Liver - Adverse Effects
(Perfluorinated chemicals)

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Adverse Effects

Liver Adverse Effects
PFOS - PFOA Index Page

• 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).

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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 excerpt: "... one of the most potent rodent hepatocarcinogens, perfluorooctanoic acid (PFOA), induces apoptosis in human HepG2 cells in a dose- and time-dependent manner... In summary, we have delineated a ROS [reactive oxygen species] and mitochondria-mediated pathway for induction of apoptosis by PFOA."
Ref: 2001. Toxicol Appl Pharmacol May 15;173(1):56-64. Reactive oxygen species and mitochondria mediate the induction of apoptosis in human hepatoma HepG2 cells by the rodent peroxisome proliferator and hepatocarcinogen, perfluorooctanoic acid; by Panaretakis T, Shabalina IG, Grander D, Shoshan MC, DePierre JW.

Abstract excerpt: "... it is concluded that PFOA is a true liver cancer promoter that may not require extensive initial DNA damage for its promoting activity."
Ref: 2003-2004. Dis Markers;19(1):19-25. Peroxisomal enzymes and 8-hydroxydeoxyguanosine in rat liver treated with perfluorooctanoic acid; by Abdellatif A, Al-Tonsy AH, Awad ME, Roberfroid M, Khan MN.

Abstract: The maternal and developmental toxicities of perfluorooctane sulfonate (PFOS) were evaluated in the rat and mouse. PFOS is an environmentally persistent compound used as a surfactant and occurs as a degradation product of both perfluorooctane sulfonyl fluoride and substituted perfluorooctane sulfonamido components found in many commercial and consumer applications. Pregnant Sprague-Dawley rats were given 1, 2, 3, 5, or 10 mg/kg PFOS daily by gavage from gestational day (GD) 2 to GD 20; CD-1 mice were similarly treated with 1, 5, 10, 15 and 20 mg/kg PFOS from GD 1 to GD 17. Controls received 0.5% Tween-20 vehicle (1 ml/kg for rats and 10 ml/kg for mice). Maternal weight gain, food and water consumption, and serum chemistry were monitored. Rats were killed on GD 21, and mice on GD 18. PFOS levels in maternal serum, maternal and fetal livers were determined. Maternal weight gains in both species were suppressed by PFOS in a dose-dependent manner, likely attributed to reduced food and water intake. Serum PFOS levels increased with dosage, and liver levels were approximately 4-fold higher than serum. Serum thyroxine (T4) and triiodothyronine (T3) in the PFOS-treated rat dams were significantly reduced as early as one week after chemical exposure, although no feedback response of thyroid-stimulating hormone (TSH) was observed. A similar pattern of reduction in T4 was also seen in the pregnant mice. Maternal serum triglycerides were significantly reduced, particularly in the high dose groups, although cholesterol levels were not affected. In the mouse dams, PFOS produced a marked enlargement of the liver at 10 mg/kg and higher dosages. In the rat fetuses, PFOS was detected in the liver, but at levels nearly half of those in the maternal counterparts, regardless of administered doses. In both rodent species, PFOS did not alter the numbers of implantations or live fetuses at term, although small deficits in fetal weight were noted in the rat. A host of birth defects including cleft palate, anasarca, ventricular septal defect, and enlargement of the right atrium were seen in both rats and mice, primarily in the 10 and 20 mg/kg dosage groups, respectively. Our results demonstrate both maternal and developmental toxicity of PFOS in the rat and mouse.
Ref: Toxicol Sci 2003 May 28; Exposure to Perfluorooctane Sulfonate During Pregnancy in Rat and Mouse. I. Maternal and Prenatal Evaluations; by Thibodeaux JR, Hanson RG, Rogers JM, Grey BE, Barbee BD, Richards JH, Butenhoff JL, Stevenson LA, Lau C. Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.

PFOS is persistent, bioaccumulative and toxic to mammalian species. There are species differences in the elimination half-life of PFOS; the half-life is 100 days in rats, 200 days in monkeys, and years in humans. The toxicity profile of PFOS is similar among rats and monkeys. Repeated exposure results in hepatotoxicity and mortality; the dose-response curve is very steep for mortality. This occurs in animals of all ages, although the neonate may be more sensitive. In addition, a 2-year bioassay in rats has shown that exposure to PFOS results in hepatocellular adenomas and thyroid follicular cell adenomas; the hepatocellular adenomas do not appear to be related to peroxisome proliferation. Further work to elucidate the species differences in toxicokinetics and in the mode of action of PFOS will increase our ability to predict risk to humans.
-- 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. In a dietary 2-year bioassay in Sprague-Dawley rats, hepatotoxicity, characterized by centrilobular hypertrophy, centrilobular eosinophilic hepatocytic granules, centrilobular hepatocytic pigment, or centrilobular hepatocytic vacuolation was noted in male and/or female rats given 5 or 20 ppm. Hepatocellular centrilobular hypertrophy was also observed in mid-dose (2 ppm) male rats. Significant increases in the incidence of cystic hepatocellular degeneration were found in all the male treated groups (0.5, 2, 5, or 20 ppm). Based on the pathological findings in the liver, the LOAEL was 5 ppm and the NOAEL was 2 ppm in female rats. In males, the LOAEL was 0.5 ppm, and a NOAEL was not established...
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.

Abstract: 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.
Ref: 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; by Kawashima Y, Uy-Yu N, Kozuka H.

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