Table 3.
Studies (1990–2018) investigating the toxicology of per- and polyfluoroalkyl substances in animals or humans
| Study | Year | Study Design | Model/Cell Line | Exposure | Mechanistic Domain | Major Findings | |
|---|---|---|---|---|---|---|---|
| Chang et al. (41) | 2017 | Animal | Monkeys | PFOS | Clinical | No observed association: | Serum creatinine |
| BUN | |||||||
| Fair et al. (42) | 2013 | Animal | Dolphins | PFOS, PFOA, PFDA | Clinical | Association present: | ↑ Serum creatinine |
| ↑ BUN | |||||||
| Butenhoff et al. (43) | 2012 | Animal | Rats | PFOS | Clinical | Association present: | ↑ BUN (male and female) |
| Histologic | No observed kidney histologic changes | ||||||
| Lieder et al. (44) | 2008 | Animal | Rats | PFBS | Clinical | No observed association: | Body weight |
| Serum creatinine | |||||||
| BUN | |||||||
| Histologic | Effects observed: | Medullary and papillary tubular epithelial hyperplasia | |||||
| Interstitial infiltration with tubular basophilia and papillary edema | |||||||
| Papillary necrosis | |||||||
| Seacat et al. (45) | 2003 | Animal | Rats | PFOS | Clinical | Association present: | ↑ BUN |
| Histologic | No observed kidney histologic changes | ||||||
| Son et al. (46) | 2007 | Animal | Mouse (male) | PFOA | Clinical | No observed association: | Serum creatinine |
| BUN | |||||||
| Kidney weights | |||||||
| Histologic | No observed kidney histologic changes | ||||||
| Takahasi et al. (47) | 2014 | Animal | Rats | PFUA | Clinical | Association present: | ↑ BUN |
| Histologic | Effects observed: | Kidney tubular regeneration | |||||
| Xing et al. (48) | 2016 | Animal | Mouse (male) | PFOS | Clinical | Association present: | Acute toxicity, glomerular changes with peripheral edema |
| ↑ mortality | |||||||
| Chronic toxicity, ↓ body weight and kidney mass | |||||||
| Histologic | No observed kidney histologic changes | ||||||
| Klaunig et al. (49) | 2015 | Animal | Rats | PFHxA | Clinical | Association present: | Dose-dependent decrease in survival (females) |
| Histologic | Effects observed: | Papillary necrosis (females) | |||||
| Mild to moderate tubular atrophy | |||||||
| Serex et al. (50) | 2014 | Animal | Rats | Fluoro-telomers | Clinical | Association present: | ↑ mortality |
| Histologic | Effects observed: | Dose-dependent increase in kidney weights | |||||
| Kidney degeneration and necrosis, leading to death | |||||||
| Butenhoff et al. (51) | 2004 | Animal | Rats | aPFOA | Histologic | Effects observed: | ↑ kidney weights (parents and offspring) |
| ↓ body weights | |||||||
| Cui et al. (52) | 2009 | Animal | Rats | PFOA, PFOS | Histologic | Effects observed: | Cortical and medullary congestion with enhanced acidophilia and tumefaction of proximal tubule cells |
| Curran et al. (53) | 2008 | Animal | Rats | PFOS | Histologic | Effects observed: | ↑ kidney weights (male and female) |
| Tubular epithelial hyperplasia | |||||||
| Kim et al. (54) | 2011 | Animal | Rats | PFOS | Histologic | Effects observed: | Enhanced proximal tubular basophilia |
| Ladics et al. (55) | 2005 | Animal | Rats | Fluoro-telomers | Histologic | Effects observed: | ↑ kidney weights (males) |
| Tubular hypertrophy | |||||||
| Newsted et al. (56) | 2008 | Animal | Quail | PFBS | Histologic | No observed kidney histologic changes | |
| Rogers et al. (57) | 2013 | Animal | Rats | PFOS, PFNA | Histologic | Effects observed: | Fewer nephrons and elevated BP in offspring of maternal rats exposed during pregnancy |
| Chou et al. (58) | 2017 | Animal | Mouse | PFOS | Histologic | Effects observed: | Kidney tubular inflammation and apoptosis |
| Enhanced tubular fibrosis and cytosolic changes | |||||||
| In vitro | RTE | Cellular | Effects observed: | Epithelial mesenchymal transition induction and cell; migration via PPARγ deacetylation and Sirt1 sequestration | |||
| Wen et al. (59) | 2016 | Animal | RTE (rats) | PFOS | Histologic | Effects observed: | Loss of epithelial cells |
| Granular cytoplasmic changes in proximal tubules | |||||||
| In vitro | Cellular | Effects observed: | Dose-dependent reduction in cell proliferation | ||||
| Increased apoptosis | |||||||
| Enhanced oxidative stress (via NFAT3, PPARγ, and SIRT1) | |||||||
| Abbott et al. (60) | 2012 | Animal | Mouse | PFOA | Cellular | Effects observed: | Increased PPARα, β, γ mRNA expression in kidney tissue |
| Upregulation of Cyp4a14 gene expressing PPAR | |||||||
| Arukwe et al. (61) | 2011 | Animal | Salmon | PFOA, PFOS | Cellular | Effects 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) | 2015 | In vitro | RTE | PFOS | Cellular | Effects observed: | Enhanced expression of fibrotic and oxidative stress markers accompanied by apoptosis of RTE cells |
| Diaz et al. (63) | 1994 | Animal | Rats (male) | PFOA | Cellular | Effects observed: | Enhanced peroxisome proliferation |
| Induction of p450 in kidneys | |||||||
| Increased β oxidation of fatty acids | |||||||
| Eldasher et al. (64) | 2013 | Animal | Rats (male) | PFOA | Cellular | Effects observed: | Enhanced expression of Cyp4a14 in kidneys |
| Eroʇlu et al. (65) | 2011 | Animal | Rats | PFOS | Cellular | Effects observed: | Enhanced markers for oxidative stress (MDA, SOD, and catalase) |
| Gorrochategui et al. (66) | 2016 | In vitro | RTE (Xenopus laevis) | PFBS, PFOS, PFOA, PFNA | Cellular | Effects observed: | Reduced cellular proliferation |
| Spectral alterations of DNA/RNA structures, protein structures, and fatty acids | |||||||
| Hu et al. (67) | 2003 | In Vitro | RTE (dolphin) | PFOS, PFHA, PFBS | Cellular | Effects observed: | Carbon-chain length inhibition of intercellular communication at the gap junctions (PFOS and PFHA) |
| Qian et al. (68) | 2010 | In vitro | Microvascular endothelial cells | PFOS | Cellular | Effects 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) | 1991 | Animal | Rats (male) | PFOA, PFDA, PFBA | Cellular | No observed effects: | Marker of oxidative stress and DNA damage (8-hydroxydeoxyguanosine) |
| Witzman et al. (70) | 1996 | Animal | Rats (male) | PFOA, PFDA | Cellular | Effects observed: | ↑ markers for oxidative stress, including mitochondrial markers |
| Kariuki et al. (71) | 2017 | Animal | Crustacean (Daphnia magna) | PFOS | Metabolic | Effects observed: | Disrupted several energy metabolism pathways |
| Enhanced protein degradation | |||||||
| Lankadurai et al. (72) | 2012 | Animal | Earthworm | PFOS | Metabolic | Effects observed: | Increased fatty acid oxidation |
| Disrupted glucose and energy metabolism, specifically glutamate and TCA cycle metabolites | |||||||
| Peng et al. (73) | 2013 | In vitro | Human hepatocytes | PFOA | Metabolic | Effects observed: | Disrupted carnitine metabolism |
| Disrupted cholesterol biosynthesis and lipid metabolism | |||||||
| Disrupted amino acid metabolism | |||||||
| Skov et al. (74) | 2015 | Animal | Rats (male) | PFNA | Metabolic | Effects observed: | Disrupted lipid metabolism |
| Tan et al. (75) | 2013 | Animal | Mice | PFOA | Metabolic | Effects observed: | Disrupted fatty acid metabolism |
| Wagner et al. (76) | 2017 | Animal | Crustacean (Daphnia magna) | PFOS | Metabolic | Effects observed: | Disrupted amino acid metabolism |
| Wang et al. (77) | 2017 | Human | Human | PFOA, PFOS | Metabolic | Effects 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) | 2016 | Animal | Mouse | PFOA | Metabolic | Effects observed: | Disrupted amino acid metabolism |
| Disrupted lipid metabolism | |||||||
| Altered energy metabolism | |||||||
| Increased β oxidation of fatty acids | |||||||
| Zhang et al. (79) | 2011 | Animal | Rats (male) | PFDoA | Metabolic | Effects observed: | Disrupted kidney amino acid metabolism |
| Altered glucose and energy metabolism | |||||||
| Ding et al. (80) | 2009 | Animal | Rats (male) | PFDoA | Metabolic | Effects observed: | Disrupted lipid metabolism |
| Disrupted fatty acid metabolism | |||||||
| Disrupted amino acid metabolism | |||||||
| Clinical | Association 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.