Up to 1994 Abstracts


Abstracts on PFOS and PFOA for the following years:
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.

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]

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]

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]

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.

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]


1990 TOXICOL IN VITRO; 4 (1). 71-74.

The cellular effects of a unique pesticide sulfluramid (N-ethylperfluorooctanesulfonamide) on rabbit renal proximal tubules.


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

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]

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]

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]

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]

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]

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]


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.

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]

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]

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]

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]

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.

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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