• Due to length,
we are presenting this effect as a
separate section for PFOS and PFOA.
The study of the adverse effects of PFOS-PFOA chemicals is in
its infancy and we anticipate that more effects will be presented
and published over the next several years. Most of the animal
studies (as of early 2004) have been performed by the major producers
of PFOS-PFOA (3M and DuPont).
•
Click here to return to the same
section for fluorine & organofluorine pesticides.
•
This is not an exhaustive list. The
review of data was performed in 2003 to early 2004.
When time allows more information will be added,
Abstract:
The objectives of the present work were to study the effects of
certain peroxisome proliferators on xenobiotic-metabolizing enzyme
activities in the testes of normal and hypothyroid rats, i.e.
phenol sulfotransferases (pST), phenol UDP-glucuronosyl transferases
(pUDPGT), glutathione transferases (GST), catalase, epoxide hydrolase
(EH), glutathione peroxidase (GPX) and NAD(P)H quinone oxidoreductase
(QR). Adult male rats (normal and hypothyroid) were treated for
10 days with clofibrate (0.5%), perfluorooctanoic
acid (0.5%, PFOA), acetylsalisylic acid (1%, ASA) and di(2-ethylhexyl)phthalate
(2%, DEHP) in their diet. The results show that treatment of normal
rats with peroxisome proliferators dramatically affects the activities
of xenobiotic-metabolizing enzymes (40-60% reduction). The
highest effects are seen in catalase activity (50-60% with PFOA
and ASA), pUDPGT (55% with PFOA), pST (55% with PFOA) and
QR (50% with DEHP). These effects are not seen or are weaker after
induction of hypothyroidism. Taken together,
it is concluded that different classes of peroxisome proliferators
have different effects on rat testicular xenobiotic-metabolizing
enzymes.
Ref:
1997. Chem Biol Interact May 2;104(2-3):131-45. Effects
of peroxisome proliferators and/or hypothyroidism on xenobiotic-metabolizing
enzymes in rat testis; by Mehrotra K, Morgenstern R, Lundqvist
G, Becedas L, Bengtsson Ahlberg M, Georgellis A.
Abstract: Elimination
in urine and feces was compared between four perfluorinated fatty
acids (PFCAs) with different carbon chain length. In male rats,
perfluoroheptanoic acid (PFHA) was rapidly eliminated in urine
with the proportion of 92% of the dose being eliminated within
120 h after an intraperitoneal injection. Perfluorooctanoic acid
(PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid
(PFDA) was eliminated in urine with the proportions of 55, 2.0
and 0.2% of the dose, respectively. By contrast, four PFCAs were
eliminated in feces with the proportion of less than 5% of the
dose within 120 h after an injection. In female rats, the proportions
of PFOA and PFNA eliminated in urine within 120 h were 80% and
51% of the dose, respectively, which were significantly higher
compared with those in male rats. There was the tendency that
PFCA with longer carbon chain length is less eliminated in urine
in both male and female rats. Fecal elimination of PFCAs was not
different between PFCAs in female rats and comparable to those
in male rats. The rates of biliary excretion of PFCAs in male
rats were slower than those in female rats. Sex-related difference
in urinary elimination of PFOA was abolished when male rats had
been castrated. On the contrary, treatment with testosterone suppressed
the elimination of PFOA in urine in both castrated male rats and
female rats. The effect of testosterone was in a time- and dose-dependent
manner. These results suggest that PFCAs
are distinguished by their carbon chain length by a renal excretion
system, which is regulated by testosterone.
Ref:
2001. Chem Biol Interact Apr 16;134(2):203-16. Comparison
of the elimination between perfluorinated fatty acids with different
carbon chain length in rats; by Kudo N, Suzuki E, Katakura
M, Ohmori K, Noshiro R, Kawashima Y.
Abstract: Ammonium
perfluorooctanoate is a potent synthetic surfactant used in industrial
applications. It rapidly dissociates in biologic media to perfluorooctanoate
[CF3(CF2)6CO2-], which is the anion of perfluorooctanoic acid
[PFOA, CF3(CF2)6COOH]. PFOA is a peroxisome
proliferator known to increase the incidence of hepatic, pancreas
and Leydig cell adenomas in rats. The pancreas acinar cell
adenomas may be the consequence of a mild but sustained increase
of cholecystokinin as a result of hepatic cholestasis. Although
no significant clinical hepatic toxicity was observed, PFOA was
reported to have modulated hepatic responses to obesity and alcohol
consumption among production workers. To further assess these
hypotheses, we examined medical surveillance data of male workers
involved in ammonium perfluorooctanoate production in 1993 (n=111),
1995 (n=80) and 1997 (n=74). Serum PFOA was measured by high-performance
liquid chromatography mass spectrometry methods. Plasma cholecystokinin
was measured (only in 1997) by the use of direct radioimmunoassay.
Serum biochemical tests included hepatic enzymes, cholesterol
and lipoproteins. Serum PFOA levels, by year, were: 1993 (mean
5.0 ppm, SD 12.2, median 1.1 ppm, range 0.0-80.0 ppm); 1995 (mean
6.8 ppm, SD 16.0, median 1.2 ppm, range 0.0-114.1 ppm); and 1997
(mean 6.4 ppm, SD 14.3, median 1.3 ppm, range 0.1-81.3 ppm). Cholecystokinin
values (mean 28.5 pg/ml, SD 17.1, median 22.7 pg/ml, range 8.8-86.7
pg/ml) approximated the assay's reference range (up to 80 pg/ml)
for a 12 hour fast and were negatively, not positively, associated
with employees' serum PFOA levels. Our findings continue to suggest
there is no significant clinical hepatic toxicity associated with
PFOA levels as measured in this workforce. Unlike a previously
reported observation, PFOA did not appear to modulate hepatic
responses to either obesity or alcohol consumption. Limitations
of these findings include:
1) the cross-sectional design as only 17 subjects were common
for the three surveillance years;
2) the voluntary participation that ranged between 50 and 70 percent;
and
3) the few subjects with serum levels > or = 10 ppm.
Ref:
2000. Drug Chem Toxicol Nov;23(4):603-20. Plasma
cholecystokinin and hepatic enzymes, cholesterol and lipoproteins
in ammonium perfluorooctanoate production workers; by Olsen
GW, Burris JM, Burlew MM, Mandel JH.
Medical Department, 3M Company, St.
Paul, MN 55144-1000, USA.
"So far, five
different pathways have been identified that might explain how
PFOA causes cancer and other types of toxicity. These include
mitochondrial toxicity; cell membrane disruption that results
in decreased cell communication; peroxisome proliferation; increased
levels of estrogen and decreased levels
of testosterone; and decreased thyroid
hormone levels."
Ref: Environmental Working Group. 2003
report: PFCs:
a family of chemicals that contaminate the planet. Part 4: PFC
Health Concerns
Human Health... In
a mortality study, which followed workers for 37 years, mortality
risks for most of the cancer types and non-malignant causes were
not elevated. However, a statistically significant risk of death
from bladder cancer was reported. Three male employees in the
cohort died of bladder cancer (0.12 expected), and all of them
had been employed at the plant for more than 20 years. All of
them had also worked in high exposure jobs for at least 5 years.
In order to screen for morbidity outcomes, an “episode of
care” analysis was undertaken for employees who had worked
at the plant between 1993 and 1998. Many different types of cancer
and other non-malignant conditions were examined. Increased risks
were not reported for most of the conditions or did not reach
statistical significance. However, an increased
risk of episodes was reported for neoplasms of the male reproductive
system, the overall category of cancers and benign growths,
and neoplasms of the gastrointestinal tract. These
risk ratios were highest in employees with the highest and longest
exposures to fluorochemicals.
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: 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.
Ref: 1991. Biochem
Pharmacol Oct 24;42(10):1921-6. Induction by perfluorooctanoic
acid of microsomal 1-acylglycerophosphocholine acyltransferase
in rat kidney. Sex-related difference; by Kawashima Y, Matsunaga
T, Uy-Yu N, Kozuka H.
REPRODUCTIVE TOXICITY
STUDIES.
Title: COMBINED ORAL (GAVAGE) FERTILITY, DEVELOPMENTAL AND PERINATAL/POSTNATAL
REPRODUCTION TOXICITY STUDY OF PFOS IN RATS – ARGUS RESEARCH
LABORATORIES STUDY NUMBER: 6295.9, 1999. Year study performed:
1999 Species/Strain: Sprague Dawley rats. Sex (males/females/both):
Both. Number of animals per dose: 35. Route of administration:
Gavage. Dosing regimen (list all with units): Five groups of 35
rats per sex per dose group were administered PFOS by gavage for
six weeks prior to and during mating. Treatment in male rats continued
until one day before sacrifice (approximately 22 days total);
female rats were treated throughout gestation, parturition, and
lactation. Doses: 0, 0.1, 0.4, 1.6, and 3.2 mg/kg/day. Premating
exposure period for males/females (P and F1, if appropriate):
Six weeks for P; Nine and a half weeks for F1... Terminal body
weights were also significantly reduced in the 1.6 and 3.2 mg/kg/day
dose groups. Signs of reproductive toxicity in the F0 generation
males were seen at the highest dose group of 3.2 mg/kg/day and
included significant reductions in the absolute
weights of the seminal vesicles (with fluid) and the prostate.
A significant increase in the number of males with brown liver
at 3.2 mg/kg/day dose group was also reported...
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 second prenatal developmental toxicity study, groups of 25
pregnant Sprague-Dawley rats were administered 0, 1, 5, and 10
mg/kg/day PFOS in corn oil by gavage on gestation days (GD) 6-15
(Wetzel, 1983). Sexually mature Sprague-Dawley rats, one per sex
per cage, were paired until confirmation of mating or until two
weeks had elapsed. Mating was confirmed by daily vaginal examinations
for the presence and viability of sperm or the presence of a copulatory
plug. The day of confirmation of mating was designated as day
0 of gestation. Doses were adjusted according to the most recently
recorded body weight measurements... Statistically
significant increases in the incidences
in the number of litters containing fetuses with visceral anomalies,
delayed ossification, and skeletal variations were observed in
the high dose group of 10 mg/kg/day. These included external and
visceral anomalies of the cleft palate,
subcutaneous edema, and cryptorchism
as well as delays in skeletal ossification of the skull, pectoral
girdle, rib cage, vertebral column, pelvic girdle, and limbs.
Skeletal variations in the ribs and sternebrae were also observed.
Under the conditions of the study,
a NOAEL of 1 mg/kg/day and a LOAEL of 5 mg/kg/day for developmental
toxicity were indicated.
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
•
Note from FAN:
Cryptorchism:
failure of one or both testes to move into the scrotum as the
male fetus develops
3.5
Reproductive Toxicity Studies in Animals.
York (2002) conducted
an oral two-generation reproductive toxicity study of APFO, which
is summarized below. Although this preliminary risk assessment
focuses on developmental toxicity, the summary below of the two
generation reproductive toxicity study includes all endpoints.
Five groups of 30 Sprague-Dawley rats per sex per dose group were
administered APFO by gavage at doses of 0,1,3,10, and 30 mg/kg/day
six weeks prior to and during mating. Treatment of the F0 male
rats continued until mating was confirmed,and treatment of the
F0 female rats continued throughout gestation, parturition, and
lactation....
Parental Males (F0)... At necropsy,
statistically significant reductions in
terminal body weights were seen at 3,10,and 30 mg/kg/day.
Absolute weights of the left and right epididymides,
left cauda epididymis, seminal vesicles (with and without fluid),
prostate, left and right adrenals, spleen,
and thymus were also significantly reduced at 30 mg/kg/day.
The
absolute weight of the seminal vesicles without fluid was significantly
reduced in the 10 mg/kg/day dose group...
No treatment-related effects were seen at necropsy or upon microscopic
examination of the reproductive organs, with the exception of
increased thickness and prominence of the
zona glomerulosa and vacuolation of the
cells of the adrenal cortex
in the 10 and 30 mg/kg/day dosegroups.
F1 Males ... Statistically
significant (p<0.01) delays in sexual maturation (the average
day of preputial separation) were observed in high-dose animals
versus concurrent controls (52.2 days of age versus 48.5
days of age, respectively)... The ratios
of the weights of the seminal vesicles, with and without fluid,
liver and left and right kidneys to the terminal body weights
were significantly increased in all treated groups. The
ratios of the weights of the left testis, with and without the
tunica albuginea and the right testis to the terminal body weight,
were significantly increased at 3 mg/kg/day and higher.
The ratios of the weights of the left epididymis,
left cauda epididymis, right epididymis and brain to the
terminal body weight significantly increased at 10 mg/kg/day and
higher. The ratios of the weight of the seminal
vesicles with fluid to the brain weight were increased at 1 mg/kg/day
and higher, with statistical significance at 1 and 10 mg/kg/day...
The ratios of the left and right testes weight-to-brain weight
were increased in the 3 mg/kg/day and higher dosage groups. These
ratios were significantly increased at 10 mg/kg/day (right testis
only)and 30 mg/kg/day. Histopathologic examination of the reproductive
organs was unremarkable; however, treatment-related microscopic
changes were observed in the adrenal glands of high-dose animals
(cytoplasmic hypertrophy and vacuolation of the cells of the adrenal
cortex) and in the liver of animals treated with 3,10,and 30 mg/kg/day
(hepatocellular hypertrophy). No other treatment- related effects
were reported...
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.
Abstract: Perfluorooctanoic
acid (PFOA) is an octanoic acid derivative to which all aliphatic
hydrocarbons are substituted by fluorine. PFOA and its salts are
commercially used in various industrial processes. The chemical
is persistent in the environment and does not undergo biotransformation.
It was reported that PFOA is found not only in the serum of occupationally
exposed workers but also general populations. Recent studies have
suggested that the biological half-life of PFOA in humans is 4.37
years based on study of occupationally exposed workers. It is
increasingly suspect that PFOA accumulates and affects human health,
although the toxicokinetics of PFOA in humans remain unclear.
In experimental animals, PFOA seems low in toxicity. PFOA is well-absorbed
following oral and inhalation exposure, and to a lesser extent
following dermal exposure. Once absorbed in the body, it distributes
predominantly to the liver and plasma, and to a lesser extent
the kidney and lungs. PFOA is excreted in both urine and feces.
Biological half-life of PFOA is quite different between species
and sexes and the difference is due mainly to the difference in
renal clearance. In rats, renal clearance
of PFOA is regulated by sex hormones, especially testosterone.
PFOA is excreted into urine by active tubular secretion, and certain
organic anion transporters are though to be responsible for the
secretion. Fecal excretion is also important in the elimination
of PFOA. There is evidence that PFOA undergoes enterohepatic circulation
resulting in reduced amounts of fecal excretion. Elucidation of
the mechanisms of transport in biological systems leads to elimination
and detoxification of this chemical in the human body.
Ref: J Toxicol Sci. 2003 May;28(2):49-57.
Toxicity
and toxicokinetics of perfluorooctanoic acid in humans and animals;
by Kudo N, Kawashima Y.
Note from FAN:
...
The biological half-life (t1/2) of perfluorooctanoic acid (PFOA)
in male rats is 70 times longer than that in female rats.
Ref:
2002 Chem Biol Interact Mar 20;139(3):301-16. Sex
hormone-regulated renal transport of perfluorooctanoic acid;
by Kudo N, Katakura M, Sato Y, Kawashima Y.
Abstract:
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.
Ref: 1992. J Biochem Toxicol Spring;7(1):31-6.
Renal
excretion of perfluorooctanoic acid in male rats: inhibitory effect
of testosterone; by Vanden Heuvel JP, Davis JW 2nd, Sommers
R, Peterson RE.
Abstract: The
peroxisome proliferator perfluordecanoic acid (PFDA) has been
shown to exert an antiandrogenic effect in vivo by acting directly
on the interstitial Leydig cells of the testis. The objective
of this study was to examine the in vitro effects of PFDA and
identify its site of action in steroidogenesis using as model
systems the mouse tumor MA-10 and isolated rat Leydig cells.
PFDA inhibited in a time- and dose-dependent manner the hCG-stimulated
Leydig cell steroidogenesis. This effect was localized
at the level of cholesterol transport into the mitochondria. PFDA
did not affect either the total cell protein synthesis or the
mitochondrial integrity. Moreover, it did not induce any DNA damage.
Morphological studies indicated that PFDA induced lipid accumulation
in the cells, probably due to the fact that cholesterol mobilized
by hCG did not enter the mitochondria to be used for steroidogenesis.
In search of the target of PFDA, we examined its effect on key
regulatory mechanisms of steroidogenesis. PFDA did not affect
the hCG-induced steroidogenic acute regulatory protein (StAR)
levels. However, it was found to inhibit the mitochondrial peripheral-type
benzodiazepine receptor (PBR) ligand binding capacity, 18-kDa
protein, and messenger RNA (mRNA) levels. Further studies indicated
that PFDA did not affect PBR transcription, but it rather accelerated
PBR mRNA decay. Taken together, these data
suggest that PFDA inhibits the Leydig cell steroidogenesis by
affecting PBR mRNA stability, thus inhibiting PBR expression,
cholesterol transport into the mitochondria, and the subsequent
steroid formation. Moreover, this action of PFDA on PBR
mRNA stability indicates a new mechanism of action of peroxisome
proliferators distinct from the classic transcription-mediated
regulation of target genes.
Ref:
2000. Endocrinology Sep;141(9):3137-48. The
peroxisome proliferator perfluorodecanoic acid inhibits the peripheral-type
benzodiazepine receptor (PBR) expression and hormone-stimulated
mitochondrial cholesterol transport and steroid formation in Leydig
cells; by Boujrad N, Vidic B, Gazouli M, Culty M, Papadopoulos
V.
Abstract: 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.
Ref:
1990. Toxicol
Appl Pharmacol Jun 15;104(2):322-33. Androgenic deficiency in
male rats treated with perfluorodecanoic acid; by Bookstaff
RC, Moore RW, Ingall GB, Peterson RE.