Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies

Butenhoff, John L.; Bjork, James A.; Chang, Shu Ching; Ehresman, David J.; Parker, George A.; Das, Kaberi; Lau, Christopher; Lieder, Paul H.; Otterdijk, F.M. van; Wallace, Kendall B.

doi:10.1016/j.reprotox.2011.08.004

Cited by 64 publications

(44 citation statements)

References 67 publications

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“…Exposure to PFBA and PFOA resulted in the same or lower NOAELs for hepatotoxicity in CD-1 mice compared with CD rats, while the severity of hepatomegaly/hypertrophy and the range of histopathologic effects ( e.g. necrosis, increased mitotic figures) was generally greater in mice [21] , [23] , [24] , [51] . These comparisons are generally limited to one strain of each species (CD-1 mice and CD rats).…”

Section: Discussionmentioning

confidence: 87%

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

et al. 2015

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6:2 fluorotelomer alcohol (6:2 FTOH) was evaluated for potential systemic repeated-dose and reproductive toxicity in mice. 6:2 FTOH was administered by oral gavage to CD-1 mice as a suspension in 0.5% aqueous methylcellulose with 0.1% Tween-80 at dosages of 1, 5, 25, or 100 mg/kg/day. The no-observed-adverse-effect level (NOAEL) for systemic toxicity was 25 mg/kg/day (males) and 5 mg/kg/day (females), based on effects at higher doses on mortality, clinical observations, body weight, nutritional parameters, hematology (red and white blood cell), clinical chemistry (liver-related), liver weights, and histopathology (liver, teeth, reproductive tract, and mammary gland). However, 6:2 FTOH was not a selective reproductive toxicant. The NOAEL for reproductive toxicity was >100 mg/kg/day; no effects on reproductive outcome were observed at any dosage. The NOAEL for viability and growth of the offspring was 25 mg/kg/day, based on clinical signs of delayed maturation in pups, and reductions in pup survival and pup body weight during lactation at 100 mg/kg/day. While the severity of the effects was generally greater in mice than previously reported in CD rats, the overall NOAELs were identical in both species, 5 mg/kg/day for systemic toxicity and 25 mg/kg/day for offspring viability/growth. 6:2 FTOH was not a selective reproductive toxicant in either species; no effects on reproductive outcome occurred at any dose level, and any effects observed in offspring occurred at dose levels that induced mortality and severe toxicity in maternal animals.

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Section: Discussionmentioning

confidence: 87%

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

et al. 2015

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“…These findings appear similar to the toxicologic evidence in laboratory studies with perfluorooctanesulfonate (PFOS), which displaced thyroxine from binding proteins in rats, transiently increasing free thyroxine without altering overall thyroid hormone homeostasis ( Chang et al , 2007 , 2008 ; Weiss et al , 2009 ). PFOA is structurally similar to PFOS in that both compounds resemble a fatty acid in their amphiphilic nature and compete for binding with free fatty acids on albumin and liver fatty-acid binding protein ( Luebker et al , 2002 ), and therefore, PFOA can also similarly displace thyroxine ( Butenhoff et al , 2012c ). Such displacement has been shown with aspirin, heparin, and free fatty acids ( Koulouri et al , 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

Convertino

Olsen

Liu

et al. 2018

Toxicological Sciences

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A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50–1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately −1.2×10−3 mmol/l/μM and 2.8×10−3 pmol/l/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175 000–230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects.

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“…A large number of studies have shown that PFOA has liver toxicity, immunotoxicity and reproductive toxicity (Abbott et al., ). Developmental studies have shown that PFOA can lead to early abortion (Lau et al., ) and growth retardation in human (Butenhoff et al., ). To investigate the toxic effects of PFOA in utero exposure on reproduction and development in offspring mice, the present study was carried out.…”

Section: Discussionmentioning

confidence: 99%

Effects of perfluorooctanoic acid exposure during pregnancy on the reproduction and development of male offspring mice

Song

Wang

et al. 2018

Andrologia

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This study was conducted to explore the effects of maternal exposure to perfluorooctanoic acid (PFOA) on reproduction and development of male offspring mice. Pregnant mice were given 1, 2.5 or 5 mg/kg BW PFOA daily by gavage during gestation. The results showed that the survival number of offspring mice at weaning was significantly decreased. There were no differences in the testicular index of offspring mice between PFOA exposure groups and non-PFOA group. Maternal exposure to PFOA reduced the level of testosterone in the male offspring mice on PND 21 (p < 0.01) but increased in 1 mg/kg group and decreased in 2.5 and 5 mg/kg groups on PND 70 (p < 0.01). There were different degrees of damage to testis in a dose-dependent manner, and the number of Leydig cells markedly decreased (p < 0.01) in 2.5 and 5 mg/kg PFOA groups on PND 21 and PND 70. The expression of Dlk1-Dio3 imprinted gene cluster showed a decreasing trend, where Glt2, Rian and Dio3 gene expressions were significantly reduced (p < 0.05) on PND 21. Therefore, PFOA exposure during pregnancy reduces the number of survival offspring mice, damages testis, disrupts reproductive hormones and reduces the mRNA expressions of the Dlk1-Dio3 imprinted cluster in testis.

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Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies

Cited by 64 publications

References 67 publications

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

Oral repeated-dose systemic and reproductive toxicity of 6:2 fluorotelomer alcohol in mice

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

Effects of perfluorooctanoic acid exposure during pregnancy on the reproduction and development of male offspring mice

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