Issues currently complicating the risk assessment of synthetic amorphous silica (SAS) nanoparticles after oral exposure

Figures & data

Table 1. Overview of recent in vivo, oral toxicity studies performed with SAS (published after June 2014), in addition to the study by van der Zande et al. (2014).

Reference	Study design	SAS used	Effects (with a focus on liver toxicity)	Remarks
Earlier (sub-chronic) key study
(van der Zande et al. 2014)	28-day + 84-day study Male Wistar rats group size: n = 5 Dietary exposure (daily) mixed with standard feed and chocolate milk, characterized in the feed matrix • NM-202: 0, 100, 500, 1000 mg/kg bw/d • SAS: 0, 100, 1000, 2500 mg/kg bw/d Only the highest dose level tested at 84 days Studied general toxicology, blood serum biomarkers, histopathology, immunotoxicity, transcriptomics SiO2 content determined in liver, kidney, spleen, brain and testis by ICP-MS	Two pyrogenic silicas: NM-202 Constituent particle size: 10-25 nm (as reported by supplier) SAS (Aerosil 380) Constituent particle size: 7 nm (as reported by supplier)	NM-202 Induction of mild liver (periportal) fibrosis (only after 84 days) at highest dose (1000 mg/kg bw/d). No other significant histopathological changes. Induced gene expression in fibrosis-related gene sets. No relevant changes in ALP, ALT, AST and other liver injury associated biomarkers. SAS No statistically significant adverse effects.	Different pyrogenic SAS (including NM-202), compliant with E 551 specifications Three, medium-high dose levels (only highest dose tested for 84 days) Dietary exposure, particle characteristics analyzed in feed matrix and intestinal content
(Sub)chronic studies
(Boudard et al. 2019; Boudard et al. 2020)	18-months non-guideline study focusing on kidney and liver effects C57BL/6 and C57BL/6S mice (differing in expression of α-synuclein) group size: n = 5-8 Drinking water exposure (daily) Stock solution dispersed in tap water by sonication according to NANOGENOTOX protocol (Jensen et al. 2011). • 0, 4.8 mg/kg bw/d Studied general toxicology, histopathology (of kidney and liver), kidney function Si determined in liver and kidney by ICP-MS	Precipitated silica: NM-200. Analysis performed by TEM at JRC (Rasmussen et al. 2013) Particle characteristics in solution characterized by ICP-MS techniques Constituent particle size: 14-23 nm Dispersion particle size distribution showed two peaks: 113 ± 6 nm and 141 ± 1 nm	Triggered renal and liver inflammation and resulted in lesions, e.g. vacuolization of tubular epithelial cells, including amyloidosis in kidney glomeruli and in perivascular regions in liver. C57BL/6S mice showed fewer lesions.	Precipitated SAS NPs (NM-200), compliant with E 551 specifications One, low dose level Exposure via drinking water, dispersed according to NANOGENOTOX protocol Study focused on limited endpoints and was performed with one dose level and very limited number of animals (n = 5-8/group, with histopathology performed on fewer animals)
(Hu et al. 2019)	18-week non-guideline study focusing on endocrine effects and blood glucose Male ICR mice group size: n = 10 Oral gavage (daily) Dispersed by sonication (40 kHz, 400 W, 30 min) in PBS • Pyrogenic NPs: 0, 25, 50, 100, 200 mg/kg bw/d • Other SAS: 100 mg/kg bw/d Studied blood glucose levels and serum biomarkers (checked weekly), RNA sequencing, immunofluorescence Si determined in liver, pancreas, spleen, kidney, small intestine and muscle tissue by ICP-OES. Pyrogenic NPs at all dose levels, the other SAS exposed groups only at 100 mg/kg bw/d. Presence of particles confirmed by SEM and EDX in tissues exposed to pyrogenic and colloidal NPs, not MPs.	Two pyrogenic silicas and two colloidal silicas (Stöber) analyzed by TEM and SEM Particle characteristics in solution characterized by DLS Pyrogenic NPs Constituent particle size: 36 ± 5 nm Hydrodynamic size: 57 ± 5 nm Pyrogenic MPs Constituent particle size: 228 ± 10 nm Hydrodynamic size: 409 ± 10 nm Colloidal NPs Constituent particle size: 32 ± 2 nm Hydrodynamic size: 51 ± 4 nm Colloidal MPs Constituent particle size: 213 ± 3 nm Hydrodynamic size: 387 ± 8 nm	Both silica NPs caused ROS generation associated with ER stress after 7 weeks (tested at 100 mg/kg bw/d): after exposure to pyrogenic NPs blood serum biomarkers SOD↓, GSH↓ and MDA↑ indicating liver ROS. Both silica NPs affected expression of genes associated with ROS production and ER stress in liver.	Different SAS, NPs and MPs, unclear whether the pyrogenic SAS used is compliant with E 551 specifications; the colloidal SAS used is not compliant with E 551 specifications Four, low dose levels Oral gavage, dispersed by sonication, particles characterized in solution. Study focused on limited endpoints; histopathology was not performed
(Y. R. Kim et al. 2014)	90-day study (OECD TG 408) Female + male Crl:CD(SD) rats group size: n = 10-15 per sex Oral gavage (daily) Diluted in distiled water and vortexed before administration • 0, 500, 1000, 2000 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, histopathology No tissue distribution determined	Two sizes of colloidal silica, analyzed by SEM separately (K. M. Kim et al. 2014) Particle characteristics in solution analyzed by DLS separately (K. M. Kim et al. 2014) SAS 20 nm Constituent particle size: 33 ± 7 nm Hydrodynamic size: 21.0 ± 0.1 nm SAS 100 nm Constituent particle size: 90 ± 13 nm Hydrodynamic size: 91.6 ± 0.5 nm	SAS 20 nm: Granulomatous and bronchio-alveolar inflammation (at 1000 and 2000 mg/kg bw/d) in the lungs (considered not-treatment-related by authors). No treatment-related clinical changes or histopathological effects (including liver). SAS 100 nm: No treatment -related clinical changes or histopathological effects (including liver).	Two sizes colloidal SAS, compliant with E 551 specifications Three, high dose levels Oral gavage, dispersion questionable (no sonication), particles characterized in solution (low hydrodynamic size) Study was not taken into account by EFSA in the re-evaluation of E 551 in 2018.
(Liang et al. 2018)	90-day study (OECD TG 408) Female + male SD rats group size: n = 10 per sex Oral gavage (daily) Dispersed in deionized water by sonication (400 W, 2 min (3 s on/off) on ice) • 0, 167, 500, 1500 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, histopathology Si determined in blood, liver, kidney and testis by ICP-AES	Two precipitated silicas, analyzed by TEM Particle characteristics in solution analyzed by DLS NPs Constituent particle size: 26 ± 3 nm Hydrodynamic size: 247 ± 48 nm MPs Constituent particle size: 1088 ± 390 nm; Hydrodynamic size could not be determined (particles settling at bottom)	No dose-related and relevant treatment-related adverse effects (including liver); lesions in lung (focal epithelial cell proliferation, foreign body granulomas, and mild alveolar septum widening) considered not exposure route-related by authors.	Precipitated SAS, NPs and MPs, unclear whether compliant with E 551 specifications Three medium-high dose levels Oral gavage, dispersed by sonication, particles characterized in solution (MPs do not disperse well)
(Yun et al. 2015)	Acute study (OECD TG 420) + 14-day preliminary study + 90-day study (OECD TG 408) Female + male SD rats group size: n = 12 per sex (90-day) Oral gavage (daily) Dispersed in drinking water by supplier • Acute: 1959 mg/kg bw/d • 14-day: 0, 490, 980, 1959 mg/kg bw/d • 90-day: 0, 245, 490, 980 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, histopathology Si determined in liver, kidney, spleen, lung and brain by ICP-MS	SAS (not further specified), analyszd by TEM and SEM Particle characteristics in solution analyzed by DLS Constituent particle size: 12 nm Hydrodynamic size: 33.5 ± 7.5 nm	No dose-related and relevant treatment-related adverse effects (including liver).	Unclear whether SAS used is compliant with E 551 specifications Three, medium-high dose levels Oral gavage, dispersed by sonication, particles characterized in solution
(Tassinari et al. 2020)	90-day study (OECD TG 408) Female + male SD rats group size: 8 per sex Oral gavage (5 d/w) Dispersed according to NANOGENOTOX protocol (Jensen et al. 2011), but in deionized water by sonication (differences compared) • 0, 2, 5, 10, 20, 50 mg/kg bw/d Studied general toxicology, blood serum biomarkers, histopathology, immunotoxicity Si determined in liver, spleen, brain and small intestine (duodenum) by ICP-MS	Pyrogenic silica: NM-203. Analysis performed by TEM at JRC (Rasmussen et al. 2013) Particle characteristics in solution analyzed by DLS Constituent particle size: 13-45 nm Hydrodynamic size: 126.1 nm	Blood serum biomarkers affected in female rats already at 2 mg/kg bw/d: CREA↓, TSH↑. Several histopathological effects in liver including enlarged sinusoids at 10, 20 and 50 mg/kg bw/d (dose-related) in male rats.	Pyrogenic SAS (NM-203), compliant with E 551 specifications Five, low dose levels Oral gavage, dispersed according to NANOGENOTOX protocol
Subacute studies
(Li et al. 2018)	30-day non-guideline study focusing on hepatotoxicity in fructose induced metabolic syndrome mice. Male Kun-Ming mice group size: 15 Oral gavage (daily) Dispersed in drinking water by sonication (160 W, 20 kHz, 5 min) • 0, 10 mg/kg bw/d (with or without fructose) Studied hepatic histopathology, serum biomarkers (checked weekly), RNA sequencing, DNA damage (Comet assay) Si determined in liver by ICP-AES	Silica NPs (not further specified). Analyzed by TEM, amorphous structure according to XRD. Hydrodynamic particle size not analyzed upon dispersion Constituent particle size: 15.4 ± 1.8 nm	Resulted in liver injury (infiltration of inflammatory cells, indication of fibrosis (collagen deposition). Increased mRNA levels of hepatic IL-1β and TNF-α, indications of apoptosis). Effects were stronger in fructose induced metabolic syndrome mice. Comet assay suggests genotoxic effect.	Unspecified SAS, unclear whether compliant with E 551 specifications One, low dose level Oral gavage, dispersed by sonication, particles not characterized in solution
(Buesen et al. 2014)	28-day study (OECD TG 407) Female + male Wistar rats group size: 5 per sex Oral gavage (daily) Dispersed by supplier. Further diluted in PBS + 1 g/L BAS or DMEM + 10% FCS • 0, 1000 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, histopathology metabolome analysis No tissue distribution determined	Untreated and surface-modified colloidal SAS (Levasil 200). Analyzed by TEM Particle characteristics in solution analyzed by DLS SiO2-untreated Constituent particle size: 5-50 nm Hydrodynamic size: 40 nm SiO2-PEG Constituent particle size: 8-45 nm Hydrodynamic size: 50 nm SiO2-phosphate Constituent particle size: 5-50 nm Hydrodynamic size: 40 nm SiO2-amino Constituent particle size: 5-50 nm Hydrodynamic size: 42 nm	No particle-related and relevant treatment-related adverse effects (including liver).	Different colloidal SAS, including surface modifications, not compliant with E 551 specifications One, high dose level Oral gavage, dispersed by supplier, particles characterized in solution
(Yoshida et al. 2014)	28-day study Female BALB/c mice group size: n = 4-12 Oral gavage (daily) Dispersed by sonication (280 W, 5 min) and vortexed 1 min prior to use • 0, 2.5 mg/animal/d (∼150 mg/kg bw/d) Studied general toxicology, hematology, blood serum biomarkers, histopathology No tissue distribution determined	Untreated and surface modified colloidal SAS. Analyzed by TEM separately (Yamashita et al. 2011), confirmed sizes provided by supplier Particle characteristics in solution analyzed separately (Yamashita et al. 2011) by DLS nSP70: Constituent particle size: 70 nm Hydrodynamic size: 65 nm nSP300: Constituent particle size: 300 nm Hydrodynamic size: 322 nSP1000: Constituent particle size: 1000 nm Hydrodynamic size: 1140 nm nSP70-C: nSP70 surface-modified with carboxyl groups Hydrodynamic size: 70 nm nSP70-N: nSP70 surface-modified with amine groups Hydrodynamic size: 72 nm	No particle-related and relevant treatment-related adverse effects (including liver).	Different colloidal SAS sizes, including surface modifications, not compliant with E 551 specifications One, medium dose level Oral gavage Oral gavage, dispersed by supplier, particles characterized in solution (low hydrodynamic size)
(Kim et al. 2017)	7-day sub-acute toxicity with 11 week follow up (study compares oral with topical administration) Female + male SD rats group size: 5 per sex Dietary exposure (1 week) mixed with feed • 0, 100, 1000 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, histopathology No tissue distribution determined	Colloidal silica (Stöber), analyzed by SEM separately (Park et al. 2016) Mixed with feed, not characterized in the feed matrix Constituent particle size: 103 nm	No dose-related and relevant treatment-related adverse effects (including liver).	Colloidal SAS, not compliant with E 551 specifications Two, medium-high dose levels Dietary exposure, particle characteristics not analyzed in feed matrix or intestinal content.
(Cabellos et al. 2020)	5-day sub-acute toxicity study (animals were sacrificed 1 day or 3 weeks after last administration) Female Swiss mice group size: n = 8 Oral gavage (daily) Dispersed by sonication (6.21 J, 5 min) in CMC-Tween80 • 0, 100, 1000 mg/kg bw/d Studied general toxicology, hematology, blood serum biomarkers, comet assay, micronucleus test, histopathology (liver and intestine), intestinal inflammation Presence of SiO2 particles (as % of tissue coverage) determined in small intestine (jejunum) by enhanced darkfield microscopy and hyperspectral mapping	Two methylated colloidal silicas (Stöber) (and two mesoporous silicas, not described further here) Particle characteristics in solution analyzed by DLS 100 nm Constituent particle size: 128 nm Hydrodynamic size: 182 ± 16 nm 300 nm Constituent particle size: 301 nm Hydrodynamic size: 322 ± 15 nm	No dose-related and relevant treatment-related adverse effects (including liver).	Colloidal SAS, not compliant with E 551 specifications Two, medium-high dose levels Oral gavage, dispersed by sonication, particles characterized in solution
(Hassankhani et al. 2015)	5-day sub-acute toxicity study Male Wistar mice group size: n = 4 Oral gavage (daily) Dispersed in deionized water by sonication (15-20 min). • 0, 333 mg/kg bw/d Studied general toxicology, blood serum biomarkers, histopathology, No tissue distribution determined	SAS (not further specified). Analyzed by SEM according to supplier Particle characteristics in solution not analyzed Constituent particle size: 10-15 nm	Among the effects in blood serum biomarkers: ALT↑ and AST↑ indicating liver injury. Histopathological alterations in kidney, lung, testis and liver (hepatocyte swelling and cellular necrosis) were reported. The lung lesions include congestion, interstitial pneumonia, thickness of the alveolar, infiltration of the inflammatory exudates in the alveoli, and bronchopneumonia.	Unclear whether SAS used is compliant with E 551 specifications One, medium dose level Oral gavage, dispersion by sonication, particles not characterized in solution Study was performed with very limited number of animals (n = 4/group)

Studies were clustered in (sub)chronic studies and subacute studies, and are placed in order of descending study length per cluster. More details and the reproduction and developmental toxicity studies, and genotoxicity studies can be found in the Supplementary information (Table S1). Studies on (meso)porous SAS are excluded. Colors in the effects column indicate relevant positive effects in histopathology studies (RED), relevant positive effects in biomarkers/gene expression (YELLOW), or negative effects (GREEN).

Table 2. Reported mean Si (or SiO₂) concentrations (mg/kg) in liver (A) and spleen (B) as a result of different dose levels of different SAS as reported in the different recent (sub)chronic animal (toxicity) studies with oral exposure.

A
Liver Dose mg/kg bw/d	SAS used and study details	Boudard et al. 2019	Hu et al. 2019	Tassinari et al. 2020		Yun et al. 2015		Liang et al. 2018^b		van der Zande et al. 2014
	Duration	18 months	18 weeks	90 days		90 days		90 days		28 days	84 days
	Strain/species	C57BL/6 mice	male ICR mice	female SD rats	male SD rats	female SD rats	male SD rats	female SD rats	male SD rats	male SD rats
	Dosing	drinking water	oral gavage	oral gavage		oral gavage		oral gavage		diet
	Effects studied	histopath.	ROS/gene expr.	histopath./biomarkers		histopath./biomarkers		histopath./biomarkers		histopath./biomarkers/gene expr.
0 (cntrl)		∼1	∼15	∼1.0	∼1.2	∼0.19	∼0.10	∼12.5	∼9.0	∼95 (SiO2)	<75 (SiO2)
2	13–45 nm pyr. NPs			∼2.6	∼1.1
4.8	14–23 nm prec. NPs	∼8
5	13–45 nm pyr. NPs			∼3.2^a	∼1.1
10	13–45 nm pyr. NPs			∼0.6	∼1.5
20	13–45 nm pyr. NPs			∼2.8	∼0.6
25	36 nm pyr. NPs		∼25^a
50	36 nm pyr. NPs		∼45^a
	13–45 nm pyr. NPs			∼1.5	∼1.0
100	228 nm pyr. MPs		∼15
	213 nm coll. MPs		∼20
	36 nm pyr. NPs		∼125^a
	32 nm coll. NPs		∼115^a
	7 nm pyr. NPs									∼180 (SiO2)
	10–25 nm pyr. NPs									∼220 (SiO2)^a
167	16 nm prec. NPs							∼8.0	∼11.9
	1088 nm prec. MPs							∼9.2	∼10.8
200	36 nm pyr. NPs		∼180^a
245	12 nm NPs					∼0.19	∼0.25
490	12 nm NPs					∼0.24	∼0.27
500	10–25 nm pyr. NPs									∼235 (SiO2)^a
	16 nm prec. NPs							∼9.9	∼11.1
	1088 nm prec. MPs							∼8.4	∼9.6
980	12 nm NPs					∼0.22	∼0.23
1000	7 nm pyr. NPs									∼170 (SiO2)
	10–25 nm pyr. NPs									∼90 (SiO2)	<75 (SiO2)
1500	16 nm prec. NPs							∼7.9	∼10.8
	1088 nm prec. MPs							∼10.7	∼11.7
2500	7 nm pyr. NPs									∼140 (SiO2)	78 (SiO2)
		For comparison: 7.8 (±7.7) mg/kg in human liver (see Table 3)
B
Spleen Dose mg/kg bw/d	SAS used and study details	Boudard et al. 2019	Hu et al. 2019	Tassinari et al. 2020		Yun et al. 2015		Liang et al. 2018		van der Zande et al. 2014
	Duration	18 months	18 weeks	90 days		90 days		90 days		28 days	84 days
	Strain/species	C57BL/6 mice	male ICR mice	female SD rats	male SD rats	female SD rats	male SD rats	female SD rats	male SD rats	male SD rats
	Dosing	drinking water	oral gavage	oral gavage		oral gavage		oral gavage		diet
	Effects studied	histopath.	ROS/gene expr.	histopath./biomarkers		histopath./biomarkers		histopath./biomarkers		histopath./biomarkers/gene expr.
0 (cntrl)		ND	∼25	∼1.5	∼1.3	∼20	∼12	ND	ND	∼175 (SiO2)	<75 (SiO2)
2	13–45 nm pyr. NPs			∼1.8	∼1.4
5	13–45 nm pyr. NPs			∼1.7	∼1.5
10	13–45 nm pyr. NPs			∼2.2	∼1.3
20	13–45 nm pyr. NPs			∼2.7	∼1.8
25	36 nm pyr. NPs		∼30^c
50	36 nm pyr. NPs		∼45^c
	13–45 nm pyr. NPs			∼2.9^c	∼2.0
100	228 nm pyr. MPs		∼25
	213 nm coll. MPs		∼25
	36 nm pyr. NPs		∼120^c
	32 nm coll. NPs		∼115^c
	7 nm pyr. NPs									∼200 (SiO2)
	10–25 nm pyr. NPs									∼300 (SiO2)^c
200	36 nm pyr. NPs		∼170^c
245	12 nm NPs					∼8	∼24
490	12 nm NPs					∼9	∼7
500	10–25 nm pyr. NPs									∼140 (SiO2)
980	12 nm NPs					∼32	∼39
1000	7 nm pyr. NPs									∼235 (SiO2)
	10–25 nm pyr. NPs									∼160 (SiO2)	<75 (SiO2)
2500	7 nm pyr. NPs									∼160 (SiO2)	284 (SiO2)^c
		For comparison: 12 (±12) mg/kg in human spleen (see Table 3)

^a Significantly increased compared to the corresponding control value of that study.

^b Liang et al. (2018) reported significantly decreased Si-levels in liver for female, and the 1088 nm prec. SAS NPs are likely not dispersed correctly.

^c Significantly increased compared to the control value mentioned.

coll.: colloidal; MPs: microparticles; NPs: nanoparticles; prec.: precipitated, pyr.: pyrogenic; ND: spleen concentration not determined in this study.

Background colors: RED = positive effect in thehistopathology findings; YELLOW = positive effect on other endpoints, i.e. ROS generation, gene expression, relevant biomarkers; GREEN = negative effect; GRAY = effects not studied.

Table 3. Concentrations of total silicon (Total-Si) and silicon particles (Si-particles) in postmortem human tissues (both measured as mg Si/kg) as reported by Peters et al. (2020).

	Liver (n = 15)	Spleen (n = 15)	Kidney (n = 15)	Small intestine (n = 12)
				Jejunum	Ileum
Total-Si (mg Si/kg)
non-detects (n)	3	2	3	1	3
range (min-max)	3.2–26	3.0–47	4.4–21	2.7–23	5.2–191
Median	5.8	9.5	7.7	6.8	7.6
mean (±SD)	7.8 (±7.7)	12 (±12)	8.2 (±6.1)	8.9 (±6.4)	23 (±53)
Si-particles (mg Si/kg)
non-detects (n)	3	3	2	3	3
range (min-max)	0.3–2.2	0.4–6.5	0.3–4.1	0.2–2.2	0.3–25
Median	0.4	1.0	0.4	0.7	0.6
mean (±SD)	0.6 (±0.6)	1.3 (±1.6)	0.9 (±1.1)	0.7 (±0.7)	2.6 (±7.1)

The non-detects (n < LOD) were included in the calculation of median, mean and SD and were set at half of the limit of detection (LOD). SD: Standard Deviation.

Figure 1. Concentration ranges of total-Si in liver and spleen as found in control animals from different toxicity studies (‘liver background’), in exposed animals from different toxicity studies differentiated in positive (‘adverse effect’) and negative effect levels (‘no effect’), or in human postmortem tissues (‘human background’) based on information listed in Table 2(A,B). Note that tissue concentrations reported by van der Zande et al. (2014) have been converted from SiO₂ to Si, and in case values were < LOD this has been indicate by an open bullet or square.

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