Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Figures & data

Figure 1. Chemical structure of PFOS (left) and PFOA (right).

Table 1. Representative human studies reporting associations between serum levels of PFOS and/or PFOA and serum levels of lipids*.

Substance	Study information, No of subjects	Findings in serum	Serum levels (ng/mL)	Reference
Cross-sectional studies general population
PFOS/PFOA	Denmark DCH, 753 individuals	PFOS vs TC ↑	Mean PFOS 36, Mean PFOA 7.1	Eriksen et al. (2013)
		PFOA vs TC ↑
PFOS/PFOA	NHANES, USA, 860 adults	PFOS vs TC ↑	Median PFOS 20, Median PFOA 3.8	Nelson et al. (2010)
		PFOS vs non-HDL-C ↑
		PFOS vs LDL-C ↑
		PFOA vs TC ↑
		PFOA vs non-HDL ↑
		PFOA vs LDL-C ↑
PFOS/PFOA	C8 cohort, 46 000 adults	PFOS vs TC ↑	Median PFOS 20	Steenland et al. (2009)
		PFOS vs LDL-C ↑
		PFOS vs TGs ↑
		PFOA vs TC ↑	Median PFOA 27
		PFOA vs LDL-C ↑
		PFOA vs TGs ↑
PFOS/PFOA	C8 cohort, 12 500, children, 1–18 y	PFOS vs TC ↑	Mean PFOS 23	Frisbee et al. (2010)
		PFOS vs LDL-C ↑
		PFOS vs HDL-C ↑
		PFOA vs TC ↑	Mean PFOA 69
		PFOA vs LDL-C ↑
		PFOA vs HDL-C ↑
PFOS/PFOA	Sweden, 1945 adults†	PFOS vs TC ↑	Median PFOS 157	Li et al. (2020)
		PFOS vs LDL-C ↑
		PFOA vs TC ↑	Median PFOA 8.6
		PFOA vs LDL-C ↑
Cross-sectional studies occupational settings
PFOS/PFOA	USA (3 M), and Belgium, 518 individuals	PFOS vs TC ↑	High, mean PFOS and PFOA about 1000	Olsen et al. (2003)
		PFOS vs TGs ↑
		PFOA vs TC ↑
		PFOA vs TGs ↑
PFOA	USA (3 M) and Belgium, 506 individuals (re-evaluation of 2003 data)	PFOA vs HDL-C ↓	High, median PFOS of 720 (range 20–6240), median PFOA of 2210 (range 10–92 000)	Olsen and Zobel (2007)
		PFOA vs TGs ↑
PFOA	USA (DuPont), 1025 individuals	PFOA vs TC	High, median PFOA 114–494 across 4 categories (range 8–9550)	Sakr et al. (2007a)
		PFOA vs LDL-C ↑
		PFOA vs VLDL-C ↑
Longitudinal studies general population
PFOS/PFOA	C8 cohort, 560 individuals	PFOS vs TC ↑	Geometric Mean PFOS: from 10 to 8	Fitz-Simon et al. (2013)
		PFOS vs LDL-C ↑
		PFOA vs TC ↑	Geometric Mean PFOA: from 75 to 31
		PFOA vs LDL-C ↑
PFOA	C8 cohort, 32 000 individuals, general population and workers	PFOA vs TC↑	Median PFOA general population 24 and workers 113. Modeled cumulative PFOA: 20th percentile 215 ng/mL*year and 80th percentile 1820 ng/mL*year	Winquist and Steenland (2014)
Longitudinal studies occupational settings
PFOS/PFOA	USA (3 M), and Belgium, 174 individuals	PFOA vs TC ↑	High, mean PFOS and PFOA about 1000	Olsen et al. (2003)
		PFOA vs TGs ↑
PFOA	USA (DuPont), 454 individuals	PFOA vs TC ↑	High, mean PFOA about 1000	Sakr et al. (2007b)
Therapeutic studies
PFOA	49 cancer patients, phase 1 dose-escalation trial, no control group, 50–1200 mg, weekly for 6 weeks	PFOA vs TC ↓	150 000–230 000	Convertino et al. (2018)
		PFOA vs LDL-C ↓

* Only significant positive or inverse (negative) associations are mentioned in the Table. However, some studies showed also negative findings (no associations).

† Municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area.

DCH: Diet Cancer and Health; C8: study performed in the “C8” area where drinking water was contaminated by PFOA from a DuPont plant; “↑” sign illustrates a statistically significant positive association; “↓” sign illustrates inverse a statistically significant association; TC: total cholesterol; TGs: triglycerides; LDL-C: low-density lipoprotein; HDL-C: high-density lipoprotein.

Table 2. Example studies in animals reporting on lipid perturbations induced by PFOS/PFOA. Only induced effects are reported in the table.

Substance	Experimental design	Lipid perturbation-related findings	LO(A)EL (mg/kg bw/d)	Serum levels at LO(A)EL (µg/mL)	Liver levels at LO(A)EL (µg/g)	Reference
Studies in rats
PFOS	Sprague Dawley rats (m,f), 4 weeks, in feed 0, 0.14, 1.33, 3.21, 6.34 (m) 0, 0.15, 1.43, 3.73, 7.58 (f) mg/kg bw/d	↓ serum TC (m)	3.21	20.93 ± 2.36	856.90 ± 353.83	Curran et al. (2008)
		↓ serum TGs (m)	3.21	20.93 ± 2.36	856.90 ± 353.83
		↓ serum TC (f)	3.73	31.93 ± 3.6	597 ± 158
		↓ serum TGs (f)	3.73	31.93 ± 3.6	597 ± 158
PFOS	Sprague Dawley rats (m,f), 4 weeks, gavage 0, 0.312, 0.625, 1.25, 2.5, 5 mg/kg bw/d	↓ serum TC (m)	0.312	23.73 ± 1.11	87.17 ± 3.03	NTP (2019a)
		↓ serum TGs (m)	5	318.2 ± 8.86	867.1 ± 26.8
		↓ serum TC (f)	5	413.55 ± 8.07	NR
		↓ serum TGs (f)	2.5	237.5 ± 5.218	NR
PFOS	Sprague Dawley rats (m,f), 14 weeks, feed 0, 0.05, 0.2, 0.4, 1.5 mg/kg bw/d	↓ serum TC (m)	1.5	148 ± 14	568 ± 107	Seacat et al. (2003)
PFOA	Sprague Dawley rats (m), 2 weeks, gavage 0, 0.3, 1, 3, 10, 30 mg/kg bw/d	↓ serum TC	0.3	20 ± 3.2	NR	Loveless et al. (2006)
		↓ serum TGs	0.3	20 ± 3.2
		↓ non-HDL-C	0.3	65 ± 11
		↓ HDL-C	3	137 ± 18
PFOA	Sprague Dawley rats (m,f), 4 weeks, gavage 0, 0.625, 1.25, 2.5, 5, 10 (m) mg/kg bw/d 0, 6.25, 12.5, 25, 50, 100 (f) mg/kg bw/d	↓ serum TC (m)	0.625	50.69 ± 2.2	54.61 ± 2.23	NTP (2019b)
		↓ serum TGs (m)	0.625	50.69 ± 2.2	54.61 ± 2.23
		↑ serum TC (f)	50	9.32 ± 1.82	NR
		↑ serum TGs (f)	50	9.32 ± 1.82	NR
Studies in mice
PFOS	CD-1 mice (m), 3,7,14,21 days, gavage 0, 1, 5, 10 mg/kg bw	↓ serum TC	5	NR	NR	Wan et al. (2012)
		↓ serum VLCL-C	5
		↓ serum LDL-C	5
		↑ liver lipids	5
PFOA	SV129 mice (m), 7 days, gavage 0, 10 mg/kg bw	↑ liver lipids	10	NR	NR	Das et al. (2017)
PFOA	C57BL/6N mice (m), 3 weeks, standard chow or Western type diet 0, 5 mg/kg bw/d	↑ liver lipids	5	NR	NR	Tan et al. (2013)
PFOA	Crl:CD®-1(ICR)BR mice (m), 2 weeks, gavage 0, 0.3, 1, 3, 10, 30 mg/kg bw/d	↓ serum TC	3	69 ± 10	NR	Loveless et al. (2006)
		↓ HDL-C	3	69 ± 10
PFOA	29S4/SvlmJ mice (m), 4 weeks, gavage 0, 5.4, 10.8, 21.5 mg/kg bw/d	↓ serum TC	10.8	46.9 ± 3.2	198.8 ± 15.4	Minata et al. (2010)
PFOA	C57BL/6 & BALB/c mice 6 weeks, in feed, Western type diet (m,f) 0, 0.5 mg/kg bw/d	↑ serum TC (f, C56BL/6)	0.5	8.6	NR	Rebholz et al. (2016)
		↑ serum TC (m, C56BL/6)		26.9
		↑ serum TC (m, BALB/c)		28.2
		↓ liver TC (m.f BALB/c)
PFOA	BALB/c mice (m), 4 weeks, gavage 0, 0.08, 0.31, 1.25, 5, 20 mg/kg bw/d	↓ liver TC	0.31	NR		(Yan et al. 2015)
Studies in genetically modified mice
PFOS	APOE*3-Leiden. CETP mice (m) 4–6 weeks, in feed, Western type diet 0, 3 mg/kg bw/d	↓ serum TC	3	86–125 (mean range from 3 experiments)	NR	Bijland et al. (2011)
		↓ serum TGs	3	86–125
		↓ serum non-HDL-C	3	86–125
		↓ serum HDL-C	3	86–125
		↑ liver lipids	3	86–125
		↓ hepatic CYP7A1 gene expression	3	86–125
PFOA	APOE*3-Leiden. CETP mice (m) 4–6 weeks, in feed, Western type diet 0, 0.001, 0.03, 3.2 mg/kg bw/d	↓ serum TGs	3.2	90–150	NR	Pouwer et al. (2019)
		↓ serum TC	3.2	90–150
		↓ non-HDL	3.2	90–150
		↑ HDL-C	3.2	90–150
PFOS	WT and PPARa null mice (m), 7 days 0, 3, 10 mg/kg bw/d	↑ expression of genes related to liver cholesterol biosynthesis	10	NR	NR	Rosen et al. (2010)
PFOA	hPPARα mice, 6 weeks, gavage 0, 1, 5 mg/kg bw/d	↓ serum TGs	1	NR	NR	Nakagawa et al. (2012)
		↑ liver TGs	1
PFOA	hPPARα mice (m,f), 6 weeks, drinking water, Western type diet 0, 0.7 mg/kg bw/d	↑ liver lipids	0.7	48	NR	Schlezinger et al. (2020)
Studies in monkeys
PFOS	Cynomolgous monkeys (m,f) 26 weeks (182 days), gavage 0, 0.03, 0.15, 0.75 mg/kg bw/d	↓ serum TC (m)	0.03	15.8 ± 1.4	17.3 ± 4.7	Seacat et al. (2002)
		↓ serum TGs (m)	0.15	82.6 ± 25.2	58.8 ± 19.5
		↓ serum HDL-C	0.03	15.8 ± 1.4	17.3 ± 4.7
		↑ liver lipids (m)	0.75	173 ± 37	395 ± 24
		↓ serum TC (f)	0.75	171 ± 22	273 ± 14
		↓ serum HDL-C	0.75	171 ± 22	273 ± 14
		↑ liver lipids (f)	0.75	171 ± 22	273 ± 14
PFOS	Cynomolgous monkeys (m,f) 1 year, gavage applied only on certain and few days during the experimental period 11–17.2 mg/kg bw, given to achieve respective serum levels	↓ serum TC (m)	NR	74	NR	Chang et al. (2017)
		↓ serum HDL-C		74
		↓ serum TC (f)		76
		↓ serum HDL-C		76

m: males; f: females; bw: body weight; NR: not reported; TC: total cholesterol; HDL-C: high-density lipoprotein cholesterol; TGs: triglycerides; hPPARα: human peroxisome proliferator-activated receptor; WT: wild-type; “↑” sign illustrates a statistically significant increase; “↓” sign illustrates a statistically significant decrease.

Figure 2. Overview of the lipid circulation throughout the human body with their carrier molecules, the lipoproteins. LPL: lipoprotein lipase; LDL: low-density lipoprotein; VLDL: very low-density lipoprotein; TGs: triglycerides; ApoB: apolipoprotein B. Created with BioRender.com.

Figure 3. The principal steps of the hepatic cholesterol biosynthetic pathway. HMGCS1: HMG-CoA synthase 1; HMGCR: HMG-CoA reductase. HMGCS1 catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to HMG-CoA. In a following step HMG-CoA is converted by HMGCR to mevalonate. Subsequently, several enzymatic reactions are required for the synthesis of cholesterol. SQLE: Squalene epoxidase. SQLE catalyzes the first oxygenation step in sterol biosynthesis. CYP7A1: cholesterol 7-alpha hydroxylase. CYP7A1 catalyzes the transformation of excess cholesterol into bile acids. Created with BioRender.com.

Table 3. PFOS/PFOA organ concentrations in humans and calculated human organ:plasma partition coefficients (based on mean/median organ concentrations).

Organ concentrations (ng/mL)			Calculated human organ:plasma partition coefficients (mean, median, or range, accordingly)
	PFOA	PFOS	PFOA	PFOS
Blood*	1.80 ± 0.66^a	7.64 ± 3.54^c
	1.65^b	7.60^b
Plasma†	3.2 ± 1.2^a	13.6 ± 6.3^a	1	1
Liver‡	4.0^b	41.9^b	1.3	3.1
	3–98.9^c	3–405^c	0.9–30.9	0.2–29.8
Brain‡	<LOD (=2.45)	1.9^b	Not available	0.1
		3–22.5^c		0.2–1.6
Lung‡	12.1^b	28.4^b	3.8	2.1
	6–87.9^c	3–61.8^c	1.9–27.5	0.1–2.0
Kidney‡	1.5^b	55^b	0.5	4.0
	3–11.9^c	3–369^c	0.9–3.7	0.2–27.1

* Ericson et al. (2007), N = 48, age: 55. 5 ± 5.5 years.

† Fàbrega et al. (2014), applying a 0.56 blood →plasma conversion while ignoring erythrocyte binding.

‡ Perez et al. (2013), N = 20 age: 28–83 years.

^a Mean ± SD.

^b Median.

^c Range.

Table 4. Information of terminal half-lives for PFOS and PFOA in various species.

Substance	Species/terminal half-life
	Rat	Mouse	Pig	Monkey	Humans
PFOS	27.8 days (m) 24.8 days (f) (Kim et al. 2016)	42.8 days (m) 37.8 days (f) (Chang et al. 2012)	634 days (Numata et al. 2014)	132 days (m) 110 days (f) (Chang et al. 2012)	Occupational workers: 5.4 years (Olsen and Zobel 2007) Community (contaminated drinking water): 3.4 years (Li et al. 2020)
PFOA	1.6–1.8 days (m) 0.15–0.19 days (f) (Kim et al. 2016)	21.7 days (m) 15.6 days (f) (Lou et al., 2009)	236 days (Numata et al. 2014)	21 days (m) 30 days (f) (Butenhoff et al. 2004)	Occupational workers: 3.8 years (Olsen and Zobel 2007) Adults (contaminated drinking water): 2.3 years (Bartell et al. 2010), 3.3 years (Brede et al. 2010) Community (contaminated drinking water): 2.7 years (Li et al. 2020)

Source: taken from RIVM (2018) and complemented with more recent data.

m: males; f: females.

Figure 4. Summarized human- and rodent-specific differences related to PFOS/PFOA exposure, as well as species-specific differences with respect to lipoprotein metabolism and nutrition. CETP: cholesteryl ester transfer protein; LDL: low-density lipoprotein; HLDL: high-density lipoprotein; TGs: triglycerides; PPARα: peroxisome proliferator-activated receptor α; PXR: pregnane X receptor; CAR: constitutive androstane receptor; PPARγ: peroxisome proliferator-activated receptor γ (Created with BioRender.com.

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