Previously performed reviews — 15
Background and objectives of previous reviews — 15
Selection of endpoints — 17
Selection of epidemiological studies from previous reviews — 17
Update with recent studies — 17
Extraction of data from epidemiological studies and reviews — 18
Integration of findings — 18

3
3.1
3.2
3.2.1
3.2.2
3.3
3.3.1
3.3.2
3.4
3.4.1
3.4.2
3.5
3.5.1
3.5.2
3.6
3.6.1
3.6.2
3.7
3.7.1
3.7.2
3.8
3.8.1
3.8.2
3.9
3.9.1
3.9.2
3.10
3.10.1
3.10.2

Results — 19
General conclusions from previous reviews — 19
Liver enzymes and liver disease — 24
Conclusions from previous reviews — 24
Summary of studies — 25
Testicular and kidney cancer — 26
Conclusions from previous reviews — 26
Summary of studies — 27
Pregnancy-induced hypertension and preeclampsia — 28
Conclusions from previous reviews — 28
Summary of studies — 29
Birth weight — 30
Conclusions from previous reviews — 30
Summary of studies — 32
Uric acid concentration — 33
Conclusions from previous reviews — 33
Summary of studies — 34
Vaccination response — 35
Conclusions from previous reviews — 35
Summary of studies — 36
Ulcerative colitis — 37
Conclusions from previous reviews — 37
Summary of studies — 37
Thyroid effects — 38
Conclusions from previous reviews — 38
Summary of studies — 39
Blood lipid concentrations — 40
Conclusions from previous reviews — 41
Summary of studies — 41
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4
4.1
4.1.1
4.1.2
4.1.3
4.1.4
4.1.5
4.1.6
4.1.7
4.1.8
4.1.9
4.2
4.3
4.4

Discussion and Conclusions — 45
Discussion per endpoint — 45
Liver enzymes and liver disease — 46
Testicular and kidney cancer — 46
Pregnancy-induced hypertension and preeclampsia — 47
Birth weight — 47
Uric acid concentrations — 48
Decreased vaccination response — 48
Ulcerative colitis — 49
Thyroid effects — 49
Blood lipid concentrations — 50
Other endpoints — 50
Experimental data — 51
Conclusions — 52
References — 55
Appendix Tables 3-11: data extracted from epidemiological
studies — 67

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Summary

Perfluorooctanoic acid (PFOA or C8) is used for a wide range of
consumer and industrial products, such as the production of Teflon. The
exposure to PFOA of people living in the direct neighbourhood of the
Dupont/Chemours factory in Dordrecht as a result of emissions from the
factory from 1970 to 2012 has prompted questions to be raised about
the possible health effects.
In 2016 the National Institute for Public Health and the Environment
made a risk assessment based on toxicological studies. This risk
assessment used a limit value for chronic exposure based on the critical
effect (i.e. the most sensitive effect) in animals. However, a more indepth evaluation of epidemiological studies was then recommended in
order to indicate whether or not other health conditions or diseases
require further attention.
In recent years, a number of evaluations have been performed by
recognized national and international organizations in which
epidemiological evidence for associations between PFOA and biological
and physiological parameters and diseases has been reviewed. These
evaluations were based on epidemiological and toxicological studies.
The objectives of this literature review were to address the following
questions:
• What biological and physiological parameters and diseases are
associated with blood PFOA concentrations in humans?
• In what concentration ranges are these associations observed?
• And to provide an indication of the magnitude of the associations.
First, conclusions from the previous evaluations were reviewed to
determine what biological and physiological parameters and diseases are
associated with blood PFOA concentrations. Then epidemiological studies
were selected from the previous reviews and from a search done in a
digital scientific database. The epidemiological studies were not
evaluated individually in terms of things such as study quality. The
findings from the selected epidemiological studies were used to answer
the study questions regarding PFOA concentration ranges and the
magnitude of the associations.
Three types of study populations can be identified in the context of
exposure to PFOA, i.e. the general population, high-exposure
communities (i.e. communities exposed to air and/or drinking water
contaminated with PFOA, e.g. because of emissions of PFOA from a
factory nearby or land contaminated by waste from water treatment)
and occupational study populations (i.e. populations of workers in
factories using or producing PFOA). On average, concentrations of PFOA
in blood are higher in individuals that are part of a high-exposure
community than they are in the general population. Concentrations of
PFOA in blood are on average highest in occupational study populations.

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The strength of evidence for the existence of an association and the
magnitude of the associations differ between the examined biological
and physiological parameters and diseases. Conclusions drawn from
previous reviews are clearest with respect to evidence for associations
between PFOA and total blood cholesterol concentrations, blood
concentrations of the liver enzyme ALT and birth weight. For all other
examined associations, the evidence is less clear. Associations were
observed in individuals with blood PFOA concentrations as found in the
general population and at higher concentrations. But it has yet to be
established whether the associations observed in the epidemiological
studies are causal. For most biological and physiological parameters and
diseases there is supporting evidence from experimental animal studies,
but the mode of action that explains how PFOA exerts its effects has not
been fully characterized. The findings from this literature review will be
used as a background document to assess the potential health
consequences of PFOA exposure in residents living in the direct vicinity
of the DuPont/Chemours factory in Dordrecht.

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1

Introduction

1.1

Background
There is concern regarding possible health effects on people living in the
direct neighbourhood of the Dupont/Chemours factory in Dordrecht as a
result of emissions of perfluorooctanoic acid (PFOA) over many years.
PFOA is used for a wide range of consumer and industrial products, e.g.
for the production of teflon. In the Dupont/Chemours factory in
Dordrecht, PFOA was used from 1970 to 2012. Since 2012, PFOA has
not been used in the Dutch DuPont/Chemours factory.
The National Institute for Public Health and the Environment (RIVM) has
estimated the concentrations of PFOA in the blood between 1970 and
2030 of residents living in the direct neighbourhood of the
DuPont/Chemours factory in Dordrecht through model calculations
(Zeilmaker et al., 2016). The exposure to PFOA through the air, drinking
water and food was estimated based on emission data and calculations. It
was estimated that residents living in the direct vicinity of the
DuPont/Chemours factory in Dordrecht were exposed to PFOA mainly
through the air and not through food (not accounting for home-grown
food) or drinking water. Based on model calculations, PFOA
concentrations in the drinking water in Dordrecht were not elevated
compared with the rest of the Netherlands, which is to be expected as
drinking water for the area surrounding the factory in Dordrecht does not
originate from Dordrecht (Zeilmaker et al., 2016). It was estimated that
in the 1990s the residents may have had the highest serum
concentrations, with average values of up to 130 ng/mL. Current typical
serum concentrations were estimated to be around 10 ng/mL (Zeilmaker
et al., 2016).
RIVM also determined a serum limit value for chronic exposure
(Zeilmaker et al., 2016) below which no adverse health effects are
expected. This evaluation by RIVM followed previous reviews and limit
value derivations conducted by EFSA (2008), ATSDR (2015), ECHA-RAC
(2015a) and US-EPA (2014). The limit value (i.e. 89 ng/mL) as derived
by RIVM takes into account the accumulation of PFOA in the human
body during long-term exposure. In the most unfavourable case, the
limit value for chronic exposure could have been exceeded for a period
of 25 years for residents living in the direct vicinity of the
DuPont/Chemours factory in Dordrecht (Zeilmaker et al., 2016).
The limit value for chronic exposure as derived in 2016 was based on
animal data. In agreement with the evaluations conducted by other
organizations (i.e. US-EPA, EFSA, ATSDR, ECHA-RAC), RIVM concluded
that animal data were the preferred basis for dose response analysis.
Epidemiological data were considered less informative for dose-response
analysis. As is usual for these kinds of limit values, the value was based
on the critical effect (i.e. the most sensitive effect; in this case, liver
toxicity) in animals and therefore, in principle, it covers all potential
health effects. However, a more in-depth evaluation of epidemiological

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studies was recommended in order to indicate whether other health
conditions or diseases require further attention.
In recent years, a number of literature reviews have been conducted in
which epidemiological evidence for associations between PFOA and
biological and physiological parameters and diseases has been
evaluated. In the current study, these previous evaluations were
reviewed.
The result of this review should allow a further evaluation of the
likelihood of any health effects at the exposure level calculated and
measured for the residents in the direct vicinity of the Dupont/Chemours
factory in Dordrecht. Also, it should allow a further evaluation of
whether or not the health of the residents needs to be examined.
Although neither of these questions will be discussed in the current
report, they will be discussed in a different document.
1.2

Objectives
The objective of this review was to address the question of what
biological and physiological parameters and diseases are associated with
PFOA concentrations in the blood of humans. This question was
answered by evaluating reviews conducted by recognized (inter)national
authorities. In addition, the objective was to determine the ranges of
blood concentrations within which the associations are observed and to
give an indication of the magnitude of the associations. These questions
were answered by summarizing findings taken from the available
epidemiological publications.

1.3

Organization of this report
Section 1.4 provides information on the measurement of PFOA
concentrations in blood and the half-life of PFOA in humans. An overview
of the levels of measured and estimated PFOA concentrations in blood
that are reported in epidemiological studies is given in section 1.5. The
Methods, Results and Discussion of the results are described in
Chapters 2, 3 and 4, respectively.

1.4

PFOA in blood as a biomarker of exposure
In epidemiological studies, blood concentrations of PFOA are used as a
biomarker of exposure to PFOA, reflecting combined exposure from all
sources. PFOA can be measured in serum, plasma or whole blood. The
serum or plasma to whole blood ratio for PFOA is 2:1 (Ehresman et al.,
2007). In epidemiological studies, PFOA concentrations are most often
examined in the serum component (e.g. Barry et al. (2013); Gallo et al.
(2012)). In some studies, PFOA concentrations are measured in plasma
(e.g. Fei et al. (2007); Starling et al. (2014b)). In the current review, no
epidemiological study has been found in which whole blood was
examined. Concentrations of PFOA in serum and plasma are
comparable. The concentration level observed in serum will also be
observed in plasma and vice versa, i.e. a ratio of 1:1 is suggested
(Ehresman et al., 2007). So, in the current report, when blood PFOA
concentrations are mentioned, they refer to concentrations of PFOA
measured in serum or plasma.
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Blood PFOA concentrations depend on the level and duration of
exposure. Also, PFOA accumulates in the body because it is slowly
eliminated from the body. Varying half-lives have been reported. In
retired fluorochemical production workers, a mean elimination half-life
for PFOA of 3.8 years was measured (Olsen et al., 2007). In a German
population, a mean plasma concentration half-life of 3.3 years (range:
1.0-14.7 years) was measured (Brede et al., 2010). In the C8
population, a median (i.e. 50% of the examined study population had a
value equal or below that value) half-life of 2.3 years was measured
(Bartell et al., 2010). Findings from the C8 Health Study suggest that
half-lives may be concentration-dependent or time-dependent with
higher clearance at higher concentrations (Seals et al., 2011).
1.5

Blood PFOA concentrations in different populations
Three types of study populations are examined in epidemiological
studies: the general population, high-exposure communities (i.e.
communities exposed to air and/or drinking water contaminated with
PFOA, e.g. because of emissions of PFOA from a factory nearby or land
contaminated with waste from water treatment) and occupational study
populations (i.e. populations of workers in factories using PFOA).

1.5.1

General population
In the general population, median serum PFOA concentrations are
encountered between 1-5 ng/mL, i.e. ‘background’ exposure, with
extremes of up to 100 ng/mL. Many serum PFOA concentration
measurements come from the US. Mean values observed in various
studies among the general population in the US are 2.1-9.6 ng/mL
(ATSDR, 2015). In the general population, serum PFOA concentrations
range approximately from values below the limit of detection to 100
ng/mL (US-EPA, 2016a). The National Health and Nutrition Examination
Survey (NHANES) is a programme of studies designed to assess the
health and nutritional status of the general population in the United
States. In 1999-2000, a geometric mean serum PFOA concentration of
5.05 ng/mL was measured in men and 4.06 ng/mL was measured in
women (Lin et al., 2010). In 2007-2010, a geometric mean serum PFOA
concentration of 3.5 ng/mL (for both women and men) was measured
using NHANES data (Gleason et al., 2015). Concentrations in North
American populations appear to be higher than they are in European
populations, where PFOA concentrations range from 0.5 to 40 ng/mL
(Fromme et al., 2009).
The German HBM-Kommission (2009) reported on some European studies
in which serum PFOA concentrations in general populations were
measured. In Germany, the highest range of concentrations was
measured in the general population living in the South of Germany (i.e.
1.7-39.3 ng/mL), with a median serum PFOA concentration of 6.8 ng/mL.
Studies in which median serum or plasma concentrations (whole blood
concentrations were converted to be comparable with serum and plasma
blood concentrations) were measured in the general population of
Belgium, Italy, Poland and Sweden were also reported. In Belgium, a
median serum PFOA concentration of 4.3 ng/mL was measured in men
and 2.4 ng/mL was measured in women (Kannan et al., 2004). In Siena,
Italy, a median serum PFOA concentration of less than 3 ng/mL was
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measured in both men and women. In Danzig, Poland, men had a median
concentration of 18.4 ng/mL and women had a median concentration of
23.4 ng/mL. A median serum PFOA concentration of 5.0 ng/mL was
measured in men and women living in Sweden.
1.5.2

High-exposure communities
Information on blood concentrations among high-exposure communities
mainly comes from the C8 Health Study, a series of studies conducted
among residents who live in contaminated water districts in Ohio and
West Virginia near the Dupont factory in Parkersburg. The C8 Health
Study is mainly work conducted by the C8 Science Panel. The C8 Health
Study consists of a number of studies, in part based on the crosssectional data collection study, the C8 Health Project, that are conducted
among residents living in contaminated water districts in Ohio and West
Virginia in the US that are affected by PFOA emissions from a PTFE
production facility of Dupont. In the C8 Health Project, the population
median serum PFOA concentration based on over 65,000 serum samples
was 28.2 ng/mL and the mean was 82 ng/mL in the 2005-2006 period,
with variation between the different water districts, age and sex groups
(Frisbee et al., 2009). Values ranged from below the limit of detection to
over 1,000 ng/mL (http://www.hsc.wvu.edu/media/5354/overall-c8c8s-results.pdf). Median serum PFOA concentrations reported (Frisbee et
al., 2009) were 32.6 ng/mL in children aged <12 years, 25.7 ng/mL in
adolescents aged 12-19 years, 21,8 ng/mL in adults aged 20-39 years,
30.7 ng/mL in adults aged 40-59 years and 41.9 ng/mL in ≥60 yearolds in 2005-2006. It should be noted that peak emissions occurred
during the 1980s and 1990s and PFOA emissions from the factory had
declined by the 2005-2006 period (Woskie et al., 2012).
In addition to the C8 Health Project population, there is another highexposure population in the United States that was exposed to
concentrations of PFOA above background concentration, i.e. a
community living in Minnesota. Similar to the community living in Ohio
and West Virginia, residents there were also exposed to water
contamination coming from factories. In Minnesota, the blood PFOA
concentration of a selection of residents who were exposed to
contaminated drinking water was measured. Like in most Western
countries, exposure to PFOA has apparently decreased in Minnesota in
recent years. The mean PFOA concentration was 15 ng/mL in 2008, 11
ng/mL in 2010 and 5 ng/mL in 2014 (MDH, 2015).

1.5.3

Occupationally exposed populations
In workers who are occupationally exposed to PFOA, mean blood PFOA
concentrations are about three orders of magnitude higher than they are
in the general population, and maximum concentrations can reach over
100,000 ng/mL (Fromme et al., 2009). Chang et al. (2014) reports that
the highest median PFOA concentrations are found among directly
exposed workers, ranging from approximately 1,000 to 2,880 ng/mL
(Olsen et al., 2000; Olsen et al., 2003; Olsen and Zobel, 2007; Woskie
et al., 2012).

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2

Methods

Firstly, reviews previously performed by recognized national and
international organizations were used to determine which biological and
physiological parameters and diseases (referred to as ‘endpoints’ in the
current report) are associated with PFOA. Secondly, epidemiological
studies were selected from the previous reviews and from a search
made in a digital scientific database in order to determine the exposure
levels at which associations were observed.
The previously performed reviews that were used in the current review
are described below. Then the selected endpoints and the process of
selecting epidemiological studies and extracting data from the
epidemiological studies are described. Lastly, how the data from the
reviews and the epidemiological studies are integrated is described.
2.1

Previously performed reviews
A number of reviews performed by recognized national and international
organizations have been published in which epidemiological and
toxicological studies (animal and in vitro studies) on the association
between serum or plasma PFOA concentrations and endpoints were
summarized. All endpoints reported to be associated with exposure to
PFOA by these organizations were included in the present review. The
reviews considered here are those which were most recently published,
i.e. reviews performed by the C8 Science Panel (reviews focused on
various endpoints were published between 2011 and 2012) (C8 Science
Panel, 2011a; C8 Science Panel, 2011b; C8 Science Panel, 2012a; C8
Science Panel, 2012b; C8 Science Panel, 2012c; C8 Science Panel,
2012d; C8 Science Panel, 2012e), Health Council of the Netherlands
(2013), ATSDR (2015), ECHA-RAC (ECHA-RAC, 2015a; ECHA-RAC,
2015b), DWQI (2016), IARC (2016), NTP (2016) and US-EPA (2016a).

2.1.1

Background and objectives of previous reviews
Communities in the Mid-Ohio Valley in the United States were potentially
exposed to PFOA (also called C8) from the 1950s onwards (C8 Science
Panel, 2017). The C8 Science Panel carried out exposure and health
studies in the Mid-Ohio Valley communities and published their
evaluations and reviews online. The C8 Science Panel no longer exists.
The task of the C8 Science Panel was to make a judgment regarding the
evidence linking PFOA to the risk of disease. The Panel had to determine
whether there is or is not a ‘probable link’ between a disease and
exposure to PFOA. In its assessment, the C8 Science Panel implemented
a definition of ‘probable link’ as follows: ‘…given the available scientific
evidence, it is more likely than not that among class members a
connection exists between PFOA exposure and a particular human
disease’. Thus, the conclusions drawn by the C8 Science Panel refer to
the population of ‘class members’ defined as ‘individuals in West Virginia
or Ohio whose drinking water had been contaminated by quantifiable
levels of PFOA’ (Frisbee et al., 2009). Therefore, the C8 Science Panel
focused their conclusions exclusively on a high-exposure community in
the US. In all other previous reviews considered in the current review,
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the potential health effects of PFOA were evaluated for all serum or
plasma PFOA concentration ranges.
The task of the Health Council of the Netherlands is to advise the Dutch
government and parliament regarding public health and health (care)
research. This can happen on request, but the Health Council also has
an ‘alerting’ function: it can give unsolicited advice (Health council of the
Netherlands, 2017).
ATSDR (the Agency for Toxic Substances and Disease Registry) is a
federal public health agency of the United States Department of Health
and Human Services (ATSDR, 2016a). They perform functions focused
on the effect of hazardous substances in the environment on public
health, such as public health assessments of waste sites, applied
research in support of public health assessments, and education and
training with respect to hazardous substances. ATSDR is involved at a
number of sites related to perfluoroalkyl and polyfluoroalkyl substances
(PFAS), either directly or through assisting state and federal partners
(ATSDR, 2016b). ATSDR published a draft of a Toxicological Profile for
Perfluoroalkyls (ATSDR, 2015). To our knowledge, this draft has not
been updated since its publication.
The ECHA (the European Chemical Agency), for instance, helps
companies to comply with chemicals legislation, advances the safe use
of chemicals, provides information on chemicals and addresses
chemicals of concern (ECHA, 2017b). RAC (the Committee for Risk
Assessment) prepares the opinions of ECHA concerning the risks of
substances to human health and the environment. The European
Commission takes the final decision (ECHA, 2017a). ECHA-RAC
summarized the studies in their ‘Background document’ (2015a). The
Background document was used to provide background for the opinion
on the restriction proposal, based on the Persistent, Bioaccumulative,
Toxic (PBT) / very Persistent, very Bioaccumulative (vPvB) properties of
the substance. In general, the risks of PBT/vPvB substances cannot be
adequately addressed in a quantitative way due to the high uncertainties
present regarding long-term exposure and effects. However, the
background document explores the possibility of formulating an opinion
on the specific question of whether or not a potential risk of PFOA on
health can be quantified. The opinion was formulated in a separate
document; none of the evaluated endpoints were considered ‘robust
enough to include in a quantitative assessment’ (ECHA-RAC, 2015b).
The New Jersey DWQI (Drinking Water Quality Institute) Health Effects
Subcommittee develops Maximum Contaminant Levels (MCL) or
standards for hazardous contaminants in drinking water. In addition, they
are responsible for ‘recommending those standards and making
recommendations for the implementation of the drinking water quality
programme to the Commissioner of the New Jersey Department of
Environmental Protection (NJDEP)’ (State of New Jersey, 2017).
IARC is part of the World Health Organization (WHO) and is specialized
in epidemiological and laboratory research into the causes of cancer.

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A systematic review (NTP, 2016) was performed by NTP’s (National
Toxicology Program, US Department of Health and Human Services)
Office of Health Assessment and Translation (OHAT) with the purpose of
evaluating whether PFOA is associated with immune-related health.
They evaluated both epidemiological and toxicological studies.
The mission of the US-EPA (i.e. the US Environmental Protection
Agency) is to ‘protect human health and the environment’ (US-EPA,
2016b). To accomplish their mission, they develop and enforce
regulations, give grants and study environmental issues, among other
things. The US-EPA wrote the review into the potential health effects of
PFOA in order to provide a health advisory, such as developing a
regulation to control PFOA in drinking water.
2.2

Selection of endpoints
In the current review, all endpoints about which at least one
(inter)national organization has concluded that an association exists
with PFOA concentrations in blood were selected (for an overview, see
Table 1 in the Results section). Therefore, endpoints that were
evaluated in the previous reviews, but about which it was concluded that
insufficient evidence exists for an association with PFOA, were not
included in the current review.

2.3

Selection of epidemiological studies from previous reviews
To determine the ranges of concentrations in which the associations are
observed, data were extracted from epidemiological studies included in
the previous reviews. Epidemiological studies were included that present
results from studies in all different populations (general population,
high-exposure communities and occupational populations). No further
selection was made based on study quality. In the previous reviews,
findings taken from epidemiological studies were evaluated in terms of
consistency, strength of associations, biological plausibility and the
influence of chance or bias

2.4

Update with recent studies
The most recent comprehensive reviews were performed by DWQI
(2016) and the US-EPA (2016a). The DWQI literature search included
studies published up to 30 April 2015 and US-EPA studies published up
to December 2015. Therefore, relevant epidemiological studies were
searched in PubMed from 1-1-2016 to 26-10-2016 using US-EPA’s
search terms:
Search (((((((perfluorooctanoate OR “perfluorooctanoic acid” OR
“perfluoroctanoic acid” OR pfoa OR “perfluorinated chemicals” OR
“perfluorinated compounds” OR “perfluorinated homologue
groups” OR “perfluorinated contaminants” OR “perfluorinated
surfactants” OR perfluoroalkyl acids OR “perfluorinated alkylated
substances” OR “perfluoroalkylated substances” OR “fluorinated
surfactants”)) AND human* [tw] AND ("2016/01/01"[Date Publication] : "3000"[Date - Publication]))))))
In addition, the following search terms were used to determine whether
relevant epidemiological reviews had been published (after 1-1-2006)
that were not included in the reviews:
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Search ((((((((((perfluorooctanoate OR “perfluorooctanoic acid”
OR “perfluoroctanoic acid” OR pfoa OR “perfluorinated chemicals”
OR “perfluorinated compounds” OR “perfluorinated homologue
groups” OR “perfluorinated contaminants” OR “perfluorinated
surfactants” OR perfluoroalkyl acids OR “perfluorinated alkylated
substances” OR “perfluoroalkylated substances” OR “fluorinated
surfactants”)) AND human* [tw] )))))))) AND review[Publication
Type]
In total, an additional four epidemiological studies and four
epidemiological reviews were found that were relevant.
2.5

Extraction of data from epidemiological studies and reviews
Conclusions from previous reviews were summarized. From each original
publication, the following information was extracted and summarized in
tables:
• Name(s) of authors and publication year (reference).
• Details on the study characteristics: general study characteristics
were reported, i.e. study population, age range, % of men, study
design, study years and the number of individuals examined (‘N
total’).
• Blood PFOA concentration: if available, the median, mean and
range of measured or estimated concentrations (ng/mL) were
reported. Additional information was sometimes provided. For
instance, the interquartile range was provided if quartiles were
used in analyses or if the full range was not reported.
• Endpoint studied and association with PFOA: which endpoints
were studied, whether an association was found with the
examined endpoints and the magnitude of the association (effect
size).

2.6

Integration of findings
In the present review, the consistency of the conclusions taken from the
previous reviews is discussed in Chapter 4. The epidemiological data
taken from original studies were used (if possible) to give an indication
of the magnitude of the association and of the range of blood PFOA
concentrations in which associations were observed. The original studies
were not evaluated in terms of study quality, as this had already been
done in the previously performed reviews.

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3

Results

Chapter 3.2 briefly summarizes the general conclusions taken from
previous reviews regarding the endpoints that are associated with blood
PFOA concentrations. Table 1 shows the endpoints that were selected for
the current review and the wording used to describe the evidence in the
previous reviews. Table 2 shows the number of epidemiological studies
that were included in each previous review and in the current review. In
Chapters 3.3 to 3.11, the general conclusions are discussed per endpoint
and the results from epidemiological studies are discussed per endpoint.
3.1

General conclusions from previous reviews
It can be seen from Table 1 that the conclusions drawn by
(inter)national organizations differ, regarding which endpoints are
associated with PFOA, as well as the rating of the strength of the
evidence.
The C8 Science Panel concluded that there is a probable link with
testicular and kidney cancer (C8 Science Panel, 2012b), pregnancyinduced hypertension (including preeclampsia) (C8 Science Panel,
2011a), ulcerative colitis (C8 Science Panel, 2012a), thyroid disease (C8
Science Panel, 2012e), and high cholesterol (C8 Science Panel, 2012d).
Both the Health Council of the Netherlands (2013) and IARC (2016)
evaluated cancer only. A wide range of cancers, including testicular
cancer and kidney cancer, were evaluated by both. The Health Council
considered the available data to be insufficient to evaluate the
carcinogenic properties of PFOA. IARC (2016) considered PFOA as
possibly carcinogenic to humans.
ATSDR (2015) concluded that associations were consistently found
between serum PFOA and increases in liver enzymes, decreases in birth
weight, increases in uric acid levels, and serum lipid levels. They note
that other effects have been reported, but those associations were not
consistently found in similar types of studies or were only found in a
single study.
ECHA-RAC (2015b) seems to emphasize (i.e. they give more attention
to those two endpoints in their report) in their opinion document that
associations with birth weight and cholesterol were observed. They also
conclude that none of the endpoints were suitable for examining healthbased cut-off values for blood concentrations of PFOA.
The DWQI (2016) concluded that, of the endpoints they evaluated
comprehensively, the evidence for associations with PFOA was strongest
for the liver enzyme ALT, uric acid and serum levels of cholesterol. They
added that, for these endpoints, the dose-response was steepest in
serum PFOA concentrations found in the general population and
communities with drinking water exposures, with a much flatter curve at
higher serum concentrations. Associations with fetal growth and cancer
were evaluated by DWQI by evaluating comprehensive reviews
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performed by other scientific groups, which found those endpoints
potentially associated with PFOA.
The NTP (2016) presumes that PFOA is ‘an immune hazard to humans
based on a high level of evidence that PFOA suppressed the antibody
response from animal studies and a moderate level of evidence from
studies in humans.’ They further note that, from the human studies,
there is only a low level of confidence that an association exists with the
autoimmune disease ulcerative colitis and hypersensitivity responses in
childhood, but a moderate level of confidence that an association exists
with the suppression of the antibody response.
The US-EPA (2016a) concluded that human epidemiology data report
associations between PFOA exposure and increased concentrations of
liver enzymes, testicular and kidney cancer, pregnancy-induced
hypertension and preeclampsia, decreased vaccination response, thyroid
disorders and high blood cholesterol concentrations.

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Table 1. Endpoints reported to be associated1 with PFOA in at least one of the previous reviews

Selected
endpoints in
the current
review

C8 Science
Panel (2011,
2012)

Health
Council NL
(2013)

Liver enzymes

No probable
link

NE

Liver disease

No probable
link

NE

ATSDR
(2015)
Consistent
evidence
(ALT and
bilirubin)
No
association

Reviews
ECHA-RAC
(2015a;
2015b)
NE
NE

DWQI
(2016)
Consistent
evidence
(ALT)
Limited
evidence

IARC
(2016)

NTP
(2016)

(US-EPA,
2016a)

NE

NE

Consistent
evidence (ALT
and GGT)

NE

NE

Few studies and
no association

NE

Associations
were reported

NE

Associations
were reported

Evidence
credible and
unlikely to
be explained
by bias and
confounding.
Evidence
credible, but
chance, bias
and
confounding
cannot be
excluded.

Probable link

Insufficient
data for
evaluation

Evidence
was
equivocal

No firm
conclusions were
made by ECHARAC (refer to C8
and IARC)

Kidney cancer

Probable link

Insufficient
data for
evaluation

Evidence
was
equivocal

No firm
conclusions were
made by ECHARAC (refer to C8
and IARC)

Association
was observed

Pregnancyinduced
hypertension
and
preeclampsia

Probable link

NE

No firm
conclusions

Relationship is
not clearly
established

NE

NE

NE

Some evidence

NE

Consistent
findings with
small
decrease in
birth weight

Studies suggest
the existence of
a relationship

Sufficient
evidence

NE

NE

No evidence for
a relationship

Testicular
cancer

Birth weight

Evidence
insufficient to
evaluate (low
birth weight,
i.e. <2,5kg)

Association
was observed

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Selected
endpoints in
the current
review
Uric acid
concentration

Reviews
ECHA-RAC
(2015a;
2015b)

C8 Science
Panel (2011,
2012)

Health
Council NL
(2013)

NE

NE

Consistent
evidence

NE

Limited
evidence

NE

No firm
conclusions

No firm
conclusions

NE

NE

ATSDR
(2015)

Vaccination
response

NE

NE

Evidence is
not
consistent

Ulcerative
colitis

Probable link

NE

No firm
conclusions

Thyroid effects

Probable link
(thyroid
disease)

Blood lipid
concentration

Evidence of a
shift (average
cholesterol)
Probable link
(hypercholest
erolemia)

1

IARC
(2016)

NTP
(2016)

Evidence was
found

NE

NE

NE

No
association

No firm
conclusions

Limited
evidence
(thyroid
disease)
Limited or no
evidence (TSH
and thyroid
hormones)

NE

Associations
were found
(total
cholesterol)

Associations
were suggested
by studies (total
cholesterol &
LDL)

Evidence was
found of an
association
(total
cholesterol)

Blue shading: reported to be associated with PFOA
NE=Not Evaluated

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NE

DWQI
(2016)

NE

Moderate
confidence
that an
association
exists
Low confidence in
the
evidence

(US-EPA,
2016a)
An association
was observed,
but potentially
confounded
Association was
observed

No firm
conclusions

NE

Association was
observed (in
women)

NE

Associations
were found
(total
cholesterol and
LDL)

RIVM Report 2017-0086

Table 2. Number of epidemiological studies per endpoint included in previous reviews and the present review.

Selected endpoints
in the current
review

C8 Science
Panel (2011,
2012)1

Liver enzymes and
liver disease
Testicular and kidney
cancer
Pregnancy-induced
hypertension and
preeclampsia
Birth weight
Uric acid concentration
Vaccination response
Ulcerative colitis
Thyroid effects
Blood lipid
concentration

ATSDR
(2015)

7

Health
Council
NL
(2013)
NE

ECHARAC
(2015a)

DWQI
(2016)

3

IARC
(2016)

10

NE

15

NE

4

4

4

33

3

NE

4

2

8
NE
NE
Unpublished
at the time
only
10
9

NE
NE
NE
NE

12
5
3
C85

NE
NE

9
15

NTP
(2016)

(USEPA,
2016a)

This
review
(2017)

NE

10

15

4

NE

3

4

NE

NE

NE

4

6

14
NE
NE
C85

14
7
5
C85

NE
NE
NE
NE

NE
NE
4
2

12
4
3
C85

15
8
6
2

7
7

19
23

NE
NE

NE
NE

14
16

25
24

2

1

Unpublished studies are described by C8 Science Panel in their evaluation, but not included in the number of studies in this table (as no references are
available).
2
(US-EPA, 2016a) only considered the most recently updated studies.
3
Described reviews performed by IARC (2015), USEPA (2006) and C8 Science Panel.
4
Described only the meta-analysis performed by Johnson et al 2014.
5
Described only the conclusions drawn by the C8 Science Panel and/or the epidemiological studies from the C8 Science Study
NE=Not Evaluated

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3.2

Liver enzymes and liver disease
As an indication of liver health, blood concentrations of liver enzymes
can be measured. The examined liver enzymes are alanine
aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transpeptidase (GGT) and alkaline phosphatase (ALP); direct
(‘conjugated’) bilirubin and total bilirubin are examined as well. In
general, an increase in these enzymes may be indicative of liver
problems, although normally they vary so it is difficult to determine
when health is affected.

3.2.1

Conclusions from previous reviews
The C8 Science Panel (2012c) concluded that there is no probable link
between exposure to PFOA and liver disease. They did not attempt to
evaluate the link with liver enzymes. They argued that, although
associations with the blood levels of liver enzymes were observed, the
magnitude of effects on liver lay within a normal physiologic range and
there is no evidence that it results in liver disease.
ATSDR (2015) concluded in their draft review that consistent findings
were found for the association between serum PFOA and the blood levels
of liver enzymes. They refer to one study of residents who were highly
exposed to PFOA and they found significant associations between serum
PFOA and ALT and bilirubin levels. They note that, although associations
were found, the magnitude of increased blood levels of liver enzymes
were not great. In addition, in studies examining workers, no associations
were consistently found between serum liver enzymes (primarily ALT, AST
and GGT) and serum PFOA concentrations. Regarding liver disease,
ATSDR (2015) reports that studies have not found increases in deaths
from liver cirrhosis or increases in the incidence of liver disorders or
cirrhosis (only occupational populations were examined).
DWQI (2016) concluded that limited evidence of an association between
blood levels of liver enzymes GGT and AST, bilirubin and liver disease
has been found and that no evidence was found of an association with
the liver enzyme ALP. In contrast, they concluded that consistent
evidence has been found for an association between PFOA and increases
in the blood levels of the liver enzyme ALT in large studies conducted
among the general population and high-exposure communities. They
consider the evidence with ALT to be one of the strongest.
The US-EPA (2016a) concluded that epidemiological studies report an
association between exposure to PFOA and increased blood levels of
liver enzymes. They reported that studies have consistently shown an
association between serum PFOA concentrations and elevations in the
serum levels of ALT and GGT. These associations were observed in all
types of study populations, i.e. workers, high-exposure communities and
the general population in the US. (US-EPA, 2016a) discussed the
possibility that the association found between PFOA and the levels of
liver enzymes in the blood of workers might depend on co-variates (e.g.
BMI and the use of lipid lowering medicine). They also concluded that
the associations were not large in magnitude. However, the fact that
associations were found indicates the potential of PFOA to affect liver
function. Regarding liver disease, the US-EPA concluded that few studies
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have examined the relationship between PFOA and liver disease, and
they reported that most studies found no association.
3.2.2

Summary of studies
Table 3 summarizes the results of epidemiological studies. In total,
15 epidemiological studies were included.
Three cross-sectional studies were performed in a general population
(Gleason et al., 2015; Jiang et al., 2014; Lin et al., 2010). A higher ALT
concentration was observed in those with higher serum PFOA
concentrations in a study population (i.e. the NHANES study, with an
interquartile range of 2.9-5.95 ng/mL) (Lin et al., 2010). They observed
a stronger association in particularly obese individuals. Gleason et al.
(2015) observed an association between serum PFOA and higher AST,
ALT, GGT and total bilirubin (also in the NHANES study; interquartile
range: 2.5-5.2 ng/mL). Jiang et al. (2014) found no association between
serum PFOA and blood levels of liver enzymes (i.e. AST, ALT and total
bilirubin) in a general population in China (range: 1.82-33.2 ng/mL).
Three studies were performed in high-exposure communities (all part of
the C8 Health Study population) in which the relationship between
serum PFOA concentration and blood levels of liver enzymes was
examined. Two studies were cross-sectional (Emmett et al 2006; Gallo
et al 2012). One of those cross-sectional studies had PFOA
concentrations of 0-3,000 ng/mL and reported no significant association
with blood levels of liver enzymes (Emmett et al., 2006). This is,
however, a study that carried less weight because it is a relatively small
study (n=371). In the other study (Gallo et al., 2012), a median PFOA
concentration of 28.0 ng/mL (interquartile range: 13.5-70.8 ng/mL) was
observed among 47,092 individuals. They found an association between
PFOA and ALT. In addition, Gallo et al. (2012) discuss that a study
previously performed by Steenland et al (2009) observed an association
between individual serum levels of PFOA and the water district of
residence. Factors related to the water district of residence may
therefore have affected the examined association between PFOA and
ALT. For this reason, Gallo et al. (2012) examined the association within
and between water districts, thereby adjusting for those factors related
to the water district. Associations were found both within and between
water districts, which strengthens the notion that a relationship between
PFOA exposure and the blood levels of liver enzymes exists. Darrow et
al (2016) performed a longitudinal study and observed an association
between modelled PFOA concentrations and higher ALT and lower direct
bilirubin (a median serum PFOA concentration of 16.5 ng/mL was
observed and a full range of 2.6-3,559 ng/mL). No association was
found between serum PFOA and liver disease (diagnosis of liver disease
was validated by healthcare providers).
Multiple studies were performed in which occupational study populations
were examined. Similar to the results taken from studies conducted
among the general population and a high-exposure community,
associations were found, although not consistently. Cross-sectional
occupational studies observed some associations with the blood levels of
liver enzymes (although inconsistent, i.e. sometimes only in a certain
factory or certain year of examination) (Olsen et al., 2000; Olsen and
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Zobel, 2007). Those studies examined individuals with serum PFOA
concentrations ranging between 0.1-81,300 ng/mL (Olsen et al., 2000),
7-92,030 ng/mL (Olsen and Zobel, 2007), 5-9,550 ng/mL (Sakr et al.,
2007a) and 200-47,040 ng/mL (Costa et al., 2009). One occupational
study conducted among workers with 40-12,700 ng/mL of serum PFOA
concentration found no association between PFOA and the blood levels
of liver enzymes (Olsen et al., 2003). Gilliland and Mandel (1996)
observed no association between serum fluorine (examined as a proxy
for PFOA) and changes in GGT. Three longitudinal studies were
performed. One longitudinal study found some association (serum
concentration range: 0-2,266 ng/mL) (Sakr et al., 2007b). Another
longitudinal study conducted among an occupational population with
serum PFOA concentrations ranging from 0.1-10,000 ng/mL found no
association with blood levels of liver enzymes (Olsen et al., 2012). No
association of estimated cumulative PFOA concentrations with nonhepatitis liver disease was found in a longitudinal study among an
occupational population with a median PFOA concentration of 113 ng/mL
(full range not reported) (Steenland et al., 2015).
3.3

Testicular and kidney cancer

3.3.1

Conclusions from previous reviews
The (C8 Science Panel, 2012b) concluded that there is a probable link
between PFOA and both testicular and kidney cancer. The Panel gave
the most weight to studies conducted among the high-exposure
community of the C8 Health Study, as they regarded other studies to be
of limited value for assessing risk in the C8 study area because
exposures were much lower and/or were very small with little data of
value for specific cancers.
The Health Council of the Netherlands (2013) concluded that the
available data on PFOA and its salts are insufficient to evaluate its
possible carcinogenicity. Studies performed in workers cohorts, highexposure communities and among the general population were reviewed
by the Health Council of the Netherlands (2013). They conclude that a
relatively high number of longitudinal studies were conducted into the
relationship with cancer in general, but the results are of such a high
degree of inconsistency that they consider the human data as being
insufficient for drawing firm conclusions.
ATSDR (2015) reported that some increases in kidney and testicular
cancer have been found in high-exposure communities near a
production plant or in workers (i.e. the C8 Health Panel).
Yet ATSDR noted that these results should be interpreted cautiously
because the results were inconsistent, the number of cancer cases was
low and a causal relationship between PFOA and cancer cannot be
established from these studies.
It was not the objective of the background document (ECHA-RAC
2015a) to draw any firm conclusions regarding the association between
PFOA and health. So no firm conclusions were drawn regarding cancer,
but they do describe the epidemiological studies performed on the
relationship with kidney and testicular cancer in their background
document. In addition, they refer to the conclusions drawn by IARC and
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C8 regarding a potential association with cancer. As described before,
none of the endpoints evaluated by ECHA-RAC were considered ‘robust
enough to include in a quantitative assessment’ (ECHA-RAC 2015b).
DWQI (2016) used recently published comprehensive reviews performed
by other recognized scientific groups (C8 Science Panel, 2012b; IARC,
2016; US-EPA, 2005; US-EPA, 2006; US-EPA, 2016a) for their
evaluation with respect to testicular and kidney cancer. DWQI concluded
that PFOA was associated with an increased incidence of testicular and
kidney cancer in high-exposure communities. They reported that those
studies have accounted for smoking history and other relevant factors.
IARC (2016) has classified PFOA as ‘possibly carcinogenic to humans’
based on studies conducted in humans and animals. IARC (2016)
considered the evidence for specifically testicular cancer to be ‘credible
and unlikely to be explained by bias and confounding’. However, they also
noted that the estimates were based on small numbers. IARC (2016) also
considered the evidence for kidney cancer to be credible. But they
concluded that, for kidney cancer, the influence of ‘chance, bias, and
confounding could not be ruled out with reasonable confidence’.
US-EPA concluded that PFOA is ‘likely to be carcinogenic to humans’
based on animal studies. But in a peer review of the draft report it was
stated that PFOA is carcinogenic to humans (US-EPA, 2006). In a more
recent report (US-EPA, 2016a) in which the EPA reviewed
epidemiological studies, they concluded that associations between PFOA
exposure and testicular and kidney cancer have been reported in human
epidemiological studies. Two studies involving people in the C8 Health
Study area showed a positive association between PFOA concentrations
and kidney and testicular cancers (Barry et al., 2013; Vieira et al.,
2013). They also reported that two occupational cohorts do not support
an increased risk of testicular and kidney cancers, but both studies were
limited by small numbers.
Update with recent studies: reviews
One review was published after 2006 that examined the association
between exposure to PFOA and cancer (Chang et al., 2014). The project
was funded by the 3M Company, but the company was not involved in
the preparation or approval of the report. Chang et al (2014) concluded
that the existing epidemiological evidence does not provide evidence for
a relationship between exposure to PFOA and cancer. They note, for
instance, that in some epidemiological studies statistically significant
associations were observed (with cancers of the kidney and testis, as
well as prostate and thyroid), but those results were counterbalanced by
negative associations and no evidence has been observed in animals.
3.3.2

Summary of studies
Table 4 summarizes the results of epidemiological studies. In total, four
epidemiological studies were included that examined an association
between serum PFOA concentrations and kidney cancer and testicular
cancer. Two studies were conducted in the C8 study area. Of those two
studies, one study examined both workers and a high-exposure
community (i.e. the C8 Health Study) (Barry et al., 2013) and one study
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examined a high-exposure community only (also the C8 Health Study)
(Vieira et al., 2013). Two studies examined mortality in occupational
study populations (Lundin et al., 2009; Steenland and Woskie, 2012).
Barry et al. (2013) observed that individuals were significantly more
likely to have testicular cancer if they had higher estimated cumulative
ln-transformed serum PFOA concentrations (i.e. the sum of estimated
serum concentrations over the examined years; i.e. ng/mL-years;
annual serum PFOA concentrations were estimated at 2.8-9217 ng/mL,
with a median value of 19.4 ng/mL; median or range of estimated
cumulative concentrations were not reported). However, they only found
a modest, non-significant association with kidney cancer (p=0.1). In
contrast, Vieira et al. (2013) observed that individuals examined in the
high-exposure community (full range of annual estimated serum PFOA
concentration were 3.7-655 ng/mL) were more likely to have kidney
cancer when their estimated annual serum PFOA concentrations were
30.8-109 ng/mL (OR=2.0) and 110-655 ng/mL (OR=2.0), compared
with unexposed individuals (<3.7 ng/mL), assuming 10 years of
residency in a contaminated water district. Residence in the most
exposed water district was associated with a higher likelihood of
testicular cancer (OR=5.1), but the analysis of an individually modelled
serum level showed a lower and non-significant risk. In both studies
performed in occupational study populations (Lundin et al., 2009;
Steenland and Woskie, 2012) there were insufficient cases or no cases
to examine testicular cancer. Lundin et al. (2009) found no association
with kidney cancer. Steenland and Woskie (2012) observed that kidney
cancer was more likely to occur in DuPont workers in Parkersburg, who
had estimated cumulative blood concentrations of 1,819 ppm-years
(ppm=parts per million; 1 ppm=1000 ng/mL). To illustrate what ppmyears entail, Steenland and Woskie (2012) reported that, for example,
100 ppm over five years would be equal to 500 ppm-years.
3.4

Pregnancy-induced hypertension and preeclampsia
Pregnancy-induced hypertension refers to elevated blood pressure with
or without protein in the urine. Preeclampsia specifically refers to
elevated blood pressure with protein in the urine.

3.4.1

Conclusions from previous reviews
The C8 Science Panel notes that pregnancy-induced hypertension and
preeclampsia cannot be distinguished clearly in the epidemiological
studies they considered (because of reporting bias). Therefore,
pregnancy-induced hypertension refers to both pregnancy-induced
hypertension and preeclampsia in their evaluation. The C8 Science Panel
(2011a) considered the existing evidence to be sufficient. It concluded
that there is a probable link for an association between PFOA exposure
and pregnancy-induced hypertension. The Panel added that the
associations are not strong and there is no evidence of a dose-response
relationship (i.e. higher risk when exposed to higher levels of PFOA).
Nevertheless, they concluded that there is a probable link because
associations were observed in multiple, differently performed analyses,
which limits the possibility of bias influencing the results. Also, the
associations were stronger for pregnancies that were closest in time to

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the measurement of serum PFOA values, when exposure assignment is
likely to be most accurate.
ATSDR (2015) does not report a firm conclusion on whether an
association exists. They reported that Savitz et al. (2012b) found no
consistent association between PFOA (predicted serum PFOA
concentrations) and pregnancy-induced hypertension. In contrast, Darrow
et al. (2013) observed a higher risk of pregnancy-induced hypertension in
women with higher PFOA (≥6.9 ng/mL) among highly exposed residents.
Two studies (of highly exposed residents) found a (weak) association
between PFOA and preeclampsia (Savitz et al., 2012a; Stein et al., 2009),
however no dose-response relationship was found (Stein et al., 2009).
In their background document, ECHA-RAC (2015a) stated that
“pregnant women may be particularly vulnerable to PFOA-induced
increase in total cholesterol, but the relationship between elevated PFOA
serum levels and preeclampsia has not been clearly established.” None
of the evaluated endpoints by ECHA-RAC were considered to be ‘robust
enough to include in a quantitative assessment’ (ECHA-RAC 2015b).
The US-EPA (2016a) concluded that each of the studies they considered
in their evaluation (Darrow et al., 2013; Savitz et al., 2012a; Savitz et
al., 2012b; Stein et al., 2009) have provided some evidence of an
association with pregnancy-induced hypertension or preeclampsia. The
most robust findings were found in the study they considered to be the
strongest study methodologically (Darrow et al., 2013).
3.4.2

Summary of studies
Table 5 summarizes the results of six epidemiological studies that
examine the relationship between plasma, serum or full blood PFOA
concentrations and pregnancy-induced hypertension or preeclampsia in
a general population and a high-exposure community.
Two studies were performed among the general population (i.e. both in
the Norwegian Mother and Child Cohort Study), in which plasma PFOA
concentrations were measured up to 5.15 ng/mL (i.e. 95th percentile).
Both found no association with validated preeclampsia (Starling et al.,
2014a) or the biomarkers of preeclampsia (Starling et al., 2014b).
Four studies were performed in a high-exposure community, i.e. the C8
Health Study. The studies produced some inconsistent results. Two
studies examined the relationship with pregnancy-induced hypertension
(Darrow et al., 2013; Savitz et al., 2012b). Darrow et al. (2013) found a
higher risk of pregnancy-induced hypertension in those with higher serum
PFOA concentrations (i.e. with an increase in 1 lnPFOA; OR=1.27,
CI=1.05-1.55; full serum PFOA concentration range: 0.6-459.5 ng/mL).
They also observed that pregnancy-induced hypertension was more likely
in individuals with serum PFOA concentrations in the second through fifth
quintiles, compared with the lowest quintile (i.e. <6.9 ng/mL) (Darrow et
al., 2013). Savitz et al. (2012b) observed an association (i.e. OR=1.5,
CI=1.1-2.1) only in those women who had estimated PFOA
concentrations between the 60 and 80th percentiles (i.e. 19.6 to
53.1 ng/mL), compared with <40th percentile (3.9 to <8.9 ng/mL), but
not in the other percentiles (full estimated range: 3.9 - 934.3 ng/mL).
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Regarding preeclampsia in a high-exposure community, one study
modelled a higher risk of preeclampsia for an increase of 100 ng/mL (i.e.
OR=1.08, CI=1.01-1.15) and a relative risk of 1.1–1.2 was observed
across the upper three quintiles of estimated serum PFOA concentrations
(i.e. 6.1-717.6 ng/mL) (Savitz et al., 2012a). The other study found no
significantly increased risk for preeclampsia (Stein et al., 2009) (range of
measured serum PFOA concentration: 0.25-894.4 ng/mL). The study
performed by Stein et al. (2009) is possibly less accurate because they
did not model blood PFOA concentration at the time of the pregnancy, but
rather measured blood PFOA concentrations after pregnancies occurred
(i.e. pregnancies occurred within the 5 years preceding exposure
measurement), in contrast with (Savitz et al., 2012a).
Pregnancy-induced hypertension and preeclampsia can be measured by
self-reports or by birth certificate codes. It has been discussed that
pregnancy-induced hypertension and preeclampsia are often reported
incorrectly, either through self-reports or retrieved from birth certificates
(Savitz et al., 2012b). For example, Darrow et al. (2013) discussed the
fact that pregnancy-induced hypertension recorded on the birth record
generally does not specify whether it concerns pregnancy-induced
hypertension or preeclampsia.
3.5

Birth weight
Insufficient growth during pregnancy potentially affects the health of the
newly born child. Epidemiological studies have examined both absolute
birth weight and the occurrence of low birth weight (<2.5 kg). Absolute
birth weight does not necessarily provide information on whether or not
the baby’s health is affected. Low birth weight (<2.5 kg; notably
different from ‘small for gestational age’, which can be defined as an
infant with birth weight below the 10th percentile at a specific gestational
age in weeks), is a clinical outcome with potential health consequences.
On the other hand, a decrease of absolute birth weight in a large group
of people may have a relevant impact, i.e. for babies with already low
birth weight. Therefore, absolute birth weight may also be relevant from
the standpoint of public health.

3.5.1

Conclusions from previous reviews
The C8 Science Panel (2011b) reports that the evidence of an association
between PFOA exposure and low birth weight (i.e. <2.5 kg) is insufficient
to evaluate whether a probable link exists. They note that there is some
evidence, although inconsistent, suggesting small changes in average
birth weight at the highest PFOA exposure concentrations. However,
those changes are not necessarily medically relevant. The C8 Science
Panel, therefore, only considered studies that examined low birth weight
to be relevant for their evaluation.
The ATSDR (2015) concluded that there were consistent findings for an
association between serum PFOA and decreases in birth weight. They
added that, although studies found significant associations, the
decreases were small and so they considered them potentially not to be
biologically relevant.
In their background document, ECHA-RAC (2015a) stated that the
evaluated studies suggest the existence of a relationship between higher
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blood PFOA concentrations and lower birth weight. They discussed a
recently published, systematic review by Johnson et al. (2014) may
have drawn different conclusions from those of the C8 Science Panel
because the C8 Science Panel: 1) mostly considered studies that
examined low birth weight as opposed to a continuous measure of birth
weight, 2) considered studies in which PFOA exposure was determined
less accurately and 3) because Johnson et al. (2014) were able to
consider more recent studies in which some suggestions of an
association were found (although they were not necessarily significant)
(Chen et al., 2012; Maisonet et al., 2012; Whitworth et al., 2012). In
addition, ECHA-RAC (2015a) noted that, in the literature, an alternative
explanation for the association between maternal PFOA concentration
and reduced birth weight has been discussed, i.e. women who give birth
to babies with a low birth weight have a lower glomerular filtration rate
(GFR). A lower GFR, in turn, decreases the removal of PFOA from the
blood. It is therefore possible that women who give birth to babies with
a lower birth weight have higher serum PFOA concentrations because of
a lower GFR. Yet in another study conducted by the researchers of the
meta-analyses, it was reviewed whether an association exists between
GFR and foetal growth (Lam et al., 2014). The existing studies for such
a relationship are of insufficient quality and therefore, although they did
not find an association, they cannot be sure there is no association (Lam
et al., 2014). In their opinion document, ECHA-RAC (2015b) concluded
that the association was relatively small and that there are uncertainties
with respect to dose-response. On these grounds, they concluded that
the epidemiological data cannot be used for quantification.
The DWQI (2016) did not make their own evaluation of foetal growth, but
reported on the systematic review performed by Johnson et al. (2014).
The authors of the review concluded that ‘sufficient’ human evidence has
been published to establish an association between exposure to PFOA in
the general population during development and a reduction in foetal
growth (e.g. birth weight) in humans. Johnson et al. (2014) reported that
an increase of 1 ng/mL in blood PFOA concentrations is associated with a
decrease of 18.9 grams (95% confidence interval [CI] = -29.8, -7.9) in
birth weight. They assumed a linear relationship (examining
untransformed PFOA) and pooled data from various general population
studies. They discussed the fact that many studies found an association in
the same direction, i.e. a higher blood PFOA concentration was associated
with lower birth weight. However, those individual studies did not often
find statistically significant associations. By combining single studies in
the meta-analysis, the statistical power was increased, which explains
why Johnson et al. (2014) found a significant association and concluded
that there is sufficient evidence of an association between PFOA exposure
and reduced foetal growth. It should be noted that Johnson et al. (2014)
only included studies performed among the general population.
The US-EPA (2016a) evaluated individual studies, as well as the review
performed by Johnson et al. (2014). The US-EPA (2016a) reported that
higher blood PFOA concentrations were associated with lower birth
weight in several studies. Yet they also noted that the association may
have another explanation, i.e. a lower GFR, as described above.
Whether or not this is the case is uncertain. Johnson et al. (2014) also
examined whether a low GFR could explain the relationship between
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PFOA and birth weight. They concluded that the available studies on
foetal growth and GFR were inadequate to draw conclusions on the
association between both measures. So they concluded that they could
not exclude a decreased GFR as an alternative explanation for the
association between higher PFOA and lower birth weight.
Update with recent studies: reviews
Two reviews were published after 2006 that explored a relationship
between exposure to PFOA and birth weight (Bach et al 2015; Lam et al
2014). Lam et al. (2014) used similar data as Johnson et al. (2014), but
Lam et al. (2014) additionally review nonhuman evidence. Lam et al.
(2014) concluded that sufficient evidence exists for an association
between developmental exposure to PFOA and decreased foetal growth,
but, as described above, it is not yet clear whether this relationship can
be explained by the influence of GFR. Bach et al. (2015) concluded that
most studies show an association between higher PFOA concentrations
and lower birth weight, but it is often not statistically significant. For this
reason, they considered the existing epidemiological studies insufficient
to confirm or reject an association with lower birth weight.
3.5.2

Summary of studies
Table 6 summarizes the results of the epidemiological studies. In total,
15 studies were included that examined a relationship between serum
PFOA concentration (of the mother during pregnancy or the umbilical
cord) and birth weight.
Ten studies examined the general population, with measured serum or
plasma PFOA concentrations ranging up to 41.5 ng/mL. Seven studies
conducted among the general population in different countries observed
no association with birth weight (Apelberg et al., 2007; Chen et al., 2012;
Hamm et al., 2010; Lee et al., 2013; Monroy et al., 2008; Washino et al.,
2009; Whitworth et al., 2012). Maisonet et al. (2012) observed lower
birth weights in babies of mothers with serum PFOA concentrations of
>4.4 ng/mL, compared with 1-3.1 ng/mL (range: 1-16.4 ng/mL). Birth
weights did not differ in the babies of mothers with serum PFOA
concentrations of 3.1-4.4 ng/mL, compared with 1-3.1 ng/mL. Fei et al.
(2007) observed an association between higher maternal plasma PFOA
(concentrations of up to 41.5 ng/mL were measured) and babies with
lower birth weight. In contrast, Ashley-Martin et al. (2016) found that
babies’ with a higher gestational weight gain were more likely to have
above-median cord serum PFOA concentration (i.e. >0.39 ng/mL),
compared with below-median cord blood PFOA concentrations.
Four studies were performed in high-exposure communities (C8 Health
Project community) (Darrow et al., 2013; Savitz et al., 2012a; Savitz et
al., 2012b; Stein et al., 2009) with PFOA concentrations of up to
934.3 ng/mL (Savitz et al., 2012a). Darrow et al. (2013) and Savitz et
al. (2012a) did not find any association. Savitz et al. (2012b) found
some inconsistent findings with birth weight and no dose-response
relationship. Stein et al. (2009) found a higher risk of lower birth weight
in mothers with serum PFOA concentrations of 50-120.6 ng/mL
(measured after birth and not measured or estimated at the time of the
birth), compared with 0.25-<21.3 ng/mL. However, no association was
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found in mothers with blood PFOA concentrations of 21.3-50 ng/mL or
120.6-894.4 ng/mL, compared with mothers with serum PFOA
concentrations of 0.25-<21.3 ng/mL. Stein et al. (2009) therefore
concluded that no linear dose-response relationship could be found.
One study examined an occupational study population (serum PFOA
concentrations range: 5.5-58.5 ng/mL) and found an association
between higher serum PFOA concentrations in pregnant women
(selected from workers at an electronic waste recycling area and from
the general population; serum PFOA concentrations ranged from 4.4 to
58.5 ng/mL) and lower birth weight (Wu et al., 2012).
3.6

Uric acid concentration
Uric acid occurs in blood when certain foods (specifically containing
purines) and human cells are broken down in the body. Uric acid is
broken down and partly removed by the kidneys. A higher uric acid
concentration in the blood may indicate the presence of clinical
conditions. Hyperuricemia is having uric acid concentrations in the blood
above a certain cut-off value.

3.6.1

Conclusions from previous reviews
The C8 Science Panel has not evaluated a relationship between serum
PFOA and uric acid concentrations.
ATSDR (2015) concluded that consistent associations were found
between higher serum PFOA and higher uric acid concentrations. They
noted that, while the relationship with uric acid concentration was not
examined to be as good as, say, serum lipids, the five studies that were
reviewed by ATSDR (2015) all found significant associations. Those
studies were performed in disparate study populations, i.e. in
occupational populations, high-exposure communities and among the
general population. In the latter two groups, associations were also
found between higher serum PFOA concentrations and hyperuricemia.
DWQI (2016) concluded that evidence has been found for an association
between PFOA and increases in serum concentrations of uric acid. Six
out of seven studies reviewed by DWQI observed a significant
association. Those six studies examined the general population, highexposure communities and occupational studies, thus examining a wide
range of exposures. A dose-response relationship was found between
PFOA and uric acid in general population studies and a high-exposure
community study. Usually, a steep dose-response curve was found in
the general population, with a flattened slope at higher PFOA
concentrations. However, the DWQI also discussed the fact that the
epidemiological evidence still has some limitations, e.g. the primary one
being that cross-sectional studies are examined, which limits the
possibility of examining the influence of confounding. There remain
questions regarding the biological plausibility of the relationship. Still,
they concluded that uric acid is one of the endpoints for which they
considered the evidence to be the strongest.
US-EPA (2016a) also concluded that an association has been observed
between higher serum PFOA concentrations and uric acid concentrations
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measured in blood. Yet they noted that the concentration of PFOA in
serum depends on exposure and the rate at which PFOA is excreted
from the body by intestines and the kidneys. Both PFOA and uric acid
concentrations may be higher because of reduced kidney function, not
because PFOA affects uric acid concentrations. Kidney disease may
therefore confound the relationship.
3.6.2

Summary of studies
In Table 7, the total of eight epidemiological studies are summarized.
They all found an association between higher serum or plasma PFOA
concentration and higher uric acid concentration (Costa et al., 2009;
Geiger et al., 2013; Gleason et al., 2015; Qin et al., 2016; Sakr et al.,
2007a; Shankar et al., 2011; Steenland et al., 2010b) – except for one
(Lin et al., 2013a). The studies that examined a relationship with
hyperuricemia also found an association between higher serum or
plasma PFOA concentration and a higher prevalence of hyperuricemia
(Geiger et al., 2013; Shankar et al., 2011; Steenland et al., 2010b).
Five studies examined the general population in the United States
(Geiger et al., 2013; Gleason et al., 2015; Lin et al., 2013a; Qin et al.,
2016; Shankar et al., 2011). The NHANES study was the primary study
used (Geiger et al., 2014; Gleason et al., 2015; Shankar et al., 2011).
Shankar et al. (2011) observed a higher mean change in uric acid
(mg/dL), with higher plasma PFOA concentrations in blood, starting from
quartile 2 (2.4-3.4 ng/mL) up to quartile 4 (>5.1 ng/mL), compared
with quartile 1 (<2.4 ng/mL), and a higher risk of hyperuricemia in
quartiles 3 and 4. Similar results were found for hyperuricemia (Shankar
et al., 2011). Geiger et al. (2013) examined children only (12-18 years).
The children had similar serum PFOA concentrations in their blood
(75th ercentile: >5.4 ng/mL). However, in contrast to the results found
by Shankar et al. (2011), an association was found only in those with
PFOA concentrations in the highest quartile, i.e. >5.4 ng/mL, compared
with the lowest quartile (<2.9 ng/mL). Also, a higher risk (OR=1.62) of
hyperuricemia was found in children that had serum PFOA
concentrations >5.4 ng/mL, compared with those with <2.9 ng/mL
(Geiger et al., 2013). An association was observed between serum PFOA
and uric acid (75th percentile: >5.2 ng/mL) (Gleason et al., 2015). Lin et
al. (2013a) examined the association between serum PFOA and uric acid
in Taiwanese children aged 12-30 years and found no significant
association (serum PFOA concentration range: 0.75-52.2 ng/mL). Qin et
al. (2016) examined Taiwanese children aged 12-15 years and observed
an association between higher serum PFOA concentration and higher
uric acid concentrations in boys only (median serum PFOA
concentration: 0.5 ng/mL; 75th percentile: >1.3 ng/mL).
One study examined a high-exposure community (C8 Health Study) with
serum PFOA concentrations ranging up to ≥188.7 ng/mL (Steenland et
al., 2010b). Uric acid concentration in serum increased by approximately
0.2-0.3 mg/dL from the lowest (0-7.8 ng/mL) to the highest
(>=188.7 ng/mL) decile of PFOA (Steenland et al., 2010b). Also, a higher
risk of hyperuricemia was found with higher PFOA quintiles, starting at
PFOA concentrations in the second quintile (i.e. 11.4-20.6 ng/mL). For
instance, individuals with serum PFOA concentrations of 11.4-20.6 ng/mL
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had a higher risk of hyperuricemia than individuals with serum PFOA
concentrations of <11.4 ng/mL.
Costa et al. (2009) examined an occupational population in Italy with
measured blood PFOA concentrations of 200 ng/mL or higher. They
observed higher uric acid concentrations (mg/mL) with higher PFOA
concentrations (µg/mL) (β=0.026, CI=0.001-0.053). In another
occupational study (Sakr et al., 2007a), blood PFOA concentrations of 5
through 9,550 ng/mL were observed. The authors reported that they
found an association with uric acid, but did not quantify their results.
Steenland et al. (2010a) reviewed various studies in which a relationship
between PFOA and various health endpoints were examined. Regarding
the relationship with uric acid, they pointed out that causality cannot be
inferred from cross-sectional data and the relationship between uric acid
and PFOA may be a result of reverse causality due to competition
between PFOA and uric acid for renal excretion. It is, however, a matter
of speculation as to whether this hypothesis applies to humans. All
studies summarized in the current review on the relationship between
uric acid and PFOA were cross-sectional.
3.7

Vaccination response
The purpose of vaccination is to help develop immunity against an
infectious disease. Epidemiological studies have examined the
concentration of antibodies following vaccination in relation to blood
concentrations of PFOA.

3.7.1

Conclusions from previous reviews
The C8 Science Panel did not evaluate a link with vaccination response.
The ATSDR (2015) reported that limited information is available regarding
immunotoxicity (which includes vaccination response), but no firm
conclusions were drawn.
The DWQI (2016) concludes that, although an association between PFOA
and decreased antibody concentrations following vaccination has
consistently been found in longitudinal studies, most of the vaccine types
were evaluated in only one or two studies and there is limited evidence
for exposure-response relationships.
The NTP (2016) concluded that there they are moderately confident that
an association exists between PFOA exposure and suppression of the
antibody response. They observed heterogeneity in the findings, but
explain that the heterogeneity is possibly the result of differences in the
methodologies used between studies.
The US-EPA (2016a) concluded that epidemiological studies showed an
association between serum PFOA concentrations and decreased
vaccination response. They report that two studies in children (Grandjean
et al., 2012; Granum et al., 2013) and one study in adults (Looker et al.,
2014) observed a decrease in response to one or more vaccines.

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Update with recent studies: reviews
One review was published after 2006 (Chang et al., 2016). The 3M
Company was not involved in the preparation or approval of the report,
but the project was funded by 3M. The authors concluded that
associations were observed, but most studies had methodological
limitations and were unable to exclude confounding, bias or chance.
3.7.2

Summary of studies
Six epidemiological studies were summarized (Table 8); one study
examined a high-exposure community population (Looker et al., 2014)
and five studies examined a study population from the general
population (Grandjean et al., 2012; Granum et al., 2013; Kielsen et al.,
2016; Mogensen et al., 2015; Stein et al., 2016).
In a high-exposure community (full measured serum PFOA concentration
range: 0.25-2,140 ng/mL; 75% of the study population had PFOA
concentrations below 90.3 ng/mL; aged 18+ years), an association was
observed between higher serum PFOA concentration quartiles and
reduction in seroprotection (Looker et al., 2014). Higher serum PFOA
concentration quartiles were therefore associated with a reduced antibody
response to the A/H2N2 Influenza vaccine and consequently a higher risk
of not attaining the antibody threshold necessary to offer long-term
protection against this virus (Looker et al., 2014).
In four general population studies, childhood vaccinations were
examined. Childhood vaccination responses are a useful way of
examining the relationship between PFOA exposure and vaccination
response because children receive the vaccinations at approximately the
same age, thereby limiting bias from differences in vaccination and age.
Grandjean et al. (2012) found that 75% of all examined mothers had
serum PFOA concentrations below 4.01 ng/mL and 75% of all children at
the age of five had serum PFOA concentrations below 4.96 ng/mL. An
association was observed between higher serum PFOA concentrations in
children and lower serum antibody concentrations against tetanus and
diphtheria (Grandjean et al., 2012). Higher PFOA concentrations were
therefore related to reduced immune response to childhood
immunizations. Mogensen et al. (2015) extended their analyses with
additional serum PFOA concentrations in children at age seven. As a
result, they were able to examine whether the children were exposed
between the ages of five and seven. Median serum PFOA concentrations
were 4.1 ng/mL at five years old and 4.4 ng/mL at seven years old. The
researchers found a significant association between serum PFOA
concentrations at five and seven years old with reduced immune
response to antibody concentrations (diphtheria: β=-34.7, CI=-52.5,
-10.2; tetanus: β=-38.2, CI=-56.1, -13.0). Granum et al. (2013) found
that 75% of the study population of young children had plasma PFOA
concentrations below 1.4 ng/mL. They observed an association between
plasma PFOA concentrations and reduced antibody levels of the rubella
vaccine (Granum et al., 2013). The authors discussed the possibility that
prenatal exposure to PFOA may lead to immunosuppression in early
childhood. The individuals examined by Stein et al. (2016) had a
geometric mean of 4.13 ng/mL. Stein et al. (2016) found an association
between higher serum PFOA concentrations and lower levels of mumps
and rubella antibody concentrations, especially in seropositive
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individuals (i.e. it is assumed that seropositive children are children that
have been exposed to the vaccine strain of these viruses). No
association was observed with measles antibody concentration.
No significant association was observed in one study that examined
adults in the general population in Denmark (Kielsen et al., 2016) (75%
had a serum PFOA concentration below 2.79 ng/mL). Only 12 individuals
were examined and the analyses had a low statistical power, which may
explain why no association was observed.
3.8

Ulcerative colitis
Ulcerative colitis is a condition that results in inflammation and ulcers of
the colon and rectum. It is the result of an abnormal response by the
immune system. The cause of ulcerative colitis is unclear.

3.8.1

Conclusions from previous reviews
The C8 Science Panel (2012a) concluded that there is a probable link
between PFOA exposure and ulcerative colitis. They reported that,
because of a lack in other relevant epidemiological research and virtually
no toxicology (i.e. cell and animal studies) on this topic, they base their
conclusion solely on research done in the C8 cohort study. They
concluded that a very clear and positive dose-response relationship was
found, with a large elevation in the risk of ulcerative colitis developing in
the highest exposure group.
The NTP (2016) concluded that, based on two epidemiological studies,
there is a low level of confidence that exposure to PFOA is associated
with ulcerative colitis because the evidence is restricted to one study
population (C8 Health Project). There is no information available for
other study populations. This lowers their confidence in the evidence.
The ATSDR (2015), ECHA-RAC (2015a), DWQI (2016) and US-EPA
(2016a) all described the conclusions drawn by the C8 Science Panel
and/or the epidemiological studies from the C8 Science Study and did
not provide firm conclusions on whether or not an association with
ulcerative colitis exists. None of the endpoints evaluated by ECHA-RAC
were considered ‘robust enough to include in a quantitative assessment’
(ECHA-RAC 2015b).

3.8.2

Summary of studies
Table 9 summarizes the results of studies that examine an association
between serum PFOA concentrations and ulcerative colitis.
A total of two studies were found. One study was conducted in a
combination of a high-exposure community and an occupational study
population (Steenland et al., 2013). The other study was conducted in
an occupational study population (Steenland et al., 2015) (both from the
C8 Health Study). Higher quartiles of cumulative, estimated PFOA
concentrations were related to a higher incidence of ulcerative colitis in
both studies. Compared with estimated, cumulative serum PFOA
concentrations of <158 ng/mL-years, ulcerative colitis was more likely
to occur in those with serum PFOA concentrations of 158-586, 5863,500 and >3,500 ng/mL-years (i.e. OR=1.76, OR=2.63, and OR=2.86,
respectively) (Steenland et al., 2013). In the second study, it was found
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that, compared with estimated, cumulative serum PFOA concentrations
of <800 ng/mL-years, ulcerative colitis was more likely to occur in those
with estimated cumulative serum PFOA concentrations of 800-3,440,
3,440-7,040 and >7,040 ng/mL-years (i.e. OR=3.0, OR=3.26 and
OR=6.57, respectively) (Steenland et al., 2015).
3.9

Thyroid effects
Epidemiologic studies have examined associations between PFOA and TSH
(thyroid stimulating hormone), thyroglobin (TGN), thyroid stimulating
immunoglobulins (TSI) and thyroid hormones, i.e. triiodothyronine (T3)
and thyroxine (T4). Most of the T4 and T3 circulate in the blood bound to
protein. However, a small percentage is free. Either free or total T4 and
T3 are measured in studies. Total T4 and total T3 are the sum of free and
bound T4 and T3. TSH, T3, T4, TGN and TSI are all related to the
functioning of the thyroid and the production of thyroid hormones.
Thyroid hormones (T3 and T4) control numerous physiological processes,
including breathing, heart rate, digestion and body temperature. In the
case of thyroid disease, the thyroid releases not enough (hypothyroidism)
or too many (hyperthyroidism) thyroid hormones. Hypothyroidism is more
common than hyperthyroidism. The prevalence of thyroid disease is
highest among women and people over the age of 60. During pregnancy,
temporally adaptations in maternal thyroid hormone production occur.
Before approximately 20 weeks of gestation, maternal thyroid hormones
are the only source of thyroid hormones for the developing baby. Altered
thyroid metabolism of the mother during early pregnancy may therefore
influence the baby’s development.

3.9.1

Conclusions from previous reviews
The C8 Science Panel (2012e) concluded that, despite inconsistencies in
the evidence, there is a probable link between PFOA and thyroid
disease. The Panel considered the strongest positive evidence to be an
increased occurrence among the C8 community of medically validated
thyroid disease (hyperthyroidism in women, hypothyroidism in men),
with increasing blood PFOA concentrations in prospective analyses.
The ATSDR (2015) concluded that, based on the results in adolescents,
adults and pregnant women, PFOA in blood does not appear to result in
thyroid toxicity.
In their background document, the ECHA-RAC (2015a) describes the
studies and conclusions reported by the C8 Science Panel and added
some studies performed in occupational studies. As previously noted,
none of the endpoints were considered by the ECHA-RAC to be ‘robust
enough to include in a quantitative assessment’ (ECHA-RAC 2015b).
The evaluation of the DWQI (2016) is that, overall, studies in which
thyroid hormones, TSH and thyroid disease are examined provide
inconsistent evidence of any associations with PFOA. The DWQI
concluded that there is limited evidence of an association with thyroid
disease and limited or no evidence of an association between PFOA and
TSH and thyroid hormones.
The US-EPA (2016a) concluded that human epidemiology studies report
an association between PFOA and thyroid disorders. Blood PFOA
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concentrations are associated with diagnosed thyroid disease in females
and female children, most often hypothyroidism. This was the case in
the highly exposed C8 community and in the general population with
background exposure. PFOA was not consistently associated with thyroid
hormone concentrations. However, PFOA was associated with TSH
concentrations in pregnant women with anti-TPO antibodies. In contrast,
no association between PFOA and TSH was observed in women who had
not been diagnosed with thyroid disease.
Update with recent studies: reviews
In a systematic review (Ballesteros et al., 2017), studies were reviewed
that examined an association between prenatal or childhood (<19 years)
exposure to PFOA (as well as other perfluoroalkyl substances) and TSH,
T3, T4 or thyroid dysfunctions. They conclude that the heterogeneity
(i.e. study design, study setting, timing of exposure assessment, timing
and type of thyroid-related outcome assessment, adjustment for
potential confounders and statistical approach) was too great to
compare results within each of the included study populations, except
for specifically mothers (n=4 studies) and 11 to 19 year-old children
(n=3 studies). They observed no consistent evidence for an association
between PFOA concentrations and TSH, T3, T4 or thyroid dysfunctions.
3.9.2

Summary of studies
Table 10 summarizes the 25 studies that were included in one or more
of the previous reviews.
Sixteen studies examined the general population, among newborns,
children, pregnant women or adults with plasma and serum PFOA
concentrations ranging from 0.05 to 123 ng/mL (Berg et al., 2015;
Bloom et al., 2010; Chan et al., 2011; de Cock et al., 2014; Jain, 2013;
Ji et al., 2012; Kim et al., 2016; Lin et al., 2013b; Melzer et al., 2010;
Shah-Kulkarni et al., 2016; Shrestha et al., 2015; Wang Y. et al., 2014;
Wang Y. et al., 2013; Webster et al., 2014; Wen et al., 2013; Yang et
al., 2016). In eight studies (i.e. among newborns, children, pregnant
women or adults), no association was observed with any of the thyroid
effects they examined, which were TSH (Bloom et al., 2010; Ji et al.,
2012; Lin et al., 2013b; Shah-Kulkarni et al., 2016; Shrestha et al.,
2015; Wang Y. et al., 2014; Wang Y. et al., 2013), (total) T3 (ShahKulkarni et al., 2016; Shrestha et al., 2015; Wang Y. et al., 2014), (free
or total) T4 (Bloom et al., 2010; Ji et al., 2012; Lin et al., 2013b; ShahKulkarni et al., 2016; Shrestha et al., 2015; Wang Y. et al., 2014) and
hypothyroidism (Chan et al., 2011; Lin et al., 2013b). In two studies
that examined pregnant women, higher blood concentrations of PFOA
were associated with higher TSH blood concentrations (median serum
concentrations were 1.7 ng/mL (Webster et al., 2014) and 1.53 ng/mL
(Berg et al., 2015)). The authors noted that, although the associations
were modest, the observed small changes may have implications for
foetal health and development (Berg et al., 2015; Webster et al., 2014).
In three studies that examined adults, associations were found with
greater occurrence of thyroid disease in women only (Melzer et al.,
2010), changes in T3 in women only (Wen et al., 2013) and free T3
(Wen et al., 2013; Yang et al., 2016). Three studies examined newborns
or children and observed an association of blood PFOA concentrations
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with T4 in girls (de Cock et al., 2014), total T3 (Jain, 2013) and TSI
(Kim et al., 2016).
Three studies were performed in high-exposure communities
(interquartile range of serum PFOA concentrations: 184-571 ng/mL
(Emmett et al., 2006); full range of serum PFOA concentrations:
0.05-3,987 ng/mL (Lopez-Espinosa et al., 2012); full range of serum
PFOA concentrations: 0.25-564.3 ng/mL (Knox et al., 2011)). Emmett et
al. (2006) and Knox et al. (2011) found no association between serum
PFOA and TSH. Lopez-Espinosa et al. (2012) found that, in those with
higher serum PFOA concentrations, TSH decreased in girls, T4 increased
in both boys and girls and thyroid disease was more likely. Knox et al.
(2011) observed an association of higher serum PFOA concentrations
with higher T4 in women (20-50 and >50 years) and men (aged
>50 years). One study examined both workers and a high-exposure
community and observed an association between higher PFOA
concentrations and more functional thyroid disease (i.e. excluding
neoplasms), hypothyroidism and hyperthyroidism in women only
(Winquist and Steenland, 2014b).
In populations that were occupationally exposed to PFOA, serum PFOA
concentrations ranged between 7-92,030 ng/mL (Olsen and Zobel,
2007), 5-9,550 ng/mL (Sakr et al., 2007a), 10-12,700 ng/mL (Olsen et
al., 2003) and 0.00-114,100 ng/mL (Olsen et al., 1998). Steenland et
al. (2015) did not report a range, but did report a median-measured
serum PFOA concentration of 113 ng/mL. Higher serum PFOA
concentrations were associated with higher T3 (Olsen et al., 2003; Olsen
and Zobel, 2007) and lower free T4 (Olsen and Zobel, 2007). Higher
TSH was observed in those with serum PFOA concentrations of 10 to
<30 ng/mL, compared with lower (Olsen et al., 1998). In contrast, no
association was observed with T4 (Olsen et al., 2003; Olsen and Zobel,
2007), with TSH (Olsen et al., 2003; Sakr et al., 2007a) and with
thyroid disease (Steenland et al., 2015).
3.10

Blood lipid concentrations
The following blood lipids have been examined in epidemiological
studies: total cholesterol, high-density lipid (HDL), non-HDL (i.e.
LDL+VLDL), low-density lipid cholesterol (LDL), triglycerides, very lowdensity lipid cholesterol (VLDL), the ratio of total cholesterol to HDL and
the ratio of HDL to LDL.
LDL is a protein that transports cholesterol throughout the body. LDL
easily attaches to arteries and, if concentrations are too high, LDL may
cause atherosclerosis. HDL helps prevent the build-up of cholesterol in
arteries by transporting cholesterol to the liver. Insufficiently low blood
concentrations of HDL are associated with an increased risk of
cardiovascular disease. Together with cholesterol, triglycerides are
packed with LDL and VLDL for transportation in the body and are
gradually broken down in the blood stream into LDL and triglycerides.
Triglycerides are lipids that, like cholesterol, occur in blood. Enhanced
concentrations of triglycerides in combination with unfavourable
cholesterol concentrations increase the risk of cardiovascular disease.

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3.10.1

Conclusions from previous reviews
The C8 Science Panel (2012d) concluded that there is evidence of both a
shift in average cholesterol and an increased risk of high cholesterol in
relation to PFOA. The panel added that longitudinal analyses and
analyses by water district performed by the C8 Science Panel in the MidOhio Valley suggest that the association is less likely to be explained by
confounding factors. A probable link was only evaluated for high
cholesterol, which entailed cholesterol concentrations high enough for a
doctor to prescribe medication. The C8 Science Panel concluded that a
probable link exists between PFOA and high cholesterol
(hypercholesterolemia).
According to the ATSDR (2015), most but not all studies found
significant associations between PFOA and serum lipid concentrations,
most consistently for increased total cholesterol concentration and not
as strong for other serum lipids.
ECHA-RAC (2015a) described that, in addition to the conclusions drawn
by the C8 Science Panel, cross-sectional and longitudinal epidemiological
studies also support an association between higher PFOA concentrations
and total cholesterol and LDL. They noted that the studies suggest a low
dose effect, i.e. larger changes in cholesterol were observed in general
than were observed in occupational study populations. Yet they suggest
that differences in age and sex distributions between general and
occupational study populations may also explain the difference in the
observed magnitude of changes.
The DWQI (2016) concluded that limited evidence of an association with
LDL has been found and no evidence has been found for an association
with HDL. In contrast, they also concluded that evidence has been found
for an association between PFOA and increases in serum concentrations of
cholesterol. They found that studies of the general population and large
high-exposure community studies and occupational studies with
longitudinal designs found consistent evidence for an association. They
concluded that, of all health endpoints they reviewed, the evidence for an
association with PFOA is strongest for serum cholesterol (in addition to
liver enzyme ALT and uric acid). The results for that association showed
‘consistency, strength, dose-response and some evidence of temporality’.
The US-EPA (2016a) has concluded that, for total cholesterol and LDL
cholesterol, generally positive associations have been observed with
serum PFOA in studies examining workers and in studies conducted in
high-exposure communities among adults and children (aged 1–18 y).
Despite some exceptions, the results are relatively consistent and
robust. Associations were not seen with HDL cholesterol. In the general
population, associations of PFOA with total cholesterol are seen, but
because of similar results for PFOS and moderately strong correlations
between blood PFOA and PFOS concentrations, the interpretation of
findings taken from studies conducted in the general population is
limited (US-EPA 2016a).

3.10.2

Summary of studies
Table 11 summarizes the results of the epidemiological studies. A total
of nine studies were conducted among members of the general
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population, six in high-exposure communities (including two studies in
which workers were also examined, i.e. Wang J. et al. (2012) and
Winquist and Steenland (2014a)) and nine in occupational settings.
All seven studies that measured total blood cholesterol concentration in
the general population found a positive association between serum or
plasma PFOA and total cholesterol (Eriksen et al., 2013; Fisher et al.,
2013; Fu et al., 2014; Geiger et al., 2014; Nelson et al., 2010; Starling
et al., 2014b; Zeng et al., 2015). In five (Eriksen et al., 2013; Fu et al.,
2014; Geiger et al., 2014; Nelson et al., 2010; Zeng et al., 2015) of the
seven studies, the association was statistically significant. LDL was also
measured in seven studies. Three studies (Fu et al., 2014; Geiger et al.,
2014; Zeng et al., 2015) observed a positive statistically significant
association, two studies (Fisher et al., 2013; Starling et al., 2014b) a
non-significant positive association and two studies (Lin et al., 2013a;
Nelson et al., 2010) non-significant negative associations. Nelson et al.
(2010), however, although they did not find an association with LDLcholesterol, did find a positive statistically significant association
between PFOA and non-HDL (i.e. LDL + VLDL) cholesterol. HDLcholesterol was measured in seven studies. In one study positive and
negative, statistically significant associations were found in adolescent
girls and elderly men, respectively. The other six studies found
statistically non-significant positive and negative associations.
Six studies were conducted in high-exposure communities, four of which
were from the C8 Health Project (Fitz-Simon et al., 2013; Frisbee et al.,
2010; Steenland et al., 2009; Winquist and Steenland, 2014a), one was
conducted in the C8 Health Project area (Emmett et al., 2006) and one
was conducted in a community in China (Wang J. et al., 2012). Three
studies from the C8 Health Project found positive and statistically
significant associations between serum PFOA concentrations and total
and LDL-cholesterol concentrations. These studies included crosssectional studies in 46,294 adults (Steenland et al., 2009) and 12,476
children (Frisbee et al., 2010) and one longitudinal study in 560 adults
(Fitz-Simon et al., 2013). Two studies also found an association between
PFOA and elevated total cholesterol concentrations (Frisbee et al., 2010;
Steenland et al., 2009), and one study between PFOA and elevated LDLcholesterol levels (Frisbee et al., 2010) (not studied in Steenland et al.
(2009)). A longitudinal study from the C8 Health Project included both
workers and members of the high-exposure community and used
modelled serum PFOA concentrations (Winquist and Steenland, 2014a).
They also found a higher incidence of medically validated diagnosis of
hypercholesterolemia with medication in those with higher cumulative,
modelled serum PFOA concentrations, i.e. hazard ratios were
significantly higher in quintiles 2 (>142 ng/mL per year) through 5
(≥3,579 ng/mL per year) (hazard ratios in quintiles 2 through 5: 1.24,
1.17, 1.19, 1.19, see table 11) (Winquist and Steenland, 2014a). The
study conducted by Emmett et al. (2006) in the C8 Project area studied
total cholesterol levels and found a positive non-significant association
with PFOA, but this study was based on a much smaller data set
(n=371) and did not adjust for potential confounders in the statistical
analysis. The study from China (Wang J. et al., 2012) included 132
residents and did not find associations with total, LDL or HDL cholesterol
or triglyceride concentrations.
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None of the community studies found an association with HDLcholesterol. An association with triglycerides was found in the two large
cross-sectional studies from the C8 Health Project (Frisbee et al., 2010;
Steenland et al., 2009), but not in the longitudinal study (Fitz-Simon et
al., 2013) or the study from China (Wang J. et al., 2012).
Nine studies included workers from PFOA production plants. As mentioned
above, one study included both an occupational study population, as well
as a high-exposure community. Five studies (Costa et al., 2009; Olsen et
al., 2003; Olsen and Zobel, 2007; Sakr et al., 2007a; Sakr et al., 2007b)
found positive and statistically significant associations between blood
PFOA and total cholesterol concentrations. Positive non-significant
associations were reported in three studies (Gilliland and Mandel, 1996;
Olsen et al., 2000; Wang J. et al., 2012). One study reported a negative
non-significant association (Olsen et al., 2012) and one study (Steenland
et al., 2015) did not include total cholesterol concentrations (but selfreported elevated cholesterol with medication).
In six studies, LDL-cholesterol was also determined. Five studies
(Gilliland and Mandel, 1996; Olsen and Zobel, 2007; Sakr et al., 2007a;
Sakr et al., 2007b; Wang J. et al., 2012) showed positive associations
with PFOA concentrations, one of which (Sakr et al., 2007a) was
statistically significant. One study reported cholesterol concentrations
per tertile of PFOA, with no apparent positive or negative association
(Olsen et al., 2000).
HDL-cholesterol was studied in nine studies. Five studies (Gilliland and
Mandel, 1996; Olsen et al., 2000; Olsen and Zobel, 2007; Sakr et al.,
2007a; Wang J. et al., 2012) found negative associations with PFOA,
two of which (Olsen and Zobel, 2007; Wang J. et al., 2012) were
statistically significant. One study (Sakr et al., 2007b) found a nonsignificant positive association. Two studies (Costa et al., 2009; Olsen et
al., 2012) found non-significant associations that were either positive or
negative, depending on the statistical model, and in one study (Olsen et
al., 2003) the association was not quantified.

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4

Discussion and Conclusions

The objective of this literature review was to address the questions of
what biological and physiological parameters and diseases are associated
with PFOA concentrations in the blood of humans and in what
concentration ranges these associations can be observed, as well as to
give an indication of the magnitude of these associations. As
recommended in a risk assessment of the emission of PFOA (Zeilmaker et
al., 2016), an evaluation of epidemiological studies may indicate whether
there are any potential effects of PFOA for which attention should be
given to the people living in the vicinity of the Dupont/Chemours factory
in Dordrecht. In recent years, a number of reviews have been performed
by recognized (inter)national organizations (ATSDR, 2015; C8 Science
Panel, 2011a; C8 Science Panel, 2011b; C8 Science Panel, 2012a; C8
Science Panel, 2012b; C8 Science Panel, 2012c; C8 Science Panel,
2012d; C8 Science Panel, 2012e; C8 Science Panel, 2017; DWQI, 2016;
ECHA-RAC, 2015a; ECHA-RAC, 2015b; IARC, 2016; NTP, 2016; US-EPA,
2016a). In these reviews, both human (epidemiological) and toxicological
(animal and in vitro) studies were reviewed in order to assess what
biological and physiological parameters and diseases can result from
exposure to PFOA.
Nine biological and physiological parameters and diseases were evaluated
as being associated with higher PFOA concentrations in the blood by at
least one (inter)national organization: increased concentrations of levels
of liver enzymes in blood, concentrations of (total and LDL-) cholesterol in
blood, thyroid effects, kidney and testicular cancer, pregnancy-induced
hypertension and preeclampsia, reduced birth weight, increased uric acid
concentrations in the blood, decreased vaccination response, and
ulcerative colitis. The level of evidence for an association with PFOA
concentrations in the blood differs between the various endpoints. Also,
the evidence for a particular endpoint was evaluated differently in the
different reviews. For example, The ATSDR (2015) described the evidence
for an association between PFOA and uric acid concentrations in the blood
as ‘consistent evidence’ (ATSDR, 2015), while the US-EPA (2016a)
mentions that ‘an association was observed, but potentially confounded’.
In the present review, the evaluations of the epidemiological evidence for
these endpoints from the previous reviews have been summarized. The
results of the epidemiological studies were summarized in tables, but the
studies were not reviewed individually; they were used to gain an
impression of the range of PFOA concentrations in human blood in which
associations with endpoints have been observed and an impression of the
magnitude of the associations.
4.1

Discussion per endpoint
Below, for each endpoint, there will be a discussion of how strong the
evidence from epidemiological studies is, according to (inter)national
organizations, for an association with PFOA and about the study
population (i.e. general population, high-exposure community,
occupational study population) in which associations with these

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endpoints have been observed, as well as what the magnitude of these
associations is.
It was beyond the scope of the present review to provide a quantification
of the associations based on the findings of all available studies. To
provide an impression of the magnitude of these associations, examples
are given below from studies in the general population and/or highexposure communities in which associations were found. As these are
examples based on one or two studies, a formal meta-analysis may result
in smaller or larger estimates of effect sizes.
4.1.1

Liver enzymes and liver disease
The ATSDR (2015), DWQI (2016) and US-EPA (2016a) have concluded
that consistent evidence has been observed for the existence of an
association between serum PFOA concentrations and certain liver
enzymes (all agree on the liver enzyme ALT). The epidemiological studies
in which associations were observed were performed in study populations
from the general population, high-exposure communities and workers.
Three organizations (ECHA-RAC, 2015a; ECHA-RAC, 2015b; Health
Council of the Netherlands, 2013; NTP, 2016) did not evaluate blood
levels of liver enzymes or liver disease. The C8 Science Panel (2012c)
concluded that there is no probable link with liver disease, although they
did report on associations with shifts in liver function, mainly within the
normal physiologic range. The ATSDR (2015), DWQI (2016) and US-EPA
(2016a) also concluded that there is no or limited evidence of a
relationship between serum PFOA concentration and the occurrence of
liver disease. The changes in the blood levels of liver enzymes were
reported to be small. In summary, all previous reviews that evaluated
liver effects concluded that PFOA is associated with small changes in
blood concentrations of liver enzymes, but not with liver disease.

4.1.2

Testicular and kidney cancer
Of the four epidemiological studies that investigated an association with
kidney and/or testicular cancer, one was performed in a high-exposure
community, two were conducted in an occupational study population and
one in a combination of both study populations, which were all part of
the C8 Health Study. The incidence of testicular cancer and kidney
cancer (WHO, 2017) in the general population is low and large study
populations are required to obtain sufficient statistical power. This might
explain why no studies were performed in the general population. The
Health Council of the Netherlands (2013) concluded that the available
data examining PFOA and cancer was insufficient to determine a
potential association with cancer. Several international organizations, on
the other hand, have concluded that PFOA may be associated with
testicular and kidney cancer (C8 Science Panel, 2012b; DWQI, 2016;
IARC, 2016; US-EPA, 2016a). It has also been noted, however, that the
results need to be interpreted with caution because the results are
inconsistent, the number of cancer cases was low, a causal relationship
between PFOA and cancer cannot be established from these studies
(ATSDR 2015) and it cannot be ruled out that the evidence, specifically
for kidney cancer, has been influenced by chance, bias and confounding
(IARC 2016). Regarding the magnitude of an effect, a doubling in the
risk of kidney cancer was observed among residents in the community
of the C8 Health Study, with estimated blood PFOA concentrations above
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30.8 ng/mL, compared with those with concentrations <3.7 ng/mL
(Vieira et al., 2013).
In summary, four out of seven international organizations have
concluded that an association potentially exists between PFOA exposure
and testicular and kidney cancer, but the epidemiological studies still
have some limitations. It should also be noted that the number of
epidemiological studies that have investigated testicular and/or kidney
cancer is limited and were performed only in study populations that are
part of the C8 Health Study.
4.1.3

Pregnancy-induced hypertension and preeclampsia
Pregnancy-induced hypertension and preeclampsia have been studied in
the general population and the high-exposure community of the C8
Health Project. The C8 Science Panel (2011a) has concluded that the
associations were not strong and no dose-response relationship was
apparent. Still, they concluded that a probable link between exposure to
PFOA and pregnancy-induced hypertension and preeclampsia may exist in
the C8 Health Study because associations were observed in multiple,
differently performed analyses, which limits the possibility of bias
influencing the results. Also, the associations were stronger for
pregnancies that were closest in time to the measurement of serum PFOA
values, when exposure assignment is likely to be most accurate. After
publication of the probable link report, a study was published (Darrow et
al., 2013) which showed a non-monotonically increased risk of
pregnancy-induced hypertension in the 2nd (6.9-11.1 ng/mL) to 5th
quintiles (37.2-459.5 ng/mL) of PFOA, with odds ratio’s ranging from 2.4
to 3.4. The US-EPA (2016a) also concluded that a relationship exists
between exposure to PFOA and pregnancy-induced hypertension and
preeclampsia. The ATSDR did not report a firm conclusion. ECHA-RAC
(2015a) stated that the relationship has not yet been clearly established.

4.1.4

Birth weight
The C8 Science Panel (2011b) and US-EPA (2016a) have concluded that
there is not enough evidence for an association between PFOA exposure
and low birth weight (<2.5 kg) and average birth weight, respectively.
The C8 Science Panel (2011b) noted that, although a relationship with
small changes in birth weight was found in epidemiological studies, it
was not consistently observed. The ATSDR (2015) has concluded that
associations between PFOA exposure and small changes in birth weight
have been found. Both ECHA-RAC (2015a) and DWQI (2016) refer to
the meta-analysis performed by Johnson et al. (2014), in which several
studies performed in the general population were pooled and the
authors of the meta-analysis concluded that ‘sufficient’ human evidence
exists for a relationship between developmental PFOA exposure and
decreases in birth weight. In the meta-analysis performed by Johnson et
al. (2014), the decrease in birth weight was 19 g per increase of 1
ng/mL of serum PFOA. In the opinion document of ECHA-RAC (2015b),
it was noted that observed decreases were relatively small and that
there were uncertainties in dose-response. The US-EPA (2016a)
evaluated individual studies and the meta-analysis performed by
Johnson et al. (2014). The US-EPA (2016a) concluded that the
association observed between PFOA exposure and birth weight could
possibly be explained by the influence of the glomerular filtration rate
(GFR). In analyses performed by Verner et al. (2015) in which GFR was
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taken into account, the association between PFOA and a decrease in
birth weight was smaller. The DWQI (2016) concluded, on the basis of
the results of Verner et al. (2015), that GFR does not account for the
major portion of the decrease in birth weight associated with PFOA.
Johnson et al. (2014) concluded that chance, bias and confounding
could be ruled out with reasonable confidence. Nevertheless, it is not yet
clear to what extent a low GFR could contribute to the relationship
between serum PFOA concentrations and lower birth weight.
Therefore, most organizations agree that associations with birth weight
have been found in the general population, but there is some debate as
to whether or not these associations can be explained by other factors.
In addition, inconsistent results were produced in studies examining an
association between serum PFOA concentrations and birth weight in
high-exposure communities (that reflected much larger exposure
contrasts of PFOA and had more statistical power than the general
population studies). As a consequence, the association with birth weight
observed in the general population cannot be extrapolated to higher
blood concentrations of PFOA.
4.1.5

Uric acid concentrations
The ATSDR (2015) concluded that evidence was found for an association
between higher PFOA concentrations in the blood and higher uric acid
concentrations in the blood. Both the DWQI (2016) and US-EPA (2016a)
concluded that consistent evidence has been observed, but the
relationship is potentially confounded. The C8 Science Panel did not
evaluate a relationship between PFOA and uric acid concentrations
because they only evaluated diseases. Discussed in the reports is the fact
that an association with uric acid has been less frequently examined than
was done for, say, blood lipids (ATSDR 2015), that the relationship may
be confounded by the presence of kidney disease (US-EPA 2016a; DWQI
2016) and that a steep dose-response curve has been observed in the
general population, with a flattened slope at higher PFOA concentrations
(DWQI 2016). The epidemiological studies in which associations were
observed were conducted in the general population, high-exposure
communities and occupational populations. Differences in uric acid
concentrations in blood between the first category (the reference
category) and higher categories of PFOA concentrations in blood were in
the order of 0.1-0.3 mg/dL. The evidence that PFOA is associated with
hyperuricemia is limited. An association with hyperuricemia has been
observed in two studies conducted among the general population (relative
risks (RR) were 1.62 in the 4th quartile of PFOA concentrations in the
blood of adolescents (Geiger et al., 2013) and 1.90 and 1.97 in the 3rd
and 4th quartiles in adults (Shankar et al., 2011)) and one in the highexposed community from the C8 health Project (RR were 1.33 to 1.47 in
quintiles 2-5) (Steenland et al., 2010b). Although associations were
observed, they may be confounded by individual differences in kidney
clearance.

4.1.6

Decreased vaccination response
The ATSDR (2015) concluded that the evidence for an association
between blood levels of PFOA and decreased vaccination response is not
consistent. The DWQI (2016) reported consistent findings with evidence
of temporality, but also limited evidence of an exposure-response
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relationship between the blood levels of PFOA and decreased vaccination
response. The US-EPA (2016a) concluded that an association had been
observed and the NTP (2016) concluded that they have a moderate level
of confidence that an association exists. However, as discussed by the
DWQI (2016), most of the specific vaccine types were evaluated in only
one or two studies. More research is therefore needed to confirm these
findings. For this reason, most organizations have concluded that there is
not enough evidence available yet to determine whether an association
between blood levels of PFOA and decreased vaccination response exists.
Associations were observed in the general population and the C8 Health
Project. The NTP mentions decreases in circulating antibody levels of
15-35% for a doubling in blood PFOA concentrations (NTP, 2016).
Associations with inadequate seroprotection have also been reported.
For example, in a study conducted by Grandjean et al. (2012), the odds
ratios of antibody concentrations falling below the protective level for
diphtheria and tetanus in children at age seven, associated with a
doubling of PFOA concentrations at age five, were 3.27 (95% CI, 1.43 to
7.51) and 4.20 (95% CI, 1.54 to 11.44), respectively.
4.1.7

Ulcerative colitis
Two studies have been published that examined an association with
ulcerative colitis, both from the C8 Health Project. The (C8 Science
Panel, 2012a) has concluded that a probable link exists. The NTP (2016)
noted that it is not possible to evaluate consistency across populations
and this fact lowers their confidence in the evidence. The other
organizations did not evaluate ulcerative colitis themselves, but reported
the conclusions made by the C8 Science Panel.
Both published studies found an association and a dose-response
relationship. One was performed in the combined high-exposed
community and occupational study population, and one in the
occupational population of the C8 Health Project. Although no studies
were conducted in the general population, individuals with low serum
PFOA concentrations were also examined in those studies. In the
combined study population, in the 2nd – 4th quartiles of PFOA
concentrations (>158 ng/mL), an increased risk of ulcerative colitis (RR
were 1.76-2.86) was observed (Steenland et al., 2013). In workers, the
RR ranged from 3.0 to 6.57 in the 2nd to 4th quartiles (covering PFOA
concentrations of 800 to over 7,000 ng/mL) (Steenland et al., 2015).
The evidence base is limited and should be extended to other study
populations.

4.1.8

Thyroid effects
The C8 Science Panel (2012e) concluded that a probable link exists with
thyroid disease. The US-EPA (2016a) concluded that an association was
observed between serum PFOA concentrations and thyroid hormones.
The ATSDR (2015) concluded that no association was observed with
thyroid effects. DWQI (2016) reported that inconsistent findings were
provided. They concluded that limited or no evidence was found for a
relationship with blood concentrations of TSH and thyroid hormones,
and limited evidence for an association with thyroid disease. Which
means the organizations drew contradictory conclusions. PFOA in
relation to thyroid effects has been the topic of 25 studies in either the
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general population, high-exposure communities or occupational
populations. These studies provide inconsistent evidence, i.e. positive
associations, negative associations and no associations were observed
with various thyroid effects. An association with thyroid disease has
been studied less. Of the four studies in which thyroid disease has been
examined, two observed an association with PFOA concentrations in the
blood in relatively large study populations (RR=1.44 per IQR of 13.167.7 ng/mL in children from a high-exposure community population, i.e.
the C8 population (Lopez-Espinosa et al., 2012); RR=1.24, 1.27, 1.36
and 1.37 in quintiles 2 (114.7-202.2 ng/mL) through 5 (2,670-97,396
ng/mL) in women in a high-exposure community and an occupational
study population (Winquist and Steenland, 2014b).
4.1.9

Blood lipid concentrations
Associations of PFOA concentrations in the blood have quite consistently
been observed with total cholesterol concentrations (ATSDR, 2015; ECHARAC, 2015a; US-EPA, 2016a; DWQI, 2016) and, although less convincing,
LDL concentrations in the blood (ECHA-RAC, 2015a; US-EPA, 2016a;
DWQI, 2016), but not with concentrations of HDL-cholesterol. The C8
Science Panel (2012d) concluded that the relationship between PFOA
exposure and cholesterol may be causal in the high-exposure community
of the C8 Health Project and that a probable link with
hypercholesterolemia exists. The DWQI (2016) specified that an
association with cholesterol was consistently found in all three types of
study populations and, of all other examined endpoints, they considered
the evidence for blood cholesterol concentrations to be one of the
strongest). The US-EPA (2016a) notes that it is not yet clear whether the
association between PFOA and increased cholesterol in the general
population may be explained by the simultaneous presence of PFOS in the
general population. In summary, all international organizations that have
evaluated blood lipid concentrations have concluded that an association
exists with total cholesterol concentrations. Of all endpoints, the
association with blood lipid concentrations has been one of the endpoints
most often studied (see Table 2).
In the C8 Heath Study, nearly monotonic increases in total or LDLcholesterol were found with increasing PFOA concentrations in the blood.
Increases in total and LDL-cholesterol concentrations were the highest in
the range of approximately 5-40 ng/mL PFOA, after which an attenuation
of the slope of the dose-response curve was observed (Steenland et al.,
2009). A similar dose-response curve was observed in children and
adolescents (Frisbee et al., 2010). In the steep part of the dose-response
curve, increases in total and LDL cholesterol concentrations in the blood
were somewhere between 4-10 mg/dL. As reported by Winquist and
Steenland (2014a), hypercholesterolemia with medication was
significantly more likely in quintiles 2 (>142 ng/mL per year) through 5
(≥3,579 ng/mL per year) (RR in quintiles 2 through 5: 1.24, 1.17, 1.19,
1.19).

4.2

Other endpoints
A number of other endpoints have been studied in relation to serum levels
of PFOA. For these endpoints, it was generally concluded in the reviews
included in the present report that evidence for an association is limited
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or the available evidence was not evaluated in the reviews. In 2016, the
German Umwelt Bundesamt (UBA, 2016) issued a statement of the
German Human Biomonitoring Commission in which HBM I values for
PFOA and PFOS were set. The HBM I value represents the concentration
of a substance in a body matrix below which, according to the
Commission’s current assessment, adverse health effects are not
expected and therefore no exposure reduction measures are necessary.
These values are based on associations of PFOA and PFOS with fertility
and pregnancy; birth weight; lipid metabolism; immunity after
vaccination, immunological development; hormonal development, age at
puberty / menarche; thyroid metabolism; and onset of menopause. This
list thus includes a number of endpoints that were not evaluated in the
present review. For these endpoints, effects were rated as ‘well proven,
relevant and significantly associated with exposure to PFOA and/or PFOS’.
Because no background document was available at the time of publication
of the present report, it is unclear how the available epidemiological
evidence was evaluated by the German Human Biomonitoring
Commission and what effects were attributed by this Commission to
PFOA, PFOS or both.
4.3

Experimental data
Epidemiological studies, especially cross-sectional studies, have
limitations (e.g. the potential for bias and confounding) that make it
difficult to definitively draw conclusions on the causality of an
association. Evidence that PFOA is causally associated with an endpoint
is stronger if findings from epidemiological studies are supported by
results from experimental animal and in vitro studies and by knowledge
about the mode of action via which PFOA affects the endpoint in
question. An in-dept discussion of toxicological (animal) studies and the
mode of action of PFOA is provided in the reviews by ATSDR (2015), USEPA (2016a) and DWQI (2016). In summary, there is evidence from
experimental studies in animals that PFOA causes weight loss, hepatic
toxicity, effects on lipid metabolism, changes in hormone levels, immune
system effects, tumours in testis, liver and pancreas in rats (the only
species tested), and several types of developmental effects (Post et al.,
2012). It should be noted that these effects occurred at relatively high
dose levels, with serum PFOA concentrations in the mg/L range.
Nevertheless, the findings in experimental animals show that for most of
the endpoints considered in the present review, there is supporting
evidence from animal studies. A notable exception is blood cholesterol,
for which studies in rodents show a decrease rather than an increase in
total and LDL-cholesterol levels in the blood (Steenland et al., 2010a).
The biological mechanism(s) that explain(s) the effects of PFOA have not
been fully characterized. PFOA is chemically non-reactive and therefore
is not a substrate for biochemical reactions. However, PFOA may act
through the inactivation of nuclear receptors, binding to transporter and
carrier proteins and interacting with membranes (Post et al., 2012).
PFOA may also act through other mechanisms; and PFOA has estrogenic
activity (DWQI, 2016). PFOA causes peroxisome proliferation in the
liver, which may explain effects on liver size, liver enzymes and blood
lipids. Peroxisome proliferation activates the nuclear receptor PPARalpha, which has been proposed to induce tumours and cause immune
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and hormonal changes in rodents (Steenland et al., 2010a). But the
relevance of this mechanism for humans is unclear, because humans are
less sensitive to PPAR-alpha-mediated effects. This is an important point
when assessing the relevance of animal (mainly rodent) data for
humans.
4.4

Conclusions
The objective of this review was to address the questions of what
biological and physiological parameters and diseases are associated with
PFOA concentrations in the blood of humans and in what concentration
ranges these associations have been observed, as well as to give an
indication of the magnitude of these associations. Findings from
epidemiological studies provide indications that associations exist
between serum PFOA concentrations and several biological and
physiological parameters and diseases in study populations with
different levels of exposure to PFOA, i.e. the general population, highexposure communities and occupational study populations. The body of
evidence for the existence of a potential association and the magnitude
of the associations differ between endpoints, as is described in section
4.1. Conclusions from previous reviews are most consistent regarding
evidence for associations of PFOA with total blood cholesterol
concentrations, blood concentrations of the liver enzyme ALT and birth
weight. Associations were observed in individuals with PFOA
concentrations in their blood as found in the general population and at
higher concentrations. Yet it remains to be established whether the
associations observed in the epidemiological studies are causal. For
most endpoints, there is supporting evidence from experimental animal
studies, but the mode of action that explains how PFOA exerts its effects
has not been fully characterized. The findings from this literature review
will be used as a background document to assess the potential health
consequences of PFOA exposure in residents living in the direct vicinity
of the DuPont/Chemours factory in Dordrecht.

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Acknowledgements

The authors would like to thank the following persons for critically
reviewing draft versions of the report and/or for their participation in a
meeting of experts that was held on 9 January 2017 in Utrecht, the
Netherlands:
• Dr. Tony Fletcher, London School of Hygiene & Tropical Medicine
• PD Dr. med. Jürgen Hölzer, Ruhr-University Bochum
• Prof. Greet Schoeters, VITO; University of Antwerp; University of
Southern Denmark
• Dr. Michael Schümann, Free and Hanseatic City of Hamburg
• Dr. Irma de Vries, National Poisons Information Center,
University Medical Center Utrecht
• Dr. Gerard van Zoelen, National Poisons Information Center,
University Medical Center Utrecht
The autors also thank their colleagues at RIVM who contributed to the
report.

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Appendix Tables 3-11: data extracted from epidemiological studies

Table 3. Summary of associations in studies on liver enzymes

Reference

Study characteristics

General population
Lin et al.
Study population: general
(2010)
population, NHANES US
Age range: 18+ yrs
% men: 49%
Study design: Crosssectional
Study year(s): 1999-00 &
2003-04
N total=2,216
Jiang et al.
Study population: general
(2014)
population (pregnant
women), China
Age range: not reported (ca.
18-40 yrs)
% men: 0%
Study design: crosssectional
Study year(s): 2012
N total: 141

Gleason et al,

Study population: general

Blood PFOA concentration

Association with
PFOAa

Effect size

Serum PFOA:
IQR (men and women): 2.95.95 ng/mL
Geometric mean: 5.05 (men)
and 4.06 (women) ng/mL

ALT +
GGT +
Total bilirubin 0

Association between serum log PFOA
(per 1 ng/mL) and liver enzymes
(units per litre), β (p-value):
ALT: 1.86 (0.005)
Log GGT: 0.08 (0.019)
Total bilirubin: -0.09 (0.645)

Serum n-PFOA
Range: 1.8-32.9 ng/mL
Median: 3.95 ng/mL

AST 0
ALT 0
Total Bilirubin 0

Pearson correlation (r) & significance
level between concentrations of
PFOA (per 1 ng/mL) isomers and
biomarkers:
AST - n-PFOA: r=-0.037 (ns)
AST - iso-PFOA: r=0.008 (ns)
AST - 5m-PFOA: r=0.149 (ns)
AST - %n-PFOA: r=0.026 (ns)
AST - ∑PFOA: r=0.041 (ns)

Serum iso-PFOA
Range: 0.003-0.46 ng/mL
Median: 0.04 ng/mL
Serum 5m-PFOA
Range: 0.001-0.05 ng/mL
Median: 0.001 ng/mL
Serum ∑PFOA:
Range: 1.82-33.3 ng/mL
Median: 3.97 ng/mL
Serum PFOA:

AST +

ALT - n-PFOA: r=-0.071 (ns)
ALT - iso-PFOA: r=0.003 (ns)
ALT - 5m-PFOA: r=0.139 (ns)
ALT - %n-PFOA: r=-0.119 (ns)
ALT - ∑PFOA: r=-0.071 (ns)
Association between ln-PFOA (per 1

RIVM Report 2017-0086

Reference

Study characteristics

Blood PFOA concentration

2015

population, NHANES, US
population
Age range: ≥12 yrs
% men: not reported
Study design: crosssectional
Study year(s): 2007-2010
N total: 4,333

IQR: 2.5-5.2 ng/mL
Median: 3.7 ng/mL
Geometric Mean (CI): 3.5
(3.4-3.7) ng/mL

Association with
PFOAa
ALT +
GGT +
ALP 0
Total Bilirubin +

Effect size
ng/mL) and clinical biomarkers of
liver function, β (CI):
ALT: 0.038 (0.014, 0.062)
GGT: 0.058 (0.021, 0.096)
AST: 0.025 (0.007, 0.043)
ALP; -0.003 (-0.023,0.016)
Total Bilirubin: 0.048 (0.016,
0.081)
Results were reported in graphs.
From the graphs, only approximate
ORs can be read and it can be read
whether or not the association was
significant. Association between
quartiles of serum PFOA
concentration (compared to lowest
quartile; Q1) and liver enzymes:
AST:
Q2 & Q3: NS
Q4: p<0.05 (OR’s of +/- 1.0 and
1.5 can be read from the
graph)
ALT:
Q2, Q3 & Q4: p<0.05 (OR’s of
around 1.5 can be read from
the graph)
GGT:
Q2 t/m Q4: ns
ALP:
Q2 t/m Q4: ns
Total bilirubin:
Q2: ns

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Reference

Study characteristics

High-exposure community
Emmett et al.
Study population: high(2006)
exposure community
population, resided ≥2
years in Ohio (Little
Hocking) (independent of C8
Health Study)
Age range: 2-89 yrs
% men: 47%
Study design: Crosssectional
Study year(s): not reported
N total=371
Gallo et al.
Study population: high(2012)
exposure community
population, C8 Health
project, West Virginia, US
Age range: >=18 yrs
% men: 48%
Study design: Crosssectional
Study year(s): 2005-06
N total= 46,452

Blood PFOA concentration

Association with
PFOAa

Effect size

Serum PFOA:
Range: 0-3000 ng/mL
Median: 354 ng/mL

AST 0
ALT 0
GGT 0
ALP 0
Total bilirubin 0

Association between PFOA (per 1
ng/mL) and liver enzymes, β (pvalue):
AST: -0.00076 (p=0.76)
ALT: -0.00183 (p=0.65)
ALP: -0.00416 (p=0.65)
GGT: 0.00058 (p=0.89)
Total bilirubin: -0.00000467
(p=0.92)

Serum PFOA:
Median: 28.0 ng/mL
IQR: 13.5-70.8 ng/mL

ALT +
GGT +
Total bilirubin 0

Association between lnPFOA (ng/mL)
and (transformed) liver enzymes, β
(CI):
Ln ALT: 0.022 (0.018 – 0.025)
ln GGT: 0.015 (0.01 – 0.019)
ln direct bilirubin: 0.001 (-0.002 –
0.004)
Association between lnPFOA and
having abnormal values of liver
enzymes (vs. not), OR (CI):
ALT: 1.10 (1.07, 1.13)
GGT: 1.01 (0.99, 1.04)
Direct bilirubin 0.97 (0.90, 1.05)
Analysis of lnALT or lnGGT showed
increase from 0.005 to 0.030 μg/mL,

Q3 & Q4: p<0.05 (OR’s of +/1.5 and 2.0 can be read from
the graph)

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Reference

Darrow et al.
(2016)

Study characteristics

Study population: highexposure community, C8
Health Panel and additional
Mid-Ohio Residents
Age range: 20-70+ yrs
% men: 17.1%
Study design: Cohort:
longitudinal
Study year(s): 2005-06
(blood), 2008-11 (survey)
N total: liver biomarkers:
30,723 incl. 1,892 workers;
liver disease: 32,254 incl.
3,713 workers

Occupational study population
Olsen et al.
Study population:
(2000)
occupational population, 3M
Cottage Grove, US
Age range: 24-61 yrs
% men: 100%
Study design: crosssectional

Page 70 of 120

Blood PFOA concentration

Serum PFOA concentration,
measured in 2005-06:
Range: 2.6-3,559 ng/mL
Median: 16.5 ng/mL
Cumulative exposure: For
each follow-up year for each
subject, we calculated a
measure of cumulative serum
PFOA exposure by summing
all previous yearly estimates
of PFOA serum concentrations
(referred to as “cumulative
PFOA”) in units of year ×
ng/mL.

Association with
PFOAa

ALT +
GGT 0
Direct bilirubin Liver disease 0

Effect size
then levelling. However, no
association of PFOA with abnormal
values of GGT.
Association between cumulative
lnPFOA (y-ng/mL) and liver
enzymes, β (p-value):
ALT: 0.012 (0.008, 0.016)
GGT: 0.003 (-0.003, 0.008)
Direct bilirubin: -0.005 (-0.008, 0.002)
Association between measured
2005-06 PFOA (ln, ng/mL) and liver
enzymes, β (p-value):
ALT: 0.012 (0.009, 0.016)
GGT: 0.003 (-0.002, 0.008)
Direct bilirubin: -0.006 (-0.009, 0.003)
Association between cumulative
lnPFOA (y-ng/mL) and any liver
disease, HR (CI), 10y lag: 0.98
(0.93, 1.04).

Serum PFOA, all years:
Range: 0-114,100 ng/mL
Median: 1,190 ng/mL
Mean: 59,930 ng/mL
Serum PFOA, mean (range)
per year, ng/mL:
1993: 5,000 (0-80,000)

AST 0
ALT +
GGT 0
ALP 0
Total bilirubin 0
Direct bilirubin 0

Association between serum PFOA
(per ppm , i.e. 1,000 ng/mL) and
ALT, β (p-value) per year:
1993: 0.89 (p = 0.76)
1995: 0.81 (p = 0.75)
1997: 2.77 (p = 0.03)

RIVM Report 2017-0086

Reference

Olsen and
Zobel (2007)

Sakr et al.
(2007a)

Study characteristics

Blood PFOA concentration

Study year(s): 1993, 1995,
1997
N total: 111 (1993), 80
(1995), 74 (1997)
Study population:
occupational population, 3M
Cottage Grove US, Decatur
US & Antwerp.
Age range: 21-67 yrs
% men: 100%
Study design: Crosssectional
Study year: 2000
N total: 506 (all locations),
196 (Antwerp), 122
(Cottage Grove US), 188
(Decatur US)

1995: 6,800 (0-114,100)
1997: 6,400 (0.1-81,300)

Study population:
occupational population,
Washington Works US (in
C8 Health Project area).
Age range: not reported.

Serum PFOA:
Range: 5-9,550 ng/mL
Median: 189 ng/mL
Mean: 428 ng/mL

Serum PFOA, all locations:
Range: 7-92,030 ng/mL
Median: 1,100 ng/mL
Mean: 2,210 ng/mL

Association with
PFOAa

Effect size

Total:
AST 0
ALT 0
GGT +
ALP +
Total bilirubin -

Results of Antwerp and Cottage
Grove were not reported here
because no significant association
was found and limited room is
available in this table.
Association between serum lnPFOA
(ng/mL) change in liver enzymes, β
(p-value):
All locations:
ln AST: -0.005 (p=0.55)
ln ALT: 0.025 (p=0.06)
ln GGT: 0.033 (p=0.05)
ln ALP: 0.009 (p=0.25)
ln total bilirubin: All -0.033
(p=0.001)
Decatur:
ln AST: 0.011 (p=0.57)
ln ALT: 0.08 (p=0.02)
ln GGT: 0.08 (p=0.02)
ln ALP: 0.08 (p = 0.02)
ln total bilirubin: -0.054
(p=0.01)
Association between PFOA (1
ppm=1000 ng/mL) and transformed
liver enzymes, β (p-value),
excluding n=178 on lipid-lowering
medications:

Decatur:
AST 0
ALT +
GGT +
ALP +
Total bilirubin -

AST 0
ALT 0
GGT +
Total bilirubin 0

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Reference

Study characteristics

Costa et al.
(2009)

Mean age men/women:
46.5 / 44.4 yrs
% men: 76%
Study design: Crosssectional
Study year: 2004
N total=1,025
Study population:
Occupational population,
Italy
Age, range: 20-63 yrs
% men: 100%
Study design: Crosssectional
Study year: 2000-2007
N total=56

Olsen et al.
(2003)

Study population:
Occupational population, 3M
Antwerp and Decatur
Age range: mean 37 (male
Antwerp) and 43 (male
Decatur) yrs
% men: 81%
Study design: Crosssectional and longitudinal

Page 72 of 120

Blood PFOA concentration

Serum PFOA, currently
exposed:
Range: 200-47,040 ng/mL
Median: 5,710 ng/mL
Mean: 12,930 ng/mL
Serum PFOA, formerly
exposed:
Range: 530-18,660 ng/mL
Median: 4,430 ng/mL
Mean: 6,810 ng/mL

Serum PFOA:
Range: 40-12,700 ng/mL
Mean: 1,780 ng/mL (n=263
Decatur)
Mean: approximately 50%
lower among 3M Antwerp
(n=255) than Decatur plant
workers.

Association with
PFOAa

AST 0
ALT +
GGT +
ALP +
Total bilirubin –
Direct Bilirubin 0

AST 0
ALT 0
GGT 0
ALP 0
Total bilirubin 0

Effect size
ln AST: 0.023 IU/L (p=0.0.079)
ln ALT: 0.031 IU/L (p=0.071)
ln GGT: 0.05 IU/L (p=0.03)
ln total bilirubin: 0.008 IU/L
(p=0.637)
(Results including those on lipidlowering medications are similar).
Association between PFOA (1 μg/mL
= 1000 ng/mL) and liver enzymes, β
(CI):
AST: 0.038 (-0.003, 0.080)
ALT: 0.116 (0.054, 0.177)
GGT: 0.177 (0.076, 0.278)
ALP: 0.057 (0.007, 0.107)
Total bilirubin: -0.080 (-0.137, 0.024)
Direct bilirubin: -0.034 (-0.09,
0.031)
In 34 currently still exposed
individuals compared with 34
matched controls or with n=107
controls: no significant associations.
No associations found and quantified
results were not reported.

RIVM Report 2017-0086

Reference

Sakr et al.
(2007b)

Olsen et al.
(2012)

Steenland et
al. (2015)

Study characteristics
Study year(s): 1994, 1995,
2000
N total cross-sectional =
518
N total longitudinal =174
Study population:
Occupational population,
Washington works DuPont,
US
Age range: 22-63 yrs
% men: 74%
Study design: Longitudinal
Study year(s): 1979-2004
(blood measures every 1 to
2 yrs)
N total = 454 (≥2
measurements)
Study population:
occupational population, 3M
employees and contract
workers involved with
demolition of PFA, US
Age range: mean 40 yrs
% men: 95%
Study design: Longitudinal
Study year(s): 2008-2010
N total=179 workers (165
contract workers, 14 3M
employees)
Study population:
occupational population,

Blood PFOA concentration

Association with
PFOAa

Effect size

Serum PFOA, overall:
Range: 0-2,266 ng/mL
Mean: 1,130 ng/mL

AST +
ALT 0
GGT 0
ALP 0
Total bilirubin +

Association between PFOA (per
1,000ng/mL) and liver enzymes, β
(CI):
AST: (n=1326) 0.35 units (0.10,
0.60)
ALT: (n=231) 0.54 (-0.46, 1.54)
GGT: (n=233) 1.24 (-1.09, 3.57)
ALP: (n=1327) -0.21 (-0.60,0.18)
Total bilirubin: (n=1327) -0.008
mg/dL (-0.0139, -0.0021)

Serum PFOA, overall:
Range: 0.1-10,000 ng/mL

AST 0
ALT 0
ALP 0
Total bilirubin 0

Association between serum PFOA
(ng/ml) and liver enzymes, β (pvalue):
AST: 0.00515 ( p=0.46)
ALT: -0.00568 (p=0.60)
ALP: -0.00985 (p=0.29)
Total bilirubin: - 0.00011 (p=0.58)

Non-hepatitis liver
disease (n=35

Association between estimated
cumulative PFOA exposure and non-

Serum PFOA, contract
workers:
Median: 5.2 ng/mL
Mean: 28.9 ng/mL
Serum PFOA, 3M employees
at baseline:
Median: 595 ng/mL
Mean: 881 ng/mL
Serum PFOA, measured in
2005-06 (n=1,881):

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Reference

Gilliand et al,
1996

Study characteristics

Blood PFOA concentration

DuPont West Virginia
(Washington works)
Age range: mean year of
birth 1951
% men: 80%
Study design: Longitudinal
Study year(s): 2005-06
(PFOA measures), 2008 &
2011 (interviews)
N total = 3,713 (cohort of
workers)
Study population:
occupational study
population, employees of
PFOA production plant USA
Age range: 18-60 yrs
% men: 100%
Study design: crosssectional
Study year(s): 1985-1989
N total: 115

Range: not reported
Median: 113 ng/mL
Mean: 325 ng/mL

a

Association with
PFOAa
cases) 0

Historical serum levels
modelled using JEM,
residential exposure model
and PK model.
Mean cumulative occupational
exposure 8.6 ppm-years
Total serum fluorine was used
as proxy of serum PFOA.
(‘Because the vast majority of
total serum fluorine in plant
employees is in the form of
PFOA, total serum fluorine
closely reflects serum PFOA in
production workers, and its
use is unlikely to introduce
substantial error into the
study.’)
Range: 0-26 ppm
Mean serum fluoride: 3.3
ppm

Multivariate:
GGT 0
GOT GPT -

Effect size
hepatitis liver disease, HR (CI) (no
lag), Q1=ref:
Q2 (3,030-6,160 ng/mL-yrs): 0.55
(0.17 to 1.77)
Q3 (6,160-11,420 ng/mL-yrs): 1.27
(0.44 to 3.65)
Q4 (>11,420 ng/mL-yrs): 0.88
(0.27 to 2.85)
No significant trend. Also no
association when 10-year lag was
examined.
After adjusting for age, cigarette
use, alcohol use and BMI, total
serum fluorine is associated with
changes in GOT, GPT & GGT by
interactions with determinants of
hepatitic enzymes. Association
between serum fluorine (proxy for
PFOA) and liver enzymes: (β), pvalue:
GGT
-Total Fluorine (-1.93), p=0.36
GOT
-Total Fluorine
(-3.23),
p=.02
GPT
-Total Fluorine
(-15.80),
p=.0008

0, no association; +, positive association; -, negative association
β=regression coefficient, OR=Odds Ratio, HR= Hazard Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA, Q=quartile,
IQR=Interquartile range, AST = aspartate aminotransferase, ALT = alanine aminotransferase, GGT = gamma-glutamyl transpeptidase, ALP= alkaline
phosphatase.
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Reference

Table 4. Summary of associations in studies on kidney and testicular cancer

Study characteristics

High-exposure community
Vieira et al.
Study population: high-exposure
(2013)
community population, C8
community (residents living near
Washington Works plant), US
Age range: Median age cases 67
yrs
% men: 51% (among cases)
Study design: longitudinal, cohort
incidence study
Study year(s): 1951-2008
N total: 6 public water districts,
13 counties surrounding DuPont

Blood PFOA concentrations

Associatio
n with
PFOAa

Effect size

Serum PFOA, estimated annual
concentration:
Very high: 110-655 ng/mL
High: 30.8-109 ng/mL
Medium: 12.9-30.7 ng/mL
Low: 3.7-12.8 ng/mL
Reference: unexposed

Kidney
cancer +
(n=59)
Testicular
cancer 0
(n=11)

Association between annual serum PFOA and
kidney cancer, reference=unexposed, assuming
10-year residency, OR (CI):
Very high: 2.0 (1.0-3.9) (n=9 cases)
High: 2.0 (1.3-3.2) (n=22)
Medium: 1.2 (0.7-2.0) (n=17)
Low: 0.8 (0.4-1.5) (n=11)
Association between annual serum PFOA and
testicular cancer, reference=unexposed,
assuming 10-year residency, OR (CI):
Very high: 2.8 (0.8-9.2) (n=6 cases)
High: 0.3 (0.0-2.7)(n=1)
Medium: 0.6 (0.2-2.2) (n=3)
Low: 0.2 (0.0-1.6) (n=1)
Results for cumulative PFOA serum
concentrations were reported to be similar.

Kidney
cancer 0
(n=105)
Testicular
cancer +
(n=17)

Association between log estimated life-time
cumulative PFOA serum concentration and kidney
cancer, OR (CI):
No lag: 1.10 (0.98-1.24)
10-y lag: 1.09 (0.97-1.21)
Association between log estimated life-time
cumulative PFOA serum concentration and
testicular cancer, OR (CI):
No lag: 1.34 (1,00-1,79)
10-y lag: 1.28 (0.95-1.73)
(PFOA quartiles did not show significant results)

Serum PFOA, estimated
cumulative range:
Very high = 600–4,679 ng/mLyears
High = 198–599 ng/mL-years
Medium = 89–197 ng/mL-years
Low = 3.9–88 ng/mL-years

High-exposure community & occupational study population
Barry et al.
Study population: high-exposure
Serum PFOA, estimated annual
(2013)
community and occupational
concentration, community:
Range: 2.8-9,217 ng/mL
population, C8 Health Project
Median: 19.4 ng/mL
(DuPont) & Washington Works
plant (DuPont), US
Age range: >=20 yrs
Serum PFOA, estimated annual
% men: 46%
concentration, workers:
Study design: longitudinal, cohort Range: 5.2-3,683 ng/mL
incidence study
Median: 174.4 ng/mL
Study year(s): 1952-2011
N: 32,254

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Reference

Study characteristics

Occupational study population
Steenland and
Study population: Occupational
Woskie (2012)
population, Washington Works
plant (DuPont), US
Age range: mean year of birth
1984
% men: 81%
Study design: Cohort mortality
study
Study year(s): 1984-2008
N exposed: 5,791
(reference: DuPont workers
unexposed to PFOA & US
population)
Lundin et al.
(2009)

Study population: occupational
population, Minnesota PFOA
production plant, US
Age range: mean age ‘02: 59.6
yrs
% men: 80%
Study design: longitudinal cohort
mortality study
Study year(s): 1947-2002
N total= 3,993 (n=1,792 nonexposed)
a

Blood PFOA concentrations

Associatio
n with
PFOAa

Effect size

Serum PFOA, annual
estimations:
Mean: 350 ng/mL
Median: 230 ng/mL

Kidney
cancer +
(total
n=12)
Testicular
cancer
(insufficient
cases)

Association between estimated cumulative PFOA
(quartiles of ppm-years) and kidney cancer, 20year lag, Other DuPont workers = referent
group:
Q1 (0-515 ppm-years), (n=3 cases), SMR (CI):
1.34 (0.28-3.91)
Q2 (515-1057 ppm-years), (n=1 case), SMR
(CI): 0.46 (0.01-2.55)
Q3 (1057-1819 ppm-years), (n=0 cases), SMR
(CI): 0.00 (0.00-2.03)
Q4 (≥1819 ppm-years), (n=7 cases), SMR
(CI): 3.67 (1.48-7.57)
Similar results were reported for analyses
including no lag and analyses including a 10-year
lag.
Association between PFOA concentrations,
general population = referent, SMR (CI):
Ever definite: 0 (n=0 cases)
Ever probable/never definite: 1.2 (0.3-3.5) (n=3
cases)
Never: 1.4 (0.4-3.7) (n=4 cases)

Serum PFOA, estimated and
cumulativeb:
Mean: 7.8 ppm-years
Median 4.3 ppm-years

Serum PFOA (based on JEM),
definite exposure:
Median levels ranged from
2,600-5,200 ng/mL
Probable exposure:
Median levels ranged from 3001,500 ng/mL.
Nonexposed areas: no data
available
Full range is not reported.

Cancer in
bladder and
other
urinary
organs
combined 0
Testicular
cancer: no
cases

0, no association; +, positive association; -, negative association
ppm-years: e.g. 100 ppm (i.e. 100,000 ng/mL) over 5 years would be 500 ppm-years (Steenland and Woskie, 2012)
OR=Odds Ratio, SMR=Standardized Mortality Ratio, CI= 95% Confidence Interval, Q=quartile, ppm=parts per million (1ppm=1,000 ng/mL).
b

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Reference

Table 5. Summary of associations in studies on pregnancy-induced hypertension and preeclampsia

Study characteristics

General population
Starling et
Study population: general
al. (2014b) population (pregnant women),
Norway
Age range: 19-41 yrs
% men: 0%
Study design: cross-sectional
Study year(s): 2003-04
N total: 891 women
Starling et
Study population: general
al. (2014a)
population (pregnant women),
Norway
Age range: 16-44 yrs (at delivery)
%men: 0%
Study design:
Study year(s): 2003-07
N total: 976 (n=466 cases)
High-exposure community
Darrow et
Study population: High exposure
al. (2013)
C8 Health project community, US
Age range: 19+ yrs at pregnancy
(68% was 19-29 yrs)
% men: 0%
Study design: Longitudinal
Study year(s): 2005-10
N total=1,600 (106 cases)

Blood PFOA
concentrations

Association with
PFOAa

Effect size

Plasma PFOA:
IQR: 1.66-3.03 ng/mL
Median: 2.25 ng/mL
5th percentile: 1.05
ng/mL
95th percentile: 4.43
ng/mL

Biomarkers of
preeclampsia 0

Plasma PFOA:
IQR: 2.14-3.57 ng/mL
Median: 2.78 ng/mL
5th percentile: 1.43
ng/mL
95th percentile: 5.15
ng/mL

Preeclampsia 0

They observed no association between
plasma PFOA and elevated triglycerides,
total cholesterol, LDL or lower HDL
cholesterol. Because those outcomes
increase the risk of preeclampsia, they
discussed that also no evidence of an
association with preeclampsia was
observed.
Association between quartiles of PFOA
and preeclampsia, HR (CI), Q1=ref:
Q2: 1.03 (0.70-1.50)
Q3: 0.92 (0.63-1.35)
Q4: 1.01 (0.69-1.48)

Serum PFOA:
Range: 0.6-459.5 ng/mL
Median: 12.9 ng/mL
Mean: 31.1 ng/mL
95th percentile: 114.1
ng/mL

Pregnancy-induced
hypertension +

Association between ln PFOA and
preeclampsia, HR (CI):
0.89 (0.65-1.22)

Association between lnPFOA and
pregnancy-induced hypertension, OR
(CI): 1.27 (1.05, 1.55)
Association between IQR PFOA increase
and pregnancy-induced hypertension, OR
(CI): 1.06 (0.99-1.14)
Association between blood PFOA by
quintile (ref=0-6.9 ng/mL) and
pregnancy-induced hypertension, OR
(CI):

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Reference

Study characteristics

Blood PFOA
concentrations

Association with
PFOAa

Stein et al.
(2009)

Study population: High-exposure
C8 Health project community, US
Age: 82% pregnant at 20-34 yrs
% men: 0%
Study design: Longitudinal
Study year(s): births in 2000-05
and blood measures in 2005-06
N total=1,845 births in 2000-05

Serum PFOA, 2005-06
(pregnancies within the 5
years preceding exposure
measurement):
Range:0.25-894.4 ng/mL
Median (IQR): 21.2
(10.3-49.8) ng/mL
Mean: 48.8 ng/mL
>90th: 120.6-894.4
ng/mL

Preeclampsia 0

Savitz et al.
(2012a)

Study population: High-exposure
C8 Health project community, US
Age range: pregnant at 14-45 yrs
% men: 0%
Study design: cross-sectional
Study year(s): 1990-2006
N total = 11,737 pregnancies
occurring between 1990-2006
(n=730 preeclampsia)

Serum PFOA, estimated
(based on serum
collected in 2005,
residential history, and
other data) at the time of
pregnancy for
pregnancies occurring
between:
Range: 3.9 - 934.3
ng/mL
Median (IQR), ng/mL:
1990–94: 6.0 (4.5, 27.6)
1995–99: 10.7 (5.1,
50.4)
2000–2005: 15.9 (5.9,
56.2)

Preeclampsia +

Page 78 of 120

Effect size
6.9-11.1: 2.39 (1.05-5.46)
11.1-18.9: 3.43 (1.50-7.82)
18.9-37.2: 3.12 (1.35-7.18)
≥37.2 : 3.16 (1.35-7.38)
Association between >median compared
with ≤ median serum PFOA concentration
and preeclampsia, OR (CI):
1.3 (0.9-1.9)
No dose-response relationship:
Association between serum PFOA
percentiles and preeclampsia, OR (CI)
(<50th = referent):
50-75th: 1.5 (1.0-2.3)
75-90th: 1.2 (0.7-2.1)
> 90th: 0.9 (0.5-1.8)
Association between increase in lnPFOA
per IQR (2.19 ng/mL) and preeclampsia,
OR (CI) = 1.13 (1.00–1.28)
Association between increase in 100
ng/mL PFOA and preeclampsia, OR (CI):
1.08 (1.01–1.15)
Association between percentiles and
preeclampsia, < 40th (ref):
40-60th (6.1 – 10.2 ng/mL): 1.2 (1.0,
1.5)
60-80th (10.2 – 21.0): 1.1 (0.9, 1.4)
≥ 80th (21.0 – 717.6): 1.2 (1.0, 1.6)

RIVM Report 2017-0086

Reference

Study characteristics

Savitz et al.
(2012b)

Study population: High-exposure
community Mid-Ohio birth records
(study 1) & C8 Health project
community (study 2), US.
Age range: not reported
% men: 0%
Study design: Longitudinal
Study year(s): Pregnancies in
1990-2004. Serum PFOA measured
in 2005
N: 8,253 (Study 1), 4,547 (Study
2)

Blood PFOA
concentrations
Serum PFOA, estimated
for the early pregnancy
period, study 1:
IQR: 4.9-17.2 ng/mL
Median: 7.7 ng/mL
Serum PFOA, estimated
for the early pregnancy
period, study 2:
IQR: 5.6-61.2 ng/mL
Median: 13.4 ng/mL

Association with
PFOAa
Pregnancy-induced
hypertension +

Effect size
Study 1:
Association between IQR lnPFOA (1.50
ng/ml) increase and pregnancy-induced
hypertension, OR (CI): 1.02 (0.86-1.12)
Association between 100 ng/mL PFOA
increase and pregnancy-induced
hypertension, OR (CI): 1.06 (0.86-1.31)
Association between percentiles and
pregnancy-induced hypertension, OR (CI)
(ref <40th):
40-60th 1.0 (0.7-1.6)
60-80th 1.0 (0.6-1.5)
≥ 80th 1.0 (0.7-1.5)
Study 2 (Bayesian calibration of
exposure):
Association between increase per IQR
lnPFOA (2.39 ng/mL) and pregnancyinduced hypertension, OR (CI): 1.13
(0.92-1.37)
Association between increase in 100
ng/mL PFOA and preeclampsia, OR (CI):
0.97 (0.85-1.11)
Association between percentiles and
pregnancy-induced hypertension, OR (CI)
(ref <40th=3.9 to <8.9 ng/mL):
40-60th=1.0 (0.7-1.4)
60-80th(19.6-53.1 ng/mL)=1.5 (1.1,
2.1)
≥ 80th=1.2 (0.8, 1.7)

a

0, no association; +, positive association; -, negative association.
OR=Odds Ratio, HR=Hazard Ratio, CI= 95% Confidence Interval, IQR=Interquartile range, lnPFOA = natural log transformed PFOA.

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Reference

Table 6. Summary of associations in studies on birth weight

Study characteristics

General population
Fei et al.
Study population: general
(2007)
population Danish National
Birth cohort, Denmark
Age range: 39% had
maternal age at delivery of
25-29 yrs
% men: 0%
Study design: Longitudinal
Study year(s): 1996-2002
N total=1,399
Monroy et al. Study population: general
(2008)
population, Family study,
Canada
Age, mean at pregnancy:
32.7 (5.2) yrs
% men: 0
Study design: Longitudinal
Study year(s): 2004-05
N total=101

Hamm et al.
(2010)

Study population: general
population, Canada
Age, range: 18+ yrs
% men: 0
Study design: Longitudinal

Page 80 of 120

Blood PFOA
concentrations

Association with
PFOAa

Effect size

Plasma PFOA
concentrations, maternal:
Range: less than lower
limit of quantitation
(LLOQ, i.e. 1ng/mL) 41.5 ng/mL
Mean: 5.6 ng/mL

Change in birth
weight Low birth weight 0
Small for
gestational weight 0

Association between maternal
plasma PFOA and change in birth
weight (g), β (CI): -10.63 (-20.79, 0.47).

Serum PFOA, pregnant
women:
Range: 1.46-3.14 ng/mL
Median: 2.13 ng/mL

Change in birth
weight 0

Association of blood PFOA with change in
birth weight (g), β (p-value): 0.000171
(p = 0.65)

Change in birth
weight 0

Association between blood lnPFOA and
change in birth weight (g), β (CI): -37.4
(-86.0, 11.2) g

Association of blood PFOA with low birth
weight (< 2500 g) and with small for
gestational weight was also examined,
but no association was found.

Serum PFOA, maternal
serum at delivery:
Range: 1.33-2.64 ng/mL
Median: 1.81 ng/mL
Serum PFOA, umbilical
cord:
Range: 1.09-2.37 ng/mL
Median: 1.58 ng/mL
Serum PFOA, pregnant
women:
Range: LOD-18 ng/mL
Median: 1.5 ng/mL
Mean: 2.1 ng/mL

Small for
gestational age 0

Association between blood PFOA (ref:

RIVM Report 2017-0086

Reference

Study characteristics
Study year(s): 2005-07
N total = 252

Whitworth
et al. (2012)

Maisonet et
al. (2012)

Washino et
al. (2009)

Study population: general
population, Norwegian Mother
and Child Cohort Study,
Norway
Age, mean at enrolment: 31
yrs
% men: 0
Study design: Longitudinal
Study year(s): 2003-04
N total = 849
Study population: general
population, Avon Longitudinal
Study of Parents and Children
(ALSPAC), United Kingdom
Age: 80% was 25+ yrs at
delivery
% men: 0
Study design: longitudinal
Study year(s): 1991-92
N total=395
Study population: general
population, Japan
Age, mean (SD): 30.5 (4.8)
yrs
% men: 0
Study design: Longitudinal
Study year(s): 2002-05

Blood PFOA
concentrations

Association with
PFOAa

Serum PFOA, pregnant
women:
IQR: 1.7-3.0 ng/mL
Median: 2.2 ng/mL

Change in birth
weight 0

Serum PFOA, pregnant
women:
Range: 1-16.4 ng/mL
Median: 3.7 ng/mL

Change in birth
weight -

Serum PFOA, pregnant
women:
Range: non detectable 5.3 ng/mL
Median: 1.3 ng/mL
Mean: 1.4 ng/mL

Change in birth
weight 0

Effect size
<1.1 ng/mL) and being small for
gestational age, RR (CI):
1.1-2.1 ng/mL: 0.55 (0.16-1.83)
>2.1-18 ng/mL: 0.99 (0.25-3.92)
Association between blood PFOA (ref:
<1.65) and change in birth weight z
scores, β (CI):
Q 2 (1.65-2.24): -0.06 (-0.28, 0.16)
Q 3 (2.25-3.03): -0.08 (-0.32, 0.16)
Q 4 (>=3.04): -0.21 (-0.45, 0.04)
Association between blood PFOA and
change in birth weight z scores, β (CI): 0.03 (-0.10, 0.04)
Association between blood PFOA
(ref<3.1 ng/mL) and change in birth
weight (g), β (CI):
3.1-4.4 ng/mL: -56.81 (-153.05, 39.43)
>4.4 ng/mL: -133.45 (-237.37, 29.54)

Association between log10 blood PFOA
and change in birth weight (g), β (CI): 75 (-191, 42)

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Reference

Study characteristics

Apelberg et
al. (2007)

Chen et al.
(2012)

Lee et al.
(2013)

AshleyMartin et al.
(2016)

N total=428
Study population: general
population, US (Baltimore)
Age: 84% were 18-35 yrs
during pregnancy
% men: 0
Study design: Longitudinal
Study year(s): 2004-05
N total=293
Study population: general
population, Taiwan Birth
Panel Study, Taiwan
Age: 77% <35 yrs (no range)
% men: 0
Study design: Longitudinal
Study year(s): 2004-05
N total=429
Study population: general
population, South Korea
Age, median: 30 yrs
% men: 0
Study design: Longitudinal
Study year(s): 2011
N total= 59

Study population: general
population (pregnant woman,
Maternal-Infant Research on

Page 82 of 120

Blood PFOA
concentrations

Association with
PFOAa

Effect size

Serum PFOA cord blood:
Median: 1.6 ng/mL
Range: 0.3-7.1 ng/mL

Change in birth
weight 0

Association between lnPFOA and change
in birth weight (g), β (CI): -104 (-213,
5)

Plasma PFOA, cord blood:
Range: not reported
Geometric mean (SD):
1.84 (2.23) ng/mL

Change in birth
weight 0

Association between cord plasma lnPFOA
and change in birth weight (g), β (CI): 19 (-63, 25)

Serum PFOA, maternal
blood at delivery:
Range: 1.2-5.72 ng/mL
Median: 2.62 ng/mL
Mean: 2.73 ng/mL
Serum PFOA, umbilical
cord serum blood at
delivery:
Range: 0.75-5.44 ng/mL
Median: 2.08 ng/mL
Mean: 2.09 ng/mL
Serum PFOA, first
trimester maternal blood:
Range: LOD-16 ng/mL

Change in birth
weight 0

Association between >=median maternal
serum PFOA (ref: <median) and birth
weight, OR (CI):
>= median birth weight (ref=< median):
0.54 (0.17-3.03)

Gestational weight
gain + (more PFOA
is associated with

Association between >=median umbilical
cord serum PFOA (ref: <median) and
birth weight, OR (CI):
>= median birth weight (ref=< median):
0.51 (0.17-1.59)
Association between first trimester
transformed PFOA (ng/mL) and total
GWG, stratified by pre-pregnancy BMI, β

RIVM Report 2017-0086

Reference

Study characteristics
Environmental Chemicals),
Canada
% men: 0% (their infants:
52% boys)
Age range: maternal 18-49
yrs
Study design: cross-sectional
Study year(s): 2008-11
N total: 1,723 participants
with first trimester maternal
exposure data and 1,301
participants with cord blood
exposure data.

Blood PFOA
concentrations
Median: 1.70 ng/mL

Association with
PFOAa
higher gestational
weight gain)

Serum PFOA, cord blood:
Range: LOD-5.6 ng/mL
Median: 0.39 ng/mL
IQR: 0.22-0.61 ng/mL

Effect size
(CI):
Underweight / normal: 0.38 (-0.03,
0.79)
Overweight: 0.58 (-0.26, 1.42)
Obese: 0.38 (-0.81, 1.56)
Association between GWG (per 1kg
increase) and >median PFOA (i.e.
>0.39 ng/mL) cord blood, OR (CI):
1.04 (1.02-1.06)
Association between GWG (per IQR,
i.e. 25th to 75th) and >median PFOA
(i.e. >0.39 ng/mL) cord blood, OR
(CI): 1.33 (1.13, 1.56)

High-exposure community
(Stein et al.,
2009)

Savitz et al.
(2012a)

Study population: Highexposure C8 Health project
community, US
Age range: 82% pregnant at
20-34 yrs
% men: 0%
Study design: Longitudinal
Study year(s): births in 200005 and blood measures in
2005-06
N total=1,845 births in 200005
Study population: Highexposure C8 Health project

Serum PFOA, 2005-06
(not estimated at the
time of pregnancy):
Range:0.25-894.4 ng/mL
Median (IQR): 21.2
(10.3-49.8) ng/mL
Mean (SD): 48.8 (77.8)
ng/mL
>90th PFOA: 120.6-894.4
ng/mL

Low birth weight
(i.e. <2.5 kg) –

Serum PFOA, estimated
(based on serum

Term low birth
weight (i.e. <2.5

Association between ≥21.3 ng/mL PFOA
(vs. 0.25-21.3 ng/mL) and low birth
weight, OR (CI) = 0.7 (0.5-1.2)
Association between serum PFOA and
low birth weight, OR (CI) (<50th =
referent):
50-75th: 1.0 (0.6-1.7)
75-90th (50-120.6 ng/mL) : 0.3 (0.10.9)
> 90th: 0.8 (0.3-1.9)
No dose-response gradient.
Association between increase in lnPFOA
per IQR (2.19 ng/mL) and term low birth
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Reference

Study characteristics
community, US
Age range: 14-45 yrs (at time
of pregnancy)
% men: 0%
Study design:
Study year(s): 1990-2006
N total = 11,737 pregnancies
occurring between 1990-2006
(n=730 preeclampsia)

Savitz et al.
(2012b)

Study population: Highexposure community MidOhio birth records (study 1) &
C8 Health Project Community
(study 2), US.
Age range: not reported
% men: 0%
Study design: Longitudinal
Study year(s): Pregnancies in
1990-2004. Serum PFOA
measured in 2005
N total: 8,253 (Study1),
4,547 (Study 2)

Page 84 of 120

Blood PFOA
concentrations
collected in 2005,
residential history, and
other data) at the time of
pregnancy for
pregnancies occurring
between:
Range: 3.9 - 934.3
ng/mL
Median (IQR), ng/mL:
1990–94: 6.0 (4.5, 27.6)
1995–99: 10.7 (5.1,
50.4)
2000–2005: 15.9 (5.9,
56.2)
Serum PFOA, estimated
for the early pregnancy
period, study 1:
IQR: 4.9-17.2 ng/mL
Median: 7.7 ng/mL
Serum PFOA, estimated
for the early pregnancy
period, study 2:
IQR: 5.6-61.2 ng/mL
Median: 13.4 ng/mL

Association with
PFOAa
kg) 0

Effect size
weight, OR (CI) = 0.89 (0.66-1.20)
Association between increase in 100
ng/mL PFOA and term low birth weight,
OR (CI) = 0.96 (0.79-1.16)
Association between percentiles and
term low birth weight, < 40th (ref):
40-60th: 1.2 (0.8-1.9)
60-80th: 1.2 (0.7-1.9)
≥ 80th: 0.8 (0.4-1.4)

Term low birth
weight 0
Term small-forgestation-al-age 0
Continu-ous
measure of birth
weight (term birth)
-

Study 1:
Association between increase in lnPFOA
per IQR (1.50ng/mL) and term low birth
weight, OR (CI): 1.02 (0.92-1.13).
Association between increase in lnPFOA
per IQR (1.50ng/mL) and small for
gestational age, OR (CI): 0.91 (0.781.06)
Association between increase in lnPFOA
per IQR (1.50ng/mL) and change in term
birth weight, difference (CI): -10.72 (32.26, 10.82).
Association between increase in 100
ng/mL or percentiles and low birth
weight, term small for gestational age
and change in birth weight were also
examined but no significant associations
were observed.

RIVM Report 2017-0086

Reference

Darrow et al.
(2013)

Study characteristics

Study population: Highexposure C8 Health Project
Community, US
Age range: 19+ yrs at

Blood PFOA
concentrations

Association with
PFOAa

Serum PFOA:
Range: 0.6-459.5 ng/mL
Median 14.3 ng/mL
Mean 31.0 ng/mL

Low birth weight 0
Birth weight 0

Effect size
Study 2:
With Bayesian calibration of exposure:
Association between increase in lnPFOA
per IQR (2.39ng/mL) and term low birth
weight, OR (CI): 1.16 (0.86-1.58)
Association between increase in lnPFOA
per IQR (2.39ng/mL) and term small for
gestational age, OR (CI): 1.19 (1.001.43)
Association between increase in lnPFOA
per IQR (2.39ng/mL) and change in term
birth weight, difference (CI): -21.51 (43.62, 0.61)
Association between increase in 100
ng/mL PFOA and change in term
birth weight, difference (CI): -18.55
(-31.31, -5.8).
Association between increase in 100
ng/mL PFOA and low birth weight and
term small for gestational age were also
examined but no significant associations
were observed.
Association between percentiles PFOA
concentration and low birth weight, term
small for gestational age and change in
term birth weight were also examined
but no significant associations were
observed.
Association between increase in lnPFOA
and change (g) in birth weight, β (CI): 8 (-28, 12)
Association between IQR increase in
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Reference

Study characteristics
pregnancy (68% was 19-29
yrs)
% men: 0%
Study design: Longitudinal
Study year(s): Pregnancies in
2005-10
N total=1,470

Blood PFOA
concentrations
95th percentile: 114.1
ng/mL

Association with
PFOAa

Effect size

Serum PFOA, maternal,
workers:
Range: 5.5-58.5 ng/mL
Median: 16.95 ng/mL

Birth weight -

Association between maternal
serum PFOA (per lg unit) and birth
weight (grams), β (including both
workers and controls):
-267.3g (CI=-573.27 to -37.18)

Occupational study population
Wu et al.
(2012)

Study population:
occupational study population
(pregnant woman, working at
Guiyu (an electronic waste
recycling area)).
% men: 0%
Age mean: 26.6 yrs
(controls: 26.0 yrs)
Study design: cross-sectional
Study year(s): 2007
N total: 108 (workers), 59
(controls)
a

Serum PFOA, maternal,
controls:
Range: 4.4-30.0 ng/mL
Median: 8.7 ng/mL

PFOA and change (g) in birth weight, β
(CI): -5 (-13, 2)
Association between blood PFOA by
quintile (ref=0-6.9 mg/mL) and change
(g) in birth weight, β (CI):
6.9-11.1 ng/mL: 35 (-33,105)
11.1-18.9 ng/mL: -9 (-79, 61)
18.9-37.2 ng/mL: 4 (-65, 72)
≥37.2 ng/mL: 0 (-68, 69)
Low birth weight (< 2500 g) was also
examined and, similar to change in birth
weight, no significant associations were
found.

0, no association; +, positive association; -, negative association.
β=regression coefficient, OR=Odds Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA, Q=quartile, IQR=Interquartile range.

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Reference

Table 7. Summary of associations in studies on uric acid

Study characteristics

General population
Geiger et al.
Study population: general
(2013)
population, NHANES, US
Age range: 12-18 yrs
% men: 52%
Study design: cross-sectional
Study year(s): 1999-00 and
2003-08
N total=1,772

Gleason et
al, 2015

Lin et al.
(2013a)

Study population: general
population, NHANES, US
population
Age range: ≥12 yrs
% men: not reported
Study design: cross-sectional
Study year(s): 2007-2010
N total: 4,333
Study population: general
population, Young Taiwanese
Cohort Study
Age range: 12-30 yrs
% men: 39%
Study design: cross-sectional
Study year(s): 2006-08

Blood PFOA
concentration

Association
with PFOAa

Effect size

Serum PFOA:
Mean: 4.3 ng/mL

Uric acid +
Hyperuricemia
+

Association between PFOA quartiles and mean change
in serum uric acid (mg/dL), (Q1=ref), β (CI):
Q2: 0.02 (-0.10-0.14)
Q3: 0.03 (-0.11-0.17)
Q4: 0.30 (0.17-0.43)
Association between serum lnPFOA and serum uric
acid (mg/dL), β (CI): 0.20 (0.11-0.29)
Association between PFOA quartiles and
hyperuricemia, OR (CI), (Q1=ref):
Q2: 0.94 (0.58-1.53)
Q3: 1.01 (0.62-1.63)
Q4: 1.62 (1.10–2.37)
Association between serum lnPFOA and
hyperuricemia, OR (CI): 1.59 (1.19-2.13)
Association between transformed serum PFOA and
uric acid, β (CI): 0.303 (0.238-0.367)

Quartile 1 (Q1): <2.9
ng/mL
Q2: 2.9-4.0 ng/mL
Q3: 4.1-5.4 ng/mL
Q4: >5.4 ng/mL
(highest value of the
range not reported)

Serum PFOA:
IQR: 2.5-5.2 ng/mL
Median: 3.7 ng/mL
Geometric Mean: 3.5
ng/mL

Uric Acid +

Serum PFOA:
Range: 0.75-52.2
ng/mL
Median: 3.49 ng/mL
Geometric mean: 2.61
ng/mL (age and sex
adjusted)

Uric Acid 0

Association between serum PFOA quartiles and high
uric acid (i.e. ≥75th percentile), OR (CI), ref=Q1:
Q2: 1.46 (1.16-1.85)
Q3: 1.74 (1.35-2.25)
Q4: 1.88 (1.37-2.58)
Association between serum PFOA (ng/mL) and uric
acid (mg/dL), mean (SE):
PFOA ≤3.49 (≤50th): 6.08 (0.10)
PFOA ≤6.54 (50th-75th): 6.08 (0.11)
PFOA ≤9.62 (50th-90th): 6.11 (0.14)
PFOA >9.62 (>90th): 6.13 (0.17)
P for trend = 0.983

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RIVM Report 2017-0086

Shankar et
al. (2011)

N total: 644
Study population: general
population, NHANES, US
Age range: >=20 yrs
% men: 48%
Study design: cross-sectional
Study year(s): 1999–00,
2003–04, 2005–06
N total=3,883

Qin et al.
(2016)

Study population: general
population, Taiwan
Age range: 12-15 yrs
% men: 45% boys
Study design: cross-sectional
Study year(s): 2009-2010
N total: 225
High-exposure community
Steenland et Study population: highal. (2010b)
exposure community, C8
Health Study, West Virginia,
US
Age range: 20-80 yrs
% men: 48%
Study design: cross-sectional
Study year(s): 2005-06
N total=53,458

Page 88 of 120

Plasma PFOA:
IQR: 2.4-5.1 ng/mL
Median: 3.4 ng/mL
(highest value of the
range not reported)

Uric acid +
Hyperuricemia
+

Serum PFOA:
IQR: 0.4-1.3 ng/mL
Median: 0.5 ng/mL

Uric Acid +

Serum PFOA, measured
in 2005-06:
Range: 0-≥188.7 ng/mL
Mean: 86.4 ng/mL
Median: 27.9 ng/mL

Uric acid +
Hyperuricemia
+

Association between plasma PFOA quartiles and mean
change uric acid (mg/dL), β (CI), (Q1=ref):
Q2: 0.14 (0.04–0.25)
Q3: 0.37 (0.25–0.49)
Q4: 0.44 (0.32–0.56)
Association between plasma lnPFOA and mean
change uric acid (mg/dL), β (CI): 0.22 (0.15–0.30)
Association between plasma PFOA quartiles and
hyperuricemia, OR (CI), Q1=ref:
Q2: 1.14 (0.78–1.67)
Q3: 1.90 (1.35–2.69)
Q4: 1.97 (1.44–2.70)
Association between plasma lnPFOA and
hyperuricemia, OR (CI): 1.43 (1.16–1.76)
Association between transformed serum PFOA and
serum uric acid (mg/dL) (adjusted for age, BMI,
parental education level, exercise, environmental
tobacco smoke exposure, serum creatine), β (CI):
Total: 0.15 (0.01-0.28)
Boys: 0.24 (0.06-0.42)
Girls: 0.02 (-0.19-0.22)
Association between serum PFOA concentration
(ng/mL) and uric acid (mg/dL), estimate (SE):
0-7.8: 0
7.9-11.4: 0.09 (0.02)
11.5-15.4: 0.16 (0.02)
15.5-20.6: 0.18 (0.02)
20.6-27.8: 0.21 (0.02)
27.9-38.9: 0.21 (0.02)
39.0-56.9: 0.22 (0.02)
57.0-88.6: 0.22 (0.02)

RIVM Report 2017-0086

Occupational study population
Sakr et al.
Study population: occupational
(2007a)
population, Washington Works
US.
Age, mean: 46.5 (men), 44.4
(women) yrs
% men: 76%
Study design: cross-sectional
Study year(s): 2004
N total=1,025
Costa et al.
Study population: occupational
(2009)
population, Italy
Age, range: 20-63 yrs
% men: 100%
Study design: cross-sectional
Study year(s): 2000-2007
N total=56

88.7-188.6: 0.25 (0.02)
≥188.7: 0.28 (0.02)
Association between PFOA quintiles (ref=quintile 1;
0-11.4) and hyperuricemia:
Quintile 2 (11.5-20.6) : 1.33 (1.24-1.43)
Quintile 3 (20.7-38.9): 1.35 (1.26-1.45)
Quintile 4 (39.1-88.6): 1.47 (1.37-1.58)
Quintile 5 (>=88.7 ng/mL): 1.47 (1.37-1.58)
Serum PFOA:
Range 5-9,550 ng/mL
Median: 189 ng/mL
Mean: 428 ng/mL

Uric acid +

Quantified results not reported.

Serum PFOA, currently
exposed:
Range: 200-47,040
ng/mL
Median: 5,710 ng/mL
Mean: 12,930 ng/mL
Serum PFOA, formerly
exposed:
Range: 530-18,660
ng/mL
Median: 4,430 ng/mL
Mean: 6,810 ng/mL

Uric acid +

Association between change per 1 μg/mL (=1,000
ng/mL) PFOA and uric acid (mg/mL), β (CI):
0.026 (0.001-0.053)

a

0, no association; +, positive association; -, negative association
β=regression coefficient, OR=Odds Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA, Q=quartile, IQR=Interquartile range.

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Reference

Table 8. Summary of associations in studies on vaccination response

Study characteristics

General populations
Grandjean et
Study population: general
al. (2012)
population, Farou Islands
Age range: 3rd trimester
(PFOA measurement), 5
years (pre-booster
vaccination and 4 weeks
after), 7 years.
% men: 53% boys
Study design: longitudinal
Study year(s): 1997-2000,
follow-up in 2008
N total=587

Mogensen et
al. (2015)

Study population: general
population, Faroese birth
cohort
Age range: 7 years
% men: 52%
Study design: longitudinal
Study year(s): 1997-2000

Page 90 of 120

Blood PFOA
concentration

Association
with PFOAa

Effect size

Serum PFOA, maternal:
IQR: 2.56-4.01 ng/mL
Geometric mean: 3.2
ng/mL

Immune
response to
tetanus vaccine:
Maternal PFOA:
Pre-booster 0
Post-booster 0
Year 7 0
Child PFOA
Pre-booster 0
Post-booster 0
Year 7 –
Immune
response to
diphtheria
vaccine:
Maternal PFOA:
Pre-booster, 0
Post-booster 0
Year 7 Child PFOA
Pre-booster 0
Post-booster 0
Year 7 –
Immune
response to
vaccines:
Anti-diphtheria: Anti-tetanus: -

Association between Log maternal PFOA and
change in log antibody tetanus (%), β (CI): NS
Association between Log child’s PFOA at 5 yrs
and change in log antibody tetanus (%), β (CI):
Pre-booster: -13.3 (-31.6, 9.9)
Post-booster: -9.7 (-30.7, 17.7)
Year 7: -35.8 (-51.9, -14.2)
Year 7 (adjusted for age 5): -28.2 (-42.7 to
-10.1)
Association between Log maternal PFOA and
change in log antibody diphtheria (%), β (CI):
Pre-booster: -16.2 (-34.2, 6.7)
Post-booster: -6.2 (-22.4, 13.3)
Year 7: -22.8 (-39.4, -1.7)
Year7 (adjusted for age 5): -16.8 (-32.9, 3.3)
Association between Log child’s PFOA at 5 yrs
and change in log antibody diphtheria (%), β
(CI):
Pre-booster: -6.8 (-28.3, 21.0)
Post-booster: -6.1 (-23.6, 15.5)
Year 7: -25.2 (-42.9, -2.0)
Year 7 (adjusted for age 5): -23.4 (-39.3, 3.4)
Association between Log child’s PFOA at 5 and 7
yrs and change in log antibody diphtheria (%), β
(CI): -34.7 (-52.5, -10.2)
Association between Log child’s PFOA at 5 and 7
yrs and change in log antibody diphtheria (%), β
(CI): -38.2 (-56.1, -13.0)

Serum PFOA, at 5 yrs:
IQR: 3.33-4.96 ng/mL
Geometric mean: 4.06
ng/mL

Serum PFOA, at 5 yrs:
IQR:3.3-5.0 ng/mL
Median:4.1 ng/mL
Serum PFOA, at 7 years:
IQR: 3.5-5.7 ng/mL
Median:4.4 ng/mL

RIVM Report 2017-0086

Reference
Granum et al.
(2013)

Kielsen et al,
2015

Stein et al,
2016

Study characteristics
N total = 464
Study population: general
population, Norwegian
mother and child cohort
study, Norway
Age range: birth and 3 years
% men: 55% boys
Study design: longitudinal
Study year(s): Pregnancies
1999-08
N total=56
Study population: general
population, healthy
volunteers among staff
Copenhagen University
Hospital
Age range: 23-66 years
% men: 50%
Study design: vaccination
intervention study
Study year(s): 2012
N total: 12
Study population: general
population, US population in
NHANES 1999-2004
Age range: 12-19 years
% men: 53%
Study design: cross-sectional
Study year(s): 1999-2004
N total: 1,191

Blood PFOA
concentration

Association
with PFOAa

Effect size

Plasma PFOA, maternal at
delivery:
Range: 0.2-2.7 ng/mL
Median: 1.1 ng/mL
Mean: 1.1 ng/mL

Immune
response to
vaccines:
Rubella Measles 0
Tetanus 0
Hib 0

Association between pre-natal exposure to
PFOA and Rubella, β (CI): -0.40 (-0.64, 0.17)
Association between pre-natal exposure to PFOA
and Measles, β (CI): -0.13 (-0.35, 0.09)
Association between pre-natal exposure to PFOA
and Tetanus, β (CI): 0.01 (-0.01, 0.10)
Association between pre-natal exposure to PFOA
and Hib, β (CI): -0.05 (-3.85, 3.74)

Serum PFOA:
IQR: 1.30-2.79 ng/mL
Median: 1.69 ng/mL

Antibodies
Tetanus: 0
Antibodies
Diphteria: 0

Association between transformed PFOA and
%change in antibody concentration between day
4 and 10 post-vaccination, β (CI):
Diphteria:-8.2% (6.4 to -20.9)
Tetanus: 0.2% (12.1 to -10.4)

Serum PFOA
Geometric mean: 4.13
ng/mL
CI: 3.76-4.53 ng/mL
Median and range not
reported.

Endpoints of
Antibody Study:
(seropositive
subset)
Measles: 0
Rubella: Mumps: -

% change (95% CI) in antibody titer associated
with a doubling in blood PFOA:
TOTAL POPULATION:
Measles:-0.1% (-13.8 to 15.6)
Mumps: -6.0% (-12.4 to 0.9)
Rubella: -2.5% (-9.1 to 5.3)
ONLY SEROPOSITIVE (‘All models were run
twice: once for the full population and once
restricted to the seropositive population with the

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Reference

Study characteristics

High-exposure community
Looker et al.
Study population: High(2014)
exposure community
population, C8 Health Project,
West Virginia, US
Age range: 18+
% men: 51%
Study design: Longitudinal
Study year(s): 2005-06 and
2010
N total=411

Blood PFOA
concentration

Association
with PFOAa

Effect size

Serum PFOA:
Range: 0.25-2140 ng/mL
Q1: 0.25-13.7 ng/mL
Q2: 13.8-31.5 ng/mL
Q3: 31.6-90.3 ng/mL
Q4: 90.4-2,140 ng/mL

Immune
response to
influenza type B,
A H1N1, A H3N2
vaccine:
Antibody titer
rise 0
Seroconversion 0
Seroprotection -

The most consistent finding was evidence of a
reduced antibody response to A/H3N2 influenza
vaccine by higher PFOA concentration, reflected
in the results for titer rise, titer ratio, and
seroprotection, though not seroconversion.

assumption that seropositive children have been
exposed to the vaccine strain of these viruses’
Stein et al 2016):
Measles:-3.4% (-16.7 to 11.9)
Mumps: -6.6% (-11.7 to -1.5)
Rubella: -8.9% (-14.6 to -2.9)

Association (adjusted) between PFOA quartiles
(ref=Q1) and seroprotection - A/H2N2 Influenza,
OR (CI):
Q2 0.34 (0.14-0.83)
Q3 0.28 (0.11-0.70)
Q4 0.36 (0.15-0.99)
No significant associations with Influenza type B
and A H1N1.
Association (adjusted) between transformed
PFOA and transformed antibody titer rise, β (CI):
-.01 (-.17-0.14)
Association (adjusted) between transformed
PFOA and transformed antibody titer ratio, β
(CI):
-.12 (-.25-0.02)

a

0, no association; +, positive association; -, negative association
β=regression coefficient, OR=Odds Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA, Q=quartile, IQR=Interquartile range.

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Table 9. Summary of associations in studies on ulcerative colitis

Study characteristics

Blood PFOA concentration

High-exposure community & occupational study population
Steenland et
Study population: C8 High
Serum PFOA, measured in 2005-06,
al. (2013)
exposure population & occupational total:
IQR: 13-68 ng/mL
population, West Virginia, US
Age range: median year at birth
Median: 26 ng/mL
1958 (=53 years in 2011)
Serum PFOA, measured in 2005-06,
% men: 46%
workers (only n=1,881 has blood
Study design: Longitudinal
measurements):
Study year(s): 2005-06 (PFOA
IQR: 56-256 ng/mL
tests), 2008 & 2011 (interviews)
Median: 113 ng/mL
N total: 3,713 workers and 28.541
Serum PFOA, measured in 2005-06,
population (n=151 cases with
community:
ulcerative colitis)
IQR: 12-59 ng/mL
Median: 24 ng/mL
Occupational study population
Steenland et
Study population: occupational
Serum PFOA, measured in 2005-06
al. (2015)
population, DuPont, West Virginia
(n=1881):
Range: not reported
(Washington works)
Age range: mean year of birth
Median: 113 ng/mL
1951
Mean: 325 ng/mL
% men: 80%
Historical serum levels modelled using
Study design: Longitudinal
JEM, residential exposure model and PK
Study year(s): 2005-06 (PFOA
model.
measures), 2008 & 2011
Mean cumulative occupational exposure
(interviews)
8.6 ppm-years
N total = 3,713 (cohort of workers)
a

Association
with PFOAa

Effect size

Ulcerative
colitis +

Association between estimated
cumulative serum PFOA
(quartiles) and ulcerative colitis
(vs not), Q1 (<13)=referent, no
lag, RR (CI):
Q2 (158-586 ng/mL-years):
1.76 (1.04, 2.99)
Q3 (586-3,500 ng/mL-years):
2.63 (1.56, 4.43)
Q4 (>3,500 ng/mL-years):
2.86 (1.65, 4.96).

Ulcerative
colitis +

Association between estimated
cumulative serum PFOA
(quartiles) and ulcerative colitis
(vs. not), 10-year lag, Q1
(<800ng/mL-years)= referent,
RR (CI):
Q2 (800-3,440 ng/mL-years):
3.00 (0.82-11)
Q3 (3,440-7,040 ng/mLyears): 3.26 (0.7-15.1)
Q4 (>7,040 ng/mL-years):
6.57 (1.47-29.4)

0, no association; +, positive association; -, negative association.
RR=relative risk, CI= 95% Confidence Interval, Q=quartile, IQR=Interquartile range.

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Reference

Table 10. Summary of associations in studies on thyroid effects

Study characteristics

General population
Bloom et
Study population: general
al. (2010) population, US (New York State
Anglers Cohort Study) Age
range: 31-45 yrs
% men: 87%
Study design: cross-sectional
Study year(s): 2003
N total: 31
Melzer et
Study population: general
al. (2010) population, NHANES, US
Age range: 20 yrs and older
% men: 48%
Study design: cross-sectional
Study year(s): 1999-2006
N total: 3,974

Blood PFOA levels

Association
with PFOAa

Effect size

Serum PFOA:
Range: 0.57-2.58 ng/mL
Geometric mean (95% CI)
1.33 (1.15–1.53) ng/mL

TSH: 0
Free T4: 0

Association between log-PFOA and log-TSH,
β(CI):
-0.06 (-0.78, 0.67)
Association between log-PFOA and log-T4,
β(CI):
-0.01 (-0.16, 0.14)

Serum PFOA, men:
Q1: 0.1-3.6 ng/mL
Q2: 3.7-5.2 ng/mL
Q3: 5.3-7.2 ng/mL
Q4: 7.3-45.9 ng/ml
Geometric mean (CI):
4.91 (4.64-5.2) ng/mL

Thyroid disease
ever:
Women: +
Men: 0

Association between serum PFOA quartiles
and:
Thyroid Disease Ever, OR (CI):
Women:
Q2: 0.95 (0.62-1.47)
Q3: 1.11 (0.67-1.83)
Q4: 1.64 (1.09-2.46)
Q4 vs Q1 & Q2: 1.68 (1.14-2.49)
Men:
Q2: 1.11 (0.62-1.99)
Q3: 0.57 (0.19-1.66)
Q4: 1.58 (0.74-3.39)
Q4 vs Q1 & Q2: 1.5 (0.66-3.39)
Thyroid Disease current & medication, OR (CI)
:
Women:
Q2: 0.7 (0.41-1.22)
Q3: 0.89 (0.49-1.59)
Q4: 1.86 (1.12-3.09)
Q4 vs Q1 & Q2: 2.24 (1.38-3.65)
Men:
Q2: 1.12 (0.52-2.39)

Serum PFOA, women:
Q1: 0.1-2.6 ng/mL
Q2: 2.7-4.0 ng/mL
Q3: 4.1-5.7 ng/mL
Q4: 5.7-123.0 ng/mL
Geometric mean (CI):
3.77 (3.52-4.04) ng/mL

Page 94 of 120

Thyroid disease
current &
medication:
Women: +
Men: 0

RIVM Report 2017-0086

Reference

Ji et al.
(2012)

Wen et al.
(2013)

Study characteristics

Study population: general
population, Korea
Age range: 12-75 yrs
% men: 41%
Study design: cross-sectional
Study year(s): 2008
N total: 633
Study population: general
population, US, NHANES
Age range: ≥ 20 yrs
% men: 57%
Study design: cross-sectional
Study year(s): 2007-08 and
2009-10
N total: 1,181

Blood PFOA levels

Association
with PFOAa

Serum PFOA:
IQR: 2.04-3.64 ng/mL
Median: 2.74 ng/mL

TSH: 0
T4: 0

Serum PFOA:
Geometric mean (CI):
4.15 (4.02– 4.29) ng/mL

TSH: 0
T3: 0 (men), +
(women)
Free T3: +
T4: 0
Free T4: 0

Effect size
Q3: 0.49 (0.18-1.38)
Q4: 1.89 (0.60-5.90)
Q4 vs Q1 & Q2: 2.12 (0.93-4.82)
Association between serum PFOA and TSH and
T4, β (CI):
TSH: −0.066 (−0.220, 0.089)
T4: −0.020 (−0.051, 0.012)

Association between lnPFOA and ln-TSH, β
(CI):
Men: 0004 (-0.081, 0.090) (p = 0.92)
Women: -0.030 (-0.2157, 0.154) (p =0.73)
Association between lnPFOA and ln-T3, β (CI):
Men: 0.775 (-3.048, 4.598) (p =0.67)
Women: 6.628 (0.545, 12.7) (p = 0.035)
Association between lnPFOA and ln-FT3, β
(CI):
Men: 0.016 (0.001, 0.031) (p = 0.04)
Women: 0.027 (0.009, 0.044) (p
=0.002)
Association between lnPFOA and ln-T4, β (CI):
Men: 0.000 (-0.28, 0.28) (p = 1.0)
Women: 0.082 (-0.369, 0.532) (p = 0.71)
Association between lnPFOA and ln-FT4, β
(CI):
Men: -0.010 (-0.041, 0.022) (p = 0.53)
Women: -0.004 (-0.047, 0.039) (p = 0.83)
Association between lnPFOA and ln-T3, β (CI):
In women increased T3 in Q3 (3.6 - 5.3

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Reference

Study characteristics

Blood PFOA levels

Association
with PFOAa

Lin et al.
(2013b)

Study population: general
population, Young Taiwanese
Cardiovascular Cohort Study
Age range: 12-30 yrs
% men: 38%
Study design: cross-sectional
Study year(s): 2006-08
N total: 545

Serum PFOA:
Median: 3.64 ng/mL
GM (GSD): 2.67 (2.96)
ng/mL
75th: 6.66 ng/mL
90th: 9.71 ng/mL

TSH: 0
Free T4: 0
Hypothyroidism:
0

de Cock et
al. (2014)

Study population: general
population, Netherlands
Age range: newborns
% men: 62% boys
Study design: cross-sectional
Study year(s): 2011-13
N total: 83 newborns

Plasma PFOA, cord blood:
Range: 0.2–2.7 ng/mL
Median: 0.885 ng/mL
Mean: 0.943 ng/mL

T4: 0 (boys), +
(girls)

Shrestha
et al.
(2015)

Study population: general
population, US (Upper Hudson
River Valley)
Age range: 55-74 yrs
% men: 59

Serum PFOA:
Range: 0.6 – 42.7 ng/mL
IQR: 7.1–13.1 ng/mL
Median: 9.3 ng/mL
Geometric mean: 9.2

TSH: 0
T3: 0
T4: 0
Free T4: 0

Page 96 of 120

Effect size
ng/mL) and Q4 (>5.3 ng/mL) relative to Q1
(≤2.4 ng/mL)
Association between PFOA and ln TSH, per
percentile, mean (SE) in linear regression
models:
<50th: 0.48 (0.08) (not significant; NS)
50th-75th: 0.45 (0.09) (NS)
75th-90th: 0.36 (0.11) (NS)
>90th: 0.41 (0.12) (NS)
Association between PFOA and FT4, per
percentile, mean (SE) in linear regression
models:
<50th: 1.07 (0.01) (NS)
50th-75th: 1.08 (0.02) (NS)
75th-90th: 1.10 (0.02) (NS)
>90th: 1.06 (0.02) (NS)
Association between quartile PFOA and T4, β
(CI):
Boys (Q1=ref):
Q2 (0.59-0.87 ng/mL): 7.9 (-18.04, 33.92)
Q3 (0.87-1.2 ng/mL): -2.1 (-20.94, 16.78)
Q4 (>1.2 ng/mL): 6.2 (-16.08, 28.50)
Girls (Q1=ref):
Q2 (0.59-0.87 ng/mL): -5.9 (-26.75, 14.94)
Q3 (0.87-1.2 ng/mL): 11.8 (-19.08, 42.72)
Q4 (>1.2 ng/mL): 38.6 (13.34, 63.83)
Association between log-PFOA and log-TSH, β
(CI):
0.102 (-0.047, 0.25)
Association between log-PFOA and log-T3, β
(CI):

RIVM Report 2017-0086

Reference

Chan et
al. (2011)

Wang Y.
et al.
(2013)

Webster
et al.
(2014)

Study characteristics

Blood PFOA levels

Association
with PFOAa

Effect size

Study design: cross-sectional
Study year(s): blood collection
in 2000-02
N total: 87

ng/mL

Study population: general
population, Canada, pregnant
women.
Age range: 20-45 yrs
% men: 0
Study design: cross-sectional
Study year(s): 2005-06. Blood
sample in 2nd trimester.
N total: n=96 hypothyroxinemia
cases and n=175 matched
controls
Study population: general
population, Norway, pregnant
women
Age range: 18-44 yrs
% men: 0
Study design: cross-sectional
Study year(s): 2003-04, blood
sample in 2nd trimester
N total: 903
Study population: general
population, Canada, pregnant
women
Age range: 25-34 yrs

Serum PFOA, pregnant
women cases and
controls:
Geometric mean: 1.35
ng/mL

Hypothyroidism:
0

Plasma PFOA, pregnant
women:
IQR: 1.57- 2.95 ng/mL
Median: 2.15 ng/mL
GM (CI): 2.13 (2.07, 2.20)
ng/mL

TSH: 0

Association between ln PFOA and TSH, β (CI):
−0.0001 (−0.045, 0.044)

Serum PFOA, pregnant
women:
Range: <0.5 -4.6 ng/mL
IQR: 1.4 ng/mL

Normal antithyroid oxidase
(TPO) antibody
TSH: 0

Association between IQR PFOA and TSH, β
(CI):
Normal TPO antibody: 0.07 (-0.1, 0.2)
High TPO antibody: 0.7 (0.09, 1)

3.03 (-1.73, 7.79)
Association between log-PFOA and log-T4, β
(CI):
0.38 (-0.07, 0.83)
Association between log-PFOA and log-FT4, β
(CI):
0.016 (-0.036, 0.069)
Association between lnPFOA and
hypothyroidism, OR (CI):
0.94 (0.74–1.18)

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Reference

Berg et al.
(2015)

Jain
(2013)

Study characteristics

Blood PFOA levels

% men: 0
Study design: cross-sectional
Study year(s): 2007-08, blood
samples in 2nd trimester
N total: 152

Median: 1.7 ng/mL
Mean: 1.8 ng/mL

Study design: general
population, Norway, pregnant
women
Age range: not reported Median
age: 32 yrs
% men: 0
Study design: longitudinal
Study year(s): 2007-09
N total: 375
Study population: general
population, NHANES, US
Age range: age 12 and older
% men: not reported
Study design: cross-sectional
Study year(s): 2007-08
N total: 1,540

Serum PFOA, maternal
during and after
pregnancy:
Median: 1.53 ng/mL

Serum PFOA:
tertile 1: ≤3.3 ng/mL
tertile 2: 3.3-5.0 ng/mL
tertile 3: ≥5.1 ng/mL

Association
with PFOAa
Free T4: 0
High TPO
antibody
TSH: +
Free T4: 0
TSH: +

TSH: 0
Free T3: 0
Free T4: 0
Total T3: +
Total T4: 0
TGN: 0

Effect size
Association between IQR PFOA and FT4, β
(CI):
Normal TPO antibody: -0.03 (-0.3, 0.2)
High TPO antibody: -0.4 (-1, 0.5)
Results not quantified. Women in the
extreme quartiles of PFOA had higher
concentrations of TSH compared with the
lowest quartiles, but not significantly so after
adjustment for PFOS

Association between tertiles serum PFOA
concentration and TSH concentration (ORs
were not reported, only p-values):
TSH was significantly (p<0.01) higher in the
third tertile (>=5.1 ng/mL) compared to the
first tertile (<=3.3 ng/mL). Therefore, TSH
levels increased with increase in PFOA
concentration.
Association between transformed serum PFOA
concentration and transformed thyroid function
variables (in a model including all thyroid
function variables), β (p-value; CI not
reported):
FT3 0.012 (p=0.09)
FT4 0.003 (p=0.83)

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Reference

Wang Y.
et al.
(2014)

Kim et al.
(2016)

ShahKulkarni
et al.

Study characteristics

Study population: general
population, pregnant women
and their children (Taiwan
Cohort)
Age range: not reported. Mean
age: 28.8 yrs (SD 4.3)
% men: 0% (only pregnant
women) and 49% of neonates
Study design: longitudinal
Study year(s): 2000-2001
N total: 285 women and 116
neonates
Study population: general
population (patients hospital
South Korea)
Age range: 1-3 months after
birth
% men: unknown
Study design: cross-sectional
Study year(s): 2009-2010
N total: 27 patients and 13
controls
Study population: general
population
Age range: adults 70% ≥30 yrs,

Blood PFOA levels

Association
with PFOAa

Effect size

Serum PFOA, maternal,
during pregnancy:
Median: 2.39 ng/mL
25th percentile: 1.54
ng/mL
75th percentile: 3.40
ng/mL
90th percentile: 5.20
ng/mL

Thyroid effects,
maternal & cord
Free T4: 0
Total T4: 0
Total T3: 0
TSH: 0

Association between maternal serum PFOA
concentration and thyroid effects, β (CI):
Free T4: -0.003 (0.012, 0.005) ng/dl (not
significant; NS)
Total T4: 0.011 (-0.108, 0.130) µg/dl (NS)
Total T3: -0.000 (-0.002-0.009) ng/dl (NS)
TSH: 0.011 (-0.057, 0.078) µlU/ml (NS)

Serum PFOA:
Range: 0.8–15.7 ng/mL
Mean: 5.4 ng/ml

TSH: 0
Free T4: 0
T3: 0
Micro/Ab: 0
TSI: -

Association between PFOA and TSI vs control
group, Spearman’s correlation coefficients
(R2):
-0.482 (p<0.05)

T3: 0
T4: 0
TSH: 0

Association between prenatal PFOA and thyroid
effects adjusted for mother's age, education,
pre-pregnancy body mass index, alcohol intake

Serum PFOA, cord blood:
Range: 0.05-2.4 ng/mL
Geometric mean: 0.78

TT3 0.032 (p=0.01)
TT4 0.012 (p=0.43)
TGN 0.057 (p=0.17)

Non-significant results were not quantified.

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Reference

Study characteristics

Blood PFOA levels

(2016)

babies at birth
% men: 0% male adults (their
children: 47% boys)
Study design: cross-sectional
and longitudinal
Study year(s): 2006-10
N total: 279
Study population: general
population (no occupational
experience with PFOA and
generally did not smoke)
Age range: not reported. Mean
age: 30 yrs
% men: 0% (their children:
55% boys)
Study design: cross-sectional
Study year(s): 2013
N total: 157

ng/mL

Yang et
al. (2016)

High-exposure community
Emmett et
Study population: Highal. (2006)
exposure community
population. Residents Ohio in
C8 Health Project area (Little
Hocking)
Age range: 2-89 yrs
% men: 47%

Page 100 of 120

Serum PFOA, maternal:
Range: 0.73-8.11 ng/mL
Median: 1.64 ng/mL
Serum PFOA, cord blood:
Range: 0.4-5.06 ng/mL
Median: 1.15 ng/mL

Serum PFOA:
IQR: 184–571 ng/mL
Median: 354 ng/mL

Association
with PFOAa

Effect size

Free T3: Free T4: 0
T3: 0
T4: 0
TSH: 0

Association between maternal PFOA and
maternal thyroid effects, Spearmans
correlation:
Free T3: 0.024 (not significant=NS)
Free T4: 0.000 (NS)
T3: 0.102 (NS)
T4: 0.062 (NS)
TSH: -0.124 (NS)
Association between cord (i.e. fetal) PFOA and
maternal thyroid effects, Spearmans
correlation:
Free T3: -0.169 (p<0.05)
Free T4: 0.089 (NS)
T3: -0.069 (NS)
T4: -0.069 (NS)
TSH: -0.065 (NS)

TSH: 0

PFOA in individuals with normal TSH compared
with abnormal TSH, t-test (p-value):
r=0.046 (0.38)

history, child's parity, gestational age and
gender, β (CI):
T3: -0.01 (-2.22, 2.20)
T4: 0.001 (-0.26, 0.26)
TSH: -0.79 (-2.13, 0.55)

RIVM Report 2017-0086

Reference

LopezEspinosa
et al.
(2012)

Study characteristics
Study design: cross-sectional
Study year(s): 2004-2005
N total=371
Study population: Highexposure community population
(C8 Health Project), US
Age range: 1-17 yrs
% men: 51.5% boys
Study design: cross-sectional
Study year(s): 2005-06
N total: 10,725 children

Blood PFOA levels

Association
with PFOAa

Effect size

Serum PFOA, modelled in
utero:
Median: 12 ng/mL
Q1: 0.05–5.4 ng/mL
Q2: 5.5–11.6 ng/mL
Q3: 11.7–38.4 ng/mL
Q4: 38.5–3,987 ng/mL

TSH: - (in girls ≤
5 yrs)
T4: + (in children
≤ 5 yrs)
Thyroid disease:
+

Association between quartiles of modelled or
measured PFOA or IQR and transformed %
change in TSH compared: not significant
Change in measured serum PFOA from 16
to 83 ng/mL was associated with a 4%
drop in TSH in all children ≤ 5 yrs, but
only in girls.
Association between quartiles of modelled or
measured PFOA or IQR of lnPFOA and
transformed % change in T4: not significant
IQR contrast of 10 to 57 ng/mL for
modelled in utero PFOA was associated
with a 2% increase in T4 in children up to
5 yrs of age (95% CI 0.1, 3.9)

Serum PFOA, measured:
Median : 29.3 ng/mL
Q1: 0.7–13 ng/mL
Q2: 13.1–29.2 ng/mL
Q3: 29.3–67.6 ng/mL
Q4: 67.7–2,071 ng/mL

Thyroid disease
Association per IQR modelled PFOA and thyroid
disease, OR (CI):
Any thyroid disease (n = 27) 1.47 (0.95, 2.27)
Hypothyroidism (n = 20) 1.61(0.96, 2.63)
Subclinical hypothyroidism (n = 155) 0.94
(0.76, 1.16)
Subclinical hyperthyroidism (n = 31) 1.10
(0.69, 1.74)
Measured PFOA:
Any thyroid disease (n = 61) 1.44 (1.02,
2.03)
Hypothyroidism (n = 39) 1.54 (1.00, 2.37)
Subclinical hypothyroidism (n = 365) 0.98
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Reference

Study characteristics

Knox et al.
(2011)

Study population: Highexposure community population
(C8 Health Study), US
Age range: >20 yrs
% men: 50% boys
Study design: cross-sectional
Study year(s): 2005-06
N total: 52,296

Blood PFOA levels

Serum PFOA:
Range: 0.25-564.3 ng/mL
Mean (SD):
Women 20-50 yrs: 52.6
(192.8) ng/mL
Women >50 yrs: 98.6
(230.2) ng/mL
Men 20-50 yrs: 91.0
(261.5) ng/mL
Men >50 yrs: 124.3
(380.8) ng/mL
High-exposure community & occupational study populations
Winquist
Study population: highSerum PFOA (measured in
and
exposure community and
2005-06):
Steenland
occupational study (C8 Health
IQR: 12.8-68.1 ng/mL
(2014b)
Study), US
Median: 26.1 ng/mL
Age range: ≥20 yrs
Mean: 86.6 ng/mL
% men: 54%
Study design: longitudinal
Study year(s): 2005-06, 200811
N total: 32,254

Page 102 of 120

Association
with PFOAa

TSH: 0
T4:
Women 20-50
yrs, women >50
yrs, men >50
yrs: +
Men 20-50 yrs: 0

Functional
thyroid disease:
+ (women)
Hyperthyroidis
m: + (women,
yearly exposure
estimates)
Hypothyroidism
: + (women)

Effect size
(0.86, 1.15)
Subclinical hyperthyroidism (n = 78) 0.81
(0.58, 1.15)
Association between PFOA and TSH: results
not quantified
Association between PFOA and T4, β (p-value):
Women 20-50 yrs: 0.05 (<0.0001)
Women >50 yrs: 0.08 (<0.0001)
Men 20-50 yrs: not reported (NS)
Men >50 yrs: 0.06 (0.001)

Women:
Association between cumulative PFOA exposure
quintiles and functional thyroid disease (i.e.
excludes neoplasms), HR (CI), ref=quintile 1:
Quintile 2 (114.7-<202.2 ng/mL-yrs): 1.24
(1.02-1.51)
Quintile 3 (202.2-<497.3 ng/mL-yrs): 1.27
(1.04-1.55)
Quintile 4 (497.3-<2676 ng/mL-yrs): 1.36
(1.12-1.66)
Quintile 5 (2,670-97,396 ng/mL-yrs): 1.37
(1.11-1.68)
Similarly, significant associations were
observed between cumulative PFOA
exposure quintiles and hypothyroidism and
yearly exposure estimates with functional

RIVM Report 2017-0086

Reference

Study characteristics

Occupational study population
Olsen and
Study population: occupational
Zobel
population, 3M Cottage Grove
(2007)
US, Decatur US & Antwerp
Age range: 21-67 yrs
% men: 100%
Study design: cross-sectional
Study year(s): 2000
N total: 506 (all locations), 196

Blood PFOA levels

Association
with PFOAa

Effect size
thyroid disease, hyperthyroidism and
hypothyroidism. No significant associations
were observed between cumulative PFOA
exposure quintiles and hyperthyroidism.
Men:
Association between cumulative PFOA exposure
quintiles and functional thyroid disease, HR
(CI), ref=quintile 1:
Quintile 2 (114.7-<202.2 ng/mL-yrs): 1.12
(0.69-1.79)
Quintile 3 (202.2-<497.3 ng/mL-yrs): 0.83
(0.51-1.37)
Quintile 4 (497.3-<2676.0 ng/mL-yrs ): 1.01
(0.63-1.62)
Quintile 5 (2,670.0-97,396 ng/mL-yrs): 1.05
(0.66-1.66)
Similarly, no significant associations were also
observed when hyperthyroidism and
hypothyroidism were examined and when
yearly exposure estimates were examined in
men.

Serum PFOA, all locations:
Range: 7-92,030 ng/mL
Median: 1,100 ng/mL
Mean: 2,210 ng/mL

TSH: 0
T3: +
T4: 0
Free T4: -

Association between ln PFOA and ln TSH, β(SE)
(p-value):0.0360 (± 0.0207) (p = 0.08)
Association between ln PFOA and ln T3,
β(SE) (p-value): 0.0105 (± 0.0053) (p =
0.05)
Association between ln PFOA and ln T4, β(SE)
(p-value): -0.0057 (± 0.0054) (p = 0.29)
Association between ln PFOA and ln FT4,

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Reference

Study characteristics

Blood PFOA levels

(Antwerp), 122 (Cottage Grove
US), 188 (Decatur US)

Association
with PFOAa

Steenland
et al.
(2015)

Study population: occupational
population, DuPont West
Virginia (Washington works)
Age range: mean year of birth
1951
% men: 80%
Study design: longitudinal
Study year(s): 2005-06 (PFOA
measures), 2008 & 2011
(interviews)
N total = 3,713 (cohort of
workers)

Serum PFOA, measured in
2005-06 (n=1,881):
Range: not reported
Median: 113 ng/mL
Mean: 325 ng/mL
Historical serum levels
modelled using JEM,
residential exposure model
and PK model.
Mean cumulative
occupational exposure 8.6
ppm-years

Thyroid disease
(self-reported,
with medical
record
validation): 0

Sakr et al.
(2007a)

Study population: occupational
population, Washington Works
US (in C8 Health Project area).
Age range: not reported. Mean
age men/women: 46.5 / 44.4
yrs
% men: 76%
Study design: cross-sectional

Serum PFOA:
Range: 5-9,550 ng/mL
Median: 189 ng/mL
Mean: 428 ng/mL

TSH:
association with
PFOA not
studied.
Authors note
that all mean
clinical
endpoints were

Page 104 of 120

Effect size
β(SE) (p-value): -0.0117 (± 0.0043) (p =
0.01)
Not considered clinically relevant by the authors
because results were within normal reference
ranges.
Association between cumulative estimated
exposure PFOA quartiles and self-reported
thyroid disease, no lag, ref=Q1, HR (CI):
Men (n=82 cases):
Q2 (3,030-6,160 ng/mL-yrs): 1.64 (0.82, 3.29)
Q3 (6,160-11,420 ng/mL-yrs): 1.13 (0.50,
2.54)
Q4 (>11,420 ng/mL-yrs): 2.16 (0.98, 4.77)
Women (n=77 cases):
Q2 (3,030-6,160 ng/mL-yrs): 1.00 (0.54, 1.87)
Q3 (6,160-11,420 ng/mL-yrs): 1.02 (0.48,
2.17)
Q4 (>11,420 ng/mL-yrs): 0.33 (0.08, 1.26)
Association between cumulative exposure PFOA
quartiles and self-reported thyroid disease, 10year lag, ref=Q1, HR (CI): no significant
association was observed.

RIVM Report 2017-0086

Reference

Study characteristics
Study year: 2004
N total=1,025
Study population: Occupational
population, 3M Antwerp and
Decatur
Age range: mean 37 (male
Antwerp) and 43 (male
Decatur) yrs
% men: 81% (Antwerp), 82
(Decatur)
Study design: cross-sectional
and longitudinal
Study year(s): 1994, 1995,
2000
N total cross-sectional = 518
N total longitudinal =174
Study population: occupational
population, PFOA male
production workers, US, 3M
Age range: median 32.5 yrs in
1993 and in those with ≥30,000
ng/mL
% men: 100
Study design: cross-sectional
Study year(s): 1993 & 1995
N total: 111 in 1993, n=80 in
1995, n=68 in both years

Olsen et
al. (2003)

Olsen et
al. (1998)

Blood PFOA levels

Association
with PFOAa
within the
normal range
Serum PFOA:
TSH: 0
Decatur:
T3: +
Range = 40-12,700 ng/mL T4: 0
Mean = 1,780 ng/mL
Free T4: 0
(n=263)

Effect size

Association between serum PFOA and ln T3, β
(p-value): 0.016 (0.01)

Antwerp:
Range = 10-7,040 ng/mL
Mean = 840 ng/mL

Serum PFOA, 1995:
Range: 0-114,100 ng/mL
Median concentrations per
PFOA group:
0-<1,000 ng/mL: 310
ng/mL
1,000-<10,000 ng/mL:
3,030 ng/mL
10,000-<30,000 ng/mL:
17,110 ng/mL
≥30,000 ng/mL: 55,960
ng/mL

TSH:
1993: 0
1995: + (in 3rd
category)

Significantly different mean TSH was found
between categories of serum PFOA
concentrations in 1995, but only in category
10,000-<30,000 ng/mL:
0-<1,000 ng/mL: 1.7
1,000-<10,000 ng/mL: 1.7
10,000-<30,000 ng/mL: 2.9
≥30,000 ng/mL: 1.7
P=0.002
No significant difference was observed in 1993.

a

0, no association; +, positive association; -, negative association.
β=regression coefficient, OR=Odds Ratio, HR= Hazard Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA, Q=quartile,
IQR=Interquartile range, TSH=Thyroid stimulating hormone, T3=triiodothyronine, T4=thyroxine, TGN=thyroglobin, TSI=thyroid stimulating
immunoglobulins
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Reference

Table 11. Summary of associations in studies on blood lipid levels

Study characteristics

General population
Nelson et
Study population: general
al. (2010)
population, NHANES, US
Age range: 20-80 yrs
% men: 52%
Study design: cross-sectional
study
Study year(s): 2003-04
N total: 860

Blood PFOA levels

Association
with PFOAa

Effect size

Serum PFOA:
Range: 0.1–37.3 ng/mL
Median 3.8 ng/mL
Mean 4.6 ng/mL

TC +
LDL 0 (based on
416 persons)
HDL +
(adolescent
girls); - (men 6080 y)
Non-HDL +

Association between 1 ng/mL PFOA and change in
cholesterol (mg/dL), β (CI):
TC: 1.22 (0.04, 2.40)
HDL: –0.12 (–0.41, 0.16)
Non-HDL: 1.38 (0.12, 2.65)
LDL: –0.21 (–1.91, 1.49)

Median (range):
Q1: 2.1 (0.1–2.7) ng/mL
Q2: 3.4 (2.8–3.9) ng/mL
Q3: 4.6 (4.0–5.4) ng/mL
Q4: 6.9 (5.5–37.3)
ng/mL

Indication of linear increase between quartiles
with bottom/top medians of 2.1 / 6.9 ng/mL;
TC 9.8‑mg/dL (95% CI, –0.2 to 19.7) increase
from top to bottom quartile;
HDL 4.3 (95% CI 0.1 to 8.5) increase from top to
bottom quartile in adolescent girls;
8.7 (95% CI 1.1 to 16.3) decrease in men 60-80
y;

Lin et al.
(2011)

Study population: Young
Hypertension Cohort in
Taiwan
Age range: 12-30 yrs
% men: 42%
Study design: cross-sectional
Study year(s): 2006-2008
N total: 287

Page 106 of 120

Serum PFOA:
Median: 2.39 ng/ml
Range: 27.38 ng/ml
median (range) per
category (< 50th, 50 –
74, 75 –89 and >= 90th
percentiles): 0.75 (0.752.37) ng/ml, 3.86 (2.395.92) ng/ml, 7.89 (6.019.62) ng/ml, 11.54

HDL 0
TRIG 0

non-HDL similar to TC
Mean (SE) concentrations per PFOA category
HDL:
48.06 (1.35)
47.74 (1.39)
47.69 (1.72)
47.70 (2.05)
P trend 0.937
Log(TRIG):

RIVM Report 2017-0086

Reference

Study characteristics

Blood PFOA levels
(9.64-28.13) ng/ml,
respectively

Association
with PFOAa

Eriksen et
al. (2013)

Study population: general
population, Denmark
Age range: 50-65 yrs
% men: 88%
Study design: cross-sectional
Study year(s): 1993-97
N total: 753

Plasma PFOA:
Range: 1-28 ng/mL
Mean 7.1 ng/mL

TC +

Fisher et al.
(2013)

Study population: general
population, Canada
Age range: 18-74 yrs
% men: 48% men
Study design: cross-sectional
Study year(s): 2007-09
N total: 2,368

Serum PFOA:
Geometric mean: 2.46
ng/mL
Q1: 0.15–1.85 ng/mL
Q2: 1.86–2.58 ng/mL
Q3: 2.59–3.55 ng/mL
Q4: ≥3.56 ng/mL

TC 0
LDL 0
HDL 0
Non-HDL 0
HDL/TC ratio 0
TRIG 0
high C 0

Lin et al.
(2013a)

Study population: general
population, Young Taiwanese
Cohort Study

Serum PFOA:
Range: 0.75-52.2 ng/mL
Median: 3.49 ng/mL

LDL: 0
TRIG: -

Effect size
4.39 (0.07)
4.32 (0.07)
4.25 (0.09)
4.14 (0.11)
P trend 0.061
4.4 (95% CI = 1.1–7.8) mg/dL higher TC per IQR
of plasma PFOA. Stronger association among
women than men

Beta (95% CI) for log(PFOA)
TC: 0.03 (-0.017, 0.07)
LDL: 0.02 (-0.06, 0.091)
HDL: 0.0009 (-0.04, 0.04)
Non-HDL: 0.036 (-0.01, 0.08)
HDL/TC ratio: 0.02 (-0.016, 0.06)
TRIG: -0.003 (-0.13, 0.12)
High C: 1.22 (0.89, 1.67)
High C, OR (95% CI), weighted
Q1 ref
Q2 1.61 (1.02, 2.53)
Q3 1.26 (0.76, 2.07)
Q4 1.5 (0.86, 2.62)
P for Trend=0.10
Association between PFOA categories and LDL
(mg/dL), mean (SE):
107.4 (3.07)

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Reference

Fu et al.
(2014)

Study characteristics

Blood PFOA levels

Age range: 12-30 yrs
% men: 39%
Study design: cross-sectional
Study year(s): 2006-08
N total: 644

Geometric mean: 2.61
ng/mL (age and sex
adjusted)

Study population: Participants
of health check-up in Red
Cross Hospital (China).
Age range: 0.3-88 yrs
% men: 60%
Study design: cross-sectional
Study year(s): 2011
N total: 133

Serum PFOA:
Median: 1.43 ng/ml
Range: 0.32-39.46 ng/ml
Mean: 2.95 ng/ml
SD: 4.65 ng/ml
Median; mean (SD);
range per quartile
Q1: 0.71; 0.72 (0.17);
0.32–0.99
Q2: 1.24; 1.23 (0.12);
1.02-1.43
Q3: 1.97; 2.03 (0.47);
1.44-2.85
Q4: 4.88; 7.89 (7.40);
2.95-39.46

Association
with PFOAa

Effect size
105.5 (3.42)
100.3 (3.95)
100.4 (4.66)
P trend 0.117
Association between PFOA categories and
triglyceride (mg/dL), mean (SE):
4.37 (0.04)
4.39 (0.05)
4.32 (0.06)
4.20 (0.07)
P trend 0.015

TC: +
TG: 0
HDL: 0
LDL: +

Logistic regression analysis: risk of abnormal
serum lipids based on PFOA quartiles
(Crude OR, Adjusted OR (95% CI), P value for
trend for differences in lipid concentrations
between quartiles
TC (Total Cholesterol): P trend = 0.015
Q2 1.20; 0.82 (0.14-4.81)
Q3 5.95; 2.60 (0.56-12.09)
Q4: 2.80; 0.55 (0.09-3.31)
LDL (Low Density Lipoprotein): P trend = 0.022
Q2 0.96; 0.55 (0.11-2.82)
Q3 5.04; 1.70 (0.40-7.19)
Q4: 2.74; 0.71 (0.14-3.49)
TG: not significant; p trend = 0.298
Q2 1.73(0.57–5.21)
Q3 1.03(0.33–3.20)

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Reference

Study characteristics

Blood PFOA levels

Association
with PFOAa

Effect size
Q4 1.97(0.59–6.55)
HDL: not significant: p trend = 0.268
Q2 0.35(0.57–2.16)
Q3 0.89(0.19–4.19)
Q4 0.67(0.13–3.51)
Beta (95% CI) adjusted regression models:
ln(TC): 0.054 (0.011, 0.098)
ln(TRIG): 0.050 (-0.045, 0.144)
HDL: 0.041 (-0.030, 0.112)
ln(LDL): 0.065 (0.010, 0.121)

Geiger et
al. (2014)

Study population: general
population, US
Age range: 12-18 yrs
% men: 52
Study design: cross-sectional
Study year(s): merged data
from NHANES 1999–00,
2003–04, 2005–06, and
2007–08
N total: 815

Mean (SE) 4.2 (0.2)
ng/mL,
tertiles
T1 <3.2
T2 3.2–4.7
T3 >4.7 ng/mL

TC +
LDL +
HDL 0
TRIG 0
High TC +
High LDL +
Low HDL 0

Beta (95% CI) per ln-unit increase in PFOA
TC 4.55 (0.90, 8.20)
LDL 5.75 (2.16, 9.33)
HDL -1.52 (-3.02, -0.03)
TRIG 1.74 (-2.88, 6.36)
Adjusted mean change (95% CI) relative to first
PFOA tertile
TC
T2: 4.72 (-1.23, 10.67)
T3: 7.00 (1.40, 12.60)
P trend=0.017
LDL
T2: 3.61 (-1.13, 8.36)
T3: 8.18 (3.04, 13.32)
P trend=0.0027
HDL
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Reference

Study characteristics

Blood PFOA levels

Association
with PFOAa

Effect size
T2: 0.53 (-1.23, 2.30)
T3: -1.19 (-2.94, 0.56)
P trend=0.1769
TRIG
T2: 3.00 (95% CI -5.68, 11.68)
T3: 0.09 (95% CI -6.11, 6.30)
P trend=0.9943
Positive association between PFOA exposure and
high TC and high LDL in categorical outcome
models, but not with low HDL-C or high TRIG
OR (95% CI) for dyslipidemia
TC
T2: 1.49 (0.97, 2.29)
T3: 1.49 (1.05, 2.12)
LDL
T2: 1.26 (0.74, 2.15)
T3: 1.56 (0.98, 2.48)
HDL
T2: 1.06 (0.65, 1.73)
T3: 1.45 (0.87, 2.41)
TRIG
T2: 1.35 (0.60, 3.01)
T3: 0.86 (0.46, 1.64)

Starling et
al. (2014b)

Study population: general
population (pregnant

Page 110 of 120

Plasma PFOA, (ng/mL):
Median: 2.25 ng/mL

TC 0
LDL 0

Beta (95% CI)

RIVM Report 2017-0086

Reference

Study characteristics

Blood PFOA levels

women), Norway
Age range: 19-41 yrs
% men: 0%
Study design: cross-sectional
Study year(s): 2003-04
N total: 891

Range: not reported
IQR: 1.66-3.03 ng/mL
5th percentile: 1.05
ng/mL
95th percentile: 4.43
ng/mL

Association
with PFOAa
HDL 0
TRIG 0

Effect size
TC
Q1 ref
Q2 1.49 (-6.49, 9.48)
Q3 3.54 (-4.51, 11.59)
Q4 3.90 (-5.00, 12.80)
Per ln-ng/mL 2.58 (-4.32, 9.47)
IQR 1.55 (-2.60, 5.69)
LDL
Q1 ref
Q2 0.94 (-6.08, 7.96)
Q3 4.16 (-3.19, 11.50)
Q4 3.35 (CI -4.35, 11.06)
Per ln-ng/mL 2.25 (-3.97, 8.48)
IQR 1.36 (-2.38. 5.10)
HDL
Q1 ref
Q2 0.22 (-2.38, 2.83)
Q3 2.31 (-0.59, 5.20)
Q4 3.42 (0.56, 6.28)
Per ln-ng/mL 2.13 (-0.26, 4.51)
IQR 1.28 (-0.15, 2.71)

Zeng et al.

Study population: Taiwanese

Serum PFOA boys:

TC +

Ln-TRIG
Q1 ref
Q2 0.03 (-0.04, 0.11)
Q3 0.01 (-0.08, 0.09)
Q4 -0.04 (-0.12, 0.04)
Per ln-ng/mL 0.00 (-0.07, 0.06)
IQR 0.00 (-0.04, 0.04)
Multivar linear regression: β coefficient, 95%CI, p
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Reference

Study characteristics

Blood PFOA levels

(2015)

children
Age range: 12-15 yrs
% men: 45%
Study design: cross-sectional
Study year(s): 2009-10
N total: 225

Mean: 1.1 ng/ml
SD: 1.4 ng/ml
Median: 0.5 ng/ml
Range: LOQ-3.9
Serum PFOA girls:
Mean: 0.92 ng/ml
SD: 0.79 ng/ml
Median: 0.5 ng/ml
Range: LOQ–11.3

High exposure communities
Emmett et
Study population: highal. (2006)
exposure community (in area
C8 Health Project), including
18 workers from a
fluoropolymer production
facility, US
Age range: 2.5-89 yrs
% men: 46%
Study design: cross-sectional
Study year(s): 2004-05
N total: 371
Steenland
Study population: high
et al.
exposure community (C8
(2009)
Health Project, US
Age range: ≥18 yrs
% men: 46%
Study design: cross-sectional
Study year(s): 2005-06
N total: 46,294

Page 112 of 120

Association
with PFOAa
HDL – (ns)
LDL +
TG +

Change in cholesterol/blood lipids level (ng/ml)
per ln(ng/ml) increase in PFOA (adjusted model).
TC:
6.57 (2.72 to 10.42); p=0.001
HDL: -1.56 (-3.20 to 0.08); p=0.06
LDL: 4.66 (1.67 to 7.65); p=0.002
TG:
19.63 (14.82 to 23.34); p<0.001
Difference between first and fourth quartile PFOA:
TC 12.9 mg/dL

Median 354 ng/mL; IQR
184-571 ng/mL

TC 0

mean (SD) 80.3 (236.1)
ng/mL; median 26.6;
range 0.25–17,556.6

TC +
LDL +
HDL 0
Non-HDL +
TC/HDL ratio +
TRIG +
High TC +

Q1 0–13.1
Q2 13.2–26.5
Q3 26.6–66.9
Q4 ≥67.0 ng/mL

Effect size

TC beta 0.00021305, p=0.38
t-test PFOA in abnormal (49% of study
population) vs. normal TC: p-value 0.79

Largely monotonic increase in log cholesterol with
each decile of PFOA. Similar trends for LDL, nonHDL, and TC/HDL ratio. Positive trend with TRIG.
Explained variance 10-27%.
Beta (SD) log(PFOA) and log(lipids)
TC 0.01112 (0.00076)
LDL 0.01499 (0.00121)
HDL 0.00276 (0.00094)

RIVM Report 2017-0086

Reference

Frisbee et
al. (2010)

Study characteristics

Study population: highexposure community, C8
Health Project, US
Age range: 1-18 yrs
% men: 51% boys
Study design: cross-sectional
Study year(s):
2005-06
N total: 12,476

Blood PFOA levels

Serum PFOA
concentration:
Mean (SD) children:
32.6/77.7 (124.9)
ng/mL; adolescents
26.3/61.8 (98.8) ng/mL

Association
with PFOAa

TC +
LDL +
HDL 0
TRIG +
Increased TC +
Increased LDL +
Increased HDL 0
Increased TRIG 0

Effect size
Non-HDL 0.01406 (0.00104)
TC/HDL ratio 0.00831 (0.00110)
TRIG 0.00169 (0.00219)
P<0.05 for all except HDL
OR (95% CI) high TC (240 mg/dL)
Q1 ref
Q2 1.21 (1.12, 1.31)
Q3 1.33 (1.23, 1.43)
Q4 1.38 (1.28, 1.50)
Nonlinear dose-response relationships with larger
increases in lipids at the lower range of PFOA
concentration
Difference in mg/dL (p trend) between 1st and 5th
quintile PFOA
TC: children 5.8 (<0.001), adolescents 4.2
(<0.001);
LDL: children 4.9 (0.001), adolescents 3.2
(0.004);
HDL: children <1.0 (0.88), adolescents <1.0
(0.20);
TRIG: children 2.0 (0.10), adolescents 3.8 (0.10)
OR (95% CI) abnormal lipid levels (Q1=ref)
TC
Q2: 1.1 (1.0-1.3)
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Reference

Study characteristics

Blood PFOA levels

Association
with PFOAa

Effect size
Q3: 1.2 (1.0-1.4)
Q4: 1.2 (1.1-1.4)
Q5: 1.2 (1.1-1.4)
LDL
Q2: 1.2 (1.0-1.5)
Q3: 1.2 (1.0-1.4)
Q4: 1.2 (1.0-1.4)
Q5: 1.4 (1.2-1.7)
HDL
Q2: 1.0 (0.8-1.2)
Q3: 1.0 (0.8-1.2)
Q4: 1.0 (0.9-1.2)
Q5: 0.9 (0.8-1.1)

Fitz-Simon
et al.
(2013)

Study population: highexposure community, C8
Health Project.
Age range: 20-60 yrs at
baseline
% men: 46%
Study design: longitudinal
study
Study year(s): 2005-06
(baseline), 2010 (follow-up)
N total: 560

Page 114 of 120

baseline
GM 74.8 ng/mL
Min 1.0
P33 44.4
P66 118.6
Max 2,495
follow-up
GM 30.8
Min 0.25
P33 16.3

TC +
LDL +
HDL 0
TRIG 0

TRIG
Q2: 1.0 (0.7-1.5)
Q3: 1.3 (0.9-1.9)
Q4: 1.6 (1.1-2.3)
Q5: 1.0 (0.7-1.6)
Predicted % decrease (95% CI) per halving serum
PFOA
TC 1.65 (0.32, 2.97)
LDL 3.58 (1.47, 5.66)
HDL 1.33 (−0.21, 2.85)
TRIG −0.78 (−5.34, 3.58)

RIVM Report 2017-0086

Reference

Study characteristics

Blood PFOA levels

P66 54.2
Max 2,140
High-exposure community & Occupational study population
Wang J. et
Study population:
Nearby residents:
al. (2012)
occupational study population Mean 378.30 ng/ml
and nearby community
Median 284.34 ng/ml
residents, China
Minimum: 10.20 ng/ml
Age range: adults
Maximum: 2,436.91
% men: residents 57%,
Range: 2,436.71
workers 100%
Occupational workers:
Study design: cross-sectional Mean 2,157.74 ng/ml
Study year(s): 2010-11
Median 1,635.96 ng/ml
N total: 132 residents, 55
Minimum: 84.89 ng/ml
workers
Maximum: 7,737.13
ng/ml
Range: 7,652.15 ng/ml

Winquist
and
Steenland
(2014a)

Study population: highexposure community &
occupational, C8 population
Age range: >20 years
% men:
Study design: longitudinal
Study years(s): worked at
plant 1984-2002, diagnosis
2008-2011

Measured serum PFOA
concentration (2005-06):
Median: 26.1 ng/mL
IQR: 12.8-68.1 ng/mL

Association
with PFOAa

Effect size

Total Cholesterol
- residents 0
- workers 0
HDL
- residents 0
- workers LDL
- residents 0
- workers 0
HDL/LDL
- residents 0
- workers –
TRIG
- residents 0
- workers 0

Linear Multivariate Regression of Lipids on PFOA,
adjusted BMI & age (stand coeff., 95% CI, p)
Ln TC
–residents:-0.00 (-0.04 to 0.03), p=0.85
-workers: 0.02 (-0.03 to 0.07), p=0.36
Ln HDL:
-residents: 0.02 (-0.02 to 0.05). p=0.39
-workers: -0.07 (-0.12 to -0.01), p=0.01
Ln LDL:
-residents: -0.00 (-0.05-0.05), p=0.97
-workers: 0.03 (-0.04 to 0.09), p=0.43
Ln HDL/LDL:
-residents: 0.02 (-0.04 to 0.08), p=0.57
-workers: -0.09 (-0.16 to -0.02), p=0.01
Ln TRIG:
-residents: 0.02 -0.08 to 0.11)
-workers: -0.05 (-0.17 to 0.06)
Association between estimated serum PFOA
concentration quintiles and hypercholesterolemia
with medication, ref=1, HR (CI):
Q2 (0.142 to < 0.234 μg/mL per year) = 1.24
(1.15-1.33)
Q3 (0.234 to < 0.630 μg/mL per year) = 1.17
(1.09-1.26)
Q4 (0.630 to < 3.579 μg/mL per year) = 1.19
(1.11-1.27)
Q5 (>=3.579 μg/mL per year) = 1.19 (1.111.28)

Hypercholesterol
emia with
medication: +

Page 115 of 120

RIVM Report 2017-0086

Reference

Study characteristics

Association
with PFOAa

Effect size

Total serum fluorine was
used as proxy of serum
PFOA
Mean serum fluoride: 3.3
ppm
Range: 0-26 ppm

Univariate:
TC 0
LDL 0
HDL 0

Pearson correlation coefficient
TC: 0.07 (NS)
LDL: 0.02 (NS)
HDL: -0.01 (NS)

Moderate
drinkers:
TC 0
LDL 0
HDL +

Study population:
occupational population, 3M
Cottage Grove US
Age range: 24-61 yrs
% men: 100%
Study design: cross-sectional
Study year(s): 1993, 1995,
1997
N total: 111 (1993), 80
(1995), 74 (1997)

Serum PFOA, all years:
Range: 0-114,100 ng/mL
Median: 1,190 ng/mL
Mean: 59,930 ng/mL

For all three
study years:
TC 0
LDL 0
HDL 0
TRIG 0

Effect modification by alcohol intake. Adjusted
Linear multivariate regression of factors predicting
HDL (β, SE(β)), p-value
-Intercept (65.00, 10.07), p=0.001)-Total Fluorine
(-1.61, 0.77), p=0.04
-Alcohol
Low alcohol (-9.92, 3.51), p=0.006
Low alcohol * Total Fluorine (1.62, 0.80), p=0.04
Hypolipidemia not associated with serum PFOA
(not quantified)

Study population:
Occupational population, 3M

Serum PFOA:
Decatur:

Occupational study population
Gilliland
Study population: Employees
and Mandel of PFOA production plant USA
Age range: 18-60 yrs
(1996)
% men: 100%
Study design: cross-sectional
Study year(s):
N total: 115

Olsen et al.
(2000)

Olsen et al.
(2003)

Page 116 of 120

Blood PFOA levels

Serum PFOA, mean
(range) per year, ng/mL:
1993: 5,000 (0-80,000)
1995: 6,800 (0-114,100)
1997: 6,400 (0.181,300)

Cross-sectional
and longitudinal

No association was observed with hypertension
and coronary artery disease.

HDL, Beta (SE; p-value) for PFOA:
1993: -0.14 (0.33; 0.67)
1995: -0.10 (0.08; 0.18)
1997: -0.19 (0.13; 0.16)
No significant differences in any study year for TC,
LDL, HDL and TRIG between the categories
0 to < 1, mean ~ .400 ng/mL
(2) 1 to < 10, mean ~ 3000 ng/mL
(3) ≥ 10, mean ~ 30,000 ng/mL
Positive association (not quantified) primarily
attributed to 21 Antwerp employees whose serum

RIVM Report 2017-0086

Reference

Olsen and
Zobel
(2007)

Sakr et al.
(2007a)

Study characteristics

Blood PFOA levels

Antwerp and Decatur
Age range: mean 37 (male
Antwerp) and 43 (male
Decatur) yrs
% men: 81% (Antwerp), 82
(Decatur)
Study design: Cross-sectional
and longitudinal
Study year(s): 1994, 1995,
2000
N total: cross-sectional =
518, longitudinal =174
Study population:
occupational population, 3M
Cottage Grove US, Decatur
US & Antwerp.
Age range: 21-67 yrs
% men: 100%
Study design: cross-sectional
Study year: 2000
N total: 506 (all locations),
196 (Antwerp), 122 (Cottage
Grove US), 188 (Decatur US)

GM = 1130 ng/mL
Range = 40-12700
ng/mL
Mean = 1780 ng/mL
(n=263)

Study population:
occupational population,
Washington Works US (in C8

Serum PFOA:
Range: 5-9550 ng/mL
Median: 189 ng/mL

Association
with PFOAa
analyses:
TC +
HDL 0
TRIG +

Effect size

TC 0
LDL 0
HDL TRIG +

Beta (SE) for log(PFOA)

PFOA increased from 1,320 ng/ml in 1994/1995 to
2,060 in 2000, while TC increased from 208 to
229 and TRIG from 85 to 123 mg/dL

Antwerp:
GM=330 ng/mL
Range = 10-7040 ng/mL
Mean = 840 ng/mL
Serum PFOA, all
locations:
Range: 7-92,030 ng/mL
Median: 1,100 ng/mL
Mean: 2,210 ng/mL
Mean (median) PFOA
decile concentrations
ranged from
the lowest decile of 60
(60) ng/mL (range 7–
130) to the highest decile
of 12,150 (4,940) ng/mL
(range 3,710–92,030)
TC +
LDL +
VLDL +

TC: 0.0076 (0.0059) (p = 0.20)
LDL: 0.0021 (0.0090) (p = 0.81)
HDL: -0.0183 (0.0069) (p = 0.01)
TRIG: 0.0711 (0.0169) (p = 0.0001)
HDL lower (44 vs. 50 mg/dL) and TRIG higher
(172; 165; 208 vs. 145 mg/dL) in 10th and 8-10th
decile of PFOA, respectively.
OR for HDL ≤ 40 mg/dl and TRIG ≥150 mg/dl
elevated in 10th and 8-10th decile of PFOA,
respectively, but non-significant after adjustment
for location. For separate locations only
association with TRIG in Antwerp (n=5 in highest
decile).
Increase lipids (SE) (mg/dL) per increase of 1,000
ng/mL PFOA:
TC: 4.036 (1.284) (p = 0.002)

Page 117 of 120

RIVM Report 2017-0086

Reference

Sakr et al.
(2007b)

Costa et al.
(2009)

Study characteristics

Blood PFOA levels

Health Project area).
Age range: not reported.
Mean age men/women: 46.5
/ 44.4 yrs
% men: 76%
Study design: cross-sectional
Study year: 2004
N total=1,025

Mean: 428 ng/mL

Study population:
occupational population,
Washington works DuPont,
US
Age range: 22-63 yrs
% men: 74%
Study design: longitudinal
Study year(s): 1979-2004
(blood measures every 1 to 2
years)
N total = 454 (≥2
measurements)
Study population:
occupational population, Italy
Age, range: 20-63 yrs
% men: 100%

Serum PFOA, overall:
Range: +/-0 through
2,266 ng/mL
Mean: 1,130 ng/mL

TC +
LDL 0
HDL 0
TRIG 0

Serum PFOA currently
exposed:
Range: 200-47040 ng/mL
Mean: 12,930 ng/mL

TC +
HDL 0
TRIG 0

Page 118 of 120

Association
with PFOAa
HDL 0
TRIG 0

Effect size
Excluding workers taking lipid-lowering
medications: 5.519 (1.467) p = < 0.001)
LDL: 2.834 (1.062) (p = 0.008)
Excluding workers taking lipid-lowering
medications: 3.561 (1.213) (p = 0.003)
HDL: -0.178 (0.432) (p = 0.68)
Excluding workers taking lipid-lowering
medications: 0.023 (0.058) (p = 0.96)
TRIG (log transformed): 0.018 (0.021) (p = 0.38)
Excluding workers taking lipid-lowering
medications: 0.030 (0.024) (p = 0.21)
VLDL (log transformed): 0.045 (0.021) (p =
0.031)
Excluding workers taking lipid-lowering
medications: 0.055 (0.025) (p = 0.026)
Beta (95% CI): increase in mg/dL lipids) per
increase of 1000 ng/mL PFOA
TC: 1.06 (0.24, 1.88)
LDL: 0.46 (-0.87, 1.79)
HDL: 0.16 (-0.39, 0.71)
TRIG: (0.79 (-5.99, 7.57)

Analysis 1: t-test, 34 currently exposed matched
to 34 controls
Analysis 2: Linear regression, 34 currently
exposed, 107 controls

RIVM Report 2017-0086

Reference

Study characteristics

Blood PFOA levels

Study design: Cross-sectional
Study year(s): 2000-2007
N total=56

Geometric mean: 4,020
ng/mL
Median: 5,710 ng/mL

Association
with PFOAa

Study population:
occupational population, 3M
employees and contract
workers involved with
demolition of PFA
manufacturing facilities, US
Age range: mean 40 yrs
% men: 95%
Study design: Longitudinal

Serum PFOA, contract
workers:
Mean: 28.9 ng/mL
Median: 5.2 ng/mL
Mean change end-of –
project to baseline +32.1
ng/mL
Serum PFOA, 3M
employees at baseline:

Analysis 3: linear regression (GEE modelling), 56
with concurrent PFOA and lipid measure
TC, Analysis 1: Currently exposed: 237.0 mg/dl,
Controls: 206.4 mg/dl (p = 0.003)
TC Analysis 2: Beta = 21.7 (95% CI 6.83, 36.6)
(p = 0.005)
TC Analysis 3: Beta = 0.028 (95% CI 0.002,
0.055) (p < 0.05)

Serum PFOA, formerly
exposed:
Range: 530-18,660
ng/mL
Mean: 6,810 ng/mL
Geometric mean: 3,760
ng/mL
Median: 4,430 ng/mL

Olsen et al.
(2012)

Effect size

HDL, Analysis 1: Currently exposed: 56.68 mg/dl,
Controls: 57.82 mg/dl (p > 0.05)
HDL, Analysis 2: Beta = 2.42 (95% CI -2.30,
7.13) (p > 0.05)
HDL, Analysis 3: Beta = -0.018 (95% CI -0.047,
0.012) (p > 0.05)

TC 0
HDL 0
non-HDL 0
TC/HDL -

TRIG, Analysis 1: Currently exposed: 150.03
mg/dl, Controls: 155.35 mg/dl (p > 0.05)
TRIG, Analysis 2: Beta = -0. 15 (95% CI -34.6,
34.3) (p > 0.05)
TRIG, Analysis 3: Beta = 0.055 (95% CI -0.036,
0.147) (p > 0.05)
NB complete with results of analysis
Range in beta (increase cholesterol in mg/dL per
increase in PFOA of 1 ng/mL) in four subgroups of
workers:
TC -0.029 to -0.003
Non-HDL -0.033 to -0.007
HDL -0.014 to 0.009
TC/HDL -0.002 to 0.000
Page 119 of 120

RIVM Report 2017-0086

Reference

Steenland
et al.
(2015)

Study characteristics

Blood PFOA levels

Study year(s): 2008-2010
N total=179 workers (165
contract workers, 14 3M
employees)

Mean: 881 ng/mL
Median: 595 ng/mL
Mean change end-of –
project to baseline -218.3
ng/mL
Serum PFOA, range
overall: 0.1-10,000
ng/mL
Serum PFOA, measured
in 2005-06 (n=1,881):
Range: not reported
Median: 113 ng/mL
Mean: 325 ng/mL
Historical serum levels
modelled using JEM,
residential exposure
model and PK model.
Mean cumulative
occupational exposure
8.6 ppm-years

Study population:
occupational population,
DuPont West Virginia
(Washington works)
Age range: mean year of
birth 1951
% men: 80%
Study design: longitudinal
Study year(s): 2005-06
(PFOA measures), 2008 &
2011 (interviews)
N total = 3,713 (cohort of
workers), 1,298 cases
a

Association
with PFOAa

Effect size

Self-reported
high cholesterol
with medication 0

Association between quartiles of estimated
cumulative serum PFOA and self-reported high
cholesterol, with medication, no lag, ref=Q1, OR
(CI):
Q2 (3,030-6,160 µg/mL-yrs): 1.11 (0.94 to 1.30)
Q3 (6,160-11,420 µg/mL-yrs): 1.06 (0.89 to
1.27)
Q4 (>11,420 µg/mL-yrs): 1.05 (0.87 to 1.27)
Association between quartiles of estimated
cumulative serum PFOA and self-reported high
cholesterol, with medication, 10-year lag, ref=Q1,
OR (CI):
Q2 (800-3,440 ng/mL-yrs): 0.93 (0.79 to 1.10)
Q3 (3,440-7,040 ng/mL-yrs): 1.01 (0.84 to 1.22)
Q4 (>7,040 ng/mL-yrs): 0.96 (0.78 to 1.18)

0, no association; +, positive association; -, negative association.
β=regression coefficient, OR=Odds Ratio, HR= Hazard Ratio, CI= 95% Confidence Interval, lnPFOA = natural log transformed PFOA,
Q=quartile, IQR=Interquartile range, TC=total cholesterol, HDL=high-density lipid, non-HDL=LDL+VLDL, LDL=low-density lipid
cholesterol, TC=triglyceride, VLDL=very low-density lipid cholesterol.

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