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January 8, 2009
Q�
Q Provisional Health Advisories for
Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS)
1. Introduction
EPA recently concluded limited testing of agricultural sites in Alabama where sewage
sludge was applied from a local wastewater treatment plant that receives wastewater from
numerous industrial sources, including facilities that manufacture and use
perfluorooctanoic acid (PFOA) and other perfluorinated chemicals (PFCs). The results
from this limited testing indicated elevated levels of PFCs in the sludge and the soil that
received the sludge. As a result, EPA has conducted sampling of public drinking water.
The levels of PFOA and perfluorooctane sulfonate (PFOS) recently analyzed in
community water systems in Lawrence and Morgan Counties are all lower than 0.04 ppb.
Based on its current understanding, EPA believes these levels are not of concern and
residents may rely upon public water systems. EPA will soon begin groundwater and
surface water sampling to determine if PFOA or PFOS has migrated into any private
drinking water supplies and ponds in the affected area.
The Office of Water (OW) has developed Provisional Health Advisory values for PFOA
and PFOS to assess potential risk from exposure to these chemicals through drinking
water. Other PFCs have been found at this site. However, information on the toxicity of
PFCs other than PFOS and PFOA is limited and therefore no attempt is made at the
present time to develop Provisional Health Advisory values for these other PFCs.
2. Summary of Data for PFOA
Epidemiological studies of exposure to PFOA and adverse health outcomes in humans
are inconclusive at present.
Several animal toxicological studies have been conducted using PFOA. These include
subchronic, developmental/reproductive, and chronic toxicity/carcinogenicity studies in
several animal species, in both sexes. An evaluation of these studies was conducted by
the European Food Safety Authority (EFSA) and no -observed -adverse -effect level
(NOAEL), lowest -observed -adverse -effect level (LOAEL), and critical endpoints
identified (EFSA, 2008).
Among these studies, a recent and well conducted developmental toxicity study in mice
was selected by the Office of Water (OW) as the critical study for the derivation of the
1 Provisional Health Advisory values are developed to provide information in response to an urgent or
rapidly developing situation. They reflect reasonable, health -based hazard concentrations above which
action should be taken to reduce exposure to unregulated contaminants in drinking water. They will be
updated as additional information becomes available and can be evaluated.
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Provisional Health Advisory for PFOA (Lau et al., 2006). In this study, CD-1 mice were
given the ammonium salt of PFOA by oral gavage from gestational day (GD) 1 to 17 at
doses of 0, 1, 3, 5, 10, 20 or 40 mg/kg/day. Significant increase in the incidence of full -
litter resorption occurred at 5 mg/kg/day and higher doses. Weight gain in dams that
carried pregnancy to term was significantly lower in the 20-mg/kg/day group. At GD 18,
some dams were sacrificed for maternal and fetal examinations (group A), and the rest
were treated once more with PFOA and allowed to give birth (group B). Postnatal
survival, growth, and development of the offspring were monitored. PFOA induced
enlarged liver in group A dams at all dosages, but did not alter the number of
implantations. The percent of live fetuses was lower only in the 20-mg/kg/day group (74
vs. 94% in controls), and fetal weight was also significantly lower in this group.
However, no significant increase in malformations was noted in any treatment group. The
incidence of live birth in group B mice was significantly lowered by PFOA: ca. 70% for
the 10- and 20-mg/kg/day groups compared to 96% for controls. Postnatal survival was
severely compromised at 10 or 20 mg/kg/day, and moderately so at 5 mg/kg/day. Dose -
dependent growth deficits were detected in all PFOA-treated litters except the 1-
mg/kg/day group. Significant delays in eye-opening (up to 2-3 days) were noted at 5
mg/kg/day and higher dosages. Accelerated sexual maturation was observed in male
offspring, but not in females. These data indicate maternal and developmental toxicity of
PFOA in the mouse, leading to early pregnancy loss, compromised postnatal survival,
delays in general growth and development, and sex -specific alterations in pubertal
maturation (Lau et al., 2006).
Toxicity endpoints identified in the Lau et al. (2006) study included a number of
developmental landmarks: neonatal eye opening, neonatal survival and body weight at
weaning, reduced phalangeal ossification at term, live fetus weight at term, maternal liver
weight at term, and maternal weight gains during pregnancy. The most sensitive
endpoint was for increased maternal liver weight at term. This endpoint for liver effects
was identified in a number of other studies described in EFSA (2008).
Benchmark dose (BMDIO) and the 95% lower bound on the BMD (BMDLIO) were
calculated for these toxicity endpoints by the EFSA on the basis of raw data provided by
the principal author (Lau, personal communication, November 18, 2008). The lowest
BMDLIO in the Lau et al. (2006) study was 0.46 mg/kg/day for increase in maternal liver
weight at term. This value was used as the point of departure for the derivation of the
Provisional Health Advisory value for PFOA. It should be noted that liver effects were
also reported in studies in rats and monkeys. BMDLIO values for increased liver weight
in studies in mice and rats ranged from 0.29 to 0.74 mg/kg/day (EFSA, 2008). The
BMDLIO for Lau et al. (2006) was in the middle of this range.
3. Summary of Data for PFOS
Epidemiological studies of exposure to PFOS and adverse health outcomes in humans are
at present inconclusive at present.
2
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Several animal toxicological studies have been conducted with PFOS. These include
subchronic, developmental/reproductive, and chronic toxicity/carcinogenicity studies in
several animal species, in both sexes. An evaluation of these studies was conducted by
the F.FSA (2008) and NOAEL, LOAEL and critical endpoints identified.
The subchronic toxicity study in Cynomolgus monkeys (Seacat et at., 2002) was selected
by the OW as the critical study for the derivation of the Provisional Health Advisory
value for PFOS. In the study by Seacat et al. (2002), groups of male and female monkeys
received orally potassium PFOS at doses of 0, 0.03, 0,15 or 0.75 mg/kg/day for 183 days.
Compound -related mortality in 2 of 6 male monkeys, decreased body weights, increased
liver weights, lowered serum total cholesterol, lowered triiodothyronine (T3)
concentration, and lowered estradiol levels were seen at the highest dose tested. At 0.15
mg/kg/day, increased levels of thyroid -stimulating hormone (TSH) in males, reduced
total T3 levels in males and females, and reduced levels of high -density lipoproteins
(FIDL) in females were seen. A NOAEL of 0.03 mg/kg/day was identified in this study.
4. Calculation of Provisional Health Advisories for PFOA and PFOS
The general equation for the derivation of a Provisional Health Advisory is:
(NOAEL or BMDL1olx BW x RSC
LJF x Extrapolation Factor x Water intake
Where BW = body weight; RSC = relative source contribution; OF = uncertainty factors
The OW is using the exposure scenario of a t0-kg child consuming 1 L/day of drinking
water to calculate the Provisional Health Advisories for PFOA and PFOS. This
population subgroup was used because children, who consume more drinking water on a
body weight basis than adults, have a higher exposure on a body weight basis than adults.
The selection of children's exposure parameters will help to ensure that this Provisional
Health Advisory is protective of sensitive populations potentially exposed. A default
relative source contribution (RSC) of 20% was used to allow for exposure from other
sources such as food, dust and soil. The relevant period of exposure for the Health
Advisory is a short term exposure. This time period is consistent with the toxicity data
used for PFOA and PFOS, both of which rely upon subchronic data. The value should be
protective of all population subgroup and lifestages.
Data derived extrapolation factors for toxicokinetics were developed to better
approximate internal doses for PFOA and PFOS. This step was deemed important
because of the marked differences in retention time among humans and the test species in
which toxicologic data were collected. Available data for PFOA from female mice
indicate a half-life of 17 days and from humans, a half-life of 3.8 years (1387 days).
Critically, measures of internal exposure should be used as the basis for interspecies
extrapolation; the assessment is somewhat complicated by the lack of area under the
curve (AUC) or clearance (CL) data. However, the one -compartment model foundation
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is useful to convert half-life data to clearance data, assutnin2 steady-state has been
reached (Equation 1). v
Half-life = (In 2 or 0.693) x Volume of Distribution / CL (1)
The volume of distribution of 198 ± 69 ml/kg has been estimated in female monkeys
(Butenhoff et at., 2004). Olsen et al. (2007) summarized other findings on PFOS and
PFOA as indicating primarily an extracellular distribution volume. Olsen et al. (2007)
also cited other reports that these agents were highly bound to plasma proteins in rats,
monkeys and humans. Together, these data support using the same volume of
distribution for rodents and humans, based on the findings (198 ml/kg) in monkeys.
The mouse half-life of 17 days converts:
CL = (0.693 x 198 mUkg) / 17 days = 8.07 mUkg/day
The human half-life of 1387 days converts:
CL = (0.693 x 198 mUkg) / .1387 days = 0.10 ml/kg/day
Calculating the toxicokinetic portion of the interspecies on the basis of plasma CL would
be:
CL, animal / CL human = 8.07 ml/kg/day / 0.10 ml/kg/day = 80.7
The total interspecies correction derived from using a 3X for toxicodynamics and 81X for
toxicokinetics is 243X.
To calculate the Provisional Health Advisory for PFOA, a default intraspecies uncertainty
factor of 10 was applied to the BNIDLIO of 0.46 mg/kg/day to account for variation in
susceptibility within the human population. A default uncertainty factor of 3 was used
for toxicodynamic differences between animals and humans.
The following Provisional Health Advisory is obtained
PFOA Provisional Health Advisory = 0.46 x 1000 x 10 x 0.2 = 0.4 µg/L
10x3x81x1
Similarly, a data -derived extrapolation factor was developed for PFOS. The half-lives of
PFOS in humans and in male and female monkeys were estimated by Lau et al., (2007) to
be 5.4 years and 150 days, respectively.
The monkey half-life of 1.50 days converts:
CL = (0.693 x 198 mUkg) / 150 days = 0.915 ml/kg/day
The human half-life of 1971 days converts:
CL = (0.693 x 198 ml/kg) / 1971 days = 0.07 tnl/kg/day
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Calculating the toxicokinetic portion of the interspecies on the basis of plasma clearance
would be:
CL animal / CL human = 0.915 ml/kg/day / 0.07 ml/kg/day = 13A
The total interspecies correction derived from using a 3X for toxicodynamics and 13X for
toxicokinetics is 39X.
To calculate the Provisional Health Advisory for PFOS, a default intrrspecies uncertainty
factor of 10 was applied to the NOAEL of 0.03 mg/kg/day to account for variation in
susceptibility within the human population. A default uncertainty factor of 3 was used for
toxicodynamic differences between animals and humans.
The following value is obtained:
PFOS Provisional Health Advisory = 0.03 x 1000 x 10 x 0.2 = 0.2 µg/L
10x3x 13x 1
REFERENCES
Butenhoff JL, Kennedy GL Jr, Hinderliter PM et al. (2004). Pharmacokinetics of
perfluorooctanoate in cynomolgus monkeys. Toxicol Sci. 82:394-406.
EFSA (2008) European Food Safety Authority. Opinion of the Scientific Panel on
Contaminants in the Food Chain on Perfluorooctane sulfonate (PFOS) and
Pertluorooctanoic acid (PFOA) and their Salts. EFSA Journal, 2008, Journal number
653, 1-131; available at http://www.cfsa.europa.eu/EFSA/efsa locale
1178620753812 1211902012410.htm).
Lau C, Thibodeaux JR, Hanson RG et al. (2006). Effects of perfluorooctanoic acid
exposure during pregnancy in the mouse. Toxicol. Sci. 90 (2) 510-518.
Lau C, Anitole K, Hodes C et al. (2007), Perfluoroalkyl acids: A review of monitoring
and toxicological findings. Toxicol. Sci. 99 (2) 366-394.
Olsen GW, Burris JM, Ehresman DJ et al. (2007). Half-life of serum elimination of
perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired
fluorochemical production workers. Environ Health Perspect. 115: 1298--1305.
Seacat AM, Thomford PJ, Hansen KJ et al. (2002). Subchronic toxicity studies on
perfluorooctanesulfonate potassium salt in Cynomolgus monkeys. Toxicol. Sci. 68, 249-
264.
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