DEQ-CFW_00002167

Recommended Water Screening Level for Perfluorooctanoic Acid (PFOA or C8)
1. Summary
A water screening level has been developed for PFOA:
Recommended PFOA water screening level = 0.0021 mg/L or 2.1 µg/L
Basis for level: RfD = 0.0003 mg/kg-day; Critical endpoints = Reduction in mean body weight
and body weight gain from F, male rat pups and F, adult male rats (Fl generation from Fo adult
rats) and increased liver weights in Fo parental males; Critical study = Two generation rat gavage
study by York et al., 2002 and Butenhoff et al., 2004.
2. Background
The chemical name for C8 is Perfluorooctanoic acid (PFOA). It has a CAS number of
335-67-1 and a molecular formula of C8BF1502. One of its salts, ammonium
perfluorooctanoate (APFO; C8F1502NH4; CAS No. 3825-26-1) is the compound that is
the most widely used in industry and most of the animal toxicology studies have been
carried out with this compound. Once absorbed in the body, APFO disassociates to the
PFOA anion.
3. Basis for Screening Levels
The first step in developing a water screening level for PFOA involves determining
whether the level should be based on the carcinogenic or noncarcinogenic effects of the
chemical. If the screening level is based on carcinogenic effects, then the chemical is
assumed to not exhibit a threshold and a risk approach is used to develop the basis for the
screening levels. In the risk approach, a study (usually animal but can be human) that
examined carcinogenic effects is selected to be the basis for the assessment.
Mathematical models are used to determine a cancer slope factor based on the results
seen in the study. A cancer slope factor is an upper -bound estimate of risk per increment
of dose. From the cancer slope factor, unit risk estimates are developed. Unit risk
estimates convert the cancer slope factor to units of drinking water (µg/L) or air (µg/fn).
From the unit risk, risk -specific doses can be derived that estimate the dose associated
with a specific risk level, for example, a one -in -a -million (1 x 10-6) increased lifetime
risk.
If the screening level is based on noncarcinogenic effects, then the chemical is assumed
to exhibit a threshold and a Reference Dose (RfD) is developed. The Rfl) is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the
human population (including sensitive subgroups) that is likely to be without an
appreciable risk of deleterious effects during a lifetime. The Rfl) is calculated to be
protective against a critical effect, which also results in protection against other effects at
higher doses. The RfD is expressed in units of mg/kg (body weight) -day.
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Epidemiological studies in workers have not seen an increase in cancer from exposure to
PFOA. Two animal carcinogenicity studies have been carried out. One study reported
increases in Leydig cell adenomas and mammary gland fibroadenomas. The second study
reported increases in tumors in the liver, Leydig cells, and pancreas. EPA's draft risk
assessment on PFOA (EPA, 2005a) concluded "overall, based on no adequate human
studies and uncertain human relevance of the tumor triad (liver, Leydig cell and
pancreatic cell tumors) from the rat studies, PFOA may be best described as "suggestive
evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential"
under the draft 1999 Guidelines for Carcinogen Risk Assessment."
EPA's SAB submitted a report on January 20, 2006 on EPA's draft risk assessment. In
this report, they stated that the majority of panel members concluded that the
experimental weight of evidence with respect to the carcinogenicity of PFOA was
stronger than proposed in the draft document, and suggested that PFOA is a "likely"
carcinogen in humans. This was based on the following:
• While human data is ambiguous, two animal studies have shown carcinogenic
effects at several sites.
• There exist too many uncertainties in the mode of action for liver tumors to say
that they are not relevant to humans.
• Mammary gland adenocarcinomas seen in the animal study should be considered
related to PFOA treatment.
• Insufficient data are available to determine the mode of action for the Leydig
cell, pancreatic, and mammary gland tumors, and thus they must be presumed to
be relevant to humans.
A few members of the SAB did not find the weight of evidence sufficient to support the
"likely" descriptor and agreed with the EPA's conclusion that PFOA showed suggestive
evidence of carcinogenicity. This was based on the opinion that the mode of action for
the liver tumors was not relevant to humans and that the mammary gland tumors were not
demonstrated in animals when compared to historical controls.
The following are the key reasons why the West Virginia Assessment of Toxicity Team
for PFOA (CATT) did not conclude that the animal carcinogenicity data indicates that
PFOA is probably carcinogenic in humans (WV DEP, 2002):
• PFOA has not been shown to be genotoxic. Genotoxic compounds bind to DNA
and are more likely to be carcinogenic than nongenotoxic compounds. Although
nongenotoxic compounds can be carcinogenic, they are usually much weaker
carcinogens that pose a lesser risk to human health.
• The liver tumors seen in the animals were probably caused by a mechanism of
action that is not relevant in humans.
• The Leydig cell tumors are rarely seen in humans and the mechanism of action
appears to be non -linear.
• Technical questions on whether the mammary gland adenocarcinomas and
pancreatic tumors were related to the PFOA treatment.
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The EPA has not calculated a cancer slope factor for PFOA. The West Virginia CATT
concluded that they would base their water and soil screening levels on the
noncarcinogenic endpoints of PFOA (the RfD). They stated that they believed that the
RM would be protective against the possibility of liver tumors and Leydig cell tumors,
since these tumors, if shown to be relevant to humans, would operate under a
nongenotoxic, non -linear mechanism (WV DEP, 2002). The EPA Guidelines for
Carcinogen Risk Assessment state that, "For cases where the tumors arise through a
nonlinear mode of action, an oral Reference Dose or inhalation Reference Concentration
should be developed in accordance with EPA's established practice. This approach
expands the past focus of such reference values (previously reserved for effects other
than cancer) to include carcinogenic effects determined to have a nonlinear mode of
action" (EPA, 2005b).
Based on the reasons outlined in the above paragraph, the water screening level for
PFOA has been calculated based on the RfD of 0.0003 mg/kg-day considering
noncarcinogenic effects. According to Dr. Luanne Williams, a toxicologist with the North
Carolina Department of Health and Human Services, there is some uncertainty in using
the chronic oral reference dose of 0.0003 mg/kg-day for calculating a water screening
level for PFOA. There is uncertainty associated with the reference dose of 0.0003
mg/kg-day because of the serious critical data gaps in the carcinogenicity and toxicity of
PFOA (Williams L, 2006).
4. RiD Development
An RfD is calculated as follows:
• Review available human and animal studies on the chemical
Weigh studies for applicability to be used as the critical study for RM
determination. Some of the determining factors are:
o Length of study
o Number of animals used
o Endpoints examined
o Relevance of route of exposure
o Quality of study (follows EPA or other guidelines)
o Exposure levels defined (often a problem in epidemiology studies)
o Critical effect determined
• Determine critical study
• Determine highest dose level at which a critical adverse effect does not occur
(NOAEL) or the lowest dose level at which a critical adverse effect does occur
(LOAEL) from the critical study
• Determine appropriate uncertainty factor (UF) to be applied to the NOAEL or
LOAEL
• Divide NOAEL or LOAEL by UF.
Table 1 presents a summary of the studies that were considered for RM derivation. The
human studies were determined to be inadequate for RM determination (all studies
reviewed and summarized in EPA, 2005a and West Virginia DEP, 2002).
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Table 1. Studies Considered for RfD Derivation
Study
Animal (sex)
Length
Doses
NOAEL
LOAEL
Effects
(route)
(mg/kg-day)
(mg/kg-
(mg/kg-
for APFO
day)
day)
and PFOA
as indicated
Thomford et
Cynomolgus
26 weeks
0, 3, 10, 30
ND
3
Increased
al, 2001
monkey (1VI)
(oral capsule)
APFO
liver weights,
possible
mortality
Goldenthal,
Rhesus
13 weeks
0, 3, 10, 30,
ND
3
Clinical signs
1978b
monkey
(gavage)
100 PFOA
(M,F)
Goldenthal,
CD rats
13 weeks
0, 0.56, 1.72,
1978a
M
(diet)
5.64, 17.9,
0.56
1.72
Increased
63.5 PFOA
liver weights
(F)
0, 0.74, 2.3,
7.7, 22.4,
22.4
76.5
Increased
76.5 PFOA
liver weights
Palazzolo,
ChR-CD rats
13 weeks
0, 0.06, 0.64,
0.06
0.64
Increased
1993; Perkins
(M)
(diet)
1.94, 6.50
liver weights,
et al., 2004
APFO
liver
hypertrophy
Sibinski,1987
Sprague-
2 years (diet)
Dawley rats
(NI)
0, 1.3, 14.2
1.3
14.2
Increased
liver weights,
1.6, 16.1
liver
(F)
APFO
1.6
16.1
hypertrophy
Decreased
body
weights,
effects on
blood
Cook et al.,
Sprague
2 years (diet)
0, 14.2 NR*
ND
14.2
Increased
1994
Dawley rats
liver weights
(M,F)
Riker
Rats
2 years (diet)
Laboratories,
(M)
0, 1.3, 14
1.3
14
Increased
1983
0, 1.6, 16
liver weights
(F)
NR*
ND
1.6
Ovarian
hyperplasia.
York et al.,
Sprague-
2-generation
0, 1, 3, 10, 30
ND
1
Increased
2002;
Dawley rats
reproductive
APFO
liver weight
Butenhoff et
(M, F)
study
**
al., 2004
(gavage)
ND
1
Significant
reduction in
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mean body
weight gain
ND
1
Decreased
body weight
and body
weight gain
Gortner, 1981
Sprague
GD 6-15
0, 0.05, 1.5,
150
ND
No effects
Dawley rats
5,150 APFO
(M, F
Staples, 1984
Sprague-
GD 6-15
0, 100 APFO
100
ND
No effects
Dawley rats
(M,F)
Gortner, 1982
New Zealand
GD 6-18
0, 1.5, 5, 50
5
50
Development
white rabbits
APFO
al effects,
such as extra
rib
* NR = compound (APFO or PFOA) not reported
**Effect noted in Fo parental males (shown on page 72 of EPA 2005a). However, a mode of action analysis has
demonstrated that the liver effects on rats are due to a peroxisome proliferator-activated receptor alpha or PPAR a
—agonism According to EPA, this mode of action is unlikely to occur in humans (shown on page 8 of EPA
2005a).
***Effect noted in FI male pups (pups from Fo adult rats) (shown on page 68 of EPA 2005a).
****Effect noted in Fl adult males (pups from Fo adult rats) (shown on page 73 of EPA 2005a).
GD = gestational day
ND = not determined since effects were seen at all doses tested
APFO = Ammonum pertluorooctanoate
PFOA = Perfluorooctanoic acid
York et al., 2002; Butenhoff et al., 2004 was selected as the critical study for the
derivation of the RM. The reasons for this include the fact that the study:
• Is of excellent quality
• Follows EPA OPPTS guidelines for conducting reproductive/developmental
studies
• Examined for multiple organ effects as well as developmental effects from two
rat generations.
• Presents the lowest LOAEL of all the chronic and developmental studies (the only
study with a lower LOAEL (0.64 mg/kg-day) Palazzolo, 1993; Perkins et al. 2004
is only 13 weeks duration).
Table 2 presents the study and factors used to calculate the RM for PFOA:
Tahle 2. RfD for PFOA
Study
Critical
NOAEL
LOAEL
OF
RtD
Effect
York et al.
Reduction in
NOAEL was
1 mg/kg-
3,000
0.0003
2002;
mean body
not
day APFO
mg/kg-day*
weight and
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Butenhoff et
body weight
determined
al. 2004
gain from F,
since effects
male rat pups
were seen at
and Fl male
all doses
adults
tested.
`According to Dr. Luanne Williams, a toxicologist with the North Carolina Department of Health and Human
Services, the 1 mg/kg-day LOAEL for APFO could be used with some caution to derive a chronic oral reference dose
of 0.0003 mg/kg-day for calculating groundwater and soil screening levels for PFOA. There is uncertainty associated
with the reference dose of 0.0003 mg/kg-day because of the serious critical data gaps in the carcinogenicity and toxicity
of PFOA (Williams L, 2006).
A total uncertainty factor (UF) of 3,000 (UF = UFH (10) x UFA (10) x UFs (1) x UFL (10)
x UFD (3) = 3,000) was used, consisting of the following areas of uncertainty:
1. Intraspecies variability (UFH). This factor accounts for the natural differences that
occur between human subpopulations and for the fact that some individuals may
be more sensitive than the average population. EPA recommends values of 3-10
for this factor. UFH =10 because have not defined the most sensitive
subpopulation for C8.
2. Interspecies variability (UFA). This factor is used to account for differences in
response between animals and humans. EPA recommends values of 1-10 for this
factor. UFA =10 because no data available on quantitative differences between
animals and humans in pharmacokinetics of C8.
3. Subchronic to Chronic Extrapolation (UFs). This factor is applied when the
database lacks information on the health effects of the chemical following lifetime
exposure. EPA recommends values of 1-10 for this factor. UFs =1 because many
chronic studies available on C8.
3. LOAEL to NOAEL Extrapolation (UFL). This factor is applied when
extrapolating from a LOAEL to a NOAEL. UFL =10 since a LOAEL (reduction
in mean body weight gain) was used in the calculations.
4. Database (UFD). This factor is applied when there are significant data gaps on the
chemical. EPA recommends values of 1-10 for this factor. UFD = 3 since there are
database gaps on the toxicity of PFOA.
5. Water Screening Level
A water screening level is derived from the multiplication of the RfD by the assumed
body weight of an adult and divided by the assumed daily water consumption of an adult.
This value is then multiplied by a relative source contribution to take into account
exposures from other sources i.e., the relative source contribution (RSC). The RSC is
assumed to be 20% for organic chemicals and 10% for inorganic chemicals. The
following equation is used (NC, 2005a):
Water Screening Level for PFOA = RfD x BW x RSC
DI
Where: RfD = RfD PFOA = 0.0003 mg/kg-day
BW = Body weight of an adult, default = 70 kg
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RSC = Relative source contribution, default = 20% for organics
DI = Daily water intake for an adult, default = 2 L/day
Water Screening Level for PFOA
= 0.0003 mg/kg-du x 70 kg x 0.20 = 0.0021 mg/L = 2.1 µg/L
2 L/day
6. References
EPA, 2005a. Draft Risk Assessment of the Potential Human Health Effects Associated
with Exposure to Perfluorooctanoic acid and its Salts. Office of Pollution Prevention and
Toxics, Risk Assessment Division. SAB Review Draft. Available at:
hUp://www.epa.g_ov/opptigtr/pfoa/pfoarisk.htm
EPA, 2005b. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/001F.
EPA, 2004. Users Guide and Background Technical Document for USEPA Region 9's
Preliminary Remediation Goals (PRG) Table.
North Carolina Department of Environment and Natural Resources, 2005a.
Classifications and Water Quality Standards Applicable to the Groundwaters of North
Carolina. Subchapter 2L. Division of Water Quality.
North Carolina Department of Environment and Natural Resources, 2005b. Guidelines
for Establishing Remediation Goals at RCRA Hazardous Waste Sites. Division of Waste
Management, Hazardous Waste Section.
Prevedouros K, Cousins, IT, Buck, RC, Korzeniowski, SH. Sources, Fate and Transport
of Perfluorocarboxylates. 2006. Environ Sci Technol. 40(1):32-44.
West Virginia Department of Environmental Protection, 2002. Final Ammonium
Perfluorooctanoate (C8) Assessment of Toxicity Team (CATT) Report. Available at:
hqp://www.depstate wv us/item cfm?ssid=l l&sslid=665
Williams L, 2006. Dr. Luanne K. Williams, Toxicologist with the North Carolina
Department of Health and Human Services.
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