Table 9

PFOA

CAS No. not given

96%.

Botelho et al. (2015)

C57BL/6, mice,

Male,

4/dose.

0, 0.002, 0.005, 0.01 or 0.02% equivalent to 2.4, 6, 12 or 24**.

Water,

Diet,

10 days,

Non-GL study,

GLP not stated.

NR

Males (mean ± SE):

↑ relative liver weight (g): 5.04 ± 0.20 vs 7.84 ± 0.22.

↑ Hypertrophy of centrilobular hepatocytes: data only shown in figures.

Recovery not assessed.

Males:

NA / 2.4*

The production of complement products in the liver can trigger the release of inflammatory mediators, which may eventually lead to enhanced susceptibility to complement-mediated toxicity (as evidenced by increases in ALT, AST and bilirubin. This suggests the role of complement in liver damage following exposure to PFOA.

K2

The study hypothesized that exposure to PFOA exerts adverse effects on the activities of the complement system and that these effects play a role in the hepatotoxicity caused by PFOA.

Only male animals were used.

Apart from increased liver weight and hypertrophy, other liver effects cited by the author were only seen at the highest dose.

Study was funded by 3M Company

PFOA (ammonium salt)

CAS No. not given

97.99%.

Butenhoff et al. (2012a)

Sprague-Dawley rats

Male and female.

10-20/sex/dose.

Recovery group:

Male and female

10/sex/dose.

0 or 30 (actual dose 0 or 27.8).

Milli-Q or Milli-U water.

Gavage,

28 days,

Non-GL study,

GLP not stated.

Recovery group:

0 or 30,

3 weeks.

At 30 mg/kg bw/day in males at end of treatment (mean ± SD)

Serum: 145.60 ± 28.25

Liver: 166.10 ± 28.45.

At 30 mg/kg bw/day in males at end of recovery.

Serum: 14.67 ± 5.30

Liver:  16.32 ± 6.69.

At 30 mg/kg bw/day in females at end of treatment.

Serum: 7.98 ± 4.03

Liver: 11.15 ± 4.91.

At 30 mg/kg bw/day in females at end of recovery:

Serum: 0.03 ± 0.02

Liver: <0.05.

Males (mean ± SD):

↓ body weight gain (g): 357 ±  23 vs 268 ± 26.

↑ absolute liver weight (g): 8.08 ± 0.73 vs 15.54 ± 2.18.

↑ relative liver weight: 2.42 ± 0.17 vs 6.19 ± 0.39.

↑ ALT (IU): 55.8 ± 22.1 vs 66.5 ± 16.2.

↑ ALP (IU): 234 ± 51 vs 320 ± 67.

↑ Urea (mmol/L): 6.3 ± 1.5 vs 9.0 ± 1.5.

↓ TP (g/L): 60.3 ± 3.5 vs 56.2 ± 3.2.

↑ albumin (g/L): 31.3 ± 1.9 vs 33.1 ± 1.7.

↓ food consumption: data NR.

↑ Hepatocellular hypertrophy: 0 vs 10 (1 minimal; 6 slight; 3 moderate).

↑ hepatocellular coagulative necrosis: 0 vs 4 (3 minimal; 1 slight).

↑ mRNA of Acaca, Acox, Cyp4A1, Cyp2B2, Malic, Por, Thrsp, Fasn, Dio1, Ugt1A1, Ugt1A6, Ugt2B and ApoA1: data only shown in figures.

Females (mean ± SD):

↑ ALT (IU): 38.4 ± 8.7 vs 47.4 ± 11.7.

↑ albumin (g/L): 34.4 ± 2.2 vs 36.2 ± 2.0.

↑ mRNA of Acox, Cyp3A1, Malic, Cyp7A1: data only shown in figures.

Recovery:

Males (mean ± SD):

↓ body weight gain (g): 434 ± 36 vs 370 ± 26.

Absolute liver weight comparable to controls (g): 9.57 ± 1.42 vs 9.71 ± 1.16.

↑ relative liver weight: 2.31 ± 0.19 vs 2.77 ± 0.22.

↑ Hepatocellular hypertrophy: 0 vs 4 (minimal).

↑ mRNA of Cyp4A, Malic, Thrsp: data only shown in figures.

Females (mean ± SD):

↑ mRNA of Malic: data only shown in figures.

↑ ALT: data NR.

↓ TP: data NR.

Males:

NA / 30*.

Females:

NA / 30*.

Recovery:

Males:

NA / 30*.

Females:

NA / 30*.

The greater liver weight and hepatocellular hypertrophic response observed in rats treated with NH4+PFOA as compared to those treated with NH4+PFBA correlated with a somewhat greater increase in liver concentrations of mRNA transcripts regulated by PPAR (Acox and Cyp4A1) and an increase in the CAR-regulated Cyp2B2 that was more than 20 times the control.

Although decreased by the end of the recovery period, Cyp4A1 and Cyp2B2 mRNA transcript levels remained elevated in NH4+PFOA-treated males as compared to controls, corresponding to the 20% increase in relative liver weight and 40% incidence of slight hepatocellular hypertrophy observed at the end of recovery.

The 30 mg/kg-d NH4+PFOA dose was included in the design of the 28-day study in order to provide context back to the rather large toxicological database for PFOA.

K2

This was a comparative study investigating oral toxicity of PFBA and PFOA.

As it was a comparative study, only two dose groups i.e. control and single treatment group were used.

Only data for significantly different clinical chemistry parameters were presented in the text.

Study was funded by US EPA. Authors are affiliated to 3M Company.

PFOA (ammonium salt)

CAS No. not given

98%.

Elcombe et al. (2010)

SD (CD) rats Male

30/dose.

0 or 300 ppm in diet equivalent to 27** .

Powdered RMI feed.

Diet,

7 days,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↓ body weight (g): 372 ± 22 vs 328 ± 30 on day 8.

↑ absolute liver weight (g): 15.3 ± 1.3 vs 19.2 ± 3.1 on day 8.

↑ relative liver weight (g/kg): 4.10 ± 0.26 vs 5.83 ± 0.55 on day 8.

↑ hepatic cell proliferation (%):1.42 ± 0.65 vs 5.94 ± 2.12 on day 8.

↓ liver DNA concentration (mg DNA/g liver): 2.07 ± 0.16 vs 1.61 ± 0.28 on day 8.

↓ cholesterol (mmol/L): 2.17 ± 0.25 vs 0.84 ± 0.37 on day 8.

↓ glucose (mmol/L): 19.41 ± 1.79 vs 12.12 ± 2.20 on day 8

↓ TGs: 1.21 ± 0.45 vs 0.30 ± 0.16 on day 8.

↓ periportal hepatocellular glycogen: grade 1.

↑ hepatocellular hypertrophy: grade 1-2 and 3-4.

↑ fatty vacuolation: grade 1-2.

NA / 27*

The objective of the work was to characterize PFOA-induced hepatomegaly in male rats, particularly with respect to the potential role of PPAR-mediated cell proliferation and possible decreased apoptosis.

Clinical chemistry findings were consistent with those associated with PPAR activation, notably decreased serum total cholesterol and triglycerides.

APFO did not increase activities of either ALT or AST, consistent with a lack of histologically identified hepatocellular damage. Histopathology demonstrated that APFO caused hepatocellular glycogen loss, hypertrophy, and hyperplasia. The hypertrophy was characterized by increased cyanide-insensitive palmitoyl CoA oxidation (a marker of peroxisome proliferation) and the induction of cytochrome P450 CYP4A1 (accompanied by smooth endoplasmic reticulum proliferation).

K2

This study investigated the PFOA-induced hepatomegaly in male rats.

Only data from study 1 are presented here but data from study 2 are similar.

Only two dose groups were used i.e. control and single treatment group and only male animals were used.

All authors represent organizations that have a current or former financial interest in ammonium perfluorooctanoate. Some authors are affiliated to 3M Company.

PFOA (ammonium salt)

CAS No. not given

98%.

Elcombe et al. (2010)

SD (CD) rats Male

30/dose.

0 or 300 ppm in diet equivalent to 27**.

Powdered RMI feed.

Diet,

28 days,

Non-GL study,

GLP not stated.

No Data.

Males (mean ± SD):

↓ body weight (g): 462 ± 43 vs 358 ± 53.

↑ absolute liver weight (g): 18.3 ± 2.5 vs 20.8 ± 3.2.

↑ relative liver weight (g/kg): 3.96 ± 0.36 vs 5.83 ± 0.56.

↓ liver DNA concentration (mg DNA/g liver): 1.87 ± 0.16 vs 1.63 ± 0.15.

↑ AST (U/L): 138.35 ± 30.25 vs 112.15 ± 16.29.

↓ cholesterol (mmol/L): 2.04 ± 0.36 vs 1.24 ± 0.27.

↓ glucose (mmol/L): 16.98 ± 1.42 vs 10.56 ± 1.60.

↓ TGs: 1.89 ± 0.60 vs 0.51 ± 0.12.

↓ periportal hepatocellular glycogen: grade 1.

↑ hepatocellular hypertrophy: grade 1-2 and 3-4.

↑ hepatocellular hyperplasia: grade 2.

NA / 27*

Same as above.

K2

Same as above.

PFOA (ammonium salt)

CAS No. 3825-26-1

98%.

Guo et al. (2019)

Balb/c mice Male  12/dose.

0, 0.4, 2 or 10. 

Milli-Q water,

Gavage,

28 days,

Non-GL study,

GLP not stated.

Data only provided in figures.

Males (mean ± SE):

↑ relative liver weight (g): 1.03 ± 0.02 vs 1.68 ± 0.05.

↑ TP (g/L): 57.15 ± 0.68 vs 60.40 ± 0.89.

↑ albumin (g/L): 23.54 ± 0.32 vs 24.06 ± 0.36.

↑ globulin (g/L): 34.60 ± 0.47 vs 36.34 ± 0.63.

↑ hepatocellular hypertrophy: data only provided in figures.

Recovery not assessed.

Males:

NA / 0.4*

After 28 days of exposure, PFO4DA and PFOA exhibited similar toxic mechanisms leading to liver dysfunction, although PFO4DA showed less severity than the same dosage of PFOA. PFO4DA displayed a weaker accumulation potential than PFOA; whereas PFO2HxA and PFO3OA demonstrated no accumulation, and thus did not cause liver injury.

K2

This was a comparative study that compared the hepatotoxicity of PFOA with other new PFSAs.

Results were provided in a supplementary document and didn’t always mirror the methodology section. Overall, PFOA showed similar accumulation and toxicity compared with PFO4DA but was more toxic than PFO2HxA and PFO3OA.

Only male animals were used.

This study was supported by the National Natural Science Foundation of China and Strategic Priority Research Program of the Chinese Academy of Sciences.

PFOA

CAS No. 335-67-1

95%.

Guruge et al. (2006)

Sprague-Dawley rats

Male

6/dose.

0, 1, 3, 5, 10 or 15.

2% Tween® 80.

Gavage.

21 days.

Non-GL study.

GLP not stated.

NR

Males:

↑ expression of genes involved in transport and metabolisms of fatty acids and lipids, cell communication, adhesion, growth, apoptosis, regulation of hormone, proteolysis and peptidolysis and signal transduction: data only provided in figures.

↓ expression of genes involved in apoptosis, regulation of hormone, metabolisms and G-protein coupled receptor protein signalling pathway: data only provided in figures.

Recovery not assessed.

Males:

NA / 1*

The effects seen were dose-dependent with exposure to 10mg PFOA/kg/bw/day causing alteration in expression of the greatest number of genes (over800).

Results showed that a large number of genes associated with lipid or fatty acid metabolism were altered by PFOA and some of the genes were linked with pathways of fatty acid degradation and mitochondrial fatty acid b-oxidation in all concentrations of PFOA-treated rats.

The PFOA induced peroxisomal and mitochondrial fatty acid b-oxidation and the peroxisomal b-oxidation might create oxidative stress on DNA and protein. The reduction of cholesterol synthesis would be consistent with the down-regulation of the gene Hmgcr observed in this study.

The study suggests that the suppression of organic anion transport genes may explain the delayed urinary clearance of PFOA.

There were a number of genes related to tumour progression and inflammation affected by exposure to PFOA, which suggests that exposure to PFOA might enhance the risk of cancer.

K2

This study only looked at gene expression profiles and proposed mechanisms of toxicity.

This research work was partially supported from the Japanese Ministry of Environment under the Global Environment Conservation Research Fund and by a CERG grant from the Hong Kong Research Grants Council.

PFOA (ammonium salt)

CAS No. 3825-26-1

99%.

Kennedy Jr (1987)

Crl:CD-1 mice.

Male and female, 5/sex/dose.

0, 30, 300 and 3000 ppm in diet equivalent to 2.7, 27 or 270**.

Diet,

14 days,

Non-GL study,

GLP not stated.

NR

Males (mean):

↑ absolute liver weight (g): 1.76 vs 4.06.

↑ relative liver weight (g/100g): 5.1 vs 12.3.

Females (mean):

↑ absolute liver weight (g): 1.31 vs 3.35.

↑ relative liver weight (g/100g): 5.0 vs 12.4.

Recovery not assessed.

Males:

NA / 30*

Females:

NA / 30*

Differences in the disposition of ammonium perfluorooctanoate probably are responsible for the differing response seen between male and female rats. Rats excrete the chemical in the urine rather rapidly whereas mice do not. The greater sensitivity of the male compared to the female rat to ammonium perfluorooctanoate is not seen in the mouse. While the retention of this chemical in the blood of mice over time has not been studied, the slower excretion suggests that the residence time in the body is longer than in the rat.

Mice fed 1 ppm ammonium perfluorooctanoate for 14 days showed no increase in liver weight or in the liver-to-body weight ratio. Ammonium perfluorononanoate led to death of mice at feeding concentrations of 300 ppm and liver weight increases at the lowest level tested, 3 ppm. This material appears to be more toxic than ammonium perfluorooctanoate and the liver weight response, in terms of both dose required to produce the change and the magnitude of the liver weight increase, is simiIar.

K2

This was a comparative study with PFOA and other fluorochemicals using liver weight as a means to compare the toxicological response between chemicals.

Only liver weight was measured.

Authors are affiliated to Central Research and Development Department, E.I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine. Study funding was not reported.

PFOA (ammonium salt)

CAS No. 3825-26-1

99%.

Kennedy Jr (1987)

Crl:CD-1 mice.

Male and female, 5/sex/dose.

0, 0.01, 0.03, 0.1, 0.3, 1, 3, 10 or 30 ppm in diet equivalent to 0.0009, 0.0027.0.009, 0.027, 0.09, 0.27, 0.9 or 2.7 **.

Diet,

21 days,

Non-GL study,

GLP not stated.

NR

Males (mean):

↑ absolute liver weight (g): 1.82 vs 2.45.

↑ relative liver weight (g/100g): 5.4 vs 7.1.

Females (mean):

↑ absolute liver weight (g): 1.40 vs 1.85.

↑ relative liver weight (g/100g): 5.2 vs 6.7.

Recovery not assessed.

Males

1 / 3*.

Females:

1 / 3*.

See above.

K2

See above.

PFOA (ammonium salt)

CAS 3825-26-1

>98%.

Li et al. (2019)

C57BL/6 mice.

Male

5/dose.

0 or 1.

Distilled water,

Gavage,

2 weeks,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↑ hepatocyte DNA synthesis: data only provided in figures.

↑ expression of genes related to fatty acid metabolism: cd36, Acox1, Srebf1, Srebf2, Cpt-1α, ApoB.

↑ expression of genes related to nuclear receptors: Cyp4a10, Car, Cyp2b10, Pxr, Cyp3a11.

Recovery not assessed.

Males:

NA / 1*

Pre-existing non-alcoholic fatty liver disease (NAFLD) changed the lipid accumulation effect of PFOA in the liver. Modulation on the lipid metabolism by PFOA might be time-dependent. PFOA increased the expression of Srebf1 and Srebf2 compared to vehicle controls after 2 weeks, regardless of diet. However, such effect diminished at the later time points studied.

K2

The study investigated if the predisposition of NAFLD may enhance the toxicity of PFOA in the liver, and PFOA exposure may change the progression of(NAFLD. Only data for PFOA alone is presented.

Only two dose groups were used i.e. control and single treatment group

ALT and TG were only increased in animals fed a high fat diet and PFOA.

The study was supported in part by Internal Funding to the Klaunig Lab at Indiana University.

PFOA (ammonium salt)

CAS 3825-26-1

>98%.

Li et al. (2019)

C57BL/6 mice

Male

5/dose.

0 or 1.

Distilled water,

Gavage,

8 weeks,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↓ body weight: data only provided in figures.

↑ absolute liver weight: data only provided in figures.

↑ relative liver weight: data only provided in figures.

↑ hepatocyte DNA synthesis: data only provided in figures.

↑ expression of genes related to fatty acid metabolism; Cd36.

↑ expression of genes related to nuclear receptors: Ppar-α, Ppar-γ, Car, Cyp2b10, Pxr, Cyp3a11.

Recovery not assessed.

Males:

NA / 1*

Pre-existing NAFLD changed the lipid accumulation effect of PFOA in the liver. Modulation on the lipid metabolism by PFOA might be time-dependent. PFOA increased the expression of Srebf1 and Srebf2 compared to vehicle controls after 2 weeks, regardless of diet. However, such effect diminished at the later time points studied.

K2

The study investigated if the predisposition of NAFLD may enhance the toxicity of PFOA in the liver, and PFOA exposure may change the progression of NAFLD. Only data for PFOA alone is presented.

Only two dose groups were used i.e. control and single treatment group.

ALT and TG were only increased in animals fed a high fat diet and PFOA.

The study was supported in part by Internal Funding to the Klaunig Lab at Indiana University.

PFOA (ammonium salt)

CAS 3825-26-1

>98%.

Li et al. (2019)

C57BL/6 mice

Male

5/dose.

0 or 1.

Distilled water,

Gavage,

16 weeks,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↑ relative liver weight after 8 weeks: data only provided in figures.

↑ hepatocyte DNA synthesis: data only provided in figures.

↑ expression of genes related to fatty acid metabolism; Cd36, Fasn.

↑ expression of genes related to nuclear receptors: Cyp4a10, Ppar-γ, Car, Cyp2b10, Pxr, Cyp3a11.

Recovery not assessed.

Males:

NA / 1*

Pre-existing NAFLD changed the lipid accumulation effect of PFOA in the liver. Modulation on the lipid metabolism by PFOA might be time-dependent. PFOA increased the expression of Srebf1 and Srebf2 compared to vehicle controls after 2 weeks, regardless of diet. However, such effect diminished at the later time points studied.

K2

The study investigated if the predisposition of NAFLD may enhance the toxicity of PFOA in the liver, and PFOA exposure may change the progression of NAFLD. Only data for PFOA alone is presented.

Only two dose groups were used i.e. control and single treatment group

ALT and TG were only increased in animals fed a high fat diet and PFOA.

The study was supported in part by Internal Funding to the Klaunig Lab at Indiana University.

PFOA

CAS No. 335-67-1

>98%.

NTP. (2022b)

Sprague-Dawley rats.

Male and female. 10/sex/dose.

0, 0.625, 1.25, 2.5, 5 or 10 (males) or 0, 6.25, 12.5, 25, 50 or 100 (females)

2% Tween® 80 in deionized water.

Gavage,

28 days,

NTP protocol,

GLP study.

At 0 mg/kg bw/day in males (mean ± SE)

Plasma: 0.098 ± 0.006

Liver: <LOD.

At 0.625 mg/kg bw/day in males:

Plasma: 50.7 ± 2.2

Liver (ng/mL): 54.6 ± 2.2.

At 0 mg/kg bw/day in females

Plasma: <LOD.

At 0.625 mg/kg bw/day in females:

Plasma: 0.491 ± 0.072.

Males (mean ± SD):

↑ absolute liver weight (g): 12.96 ± 0.41 vs 14.94 ± 0.32.

↑ relative liver weight (mg/g body weight): 37.34 ± 0.72 vs 43.41 ± 0.55.

↑ ALT (IU/L): 57 ± 3 vs 68 ± 3

↑ ALP (IU/L): 207 ± 9 vs 233 ± 8.

↓ TP (g/dL): 6.6 ± 0.1 vs 6.0 ± 0.1.

↓ globulin (g/dL): 2.3 ± 0.1 vs 1.7 ± 0.1.

↑ albumin/globulin ratio: 1.9 ± 0.0 vs 2.5 ± 0.1.

↓ cholesterol (mg/dL): 114 ± 6 vs 72 ± 2.

↓ TG (mg/dL): 138 ± 12 vs 101 ± 8.

↑ hepatocytic cytoplasmic alterations: 0 vs 4 (minimal).

↑ gene expression of Acox1: 1.09 ± 0.14 vs 3.78 ± 0.41.

↑ gene expression of Cyp4a1: 1.07 ± 0.13 vs 22.17 ± 2.17.

↑ gene expression of Cyp2b1: 1.26 ± 0.27 vs 5.75 ± 1.39.

↑ gene expression of Cyp2b2: 1.09 ± 0.15 vs 3.88 ± 0.50.

Females (mean ± SD):

↑ ALP (IU/L): 154 ± 7.

↑ gene expression of Cyp2b1: 1.29 ± 0.21 vs 6.18 ± 1.76.

↑ gene expression of Cyp2b1: 1.42 ± 0.35 vs 5.87 ± 1.68.

Recovery not assessed.

Males:

NA / 0.625.

Females:

NA / 6.25.

A major target organ of toxicity for PFOA was the liver.

Cyp2b1/Cyp2b2 activation indicates CAR-mediated activity, and Acox1/Cyp4a1 activation suggests PPAR-α activity.

PFAS administration increased the levels of serum biomarkers associated with hepatobiliary injury.

K1

This study investigated toxicity of a number of PFAS, including PFHxA, following a 28-day exposure.

No treatment-related clinical observations were reported.

Changes in liver weight and clinical chemistry, apart from ALP, were only seen at higher doses in females. Histopathological changes were only seen at higher doses in both sexes.

Although females were administered a 10-fold higher dose of PFOA, males had a higher plasma concentration compared to females across the dose groups. Liver concentrations of PFOA were measured in males only and increased with dose, but when normalized to dose administered, liver concentrations decreased with increasing dose.

Government funded study. Study was audited retrospectively by an independent QA contractor.

PFOA

CAS No. not given

96%.

Qazi et al. (2010a)

C57BL/6 mice.

Male

4/dose.

0 or 0.002% equivalent to 4**.
Water,

Diet,

10 days,

Non-GL study,

GLP not stated.

At 0 mg/kg bw/day (mean ± SE)

Serum: 0.070 ± 0.004.

At 2.4 mg/kg bw/day

Serum: 87.6 ± 2.1.

Males (mean ± SEM):

↑ liver mass: 6.95 ± 0.42 vs 11.64 ± 0.67.

↑ ALP (µkat/L): 2.42 ± 0.14 vs 3.54 ± 0.16.

↓ cholesterol (mmol/L): 2.34 ± 0.09 vs 1.80 ± 0.11.

↓ TGs (mmol/L): 1.80 ± 0.20 vs 1.15 ± 0.06.

↑ centrilobular hepatocellular hypertrophy, with elevated numbers of cytoplasmic acidophilic granules and occasional mitosis.: data only provided in figures.

↓ TNF-α (ng/mL): 0.43 ± 0.03 vs 0.29 ± 0.04.

↓ INF-γ (ng/mL): 0.65 ± 0.02 vs 0.41 ± 0.03.

↓ IL-4 (ng/mL): 0.13 ± 0.01 vs 0.09 ± 0.01.

↑ granulocytes, myeloid suppressor cells, macrophages, T- helper cells, natural killer cell and presumptive erythrocyte progenitor cells expressing TER119 cells.

Recovery not assessed.

Males:

NA / 4*

PFOA causes histological alterations in the liver and that centrilobular hepatocytes are the main hepatic parenchymal target cells for these fluorochemicals. These hepatocytes, located in zone III of the hepatic acinus, are primarily responsible for the detoxification of toxic compounds as well as being most sensitive to up-regulation of cytochrome P450 and peroxisomal enzymes of fatty acid β-oxidation.

In the histological examination, no sign of necrosis in the livers of PFOA-treated animals. This and the finding that these animals exhibited virtually no change in serum activities of ALT and AST, in combination with a moderate increase in serum ALP, suggest that the doses administered induced hepatomegaly without causing liver damage. Overall, the results demonstrate that exposure of mice to PFOA induces pronounced hypertrophy in centrilobular hepatocytes and alters the hepatic immune status in mice.

K2

This study focussed on histology and immune status of the liver.

Only 4 male animals and only two dose groups were used i.e. control and single treatment group

ALT and AST were unchanged by treatment.

Liver mass is calculated as liver weight (g) / body weight (g) x100

The study was financed by an unrestricted research grant from the 3M Company.

PFOA

CAS No. not given

Purity not given.

Soltani et al. (2023)

C57BL/6J mice.

Male 

5/dose.

0, 1, 5, 10 or 20.

2% Tween® 80.

Gavage,

28 days,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↑ liver weight: data only provided in figures.

↑ AST and ALT: data only provided in figures.

↑ cytokines IL-6, INF-γ and TNF-α: data only provided in figures.

Moderate to severe steatosis and inflammation: data only provided in figures.

Recovery not assessed.

Males: 1 / 5*

It has been shown that PFOA causes tissue changes in the liver by damaging the centrilobular cells of the parenchyma, the main target of fluorochemicals. According to liver weight increase, liver damage and degeneration were seen in all PFOA-treated groups in the current investigation, and normal liver function was compromised, as seen in the group’s pathology slides (PFOA 1, 5, 10, and 20 mg/kg/day). Analysing liver tissue was another indicator of overt liver damage following PFOA exposure, as oxidative stress and inflammatory markers of the liver revealed an increase. Hepatocytes displayed various degrees of alteration, with the high-dose group exhibiting the greatest modifications.

K2

The study investigated the effect symbiotic pre-treatment on PFOA-induced liver damage.

Only data for PFOA alone are presented. 

Only male mice were used.

Study was funded by the Vice Chancellery of Research of Isfahan University of medical Sciences

PFOA (ammonium salt)

CAS No. not given

98%.

Son et al. (2008)

ICR mice. Male

10/dose.

0, 2, 10, 50 or 250 ppm in diet equivalent to 0.49, 2.64, 17.63, 47.21.

Deionized water.

Drinking water.

21 days.

Non-GL study.

GLP not stated.

NR

Males (mean ± SE):

↑ liver weight/body weight ratio (g/100g): 5.05 ± 0.10 vs 6.43 ± 0.18.

Mild lymphocytic infiltration around the central vein.

Recovery not assessed.

Males:

NA / 0.49*

An inflammatory reaction in the liver after PFOA treatment was expected. However, no remarkable inflammatory reaction in the liver of PFOA-treated mice was detected. Considering the decrease of gene expression of TNF-α along with the increase of hepatotoxicity in PFOA-treated mice in our experiments, PFOA may cause hepatotoxicity via decreasing TNF- α by means of impeding the liver tissue repair. Overall, the study showed that PFOA induced hepatotoxicity.

K2

This study investigate liver toxicity following PFOA exposure via drinking water.

ALT, AST, hepatic cytokines and body weight gain were only affected at higher doses.

Study was funded by a grant from the National Fisheries Research and Development Institute (NFRDI), Korea.

PFOA

CAS No. not given

98%.

Wu et al. (2018)

Kunming mice.

Male

8/dose.

0, 1 or 5.

Peanut oil and DMSO,

Gavage,

21 days,

Non-GL study,

GLP not stated.

NR

Males:

↑ liver mass and liver index: data only provided in figures. ↑ GPT and GOT: data only provided in figures.

↑ TG: data only provided in figures.

↓ FGF21 protein: data only provided in figures.

↑ visible vacuoles around liver portal area: data only provided in figures.

↑ CD36-positive cells: data only provided in figures.

↓ ApoB-labelled cells: data only provided in figures.

Recovery not assessed.

Males:

1 / 5

Authors noted that the current data suggested that PFOA-dosed mice resulted in the potential trend of body weights implying PFOA-induced abnormal energy expenditure and utilization. Liver weights in PFOA-dosed mice were elevated, accompanied with increased liver functional transaminases (GPT, GOT) in serum. Overall, the current observations suggest that immediate PFOA exposure can lead to perturbation of liver metabolism in adult mice via affecting vital hormonal expressions.

K2

The study investigated the biological impact of PFOA exposure on pancreatic islet cells and insulin-sensitive liver cells, as well as the molecular mechanisms involved.

No change in body weight was observed at any dose. Biochemical measurements were limited to GPT and GOT.

Only male animals were used and only two dose groups were used i.e. control and single treatment group

PFOA

CAS No. not given

>98%.

Zou et al. (2015)

Kunming mice.

Male

8/dose.

0 or 10.

Vehicle,

Gavage,

14 days,

Non-GL study,

GLP not stated.

NR

Males (mean ± SD):

↑ AST, ALT, ALP, LDH and TBA: data only provided in figures.

↑ deranged liver architecture, marked oedema, vacuolar degeneration, hepatocellular necrosis, and inflammatory cell infiltration: data only provided in figures.

↑ MDA, H2O2 and 8-OHdG: data only provided in figures

↓ SOD, CAT, CRP, IL-6 and COX-2: data only provided in figures.

↓ nuclear DNA fragmentation: data only provided in figures.

Recovery not assessed.

Males:

NA / 10*

A significant increase in the serum levels of AST, ALT, ALP, LDH and TBA was observed after administration of PFOA.

MDA production, H2O2 generation and 8-OHdG formation significantly increased after exposure to PFOA in the liver of mice. Moreover, the activities of endogenous antioxidants SOD and CAT significantly decreased.

K1

This study investigated the ameliorative effect of quercetin on PFOA-induced liver damage.

Only data for PFOA are presented.

As the study focused on the effects of quercetin, only 1 dose of PFOA was used. No clinical signs were measured.

Only male animals were used.

This study was supported by the National Natural Science Foundation of China and Jiangxi Provincial Education Development