Adverse signs of toxicity
observed in Rhesus monkey studies included anorexia,
emesis, diarrhea, hypoactivity, prostration, convulsions, atrophy
of the salivary glands and the pancreas, marked
decreases in serum cholesterol, and lipid
depletion in the adrenals. The dose
range for these effects was reported between 1.5-300 mg/kg/day.
No monkeys survived beyond 3 weeks into treatment at 10 mg/kg/day
or beyond 7 weeks into treatment at doses as low as 4.5 mg/kg/day.
Ref:
November 21, 2002 report: Hazard Assessment of Perfluorooctane
sulfonate (PFOS) and its salts. Organisation for Economic Co-operation
and Development. ENV/JM/RD(2002)17/FINAL.
http://www.fluorideaction.org/pesticides/pfos.final.report.nov.2002.pdf
In a 6-month study
of Cynomolgus monkeys, low food consumption, excessive salivation,
labored breathing, hypoactivity, ataxia, hepatic vacuolization
and hepatocellular hypertrophy, significant
reductions in serum cholesterol levels, and death were
observed at 0.75 mg/kg/day. No effects were observed at doses
of 0.15 or 0.03 mg/kg/day. No effects were noted in animals at
any dose level following a 52-week recovery period. The average
concentration of PFOS in the serum following 26 weeks of treatment
was 11.1 + 1.52, 58.5 + 4.67 and 160 + 23.9 µg/ml for the
females in the 0.03, 0.15 and 0.75 mg/kg/day groups, respectively;
for males, the average concentrations were 15.9 + 5.54, 68.1 +
5.75 and 194 + 8.93 µg/ml in the 0.03, 0.15 and 0.75 mg/kg/day
groups, respectively. After the
52-week recovery period, the serum levels were 21.4 + 2.01
and 41.4 + 1.15 µg/ml for the females in the 0.15 and 0.75
mg/kg/day groups, respectively; for males, the average concentrations
were 19.1 + 0.805 and 41.1 + 25.9 µg/ml in the 0.15 and
0.75 mg/kg/day groups, espectively.
Ref:
November 21, 2002 report:
Hazard Assessment of Perfluorooctane sulfonate
(PFOS) and its salts.
Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.
http://www.fluorideaction.org/pesticides/pfos.final.report.nov.2002.pdf
Numerous repeat-dose
oral toxicity studies on PFOS have been conducted in rats and
primates. In general, exposure to PFOS results in hepatotoxicity
and mortality; the dose-response curve for mortality is very steep
for rats and primates. Adverse signs of toxicity observed in 90-day
rat studies included increases in liver enzymes, hepatic vacuolization
and hepatocellular hypertrophy, gastrointestinal effects,
hematological abnormalities, weight loss, convulsions,
and death. These effects were reported at
doses of 2 mg/kg/day and above...
2.4.2
Non-occupational Exposures...
Sera pooled from 18 regional blood banks in various geographic
regions of the U.S. were analyzed for PFOS in 1998 (3M Report,
1999). There were 68 pools and an estimated 340-680 donors. The
overall mean PFOS serum level across the pools was 29.7 ppb. The
PFOS levels varied quite a bit depending on the geographic location
of the blood bank. The range of the levels across geographic regions
was 9 to 56 ppb, while the range of the averages was 14 to 52
ppb. Pooled sera from blood banks in Belgium (6 pools), the Netherlands
(5 pools), and Germany (6 pools) also have been analyzed for PFOS.
Each pool had 15-20 donors. The Netherlands
had the highest PFOS levels (mean = 53 ppb) and Belgium had the
lowest (mean = 17 ppb). Individual blood samples from 3
different age populations were recently analyzed for PFOS and
other fluorochemicals using high-pressure liquid chromatography/electrospray
tandem mass spectrometry (HPLC/ESMSMS) (Olsen et al., 2002a, 2002b,
2002c). The studies’ participants included adult blood donors,
an elderly population participating in a prospective study in
Seattle, WA, and children from 23 states participating in a clinical
trial. Overall, the PFOS geometric means were similar across all
3 populations (34.9 ppb, 31.0 ppb, and 37.5 ppb, respectively).
The geometric means and 95% tolerance limits and their upper bounds
were comparable across all 3 studies. However,
the upper ranges for the children and adults were much higher
than for the elderly population. It is not clear whether
this is the result of geographic differences in PFOS levels or
some other factor. It should be noted that PFOS and PFOA were
highly correlated in all three studies (r = .63, r = .70, and
r = .75). The details of each study are provided...
The highest serum PFOS measurement in this sample was 1656 ppb
from a male blood donor, 67 years old from Portland. The next
highest donor level was 329 ppb from a male donor, 62 years old
also from Portland. The next 8 highest serum PFOS values (range
139 – 226 ppb) were measured in 4 females and 4 males representing
Charlotte (n=4), Hagerstown (n=2), Los Angeles (n=1) and Minneapolis/St.
Paul (n=1). In bootstrap analyses, the mean of the 95% tolerance
limit for PFOS was 88.5 ppb with an upper 95% confidence limit
of 100.0 ppb.
Ref: November 21, 2002 report:
Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its
salts. Organisation for Economic Co-operation and Development.
ENV/JM/RD(2002)17/FINAL.
http://www.fluorideaction.org/pesticides/pfos.final.report.nov.2002.pdf
Abstract
excerpt: ... On the basis of results
from size-exclusion chromatography and ligand blotting, most
PFOA was in protein-bound form in male and female rat plasma,
and the primary PFOA binding protein in plasma was serum albumin...
On the basis of these binding parameters and the estimated plasma
concentration of serum albumin, greater
than 90% of PFOA would be bound to serum albumin in both rat and
human blood."
Ref: 2003. Chem Res Toxicol. Jun;16(6):775-81.Binding
of perfluorooctanoic Acid to rat and human plasma proteins;
by Han X, Snow TA, Kemper RA, Jepson GW.
Abstract: The 3M Company
manufactures fluorochemicals, which have as a precursor perfluorooctane
sulfonyl fluoride (C8F17SO2F). These compounds may be expected
to transform metabolically, to an undetermined degree, to perfluorooctane
sulfonate (PFOS, C8F17SO3-) as an end-stage metabolite. Subchronic
studies in rats and primates indicate a potential for cumulative
toxicity with PFOS with the primary effect related to metabolic
wasting with hypolipidemia as a consistent finding.
Biennial medical surveillance has been offered to the company's
fluorochemical production workers located in Decatur, Alabama,
and Antwerp, Belgium. In 1995, the mean serum PFOS level, as measured
by high-performance liquid chromatography mass spectrometry, for
178 male employees was 2.19 parts per million (ppm; range, 0.00
to 12.83 ppm), and in 1997, for 149 male employees, it was 1.75
ppm (0.10 to 9.93 ppm). Our analyses suggest that among these
production employees, there were no substantial changes in serum
hepatic enzymes, cholesterol, or lipoproteins associated with
PFOS levels less than 6 ppm. It was not possible to derive inferences
from the few employees who had serum PFOS levels > or = 6 ppm.
These results may be due to the lower levels of serum PFOS measured
among these production employees, compared to those suspected
to cause effects in laboratory animals.
Ref:
1999. J Occup Environ Med Sep;41(9):799-806. Serum
perfluorooctane sulfonate and hepatic and lipid clinical chemistry
tests in fluorochemical production employees; by Olsen GW,
Burris JM, Mandel JH, Zobel LR.
Medical Department,
3M Company, St. Paul, MN 55144, USA.
•
Notes from FAN:
Hypolipidemia - Excess of fats (lipids)
in the blood
To
understand "metabolic wasting", the following discussion
on AIDS offers some insight:
".. In recent years, a significant amount of research has
focused on metabolic problems that can cause wasting. Metabolism
- an intricate system by which nutrients are either broken down
(catabolism) for energy purposes or stored (anabolism) for later
use - has been shown to become highly irregular in people with
HIV. More simply, metabolism is the body's utilization of energy
from foods. To fuel its energy needs, the body first catabolizes
glucose and lipids circulating in the blood ('free floating'
nutrients); amino acids are spared so that they can be used
to build muscle mass and other substances such as enzymes and
antibodies. If free-floating nutrients are used up and not adequately
replaced, the body will then begin breaking down stored nutrients
- usually lipid and cholesterol deposits (fat mass) - to keep
up with its energy needs; stored amino acids, such as those
in muscle, are spared during prolonged fasting and used as energy
only as a last resort. In people with HIV, this entire process
is often reversed. We know this because people with HIV often
have elevated glucose levels and fat levels (hyperlipidemia)
and, especially during an OI, have a negative nitrogen balance
(a marker of muscle loss). While negative nitrogen balances
are certainly a sign that muscle wasting is occurring, the connections
between elevated glucose levels, lipid levels and muscle loss
have not yet been fully determined. However they are characteristic
of cachexia."
Ref:AIDS
Community Research Initiative of America. ACRIA Update. Summer
1998 - Vol. 7, No. 3. Wasting and Metabolic Changes in the Era
of HAART. By Tim Horn. http://www.criany.org/treatment/treatment_edu_summerupdate98_wasting.html
Abstract: Perfluorooctane
sulfonate (PFOS) is a degradation product of sulfonyl-based fluorochemicals
that are used extensively in industrial and household applications.
Humans and wildlife are exposed to this class of compounds from
several sources. Toxicity tests in rodents have raised concerns
about potential developmental, reproductive, and systemic effects
of PFOS. However, the effect of PFOS on the neuroendocrine system
has not been investigated thus far. In this study, adult female
rats were injected intraperitoneally with 0, 1, or 10 mg PFOS/kg
body weight (BW) for 2 weeks. Food and water intake, BW, and estrous
cycles were monitored daily. At the end of treatment, PFOS levels
in tissues were measured by high-performance liquid chromatography
(HPLC) interfaced with electrospray mass spectrometry. Changes
in brain monoamines were measured by HPLC with electrochemical
detection, and serum corticosterone and leptin were monitored
using radioimmunoassay. Treatment with PFOS
produced a dose-dependent accumulation of this chemical in various
body tissues, including the brain. PFOS exposure decreased food
intake and BW in a dose-dependent manner. Treatment with PFOS
affected estrous cyclicity and increased
serum corticosterone levels while decreasing serum leptin concentrations.
PFOS treatment also increased norepinephrine concentrations in
the paraventricular nucleus of the hypothalamus.
These results indicate that exposure to PFOS can affect
the neuroendocrine system in rats.
Ref: Environ Health Perspect. 2003 Sep;111(12):1485-9.
Neuroendocrine
effects of perfluorooctane sulfonate in rats; by Austin ME,
Kasturi BS, Barber M, Kannan K, MohanKumar PS, MohanKumar SM.
Abstract excerpt: "In
a previous investigation, we demonstrated that severe thymus and
spleen atrophy occurs in mice upon dietary exposure to several
potent peroxisome proliferators (PPs). In the present investigation,
the effects of the potent PP perfluorooctanoic acid (PFOA) on
the adaptive immunity of mice was evaluated both in vivo and ex
vivo... the relatively metabolically inert PP PFOA may exert adaptive
immunosuppression in mice by an indirect mechanism. The
possible relevance of this immunosuppression to the alterations
in plasma lipids caused by PPs is discussed."
Ref:
2002. Int Immunopharmacol Feb;2(2-3):389-97. Potent
suppression of the adaptive immune response in mice upon dietary
exposure to the potent peroxisome proliferator, perfluorooctanoic
acid; by Yang Q, Abedi-Valugerdi M, Xie Y, Zhao XY, Moller
G, Nelson BD, DePierre JW.
Abstract excerpt:
"...
Liver-fatty acid binding protein (L-FABP) is an abundant intracellular
lipid-carrier protein... this work provides
evidence to support the hypothesis that displacement of endogenous
ligands from L-FABP may contribute to toxicity in rodents fed
these fluorochemicals.
Ref: 2002. Toxicology Jul 15;176(3):175-85. Interactions
of fluorochemicals with rat liver fatty acid-binding protein;
by Luebker DJ, Hansen KJ, Bass NM, Butenhoff JL, Seacat AM.
Abstract excerpt:
"The
influence of the peroxisomal proliferators perfluorooctanoic acid
(PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric acid
on lipid metabolism in rats was studied...
The present data suggest that the hypolipemic
effect of these compounds may, at least partly, be mediated via
a common mechanism; impaired production of lipoprotein particles
due to reduced synthesis and esterification of cholesterol together
with enhanced oxidation of fatty acids in the liver."
Ref:
1992. Biochim Biophys Acta Sep 22;1128(1):65-72. The
mechanism underlying the hypolipemic effect of perfluorooctanoic
acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric
acid; by Haughom B, Spydevold O.
Type: Biopersistence Screening
Study
Species/Strain: Rats/Crl:CD SD(IGS)BR
Sex/Number: Male/5/group
Exposure Period: 5 or 10 days; 94
days of recovery
Frequency of Treatment: Ad libitum
for 5 or 10 days
Exposure Levels; Method:
Reference:
DuPont Co. (2000). Unpublished Data,
Haskell Laboratory Report
No. 2922.
Ammonium perfluorooctanoate: 20 mgkg
Potassium perfluoroalkyl sulfonate (PFOS): 10 mg/kg
Six groups of rats were administered ammonium perfluorooctanoate,
1 group received the test substance for 5 consecutive days and
the other 5 groups received the test substance for 10 days. Approximately
2 hours after the first dose, blood was collected from each rat
from the group designated for 5 doses. These same rats were sacrificed
on test day 5 approximately 2 hours post-dosing, and blood and
livers were collected. The remaining groups received the test
substance for 10 days. Five rats were sacrificed and had blood
and livers collected on test days 10 (2 hours post-dose), 13,24,
52, or 93/94. The total fluorine content
of the blood was determined by using a Wickbold torch combustion
method, followed by analysis with a fluoride ion selective electrode.
Results:
Rats dosed with ammonium perfluorooctanoate exhibited wet perineum
and diarrhea during the dosing period. Alopecia was observed during
the recovery period. The normalized pM equivalents
(blood organofluoride levels) in rat blood peaked after
5 days of dosing and then decreased throughout
the testing period.
The Cmax was 518.12 _+ 44.89 ppm with a terminal half-life of
8.3 days. The AI (Accumulation Index) was 12.5 and the BI (Bioaccumulation)
was 6497.5. An area under the curve (estimated to infinity) (AUCLNF/D)
was calculated and normalized for fluorine content. The AUCINFD
was calculated as 70,789.6.
Rats dosed with potassium perfluoroalkyl sulfonate exhibited diarrhea,
salivation, alopecia, black ocular discharge, and staining of
various parts of the body during the dosing period. Alopecia was
observed during the recovery period. The
normalized phi
equivalents (blood organofluoride levels) in rat blood continued
to rise throughout the dosing period and may not have reached
steady-state. The Cmax was 989.85 k 116.90 ppm with a terminal
half-life of 40.5 days. The AI was 59.0 and the BI was 58382.2.
The AUCINFD was calculated as 566,479.1.
Ref: DuPont
summary of studies conducted with PFOS and PFOA.
Type: 14-Day Feeding Study
SpeciesIStrain: Rat/Crl:CD BR
SexNurnber: Male/20/group
Exposure Period: 14 days; 56 days
of recovery
Frequency of Treatment: ad libitum
for 14 days
Exposure Levels: 0,30,300 ppm
Test Substance: Ammonium
perfluorooctanoate, purity approximately 100%
Reference: DuPont Co. (1995).
Unpublished Data, Haskell Laboratory Report Reference:
NO. 326-95.
Method:
Rats were approximately 6 weeks old at arrival. At study start,
the body weights ranged from 196 to 240 g. Rats were housed singly
and were fed food and water ad libitum. During the test period
each group were fed diet that contained 0, 30, or 300 ppm of the
test substance. Diets were prepared once for the 2-week feeding
period and were stored refrigerated until used. All rats were
weighed and observed for clinical signs of toxicity. Rats not
sacrificed at the end of the feeding period were weighed and observed
during the recovery period. Cageside examinations to detect moribund
or dead rats were conducted twice daily. Five rats/group were
sacrificed at the end of the 14-day feeding period, and on recovery
days 7,28, and 56. Livers were removed and weighed at each sacrifice
period. Blood samples were taken for organofluoride
concentration analysis from rats sacrificed at the end of the
feeding period and on recovery day 7.
Results: Mean
blood organofluoride concentrations of rats sacrificed on recovery
day 0 were 0.3 ppm in control rats, 33.2 ppm in the 30 ppm rats,
and 7 1.5 ppm in the 300 ppm rats. On recovery day 7, mean blood
organofluoride concentrations were 0.9 ppm for
controls, 19.3 ppm for the 30 ppm group, and 22.2 ppm for the
300 ppm group.
Ref: DuPont
summary of studies conducted with PFOS and PFOA.
Type: Repeated Exposure
Inhalation Study
Species/Strain: Rats/CrI:CD
Sex/Number: Male/24/group
Exposure Period: 2 weeks; 84 days
of recovery
Frequency of Treatment: 6 hourslday,
5 days/week
Exposure Levels: 0, 1, 8, 80 mg/m3
References:
• DuPont Co. (198 1). Unpublished Data, Haskell Laboratory
Report No. 205-81.
• Kennedy, G. L., Jr. et al. (1983). The Toxicologist, 3:22.
• Kennedy, G. L., Jr. et al. (1986). Food Chem. Toxicol.,
24: 1325-1329.
Method:
Dust atmospheres of ammonium perfluorooctanoate
were generated by passing air through a glass generator. For the
high concentration (80 mg/m3), chamber atmosphere concentrations
were primarily determined by gravimetric analysis. For the intermediate
and low concentrations (8 and 1 mg/m', respectively), chamber
atmospheres were determined by a chemical analyses.
Male rats (age 7-8 weeks, weighing 240-279 g) were exposed head-only
to dust atmospheres for 6 hours/day, 5 daydweek for 2 weeks (weekends
excluded). During exposure, rats were observed and clinical signs
were noted. Post-exposure rats were weighed and observed daily
for 14 recovery days, then weighed and observed 2 times/week through
84 days of recovery. Five rats/group were sacrificed at 0, 14,
28,42, and 84 days of recovery, for a total of 96 test days. Clinical
laboratory examinations were performed on 5 rats from each group
at 0, 14,28,42, and 84 days post-exposure. After a total of 10
exposures, 5 rats from each group were pathologically evaluated
at 0, 14, 28,42, and 84 days post-exposure.
Results:
... Blood organofluoride analysis clearly
demonstrated an exposure-related presence in all groups (including
the controls, this finding remains unexplained). Blood organofluoride
levels
decreased with time, but was detectable after 84 days of recovery
in both the control and 80 mg/m3 exposure levels.
Ref: DuPont
summary of studies conducted with PFOS and PFOA.
Ylinen et al.(1990) studied the difference between male and female
Wistar rats in the distribution and accumulation of PFOA after
single and subchronic administration. For the single dose study,
50 mg/kg of PFOA was administered by ip injection to groups of
20 male and 20 female 10 week old rats. For the subchronic study,
PFOA was administered by gavage at doses of 3, 10, and 30 mg/kg/day
to groups of 18 male and 18 female newly weaned rats. For both
studies, samples were collected for determination of PFOA levels
12 hr after treatment, at 24-168 hr at 24 hr intervals, at 244
hr and at 336 hrs after treatment. For the subchronic study, samples
were also taken on Day 28. ... In the single-dose
study, concentrations of PFOA in the serum and tissues were higher
in males than females at all time periods.Twelve hours
after the administration of PFOA about 10% of the administered
dose was found in the serum of females, whereas about 40%of the
administered dose was in the serum of males. ...
Samples taken on the 28th day indicated
significantly higher PFOA concentrations in the serum and tissues
of males versus females at all three dose levels. After
subchronic, as well as single- dose administration, PFOA was mainly
distributed in the serum of rats. High concentrations of PFOA
were also found in the liver, kidney, and
lung of males and females. ...
A significant positive correlation existed between the administered
dose and the concentration of PFOA in the liver, kidney, spleen,
and lung of females. On the
contrary, no significant correlation between the administered
dose and the concentration of PFOA was observed in the males,
as 10 mg/kg/day produced higher PFOA concentrations
in the serum and organs than 30 mg/kg/day. However, in
males, the concentration in the spleen, testis, and brain correlated
positively with the concentration in the serum.
Ref:
April
10, 2003: Preliminary
Risk Assessment of the Developmental Toxicity associated with
Exposure to Perfluorooctanoic Acid and its Salts. US
EPA Office of Pollution Prevention and Toxics. 63 pages.
