Occup.
Hyg., pp. 1–13
Ann. Occup. Hyg., Vol. 56, Ann.
No. 9,
pp. 1025–1037,
2012
©The
TheAuthor
Author2012.
2012.Published
Publishedby
by Oxford
Oxford University
University Press
Press
on
onbehalf
behalfofofthe
theBritish
British Occupational
Occupational Hygiene
Hygiene Society
Society
doi:10.1093/annhyg/mes023
doi:10.1093/annhyg/mes023
Retrospective Exposure Assessment of
Perfluorooctanoic Acid Serum Concentrations at
a Fluoropolymer Manufacturing Plant
SUSAN R. WOSKIE1*, REBECCA GORE1 and KYLE STEENLAND2
1
Department of Work Environment, University of Massachusetts Lowell, One University Avenue, Lowell,
MA 01854, USA; 2Department of Environmental Health, Emory University, Atlanta, GA 30322, USA
Received 21 October 2011; in final form 27 February 2012 ; published online 26 April 2012
Perfluorooctanoic acid (PFOA) is a suspect human carcinogen, causes neonatal loss, liver enlargement, and a variety of tumors in rodents, and has been associated with increased cholesterol levels in humans. Mortality analyses of worker cohorts have not been conclusive or
consistent. As part of a series of epidemiologic studies of workers in a West Virginia plant that
manufactures fluoropolymers, estimates of serum PFOA for the worker cohort were developed
for the period of 1950–2004. An existing database of 2125 worker biomarker measurements of
serum PFOA was used to model retrospective exposures. Historical PFOA serum levels for
eight job category/job group combinations were modeled using linear mixed models to account
for repeated measures, along with exposure determinants such as cumulative years worked in
potentially exposed jobs, the amount of C8 used or emitted by the plant over time, as well as
a four-knot restricted cubic spline function to reflect the influence of process changes over calendar time on exposure. The modeled biomarker levels matched well with measured levels, including those collected independently as part of a community study of PFOA levels (Spearman
correlations of 0.8 for internal data comparisons and 0.6 for external data comparisons). These
annualized PFOA serum estimates will be used in a series of morbidity and mortality studies of
this worker cohort.
Keywords: exposure assessment; exposure determinants; exposure science; historical exposure assessment;
retrospective exposure assessment exposure metric; Teflon
INTRODUCTION
Ammonium perfluorooctanoate (APFO), the ammonium salt of perfluorooctanoic acid (PFOA), is used
as a surfactant in the polymerization of tetrafluoroethylene to make certain fluoropolymers such as polytetrafluoroethylene (PTFE). This perfluorooctanoate
is also known as C8. PTFE products marketed as Teflon and Gore-tex among others have a variety of
uses including a coatings for non-stick pans, waterrepellent clothing, dome materials, wire and cable, inert tubing and laboratory supplies, and semiconductor
applications among many others.
*Author to whom correspondence should be addressed.
Tel: þ978-934-3295; fax: þ978-452-5711;
e-mail: [email protected]
PFOA is a suspect human carcinogen and causes
neonatal loss in mice (US EPA, 2005). PFOA has
been shown to cause tumors of the pancreas, liver,
and testes in rodents. It also causes liver enlargement
in rodents and non-human primates (Steenland et al.,
2010). There are two worker cohorts exposed to
PFOA that have been studied for mortality and morbidity outcomes: one at a 3M plant in Minnesota and
one at a Dupont plant in West Virginia. Studies of
the Dupont cohort have reported associations with
higher cholesterol (Sakr et al., 2007a,b). However,
mortality analyses have not been conclusive or consistent across the two cohorts (Steenland et al., 2010).
Elevated standardized mortality ratios for the Dupont
cohort for diabetes and a kidney cancer were found
when the referent group was workers at other Dupont
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S. Woskie, R. Gore and K. Steenland
plants (Leonard et al., 2008). A positive exposure–
response trend for heart disease was reported when
cumulative exposure cutpoints were chosen from all
exposed workers at Dupont and a 10-year lag was
used (Sakr et al., 2009). Although not significant, suggestive positive trends in internal exposure–response
analyses for diabetes, stroke, prostate cancer, and
pancreatic cancer were reported in the 3M cohort
by Lundin et al. (2009).
Non-differential exposure misclassification can
impact the validity and reduce the precision of a cohort study. In studies where exposures are dichotomous, it can bias estimates toward the null. In
studies using exposure–response analysis with exposure measured on a continuous scale, the impact of
mis-measured exposure is more complex but often
results in biased exposure–response trends, making
interpretation of exposure–disease associations more
difficult (Armstrong, 1990; Dosemeci et al., 1990;
Steenland et al., 2000). In theory, improvements in
exposure assessment that eliminate misclassification
can have dramatic effects on relative risk estimates;
however, it is difficult to evaluate the impact in realworld studies (Blair et al., 2007).
Previous PFOA worker cohort exposure assessments
The historical exposure reconstruction described
here attempts to improve the exposure assessments
used to date for the occupational studies of PFOA
workers. The PFOA exposure assessment for the
mortality study of the 3M plant was confined to categorizing workers into not exposed, probably exposed, and definitely exposed (Lundin et al.,
2009). A more extensive exposure assessment was
conducted for the Dupont plant (Kreckmann et al.,
2009). Using a dataset from a cross-sectional survey
of serum levels for 1000 workers in 2004, 60 job
groups were assigned to one of three exposure categories, primarily based on their median 2004 job
serum level. Then cohort members were given a cumulative serum PFOA level calculated as the sum of
the number of years (1950–2004) in each of the three
job categories times the job category mean exposure
level for all of the jobs in the category in the 2004
survey (Kreckmann et al., 2009). The exposure assessment reported here differs in that it does not
use the 2004 serum measurements to assign jobs to
similar exposure groups (which we define via job
category and job groups within a job category, see
below); rather, work process and potential contact
with PFOA were used to assign jobs to similar exposure groups (job category/job group combinations).
In addition, this job exposure matrix increases the
number of similar exposure groups from three to
eight, and, perhaps most important, unlike the previous assessment, it uses observed serum levels by job
from 1979 to 2004 to model predicted serum levels
over time.
METHODS
Worker blood samples
The first measurements of worker exposures to
PFOA were in 1972. From 1972 to 1981, the blood
analysis for PFOA was done on whole blood by Dupont using the Wickbold torch method. This method
measured total organic fluorine using an oxyhydrogen torch/bomb decomposition method followed
by a spectrophotometric method of detection. During that time, all organic fluorine was assumed to
be related to PFOA. The limit of detection (LOD)
for this method was not available in the Dupont documentation; however, for this method, the lowest
concentration reported in our modeling dataset was
0.015 ppm and no non-detectable values were reported. In 1981, the blood analysis was converted
to a gas chromatography with electron capture detector (GC-ECD) method. Whole-blood samples underwent lyophilization, and then the dried residue was
combined with methanolic HCl followed by extraction of the methyl esters into hexane. An internal standard was used to correct for analytical variations. The
GC-ECD LOD was reported as 0.01 ppm by Dupont.
However, out of 1248 analyzed by this method, in
our modeling dataset, only one was reported as nondetectable. Based on replicate analysis of 114 samples
by two different methods, correction factors (average
1.28) were developed by Dupont and applied to the
collected blood data to convert samples analyzed by
Wickbold torch to GC-ECD PFOA analysis equivalents.
Beginning in 2003, worker samples were analyzed
by an high pressure liquid chromatography with
tandem mass spectrometry (LC-MS/MS) method,
which uses serum, not whole blood. The LOD for
the LC/MS/MS method was reported as 0.005 ppm
and none of the samples in the modeling dataset were
non-detectable. PFOA binds to serum proteins (Han
et al., 2003; Jones et al., 2003; Wu et al., 2009).
A study comparing serum, plasma, and whole-blood
samples of 12 humans found that the average ratio
of PFOA in serum to ethylenediaminetetraacetic acid
(EDTA) treated whole blood was 2.1 (1.7–2.8)
(Ehresman et al., 2007). Another study with five
human samples found a mean PFOA ratio of 1.37
plasma/whole blood (range 1.19–1.82) (Karrman
et al., 2006). When both datasets are combined, the
Retrospective workplace PFOA serum concentrations
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average ratio is 1.8 (1.19–2.8). All whole-blood data
collected before 2003 were adjusted to the serum
equivalent by multiplying by 1.8. Results are reported
in parts per million (1 ppm 1 lg ml1 PFOA).
For the model development, the biomarker dataset
of serum PFOA concentrations was confined to those
samples where the subject had been in the job group
for at least 1 year before the sample was collected
(2125 samples from 1308 workers).
Similar exposure groups (job category/job group
combinations)
Through a series of interviews and group discussions with current and retired Dupont staff familiar
with plant processes, work history entries (division,
department, and job title) were categorized into similarly exposed job groups (30) and larger job categories (5). Within the five larger job categories, the job
groups were evaluated by stem and leaf plots and
multiple comparison least squares means (LS means)
tests, from a mixed model of the log serum concentration that included calendar year, job group, and total years in potentially C8-exposed jobs prior to
a specific serum sample. Based on sample size and
the LS means tests, only three of the five larger job
categories retained subdivisions of job groups (for
a total of eight job category/job group combinations).
Fine powder/granular PTFE job category (direct
exposure to PFOA). Fluropolymers have been produced since 1951 at the Dupont chemical plant in
Washington, West Virginia. Within this area, the
chemical operator job group runs the reactors and
were in charge of measuring the powdered C8 (APFO) for introduction into the reactors. Fine powder/
dispersion used C8 from the start and granular began
use in 1965. Both used powdered C8 up until 1989
when introduction of a premixed liquid C8 was begun. The finishing operator job group works in the
powder drying and packaging area and transfer liquid polymer dispersions into shipping totes. Finishing operators also do dryer cleanout and help with
maintenance of the dryers. In the analysis, this job
category included a dichotomous variable for working in the chemical operator job group, resulting in
two job category/job group combinations.
Fluorinated ethylene propylene and perfluoroalkoxy fluoropolymer job category (direct exposure
to PFOA). The first co-polymer [fluorinated ethylene
propylene (FEP)] began pilot operations in 1953 but
only used C8 in powder form from 1975 to 1991, and
then they converted to the premixed liquid form
of C8. The second co-polymer [perfluoroalkoxy
(PFA)] was co-manufactured with FEP and used
powdered C8 from 1973 to 1982. Then production
was transferred to a non-aqueous, non-C8 process.
In 1998, PFA manufacture was again switched back
to an aqueous C8 process. Beginning in 1995, the
FEP/PFA chemical operators and finishing operators
rotated jobs, eliminating any finer distinction in
potential exposures based on job tasks.
Non-PFOA (C8) use in Teflon polymer/co-polymer
production job category (intermittent direct or plant
background PFOA exposure). This job category included a number of jobs that were associated with
and housed in buildings adjacent to the Teflon
polymer/co-polymer production departments. These
included a combined job group of Teflon polymer/
co-polymer laboratorians, engineers, upper level
supervisiors, and clerks as well as production
jobs in Teflon polymer/co-polymer production
operations that never used C8, such as the ethylenetetrafluoroethylene fluoropolymer (Tefzel) and fluorotelomer (telomer) co-polymer operations. The
tetrafluorethylene (TFE) monomer operation, which
never used C8, began in 1950, was treated as a separate job group due to their work location adjacent to
the PTFE operations. In the analysis, this job category included a dichotomous variable for working
in the monomer operator job group, resulting in two
job category/job group combinations.
Maintenance job category (intermittent direct or
plant background PFOA exposure). Until 1983,
most maintenance workers were assigned to a centralized ‘mechanical’ or ‘utility’ division, even
though much of their work may have been in the
Teflon polymer/co-polymer area. From 1983 on,
workers could be assigned either to a centralized
division job group or to a Teflon polymer/co-polymer
division job group. In the analysis, this job category included a dichotomous variable for having
been assigned to Teflon/co-polymer maintenance
job group, resulting in two job category/job group
combinations.
Non-Teflon/co-polymer production division with
no PFOA use job category (plant background PFOA
exposure). This group included the other production
divisions in the plant that did not use C8 (acrylics,
Butacite, Delrin, engineering polymers, compounding, nylon filaments, specialty compounding,
as well as power services, utility pool, and non-Teflon
polymer/co-polymer-associated administrative jobs
in engineering, business services, and other plant
services).
Jobs considered potentially exposed to C8 included the job categories of fine powder/granular,
FEP/PFA, non-PFOA (C8) use jobs in Teflon and
co-polymer production, and the Teflon/co-polymer
maintenance job group.
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S. Woskie, R. Gore and K. Steenland
Exposure modeling using biological monitoring data
The goal of the modeling reported here was to develop the best fitting predictive models using serum
data collected on a subset of individual workers over
time, in order to predict serum levels for each individual worker in the cohort over time. Therefore,
we developed five separate regression models, one
for each of the job categories representing similar
exposure conditions, to best capture the timerelated process changes in each job category. Since
serum concentrations were highly skewed and more
lognormal than normal based on evaluation of probability plots and histograms, the natural log of the
serum concentrations were used in the modeling.
The natural log of the serum concentrations were
examined using a variety of methods of modeling
time trends; either mixed models with a continuous
measure for time or broken stick regression (two or
three piece linear) modeling of time, lowess smoothing, or restricted cubic splines. Continuous measures
were unsatisfactory because serum samples were
clustered in time due to a sampling campaign approach. Piece-wise linear models were unsatisfactory
since process change in manufacturing is more likely
to result in a smoother and more gradual continuous
change in serum levels, since the half-life of PFOA
in serum is estimated to be 3.5 years (Olsen et al.,
2007). Smoothing was judged to be a more realistic
approach to modeling time; however, lowess models
do not produce model predictors that can be used with
other datasets to estimate an outcome based on independently available X values. Since the goal of our
modeling was to estimate serum levels for individuals
for each year of their work history, lowess models did
not work. Instead, we used a restricted cubic spline
(RCS) model, which produces model predictions by
forcing the first and second derivatives of the function
to agree at the knots. By using the RCS model, the
function is also constrained to be linear at the tails,
avoiding some of the problems with using unconstrained cubic spline models. These RCS models were
developed using the RCSPLINE SAS macro developed by Frank Harrell who also reported that the location of the knots in an RCS model is not as important
as the number of knots (Harrell et al., 1988; Harrell,
2001).
For the job categories with direct C8 exposure,
process changes over calendar time were modeled
with a four-knot RCS function that utilized a linear
term (T1) and two additional terms defined by the
knots and cubic powers (T2 and T3). The number
of knots (three to five) was determined by the model
fit (Akaike information criterion using restricted
maximum likelihood) as well as by comparing the
predicted to the measured values across 5-year
time windows. Although we tried a series of knot
locations for each number of knots, in the end,
the quantiles for knot location suggested by
Harrell (2001) for each number of knots provided
the best fit. For four knots, this was the 5, 35, 65,
and 95 percentile of the distribution of number
of years after 1970 that the serum samples were
collected. For fine powder/granular, the knots were
at 11, 13, 17, and 34 years after 1970. For FEP/
PFA, the knots were at 9, 13, 25, and 34 years after
1970. For each model, covariates that most improved model fit and therefore predictive power
were chosen, at the cost of some cross-model consistency. These covariates included the cumulative
number of prior years in potentially C8-exposed
job, job group, the annual amount of PFOA (product C8) used at the plant (units of 1000 lbs year1),
or the estimated annual PFOA emissions from the
plant (Paustenbach et al., 2007; Shin et al., 2011a)
(Fig. 1).
All models were developed using the SAS mixed
model procedure where the natural log of the serum
PFOA concentration was the outcome, and a repeated measures covariance structure was used to
account for the presence of multiple samples on
some of the subjects within a job category. Several
covariance structures were examined including
compound symmetry, autoregressive, and unstructured. Due to the structure of the data, some covariance structures would not allow model convergence
and there was little difference in the results of those
structures that were fit. Therefore, a compound
symmetry structure was used. Final model diagnostics from SAS mixed influence and residual analyses were examined and where highly influential
values were identified by the press statistic and
restricted likelihood distance, they were removed
so that models would have maximum generalizability. For the fine powder and granular job group, four
samples were removed and one person who moved
between chemical operator and finisher jobs was
removed (10 samples). For PFOA non-production
jobs, two samples were removed and for maintenance
jobs one sample was removed.
To evaluate the impact of the modeling effort on
variance components, mixed models with only the
random effect were run to determine the baseline total, between- and within-worker variance estimates.
Then the variance components for the models that
included the fixed effects were determined and the
percent change in the between- and within-worker
variance calculated.
Retrospective workplace PFOA serum concentrations
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Fig. 1. The annual amount of PFOA (product C8) used at the plant (lbs/year) and the estimated annual PFOA emissions from the
plant (Paustenbach, et al. 2007 and Shin, et al. 2011a).
Annual exposure estimates
To estimate each worker’s work life exposure, for
each work history record, a job category/job group
assignment was made, cumulative prior years in potentially PFOA-exposed jobs were calculated for
each year, and then the retrospective serum estimates
were made for each job held in each year. For years
when multiple jobs were held, an annual weighted
average serum level was calculated as the timeweighted combination of the serum level in each
job times the time in that job for the year. For people
missing job information within a year, we used
a background serum level of 0.03 ppm, based on
a median value for community residents living near
the plant in 2005, who were drinking water contaminated with PFOA (Steenland et al., 2009a). If an
entire year is missing and the person had an annual
exposure estimate greater than 0.03 in the previous
year, then the data gap year is assigned 0.82 times
the previous estimate; otherwise, the year is assigned
0.03. The decay to 82% of the previous year is based
on the half-life estimate of 3.5 years (Olsen et al.,
2007).
When a worker left employment at the West
Virginia plant, their serum level in the last year
worked was allowed to decay in subsequent years using a half-life of 3.5 years. If they did not work for
a full year during their last year, they were given
the time-weighted average serum level using their
working time serum level plus 0.82 times their work-
ing time serum level for their non-working time during that year.
RESULTS
Prediction models
The overall dataset had 2125 samples, covering
1308 workers from the years of 1979–2004.
Twenty-six percent of the workers had two or more
samples, with the range being 1–15 samples per person (Table 1). The serum concentration models
were developed individually for each job category
(Table 2). Where job groups within a job category
showed significant differences in serum levels in
the model, the job group was included as a predictor.
Examples of job groups modeled within job categories included finish versus chemical operators within
the fine powder/granular PTFE job category, monomer operators versus all other workers within the
non-C8 use Teflon/co-polymer production job category, and Teflon/co-polymer versus general maintenance workers within the maintenance job category.
With one exception (FEP/PFA), the models predicting
serum levels all used either the amount of C8 used in
the plant in the year the sample was collected or the
amount of C8 emitted by the plant in the year the sample was collected as a predictor (r 5 0.57). Both these
were significant positive variables with a consistent
beta resulting in a 3% increase in serum PFOA level
per increase in 1000 pounds of C8 emitted per year
0.007–4.14
0.06–6.81
0.50 (0.89)
0.16 (0.24)
0–30
0–22
3.6 (5.2)
1.9 (4.3)
2004
1982
1–3
1–4
7
200
463
246
504
Maintenance
Non-Teflon/co-polymer
production division
jobs with no PFOA use
19
0.008–14.58
0.13–14.04
1.69 (2.53)
0.44 (0.84)
1–35
1–35
12.7 (8.4)
11.6 (8.0)
2000
1986
1–9
1–8
626
48
96
480
208
FEP/PFA
Non-PFOA (C8) use jobs in
Teflon and co-polymer
production
20
0.007–59.40
0.09–59.40
0.58 (2.05)
2.88 (5.47)
0–36
1–36
8.5 (8.6)
11.8 (9.0)
1995
1985
1–15
1–15
1308
170
2125
541
Total
Fine powder and
granular PTFE
26
57
Median (mean)
of serum PFOA
samples (ppm)
Min-max of
cumulative
years in potentially
exposed jobs
Mean (SD)
of cumulative
years in
potentially
exposed jobs
Year by
which 50%
samples
collected
Number of
samples
per worker
(min–max)
Percent
workers
with 2
samples
Number
of serum
samples
Number
of workers
sampled
S. Woskie, R. Gore and K. Steenland
Job categories
Table 1. Description of PFOA serum dataset used in retrospective modeling. All subjects were in their job category/job group for at least 1 year prior to serum sample.
Range of serum
PFOA samples
(ppm)
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for models using the amount of C8 emitted as a covariate. For the model with the amount of C8 used in the
plant, the positive beta resulted in an increase in serum
PFOA level of 1% per 1000 pounds C8 used per year.
The resulting models were used to predict serum
PFOA for each worker in each year for the cohort.
The earliest samples used to develop the models were
in 1978 and 1979, although PFOA began use in 1951
at the West Virginia plant. For the job categories with
direct exposure to C8 that used the RCS models to account for process changes over time, we set calendar
year to 1979 for the pre-1979 years. This prevented
overestimation of early serum levels where we do
not know how process changes may have influenced
serum concentrations. For these job categories,
changes in serum levels predicted prior to 1979 are
largely influenced by the annual amount of PFOA
(product C8) used at the plant (units of 1000 lbs
year1) as well as the individuals’ tenure in jobs with
potential C8 exposure. Since the FEP/PFA operation
started in 1953, but did not begin use of C8 until
1975, the level in 1974 was due to plant background
exposures, not direct use. Therefore, the average for
the intermittent direct/plant background-exposed jobs
in the Teflon/co-polymer area (Teflon engineers, laboratory, supervisor, office workers, monomer operators, and Teflon/co-polymer maintenance) in 1974
was used to extrapolate back to a zero concentration
in 1953 when FEP began pilot operations.
For job categories with intermittent or plant background PFOA exposures, the estimated annual
PFOA emissions from the plant were a significant
predictor in the models. However, the models did
not predict zero exposures in 1950 when C8 began
use at the plant. Examination of the annual amount
of C8 used/emitted from the plant showed a relatively
linear increase until about 1964 when fluctuations in
use/emission began (Fig. 1). Therefore, retrospective
estimation was modified so that model predictions
were used retrospectively through 1964, and then
a linear extrapolation back to zero in 1950 was used
for these job groups.
Since the retrospective serum exposure estimates
include an individual-level predictor (cumulative
prior years in potentially exposed jobs), determining
the pattern of serum levels over time required calculating the median serum exposure level for all workers in each job category/job group in a given year.
This was done in 5-year increments for each job category/job group for those directly exposed to C8
(Fig. 2) and those with intermittent or plant background PFOA exposures (Fig. 3). For the fine powder/granular job category, the chemical operators
run the reactors and were in charge of measuring
Retrospective workplace PFOA serum concentrations
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Table 2. Mixed models using repeated measures for natural log of serum PFOA concentration (ppm).
Separate mixed models job categories ln PFOA serum concentration (ppm) as outcome
Beta
Standard error
P value
Fine powder/granular PTFE job category (direct exposure to PFOA)a
Intercept
T1 time (number of years after 1970 when serum sample taken)
T2 time (spline function)
T3 Time (spline function)
Cumulative prior years in potentially exposed jobs
Annual amount of PFOA (C8) used (units 5 1000 lbs year�1)
Chemical operator job group (0/1: yes 5 1)
FEP/PFA job category (direct exposure to PFOA)b
Intercept
T1 time (number of years after 1970 when serum sample taken)
T2 time (spline function)
T3 time (spline function)
Cumulative years in potentially exposed jobs
1.61
0.32
,0.0001
�0.13
0.03
,0.0001
0.46
0.63
0.46
�0.47
1.01
0.64
0.02
0.01
,0.01
0.01
,0.01
1.03
0.11
0.001
,0.0001
2.81
0.39
,0.0001
�0.23
0.03
,0.0001
1.61
0.19
,0.0001
�2.54
0.28
,0.0001
0.01
,0.0001
0.03
Non-PFOA (C8) use in Teflon and co-polymer production
job category (intermittent direct or plant background PFOA exposure)c
0.08
,0.0001
0.03
,0.01
,0.0001
Annual amount of PFOA (C8) emitted from plant (units 5 1000 lbs year�1)
0.03
,0.01
,0.0001
TFE monomer operator job group (0/1: yes 5 1)
0.94
0.12
,0.0001
�1.30
0.11
,0.0001
0.03
0.01
0.01
Annual amount of PFOA (C8) emitted from plant (units 5 1000 lbs year�1)
0.03
0.01
0.0001
Teflon/co-polymer maintenance job group (0/1: yes 5 1)
0.47
0.14
0.002
�2.24
0.05
,0.0001
0.07
0.01
,0.0001
0.03
,0.01
,0.0001
Intercept
Cumulative prior years in potentially exposed jobs
Maintenance job category (intermittent direct or plant background PFOA exposure)c
Intercept
Cumulative prior years in potentially exposed jobs
Non-Teflon/co-polymer production division job category with
no PFOA use (plant background PFOA exposure)d
Intercept
Cumulative prior years in potentially exposed jobs
Annual amount of PFOA (C8) emitted from plant (units 5 1000 lbs year�1)
�1.74
a
Model for fine powder/granular PTFE job category:
Yij 5b0 þ b1 Cum yearsij þ b2 C8 Usedij þ b3 Chem operatorij þ b4 T1 ðtÞij þ b5 T2 � ðtÞij þ b6 T3 � ðtÞij þ wi þ eij ; where Yij 5
the natural log of the serum concentration of the jth sample for the ith worker. The b’s are fixed effects, wi is the random effect for
the worker and eij is the error term. T1 (t)ij 5 t, where t 5 number of years post-1970.
ðt�11Þ 3
ðt�17Þ 3
ðt�34Þ 3
ðt�13Þ 3
ðt�17Þ 3
ðt�34Þ 3
T2 � t 5 kd � þ � 1:35 kd � þ þ 0:358 kd � þ
T3 � t 5 kd � þ � 1:24 kd � þ þ 0:24 kd � þ
2
weighting for numerical stability5kd � 5ð34 � 11Þ3 ; ðt � cÞþ 5t � c if t � c . 0; elseðt � cÞþ 50;
where c 5 knot in units of years post-1970.
b
Model for FEP/PFA job category: Yij 5b0 þ b1 Cum yearsij þ b4 T1 ðtÞij þ b5 T2 � ðtÞij þ b6 T3 � ðtÞij þ wi þ eij ; where Yij 5 the
natural log of the serum concentration of the jth sample for the ith worker. The b’s are fixed effects, wi is the random effect for the
worker and eij is the error term. T1 (t)ij 5 t, where t 5 number of years post-1970.
ðt�9Þ 3
ðt�25Þ 3
ðt�34Þ 3
ðt�13Þ 3
ðt�25Þ 3
ðt�34Þ 3
T2 t 5 kd þ � 2:78 kd þ þ 1:78 kd þ
T3 t 5 kd þ � 2:33 kd þ þ 1:33 kd þ
2
weighting for numerical stability5kd5ð34 � 9Þ3 ; ðt � cÞþ 5t � c if t � c . 0; elseðt � cÞþ 50;
where c 5 knot in units of years post-1970.
c
Models for non-PFOA (C8) use in Teflon and co-polymer production job category or maintenance job category:
Yij 5b0 þ b1 Cum yearsij þ b2 C8 Emittedij þ b3 jobgroupij þ wi þ eij ; where Yij 5 the natural log of the serum concentration
of the jth sample for the ith worker. The b’s are fixed effects, wi is the random effect for the worker and eij is the error term.
d
Model for non-Teflon/co-polymer production division job category with no PFOA use:
Yij 5b0 þ b1 Cum yearsij þ b2 C8 Emittedij þ wi þ eij ; where Yij 5 the natural log of the serum concentration of the jth sample
for the ith worker. The b’s are fixed effects, wi is the random effect for the worker and eij is the error term.
8 of 13
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S. Woskie, R. Gore and K. Steenland
Fig. 2 Median serum levels estimated from models for workers in job groups with direct exposure to C8 during that year.
Fig. 3 Median serum levels estimated from models for workers in a job groups with intermittent direct or plant background PFOA
exposure to C8 during that year. Models used to estimate levels until 1965 then from 1964 to 1950 linear decline from 1965 median
level used.
the powdered C8 (APFO) for introduction into the
reactors had higher serum levels than the finish operators who work in the powder drying and packaging
area and transfer liquid polymer dispersions into
shipping totes. No significant differences were found
between chemical and finish operators in the FEP/
PFA job category in part due to a staffing change
in 1995 so that workers rotated between these jobs.
We were unable to differentiate those workers in
FEP operations and those in PFA operations; all were
considered co-polymer operations. Within the nonPFOA (C8) use jobs in Teflon and co-polymer production job category, the TFE monomer operators
had significantly higher serum levels than the other
jobs including engineers, laboratorians, supervisors,
and office workers. Within the maintenance job category, the Teflon/co-polymer maintenance workers had
higher serum levels than general maintenance jobs.
Evaluation of the change in the variance components attributable to the modeling effort are shown
in Table 3. For all job categories, the betweenworker variance exceeded the within-worker variance both before and after inclusion of the fixed
effects, including covariates that reflect calendar
time changes in the plant operations. However, the
inclusion of fixed effects explained 27–31% of the
variance of the job categories with potential PFOA
exposure and resulted in reductions in the betweenworker variance of 27–38% while also reducing
the within-worker variance component.
Predicted versus observed serum levels
Comparison of the model predictions to sample data
job category/job group overall and by decade found
the paired predicted and sample values were not significantly different overall (average difference 0.08
ppm, P , 0.001) for about 75% of the 30 job/decade
analyses. In the job/decade analyses where there
was a significant difference, predicted geometric
mean PFOA serum concentrations were lower than
Retrospective workplace PFOA serum concentrations
9 of 13
1033
sample geometric mean (GM) concentrations in
all but one case (Teflon/co-polymer maintenance
in 1980–1989). Overall, the Spearman correlation
coefficient for the predicted and measured PFOA
concentrations was 0.8.
As part of the settlement of a community class action lawsuit, blood samples were collected and measured for serum PFOA in Ohio and West Virginia
residents who lived in water districts surrounding
the Dupont chemical plant (Shin et al., 2011b). Of
those residents, 2034 were Dupont workers in our
cohort. We compared the serum PFOA concentration
predicted by our models for 2004 with that measured
during the community study (2005–2006). The overall Spearman correlation for this comparison was
0.6 with a median predicted of 0.11 ppm (mean
0.26 ppm) and a median measured of 0.11 ppm
(mean 0.32 ppm). This comparison included 1025
subjects who were no longer working at the plant
in 2004 (median predicted and measured 5 0.08
ppm). For the 1009 subjects working at the plant in
2004, the median predicted was 0.13 ppm (mean
0.36 ppm) and the median measured was 0.16 ppm
(mean 0.47 ppm).
Annual exposures
The study cohort of over 6000 workers had over
56,000 work history records. The model-based retrospective serum estimates were made for each job
held by a worker in each year. For years when multiple jobs were held, an annual weighted average serum level was calculated as the time-weighted
combination of the serum level in each job times
the time in that job for the year. Fig. 4 shows stem
and leaf plots of weighted annual average serum
PFOA levels (parts per million) for the full cohort
of workers by those in job category/job groups with
potential C8 exposure during each year and those in
job categories without potential C8 exposure during
each year.
DISCUSSION
Interpretation of the retrospective estimates
The trends in predicted serum PFOA levels over
time shown in Figs 2 and 3 reflect a complex plant
history including changes in production levels, engineering controls, and personal protective equipment
use instituted to decrease C8 exposures. For the fine
powder/granular job category (finish operator and
chemical operator job groups), the increases up until
1980 (Fig. 2) reflect a gradual increase in C8 use
(Fig. 1). However, between 1980 and 2000, despite
the increase in use, serum levels declined due to
the incorporation of a number of exposure controls
including a change to liquid injection pumps for addition of C8 into reactors, replacement of weighing
powdered C8 with premixed liquid C8, addition of
a dryer scrubber, use of personal protective equipment (Lin et al., 2005) when weighing C8, entering
the dryers, cleaning tanks, changing dispersion filters or loading liquid dispersions into totes loading
operations, and when changing filters in the dispersion operation (Fig. 2).
For the FEP/PFA job category, the amount of C8
used in the plant was not a useful predictor in part
because between 1982 and 1997, the PFA operation
became a non-aqueous/non-C8 operation and in part
because the proportion of C8 used in the plant by this
operation changed as production increased with the
addition of a new reactor and the new bead facility.
The lower serum levels in the 1980s appear to be a result of the elimination of C8 in the PFA operation as
well as the change to premixed C8 and the sealing of
the dryer room for the FEP operation. Higher levels
Table 3. Variance components for job category serum PFOA models.
Model with only worker as random effect
Full models from Table 2a
Total
variance
r2T
%
Between-worker
variance r2B
%
Within-worker
variance r2W
%
Between-worker
variance r2B
%
Within-worker
variance r2W
%
Fixed effect
variance r2F
Fine powder/granular
1.55
81
19
58
11
31
FEP/PFA
1.05
78
22
58
13
30
Non-PFOA use in
Teflon and
co-polymer
production
Maintenance
1.14
66
34
41
33
27
0.92
58
42
41
33
27
Non-Teflon/co-polymer
production
0.82
73
27
68
13
18
Job category
a
The total variance from the model containing only worker as a random effect was used to calculate the contribution of fixed
effects to partitioning of the variance components.
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S. Woskie, R. Gore and K. Steenland
Fig. 4 Stem and leaf plots of the model estimated weighted annual average serum PFOA levels (ppm) for the full cohort of workers
by those in job category/job groups with potential C8 exposure during the year (A) and those in job categories without potential C8
exposure during the year (B). Box plots show the minimum and maximum on the whiskers, the 25 th and 75 th percentile in the box
and the bar in the box is the median.
in the 1990s can be attributed to the startup of the
bead facility, the addition of a new reactor, and the
re-addition of C8 into the PFA operation. The plateau of levels in the late 1990s and 2000s may reflect
the addition of dryer scrubbers that offset the increasing production levels.
For workers in job groups with intermittent or
plant background PFOA exposures (Fig. 3), serum
levels reached a peak in 2000 that corresponded
to the period of highest use of C8 in the plant
(Fig. 1), the subsequent decrease reflects lower use
and also the addition of deep bed scrubbers in the
dryer operations. The Teflon polymer/co-polymer
maintenance job group within the maintenance job
category had a peak level in 1980 but that is the
one case where the exposure models predicted higher levels than the serum sample data. For the nonPFOA (C8) Teflon polymer/co-polymer production
job category, the job group of TFE monomer operator had higher exposures than other jobs with intermittent exposures to C8 during visits to the
production areas or use in QC/QA procedures including engineers, laboratorians, higher level supervisors, and clerks. This is likely due to the location of
the monomer operation adjacent to the fine powder/
granular operations, with the monomer control room
directly above the fine powder dryers.
Little is known about the toxicokinetics of PFOA
in humans. In this study, we found a consistent 2–3%
increase in serum PFOA level per cumulative prior
years of work in a potentially PFOA-exposed job
for all models. This suggests that PFOA may result
in a significant body burden in chronically exposed
workers. The only other report of body build up of
PFOA is in the study of community members exposed through contaminated water supplies. An average of 1% increase in serum PFOA per year of
residence in an exposed water district has been reported for the area of the plant (Seals et al., 2011).
It has been suggested that the longer elimination
half-life for PFOA in humans than in other species
may be due to differences in biliary excretion and
gut resorption (Olsen et al., 2007). These mechanisms may also explain the potential for accumulation of PFOA in humans.
Comparison of the serum levels measured here
with other datasets is difficult. The occupational data
from studies of 3M employees have been reported
cross-sectionally for the years of data collection,
which ranged from 1993 to 2000 (Olsen et al.,
2000; Olsen and Zobel, 2007). The data reported
here cover the time period of 1979–2004. Samples
collected for this study from 2000 to 2004 represent
all job categories and have a median serum level
of 0.24 ppm (mean 0.77 ppm) with a range of
0.007–16.20 ppm. Samples from a 2000 survey of
three 3M plants where PFOA was manufactured and
used in fluoroelastomer production had a median of
1.10 ppm (mean 2.21 ppm with a range of 0.01–
92.03 ppm; Olsen and Zobel, 2007). Lower overall levels in the present study may be a reflection of the high
percentage of workers either unexposed (27%) or intermittently exposed (42%) in the 2000–2004 samples
(n 5 731). While at the 3M plants, about 75% of
the males at two of the plants were reported to be in
production jobs (Olsen et al., 2003).
Workers unexposed to C8 in this study were those
in non-Teflon and non-co-polymer production
Retrospective workplace PFOA serum concentrations
11 of 13
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divisions and business staff. Their overall exposures
were a median of 0.16 ppm (mean of 0.24) with
a range of 0.007–4.14 ppm. In the 2000–2004 period
levels, this job category had a GM serum level of
0.14 ppm. These values are higher than those reported for the local community, who had a median
serum level in 2005–2006 of 0.04 ppm for current
residents of any water district in the area of the plant
(Steenland et al., 2009a) and higher than the
National Health and Nutrition Examination Survey
results for the general US population from the
1999–2000 or 2003–2004 surveys which ranged
from 0.004 to 0.005 ppm for subjects aged 20–39
and 40–59 years (Kato et al., 2011).
Retrospective exposure assessment using biomarkers
Although much has been said regarding the future
of molecular epidemiology and the utility of biomarkers in accounting for all routes of exposure,
few studies have been able to use biomarkers to look
at health effects caused by chronic exposures. In
part, this is due to the paucity of biomarker data
for target cohorts over the extended periods of time
necessary to account for disease latency. External
exposure data are more commonly available. Where
there is matched external and biomarker data, toxicokinetic models can be used to retrospectively estimate internal dose (biomarker level) from intake of
external exposures (Steenland et al., 2001).
This sub-cohort of workers represents a unique situation with over 2100 samples, covering over 1300
workers over a 25-year period with 26% of the workers having two or more samples. In addition, detailed
work histories were available for this sub-cohort and
the full cohort of over 6000 people. This enabled the
development of retrospective models for serum levels based on time and job which could be applied
to the full cohort. A unique feature of this approach
is the use of RCS models to account for non-linear
and non-step changes in serum levels over time that
are reflective of the variation in fluctuating usage/
emissions of C8 by the plant and the progressive introduction of engineering and work practice controls
over time. The X values (T1–3) from the RCS function were then used in linear mixed models to develop terms to use with calendar time for the
estimation of historical exposures for the cohort.
RCS models in conjunction with linear mixed effect
models were also used to evaluate atrazine exposures
among pesticide applicators (Hines et al., 2006).
However, those models were not used for developing
retrospective exposure estimates. The modeling described here found more between-worker than
within-worker variance. This has also been noted
by the few other occupational studies that have examined this topic for more persistent chemicals like
mercury and lead (Symanski and Greeson, 2002).
Several authors have described how adding fixed effects to models alter variance components for air
samples, but this has not been widely done for biomarkers (Peretz et al., 2002; McClean et al.,
2004). In this study, the fixed effects including covariates that reflect calendar time changes in the plant
operations explained 27–31% of the variance of the
jobs with potential PFOA exposure. One measure
that has been used to describe the potential bias
introduced when modeling exposure response relationships is the estimated within-worker
to be
tween-worker variance ratio k5r2W r2B . When k
is smaller, the potential bias is less. A study of 127
datasets found that biomarker data had a lower median variance ratio (1.04) than air sampling data
(2.40), suggesting that biomarker can provide a less
biased surrogate for exposures than typical air sampling (Lin et al., 2005). In our own data, lambda
ranged from 0.20 to 0.80 across the five regression
models.
Use of biomonitoring data collected for surveillance purposes to model retrospective exposures
has inherent limitations. In this study, the frequency
of monitoring varied over time and exposure category and although attempts at adjustment have been
made, the methods of analysis changed over time as
well. Nevertheless, we believe the approach described here represents an improvement in the specificity of exposure characterization for this cohort.
We believe that the use of smoothing better accounts
for the gradual changes in serum levels over time due
to process changes; however, it cannot predict levels
beyond the range of the data. Thus, for the direct exposure jobs where we lack data, we have presumed
that process changes (our interpretation the spline
function) did not have a significant impact on exposures before 1979 (earliest serum data). Nevertheless, there remained some aspect of time in the
prediction models since the amount of C8 used in
the plant did remain an important predictor of exposure before 1979 for the fine powder/granular PTFE
jobs. In addition, the models described here do not
include important personal characteristics that may
influence serum levels. For example, studies have reported that age, race, and gender are associated with
PFOA serum levels (Calafat et al., 2007; Steenland
et al., 2009a). Although we do not include age in
our models, to some extent, age is implicitly included since workers tended to stay at the plant
and all serum prediction models included a covariate
for cumulative years in potentially exposed jobs.
12 of 13
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Another influence on worker serum levels may have
come from personal exposures via water in communities surrounding the plant (Emmett et al., 2006;
Steenland et al., 2009a). The exposure estimates reported here do not explicitly account for residential
exposures over time, although it is believed that relative to workplace exposures these are relatively
small. For example, current workers were reported
to have a median serum PFOA level of 0.147 versus
0.074 ppm for former workers and 0.028 ppm for
current/former residents in the study of the nearby
community member PFOA levels (Steenland et al.,
2009b).
To evaluate the health effects of chronic exposure
to PFOA in this cohort, it would be ideal to have personal biomarker data for the full historical period for
each cohort member. However, since that is not possible, a method to retrospectively estimate exposures
with minimal misclassification is needed. We believe
the method described here has strengths in accommodating gradual changes over time in serum PFOA
levels by tying exposure levels to process changes
and plant usage patterns and maximizing the number
of job groups for which historical estimates are
made. Our comparisons of predicted with internal
and external measurement data were favorable
(Spearman correlations of 0.8 and 0.6, respectively),
suggesting the models perform well in predicting
worker exposures. The annualized PFOA serum
estimates developed here will be used in a series of
morbidity and mortality studies of this worker cohort.
FUNDING
C8 Class Action Settlement Agreement (Circuit
Court of Wood County, West Virginia) between
DuPont and Plaintiffs.
Acknowledgements—Many thanks to the Teflon employees and
retirees who assisted in gathering historical information to help
us understand historical process changes and how to assign
work record department/division/job combinations to job
groups similarly exposed to C8. Thanks to Dr James Deddens
for advice and assistance with the RCS approach and SAS
Macro. This research was funded by the C8 Class Action Settlement Agreement (Circuit Court of Wood County, West Virginia) between DuPont and Plaintiffs, which resulted from
releases into drinking water of the chemical PFOA (C8). Funds
are administered by an agency that reports to the court. The work
and conclusions are independent of either party to the lawsuit.
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