A review of hepatic nanotoxicology – summation of recent findings and considerations for the next generation of study designs

Figures & data

Table 1. The summary of the accumulation and adverse effects of nanomaterials on the liver from studies 3013–2019 following exposure via IV, oral, inhalation, IT, intranasal, IP and dermal routes.

NM	Size	Route of NM exposure	Species	Dose	Number of exposures	Exposure duration	Hepatic effects	Histopathology	Recovery period included/ Hepatic recovery observed	Reference
Ag	20 nm	IV	Sprague-Dawley rats	50 mg/kg	1	24 hr	Increased AST, ALT, ACP, ALP, TBARS and decreased CAT, SOD	Necrosis of hepatocytes, dilated central vein and focal inflammatory cell infiltration	No	Kumar and Abraham 2016
PVP-coated Ag PVP-coated Ag silicon-coated Ag	5 nm 50 nm 45 nm	IV	B6C3F1 mice	25 mg/kg	1 or 3	24 hr	All NMs induced oxidative DNA damage	Not analyzed	No	Li et al. 2014
Citrate or PVP coated Ag	10 nm 40 nm 100 nm	IV	CD-1 mice	10 mg/kg	1	24 hr	Not analyzed	Lesions in the liver present and NM size-dependent	No	Recordati et al. 2015
Ag	50 nm	IV	C57BL/6 mice	24 µg/animal	1	24, 48 or 72 hr	KC mediated anti-inflammatory response	Not analyzed	No	Kermanizadeh et al. 2014a
Ag	30 nm	IV	Healthy and alcohol fed C57BL/6 mice	25 or 100 µg/animal	1	24 or 168 hr	Inflammatory response, changes in blood biochemistry, acute phase response (all aggravated in the diseased animals)	Changes in intrahepatic architecture, granuloma formation, hepatocyte necrosis, parenchymatous degeneration and the destruction of the liver plates	Yes/Yes	Kermanizadeh et al. 2017a
Au Ag or mix	10 nm 10 nm	IV	Sprague-Dawley rats	10 or 100 µg/kg/day	1	Up to 4 weeks	NM accumulation only/no adverse effects	Not analyzed	No	Lee et al. 2018
Superparamagnetic zinc-cobalt ferrite	8 nm	IV	New Zealand rabbits	20 mg/animal	1	4 hr	Not analyzed	Granuloma formation and multiple congestions	No	Hanini et al. 2016
ZnO QD PEGylated-ZnO QD	5 nm 95 nm	IV	Kunming mice	5 mg/kg	7 daily doses	1–7 days	No changes in ALT and AST activity	Not analyzed	No	Yang et al. 2014
Zn-labeled CdSe/CdS/ZnS-QD	11 nm	IV	FVB/N mice	50–100 pmol/animal	1	2 hr	Not analyzed	Accumulation in KCs but not hepatocytes	No	Bargheer et al. 2015
MEA and MPA coated Ag2Se QD	5 nm 5 nm	IV	CD-1 mice	8 µmol/kg	1	2 min – 28 days	Not analyzed	Mild edema in the liver in the QDs-MEA group	Yes/No	Tang et al. 2017
Oleic acid PEGylated CdSeS/ZnS QD	60 nm 100 nm	IV	Wistar rats	14 µg/animal	1	12 hr	QDs predominately taken up by KCs	Not analyzed	No	Tsoi et al. 2016
CdTe-QD	~ 15 nm	IV	BALB/c mice	0.4, 2, 5, 6, 7 or10 mg/kg	1	24 hr	Increases in AST, ALT, total bilirubin and SAA levels, reduced albumin levels at the highest doses	6 mg/kg bw and higher induced liver hemorrhage observed in the periportal areas of the hepatic lobules accompanied by apoptotic and necrotic liver cells in those areas	No	Nguyen et al. 2019
Carboxyl coated CdSe/ZnS QD	20 nm	IV	Pregnant and offspring Sprague-Dawley rats	1 or 5 nmol	1	Up to 180 days	Increased ALT, AST, bilirubin and gamma glutamyl transaminase in the mothers	Hepatic cellular apoptosis, necrosis, cytolysis, loss of hepatic lobules in the livers of exposed animals at day 1 post exposure	Yes/Yes	Yang et al. 2018a
SiO2	~ 150 nm	IV	Sprague-Dawley rats	50 mg/kg	1	48 hr	Increased AST, total bile acid, cholesterol, and low-density lipoprotein levels	Increase in the number of the KCs	No	Chen et al. 2017
SiO2	50 nm	IV	Athymic nude mice	20 mg/kg	1	Up to 7 days	Increase in ALT and catalase activity	Not analyzed	Yes/Yes	Baati et al. 2016
SiO2 Fe-SiO2 hollow nano shells	500 nm 500 nm	IV	Swiss white mice	2–20 mg/kg	1	24 hr	No changes in serum biochemistry	Only mild pathology manifested as lymphocytic infiltration	Yes/Yes	Mendez et al. 2017
SiO2	110 nm	IV	WT BALB/c or NLRP3^−/− or Caspase 1^−/− mice	25 or 50 mg/kg	3 doses every other day	3 weeks	Increased serum ALT and AST, inflammatory response	Not analyzed	Yes/Yes	Zhang et al. 2018
Hexagonal copper sulfide nanoplate	Length of 59 nm and thickness of 24 nm	IV	ICR mic	7.7 to 550 mg/kg	1	48 hr	Not analyzed	No pathology	No	Feng et al. 2015
Polyacrylic acid-coated iron oxide	~ 10 nm	IV	CD-1 mice	8, 20 or 50 mg/kg	1	24 hr	Not analyzed	Necrotic hepatocytes, NM only visible in KCs	No	Rodrigues et al. 2017
Iron oxide magnetic NMs coated with PEG, BSA and COOH	all ~ 50 nm	IV	Sprague-Dawley rat	50 mg/kg	2	Up to 24 days	Day 1 postinjection ALT, AST, total protein increased by PEG and COOH NMs; ALT, AST, total protein increased by BSA and COOH NMs	No significant histological alternations were detected	Yes/Yes	Yang et al. 2018b
Au/FeO4 NMs coated with amphiphilic polymer or PEG	~ 100 nm	IV	C57/BL6 mice	56 µg iron	1	Up to 365 days	NMs detectable in KCs for up to 1 year	No pathology	Yes/NA	Kolosnjaj-Tabi et al. 2015
Au nanorod	220 nm	IV	CD-1 mice	5 mg/kg	1	Up to 28 days	Increased ϒ-glutamyltransferase, bilirubin and total bile decreased SOD, GSH and GSH-Px	No histological alternations were detected – exclusively in the KCs	Yes/Yes	Cai et al. 2016
Au	~ 15 nm	IV	BALB/c mice F344 rats	1000 mg/kg	1	Up to 28 days	No changes in serum biochemistry	Micro-granulomas, NMs predominately in KC	Yes/Yes	Bahamonde et al. 2018
Au prisms	10 nm with three edge lengths of ~150 nm	IV	Swiss mice	6 µg/g	1	72 hr or 4 months	No serum biochemistry alterations	Enlarged vacuoles, NM accumulation in KCs	Yes/NA	Pérez-Hernández et al. 2017
Au	10 nm 50 nm rods 60 × 30 nm stars 55 nm	IV	CD-1 mice	1.54 × 10^10 NMs	1	Up to 120 hr	Not analyzed	No pathology	No	Talamini et al. 2017
Chitosan-capped star Au Au nanorod	~ 110 nm 18 nm width, 58 nm length	IV	BALB/c mice	2 mg/kg	1	2 mg/kg	Toxicity not analyzed/NM accumulation in the liver	Not analyzed	No	Wang et al. 2015
PEGylated Au	~ 6 nm 25 nm 40 nm 60 nm	IV	Kunming mice	3 mg/kg	1	Up to 90 days	No serum biochemistry alterations	Not analyzed	Yes/NA	Li et al. 2018b
Dextran coated Au	20 nm	IV	Athymic nude mice	1 mg/kg	1	24 hr, 7 or 14 days	No serum biochemistry alterations	No pathology	Yes/NA	Bailly et al. 2019
TiO2	~ 150 nm	IV	C57BL/6 J gpt mice	2, 10 and 50 mg/kg	4 (once a week)	4 weeks	No genotoxic effect observed	NM accumulation in KCs	No	Suzuki et al. 2016
TiO2	~ 20 nm	IV	C57BL/6 mice (with pUR288 plasmid)	10 or 15 mg/kg/day	2	28 days	No genotoxic effect observed	Not analyzed	Yes/NA	Louro et al. 2014
Ni	~ 50 nm	IV	Sprague Dawley rats	1, 10 or 20 mg/kg	1	14 days	Increase in biomarkers of liver damage	Mild damage – distorted architecture of the sinusoids	Yes/No	Magaye et al. 2014
PEGylated platinum	2–4 nm	IV	BALB/c mice	5, 10, 15 and 20 mg/kg	1	24 hr	No serum biochemistry alterations	No pathology	No	Brown et al. 2018
Alumina nanotube	~ 700 nm long and 90 nm in diameter)	IV	BALB/c mice	20, 50, 100 m/kg	1	Up to 28 days	Infiltration of inflammatory cells in the livers	No pathology	Yes/Yes	Wang et al. 2017
AlO	90 nm 110 nm	IV	ICR mice	1.5 or 5 mg/kg	1	Up to 14 days	No changes in serum biochemistry	Inflammatory cell infiltration	Yes/NA	Park et al. 2016a
ZrO2	150 nm	IV	ICR mice	300, 400, 500 and 600 mg/kg	1		Increased serum ALT levels at 500 mg/kg	No pathology	No	Yang et al. 2019
Reduced graphene oxide	~ 350 nm	IV	Wistar rats	7 mg/kg	1	1, 3 hr or 7 days	No serum biochemistry alterations were detected	No pathology	No	Mendonça et al. 2016
Graphene oxide functionalized with poly sodium 4-styrenesulfonate	~ 700 nm	IV	BALB/c mice	Up to 16 mg/kg	1	Up 180 days	Increase in ALT and AST activity	Black lesions mostly in the KCs	Yes/Yes	Wen et al. 2015
Nanoclay	Mixed material size of ~ 60 or ~ 650 nm	IV	BALB/c male mice	Up to 20 mg/kg	1	24 hr	Increased ALT and AST activity	Large regions of cellular necrosis	No	Isoda et al. 2017
Mesoporous Si coated bioactive glass NMs	~ 250 nm	IV	ICR mice	20, 100 and 180 mg/kg/day	14	14 days	Increased ALP at the highest dose	Lymphocytic infiltration and granuloma formation	No	Mao et al. 2016
SiO2	200 nm	IV	C57BL/6 mice	100 mg/kg	1	24 hr	Increased LC3-II in hepatocytes	Not analyzed	No	Zhang et al. 2017
Lanthanide-based upconversion NM	~ 40 nm	IV	WT and KC depleted C57BL/6 mice	150 mg/kg	1	24 hr	Increased ALT and most evident in KC depleted mice	Infiltration of inflammatory cells and most evident in KC depleted mice	No	Zhu et al. 2017
Ag stabilized by PVP or citrate stabilized	20 nm 110 nm	Oral	C57BL/6 mice	0.1, 1 or 10 mg/kg/day	3	Up to 9 days	Not analyzed	No pathology	No	Bergin et al. 2016
Ag	~ 10 nm	Oral	Sprague-Dawley rats	Up to 100 mg/kg/day	5	5 days	Increased ROS, DNA damage, ALT, AST and ALP at highest doses)	Hepatocytes disruption, hepatocellular vacuolation, and central vein injury	No	Patlolla, Hackett, and Tchounwou 2015
Citrate-modified Ag	20 nm	Oral	Wistar rats	40 mg/kg	1	4 weeks	Changes in proteins expression associated with oxidative stress, inflammatory response, oxidation and deamination	Lymphocyte infiltration and swelling of hepatocytes	Yes/NA	Xie et al. 2018
Ag	~ 10 nm	Oral	Pregnant Sprague-Dawley rats	Up to 1000 mg/kg	13	13 days	Decrease in catalase and GSH in maternal livers at the higher doses	Not analyzed	No	Yu et al. 2014
Ag MWCNT	~ 10 nm Diameter 20–30 nm and length 5–50 µm	Oral	Swiss albino mice	50 or 100 mg/kg	14	28 days	Dose dependant DNA damage for both NMs	Not analyzed	No	Awasthi et al. 2015
ZnO	~ 30 nm	Oral	Sprague-Dawley rats	125, 250 or 500 mg/kg	90	90 days	Decrease in total serum protein and albumin at the highest dose	No pathology	Yes/NA	Park et al. 2014
Silica shell with either fluorescent Rhodamine 6 G core or CdSe/CdS/ZnS QDs as the core	~ 30 nm	Oral	Mice (species not specified)	0.1 or 0.67 mg/animal	4	4 days	NM accumulation in the liver	Not analyzed	No	Zane et al. 2015
ZnO	50 nm	Oral	ICR mice	Up to 10,000 mg/kg	14	14 days	Increased serum AST and ALT activity	Infiltration of inflammatory cells in the portal regions of liver	No	Kong et al. 2018
ZnO	20 and ~ 200 nm	Oral	ICR mice- model of IBD	1 g/kg	1	24 hr	Higher quantities of ZnO detected in the diseased animals	Not analyzed	No	Du et al. 2018
ZnO NMs and elemental Pb	~ 14 and 60 nm	Oral	C57BL/6 mice normal or high fat diets	NMs only – 200 mg/kg or NMs/Pb – 200 and 150 mg/kg daily	14	14 days	Reduction in SOD and increase in MDA	Spotty cell necrosis and a mild vacuolar degeneration	No	Jia et al. 2017
ZnO nanorod	~ 20 nm	Oral	Swiss albino mice	Up to 6 mg/kg	7	7 days	Not analyzed	No pathology	No	Bollu et al. 2016
ZnO TiO2 Al2O3	80–100 nm 50–75 nm 40–50 nm	Oral	Swiss albino mice	500 mg/kg/day	21	21 days	Increased ROS and decreased SOD and catalase activity	No histological alternations were detected, TiO2 detectable only in KCs	No	Shrivastava et al. 2014
SiO2	~ 15 nm	Oral	Kun-Ming mice – healthy or metabolic syndrome model	10 mg/kg/day	30	30 days	Increased hepatic DNA damage in the metabolic syndrome mice post NM administration	Increased hepatocyte ballooning and infiltration of inflammatory cells, collagen deposition in metabolic syndrome mice post NMs administration	No	Li et al. 2018a
SiO2	~ 20 nm	Oral	C57BL/6 transgenic mouse model, expressing the human mutated (A53 T) a-synuclein protein (TgHuA53 T)	NMs in drinking water for up to 18 months	-	Up to 18 months	Not analyzed	Minor inflammatory cell infiltration in the portal and lobular regions	No	Boudard et al. 2019
SiO2 Ag Fe2O3	~ 35 nm ~ 20 nm ~ 120 nm	Oral	Sprague-Dawley rats	1000 mg/kg	91	13 weeks	Ag NM induced slight increase in serum ALP	Not analyzed	No	Yun et al. 2015
Zn^2+ doped Fe3O4	~ 10 nm	Oral	Mice (species unspecified)	50 mg/kg/day	30	30 days	Increased LDH, ALT, AST, TBIL and GSH-Px	No pathology	No	Zhu et al. 2016
Cu NM Cu microparticle	~ 30 nm ~ 25 µm	Oral	Sprague-Dawley rats	100, 200 and 400 mg/kg/day	28	28 day	NM-induced increased AST, ALT and total bilirubin activity but not microparticles	Not analyzed	No	Lee et al. 2016
Tin sulfide nanoflowers	50, 80 and 200 nm	Oral	ICR mice	250–1000 mg/kg	14	14 day	Increased serum ALT and AST and altered liver metabolic genes – 50 nm NMs at the highest dose	Slightly disrupted cellular arrangement, moderate interstitial hyperemia, sporadic and focal infiltration of inflammatory cells at the highest dose	No	Bai et al. 2018
CdS nanorod and cubic CdS nanodot	30–50 nm diameter, 500–1100 nm length ~ 5 nm	Oral	Kunming mice	Up to 200 mg/kg	18 or 35	18 or 35 days	Not analyzed	Infiltration of inflammatory cells and hepatocellular vacuolation, higher for nanodots	No	Liu et al. 2014
Au	~ 8 nm	Oral	Healthy and alcohol and methamphetamine injury Wistar rats	181.48, 362.48 or 724.96 µg/kg	3	28 days	NM induced protective effects against alcohol and methamphetamine disease	No pathology	No	de Carvalho et al. 2018
TiO2	~ 300 nm	Oral	Swiss albino mice	10, 50 or 100 mg/kg/day	14	14 days	Increased AST and decreased GSH levels, Increased DNA damage, p53, BAX, caspase 3 and 9	Not analyzed	No	Shukla et al. 2014
TiO2	~ 75 nm	Oral	Young and old Sprague-Dawley rats – aging model	200 mg/kg/day	30	30 days	Small changes in serum biochemistry relating to liver damage	Edema, hepatic cord disarray, cell swelling, vacuolization and hydropic degeneration in young but not old rats	No	Wang et al. 2013
TiO2	~ 100 nm	Oral	Wistar rats	0.5, 5, and 50 mg/kg/day	14	14 days	No change in GSH levels, significant decrease in TBARS levels	Not analyzed	No	Canli et al. 2020
TiO2	~ 100 nm	Oral	Wistar rats	0.5, 1; 4; and 16 g/kg	1	4 days, 30 days or 60 days	Not analyzed	Necrosis in the hepatocytes located around the centrilobular veins only, TiO2 aggregates visible inside Kupffer cells located in the sinusoids	Yes/NA	Valentini et al. 2019
TiO2	29 nm	Oral	Sprague Dawley rats	2,10 and 50 mg/kg daily	90	90 days	Increased levels of total protein, albumin and globulin, decreased levels of total bilirubin, ALT, AST, decreased GSH, lipid peroxidation and increased GSH-Px and SOD activity	Fatty degeneration of hepatocytes	No	Chen et al. 2019
Cr2O3	~ 24 nm	Oral	Wistar rats	100 or 200 µg/g	1, 7 or 14	1, 7 or 14 days	Dose dependant increase in AST, ALT, ALP, γGT, and total bilirubin levels	7 day exposures resulted in severe hemorrhage, hepatocyte degeneration, and parenchymal distortions	No	Fatima and Ahmad 2019
Fullerene C60		Oral	Sprague-Dawley rats	1 day −2000 mg/kg 30 days- 250 mg/kg/day	1 or 30	24 hr or 30 days	No hematological or serum biochemistry alterations were detected	Not analyzed	No	Hendrickson et al. 2015
Graphene oxide		Oral	Swiss albino mice	10, 20 or 40 mg/kg daily	1 or 5	1 or 5	Not analyzed	Apoptosis, necrosis and cells degeneration	No	Mohamed et al. 2019
γ-aluminum oxide hydroxide γ- and α-aluminum oxide NMs	All 180–200 nm	Oral	ICR mice	5 or 10 mg/kg	1	24 hr	Accumulation in the liver	Not analyzed	No	Park et al. 2016b
Al2Si2O5(OH)4nanotube	~ 400 nm	Oral	Kunming mice	5–300 mg/kg	30	30 days	Decreased GSH-Px and SOD activity	At the highest dose – hydropic degeneration with swelling of hepatocytes	No	Wang et al. 2018b
Co-exposure Ag and TiO2	Ag – ~ 90 nm TiO2 – ~ 50 nm	Oral	Wistar rats	0.5 mg/kg daily dose	45	45 days	Decreased GSH-Px, no genotoxicity	Not analyzed	No	ADC et al. 2017
Ag Non-functionalized and coated ZnO	~ 20 nm 100 nm	IT	C57/BL6 mice	Up to 128 µg/animal	1	24 hr	Dose dependant decrease in GSH levels	Not analyzed	No	Gosens et al. 2015
Zn	~ 40 nm	Inhalation	C57BL/6 mice	4 hr/day-~ 3.5 mg/m^3	14 or 91	2 or 13 weeks	No hepatic toxicity or accumulation	No pathology	Yes/NA	Adamcakova-Dodd et al. 2014
Pristine TiO2 Pristine Ag Pristine SiO2 Aged paints containing NMs	~ 400 nm ~ 90 nm ~ 190 nm	Oropharyngeal aspiration	BALB/c mice	20 µg/animal/week	5	5 weeks	Accumulation of Ag and SiO2 in the liver	Not analyzed	Yes/NA	Smulders et al. 2014
ZnO	~ 30 nm	Nose only	Sprague-Dawley rats	2.56 mg per exposure	1 or 7	Up to 7 days	Significant increases in serum (IL-1α., IL-1β, IL-10 and TNFα Elevated SOD and CAT, MDA and ROS in liver	Not analyzed	No	Guo et al. 2020a
CuO	~ 10 nm	Nose-only	Wistar rat	0.6–13.2 mg/m^3	5	5 days	No NM accumulation or adverse effects in the liver	No pathology	No	Gosens et al. 2016
CeO2	~ 35 nm ~ 300 nm	Nose only	ICR mice	40 mg/kg per day	3	7 days	Decreased serum levels of total bilirubin and ALP	Hydropic degeneration	No	Liu et al. 2019
4 different NiO NMs	Fully characterized	IT	F344 rats	Up to 6 mg/kg	1	91 days	No NM accumulation or adverse effects in the liver	Not analyzed	Yes/NA	Shinohara et al. 2017
NiO	~ 80 nm	IT	Wistar rats	0.015–0.24 mg/kg	12	6 weeks	Small decreases in catalase, GSH Px and SOD activity	Highest NM dose – neutrophil and lymphocyte infiltration and sporadic spotty necrosis	No	Yu et al. 2018
TiO2	~25 nm	IT	Sprague-Dawley rats	0.5, 2.5 and 10 mg/kg	3	3 or 35 days	Increased DNA damage – not dose dependant	Not analyzed	Yes/NA	Relier et al. 2017
TiO2	-ve ~ 50 nm +ve ~ 1500 nm	IT	C57BL/6 mice	18, 54 or 162 µg/animal	1	24 hr	Increased DNA damage and saa3 mRNA levels	Not analyzed	No	Wallin et al. 2017
TiO2	10 nm	IT	C57BL/6 mice	Up to 128 µg/animal	1	24 hr	Increased GSH levels	Not analyzed	No	Vranic et al. 2017
Graphite nanoplates	20 μm lateral, 5 μm lateral <2 μm lateral and 8–25 nm	Pharyngeal aspiration	C57BL/6 mice	4 or 40 μg	1	4 hr, 1 day, 7 days, 1 month or 2 months	Increased acute phase genes at higher dose at 4 hr and 1 day post exposure	Not analyzed	Yes/Yes	Roberts et al. 2015
CNT Sanding dust from an epoxy composite with (0.2%) or without CNT	Diameter – ~ 15 nm; length 4 μm	IT	C57BL/6 mice	NM – 18, 54 and 162 μg/animal Dust −54, 162 and 486 µg/animal	1	Up to 28 day	Increased Saa1 expression	CNT and epoxy dust with CNTs – inflammatory cell infiltrations	Yes/Yes	Saber et al. 2015
ZnO	10–30 nm	IP	Wistar rats	50–200 mg/kg/daily	10	10 days	Increased ALT at the highest doses	Increased numbers of KCs, inflammation in the liver parenchyma, hepatocyte ballooning and chromatin condensation.	No	Abbasalipourkabir et al. 2015
ZnO	~ 35 nm	IP	Wistar albino rats	2 mg/kg/day	21	21 days	Not analyzed	Sinusoidal dilatation, KC hyperplasia, inflammatory cells infiltration, necrosis, hydropic degeneration, apoptosis	No	Almansour et al. 2017
Ag:Cu:B sphere	~ 100 nm	IP	C57BL/6 NLRP3 KO BALB/c mice	1–20 mg/kg	1	24 or 96 hr	WT had increased AST, ALT and LDH, KO mice had diminished immune response	Hepatic necrosis, increased sinusoidal KCs, granuloma formation	No	Ramadi et al. 2016
Fe3O4	~ 35 nm	IP	Kun Ming mice	NM – 30 mg/kg/day and elemental CdCl2 – 1 mg/kg/day	7	7 days	No serum biochemistry alterations	Swelling in hepatocytes around the central vein NM reduced CdCl damage.	No	Zhang et al. 2016
TiO2 nanosheets	92.5 nm	IP	C57BL/6 mice	10 mg/kg	1	Up to 30 days	NM accumulation in the liver	No pathology	Yes/NA	Song et al. 2014
TiO2	~ 50 nm	IP	Swiss Webster mice	500, 1000 or 2000 mg/kg/day	5	5 days	Co-administration of anti-oxidant and TiO2 decreased NM-induced increases in MDA, GSH, SOD, catalase, GSH Px and DNA damage	Not analyzed	No	El-Ghor et al. 2014
MWCNT mesoporous SiO2 NMs	110–170 nm and 5–9 mm length ~ 8 nm	IP	Swiss albino mice	MWCNT – 1.5, 2 and 2.5 mg/kg SiO2 – 10, 25 and 50 mg/kg	1	7 days	Increase in AST activity for MWCNT not SiO2	Not analyzed	Yes/NA	Rawat et al. 2017
Dextran coated ferrite NM	~ 85 nm	Dermal	Guinea pig	80 mg/animal/3 times a week	9	3 weeks	No serum biochemistry alterations	Not analyzed	No	Mohanan et al. 2014
Tattoo ink	NA	Dermal	C3.Cg/TifBomTac hairless mice	NA	1	365 days	Ink pigment deposits in KCs one year after exposure	Not analyzed	Yes/NA	Sepehri et al. 2017
MULTIPLE ROUTES OF EXPOSURE
Ag	10 nm 50 nm 100 nm	IV Oral	Lactating BALB/c mice	1.5 mg/kg 1.5 mg/kg	4 x 4 hr exposure 1	21 days 4 hr	No adverse effects reported	Not analyzed	No	Morishita et al. 2016
ZnO	~ 35 nm	IV Oral	Sprague-Dawley rats	3 mg/kg 30 mg/kg	1	Up to 7 days	Significant elevation in levels of AST in IV exposed animals No changes in serum biochemical parameters were observed in orally administered	No Pathology	No	Choi et al. 2015
Cu ZnO	16–96 nm 16–96 nm	IP IV	Wistar rats	Cu −6.1–19.82 µg/kg ZnO – 11.14–30.3 µg/kg	1	14 or 28 days	Increased serum creatinine, ALT, ALP and AST levels (more significant for the IP route)	Not analyzed	Yes/NA	Ashajyothi et al. 2018
SiO2	110 nm	IV Hypodermic Intramuscular Oral	ICR mice	50 mg/kg	1	24 hr or 7 days	NM accumulation in the liver – highest quantities following IV exposure	No pathology	Yes/NA	Fu et al. 2013
SiO2	~ 20 nm	IT IV	Sprague-Dawley rats	9, 18 or 36 mg/kg 15, 30 or 60 mg/kg	1	Up to 48 hr	No DNA damage	Not analyzed	No	Guichard et al. 2015
5 different TiO2 NMs	NMs fully characterized	Oral IV	Wistar rats	2.3 mg/rats	1 or 5	24 hr or 5 days	NM accumulation and bio-persistence in the liver	Not analyzed	Yes/NA	Geraets et al. 2014
PEGylated Pd nanosheets	40 nm 86 nm 146 nm	Oral IP	ICR mice	200 µg/animal	1	Up to 8 days	No NM-induced hepatic damage	No pathology	Yes/NA	Chen et al. 2017
BaSO4	~ 150–350 nm	IT Oral IV	Wistar rats	1 mg/kg 5 mg/kg 1 mg/kg	1	24 hr	NM accumulation in the liver following IV injection but very little for the other route of exposure	Not analyzed	No	Konduru et al. 2014
C60		IV Oral	ICR mice	400 µg/animal	1	24 hr	NM accumulation in the liver following IV injection	Not analyzed	No	Wang et al. 2016
Polyurethane	~ 250 nm	Oral IP	Swiss albino mice	2, 5 or 10 mg/kg	1	Up to 10 days	Increased ALT and inflammatory response – much higher levels following IP exposure	Vascular congestion, vacuolization of hepatocytes and inflammatory cell infiltration	Yes/Unclear$	Silva et al. 2016

NA – There is no significant initial NM-induced hepatic damage to recover from.

$ – The authors do not state the time-point in which histological analysis was carried out.

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