Toxicity Assessment of Herbal Medicine Using Zebrafish Embryos: A Systematic Review

Table 2

Evaluation of toxicity of crude preparations and active fractions of herbal medicine using the Zebrafish embryotoxicity model.

No	Medicinal/herbal plant			Medicinal value	Toxic effects		References	Toxicity compared with other assays
	Scientific name	Common name	Part of the plant		Survival/mortality rate	Teratogenic and other toxic effects
1	Andrographis paniculata	Green chireta	Leaves	Recommended for various illness antioxidant Potentials	LC50: 0.52 mg/mL (48 hrs); LC50: 0.52 mg/mL (96 hrs)	Teratogenic effect such as abnormal organ development demonstrated bent spine, enlarged yolk sac, pericardial oedema, slow heartbeat, and delayed hatching (>72 hpf)	[22]	LC50: 48 hpf and IC50: 3T3-L1 was the closest correlation.
2	Curcuma xanthorrhiza	Temulawak, java ginger	Rhizome		LC50: 0.74 mg/mL (48 hrs); LC50: 0.70 mg/mL (96 hrs)
3	Cinnamon zeylanicum	Cinnamon	Bark		LC50: 0.98 mg/mL (48 hrs); LC50: 0.051 mg/mL (96 hrs)
4	Eugenia polyantha	Indian bay leaf and Indonesian bay leaf	Leaves		LC50: 0.92 mg/mL (48 hrs); LC50: 0.06 mg/mL (96 hrs)
5	Orthosiphon stamineus	Java or Cat’s whiskers	Whole plant		LC50: 1.68 mg/mL (48 hrs); LC50: 1.68 mg/mL (96 hrs)
6	Tinospora cordifolia,	Makabuhay	Leaves and bark	Antibacterial, analgesic, antipyretic, and also for the treatment of jaundice, skin diseases, and anaemia	5% and 10% of leaf extracts exhibited the highest mortality of 100%. Bark extract showed mortality of 11.11% and 33.33% at 5% and 10% concentrations	Head and tail malformations, delayed growth, limited movement, scoliosis/flexure, and stunted tail and these are dose- and plant parts-dependent. Leaf extract is more toxic than bark	[23]	Not compared
7	Punica granatum L	Pomegranate	Peel	Antimicrobial	LC50 of 196,037 ± 9,2 µg/mL (96 hrs) considered as safe	No teratogenic and other effects	[24]	ADMET Predictor; 7.1 program.
8	Geissospermum reticulatum a		Bark	Antimalarial, antitumoral, antioxidant, nociceptive, and antibacterial activities	Did not cause any visible death	Deformation or teratogenic effect were not observed	[25]	THP-1 and HL: 60 cells cytotoxic
9	Curcuma longa	Turmeric	Rhizome	Antioxidant activity, cardiovascular and antidiabetic effects, inflammatory and edematic disorders, anticancer, antimicrobial, and hepatoprotection	The LC50 values for 24, 48, 72, 96, and 120 are 92.41, 79.19, 68.31, 56.67, and 55.89 μg/mL, respectively	Dosage at 62.5 μg/mL indicated teratogenic effect of the extract was severe at higher concentrations producing physical body deformities such as kink tail, bend trunk, and enlarged yolk-sac oedema	[26]	Not compared
10	Carthamus tinctorius L.	Safflower	Flowers	Blood stasis syndrome with dysmenorrhea, amenorrhea, postpartum abdominal pain and mass, and trauma and pain in the joints	The 96 h LC50 of safflower to zebrafish embryos was reported as 345.6 mg/L; Delayed hatching was reported	Abnormal spontaneous movement, depressed heart rate, pericardial oedema, yolk-sac oedema, abnormal head-trunk angle, inhibition of melanin release, enlarged yolk, short body length, and significant inhibition of heartbeat	[27]	Not compared
11	Aconitum carmichaeli; Debx.	Fuzi	Lateral root	Cardiotonic, analgesic, anti-inflammatory, and diuretic agents to treat colds, polyarthralgia, diarrhea, heart failure, beriberi, and oedema	FZ-120 caused the death of zebrafish from 700 to above 1000 μg/mL indicating potential toxicity	Abnormalities of heart, liver, yolk sac, swim bladder, and body length mainly at doses ranging from 288 to 896 μg/ml	[28]	Acute toxic effect of mice. Similar results were observed
12	Carpesium abrotanoides L	Carpesii fructus	Dried fruit	Used against intestinal worms in children	LC50 value of Carpesii Fructus as 230.40 mg/L	Increased spontaneous movement, heartbeat inhibition, pericardial oedema, yolk-sac oedema, bleeding tendency, yolk malformation, enlarged yolk, and shortened body length	[29]	Not compared
13	Sutherlandia frutescens		Whole plant	Used for asthma, dysentery, fever, gastritis, diabetes; immune boost	A treatment of 300 μg/mL with both extracts; The highest concentration, resulted in acute lethal toxicity and no embryo was hatched at this concentration	Chronic teratogenic toxicities, leading to pericardial oedema, yolk-sac swelling, and other abnormal developmental characteristics	[30]	Not compared
14	Leonurus japonicus Houtt.	Motherwort	Essential oil	Against gynaecological and obstetrical conditions, such as menstrual blood stasis, menstrual disturbances, dysmenorrhea, amenorrhea, postpartum haemorrhage, and postpartum recovery	The LC50 of zebrafish embryos treated at 2 hpf, 10 hpf, and 24 hpf (around 10 μg/mL) were much lower than those of zebrafish embryos treated at 48 hpf (around 60 μg/mL), indicating early stages are more sensitive to motherwort essential oil	The TC50 (teratogenic effect) of 2 hpf embryos was much lower (1.67 ± 0.23 μg/mL) compared to that of 10 hpf and 24 hpf (TC50: 10 μg/mL) and 48 hpf (TC50: 20 μg/mL). Yolk-sac oedema and spine and the average embryonic heart rate was also decreased in embryos exposed to 25, 50, or 100 μg/mL	[31]	Not compared
15	Radix Sophorae tonkinensis	Shandougen	Dried root fractions	Cure infectious and inflammatory diseases	RSTE and RST active fractions in zebrafish, concentration-dependent mortality were demonstrated (LC50 has not calculated)	Pericardial oedema and/or reduced heart rates were observable in different fractions of RSTE and RST	[32]	Compared with mice and similar results obtained
16	Euphorbia kansui		Dried root of Euphorbia kansui (KS-1) and Euphorbia kansui fry-baked with vinegar (KS-2)	Cancer, pancreatitis and intestinal obstruction	The LC50 value for Euphorbia kansui (KS-1) and fry-baked with vinegar KS-2 was reported as 2.78 ± 0.86 μg/mL and 6.62 ± 1.24 μg/mL, respectively	Pericardial oedema and scoliosis	[33]	Not compared