Table 3.

Studies (1990–2018) investigating the toxicology of per- and polyfluoroalkyl substances in animals or humans

StudyYearStudy DesignModel/Cell LineExposureMechanistic DomainMajor Findings
Chang et al. (41)2017AnimalMonkeysPFOSClinicalNo observed association:Serum creatinine
BUN
Fair et al. (42)2013AnimalDolphinsPFOS, PFOA, PFDAClinicalAssociation present:↑ Serum creatinine
↑ BUN
Butenhoff et al. (43)2012AnimalRatsPFOSClinicalAssociation present:↑ BUN (male and female)
HistologicNo observed kidney histologic changes
Lieder et al. (44)2008AnimalRatsPFBSClinicalNo observed association:Body weight
Serum creatinine
BUN
HistologicEffects observed:Medullary and papillary tubular epithelial hyperplasia
Interstitial infiltration with tubular basophilia and papillary edema
Papillary necrosis
Seacat et al. (45)2003AnimalRatsPFOSClinicalAssociation present:↑ BUN
HistologicNo observed kidney histologic changes
Son et al. (46)2007AnimalMouse (male)PFOAClinicalNo observed association:Serum creatinine
BUN
Kidney weights
HistologicNo observed kidney histologic changes
Takahasi et al. (47)2014AnimalRatsPFUAClinicalAssociation present:↑ BUN
HistologicEffects observed:Kidney tubular regeneration
Xing et al. (48)2016AnimalMouse (male)PFOSClinicalAssociation present:Acute toxicity, glomerular changes with peripheral edema
↑ mortality
Chronic toxicity, ↓ body weight and kidney mass
HistologicNo observed kidney histologic changes
Klaunig et al. (49)2015AnimalRatsPFHxAClinicalAssociation present:Dose-dependent decrease in survival (females)
HistologicEffects observed:Papillary necrosis (females)
Mild to moderate tubular atrophy
Serex et al. (50)2014AnimalRatsFluoro-telomersClinicalAssociation present:↑ mortality
HistologicEffects observed:Dose-dependent increase in kidney weights
Kidney degeneration and necrosis, leading to death
Butenhoff et al. (51)2004AnimalRatsaPFOAHistologicEffects observed:↑ kidney weights (parents and offspring)
↓ body weights
Cui et al. (52)2009AnimalRatsPFOA, PFOSHistologicEffects observed:Cortical and medullary congestion with enhanced acidophilia and tumefaction of proximal tubule cells
Curran et al. (53)2008AnimalRatsPFOSHistologicEffects observed:↑ kidney weights (male and female)
Tubular epithelial hyperplasia
Kim et al. (54)2011AnimalRatsPFOSHistologicEffects observed:Enhanced proximal tubular basophilia
Ladics et al. (55)2005AnimalRatsFluoro-telomersHistologicEffects observed:↑ kidney weights (males)
Tubular hypertrophy
Newsted et al. (56)2008AnimalQuailPFBSHistologicNo observed kidney histologic changes
Rogers et al. (57)2013AnimalRatsPFOS, PFNAHistologicEffects observed:Fewer nephrons and elevated BP in offspring of maternal rats exposed during pregnancy
Chou et al. (58)2017AnimalMousePFOSHistologicEffects observed:Kidney tubular inflammation and apoptosis
Enhanced tubular fibrosis and cytosolic changes
In vitroRTECellularEffects observed:Epithelial mesenchymal transition induction and cell; migration via PPARγ deacetylation and Sirt1 sequestration
Wen et al. (59)2016AnimalRTE (rats)PFOSHistologicEffects observed:Loss of epithelial cells
Granular cytoplasmic changes in proximal tubules
In vitroCellularEffects observed:Dose-dependent reduction in cell proliferation
Increased apoptosis
Enhanced oxidative stress (via NFAT3, PPARγ, and SIRT1)
Abbott et al. (60)2012AnimalMousePFOACellularEffects observed:Increased PPARα, β, γ mRNA expression in kidney tissue
Upregulation of Cyp4a14 gene expressing PPAR
Arukwe et al. (61)2011AnimalSalmonPFOA, PFOSCellularEffects observed:PFOA: increased PPARα, γ mRNA, ACOX1, CAT expression
PFOS: decreased PPARα, γ mRNA expression in kidney tissue and increased expression of PPARβ, ACOX1, CAT
Chung (62)2015In vitroRTEPFOSCellularEffects observed:Enhanced expression of fibrotic and oxidative stress markers accompanied by apoptosis of RTE cells
Diaz et al. (63)1994AnimalRats (male)PFOACellularEffects observed:Enhanced peroxisome proliferation
Induction of p450 in kidneys
Increased β oxidation of fatty acids
Eldasher et al. (64)2013AnimalRats (male)PFOACellularEffects observed:Enhanced expression of Cyp4a14 in kidneys
Eroʇlu et al. (65)2011AnimalRatsPFOSCellularEffects observed:Enhanced markers for oxidative stress (MDA, SOD, and catalase)
Gorrochategui et al. (66)2016In vitroRTE (Xenopus laevis)PFBS, PFOS, PFOA, PFNACellularEffects observed:Reduced cellular proliferation
Spectral alterations of DNA/RNA structures, protein structures, and fatty acids
Hu et al. (67)2003In VitroRTE (dolphin)PFOS, PFHA, PFBSCellularEffects observed:Carbon-chain length inhibition of intercellular communication at the gap junctions (PFOS and PFHA)
Qian et al. (68)2010In vitroMicrovascular endothelial cellsPFOSCellularEffects observed:Induced reactive oxygen species leading to increased vascular permeability and actin filament re-modeling, with disruption of cell junction and cell adhesions
Takagi et al. (69)1991AnimalRats (male)PFOA, PFDA, PFBACellularNo observed effects:Marker of oxidative stress and DNA damage (8-hydroxydeoxyguanosine)
Witzman et al. (70)1996AnimalRats (male)PFOA, PFDACellularEffects observed:↑ markers for oxidative stress, including mitochondrial markers
Kariuki et al. (71)2017AnimalCrustacean (Daphnia magna)PFOSMetabolicEffects observed:Disrupted several energy metabolism pathways
Enhanced protein degradation
Lankadurai et al. (72)2012AnimalEarthwormPFOSMetabolicEffects observed:Increased fatty acid oxidation
Disrupted glucose and energy metabolism, specifically glutamate and TCA cycle metabolites
Peng et al. (73)2013In vitroHuman hepatocytesPFOAMetabolicEffects observed:Disrupted carnitine metabolism
Disrupted cholesterol biosynthesis and lipid metabolism
Disrupted amino acid metabolism
Skov et al. (74)2015AnimalRats (male)PFNAMetabolicEffects observed:Disrupted lipid metabolism
Tan et al. (75)2013AnimalMicePFOAMetabolicEffects observed:Disrupted fatty acid metabolism
Wagner et al. (76)2017AnimalCrustacean (Daphnia magna)PFOSMetabolicEffects observed:Disrupted amino acid metabolism
Wang et al. (77)2017HumanHumanPFOA, PFOSMetabolicEffects observed:Disrupted lipid and fatty acid metabolism
Disrupted energy metabolism, including TCA cycle and glutathione pathways
Disrupted xenobiotic detoxifying, anti-oxidation, and nitric oxide signal pathways
Yu et al. (78)2016AnimalMousePFOAMetabolicEffects observed:Disrupted amino acid metabolism
Disrupted lipid metabolism
Altered energy metabolism
Increased β oxidation of fatty acids
Zhang et al. (79)2011AnimalRats (male)PFDoAMetabolicEffects observed:Disrupted kidney amino acid metabolism
Altered glucose and energy metabolism
Ding et al. (80)2009AnimalRats (male)PFDoAMetabolicEffects observed:Disrupted lipid metabolism
Disrupted fatty acid metabolism
Disrupted amino acid metabolism
ClinicalAssociation present:Serum creatinine
BUN
  • PFOS, perfluorooctane sulfonate; PFOA, perfluorooctanoic acid; PFDA, perfluorodecanoic acid; PFBS, perfluorobutane sulfonate; PFUA, perfluoroundecanoic acid; PFHxA, perfluorohexanoic acid; aPFOA, ammonium perfluorooctanoic acid; PFNA, perfluorononanoic acid; RTE, kidney tubular epithelial; PPAR, peroxisome proliferator receptor; Sirt1, sirtuin 1; NFAT3, nuclear factor of activated T-cells 3; Cyp4a14, cytochrome p450 4A14; ACOX1, Acyl-CoA oxidase 1; CAT, catalase; P450, cytochrome P450; MDA, malondialdehyde; SOD, superoxide dismutase; PFHA, perfluoroheptanoic acid; PFBA, perfluorobutyrate; TCA, tricarboxylic acid; PFDoA, perfluorododecanoic acid.