| Abstracts
on PFOS and PFOA for the following years: |
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up
to 1994 |
NOTE:
The
interest of the FAN Pesticide Project in this issue is directly
related to the fact that several PFOS and PFOA chemicals were
used as "inerts" in pesticides. However, most, but
not all, have been deleted from use since 2001. The so-called
"inerts" are used in pesticides and can account for
as much as 99%, or more, of a pesticidal formulation. US EPA's
policy is to allow the public information only on the "active
substance" and to deny the public the names of the chemicals
used as "inerts" in specific pesticide products --
even though the majority of inerts are toxic and biologically
active.
• See the molecular
structure for some of these chemicals
• The following
is a selected list of abstracts. For more see PubMed
or Toxnet.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7974521&dopt=Abstract
1994
Toxicology Nov 11;93(2-3):85-97
Effects
of prolonged administration of perfluorooctanoic acid on hepatic
activities of enzymes which detoxify peroxide and xenobiotic
in the rat.
Kawashima Y, Suzuki S, Kozuka H, Sato
M, Suzuki Y.
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Japan.
Male and female rats were fed a diet containing 0.01% (w/w)
perfluorooctanoic acid (PFOA) for 2 or 26 weeks, and the effects
on enzymes that participate in the metabolism of peroxides and
xenobiotics in liver were studied. Elevated activity of peroxisomal
beta-oxidation persisted throughout the treatment of male
rats with PFOA for 26 weeks. The
activity of glutathione (GSH) peroxidase towards hydrogen peroxide
was depressed significantly by the prolonged administration.
The long-term treatment of male
rats with PFOA decreased the activity of GSH peroxidase
towards cumene hydroperoxide and increased the activity of microsomal
NADPH-dependent lipid peroxidation. The activities of GSH reductase
and hepatic content of GSH remained unchanged. There was no
difference in the content of conjugated dienes in microsomal
lipid between male rats exposed to PFOA for 26 weeks and age-matched
control. The activities of GSH S-transferase towards 1-chloro-2,4-dinitrobenzene
and 1,2-dichloro-4-nitrobenzene were depressed by the short-term
administration of PFOA to male rats,
and this inhibition became pronounced
during the prolonged treatment. Microsomal cytochrome
P450 was induced by the short-term treatment of male rats with
PFOA, and elevated levels persisted throughout the treatment
for 26 weeks. Upon the administration of PFOA to male
rats for 2 weeks, the activity of 7-ethoxycoumarin O-deethylase
was increased markedly, whereas the activities of either aniline
p-hydroxylase or aminopyrine N-demethylase were unchanged. Although
an age-dependent decrease was observed in the activity of 7-ethoxycoumarin
O-deethylase, the activity in male rats
treated with PFOA for 26 weeks was higher than that of age-matched
control, to the same extent as was observed with the short-term
treatment. The prolonged administration
of PFOA to male rats caused a significant increase in the activity
of both aniline p-hydroxylase and aminopyrine N-demethylase.
Little changes were found in the same parameters tested in female
rats even after the prolonged administration of PFOA.
PMID:
7974521 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8011682&dopt=Abstract
1994
Biochim Biophys Acta Jun 23;1213(1):63-74
Effects
of perfluorooctanoic acid--a potent peroxisome proliferator
in rat--on Morris hepatoma 7800C1 cells, a rat cell line.
Sohlenius AK, Andersson K, Bergstrand
A, Spydevold O, De Pierre JW.
Department of Biochemistry, Wallenberg Laboratory, Stockholm
University, Sweden.
In this study, Morris hepatoma 7800C1 cells (from rat) were
exposed to 500 microM perfluorooctanoic acid (PFOA) in the culture
medium for 7 days. This treatment resulted in inductions of
catalase, lauroyl-CoA oxidase (which catalyzes the first step
in peroxisomal beta-oxidation) and of cytochrome P-450IVA (specialized
for omega- and omega-1 hydroxylation of fatty acids). Northern
blot analysis revealed that the level of mRNA for peroxisomal
fatty acyl-CoA oxidase was enhanced in cells treated with PFOA.
Inductions of the enzymes mentioned above are generally connected
with peroxisome proliferation in vivo. This work also includes
a comparison between the activities of catalase, lauroyl-CoA
oxidase, DT-diaphorase and glutathione transferase in rat liver
homogenate and 7800C1 cells in order to investigate to what
extent this cell line differs from the situation in vivo. The
findings suggest that the cells selectively lost most of their
peroxisomes during transformation into a cell line and subsequent
propagation. The control activities of catalase and lauroyl-CoA
oxidase (marker enzymes for peroxisomes) were only about 2%
of the corresponding enzyme activities in rat liver. In addition,
a morphological study revealed that the frequency of peroxisomes
in 7800C1 cells is very low. The control activity of glutathione
transferase in 7800C1 cells was 11% of the corresponding activity
in rat liver homogenate, whereas the level of DT-diaphorase
was virtually the same in 7800C1 cells as in rat liver. Electron
microscopic investigation of the control cultures revealed all
signs of viable cells, with well-developed cell organelles.
Treatment of 7800C1 cells with 500 microM PFOA has little effect
on cellular morphology.
PMID: 8011682 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8122261&dopt=Abstract
1994
Toxicol Appl Pharmacol Feb;124(2):165-73
Effects
of perfluoro-n-octanoic acid, perfluoro-n-decanoic acid, and
clofibrate on hepatic phosphorus metabolism in rats and guinea
pigs in vivo.
Reo NV, Goecke CM, Narayanan L, Jarnot
BM.
Department of Biochemistry and Molecular Biology/Kettering-Scott
Magnetic Resonance Laboratory, Wright State University, Dayton,
Ohio.
Phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy
was used to study the effects of perfluoro-n-octanoic acid (PFOA),
perfluoro-n-decanoic acid (PFDA), and clofibrate (CLOF) on liver
phosphorus metabolism in rats and guinea pigs in vivo. All three
compounds are known to cause peroxisome proliferation in rats
but not in guinea pigs. The data indicate that indices related
to overall tissue viability (i.e., adenosine triphosphate levels)
remain unaffected at the doses and experimental times investigated
for all treatments and both species. PFDA-treated rats revealed
a marked increase in a liver phosphomonoester resonance compared
with corresponding controls (p < or = 0.01); no such effect
was observed in guinea pigs. This particular 31P NMR signal
was identified as phosphocholine (PCho) and was found to steadily
increase in concentration at consecutive days post-PFDA treatment,
reaching 6.26 +/- 0.29 mumol/g liver at 5 days. This is fourfold
greater than the PCho levels determined in livers from corresponding
pair-fed control rats. The elevation in liver PCho is a specific
response of PFDA treatment in rats and is not simply related
to peroxisome proliferation in general, since neither PFOA nor
CLOF produce such an effect. The data
suggest a unique effect of PFDA on liver phospholipid metabolism,
specifically phosphatidylcholine, which may involve enhanced
phospholipid turnover via phosphatidylcholine-specific phospholipase
C activity.
PMID: 8122261 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8134918&dopt=Abstract
1994
Toxicology Jan 26;86(1-2):109-22
Induction
of cytochrome P4504A by the peroxisome proliferator perfluoro-n-octanoic
acid.
Diaz MJ, Chinje E, Kentish P, Jarnot B,
George M, Gibson G.
University of Surrey, School of Biological Sciences, Guildford,
UK.
The influence of a single dose of the peroxisome proliferator,
perfluoro-n-octanoic acid (PFOA) on hepatic and renal mixed-function
oxidase activities has been examined in rats. Peroxisome proliferation
was confirmed by increases in peroxisomal palmitoyl-CoA oxidation
and carnitine acetyl transferase activity, particularly in liver.
The liver was also more susceptible than the kidney to PFOA-dependent
induction of the 12-hydroxylation of lauric acid, suggesting
induction of the CYP4A sub-family. This was further confirmed
by Western blot analyses, wherein an anti-CYP4A1 antibody revealed
a substantial PFOA-dependent induction of CYP4A1 in a pattern
similar to that observed for the classical peroxisome proliferator,
clofibrate. In addition, using a cDNA probe to CYP4A1 in Northern
blot analysis, PFOA treatment resulted in a marked increase
in the steady state level of CYP4A1 mRNA, again more extensively
in liver than in kidney. Taken collectively, our data provide
compelling evidence that PFOA, like other peroxisome proliferators,
is also an inducer of the CYP4A subfamily.
PMID: 8134918 [PubMed - indexed for MEDLINE]
1994
Surface Science Spectra -- October -- Volume 3, Issues 1-4, p.
299
Characterization
of 1,1-Dihydroperfluorooctyl Acrylate (PFOA) by XPS
Camille
M. Kassis
Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599-3290
Jack K. Steehler
Department of Chemistry, Roanoke College, 221 College Lane, Salem,
VA 24153-3794
Richard W. Linton
Department of Chemistry, University of North Carolina at Chapel
Hill, Chapel Hill, NC 27599-3290
A sample of 1,1-dihydroperfluorooctyl
acrylate (PFOA), a low surface energy polymeric material prepared
by homogeneous free radical solution polymerization in supercritical
CO2, has been investigated by x-ray photoelectron spectroscopy
(XPS) using a Perkin-Elmer Physical Electronics Model 5400 spectrometer
with monochromatic Al K x rays. Knowledge of the surface composition
of PFOA is significant since potential applications of this
homopolymer include use in polymer blends where this material
would be expected to be the surface active species. Controlled
surface studies were conducted on a thick polymer film (~ 0.5
µm) spun cast from solution onto silicon. Although the
F 1s and O 1s regions were structurally straightforward to interpret,
the C 1s window showed the expected pattern of functional group
components. ©1997 American Vacuum
Society.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8229349&dopt=Abstract
1993
J Occup Med Sep;35(9):950-4
Mortality
among employees of a perfluorooctanoic acid production plant.
Gilliland FD, Mandel JS.
Division of Environmental and Occupational Health, School of
Public Health, University of Minnesota, Minneapolis.
Perfluorooctanoic acid (PFOA) has been found at low levels (10
to 100 parts per billion) in sera of the general population
and at higher levels in occupationally exposed workers. Although
PFOA has been reported to be a promoter of rodent hepatocarcinogenesis
and to alter reproductive hormones in humans and rodents, there
is little information on human health effects associated with
PFOA exposure. The present study examined the relationship between
PFOA and mortality using a retrospective cohort mortality design.
The cohort consisted of 2788 male and
749 female workers employed between 1947 and 1983 at a plant
that produced PFOA. The all-causes standardized mortality
ratio was .75 (95% confidence interval [CI], .56 to .99) for
women and .77 (95% CI, .69 to .86) for men. Among men the cardiovascular
standardized mortality rate was .68 (95% CI, .58 to .80) and
the all-gastrointestinal diseases was .57 (95% CI, .29 to .99).
There was no significantly increased cause-specific standardized
mortality ratio for either men or women. Ten
years of employment in exposed jobs was associated with a 3.3-fold
increase (95% CI, 1.02 to 10.6) in prostate cancer mortality
compared to no employment in PFOA production. There
were only six prostate cancer deaths overall and four among
the exposed workers; thus, the results must be interpreted cautiously.
If prostate cancer mortality is related
to PFOA, PFOA may increase prostate cancer mortality by altering
reproductive hormones in male workers.
PMID: 8229349 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1526368&dopt=Abstract
1992
Fundam Appl Toxicol May;18(4):557-69
Assessment
of the potential genotoxicity of
perfluorodecanoic acid and chlorotrifluoroethylene trimer and
tetramer acids.
Godin CS, Myhr BC, Lawlor TE, Young RR,
Murli H, Cifone MA.
ManTech Environmental Technology Incorporated, Dayton, Ohio
45431-0009.
Perfluoro-n-decanoic acid (PFDA)
is a perfluorinated fatty acid that produces hepatomegaly and
increased peroxisomal beta-oxidation when administered to rodents.
Chlorotrifluoroethylene (CTFE) trimer acid and CTFE tetramer
acid are metabolites of the six- and eight-carbon oligomers
of CTFE, respectively. They are structurally related to PFDA,
and CTFE tetramer acid has caused toxic effects in rodents that
are similar to those observed following PFDA administration.
Because of the correlation between peroxisome proliferation
and hepatocarcinogenesis, CTFE trimer acid, CTFE tetramer acid,
and PFDA were evaluated in in vitro and in vivo/in vitro bioassays
to assess their potential genotoxic activity. The assays conducted
were the Ames Salmonella/microsomal mutagenicity assay, the
hypoxanthineguanine phosphoribosyltransferase (HGPRT) locus
Chinese hamster ovary gene mutation assay, the sister chromatid
exchange (SCE) assay, chromosomal aberration assay, and an in
vivo/in vitro unscheduled DNA synthesis (UDS) and S-phase DNA
synthesis assay. All test articles were negative in the Ames
assay, the HGPRT assay, and the SCE assay. In the chromosomal
aberration assay CTFE trimer acid and CTFE tetramer acid were
negative in cultures with and without S9 metabolic activation.
PFDA was also negative in the absence of metabolic activation,
but chromosomal aberrations were observed when PFDA was incubated
in the presence of S9 fraction. All test articles were negative
for inducing UDS but all induced S-phase replicative DNA synthesis
16 hr after administration of the test article to the test animals;
only CTFE tetramer acid and PFDA induced S-phase synthesis 48
hr after dosing: the usual timepoint examined for this response.
PMID:
1526368 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1327145&dopt=Abstract
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.
Haughom B, Spydevold O.
Institute of Medical Biochemistry, University Oslo, Norway.
The influence of the peroxisomal proliferators perfluorooctanoic
acid (PFOA), perfluorooctane sulphonic acid (PFOSA) and clofibric
acid on lipid metabolism in rats was studied. Dietary treatment
of male Wistar rats with these three compounds resulted in rapid
and pronounced reduction in both cholesterol and triacylglycerols
in serum. The concentration of liver triacylglycerols was increased
by about 300% by PFOSA. Free cholesterol was increased by both
perfluoro compounds. Cholesteryl ester was reduced to 50% by
PFOSA as well by clofibrate. In hepatocytes from fed rats, all
the compounds resulted in reduced cholesterol synthesis from
acetate, pyruvate and hydroxymethyl glutarate, but there was
no reduction of synthesis from mevalonic acid. The oxidation
of palmitate was also increased in all groups. The perfluoro
compounds, but not clofibrate, caused some reduction in fatty
acid synthesis. The activity of liver HMG-CoA reductase was
reduced to 50% or less in all treatment groups and all three
compounds led to lower activity of acyl-CoA:cholesterol acyltransferase
(ACAT). Changes in other enzymes related to lipid metabolism
were inconsistent. 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.
PMID:
1327145 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1497616&dopt=Abstract
1992
Biochem J Aug 1;285 ( Pt 3):779-83
The
effects of perfluoro-octanoic acid on hepatic peroxisome proliferation
and related parameters show no sex-related differences in mice.
Sohlenius AK, Andersson K, DePierre JW.
Department of Biochemistry, Wallenberg Laboratory, Stockholm
University, Sweden.
Male and female C57Bl/6 mice were administered perfluor-octanoic
acid PFOA; 0.02-0.05% w/w; 5-10 days) in their diet. This treatment
resulted in a several-fold induction of hepatic peroxisomal
fatty acid beta-oxidation (monitored as increases in cyanide-insensitive
palmitoyl-CoA oxidation, lauroyl-CoA oxidase and catalase activity)
in all animals. The protein content of the hepatic mitochondrial
fraction was also increased in all mice exposed to PFOA. Furthermore,
studies on xenobiotic-metabolizing enzymes revealed no sex-related
difference in the response to PFOA. All
mice demonstrated a dramatic increase in omega-hydroxylation
of lauric acid. Cytosolic epoxide hydrolase, glutathione
transferase and DT-diaphorase activities were increased about
2-5-fold. These results with mice differ dramatically from previous
studies and our own experiments here with Wistar rats, in which
exposure to PFOA causes hepatic peroxisome proliferation in
male animals, whereas females are unaffected.
PMID: 1497616 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1625184&dopt=Abstract
1992
J Environ Pathol Toxicol Oncol May-Jun;11(3):145-9
Hepatomegaly
is an early biomarker for hepatocarcinogenesis
induced by peroxisome proliferators.
Takagi A, Sai K, Umemura T, Hasegawa R,
Kurokawa Y.
Division of Toxicology, National Institute of Hygienic Sciences,
Tokyo, Japan.
The relationship between hepatomegaly and the hepatocarcinogenesis
associated with by peroxisome proliferators was examined. (1)
Male F-344 rats were maintained on diets containing clofibrate,
ciprofibrate, nafenopin, gemfibrozil, Wy-14, 643, di(2-ethylhexyl)phthalate
(DEHP), or di(2-ethylhexyl)adipate (DEHA) at carcinogenic doses
for 1 week. A close correlation between relative liver weights
and hepatocarcinogenicity was observed (r = 0.910). (2) Administration
of perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA),
simfibrate, or DL-040, for which hepatocarcinogenicity is not
known, resulted in hepatomegaly in all treated groups, this
being especially marked in the PFOA case. Therefore, PFOA may
have strong hepatocarcinogenic potential. (3) Administration
of the antioxidants butylated hydroxyanisole (BHA) or vitamin
E (VE) did not affect the hepatomegaly induced by DEHP.
These results suggest that the hepatomegaly may be an early
biomarker for prediction of the potential hepatocarcinogenicity
of peroxisome proliferators. However, this requires further
clarification in terms of its relation to the oxidative stress
thought to be involved in peroxisome proliferator-induced hepatocarcinogenesis.
PMID: 1625184 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1606626&dopt=Abstract
1992
Chem Biol Interact May;82(3):317-28
Covalent
binding of perfluorinated fatty acids to proteins in the plasma,
liver and testes of rats.
Vanden Heuvel JP, Kuslikis BI, Peterson
RE.
Environmental Toxicology Center, University of Wisconsin, Madison
53706.
Perfluorinated fatty acids alter hepatic lipid metabolism and
are potent peroxisome proliferators in rodents. Two such perfluorinated
acids, perfluorodecanoic acid (PFDA) and perfluorooctanoic acid
(PFOA), were examined to determine if they covalently bind cellular
proteins. PFDA and PFOA were found to covalently bind proteins
when administered to rats in vivo. The liver, plasma and testes
of male rats treated with [1-14C]PFDA or PFOA (9.4 mumol/kg)
contained detectable levels of covalently bound 14C (0.1-0.5%
of the tissue 14C content). Characterization of PFDA covalent
binding to albumin in vitro showed that cysteine significantly
decreased binding with no effect of methionine, suggesting protein
sulfhydryl groups are involved. In cytosolic and microsomal
incubation there was no effect of the addition of CoA, ATP or
NADPH on the magnitude of the covalent binding of PFDA. Therefore
PFDA need not be metabolically activated to form covalent adducts.
Despite demonstration of covalent binding of PFDA and PFOA to
proteins both in vivo and in vitro, the role of this macromolecular
binding in perfluorinated fatty acid toxicity is not known.
PMID: 1606626 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1375295&dopt=Abstract
1992
J Biochem Toxicol Spring;7(1):31-6
Renal
excretion of perfluorooctanoic acid in male rats: inhibitory
effect of testosterone.
Vanden Heuvel JP, Davis JW 2nd, Sommers
R, Peterson RE.
Environmental Toxicology Center, University of Wisconsin, Madison
53706.
There is a marked sex difference in the
whole-body elimination of perfluorooctanoic acid (PFOA) in rats,
with females excreting the perfluorinated acid much more rapidly
(half life [t1/2] less than 1 day) than males (t1/2 = 15 days).
Our objective was to determine if androgens or estrogens are
involved in causing this sex difference in PFOA elimination.
Castration of males greatly increased the elimination of [1-14C]PFOA
(9.4 mumol/kg, i.p.) in urine, demonstrating that a factor produced
by the testis was responsible for the slow elimination of PFOA
in male rats. Castration plus 17 beta-estradiol had no further
effect on PFOA elimination whereas castration plus testosterone
replacement at the physiologic level reduced PFOA elimination
to the same level as rats with intact testes. Thus, in male
rats, testosterone exerts an inhibitory effect on renal excretion
of PFOA. In female rats, neither ovariectomy nor ovariectomy
plus testosterone affected the PFOA urinary elimination, demonstrating
that the inhibitory effect of testosterone on PFOA renal excretion
is a male-specific response. Probenecid decreased the high rate
of PFOA renal excretion in castrated males but had no effect
on male rats with intact testes. We conclude
that testosterone is a key determinant of the sex difference
in PFOA elimination in rats.
PMID: 1375295 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1346072&dopt=Abstract
1992
Toxicology;71(1-2):151-60
Cytosolic
long-chain acyl-CoA hydrolase, a suitable parameter to measure
hepatic response to peroxisome proliferators.
Kawashima Y, Kozuka H.
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Japan.
The possibility of using cytosolic long-chain acyl-CoA as a
parameter to measure the response of liver to peroxisome proliferators
was studied. A subcutaneous (s.c.) injection of perfluorooctanoic
acid (PFOA) to male Wistar rats caused an increase in activity
of cytosolic long-chain acyl-CoA hydrolase. This increase in
activity seems to be due to enzyme induction, since it was prevented
by simultaneous administration of cycloheximide or actinomycin
D with PFOA. The activity of cytosolic long-chain acyl-CoA hydrolase
was increased in a dose-dependent manner by the administration
of three peroxisome proliferators with diverse chemical structures:
alpha-(p-chlorophenoxy)isobutyric acid (clofibric acid), 2,2'-(decamethylenedithio)diethanol
(tiadenol) and PFOA. The increased activity produced by clofibric
acid lasted throughout a 22-week treatment. A good correlation
was found between the activities of cytosolic long-chain acyl-CoA
hydrolase and peroxisomal beta-oxidation induced by the administration
of the peroxisome proliferators. These results indicate that
cytosolic long-chain acyl-CoA hydrolase is a suitable parameter
for measuring the response of rat liver to challenges by peroxisome
proliferators.
PMID: 1346072 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1293309&dopt=Abstract
1992
J Biochem Toxicol Winter;7(4):205-12
Perfluorooctanoic
acid has persistent effects on peroxisome
proliferation and related parameters in mouse liver.
Sohlenius AK, Lundgren B, DePierre JW.
Department of Biochemistry, Wallenberg Laboratory, Stockholm
University, Sweden.
Male C57Bl/6 mice were treated for 5 days with 0.05% perfluorooctanoic
acid (PFOA) in their diet. This treatment resulted in a potent
induction of peroxisomal fatty acid beta-oxidation in the liver.
In order to investigate recovery from treatment with PFOA, mice
were given normal laboratory chow for up to 20 days after termination
of PFOA administration. It was established that the activities
of peroxisomal lauoryl-CoA oxidase and palmitoyl-CoA oxidation
were still elevated 2-3 weeks after termination of treatment.
The catalase activity recovered in the cytosolic fraction was
also still significantly elevated after 20 days with normal
laboratory chow. Furthermore, the protein content of the mitochondrial
fraction was increased by PFOA and had not returned to control
level at the end of the recovery period. Perfluorooctanoic acid
also caused a persistent effect in omega hydroxylation of lauric
acid (cytochrome P-452). The activities of cytosolic DT-diaphorase
and glutathione transferase were also enhanced by PFOA. However,
these two enzymes recovered relatively rapidly from the treatment
(2-20 days). This study reveals two different patterns of recovery
from PFOA treatment, one involving parameters that recovered
completely, or almost completely, from PFOA treatment after
20 days and another involving parameters that were still elevated
at the end of the recovery period.
PMID: 1293309 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1684073&dopt=Abstract
1991
Toxicol Appl Pharmacol Dec;111(3):530-7
The
modulation of rat liver carcinogenesis
by perfluorooctanoic acid, a peroxisome proliferator.
Abdellatif AG, Preat V, Taper HS, Roberfroid
M.
Unite de Biochimie Toxicologique et Cancerologique, Ecole de
Pharmacie, Universite Catholique de Louvain, Brussels, Belgium.
Perfluorooctanoic acid (PFOA) is a peroxisome proliferator.
The aim of this study was to test for its ability to act as
a positive modulator of hepatocarcinogenesis, in the so-called
biphasic (initiation by diethylnitrosamine 200 mg/kg ip followed
by treatment with the suspected modulators) and triphasic (initiation
by the same dose of diethylnitrosamine followed by a selection
procedure for 2 weeks consisting of giving 2-acetylaminofluorene
and in the middle of this treatment a single dose of CCl4 followed
by treatment with the suspected modulators) protocols of liver
carcinogenesis. In both protocols treatment with PFOA increased
the incidence of malignant hepatocellular carcinoma (HCC). As
compared to phenobarbital, the modulating effect of PFOA is
more pronounced in a biphasic than in the triphasic protocol.
In parallel with positive modulation of HCC, PFOA also selectively
induced the peroxisomal acyl-CoA oxidase activity and, to a
lesser extent, catalase activity.
PMID: 1684073 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1741769&dopt=Abstract
1991
Biochem Pharmacol Oct 24;42(10):1921-6
Induction
by perfluorooctanoic acid of microsomal 1-acylglycerophosphocholine
acyltransferase in rat kidney. Sex-related
difference.
Kawashima Y, Matsunaga T, Uy-Yu N, Kozuka
H.
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Japan.
Response of rat kidney to the challenges by perfluorooctanoic
acid (PFOA) was studied using microsomal 1-acyglycerophosphocholine
(1-acyl-GPC) acyltransferase as a parameter. Marked
induction of the enzyme was brought about in kidney of male
rats, whereas the induction in kidney of female rats was far
less pronounced. The sex-related difference in the response
of kidney to PFOA was much more marked than those seen with
p-chlorophenoxyisobutyric acid (clofibric acid) or 2,2'-(decamethy-lenedithio)diethanol
(tiadenol). Hormonal manipulations revealed that the sex-related
difference in the response of kidney to PFOA
was strongly dependent on the state of gonadal hormones of rats.
Even after a prolonged administration of PFOA for up to 26 weeks,
this sex-related difference was still evident. Induction of
peroxisomal beta-oxidation was brought about concurrently with
microsomal 1-acyl-GPC acyltransferase and a high correlation
was confirmed between the inductions of these two parameters.
PMID: 1741769 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2025879&dopt=Abstract
1991
Cancer Lett Apr;57(1):55-60
Short-term
exposure to the peroxisome proliferators, perfluorooctanoic
acid and perfluorodecanoic acid, causes significant increase
of 8-hydroxydeoxyguanosine in liver DNA
of rats.
Takagi A, Sai K, Umemura T, Hasegawa R,
Kurokawa Y.
Division of Toxicology, National Institute of Hygienic Sciences,
Tokyo, Japan.
To elucidate the relationship between peroxisome proliferation
by perfluorinated compounds and oxidative DNA damage, perfluorooctanoic
acid (PFOA), perfluorodecanoic acid (PFDA), perfluorobutyric
acid (PFBA) and perfluorooctane (PFO) were administered to 6-week-old
F-344 male rats. After a single intraperitoneal (i.p.) injection
of PFOA, PFBA or PFO in corn oil at a dose of 100 mg/kg, significant
increases of liver weight and 8-hydroxydeoxyguanosine (8-OH-dG)
levels in liver DNA were observed in PFOA-treated rats. Oral
administration of powdered diet containing 0.02% PFOA or 0.01%
PFDA for 2 weeks resulted in significant increases of liver
weight and 8-OH-dG levels in liver DNA in rats given both chemicals.
On the other hand, no increase in 8-OH-dG levels in kidney DNA
was found in either of the studies. Our results demonstrate
that, as with other peroxisome proliferators (phthalic ester
plasticizers and hypolipidemic drugs), PFOA
and PFDA induced peroxisome proliferation also leads to organ
specific oxidative DNA damage.
PMID: 2025879 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1941903&dopt=Abstract
1991
J Biochem Toxicol Summer;6(2):83-92
Tissue
distribution, metabolism, and elimination
of perfluorooctanoic acid in male and female rats.
Vanden Heuvel JP, Kuslikis BI, Van Rafelghem
MJ, Peterson RE.
Environmental Toxicology Center, University of Wisconsin, Madison
53706.
The elimination, tissue distribution, and metabolism of [1-14C]perfluorooctanoic
acid (PFOA) was examined in male and female rats for 28 days
after a single ip dose (9.4 mumol/kg, 4 mg/kg).
A sex difference in urinary elimination of PFOA-derived 14C
was observed. Female rats eliminated PFOA-derived radioactivity
rapidly in the urine with 91% of the dose being excreted in
the first 24 hr. In the same period, male rats eliminated only
6% of the administered 14C in the urine. The sex-related difference
in urinary elimination resulted in the observed difference in
the whole-body elimination half-life (t1/2) of PFOA in males
(t1/2 = 15 days) and females (t1/2 less than 1 day). Analysis
of PFOA-derived 14C in tissues showed that the liver and plasma
of male rats and the liver, plasma, and kidney of female rats
were the primary tissues of distribution. The relatively
high concentration of PFOA in the male
liver was further examined using an in situ nonrecirculating
liver perfusion technique. It was shown that 11% of the PFOA
infused was extracted by the liver in a single pass. The ability
of the liver to eliminate PFOA into bile was examined in rats
whose renal pedicles were ligated to alleviate sex differences
in the urinary excretion of PFOA. In a 6-hr period following
IP administration of PFOA, there was no apparent difference
in biliary excretion, where both males and females eliminated
less than 1% of the PFOA dose via this route.
We hypothesized that the sex difference in the persistence of
PFOA was due to a more rapid formation of a PFOA-containing
lipid (i.e., a PFOA-containing mono-, di-, or triacylglycerol,
cholesteryl ester, methyl ester, or phospholipid) in the male
rat. Also, the increased urinary elimination of PFOA
in females may have been due to increased metabolism to a PFOA-glucuronide
or sulfate ester. However, no evidence that PFOA is conjugated
to form a persistent hybrid lipid was obtained, nor were polar
metabolites of PFOA in urine or bile detected. In addition,
daily urinary excretion of fluoride in male and female rats
before or after PFOA treatment were similar, suggesting
that the parent compound is not defluorinated. Thus,
the more rapid elimination of PFOA from female rats is not due
to formation of a PFOA metabolite.
PMID: 1941903 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2363183&dopt=Abstract
1990
Toxicol Appl Pharmacol Jun 15;104(2):322-33
Androgenic
deficiency in male rats treated with perfluorodecanoic
acid.
Bookstaff RC, Moore RW, Ingall GB, Peterson
RE.
School of Pharmacy, University of Wisconsin, Madison 53706.
Effects of perfluorodecanoic acid (PFDA,
20-80 mg/kg, ip) on the androgenic status of sexually mature
male rats were investigated 7 days after treatment. PFDA decreased
plasma androgen concentrations in a dose-dependent fashion with
an ED50 of approximately 30 mg/kg. The highest dose of PFDA
decreased plasma testosterone and 5 alpha-dihydrotestosterone
concentrations to 12 and 18%, respectively, of ad libitum-fed
control (ALC) values. Secondary to the decreased plasma androgen
concentrations were dose-related decreases in the weights and
epithelial heights of accessory sex organs. Results from pair-fed
control (PFC) rats show that hypophagia in PFDA-treated rats
was not a major cause of the low plasma androgen concentrations.
When rats were castrated and implanted with testosterone-containing
capsules, PFDA-treated and ALC rats had similar plasma testosterone
concentrations and secondary sex organ weights. Therefore, the
androgenic deficiency in intact PFDA-treated rats does not result
from increased plasma clearance of androgens. Rather, PFDA
must cause the androgenic deficiency by decreasing the secretion
of testosterone from the testis. The decrease in testosterone
secretion does not appear to result from a decrease in plasma
luteinizing hormone (LH) concentrations, because plasma LH concentrations
were not significantly altered by PFDA treatment. This
finding suggests that PFDA treatment decreases testicular responsiveness
to LH stimulation. The observation that PFDA treatment
reduced the secretion of testosterone by testes stimulated in
vitro with the LH analog human chorionic gonadotropin demonstrates
that this is the case. In addition, since plasma LH concentrations
did not increase in response to the low plasma androgen concentrations
in PFDA-treated rats, we suggest that
PFDA disrupts the normal feedback relationship which exists
between plasma androgen and LH concentrations.
PMID: 2363183 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2308906&dopt=Abstract
1990
Pharmacol Toxicol Jan;66(1):45-8
Tissue
distribution and elimination of perfluorodecanoic acid in the
rat after single intraperitoneal administration.
Ylinen M, Auriola S.
Department of Pharmaceutical Chemistry, University of Kuopio,
Finland.
Tissue distribution, metabolism, and excretion of perfluorodecanoic
acid (PFDA) after a single intraperitoneal dose (20 mg/kg) were
studied in female and male Wistar rats. PFDA accumulated in
the serum and tissues of the rats. In the serum, more than 99%
of PFDA was bound by the serum proteins. In the liver, anionic
and esterified PFDA were detected. Metabolic oxidation of PFDA
was not observed. PFDA was not excreted in urine either by females
or males during 14 days after the administration. At the same
time, about 0.5% of the administered PFDA dose was excreted
daily in the faeces by both sexes. In spite of the analogical
structure with perfluorooctanoic acid (PFOA), which is rapidly
eliminated in urine by the female rats, PFDA accumulated similarly
in females and males. The reduced elimination of PFDA partially
explains its greater toxicity to rats in comparison with PFOA.
PMID: 2308906 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2331477&dopt=Abstract
1990
Biochim Biophys Acta Apr 26;1016(3):344-8
Perfluorooctane
sulfonamide: a structurally novel uncoupler of oxidative phosphorylation.
Schnellmann RG, Manning RO.
Department of Physiology and Pharmacology, College of Veterinary
Medicine, University of Georgia, Athens 30602.
The effects of sulfluramide (N-ethylperfluorooctane sulfonamide)
and perfluorooctane sulfonamide (DESFA)
on isolated rabbit renal cortical mitochondria (RCM) were examined.
Sulfluramid (1-100 microM) and DESFA (0.5-50 microM) increased
state 4 respiration of RCM respiring on pyruvate/malate or succinate
in a concentration dependent manner in the absence of a phosphate
acceptor. In addition, both sulfluramid and DESFA increased
state 4 respiration in the presence of oligomycin, an inhibitor
of F0F1-ATPase. The effects of sulfluramid (200 microM), DESFA
(100 microM), and the known protonophore and uncoupler of oxidative
phosphorylation, carbonyl cyanide p-trifluoromethoxyphenylhydrazone
(FCCP) (1 microM), on RCM proton movement were examined directly
by monitoring extramitochondrial pH and indirectly by monitoring
passive mitochondrial swelling. Immediately upon addition, DESFA
and FCCP, but not sulfluramid, dissipated the RCM proton gradient
and caused RCM to swell in solutions of NaCl or NH4Cl. These
results show that DESFA uncouples oxidative
phosphorylation by acting as a protonophore. RCM
were shown to metabolize sulfluramid to DESFA which suggests
that the increase in state 4 respiration observed with sulfluramid
is due to DESFA. DESFA is unique in that it is one of two uncouplers
that does not contain a ring structure and thus may be a useful
model in the study of oxidative phosphorylation.
PMID: 2331477 [PubMed - indexed for MEDLINE]
From
TOXNET
1990
TOXICOL IN VITRO; 4 (1). 71-74.
The cellular
effects of a unique pesticide sulfluramid (N-ethylperfluorooctanesulfonamide)
on rabbit renal proximal tubules.
SCHNELLMANN
RG
Dep. Physiol. and
Pharmacol., Coll. Veterinary Med., Univ. Georgia, Athens, Ga.
30602, USA.
Abstract: BIOSIS
COPYRIGHT: BIOL ABS. The cellular effects of sulfluramid (N-ethylperfluorooctane
sulphonamide, NEPFOS) and its major metabolite perfluorooctane
sulphonamide (PFOS) were examined using a suspension of rabbit
renal proximal tubules as a model. NEPFOS and PFOS were potent
stimulators of proximal tubule basal oxygen consumptions (QO2),
with initial effects exhibited at 5-10 muM and maximal effects
at 50-200 muM. The increase in basal QO2 was ouabain insensitive,
which suggests that NEPFOS and PFOS may act by uncoupling oxidative
phosphorylation. Exposure of tubule suspensions to NEPFOS or
PFOS concentrations of 100 muM or higher for 60 min produced
tubule death, indicated by an increase in the release of lactate
dehyrogenase. The tubule death did not appear to result from
alkylation or lipid peroxidation, since glutathione and malondialdehyde
levels were unaffected. To determine the mechanism by which
NEPFOS and PFOS increased tubule QO2, the effects of NEPFOS
and PFOS on isolated renal cortical
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2749739&dopt=Abstract
1989
Toxicol Appl Pharmacol Jul;99(3):544-54
The
biochemical toxicity of perfluorodecanoic acid in the mouse
is different from that of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Brewster DW, Birnbaum LS.
Systemic Toxicology Branch, National Institute
of Environmental Health Sciences, Research Triangle Park,
North Carolina 27709.
Perfluorodecanoic acid (PFDA) is an industrial
surfactant that has been reported to produce signs of toxicity
in rats similar to those due to 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD). In order to characterize the
biochemical toxicity of PFDA in the mouse and to determine whether
PFDA toxicity is mediated by the Ah locus, congenic female C57BL/6J
mice differing only at the Ah locus (normal homozygous responsive
Ahb/b, heterozygous responsive Ahb/d, and homozygous nonresponsive
Ahd/d) were administered a single oral dose of PFDA. The wild
type (Ahb/b) mice were killed 2, 7, 14, or 30 days after administration
of 0, 40, 80, 100, 120, or 160 mg PFDA/kg. Mice from the other
two congenic strains were killed 30 days after dosing with 0,
40, 80, or 160 mg/kg. PFDA produced a 2.5-fold increase in absolute
liver weight, a 5- to 15-fold increase in hepatic fatty acyl
Co-A oxidase activity, and a 70% decrease in hepatic ethoxyresorufin
O-deethylase (EROD) activity. These effects were dose and time
dependent. Total hepatic lipids were increased at an early time
point and at the lowest dose. At later time periods and/or higher
doses, the lipid concentration was decreased approximately 20%
from that of controls. Hepatic protein concentrations were depressed
approximately 25% from control levels 30 days after treatment.
There was little difference in any of these parameters between
responsive (Ahb/b, Ahb/d) and nonresponsive (Ahd/d) mice. These
results suggest that the Ah allele has little effect in regulating
the toxicity of PFDA in the mouse and that the biochemical response
to PFDA in the mouse is markedly different from that of TCDD.
Furthermore, the biochemical response to PFDA in the mouse is
different from that reported in the rat.
PMID: 2749739 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2731659&dopt=Abstract
1989
Fundam Appl Toxicol Apr;12(3):442-8
Developmental
toxicity of perfluorodecanoic acid in C57BL/6N mice.
Harris MW, Birnbaum LS.
Systemic Toxicology Branch, National Institute
of Environmental Health Sciences, Research Triangle Park,
North Carolina 27709.
Perfluorodecanoic acid (PFDA)
is a representative of the perfluorinated carboxylic acids used
as commercial wetting agents and flame
retardants. Signs of PFDA toxicity have been reported
to resemble those seen after exposure to TCDD. To determine
if PFDA exhibits teratogenic effects similar to those of TCDD
or is a developmental toxin, time-mated C57BL/6N mice were administered
PFDA by gavage in corn oil (10 ml/kg) on gestation days (gd)
10-13 or gd 6-15 at levels of 0, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0,
16.0, or 32.0 mg/kg/day or 0, 0.03, 0.3, 1.0, 3.0, 6.4, or 12.8
mg/kg/day, respectively. Dams were killed on gd 18 and maternal
and fetal toxicity was assessed. Fetuses were examined for external,
visceral, or skeletal malformations. Maternal body weight gain
(corrected for the weight of the gravid
uterus) was significantly reduced as a result of PFDA
treatment at 6.4 and 12.8 mg/kg/day (gd 6-15) and 16.0 and 32.0
mg/kg/day (gd 10-13). Fetal viability was decreased only in
those groups showing extensive maternal body weight loss.
Fetal body weights were significantly reduced at levels as low
as 0.1 mg/kg/day (gd 6-15) and 0.5 mg/kg/day (gd 10-13).
No hydronephrosis, cleft palate, or edema was observed nor were
any other soft tissue or skeletal malformations detected. Thus,
PFDA does not produce malformations in C57BL/6N mice, and the
developmental toxicity observed (increased fetal mortality and
decreased live fetal body weight) was seen only at doses that
were maternally toxic.
PMID: 2731659 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2574572&dopt=Abstract
1989
Biochem J Nov 1;263(3):897-904
Sex-related
differences in the enhancing effects of perfluoro-octanoic acid
on stearoyl-CoA desaturase and its influence on the acyl composition
of phospholipid in rat liver. Comparison with clofibric acid
and tiadenol.
Kawashima Y, Uy-Yu N, Kozuka H.
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Japan.
The effects of the peroxisome proliferators clofibric acid (p-chlorophenoxyisobutyric
acid), tiadenol [2,2'-(decamethylenedithio)diethanol] and perfluoro-octanoic
acid (PFOA) on hepatic stearoyl-CoA desaturation in male and
female rats were compared. Treatment of male rats with the three
peroxisome proliferators increased markedly the activity of
stearoyl-CoA desaturase. Administration of clofibric acid or
tiadenol to female rats increased greatly the hepatic activity
of stearoyl-CoA desaturase, the extent of the increases being
slightly less pronounced than those of male rats. In contrast
with the other two peroxisome proliferators, however, PFOA did
not change the activity of stearoyl-CoA desaturase in female
rats. Hormonal manipulations revealed
that this sex-related difference in the effect of PFOA on stearoyl-CoA
desaturase activity is strongly dependent on testosterone.
The increase in stearoyl-CoA desaturase activity by peroxisome
proliferators was not accompanied by any notable increases in
the microsomal content of cytochrome b5 or the activity of NADH:
cytochrome b5 reductase. The administration of the peroxisome
proliferators greatly altered the acyl composition of hepatic
phosphatidylcholine and phosphatidylethanolamine (namely the
proportions of C18:1 and C20:3,n-9 fatty acids increased in
both phospholipids), and the alterations were partially associated
with the increase in stearoyl-CoA desaturase activity.
PMID: 2574572 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2587510&dopt=Abstract
1989
Pharmacol Toxicol Oct;65(4):274-7
Stimulation
by oestradiol of the urinary excretion of perfluorooctanoic
acid in the male rat.
Ylinen M, Hanhijarvi H, Jaakonaho
J, Peura P.
Department of Pharmaceutical Chemistry, University of Kuopio,
Finland.
The urinary excretion of perfluorooctanoic acid (PFOA) was studied
in male Wistar rats after castration and oestradiol administration
as well as in intact females and males. During the first 24
hr females excreted 72 +/- 5% (N = 6) of a single intraperitoneal
dose of PFOA (50 mg/kg) in urine whereas the intact males excreted
only 9 +/- 4% (N = 6). After castration followed by oestradiol
administration (500 micrograms/kg every 2nd day for 14 days),
the males excreted PFOA in urine in similar amounts as the females
(68 +/- 14% at 24 hr, N = 10). Oestradiol treatment of non-castrated
males produced similar results (61 +/- 19% at 24 hr, N = 10).
Also castration without oestradiol administration significantly
enhanced the renal PFOA excretion, but not as effectively as
oestradiol treatment. After 96 hr, the concentration of PFOA
in serum of intact males was 17-40 times higher than in the
serum of other groups. PFOA was similarly bound by the proteins
in the serum of females and males. Phase II metabolism of PFOA
was not shown either in males or females.
PMID: 2587510 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2570571&dopt=Abstract
1989
Biochem J Jul 15;261(2):595-600
Sex-related
difference in the inductions by perfluoro-octanoic acid of peroxisomal
beta-oxidation, microsomal 1-acylglycerophosphocholine acyltransferase
and cytosolic long-chain acyl-CoA hydrolase in rat liver.
Kawashima
Y, Uy-Yu N, Kozuka H.
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical
University, Japan.
Inductions by perfluoro-octanoic acid (PFOA) of hepatomegaly,
peroxisomal beta-oxidation, microsomal 1-acylglycerophosphocholine
acyltransferase and cytosolic long-chain acyl-CoA hydrolase
were compared in liver between male and female rats. Marked
inductions of these four parameters were seen concurrently in
liver of male rats, whereas the inductions in liver of female
rats were far less pronounced. The sex-related difference in
the response of rat liver to PFOA was much more marked than
that seen with p-chlorophenoxyisobutyric acid (clofibric acid)
or 2,2'-(decamethylenedithio)diethanol (tiadenol).
Hormonal manipulations revealed that this sex-related difference
in the inductions is strongly dependent on sex hormones, namely
that testosterone is necessary for the inductions, whereas oestradiol
prevented the inductions by PFOA.
PMID: 2570571 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3367697&dopt=Abstract
1988
Lipids Feb;23(2):115-9
Perfluoro-n-decanoic
acid: induction of peroxisomal beta-oxidation by a fatty acid
with dioxin-like toxicity.
Harrison EH, Lane JS, Luking S, Van Rafelghem
MJ, Andersen ME.
Department of Biological Chemistry, Wright State University,
School of Medicine, Dayton, OH.
Perfluoro-n-decanoic acid (PFDA)
produces toxic effects in rodents similar to those caused by
2,3,7,8-tetrachloro-dibenzo-p-dioxin. A single, intraperitoneal
dose (50 mg/kg) of PFDA to Sprague-Dawley rats caused disruption
of the endoplasmic reticulum, mitochondrial swelling and increases
in intracellular lipid droplets in hepatocytes similar to effects
reported previously in dioxin toxicity. PFDA treatment led to
large decreases in the activity of plasma membrane alkaline
phosphodiesterase and mitochondrial cytochrome c oxidase without
affecting lysosomal N-acetyl-beta-glucosaminidase, endoplasmic
reticulum NADPH-cytochrome c reductase or peroxisomal catalase
activities. PFDA treatment led to moderate
peroxisome proliferation and to very large (20-40-fold) increases
in the activity of fatty acyl-CoA oxidase, the rate-limiting
enzyme in the peroxisomal system of fatty acid beta-oxidation.
PMID: 3367697 [PubMed - indexed for MEDLINE]
From
TOXNET
1987
Pharmacology and Toxicology, Vol. 61, No. 1, pages 66-68, 8
references
Elimination
and Toxicity of Perfluorooctanoic Acid During Subchronic Administration
in the Wistar Rat
Hanhijarvi
H Ylinen M Kojo A Kosma VM
The urinary elimination
and toxicity of perfluorooctanoic-acid (335671) (PFO) was studied
in newly weaned rats. Wistar-rats were given doses of PFO by
gavage at levels of 3, 10, or 30mg/kg for 28 consecutive days.
The mean excretion of PFO was lower in all three groups of males.
In female animals none of the three groups excreted significantly
less PFO than they received. The mean urinary PFO concentration
of the female rats was significantly higher than males in the
lowest dose group. In the highest dose group, the PFO urinary
concentration was significantly higher in males. Concerning
organ weights, only the weight of the liver showed a significant
positive dose response. The findings indicate that the steady
state was achieved by 7 days in the female animals, because
the mean excretion of PFO in 24 hours in the three groups of
females did not deviate significantly from the daily orally
administered dose. Males did not reach steady state by the end
of the first week as evidenced by the fact that the total excretion
of PFO in 24 hours of all three groups remained significantly
less than the daily dose of the compound. PFO concentrations
in the plasma were 36 percent lower in males receiving 30mg/kg
than in the group given 10mg/kg daily.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3820341&dopt=Abstract
1987
J Toxicol Environ Health;20(3):303-16
Perfluorinated
fatty acids alter merocyanine 540 dye binding to plasma membranes.
Levitt
D, Liss A.
We have evaluated the effect of the perfluorinated fatty acids
pentadecafluoro-n-octanoic acid (PFOA) and nonadecafluoro-n-decanoic
acid (NDFDA) on the ability of a human B-lymphoblastoid cell
line to bind the lipid-binding, membrane-impermeant, fluorescent
dye merocyanine 540 (MC540). Subtoxic concentrations of perfluorinated
fatty acids (0.9 mM PFOA; 0.5 mM NDFDA) greatly diminish binding
of MC540 by normal plasma membranes, as determined by fluorescence
flow cytometry. When perfluorinated fatty acids are added to
cells at toxic or lethal concentrations (1.2 mM PFOA; 0.75 mM
NDFDA), MC540 binding increases dramatically, with entrance
of dye to internal membrane domains. Neither perfluorinated
fatty acid molecule reduces the ability of surface immunoglobulin
to migrate laterally and cap on cells. Our data suggest that
perfluorinated fatty acids either interact directly with lipid
binding sites for MC540, and thereby inhibit dye intercalation,
or alter membrane lipid architecture and lipid packing to diminish
MC540 binding. Both possibilities support a direct, physical,
membrane-altering mechanism for
perfluorinated fatty acid toxicity on mammalian cells.
PMID: 3820341 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3804135&dopt=Abstract
1986
Food Chem Toxicol. Dec;24(12):1325-9.
Inhalation
toxicity of ammonium perfluorooctanoate.
Kennedy
GL Jr, Hall GT, Brittelli MR, Barnes JR, Chen HC.
Ammonium perfluorooctanoate (CAS Registry No. 3825-26-1) is
a fine white powder which can become airborne; hence its inhalation
toxicity was studied in the male rat.
The compound was found to be moderately toxic following single
4-hr exposures, with an LC50 of 980 mg/m3. This
concentration produced both an increase in liver size and corneal
opacity. Both findings diminished with increasing time
after exposure. Subchronic head-only inhalation
exposures (6 hr/day on 5 days/wk for 2 wk to 0, 1, 8 or 84 mg/m3)
suppressed body-weight gain at 84 mg/m3. Reversible liver-weight
increases, reversible increases in serum enzyme activities,
and microscopic liver pathology, including necrosis, occurred
at exposure of 8 and 84 mg/m3. No ocular changes were
produced. Concentrations of organofluoride
in the blood showed a dose relationship with initial levels
of 108 ppm in rats treated at 84 mg/m3 falling to 0.84 ppm after
84 days with a blood half-life of 5-7 days. The no-observed-effect
level was 1 mg/m3 and a mean organofluoride blood level of 13
ppm was detected in rats immediately after the tenth
exposure to an atmospheric level of 1 mg ammonium perfluorooctanoate/m3.
PMID: 3804135 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3764929&dopt=Abstract
1986
Toxicol Appl Pharmacol Oct;86(1):1-11
Toxicity
of perfluorinated fatty acids for human and murine B cell lines.
Levitt D, Liss A.
The toxicity of two perfluorinated fatty acids, penta decafluoro-n-octanoic
acid (PFOA) and nonadecafluoro-n-decanoic acid (NDFDA), on three
mammalian B cell lines was evaluated. Cells were exposed to
the perfluorinated molecules for either 24 or 48 hr under a
variety of culture conditions. Immunoglobulin secretion and
surface membrane expression were unaffected by both PFOA and
NDFDA at sublethal concentrations. Lethal effects of PFOA and
NDFDA are diminished by either lowering culture temperature
(37 to 20 degrees C) or including fetal bovine serum or human
serum albumin in media. At lethal concentrations, both PFOA
and NDFDA possess detergent activity since they can release
IgM in soluble form from a cell line that does not secrete immunoglobulins,
and brief exposure (15 min) to 1-2 mM of both perfluorinated
fatty acids results in solubilization of F4 cells equivalent
to the anionic detergent deoxycholic acid. Our data suggest
that at subtoxic concentrations, neither PFOA nor NDFDA alters
expression or secretion of a differentiated gene product (IgM).
At lethal levels, both chemicals cause
increased solubilization of proteins from lymphoblastoid cell
lines.
PMID: 3764929 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4066651&dopt=Abstract
1985
J Biochem (Tokyo) Aug;98(2):475-82
The induction
of peroxisome proliferation in rat liver by perfluorinated fatty
acids, metabolically inert derivatives of fatty acids.
Ikeda T, Aiba K, Fukuda K, Tanaka M.
The induction of peroxisome proliferation in rat liver was examined
after administration of perfluoro-n-decanoic acid (PFDA, C10),
perfluoro-n-octanoic acid (PFOA, C8), perfluoro-n-butyric acid
(PFBA, C4), 1-H,1-H-pentadecafluoro-n-octanol (PFOL, C8) perfluorododecane
(PFD, C12), and perfluorooctane (PFO, C8). The peroxisome proliferation
in the liver was detected by the following methods; 1) measurement
of liver weight, 2) assay of hepatic catalase activity, 3) analysis
of 600 X g supernatant of liver homogenates by SDS-polyacrylamide
gel electrophoresis to observe the induction of the bifunctional
enoyl-CoA hydratase in peroxisomes (80K-protein) and 4) observation
by electron microscopy. The oral administration of powdered
chow containing 0.02%-PFOA and PFBA to male rats of the Sprague-Dawley
strain for 2 weeks and the single intraperitoneal injection
of corn oil mixed with PFDA, PFOA, and PFOL at the dose of 100
mg/kg induced peroxisome proliferation markedly. PFOL, which
has two hydrogen atoms around the hydroxylated carbon, should
be metabolized to PFOA, which is an active inducer. Perfluorinated
paraffins, PFD and PFO, did not show any induction, indicating
the importance of the carboxylic group in the molecule for the
peroxisome proliferation. Although the
participation of thyroid hormone cannot be excluded, PFOA appears
to act directly on the liver.
PMID: 4066651 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6636169&dopt=Abstract
1983
Toxicol Appl Pharmacol Sep 30;70(3):362-72
The
acute toxicity of perfluorooctanoic and perfluorodecanoic acids
in male rats and effects on tissue fatty acids.
Olson CT, Andersen ME.
The acute toxicities of single ip injections of perfluorooctanoic
(PFOA) and perfluorodecanoic (NDFDA) acids were evaluated in
male Fischer rats. The LD50/30 day for PFOA was 189 (208-175)
mg/kg and for NDFDA was 41 (47-34) mg/kg. All rats treated with
lethal doses of PFOA died within the first 5 days; with NDFDA
there was delayed lethality, with deaths in the second and third
weeks after dosing. Four groups of rats were used for a more
detailed study of toxicity and for analysis of fatty acids from
liver, testes, and whole blood. One group received a single
dose of 100 mg PFOA/kg; a second, a single dose of 2 ml of propylene
glycol-water (1:1)/kg (vehicle control); a third, a single dose
of 50 mg NDFDA/kg; the fourth was given 2 ml vehicle/kg and
pair-fed with the NDFDA group. The first three groups were fed
ad libitum. Rats from each group were killed at 2, 4, 8, and
16 days after dosing for fatty acid analysis. Rats dosed with
NDFDA lost half their body weight in 16 days and ate virtually
no food from Day 7 to Day 14 after dosing. Weight loss was less
rapid in pair-fed controls. With PFOA there were transient decreases
in food intake and body weight which were reversed by Day 7.
Liver weights of PFOA rats were slightly greater than those
from vehicle controls. With NDFDA, liver weights were much greater
than those from pair-fed controls. In the livers of PFOA rats
there were transient increases in oleic and palmitic acids and
a decrease in stearic and docosahexaenoic acids. These changes
were maximum by Day 2 and nearly resolved by Day 8. With NDFDA,
similar changes were observed and arachidonic acid was also
greatly decreased. These changes were quantitatively much larger
and more persistent.
NDFDA has unusually high toxic potency for a perfluorinated
hydrocarbon, and some of the toxic effects caused by this acid
are remarkably similar to those seen with 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD). The acute toxicity of NDFDA may be due to an ability
to interfere with fatty acid metabolism, and studies of its
toxicity may be valuable in helping to understand mechanisms
of action of TCDD.
PMID: 6636169 [PubMed - indexed for MEDLINE]
1981. Order Number: NTIS/PB87-174330,
17p
Information Profiles on Potential Occupational
Hazards: Carbonyl Fluoride. Second Draft.
Syracuse Research Corp., NY. Center for
Chemical Hazard Assessment.
Supporting Agency: National Inst. for
Occupational Safety and Health, Rockville, MD.
Information on potential occupational hazards from exposure
to carbonyl-fluoride (353504) was reviewed. Topics discussed
included chemical and physical properties, production, use,
manufacturers and distributors, manufacturing processes, occupational
exposure, and biological effects. Potential
exposure to carbonyl-fluoride occurs as a result of the thermal
decomposition of polytetrafluoroethylene (PTFE) in air. Effects
of acute exposure in animal studies included extreme malaise
and weakness which preceded death. Subchronic exposure studies
with PTFE pyrolysis products revealed pathologic changes in
the respiratory tracts and livers of exposed animals. Protein,
glucose, ketones, and occult blood appeared in the urine following
exposure. No information was available concerning chronic
exposures, carcinogenicity, mutagenicity, teratogenicity, or
reproductive effects.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6773404&dopt=Abstract
Am Ind Hyg
Assoc J. 1980 Aug;41(8):576-83.
Animal
toxicity studies with ammonium perfluorooctanoate.
Griffith
FD, Long JE.
These studies were conducted to evaluate the potential toxicity
of ammonium perfluorooctanoate, a commercial surfactant. They
include acute and subchronic feeding studies with rabbits, mice,
rats and monkeys as well as in vitro mutagenicity assays with
Salmonella typhimurium and Saccharomyces cerevisiae. The compound
was non-irritating to the skin and moderately irritating to
the eyes of rabbits. The rat oral LD50 was 540 mg/kg; no deaths
resulted from a one hour rat inhalation exposure at a nominal
concentration of 18.6 mg/L. All in vitro assays were negative.
The liver was the target organ in rodents in both the 28 day
and 90 day feeding studies with males
showing a greater response than females. Serum
and liver concentrations of organic fluorine were greater in
male than in female rats. In a
90 day oral study in rhesus monkeys the gastrointestinal tract
and the reticuloendothelial system were the sites of toxic effects.
The gastrointestinal effects were attributed to the potent surface
activity of the compound. Histopathological
effects wer noted in the spleen, lymph nodes and bone marrow.
Unlike the rats, sex related differences were not evident in
the monkeys. Toxicological evaluations of ammonium perfluorooctanoate
are continuing.
PMID: 6773404 [PubMed - indexed for MEDLINE]
DEFINITIONS:
reticuloendothelial
system definition: a widely
distributed system consisting of all the cells able to ingest
bacteria or colloidal particles etc, except for certain white
blood cells.
Another definition: Abbreviated RES.
A group of cells having the ability
to take up and sequester inert particles and vital dyes, including
macrophages or macrophage precursors, specialized endothelial
cells lining the sinusoids of the liver, spleen, and bone
Another
defintion from Henderson's
Dictionary of Biological Terms, Eleventh Edition:
"the fine fibrillar meshwork of phagocytic cells supported
on connective tissue that extends throughout on connective
tissue that extends throughout the spleen and lymph nodes
and also in other organs such as liver and kidneys and which
is involved in the uptake and clearance of foreign particulate
matter from the blood. Foreign antigens taken up by cells
of the reticulendothelial system in lymphoid organs encounter
the T cells and B cells of the immune system which then mount
a specific immune response." Author(s)
/Editors Eleanor Lawrence. Publisher Longman Singapore Publishers
(Pte) Ltd.Year 1995. ISBN 0-582-22708-9.
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