Article
pubs.acs.org/est
Human Exposure and Elimination Kinetics of Chlorinated
Polyfluoroalkyl Ether Sulfonic Acids (Cl-PFESAs)
Yali Shi,† Robin Vestergren,‡ Lin Xu,† Zhen Zhou,§ Chuangxiu Li,† Yong Liang,§,⊥ and Yaqi Cai*,†,⊥
†
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Science, Chinese
Academy of Sciences, Beijing 100085, China
‡
Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, Stockholm SE 10691, Sweden
§
Key Laboratory of Optoelectronic Chemical Materials and Devices, Ministry of Education, School of Chemical and Environmental
Engineering, Jianghan University, Wuhan 430056, China
⊥
Institute of Environment and Health, Jianghan University, Wuhan 430056, China
S Supporting Information
*
ABSTRACT: The incomplete mass-balance of organic fluorine in human serum indicates the existence of unknown per- and
polyfluoroalkyl substances (PFASs) with persistent and bioaccumulative properties. Here we characterized human exposure and
elimination kinetics of chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs) in metal plating workers (n = 19), high fish
consumers (n = 45), and background controls (n = 8). Cl-PFESAs were detected in >98% of the sampled individuals with serum
concentrations ranging <0.019−5040 ng/mL. Statistically higher median serum levels were observed in high fish consumers (93.7
ng/mL) and metal plating workers (51.5 ng/mL) compared to the background control group (4.78 ng/mL) (Kruskal−Wallis
rank sum test, p < 0.01). Cl-PFESAs could account for 0.269 to 93.3% of ∑PFASs in human serum indicating that this
compound class may explain a substantial fraction of previously unidentified organic fluorine in the Chinese population.
Estimated half-lives for renal clearance (median 280 years; range 7.1−4230 years) and total elimination (median 15.3 years;
range 10.1−56.4 years) for the eight carbon Cl-PFESA suggest that this is the most biopersistent PFAS in humans reported to
date. The apparent ubiquitous distribution and slow elimination kinetics in humans underscore the need for more research and
regulatory actions on Cl-PFESAs and PFAS alternatives with similar chemical structures.
■
Furthermore, associations with immune system disorders,11,12
endocrine disruption,13,14 reduced fetal growth15 and gestational diabetes16 have been suggested in the populations with a
low-level background exposure to PFASs.
While significant efforts are being devoted to understand the
possible health effects from exposure to PFOA and PFOS, there
is also a growing concern that current exposure assessments do
not capture the range of PFAS to which humans are exposed.
These concerns are supported by the findings that compoundspecific analysis of known PFASs can only explain 30−85% of
INTRODUCTION
Per- and polyfluoroalkyl substances have been ubiquitously
detected in human samples from all over the world and
perfluoroctanoic acid (PFOA) and perfluorooctanesulfonic acid
(PFOS) are two of the most predominant xenobiotic
compounds present in human blood today.1,2 Given this
widespread contamination, concerns have been raised about
adverse human health effects related to their toxicity.3,4
Epidemiological studies have shown that exposure to PFASs
(primarily PFOA and/or PFOS) may be associated with
biochemical or physiological alterations in human populations.5
Some of the most robust findings include probable links to
kidney and testicular cancers,6 pregnancy-induced hypertension,7 thyroid disease,8 ulcerative colitis,9 and high
cholesterol10 in populations with elevated exposure to PFOA.
© 2016 American Chemical Society
Received:
Revised:
Accepted:
Published:
2396
November 27, 2015
January 21, 2016
January 28, 2016
February 11, 2016
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
Table 1. Acronyms and Corresponding Chemical Structures of Cl-PFESAs Present in F-53B Technical Mixtures
the extractable organic fluorine in human serum samples from
China, Japan, and the U.S.17,18 Since the first detection of
PFOS and PFOA in human serum samples,19 numerous
subclasses of PFASs, including perfluorooctane sulfonamides
(FOSAs), perfluorooctane sulfonamidoacetates (FOSAAs),
polyfluoroalkyl phosphate diesters (diPAPs), perfluorooctanesulfonamidoethanol-based polyfluoroalkyl phosphate diesters
(Sam-PAPs), fluorotelomer sulfonates (FTSs), perfluorophosphonates (PFPAs), and perfluorophosphinates (PFPiAs),
have been added to the list of analytes that can regularly be
measured in human samples.20−22 Despite these discoveries,
the sum of novel PFASs typically makes a very small (<1%)
contribution to the sum of known PFASs which is dominated
by perfluoroalkane sulfonic (PFSAs) and perfluoroalkyl
carboxylic acids (PFCAs).21,22
The identification of PFASs that can accumulate in humans
represents a prerequisite for effective exposure mitigation and
innovative screening approaches have recently been reported.
Strategies to identify novel PFASs primarily involve advanced
analytical techniques employing high resolution mass-spectrometry with sophisticated deconvolution algorithms.23−25
However, studies of the patent literature and estimated
production volumes combined with physicochemical property
estimations have also been instructive for identifying PFASs
that are likely to cause significant exposure to wild-life and
humans.26,27 One group of PFASs that have been identified as
potentially problematic PFASs using both of these approaches
is the chlorinated polyfluoroether sulfonic acids (Cl-PFESAs).23,26,28 Despite that these substances have been used in
metal plating industry, under the trade name F-53B, for more
than 30 years, the occurrence of Cl-PFESAs in the abiotic
environment was only recently discovered.28,29 In a proceeding
paper, we provided the first evidence for efficient uptake and
accumulation of F-53B in crucian carp under natural
conditions.30 Combined with widespread contamination of
surface water,28 sewage sludge29 and fish samples30 from China
we postulated that Cl-PFESAs could make a significant
contribution to the body burden of PFASs in humans.
In this study, we present the first measurements of ClPFESAs in human samples from China with the specific
objectives to (i) determine the range of concentrations in
human serum under different exposure conditions, (ii) identify
important pathways of human exposure, (iii) evaluate the
contribution of Cl-PFESAs to body burden of known organic
fluorine, and (iv) estimate the elimination kinetics of ClPFESAs in humans.
■
METHODS
Nomenclature for Cl-PFESAs. According to the comprehensive terminology and classification system by Buck et al.,31
PFESAs and perfluoroalkyl ether carboxylic acids (PFECAs)
belong to the subclass of PFASs called functionalized
perfluoropolyethers (PFPEs). However, there is no commonly
accepted nomenclature for how to name specific chemical
structures within this diverse group of substances which can
have numerous possible sequences of carbon and oxygen
atoms. A previous paper by Ruan et al.29 used an X:Y
terminology to indicate the position of the ether bond of ClPFESAs. However, since this designation has often been used
for the number of fluorinated carbons (X) and hydrocarbons
(Y) of telomer-based substances,31 it may be misrepresentative
to use the same system for PFECAs and PFESAs which, unlike
many telomer-based PFASs, are believed to be highly persistent
in the environment.27,28 Herein we adopted a simplified
acronym system to describe the Cl-PFESA homologues present
in F-53B commercial mixtures based on the number of carbon
atoms of the alkyl chain. Table 1 displays the chemical
structures and the acronyms for the three Cl-PFESAs discussed
in this paper.
Human Subjects. The human subjects in this study were
selected to reflect two exposure scenarios with a hypothesized
elevated exposure to Cl-PFESAs, namely (i) metal plating
workers and (ii) high consumers of fresh water fish. One
control group with a perceived background exposure to ClPFESAs was included as a reference. In total, 72 paired blood
and morning urine samples were collected from healthy
volunteers that had signed informed consent for participation
and the sampling was approved by the ethical commission of
the Research Center for Eco-Environmental Science, Chinese
Academy of Sciences. The samples from metal plating workers
(n = 19) were collected from employees of a medium size metal
plating facility in Yantai City, Shandong province with
approximately 200 employees. All study subjects were fulltime employed process workers that spend a significant part of
2397
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
solution was concentrated to approximately 1 mL under
nitrogen. The concentrated extracts were subsequently diluted
using 50 mL ultrapure water and loaded onto a single-use Oasis
WAX cartridge (6 cc/150 mg), which was preconditioned using
4 mL 0.1% ammonium hydroxide (in methanol), 4 mL
methanol and 4 mL ultrapure water at a rate of 1 drop/s, for
cleanup. The cartridges were washed using 4 mL buffer solution
(25 mmol/L acetic acid/ammonium acetate, pH = 4), 8 mL
ultrapure water and centrifuged for 10 min at 3000 rpm to
remove the residual water. Finally, the target analytes were
eluted using 4 mL methanol and 4 mL 0.1% ammonium
hydroxide (in methanol), which was concentrated to 1 mL
under nitrogen.
Urine samples (10 mL) were spiked with 2 ng of internal
standards followed by adding 10 mL of 1% formic acid in water,
and were then subsequently vortexed for 2 min and sonicated
for 30 min. The samples were then loaded onto an Oasis WAX
SPE cartridge following the above-mentioned process. For
additional details regarding extraction and cleanup, we refer to
our previous publication.32,34
Instrumental Analysis. PFESAs, PFSAs and PFCAs in
extracts (5 μL injection volume) were quantified using high
performance liquid chromatography (HPLC, Ultimate 3000,
Thermo Fisher Scientific Co.) coupled with electrospray
ionization tandem mass spectrometry (ESI-MS/MS, API
4500, Applied Biosystems/MDS SCIEX, U.S.A.). The HPLC
instrument was equipped with a dual pump (HPG-3200RS),
autosampler (WPS-3000RS), column compartment (TCC3000RS) and DCMS Link software. Separation of the analytes
was achieved by an ACQUITY HSS PFP Column (1.8 μm, 100
Å, 5 cm × 2.1 mm, Waters Co.). The experimental conditions
for HPLC and ESI-MS/MS are described in the SI.
Quantification was performed using an 8-point standard
calibration curve (0.05, 0.1, 0.5, 1.0, 5, 10, 20, and 50 μg/L),
spiked with 2 ng of mass-labeled PFSAs and PFCAs, using a 1/
x2 weighted regression (r2 > 0.99) for Cl-PFESAs and PFOS.
The matrix-specific limits of quantification (MLQ) were
determined at the lowest concentration resulting in a signalto-noise ratio (S/N) ≥ 10 (Details shown in Table S2).
Quality Assurance. All sampling equipment, laboratory
consumables, and solvents were checked for contamination and
one procedural blank sample was conducted for every ten
samples. However, all procedural, field, and solvent injection
blanks were consistently below instrumental detection limits.
Instrumental drift was monitored by injecting a calibration
standard for every 10 sample injections and a new calibration
curve was constructed if a deviation of more than ±20% from
its initial value was observed. Spike-recovery tests using 5 ng of
PFOS and Cl-PFESAs were used to determine accuracy and
precision for fish muscle (n = 4), human blood (n = 4), and
urine (n = 4). The seven most highly contaminated samples
were diluted using methanol and reanalyzed in order to ensure
that all quantified concentrations were within the dynamic
range.
Estimation of Renal Clearance. The renal clearance rate
(CLrenal, mL/kg/day) is defined as the volume of serum from
which a chemical is removed under a given amount of time. In
line with Zhang et al.,35 we used the following equation to
calculate CLrenal from paired urine and serum samples:
their work day around the chrome plating vats where
fluorinated surfactants, including F-53B, are used as mist
suppressants. High consumers (n = 45) of fresh water fish were
selected from a cohort of fishery employees and their families in
Hubei province which have previously been studied with
respect to their exposure to PFSAs and PFCAs.32 Given their
employment at the fishery, the diet of these individuals relied
heavily on fish from Tangxun Lake consumed at the fishery
cantina or prepared in their homes. The average self-reported
consumption of fish was 93 g/day which is approximately three
times the national average for fish and seafood consumption in
China.33 The sample set from Hubei province also included a
control group of eight individuals living in the city of Wuhan
but far away from Tangxun Lake. The participants of this group
had a low to medium intake of fish and seafood and reported to
never have eaten fish from Tangxun Lake.
In addition to the human specimens, 46 fish muscle samples
were collected from Tangxun Lake. The main species prepared
in the fishery cantina were sampled in order to be
representative of the typical fish consumption of fishery
employees and their families [yellow catfish (n = 8), common
carp (n = 8), white amur bream (n = 8), grass carp (n = 8),
silver Carp (n = 6), and bighead carp (n = 8)].
Sample Collection. Urine samples were collected in 50 mL
polypropylene (PP) bottles. Whole blood samples were
obtained in a BD Vacutainer tube (Becton Dickinson
Vacutainer System, UK) with EDTA. Fish muscle samples
were stored in aluminum foil during transport to the laboratory
where they were homogenized and freeze-dried. All samples
were stored at −20 °C until analysis.
Chemicals and Standards. The standards for native and
mass-labeled PFASs (PFAC-MXA, MPFAC-MXA) were
purchased from Wellington laboratories (Guelph, ON,
Canada), while C8, C10, and C12 Cl-PFESA were purified
from a technical F-53B product purchased from Shanghai
Synica Co., Ltd. (Shanghai, China), which contained 91%, 7%,
and 0.3% C8, C10, and C12 Cl-PFESA. The purification was
performed using an autopurification HPLC/MS system,
including GILSON 215 (Gilson) and Shimadzu LCMS
2010A (Shimadzu, Kyoto, Japan) with separation on an Agela
Durashell C18 (250*20 mm, 5 μm) column. The structure and
purity of the Cl-PFESA standards were further validated by
nuclear magnetic resonance spectrometer (19F-NMR, Bruker
AVANCE III 400 Hz) and a high performance liquid
chromatography coupled with an evaporative light-scattering
and a single-quadruple MS detector (Agilent LCMS 1100−
1956A, U.S.A.). Further details regarding the HPLC conditions
and confirmation of the purified products are provided in the
Supporting Information (SI). Additional information regarding
solvents and chemical reagents is also provided in the SI.
Sample Treatment. The human serum, urine, and fish
muscle samples from high fish consumers and background
controls were analyzed as extracts from our previous study on
this cohort.32 All extracts, which had been carefully sealed and
stored at −20 °C, were sonicated and vortexed prior to the
removal of aliquots for reanalysis. Whole blood and urine
samples from metal plating workers were pretreated according
to our previous report.32 Briefly, 0.5 mL of whole blood was
spiked with 2 ng of internal standard (13C4 PFOS) and
extracted with 5 mL acetonitrile (ACN). The supernatant was
transferred into a new PP tube after shaking for 20 min at 250
rpm and centrifuged for 10 min at 4000 rpm. The sample
residues were extracted two more times and the 15 mL extract
CLrenal =
2398
Curine × Vurine
Cserum × m w
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
where Curine is the concentration in urine (ng/mL), Cserum is the
concentration in serum (ng/mL), Vurine is the daily urine
excretion volume (mL/day), and mw is the body weight (kg).
Individual measurements in serum and urine together with
recorded body weights from questionnaires were used to
calculate individual renal clearance rates for C8 Cl-PFESA and
PFOS. The urine excretion volume was estimated to 1200 mL/
day for females and 1400 mL/day for males.36 In order to
express the renal clearance rates in terms of renal elimination
half-lives (t1/2, renal, days), the following equation was used.35
t1/2,renal =
was judged as a reasonable assumption given the similarities in
uptake and tissue distribution of these compounds in crucian
carp.30
C8 and C10 Cl-PFESAs were detected in 100% and 98% of
the samples respectively while the C12 homologue was
consistently below the MLQ (0.045 ng/mL). Concentrations
of C8 and C10 Cl-PFESAs in serum for the control group, high
fish consumers and metal plating workers are presented in
Figure 1 and summary statistics are provided in Table S4.
0.693 × Vd
CLrenal
where Vd is the apparent volume of distribution (L/kg). Given
the lack of mammalian toxicokinetic data for Cl-PFESAs, it was
assumed that PFOS and C8 Cl-PFESA have the same Vd (230
mL/kg)37 based on their similar blood/tissue distribution ratios
in crucian carp.30
Exposure Mass-Balance and Calculation of Total
Elimination Half-Lives. In order to estimate total elimination
half-lives by all routes of excretion, a one-compartment model
was used to establish a mass-balance of C8 Cl-PFESA and
PFOS in high fish consumers. Assuming that the concentrations in serum had reached a steady-state situation (i.e., nochange with time) in fishery employees with >6 years of
employment the total elimination half-life (days) was calculated
according to the following equation:
t1/2, tot =
Cserum × 0.693 × Vd
I
Figure 1. Box-whisker plot of the Cl-PFESA serum concentrations in
background control (BC), high fish consumers (FC) and metal plating
workers (MW). The horizontal line in the box represents the median
value and the low and upper edge of the box mark the 25th and 75th
percentiles. The whiskers extending from the box represent the
maximum and minimum values excluding outliers.
where I (ng/kg/day) is the body weight normalized intake rate
of chemical. The dietary intake was calculated as a weighted
arithmetic mean concentration of the five sampled fish species
which was multiplied with the average fish consumption (93 g/
day) and divided by the average body weight determined from
questionnaires (see Table S3). The range of measured serum
concentrations was used to estimate inter-individual variability
in elimination half-lives.
Statistical Evaluation. Statistical analyses were executed
using the IBM PASW statistics 18.0 software (SPSS Inc., 1993−
2007) with a statistical significance threshold of p < 0.05.
Summary statistics were calculated for analytes with detection
frequencies >50% in serum/whole blood, urine, and fish
samples. Concentrations below MLQ were assigned to be
MLQ/2 in the statistical analysis. Spearman’s rho values were
calculated for correlations. Mann−Whitney U-test and
Kruskal−Wallis rank sum test was used to test differences in
concentrations and ratios between different exposure groups.
Statistically significantly higher median concentrations of C8
and C10 Cl-PFESAs were observed in high fish consumers
(93.7 and 1.60 ng/mL) and metal plating workers (51.5 and
1.60 ng/mL) compared to the background control group (4.78
and 0.08 ng/mL) (Kruskal−Wallis rank sum test, p < 0.01),
whereas no statistically significant difference was observed
between metal plating workers and high fish consumers
(Kruskal−Wallis rank sum test, p > 0.402). C8 Cl-PFESA
was detected in 74% of all urine samples ranging from 0.003 to
2.86 ng/mL. Contrastingly, C10 Cl-PFESA was only detected
in two of the most highly exposed metal plating workers at
0.002 and 0.038 ng/mL, respectively. The concentrations of C8
Cl-PFESA and PFOS in urine and serum from the same
individuals were strongly correlated (Spearman’s rho >0.827, p
< 0.01, Table S5), suggesting that measurements in urine
provide a good measure of the body burden of these two
substances. C8 and C10 Cl-PFESAs were present in all fish
muscle samples (Table S6) from Tangxun Lake whereas the
C12 homologue was consistently below MLQ (0.065 ng/g
ww). Median concentrations of C8 and C10 Cl-PFESAs ranged
0.770 to 2.17 ng/g and 0.052 to 0.099 ng/g, respectively, in the
different fish species.
Characterization of Exposure Pathways for Cl-PFESAs.
The high detection frequency of C8 and C10 Cl-PFESAs at
similar levels in background exposed individuals indicates that
this class of contaminants may be ubiquitously present in the
Chinese population. Although little is known about the
■
RESULTS AND DISCUSSION
Concentrations of Cl-PFESAs in Human Specimens
and Fish Samples. The matrix spike-recoveries for whole
blood, muscle, and urine were in the range 80.3−92.8%, 78.5−
104%, and 73.1−118% (see also Table S2). Reanalysis of linear
PFOS in the sample extracts provided excellent agreement (r2 >
0.984) with previously reported values,32 demonstrating that
storage did not have an effect on the quantified concentrations
(Figure S7). For the 19 metal plating workers, concentrations
in whole blood were transformed to serum equivalents using
the correction factor of 0.5 that has previously been estimated
for PFOS.38 Although the distribution between whole blood
and serum has not been specifically studied for Cl-PFESAs, this
2399
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
reflects a less efficient respiratory or gastrointestinal uptake of
the C10 homologue. Alternative explanations could also be (i)
a faster elimination of C10 compared to C8 Cl-PFESA or (ii) a
different distribution between serum and other body compartments. The relative importance of these explanations related to
the biological handling of C8 and C10 Cl-PFESA is further
discussed in the section on elimination kinetics.
Although a significantly elevated exposure was observed for
high fish consumers and metal plating workers compared to the
background control group, a large interindividual variability in
Cl-PFESA concentrations (ranging 2−3 orders of magnitude)
was also observed within the high exposure groups. For metal
plating workers, statistically significantly lower median values
were observed in individuals with <1 years of employment
(18.6 ng/mL) compared to those with >1 year of employment
(1347 ng/mL) (Figure S8 and Table S8). For chemicals with
relatively long elimination half-lives, serum concentrations are
expected to increase as a function of exposure duration until a
steady-state is reached after an extended period of constant
exposure.32,44 The higher serum concentrations in metal plating
workers with >1 years of exposure may, therefore, reflect a slow
elimination rate in humans.32,44 However, additional factors
related to the magnitude of occupational exposure (e.g.,
different work tasks, use of personal protection equipment)
or individual variability in elimination rates may also be
important to explain the individual variation in serum
concentrations. The high fish consumer group was divided
into five different subgroups, namely family members, > 0−1
years, > 1−3 years, > 3−6 years, and >6 years of employment at
the fishery. Although the lowest concentrations of both C8 and
C10 Cl-PFESAs were observed in the group with >0−1 years of
employment, there were no statistically significant differences in
median values of the different employment groups (Figure S8
and Table S8). The lack of a clear trend between Cl-PFESAs in
serum and length of employment at the fishery may be
explained by the fact that many individuals in this group
reported a high fish consumption prior to starting their job at
the fishery. Since the fish from Tangxun Lake was found to
contain similar or lower concentrations of Cl-PFESAs
compared to other parts of China,30 it is possible the majority
of fishery employees have had a similar dietary exposure for a
long time. Thus, the lack of a clear trend with duration of
exposure indicates that the serum concentrations in fishery
employees with >1 years of employment may be close to a
steady-state.
Contribution of Cl-PFESAs to the Sum of Known
PFASs. In addition to Cl-PFESAs, a wide range of PFSAs and
PFCAs were detected in serum and whole blood samples
(Table S4). As reported previously by Zhou et al., highly
elevated concentrations of PFOS (median 7840 ng/g) were
observed in fish consumers from Tangxun Lake compared to
the control group (median 17.4 ng/g).32 Elevated, but highly
variable concentrations of PFOS (median 40.0 ng/mL; range
2.40−1323 ng/mL) were also observed in metal plating
workers which probably reflects the parallel use of both F53B and perfluorooctane sulfonyl fluoride (POSF)-based
commercial products. In Figure 2, the median composition
profiles of identified organic fluorine attributed to ∑ClPFESAs, ∑PFSAs, and ∑PFCAs are presented for background
controls, high fish consumers and metal plating workers,
respectively. The highest contribution of Cl-PFESAs was
observed in metal plating workers (41.3%) followed by the
background control group (13.9%) and lowest contribution was
occurrence of Cl-PFESAs, the exposure of the background
population is probably occurring through several exposure
pathways (e.g., dietary intake, drinking water and dust
ingestion). At the same time, the 20-fold higher median
concentration of C8 Cl-PFESA in high fish consumers
compared to background controls demonstrates that fresh
water fish may be a particularly important vector of human
exposure. This is a sensible finding given that fish consumption
has been identified as a main predictor of human exposure to
long-chain PFSAs and PFCAs,39 which have a comparable
bioaccumulation potential in aquatic food webs with C8 ClPFESA.30 For metal plating workers, the elevated serum
concentrations were probably due to inhalation of airborne ClPFESAs. Since the chrome metal plating solutions containing
F-53B typically have a pH close to zero, volatilization of the
protonated species and subsequent inhalation is likely a major
occupational exposure pathway.40 However, additional exposure pathways including ingestion of dust particles, hand-tomouth contact or dermal uptake could also contribute to the
total exposure of Cl-PFESAs in the workplace environment.41
When comparing the exposure in high fish consumers and
metal plating workers with the background control group it
should be noted that serum concentrations were not adjusted
for demographic factors such as age/birth cohort and gender
which are known to be important predictors of human serum
concentrations for other PFASs.42,43 More comprehensive
biomonitoring studies from different regions of China are,
therefore, needed to better understand the human exposure to
PFESAs.
When investigating the relationship between Cl-PFESA
homologues in serum, strong correlations between C8 and
C10 Cl-PFESAs were observed in high fish consumers (p <
0.01; Spearman’s rho =0.795) and metal plating workers (p <
0.01; Spearman’s rho =0.911), whereas no significant
correlation was observed in the background control group (p
= 0.736; Spearman’s rho =0.143). There were also strong
correlations observed between Cl-PFESA and PFOS serum
concentrations in the above three population groups (p ≤ 0.01;
Spearman’s rho =0.602−0.823, Table S7). The strong
correlations between Cl-PFESA homologues and PFOS can
be interpreted as an indication that these substances have
similar sources of exposure in the respective exposure groups
and similar toxicokinetic properties. However, it should be
pointed out that ratios of Cl-PFESAs varied between the
exposure groups. A significantly higher median C8/C10 ratio
was observed in high fish consumers (53.3) compared to metal
plating workers (36.6) (Mann−Whitney U-test, p < 0.01). The
difference in C8/C10 ratios between metal plating workers and
high fish consumers likely reflects the difference between nearfield and far-field exposure pathways for these two groups.
While metal plating workers are exposed directly to the
commercial F-53B mixture, the higher C8/C10 Cl-PFESA ratio
in high fish consumers compared to metal plating workers may
be due to preferential accumulation of C8 Cl-PFESA in aquatic
food chains and subsequently a different homologue pattern in
the primary exposure media. Intriguingly, the C8/C10 ratio in
serum of metal plating workers was substantially higher than in
commercial F-53B products (12.9 ± 2.6).29 Since no samples of
workplace exposure media (e.g., air and dust) were analyzed in
this study, it is difficult to fully explain this observation.
However, assuming that the external exposure to Cl-PFESAs
reflects the homologue pattern of the commercial mixture it
seems plausible that the comparatively high C8/C10 ratio
2400
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
human samples from different parts of China are needed to
properly test this hypothesis.
Elimination Kinetics of Cl-PFESAs. Since previous studies
in animal models47,48 and human populations35,49 have shown
that the clearance of PFASs may be sex-dependent, we
calculated summary statistics for males and females separately
(Table S9). However, due to the limited number of females in
this study (n = 14), which also displayed a low detection
frequency of Cl-PFESAs in urine, we could not detect any
statistically significant differences between sexes. Hence, we
hereafter discuss the elimination kinetics for Cl-PFESAs
without differentiating between males and females. The median
renal clearance rate of C8 Cl-PFESA (0.0016 mL/kg/day) was
approximately five times lower than that of PFOS (0.0074 mL/
kg/day) (Mann−Whitney U test, P < 0.001). A low detection
frequency of C10 Cl-PFESA in urine samples precluded
accurate determination of the renal clearance rates. However,
the average of paired serum and urine samples from the two
most highly exposed metal plating workers (0.0006 mL/kg/
day) indicates a similar or slower excretion rate compared to
C8 Cl-PFESA. The apparent trend of decreasing renal clearance
rates in the order PFOS > C8 Cl-PFESA ≥ C10 Cl-PFESA is in
line with observations for other PFASs, for which a higher
hydrophobicity generally leads to a slower renal elimination.32,35,50 Thus, it seems unlikely that the unexpectedly high
C8/C10 Cl-PFESA ratios in serum, as discussed above, could
be explained by differences in elimination kinetics.
In order to estimate total elimination half-lives, we took
advantage of the fact that (i) the intake rate of C8 Cl-PFESA
could be determined for high fish consumers from measurements in fish muscle samples and average fish consumption
rates (Table S3) and (ii) serum concentrations of fishery
employees with >6 years of employment appeared to have
reached steady-state. In Table 2, the total and renal elimination
half-lives of C8 Cl-PFESA and PFOS from this study are
presented together with previously reported values for PFOS.
Median total elimination half-lives of C8 Cl-PFESA and PFOS
were 15.3 and 6.7 years, respectively. The substantially longer
renal and total-elimination half-life of C8 Cl-PFESA compared
to PFOS suggests that this compound is the most biopersistent
PFAS in humans reported to date.32,35,41,51 At the same time,
the 20-fold difference between renal excretion and total
elimination half-lives indicates that other routes of clearance
than urine are important for C8 Cl-PFESA. A similar, but less
pronounced, discrepancy between renal and total elimination
half-lives has also been observed for PFOS in previous studies
(Table 2). Given the high persistence of PFESAs27,28 it seems
unlikely, but not impossible, that metabolism contributes to the
Figure 2. Contribution of ∑Cl-PFESAs, ∑PFSAs and ∑PFCAs to
the total identified organic fluorine content (ng F/mL) in human
serum samples from the background control group (BC), high fish
consumers (FC), and metal plating workers (MW). The stacked bar
chart represent median values.
observed in high fish consumers (0.923%). The relatively low
contribution of Cl-PFESAs in high fish consumers was
primarily a consequence of the high PFOS concentrations,
which represented >74.9% of the ∑PFASs in these samples.
The exposure to Cl-PFESAs relative to other known PFASs via
fish consumption may, however, vary greatly between different
regions of China.26,28,29,45 In our previous study, we observed
comparable concentrations of C8 Cl-PFESA in fish samples
from Tangxun Lake, Xiaoqing River and a Beijing fish market
whereas the concentrations of PFOS varied substantially.30
Higher concentrations of Cl-PFESAs may generally be expected
in the central eastern provinces of China with heavy metal
plating industry28,29 compared to western and northeastern
China, where there are few known point sources of ClPFESAs.26,30,46 Given this anticipated geographical variability in
environmental concentrations of PFASs it may also be expected
that high fish consumers in some provinces of China have a
significantly higher proportion of Cl-PFESAs in their serum.
Transforming the serum concentrations of Cl-PFESAs to
organic fluorine equivalents resulted in median values of 2.78
and 54.9 ng F/mL for the background control group and high
fish consumers, respectively. These values are comparable to or
higher than the range of arithmetic mean values of unidentified
organic fluorine 2−18.5 ng F/mL in human serum samples
from five different cities in China by Yeung et al.18 Assuming
that Cl-PFESAs are present at a similar concentration range in
highly industrialized coastal provinces of China (as discussed
above) inclusion of this emerging class of PFASs could help to
close the mass-balance of the organic fluorine in human serum.
However, additional biomonitoring studies combining compound-specific analysis with total organic fluorine analysis of
Table 2. Estimated Biological Half-Lives via All Routes of Excretion (Total Elimination) and Renal Clearance for C8 Cl-PFESA
and PFOS in Years
C8 Cl-PFESA
total elimination
renal clearance
mean
median
min
18.5
15.3
10.1
445
280
7.1
PFOS
max
56.4
4230
mean
median
min
7.7
5.4
6.7
4.6
5.5
4.9
81.9
6.6
25
44
3.0
2.4
46.7
6.7
34
22
4.5
3.1
1.5
6
2401
max
19.1
21.7
696
11
182
2183
study population
reference
predominantly male (58 males/14 females)
predominantly male (24 males/2 females)
male
female
predominantly male (58 males/14 females)
young females (<50 years)
males and older females (>50 years)
predominantly male
this study
ref 51
ref 53
ref 53
this study
ref 35
ref 35
ref 41
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
cumulative risk assessment based on read-across extrapolations58 may be a valid and useful approach for Cl-PFESAs.
discrepancy between renal clearance and total elimination halflives. A more probable explanation is that the diminished renal
excretion, due to higher hydrophobicity27,29 and proteinophilicity, makes biliary excretion relatively more important. This
explanation finds some support in observations of a greater
biliary excretion of long-chain PFCAs in rodents.50,52 However,
more research combining in vitro sorption experiments, in vivo
animal dosing, and observational studies in humans is needed
to understand the toxicokinetics of novel PFASs.
The estimated elimination kinetics presented in Table 2
demonstrates that C8 Cl-PFESA has a very long half-life in
humans and that renal excretion cannot explain the total
clearance. Nevertheless, it should be noted that the accuracy of
elimination half-lives is limited by the underlying assumptions
of the one-compartment model. First, the steady-state
assumption may be an oversimplification of the real exposure
situation despite that prolonged exposure did not result in
significantly higher serum concentrations for the high fish
consumers. Second, the estimated total elimination half-lives
rely on estimates of the daily intake via fish consumption and
the uncertainty in the self-reported fish consumption rates will
be propagated to half-life calculations. Third, the assumption
that C8 Cl-PFESAs has the same volume of distribution as
PFOS is based on the blood/tissue distribution ratios in fish in
the absence of mammalian data.30 Despite these uncertainties,
the general agreement in total elimination half-life values for
PFOS (AM 7.7; range 3.0−19.1 years) with those reported by
Olsen et al.51 (AM 5.4; range 2.4−21.0 years) provides some
confidence to the approach.
Implications for Human Exposure and Health Risk
Assessment of PFAS Alternatives. This is the first study, to
our knowledge, of an emerging class of PFASs present in
human samples at similar concentrations as PFOA and PFOS.
So far, the main explanation for the unidentified fraction of
organic fluorine in humans has emphasized the importance of
unknown commercial fluorosurfactants used in textile- or paper
treatment and their reaction intermediates.18,54,55 One of the
underlying reasons for the strong research focus on these
substances is that they were the major commercial product
branches for the POSF- and telomer-based chemistry in Europe
and North America with production volumes of several
thousand tons per year.26 The apparent ubiquitous distribution
of Cl-PFESAs in China, however, illustrates that persistent and
bioaccumulative PFASs with significantly lower production
volumes (estimated to ∼30 tons/year for F-53B) can also cause
significant human exposure on a regional scale. Given that
chemicals with lower production volumes often require a less
rigorous hazard- and risk assessment,56 the findings of ClPFESAs in humans may serve as an important example in the
context of chemical regulation of PFAS alternatives.
The presence of Cl-PFESAs in human serum also raises
questions about the potential health risks related to this
exposure. Since the only toxicity study on Cl-PFESAs so far is
an acute dose study in Zebra fish, a traditional human health
risk assessment of this compound is not possible. Nevertheless,
the similarities between PFOS and C8 Cl-PFESA with respect
to (i) LC50 values in Zebra fish28 (ii) tissue distribution in
crucian carp30 and (iii) slow elimination kinetics in humans
(this study) certainly indicate that the biological handling of
these compounds shares some common characteristics. Studies
on the toxicity of PFECAs further support that inclusion of
ether bonds in the perfluoroalkyl chain does not seem to have
an effect on the toxicological mode-of-action.57 Thus,
■
ASSOCIATED CONTENT
S Supporting Information
*
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.est.5b05849.
Additional information regarding solvents and chemical
reagents, the HPLC conditions and confirmation of the
Cl-PFESA standard, detail experimental conditions for
HPLC and ESI-MS/MS and other materials are shown in
Tables S1−S9 and Figures S1−S8 (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*Tel: +86 (10) 62849239; fax: +86 (10) 62849182; e-mail:
[email protected] (Y.C.).
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
This work was jointly supported by the National Natural
Science Foundation of China (No. 21537004, 21377145,
21321004), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB14010201), the National
Key Basic Research Program of China (2015CB931903), and
the Swedish Research council FORMAS (No. 2014-514).
■
REFERENCES
(1) Kannan, K.; Corsolini, S.; Falandysz, J.; Fillmann, G.; Kumar, K.
S.; Loganathan, B. G.; Mohd, M. A.; Olivero, J.; Wouwe, N. V.; Yang, J.
H.; Aldous, K. M. Perfluorooctanesulfonate and related fluorochemicals in human blood from several countries. Environ. Sci. Technol.
2004, 38 (17), 4489−4495.
(2) Haines, D. A.; Murray, J. Human biomonitoring of environmental
chemicals–early results of the 2007−2009 Canadian Health Measures
Survey for males and females. Int. J. Hyg. Environ. Health 2012, 215
(2), 133−137.
(3) Lau, C.; Butenhoff, J. L.; Rogers, J. M. The developmental
toxicity of perfluoroalkyl acids and their derivatives. Toxicol. Appl.
Pharmacol. 2004, 198 (2), 231−241.
(4) Andersen, M. E.; Butenhoff, J. L.; Chang, S.-C.; Farrar, D. G.;
Kennedy, G. L., Jr; Lau, C.; Olsen, G. W.; Seed, J.; Wallace, K. B.
Perfluoroalkyl acids and related chemistries–toxicokinetics and modes
of action. Toxicol. Sci. 2007, 102 (1), 3−14.
(5) Steenland, K.; Fletcher, T.; Savitz, D. A. Epidemiologic evidence
on the health effects of perfluorooctanoic acid (PFOA). Environ.
Health Persp. 2010, 118 (8), 1100−1108.
(6) Barry, V.; Winquist, A.; Steenland, K. Perfluorooctanoic acid
(PFOA) exposures and incident cancers among adults living near a
chemical plant. Environ. Health Persp. 2013, 121 (11−12), 1313−1318.
(7) Darrow, L. A.; Stein, C. R.; Steenland, K. Serum perfluorooctanoic acid and perfluorooctane sulfonate concentrations in
relation to birth outcomes in the Mid-Ohio Valley, 2005−2010.
Environ. Health Persp. 2013, 121 (10), 1207−1213.
(8) Winquist, A.; Steenland, K. Perfluorooctanoic Acid Exposure and
Thyroid Disease in Community and Worker Cohorts. Epidemiology
2014, 25 (2), 255−264.
(9) Steenland, K.; Zhao, L.; Winquist, A.; Parks, C. Ulcerative colitis
and perfluorooctanoic acid (PFOA) in a highly exposed population of
community residents and workers in the mid-Ohio valley. Environ.
Health Persp. 2013, 121 (8), 900−905.
(10) Winquist, A.; Steenland, K. Modeled PFOA exposure and
coronary artery disease, hypertension, and high cholesterol in
2402
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
community and worker cohorts. Environ. Health Persp. 2014, 122 (12),
1299−1305.
(11) Okada, E.; Sasaki, S.; Saijo, Y.; Washino, N.; Miyashita, C.;
Kobayashi, S.; Konishi, K.; Ito, Y. M.; Ito, R.; Nakata, A.; Iwasaki, Y.;
Saito, K.; Nakazawa, H.; Kishi, R. Prenatal exposure to perfluorinated
chemicals and relationship with allergies and infectious diseases in
infants. Environ. Res. 2012, 112, 118−125.
(12) Grandjean, P.; Andersen, E.; Budtz-Jørgensen, E.; Nielsen, F.;
Mølbak, K.; Weihe, P.; Heilmann, C. Serum vaccine antibody
concentrations in children exposed to perfluorinated compounds. J.
Am. Med.Assoc. 2012, 307 (4), 391−397.
(13) Lopez-Espinosa, M. J.; Fletcher, T.; Armstrong, B.; Genser, B.;
Dhatariya, K.; Mondal, D.; Ducatman, A.; Leonardi, G. Association of
perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate
(PFOS) with age of puberty among children living near a chemical
plant. Environ. Sci. Technol. 2011, 45 (19), 8160−8166.
(14) Joensen, U. N.; Veyrand, B.; Antignac, J. P.; Blomberg Jensen,
M.; Petersen, J. H.; Marchand, P.; Skakkebaek, N. E.; Andersson, A.
M.; Le Bizec, B.; Jorgensen, N. PFOS (perfluorooctanesulfonate) in
serum is negatively associated with testosterone levels, but not with
semen quality, in healthy men. Hum. Reprod. 2013, 28 (3), 599−608.
(15) Lam, J.; Koustas, E.; Sutton, P.; Johnson, P. I.; Atchley, D. S.;
Sen, S.; Robinson, K. A.; Axelrad, D. A.; Woodruff, T. J. The
navigation guide - evidence-based medicine meets environmental
health: integration of animal and human evidence for PFOA effects on
fetal growth. Environ. Health Persp. 2014, 122 (10), 1040−1051.
(16) Zhang, C.; Sundaram, R.; Maisog, J.; Calafat, A. M.; Barr, D. B.;
Buck Louis, G. M. A prospective study of prepregnancy serum
concentrations of perfluorochemicals and the risk of gestational
diabetes. Fertil. Steril. 2015, 103 (1), 184−189.
(17) Miyake, Y.; Yamashita, N.; So, M. K.; Rostkowski, P.; Taniyasu,
S.; Lam, P. K.; Kannan, K. Trace analysis of total fluorine in human
blood using combustion ion chromatography for fluorine: a mass
balance approach for the determination of known and unknown
organofluorine compounds. J. chromatogr. A 2007, 1154 (1−2), 214−
221.
(18) Yeung, L. W. Y.; Miyake, Y.; Taniyasu, S.; Wang, Y.; Yu, H. X.;
So, M. K.; Jiang, G. B.; Wu, Y. N.; Li, J. G.; Giesy, J. P.; Yamashita, N.;
Lam, P. K. S. Perfluorinated compounds and total and extractable
organic fluorine in human blood samples from China. Environ. Sci.
Technol. 2008, 42 (21), 8140−8145.
(19) Hansen, K. J.; Clemen, L. A.; Ellefson, M. E.; Johnson, H. O.
Compound-specific, quantitative characterization of organic fluorochemicals in biological matrices. Environ. Sci. Technol. 2001, 35 (4),
766−770.
(20) Calafat, A. M.; Wong, L. Y.; Kuklenyik, Z.; Reidy, J. A.;
Needham, L. L. Polyfluoroalkyl chemicals in the US population: Data
from the National Health and Nutrition Examination Survey
(NHANES) 2003−2004 and comparisons with NHANES 1999−
2000. Environ. Health Persp. 2007, 115 (11), 1596−1602.
(21) Lee, H.; Mabury, S. A. A pilot survey of legacy and current
commercial fluorinated chemicals in human sera from United States
donors in 2009. Environ. Sci. Technol. 2011, 45 (19), 8067−8074.
(22) Gebbink, W. A.; Glynn, A.; Berger, U. Temporal changes
(1997−2012) of perfluoroalkyl acids and selected precursors
(including isomers) in Swedish human serum. Environ. Pollut. 2015,
199, 166−173.
(23) Liu, Y.; Pereira Ados, S.; Martin, J. W. Discovery of C5-C17
poly- and perfluoroalkyl substances in water by in-line SPE-HPLCOrbitrap with in-source fragmentation flagging. Anal. Chem. 2015, 87
(8), 4260−4268.
(24) Strynar, M.; Dagnino, S.; McMahen, R.; Liang, S.; Lindstrom,
A.; Andersen, E.; McMillan, L.; Thurman, M.; Ferrer, I.; Ball, C.
Identification of novel perfluoroalkyl ether carboxylic acids (PFECAs)
and sulfonic acids (PFESAs) in natural waters using accurate mass
time-of-flight mass spectrometry (TOFMS). Environ. Sci. Technol.
2015, 49 (19), 11622−11630.
(25) Rotander, A.; Karrman, A.; Toms, L. M.; Kay, M.; Mueller, J. F.;
Gomez Ramos, M. J. Novel fluorinated surfactants tentatively
identified in firefighters using liquid chromatography quadrupole
time-of-flight tandem mass spectrometry and a case-control approach.
Environ. Sci. Technol. 2015, 49 (4), 2434−2442.
(26) Wang, Z.; Cousins, I. T.; Scheringer, M.; Hungerbühler, K.
Fluorinated alternatives to long-chain perfluoroalkyl carboxylic acids
(PFCAs), perfluoroalkane sulfonic acids (PFSAs) and their potential
precursors. Environ. Int. 2013, 60, 242−248.
(27) Gomis, M. I.; Wang, Z.; Scheringer, M.; Cousins, I. T. A
modeling assessment of the physicochemical properties and environmental fate of emerging and novel per- and polyfluoroalkyl substances.
Sci. Total Environ. 2015, 505, 981−991.
(28) Wang, S.; Huang, J.; Yang, Y.; Hui, Y.; Ge, Y.; Larssen, T.; Yu,
G.; Deng, S.; Wang, B.; Harman, C. First report of a Chinese PFOS
alternative overlooked for 30 years: its toxicity, persistence, and
presence in the environment. Environ. Sci. Technol. 2013, 47 (18),
10163−10170.
(29) Ruan, T.; Lin, Y.; Wang, T.; Liu, R.; Jiang, G. Identification of
novel polyfluorinated ether sulfonates as PFOS Alternatives in
municipal sewage sludge in China. Environ. Sci. Technol. 2015, 49
(11), 6519−6527.
(30) Shi, Y.; Vestergren, R.; Zhou, Z.; Song, X.; Xu, L.; Liang, Y.; Cai,
Y. Tissue distribution and whole body burden of the chlorinated
polyfluoroalkyl ether sulfonic acid F-53B in crucian carp (Carassius
carassius): Evidence for a highly bioaccumulative contaminant of
emerging concern. Environ. Sci. Technol. 2015, 49 (24), 14156−14165.
(31) Buck, R. C.; Franklin, J.; Berger, U.; Conder, J. M.; Cousins, I.
T.; de Voogt, P.; Jensen, A. A.; Kannan, K.; Mabury, S. A.; van
Leeuwen, S. P. Perfluoroalkyl and polyfluoroalkyl substances in the
environment: terminology, classification, and origins. Integr. Environ.
Assess. Manage. 2011, 7 (4), 513−541.
(32) Zhou, Z.; Shi, Y.; Vestergren, R.; Wang, T.; Liang, Y.; Cai, Y.
Highly elevated serum concentrations of perfluoroalkyl substances in
fishery employees from tangxun lake, China. Environ. Sci. Technol.
2014, 48 (7), 3864−3874.
(33) Zhao, S.; Price, O.; Liu, Z.; Jones, K. C.; Sweetman, A. J.
Applicability of western chemical dietary exposure models to the
Chinese population. Environ. Res. 2015, 140, 165−176.
(34) Zhou, Z.; Liang, Y.; Shi, Y.; Xu, L.; Cai, Y. Occurrence and
transport of perfluoroalkyl acids (PFAAs), including short-chain
PFAAs in Tangxun Lake, China. Environ. Sci. Technol. 2013, 47
(16), 9249−9157.
(35) Zhang, Y.; Beesoon, S.; Zhu, L.; Martin, J. W. Biomonitoring of
perfluoroalkyl acids in human urine and estimates of biological halflife. Environ. Sci. Technol. 2013, 47 (18), 10619−10627.
(36) Borghi, L.; Meschi, T.; Amato, F.; Briganti, A.; Novarini, A.;
Giannini, A. Urinary volume, water and recurrences in idiopathic
calcium nephrolithiasis: A 5-year randomized prospective study. J.
Urol. 1996, 155 (3), 839−843.
(37) Thompson, J.; Lorber, M.; Toms, L. M.; Kato, K.; Calafat, A.
M.; Mueller, J. F. Use of simple pharmacokinetic modeling to
characterize exposure of Australians to perfluorooctanoic acid and
perfluorooctane sulfonic acid. Environ. Int. 2010, 36 (4), 390−397.
(38) Ehresman, D. J.; Froehlich, J. W.; Olsen, G. W.; Chang, S. C.;
Butenhoff, J. L. Comparison of human whole blood, plasma, and
serum matrices for the determination of perfluorooctanesulfonate
(PFOS), perfluorooctanoate (PFOA), and other fluorochemicals.
Environ. Res. 2007, 103 (2), 176−184.
(39) Haug, L. S.; Huber, S.; Becher, G.; Thomsen, C. Characterisation of human exposure pathways to perfluorinated compounds
-comparing exposure estimates with biomarkers of exposure. Environ.
Int. 2011, 37 (4), 687−693.
(40) Kaiser, M. A.; Dawson, B. J.; Barton, C. A.; Botelho, M. A.
Understanding potential exposure sources of perfluorinated carboxylic
acids in the workplace. Ann. Occup. Hyg. 2010, 54 (8), 915−922.
(41) Gao, Y.; Fu, J.; Cao, H.; Wang, Y.; Zhang, A.; Liang, Y.; Wang,
T.; Zhao, C.; Jiang, G. Differential accumulation and elimination
behavior of perfluoroalkyl acid isomers in occupational workers in a
manufactory in China. Environ. Sci. Technol. 2015, 49 (11), 6953−
6962.
2403
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404
Article
Environmental Science & Technology
(42) Nøst, T. H.; Vestergren, R.; Berg, V.; Nieboer, E.; Odland, J. Ø.;
Sandanger, T. M. Repeated measurements of per- and polyfluoroalkyl
substances (PFASs) from 1979 to 2007 in males from Northern
Norway: Assessing time trends, compound correlations and relations
to age/birth cohort. Environ. Int. 2014, 67, 43−53.
(43) Berg, V.; Nøst, T. H.; Huber, S.; Rylander, C.; Hansen, S.;
Veyhe, A. S.; Fuskevåg, O. M.; Odland, J. Ø.; Sandanger, T. M.
Maternal serum concentrations of per- and polyfluoroalkyl substances
and their predictors in years with reduced production and use. Environ.
Int. 2014, 69, 58−66.
(44) Russell, M. H.; Waterland, R. L.; Wong, F. Calculation of
chemical elimination half-life from blood with an ongoing exposure
source: The example of perfluorooctanoic acid (PFOA). Chemosphere
2015, 129, 210−216.
(45) Zhang, T.; Sun, H.; Lin, Y.; Wang, L.; Zhang, X.; Liu, Y.; Geng,
X.; Zhao, L.; Li, F.; Kannan, K. Perfluorinated compounds in human
blood, water, edible freshwater fish, and seafood in China: Daily intake
and regional differences in human exposures. J. Agric. Food Chem.
2011, 59, 11168−11176.
(46) Xie, S.; Wang, T.; Liu, S.; Jones, K. C.; Sweetman, A. J.; Lu, Y.
Industrial source identification and emission estimation of perfluorooctane sulfonate in China. Environ. Int. 2013, 52, 1−8.
(47) Andersen, M. E.; Clewell, H. J., 3rd; Tan, Y. M.; Butenhoff, J. L.;
Olsen, G. W. Pharmacokinetic modeling of saturable, renal resorption
of perfluoroalkylacids in monkeys–probing the determinants of long
plasma half-lives. Toxicology 2006, 227 (1−2), 156−64.
(48) Han, X.; Nabb, D. L.; Russell, M. H.; Kennedy, G. L.; Rickard,
R. W. Renal elimination of perfluorocarboxylates (PFCAs). Chem. Res.
Toxicol. 2012, 25 (1), 35−46.
(49) Zhang, T.; Sun, H.; Qin, X.; Gan, Z.; Kannan, K. PFOS and
PFOA in paired urine and blood from general adults and pregnant
women: Assessment of urinary elimination. Environ. Sci. Pollut. Res.
2015, 22, 5572−5579.
(50) Kudo, N.; Suzuki, E.; Katakura, M.; Ohmori, K.; Noshiro, R.;
Kawashima, Y. Comparison of the elimination between perfluorinated
fatty acids with different carbon Chain length in rats. Chem.-Biol.
Interact. 2001, 134 (2), 203−216.
(51) Olsen, G. W.; Mair, D. C.; Reagen, W. K.; Ellefson, M. E.;
Ehresman, D. J.; Butenhoff, J. L.; Zobel, L. R. Preliminary evidence of a
decline in perfluorooctanesulfonate (PFOS) and perfluorooctanoate
(PFOA) concentrations in American Red Cross blood donors.
Chemosphere 2007, 68 (1), 105−111.
(52) Ohmori, K.; Kudo, N.; Katayama, K.; Kawashima, Y.
Comparison of the toxicokinetics between perfluorocaboxylic acids
with different carbon chain length. Toxicology 2003, 184 (2−3), 135−
140.
(53) Wong, F.; MacLeod, M.; Mueller, J. F.; Cousins, I. T. Enhanced
elimination of perfluorooctane sulfonic acid by menstruating women:
Evidence from population-based pharmacokinetic modeling. Environ.
Sci. Technol. 2014, 48 (15), 8807−8814.
(54) Yeung, L. W.; Mabury, S. A. Bioconcentration of aqueous filmforming foam (AFFF) in juvenile rainbow trout (Oncorhyncus mykiss).
Environ. Sci. Technol. 2013, 47 (21), 12505−12513.
(55) Loi, E. I.; Yeung, L. W.; Mabury, S. A.; Lam, P. K. Detections of
commercial fluorosurfactants in Hong Kong marine environment and
human blood: A pilot study. Environ. Sci. Technol. 2013, 47 (9), 4677−
4685.
(56) Wang, Z.; Cousins, I. T.; Scheringer, M.; Hungerbuehler, K.
Hazard assessment of fluorinated alternatives to long-chain perfluoroalkyl acids (PFAAs) and their precursors: Status quo, ongoing
challenges and possible solutions. Environ. Int. 2015, 75, 172−179.
(57) Gordon, S. C. Toxicological evaluation of ammonium 4,8-dioxa3H-perfluorononanoate, a new emulsifier to replace ammonium
perfluorooctanoate in fluoropolymer manufacturing. Regul. Toxicol.
Pharmacol. 2011, 59 (1), 64−80.
(58) Borg, D.; Lund, B. O.; Lindquist, N. G.; Hakansson, H.
Cumulative health risk assessment of 17 perfluoroalkylated and
polyfluoroalkylated substances (PFASs) in the Swedish population.
Environ. Int. 2013, 59, 112−123.
2404
DOI: 10.1021/acs.est.5b05849
Environ. Sci. Technol. 2016, 50, 2396−2404