DEQ-CFW_00001469

oke
Recommended Interim Maximum Allowable Concentration for Perfluorooctanoic Acid
(PFOA or C8)
1. Summary
An Interim Maximum Allowable Concentration (IMAC) has been developed for PFOA:
Recommended PFOA IMAC = 0.002 mg/L or 2µg/L
Basis for level: RfD = 0.0003 mg/kg-day;
Critical endpoints = Reduction in mean body weight and body weight gain from Fl male rat pups
and F1 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). CAS number 335-67-1
Molecular formula of C8HF1502. One of its salts, ammonium perfluorooctanoate (APFO;
C8171502NH4; CAS Number 3825-26-1) is the compound that is the most widely used in industry and
most animal toxicology studies have been carried out with this compound. Once absorbed in the
body, APFO disassociates to the PFOA anion.
3. Basis for IMAC
The first step in developing an IMAC or ground water quality standard for PFOA, in accordance
with 15A NCAC 2L .0202, requires analysis of existing data to determining whether the proposed
concentration is based on the carcinogenic or noncarcinogenic effects. 15A NCAC 2L .0202
indicates that the level must be upon the "least of a systemic threshold concentration (non -cancer
endpoint) or a concentration which corresponds to an incremental lifetime cancer risk of 1 x 10-6
(cancer endpoint). If 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 appropriate concentration. 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/rn). From
the unit risk, risk -specific doses can be derived that estimate the dose associated with a specific risk
level, for North Carolina a one -in -a -million (1 x 10-6) increased lifetime risk is calculated.
If the IMAC is based on noncarcinogenic effects, then the chemical is assumed to exhibit a
threshold and a Reference Dose (RfD) is developed. The RfD 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 RfD 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.
DEQ-CFW 00001469

PFOA IMAC Proposal
November 7, 2006
Supporting Documentation
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 Science Advisory Board (EPA 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 EPA 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.
In August 2002, the West Virginia Department of Environmental Protection issued its "Final
Ammonium Perfluorooctanoate (C8) Assessment of Toxicity Team (CATT) Report". This report
was the result of a consent order between the State of WV and DuPont. The consent order indicated
that a scientific team was to 1) determine risk -based human health protective screening levels of C8
in air, water, and soil; 2) provide health risk information to the public, and 3) determine an
ecological health protective screening level for C8 in surface water.
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.
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Supporting Documentation
• 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.
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 RfD 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).
On November 20, 2006, EPA Regions 3 and 5 signed a Consent Order with E.I. DuPont de
Nemours & Co. lowering the site -specific action level for PFOA in drinking water sources near the
DuPont Washington Works facility, located in Parkersburg, West Virginia. This Consent Order
replaces the 2002 Order and states that DuPont must offer alternative drinking water or treatment
for public water or private water users living near the facility if the level of PFOA detected in
drinking water is equal to or greater than 0.5 ppb (µg/L). This concentration is site -specific and is
not currently being proposed as a federal Maximum Contaminant Level.
This new order establishes a temporary "site -specific action level" for drinking water of 0.5 ppb C-
8, based on new information available about blood serum levels of C-8 in the local population and
recent scientific studies. The 0.50 ppb site -specific action level for C-8 is a threshold for DuPont to
provide treatment or alternate water to public and private water users in the vicinity of the
Washington Works facility. EPA is currently conducting a risk assessment under the Toxic
Substances Control Act, 15 U.S.C. §§ 2601 et. seq; until the risk assessment process is complete
there will not be a reference dose or maximum contaminant level for drinking water. A final risk
assessment may not be completed for several years. Once a final risk assessment is completed, or if
further information about the health effects of C-8 indicate it is necessary, the WV site -specific
action level of 0.50 ppb C-8 established in this order will be reevaluated. The agency is funding
additional research regarding the toxicity of C-8 and other perfluorochemicals, as well as research
to help identify where these chemicals are coming from and how people may be exposed to them.
Information on this action is available from EPA Region 3.
Without adequate information to support a calculation of a Cancer Slope Factor, the IMAC for
PFOA has been calculated with an RfD of 0.003 mg/kg-day considering non -carcinogenic effects.
Dr. Luanne Williams, a toxicologist with the North Carolina Department of Health and Human
Services, has indicated some uncertainty in using the chronic oral reference dose of 0.0003 mg/kg-
day for calculating an IMAC for PFOA. Indicating that there is uncertainty associated with the
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PFOA IMAC Proposal
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Supporting Documentation
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. RfD 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 RfD 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 RfD derivation. The human
studies were determined to be inadequate for RfD determination (all studies reviewed and
summarized in EPA, 2005a and West Virginia DEP, 2002).
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 (M)
(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
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Cnr,r�nrtina T)nnmmnntntinn
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
(M)
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
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 (APFU or YNUA) not reportea
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PFOA IMAC Proposal
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Supporting Documentation
**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 F, 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 = Ammonium perfluorooctanoate
PFOA = Perfluorooctanoic acid
York et al., 2002; Butenhoff et al., 2004 was selected as the critical study for the derivation of the
RfD. 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 RfD for PFOA:
Table 2. RfD for PFOA
Study
Critical
Effect
NOAEL
LOAEL
OF
RfD
York et al.
Reduction in
NOAEL was
1 mg/kg-
3,000
0.0003
2002;
mean body
not
day APFO
mg/kg-day*
Butenhoff et
weight and
determined
al. 2004
body weight
since effects
gain from F,
were seen at
male rat pups
all doses
and FI male
tested.
adults
*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.
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Supporting Documentation
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. IMAC Calculation
A ground water quality standard is derived from the multiplication of the RfD by the assumed body
weight of an adult (70 kg) and divided by the assumed daily water consumption (2L) of an adult.
This value is then multiplied by a relative source contribution to take into account exposures from
other sources i.e., food, air etc. (RSC). The Groundwater regulations establish the RSC at 20% for
organic chemicals and 10% for inorganic chemicals. The following equation is used (NC, 2005a):
IMAC 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
RSC = Relative source contribution, default = 20% for organics
DI = Daily water intake for an adult, default = 2 L/day
Interim Maximum Allowable Concentration for PFOA
= 0.0003 mg/kg-day x 70 kg_x 0.20 = 0.002 mg/L = 2 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:
htlp://www.eDa.gov/opptintr/pfoL/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.
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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. Environmental Science and Technology. 40(1):32-44.
West Virginia Department of Environmental Protection, 2002. Final Ammonium
Perfluorooctanoate (C8) Assessment of Toxicity Team (CATT) Report. Available at:
htlp://www.do.state.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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