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5
State of New Jersey
Jon S. Corzine Department of Environmental Protection Lisa P. Jackson
Governor Division of Science, Research and Technology Commissioner
P.O. Box 409
Trenton, NJ 08625-0409
MEMORANDUM
TO: Barker Hamill, Assistant Director for Water Supply Operations
THROUGH: Alan Stern, Dr.P.H., DABT, Chief, Risk Analysis Section, DSRT
Eileen Murphy, Ph.D., Director, DSRT
FROM: Gloria Post, Ph.D., DABT, Research Scientist, Risk Analysis Section, DSRT
SUBJECT: Guidance for PFOA in Drinking Water at Pennsgrove Water Supply Company
This memorandum is written to assist the Bureau of Safe Drinking Water in its response to the
request from the Pennsgrove Water Supply Company for guidance in assessing the public health
implications of the recent detections of perfluorooctanoic acid (PFOA) in that system's drinking
water. Approaches for development of health -based drinking water guidance for PFOA based on
both non -cancer and cancer endpoints are discussed below.
This assessment was developed in order to provide preliminary guidance within a reasonable time
frame, and the recommendations will be reevaluated in the future as additional relevant
information becomes available. Although key primary scientific literature was reviewed as
appropriate, this assessment takes as its starting point the findings of the USEPA (2005) draft risk
assessment for PFOA and the final recommendations of the USEPA Science Advisory Board
(SAB) on the draft USEPA risk assessment (USEPA, 2006). Therefore, this memorandum does
not represent a comprehensive review of the toxicological literature on PFOA. Technical review
of the approach and recommendations presented here was provided by Dr. Alan Stern of DSRT
and Dr. Perry Cohn of DHHS.
The goal of the USEPA (2005) risk assessment was to evaluate the significance of exposure to
PFOA that is prevalent throughout the general population, as evidenced by the consistent
detection of PFOA in the blood of people in all age groups. USEPA did not attempt to develop a
human Reference Dose or cancer slope factor, nor did they develop criteria for PFOA in air,
water, or soil. For this reason, the USEPA risk assessment and the SAB review address the
external doses of PFOA which result in adverse effects in experimental animals and the blood
levels of PFOA associated with these external doses. The animal blood levels are then compared
to levels of PFOA found in the blood of the general human population in order to develop
margins of exposure (MOEs) between general human exposure and levels of concern in animals.
However, the USEPA and the SAB did not address the levels of exposure from environmental
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media such as water, food, or air which would result in a given human blood level, and this
information is needed in order to develop health -based guidance for PFOA in drinking water. A
recently completed study (Emmett et al., 2006) provides data on the relationship between PFOA
in drinking water and the human blood level of PFOA, and these data were used in the
development of the health -based guidance values for PFOA as discussed below.
Background - Use of human and animal blood levels rather than ingested dose
The risk assessment approach for PFOA developed in this memorandum is based on a target
human blood PFOA level rather than on a target external (ingested) dose of PFOA, the approach
used for assessing most other chemicals. The reason for the use of blood levels rather than
external dose is that the kinetics of PFOA are very different in humans and experimental animals
because the half-life of PFOA in humans is much longer than in the animals. For this reason, a
given external dose (in mg/kg/day) of PFOA results in very different internal doses (as indicated
by blood levels) in humans and animals. Therefore, a human health criterion should not be based
directly on the external dose found to yield effects (or no effects) in test animals. The USEPA
(2005) draft PFOA risk assessment uses the approach of evaluating No Observed Adverse Effect
Levels (NOAELs), Lowest Observed Adverse Effect Levels (LOAELs), and tumor occurrence
based on the blood levels in the animals rather than on the external dose they received, and this
approach was endorsed by the Science Advisory Board (2006) report reviewing the USEPA draft
PFOA risk assessment.
In order to derive health -based drinking water guidance for PFOA using a risk assessment
approach based on blood levels, the relationship between external dose and blood levels in
humans must be known. The approaches described below all depend on use of the data of
Emmett et al. (2006), who studied the relationship between exposure and blood levels in several
hundred individuals who drank water contaminated with PFOA in Little Hocking, Ohio. Emmett
et al. (2006) found that there is a concentration factor of approximately 100 between drinking
water and blood — that is, a person drinking water with 1 ppb PFOA would be expected to have a
PFOA blood level of approximately 100 ppb. The background blood level of PFOA in the general
population, in all age groups, is about 5 ppb. (The geometric mean is 4.6 ppb and the 901h
percentile value is 9.4 ppb, USEPA (2005)).
Interestingly, two earlier efforts to model the relationship between exposure to PFOA in drinking
water and blood levels of PFOA gave similar results. Hinderliter and Jepson (2001) used simple,
conservative compartmental kinetic modeling to develop a table which predicts a concentration
factor of 300 between drinking water and blood. Gray (2005) used pharmacokinetic modeling to
predict a concentration factor of approximately 100 in adult women and approximately 150 in
adult men.
Additional data on the relationship between exposure to PFOA in drinking water and PFOA
levels in blood, as well as human health effects of PFOA, will be available in the future from the
C8 Health Project. This project was authorized and funded through the settlement of the Class
Action, Jack Leach, et al. v. E.I. du Pont de Nemours and Co. Blood samples have been gathered
from over 68,000 individuals from Ohio and West Virginia who drank water contaminated with
PFOA for at least three years. (C8 Health Project).
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Approaches based on non -carcinogenic effects ofPFOA
USEPA (2005) identified LOAELs or NOAELs for non -cancer effects in male non -human
primates, male and female adult rats, and for developmental effects in male and female rats
exposed prenatally, during lacation, and post -weaning. They calculated Margins of Exposure
(MOEs) for these endpoints. (Additionally, developmental effects were seen in rabbits by Gortner
(1983) but those data were not used by USEPA (2005) in its assessment because information on
blood levels in rabbits was not available.) In the assessment presented here, the endpoints
identified by USEPA (2005) were evaluated as the basis for human health -based drinking water
guidance values for PFOA. As stated above, the blood levels identified in the USEPA (2005) draft
risk assessment and reviewed by the USEPA SAB (2006) are used, rather than reviewing the
primary scientific literature and identifying the NOAELs, LOAELs, and blood levels
independently.
In the assessments presented below, the uncertainty factors typically used in Reference Dose
development are applied to the PFOA blood level identified by USEPA (2005) at the NOAEL or
LOAEL in the experimental animal, rather than to the administered dose. The uncertainty factor
of 10 for interspecies extrapolation typically includes a factor of 3 for toxicokinetic difference and
a factor of 3 for toxicodynamic differences between humans and experimental animals. The
USEPA (2005) draft risk assessment and the risk assessment presented in this memorandum are
both based upon comparison of blood levels in experimental animals and humans. For this reason,
the question arose as to whether toxicokinetic differences are already considered, and whether an
interspecies uncertainty factor of 3 rather than 10 would be appropriate. However, the Science
Advisory Board (2006) addressed this issue and stated that they did not believe that overall
uncertainty about the interspecies differences in PFOA toxicity was sufficiently reduced to justify
modifying the default interspecies uncertainty factor of 10. Therefore, the interspecies uncertainty
factor of 10 was used in the assessments presented here.
As stated above, a 100-fold concentration factor between drinking water and blood was used,
based upon the results of Emmett et al. (2006). Finally, as per the policy of USEPA and New
Jersey DEP in development of human health -based drinking water values for a non -carcinogenic
endpoint, a Relative Source Contribution (RSC) is applied to account for non -drinking water
sources of exposure to the contaminant. The default value for this factor is 20% (meaning that
non -drinking water sources are assumed to provide 80% of total exposure), and 20% is also the
lowest recommended value, even if more than 80% of the recommended exposure comes from
sources other than drinking water. The relative contributions of drinking water versus non -
drinking water exposures to PFOA are not fully characterized at this time. Therefore, for PFOA,
the default value of 20% is an appropriate RSC, and was used in this assessment.
Health -based guidance values based on the NOAELs or LOAELs identified by USEPA for adult
female rats, adult male rats, non -human primates, and developmental effects in male and female
rats are presented below. The basis for these assessments is summarized in Table 1 (attached).
Adult female rats
The NOAEL for female rats identified by USEPA (2005), from a chronic (2 year) dietary
exposure study (Sibinski, 1987), was 1.6 mg/kg/day (30 ppm in diet). At 16.1 mg/kg/day,
decreased body weight gain and decreased erythrocytes, hemoglobin concentration, and
hematocrit occurred.
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In the study of Sibinski (1987), blood levels were not measured, and the blood levels and daily
area under the curve (AUC) in the female rats receiving 1.6 mg/kg/day are estimated by USEPA
(2005) from a pharmacokinetic model. This model is based on pharmacokinetic parameters
obtained from two other studies in adult female rats administered a single dose of PFOA. The
half-life of PFOA in female rats is very short, measured at approximately 3-16 hours depending
on the dose, and in the USEPA pharmacokinetic model, 3.2 hours is used as the half-life.
(USEPA, 2005). Because of the very short half-life of PFOA in female rats, steady-state is not
reached if PFOA is given as a bolus dose, and blood levels will thus fluctuate throughout the day.
As stated above, the rats in the Sibinski (1987) study were exposed through the diet, so that
exposure was more constant than if dosing was by gavage, although daily fluctuations in blood
level almost certainly occurred. The predicted daily AUC for female rats dosed chronically at 1.6
mg/kg/day is 44 ug x hr/ml, which is equivalent to a mean daily blood concentration of about
1800 ppb. Standard uncertainty factors for a NOAEL from a chronic study of 100, including 10
for interspecies extrapolation and 10 for intraspecies extrapolation, were applied to the blood
concentration at the NOAEL of 1800 ppb, resulting in a target blood level in humans of 18 ppb.
Using the 100-fold concentration factor between drinking water and blood discussed above, the
drinking water concentration estimated to result in an increase in PFOA blood level of 18 ppb
(ug/L) is 0.18 ppb, assuming drinking water is the only source of exposure. Application of the
Relative Source Contribution factor of 20% discussed above gives a drinking water concentration
of 0.04 ppb.
Adult male rats
For adult male rats, the LOAEL identified by USEPA (2005) was 1 mg/kg/day for body weight
reduction in the F 1 generation in a two -generation reproductive study using gavage, and a
NOAEL was not established (York, 2002; Butenhoff et al., 2004). Liver and kidney weights were
also increased, both as absolute weight and as their ratio to body weight and to brain weight at
this dose. The half-life of PFOA in male rats is much longer than in female rats, and a half life of
119 hours was assumed by USEPA (2005). At a dose of 1 mg/kg/day, the blood concentration
was predicted by USEPA (2005) to be 42,000 ug/ml. An uncertainty factor of 1000 for a LOAEL
from a chronic study (10 for LOAEL to NOAEL ,10 for intraspecies, and 10 for interspecies) was
applied, resulting in a target human blood level of 42 ppb. The corresponding drinking water
concentration, based on a 100-fold concentration factor between drinking water and human blood
levels and a relative source contribution factor of 20%, is 0.08 ppb.
A NOAEL of 0.06 mg/kg/day and a LOAEL for increased liver weight and hepatocellular
hypertrophy in a subchronic study in male rats (Palazzolo, 1993) of 0.64 mg/kg/day, which is
similar, but slightly lower to the one discussed above, was also identified by USEPA (2005).
USEPA discounted these liver effects by stating that PFOA's effects on the liver in male rats
(cancer and non -cancer) occur solely through a mechanism involving activation of the peroxisome
proliferator alpha receptor (PPAR-alpha) and that this mechanism is not relevant to humans.
However, the Science Advisory Board (USEPA, 2006) disagreed with the EPA's conclusions
regarding the relevance of liver toxicity and liver tumors induced by PFOA. The reasons they
provided were as follows: 1) PFOA's liver toxicity in rats is has not been proven to occur solely
through the PPAR mechanism. For example, a strain of mice that lacks PPAR-alpha (knockout
mice) showed increased liver weight in response to PFOA, but not in response to a well-
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characterized prototype PPAR-alpha agonist (WY-14643). 2) The PPAR mechanism of liver
toxicity may be relevant to humans. In particular, there is uncertainty as to whether the PPAR-
alpha agonists cause liver toxicity in human fetuses, infants, and children, and 3) Some of the
key steps in the proposed PPAR-alpha mechanism of action (liver cell proliferation and apoptosis)
in rats have not been shown to occur after exposure to PFOA. For these reasons, the liver effects
observed in male rats may actually be relevant to humans, contrary to USEPA's interpretation.
Because, as discussed above, this assessment uses as its starting point the endpoints identified by
USEPA (2005), a drinking water criterion based on this endpoint was not calculated.
Non -human primates
For non -human primates, a LOAEL of 3 mg/kg/day was observed in both of two subchronic
studies, a 13 week study in Rhesus monkeys based on clinical signs of toxicity (Goldenthal, 1978)
and a 6 month study of cynomolgus monkeys based on increased liver weight and possibly
mortality (Thomford, 2001; Butenhoff et al, 2002). No NOAEL was established in either study.
USEPA based its assessment on the cynomolgus monkey study because it was longer in duration,
included more animals, and had better serum PFOA data. PFOA levels in serum were measured
in the cynomolgus monkey study and were 77,000 ppb at the 3 mg/kg/day dose. In the case of
non -human primates, it is judged appropriate to use an intraspecies uncertainty factor of 3 rather
than 10 because of the closer relationship between non -human primates and humans, particularly
because pharmacokinetic differences are already at least partially considered. A composite
uncertainty factor of 3000 is applied, including 10 for intraspecies, 3 for interspecies, 10 for less
than chronic duration, and 10 for LOAEL to NOAEL, giving a target human blood concentration
of 26 ppb. The corresponding drinking water concentration, based on a 100-fold concentration
factor between drinking water and human blood levels and a Relative Source Contribution factor
of 20%, is 0.05 ppb.
Rat developmental/reproductive endpoints
Endpoints were also identified by USEPA (2005) from the oral rat two -generation
developmental/reproductive study using gavage doses of 1, 3, 10, and 30 mg/kg/day (York, 2002;
Butenhoff et al. 2004). In this study, male and female rats (FO generation) were dosed for six
weeks prior to and during mating, and the dosing of the females continued through gestation,
delivery, and lactation. Exposure of the F 1 generation was continued through the post -weaning
period, and effects were seen during lactation and post -weaning. During lactation, there was a
reduction in body weight on a litter basis (males and females not evaluated separately) at 30
mg/kg/day. During the post -weaning period, effects on body weight of males occurred at 10
mg/kg/day and at 30 mg/kg/day in females. Additionally, during the post -weaning period,
mortality was increased and sexual maturation was delayed at 30 mg/kg/day in both sexes. Thus,
the NOAEL was 3 mg/kg/day in male offspring and 10 mg/kg/day in female offspring, based on
the post -weaning body weight effects. An overall NOAEL for developmental effects is therefore
3 mg/kg/day.
Development of health -based drinking water concentration based on these effects is complicated
by several factors, as is the case with most multi -generational studies. It is not clear whether the
critical time period for the effects seen in the post -weaning period is during pregnancy, lactation,
or after weaning. Furthermore, for exposure during the prenatal period, it is uncertain whether the
area under the curve (AUC, related to mean blood level) or the maximum blood concentration in
the pregnant female is more relevant to toxicity. Development of the drinking water guidance
value for these endpoints is based on the pharmacokinetic information presented by USEPA
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(2005) for the pregnant mother, and for the male and female pups in the post -weaning period.
(Information is not available for the development of criteria based on exposure during lactation.)
As shown below, these endpoints are not more sensitive than the endpoints for adults discussed
above.
Prey female
Since the mean daily blood concentration in the pregnant female is several -fold lower than the
maximum blood concentration from a single daily gavage dose, the predicted mean daily blood
concentration used here as a conservative choice. As mentioned above, the NOAEL for
developmental effects provided by USEPA was 3 mg/kg/day. The AUC for the pregnant rat dose
with 3 mg/kg/day is given by USEPA (2005) as 83 ug x hr/mL, which is equivalent to a mean
daily blood concentration of about 3500 ug/L. Applying an uncertainty factor of 100 appropriate
for a NOAEL in a developmental study gives a target human blood level of 35 ug/L. The
corresponding drinking water concentration, based on a 100-fold concentration factor between
drinking water and human blood levels and a Relative Source Contribution factor of 20%, is 0.07
PPb•
Post -weaning period
For evaluation of drinking water exposure during the post -weaning period, serum concentrations
for post -weaning male and female pups are used. The AUC was determined for each of the five
post -weaning weeks 4 through 8. For males dosed with the NOAEL of 3 mg/kg/day, the lowest
value provided by USEPA (2005) for AUC, 202 ug x hr/ml, was seen at 4 weeks post -weaning,
the first time point at which it was measured, and the AUC increased dramatically at weeks 5 and
later. The week 4 value is used here, as a conservative assumption, and is equivalent to a mean
blood PFOA concentration of about 9200 ug/L. Applying an uncertainty factor of 100 appropriate
for a NOAEL in a developmental study gives a target human blood level of 92 ug/L. The
corresponding drinking water concentration, based on a 100-fold concentration factor between
drinking water and human blood levels and a Relative Source Contribution factor of 20%, is 0.18
PPb•
For female pups, the NOAEL was 10 mg/kg/day, and the AUC was more consistent throughout
the post -weaning period than in males. The lowest AUC value, 308 ug x hr/ml, was measured at
week 7 post -weaning and is conservatively used here, although effects were observed at earlier
time periods at which the AUC was higher. This AUC is equivalent to a mean blood
concentration of about 13,000 ug/L. Applying an uncertainty factor of 100 appropriate for a
NOAEL in a developmental study gives a target human blood level of 130 ug/L. The
corresponding drinking water concentration, based on a 100-fold concentration factor between
drinking water and human blood levels and a Relative Source Contribution factor of 20%, is 0.26
PPb•
Approach based on carcinogenic effects of PFOA
Another approach for developing human health -based drinking water guidance for PFOA is based
on carcinogenicity. Two chronic dietary studies of PFOA have been conducted in rats. In the
first study (Sibinksi, 1987), groups of 50 male and female Sprague-Dawley rats were fed 0, 30, or
300 ppm in the diet for two years. In this study, the incidence of Leydig cell adenomas was
increased in males in a dose related fashion, as follows: Controls - 0150; 30 ppm (1.3 mg/kg/day)
— 2/50 (4%); and 300 ppm (14.2 mg/kg/day) — 7/50 (14%). The incidence in the 300 ppm group
was statistically significant increased (p<0.05) compared to controls. The incidence of mammary
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fibroadenomas in female rats in this study was also significantly increased in both dose groups as
follows: Controls - 10/47 (21%); 30 ppm (1.6 mg/kg/day) — 19/47 (40%); and 300 ppm (16.1
mg/kg/day) — 21/49 (43%). The significance of these mammary tumors has been debated, and is
dependent upon the choice of historical control group to which the data is compared (e.g.
Sprague-Dawley rats in general or in the laboratory at which the study was conducted.)
The second study (Biegel et al., 2001) was a follow-up mechanistic study in which male
Sprague-Dawley rats were fed 300 ppm PFOA (mean dose of 13.6 mg/kg/day) for two years.
Two controls groups were used: an ad libitum fed (AL) group and a pair -fed (PF) group in which
the food intake was controlled to match the food intake of the PFOA exposed group. In this study,
there was a significant increase in Leydig cell adenomas (AL — 0/80; PF — 2/76, Treated — 8/76),
hepatic adenomas and carcinomas (AL — 2/80, PF — 3/79, Treated—10/76), and pancreatic
adenomas and carcinomas (AL — 0/80, PF- 1/79, treated — 8/76).
Thus, PFOA was found to induce liver adenomas, Leydig cell adenomas, and pancreatic acinar
cell tumors in male Sprague-Dawley rats and mammary cell fibroadenomas in female rats,
although USEPA (2005) questioned the significance of the mammary tumors compared to
historical background incidences. USEPA (2005) interpreted the liver, Leydig cell, and pancreatic
acinar cell tumors as constituting a "tumor triad" known to be caused by a class of chemicals
which are peroxisome proliferator-activated receptor -alpha (PPAR-a) agonists. USEPA (2005)
states that the relevance to humans of tumors caused by this group of chemicals is uncertain.
Additionally, they state that there are no adequate human studies of PFOA's carcinogenic
potential since the occupationally exposed cohorts are still quite young. Based upon this, USEPA
(2005) concluded that PFOA was best described as having "suggestive evidence of
carcinogenicity, but not sufficient to assess human carcinogenic potential".
The USEPA Science Advisory Board (2006) disagreed with USEPA (2005) as to the most
appropriate descriptor for the carcinogenicity of PFOA. They concluded that the PFOA cancer
data are consistent with the USEPA cancer guidelines descriptor "likely to be carcinogenic to
humans" which applies to chemicals which have been shown to cause tumors in more than one
species, sex, strain, site, or exposure route, regardless of the existence of evidence in humans.
Most SAB panel members felt that the animal data are much stronger than the type of data which
would warrant a "suggestive" descriptor. This conclusion was based on the following: 1)
existence of two positive cancer studies in animals for PFOA, 2) data suggesting that PPAR-a
activation may not be the sole mechanism of liver carcinogenesis (discussed above in regard to
liver toxicity of PFOA), 3) disagreement about the appropriateness of comparison to historical
controls rather than concurrent controls in evaluating the mammary tumor date, and 4)
disagreement about the USEPA (2005) assumptions about the mode of action for the Leydig cell
and pancreatic acinar cell being related to PPAR-alpha agonist activity, and the USEPA
comparison of mammary tumors to historical, rather than concurrent, controls. Furthermore, most
SAB (2006) members recommended that a cancer risk assessment for each of the PFOA-induced
tumors be developed, where data permit.
The approach recommended by USEPA for low -dose extrapolation for cancer risk assessment
when the mode of action has not been fully characterized is the use of linear extrapolation from a
point of departure. This approach is most appropriate for PFOA, since, as discussed above, the
mode of action is not known.
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Health -based drinking water guidance based on carcinogenicity can be devloped using the data
from Biegel et al. (2001), in which male Sprague-Dawley rats were given 300 ppm PFOA in their
diets and the mean ingested dose was 13.6 mg/kg/day. As discussed above, in this study, only
one dose of PFOA was used, although a similar incidence of Leydig cell tumors, but not liver or
pancreatic tumors, was seen in the earlier Sibinksi (1987) study.
Blood levels were not measured in this study, but can be estimated from the pharmacokinetic
model provided by USEPA (2005), just as they were estimated in the non -cancer assessment s
presented above. Based on the USEPA (2005) model, the steady state blood level in male rats
ingesting 13.6 mg/kg/day is 572 mg/L or 572,000 ug/L.
In these rats, statistically significant tumor incidences, compared to pair -fed controls, were as
follows:
Liver adenoma/carcinoma combined: Control — 4%, PFOA — 13%.
Leydig cell adenoma: Control— 3%, PFOA— 11%.
Pancreatic acinar cell adenoma/carcinoma: Control — 1 %, PFOA — 11 %.
The incidence of all three of these tumor types in the rats ingesting 13.6 mg/kg/day was
approximately 10% above the percentage incidence in the pair -fed controls.
Assuming a linear dose -response relationship between blood concentration and cancer risk, and
using the USEPA (2005) estimate of a blood concentration of about 570 ppm at the 10% tumor
incidence level as a point of departure, the blood concentration expected to correspond to a 10-6
cancer risk is 5.7 ppb. Based upon the 100-fold concentration ratio between drinking water and
blood concentration, a drinking water concentration of 0.06 ppb would correspond to a blood
concentration of 5.7 ppb. For development of drinking water guidance based on a carcinogenic
endpoint, a relative source contribution factor is not used, since the drinking water guidance is
intended to protect at a certain risk level (e.g 10-6) resulting from exposure through drinking
water, without consideration of other potential sources of exposure. Therefore, 0.06 ppb is the
health -based drinking water concentration based upon a one in one million risk level.
Discussion of uncertainties
As discussed above, the health -based drinking water guidance values developed in this document
for several non -cancer endpoints and for the cancer endpoint are based on comparisons between
target blood levels of humans exposed to PFOA and actual or predicted blood levels of
experimental animals administered PFOA. This approach involves more assumptions than the
traditional risk assessment approach based upon administered dose.
The blood levels used for some of the endpoints from experimental animals were not directly
measured, but are based on pharmacokinetic modeling provided by USEPA (2005). Uncertainty
is particularly great for the blood levels in the adult female rat which has a very short half life for
PFOA. In the female rat, PFOA levels would not reach steady state with daily bolus dosing, and
the maximum blood concentration is predicted to be several -fold higher than the average daily
blood concentration. It should be noted, however, that the fluctuation in blood levels are expected
to be less in the dietary study used in the assessment of adult female rats (Sibinski, 1987)than in a
bolus study because the entire dose is not received at one time but, rather, is spread out
throughout the day.
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Additionally, for male rats, data from the subchronic dietary study of Palazzolo (1993) suggests
that the relationship between the steady-state blood concentration and the daily dose may be less -
than -linear in the dose range of the identified NOAELs and LOAELs. Therefore, the predicted
blood levels used as the basis for the assessments for male rats presented here may actually be
somewhat higher than actual, so that the drinking water guidance values derived here likely are
higher than they would be if the blood data of Palazzolo (1993) had been used.
Furthermore, the drinking water -to -blood concentration factor in humans of 100 is based on a
study (Emmett et al., 2006) in which most of the subjects were exposed to the same concentration
of PFOA, rather than to a range of exposure concentrations. The assessment presented above also
assumes that the daily drinking water intake in the population of concern is similar to the intake in
the population study by Emmett et al., 2006. The results of the C8 Health Project are anticipated
to provide additional data on the relationship between PFOA in drinking water and PFOA in
blood from a large number of subjects over a range of PFOA concentrations.
Summary
The health -based drinking water guidance developed in this assessment based on non -cancer
endpoints and on cancer at the 10-6 risk level all fall within the same general range, with most of
the values falling into a narrow range from 0.04 to 0.26 ppb. The basis for the various health -
based drinking water values are summarized in Table 1 (attached). As discussed above, the
findings of USEPA (2005) and its Science Advisory Board (2006) were used as the starting point
for developing these health -based drinking water values. The drinking water concentration based
on the cancer endpoint is 0.06 ppb, which falls within the range of the non -cancer based drinking
water concentrations. Since the lowest drinking water value based on non -cancer effects is below
the drinking water concentration based on a 10-6 cancer risk, there is no need to incorporate an
additional uncertainty factor for potential carcinogenic effects into the non -cancer risk
assessment.
Recommendation
It is recommended that 0.04 ppb be used as preliminary health -based guidance for PFOA in
drinking water. This value is the lower end of the range of values derived based on several non -
cancer and cancer endpoints in different species, most of which cluster within a factor of two of
this value. This drinking water concentration is expected to be protective for both non -cancer
effects and cancer at the one in one million risk level. The recommendations provided here will
be reevaluated as additional data on PFOA's effects and kinetics in humans and animals become
available.
NJDEP's analytical Practical Quantitation Limit (PQL) for PFOA is 0.004 ppb or 4 ppt, as
discussed in the accompanying report NJDEP Bureau of Safe Drinking Water report
"Determination of Perfluorooctanoic Acid (PFOA) in Aqueous Samples". This PQL is below the
health -based value of 0.04 ppb recommended above. Therefore, the PQL is not the limiting factor
for the health -based concentration recommended in this memorandum.
Please let me know if I can be of further assistance with this issue.
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Table 1 — Basis for Health -Based Drinking Water Guidance for PFOA
Species
Key Study
Endpoint
NOAEL or LOAEL
Animal Blood Level (ug/L)
Uncertainty Factor
Target Human
Health -based
Blood Level u /L)
Concentration (u L)
Adult female
Chronic diet
Body Weight,
NOAEL
1800
100
18
0.04
rat
(Sibinksi, 1987)
Hematology
1.6 mg/kg/day (30
(based on modeled AUC)
(10 intraspecies, ] 0
m)
interspecies)
Adult male
Two -generation
Body Weight, liver
LOAEL
42,000
1000
42
0.08
rat
reproductive, gavage
weight and kidney
1 mg/kg/day
(USEPA model)
(10 intraspecies, 10
(York, 2002; Butenhoff et
weight in F1 generation
interspecies, 10 LOAEL to
al., 2004)
NOAEL
Non -human
6 month, male cynomolgus
Increased liver weight
LOAEL
77,000
3000
26
0.05
primate
monkey, capsule
and possible mortality
3 mg/kg/day
(measured)
(10 intraspecies, 3
(Thomford, 2001,
interspecies, 10 subchronic to
Butenhoff et al,., 2002)
chronic, 10 LOAEL to
NOAEL
Pregnant
Two -generation
Body Weight in male
NOAEL
3500
100
35
0.07
female
reproductive, gavage
F] pups during post-
3 mg/kg/day
(based on modeled AUC)
(10 intraspecies, 10
rat
(York, 2002; Butenhoff et
weaning
interspecies)
al., 2004
Male rat
Two -generation
Body Weight in male
NOAEL
9200
100
92
0.18
pups, post-
reproductive, gavage
FI pups during post-
3 mg/kg/day
(based on modeled AUC at
(10 intraspecies, 10
weaning
(York, 2002; Butenhoff et
weaning
week 4)
interspecies)
al., 2004
Female rat
Two -generation
Body Weight in
NOAEL
13,000
100
130
0.26
PUPS, post-
reproductive, gavage
female F] pups during
10 mg/kg/day
(based on modeled AUC at
(10 intraspecies, 10
weaning
(York, 2002; Butenhoff et
post -weaning
week 7)
interspecies)
al., 2004
Male rats
Chronic diet
Leydig cell, pancreatic,
13.6 mg/kg/day
572,000 ug/L
Not applicable — Target
5.7
0.06
(cancer)
Biegel et al. (2001)
and liver tumors
(300 ppm)
(USEPA model)
human blood level is based on
(Note — 20% Relative
(-10% tumor
linear extrapolation from 10-1
Source Contribution
incidence)
tumor incidence to 10-'
factor not used for cancer
(LOAEL or NOAEL
incidence.
endpoint)
not applicable
10

DEQ-CFW 00000950

References
Biegel, L.B, Hurtt, M.E., Frame, S.R., O'Connor, J.C., and Cook, J.C. (2001). Mechanisms of
extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol. Sci. 60:
44-55.
Butenhoff, J., Costa, G., Elcomebe, C., Farrar, D., Hansen, K., Iwai, H., Jung, R., Kennedy, G.,
Lieder, P., Olsen, G., and Thomford, P. (2002). Toxicity of ammonium perfluorooctanoate in
male cynomolgus monkeys after oral dosing for 6 months. Toxicol. Sci. 69: 244-257.
Butenhoff, J.L., Kennedy, G.L., Frame, S.R., O'Conner, J.C., and York, R.G. (2004). The
reproductive toxicology of ammonium perfluorooctanoate (APFO) in the rat. Toxicology 196:
95-116.
C8 Health Project. http://www.c8liealthproject.org/default.htm.
Emmett, E.A., Shofer, F.S., Zhang, H., Freeman, D., Desai, C., and Shaw, L.M. (2006).
Community exposure to perfluorooctanoate: Relationships between serum concentrations and
exposure sources. Journal of Occupational and Environmental Medicine 48 (8): 759-770.
Goldenthal, E.I. (1978). Final Report. Ninety day subacute rhesus monkey toxicity study.
International Research and Development Corporation. Study No. 137-090. November 10,
1978. USEPA AR226-0447 (cited in USEPA, 2005).
Gray, D. (2005). Comments on the draft revision of Minnesota's Health Risk Limits (HRLs)
for groundwater. Letter from Tetra Tech Inc. to Minnesota Department of Health. November 3,
2005.
Hinderliter, P.M. and Jepson, G.W. (2001). A simple conservative compartmental model to
relate ammonium perfluorooctanoate (APFO) exposure to estimate of perfluorooctanote (PFO)
blood levels in humans (draft). DuPont Haskell Laboratory for Health and Environmental
Sciences. October 10, 2001.
Palazzolo, M.J. (1993). Thirteen -week dietary toxicity study with T-5180, ammonium
perfluorooctanoate (CAS No. 3825-26-1) in male rats. Final Report. Laboratory Project
Identification HWI 6329-100. Hazleton Wisconsin, Inc. (sited in USEPA, 2005).
Sibiniski, L.J. (1987). Final report of a two year oral (diet) toxicity and carcinogenicity study of
fluorochemical FC-143 (perfluorooctanate ammonium carboxylate) in rats. Vol 1-4, 3M
Company/RIKER. October 16, 1987 (cited in USEPA, 2005).
Thomford, P.J. (2001). 26-Week capsule toxicity study with ammonium perfluorooctanoate
(APFO) in cynomolgus monkeys. Study performed by Covance Laboratories Inc., Madison,
Wisoconsin. Study No. Covance 6329-231. Dece,ber 18, 2001. USEPA AR226-1052a (cited in
USEPA, 2005).
IF
DEQ-CFW 00000951

DEQ-CFW 00000952

USEPA (2005). Draft Risk Assessment of the Potential Human Health Effects Associated with
Exposure to Perfluorooctanoic Acid and Its Salts. Office of Pollution Prevention and Toxics.
January 4, 2005.
USEPA (2006). SAB Review of EPA's Draft Risk Assessment of Potential Human Health
Effects Associated with PFOA and Its Salts. May 30, 2006.
York, R.G. (2002). Oral (gavage) two -generation (one litter per generation) reproduction study
of ammonium perfluorooctanoate (APFO) in rats. Argus Research Laboratories, Inc. (Cited in
USEPA, 2005).
Cc: Joe Aiello, Office of Quality Assurance, DEP
Betty Boros-Russo, Safe Drinking Water, NJDEP
Perry Cohn, Consumer and Environmental Health Service, DHSS
Frank Faranca, Site Remediation, DEP
Karen Fell, Safe Drinking Water, DEP
Barry Frasco, Hazardous Site Science, DEP
James Hamilton, Enforcement, DEP
Jeanne Herb, Policy, Planning, &Science, DEP
Mark Mauriello, Land Use Management, DEP
Leslie McGeorge, Water Monitoring and Standards, DEP
Edward Post, Enforcement, DEP
Ed Putnam, Remedial Response Element, DEP
Michele Putnam, Water Supply, DEP
Jeff Reading, Watershed Permitting, DEP
Rocky Richards, Wellfield Remediation, DEP
Suzanne Rosenwinkel, Point Source Permitting, Region 2, DEP
Bernie Wilk, Office of Quality Assurance, DEP
Nancy Wittenberg, Environmental Regulation, DEP
12
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DEQ-CFW 00000954