Abstract There were many researches concerning toxicology of traditional medicine (TM) and active natural products during the past 12 months. This annual toxicology review summarized different analysis methods of toxicology research, common evaluated models, toxic target organs, toxic mechanisms, and popular research issues and herbs in 2018. The emphasis was on hepatorenal toxicity induced by TM through cell apoptosis, metabolic disorder, oxidative stress, inflammatory damage, liver and renal fibrosis and even inducing carcinogenesis. Meanwhile, traditional herbs were listed in this review. Taken together, the herbs mentioned in this paper should be used with caution. Combination of TM, processing drugs, quality control and dose control can be used in the prevention of TM toxicology in the future.

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Annual advances of traditional medicine toxicity in 2018
Shu-Li Mana, 1
, Gen-Bei Wangb, c, d, 1
, Chang-Xiao Liue
, Wen-Yuan Gaob
*
a
State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of
Education, Tianjin Key Laboratory of Industry Microbiology, China International Science and Technology
Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University
of Science & Technology, Tianjin, 300457, China. b
Tianjin Key Laboratory for Modern Drug Delivery and High
Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, 300072, China. c
Tasly
Academy, Tasly Holding Group Co., Ltd., No. 2 Pujihe East Road, Tasly TCM Garden, Beichen District, Tianjin
300410, China. d
State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Holding Group
Co., Ltd., No. 2 Pujihe East Road, Tasly TCM Garden, Beichen District, Tianjin 300410, China. e
The State Key
Laboratories of Pharmacodynamics and Pharmacokinetics, Tianjin 300193, China.
1
They are regarded as co-first authors and contributed equally to this work.
*Corresponding to: Wen-Yuan Gao, Tianjin Key Laboratory for Modern Drug Delivery and High Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China. E-mail:
pharmgao@tju.edu.cn.
Highlights
1. Liver and kidney are the mainly toxic target organs of traditional medicine.
2. Recently, zebrafish embryoes are popular to evaluate the safety of traditional medicine.
3. The safety assessment of Aconitum, Tripterygium, Strychnine, etc. is still hot issue.
Traditionality
This annual review summarized different analysis methods of toxicology research, common evaluated
models, toxic target organs, toxic mechanisms, and popular research issues and herbs in 2018. China, India,
USA and Morocco were ranked from the first to fourth important countries researching the toxicology of
traditional medicine.

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TMR | May 2019 | vol. 4 | no. 3 |
Abstract
There were many researches concerning toxicology of traditional medicine (TM) and active natural products during
the past 12 months. This annual toxicology review summarized different analysis methods of toxicology research,
common evaluated models, toxic target organs, toxic mechanisms, and popular research issues and herbs in 2018.
The emphasis was on hepatorenal toxicity induced by TM through cell apoptosis, metabolic disorder, oxidative
stress, inflammatory damage, liver and renal fibrosis and even inducing carcinogenesis. Meanwhile, traditional
herbs were listed in this review. Taken together, the herbs mentioned in this paper should be used with caution.
Combination of TM, processing drugs, quality control and dose control can be used in the prevention of TM
toxicology in the future.
Keywords: Traditional medicine, Natural product, Herb, Toxicity, Toxic target organs, Risk assessment, Safety
evaluation
Abbreviations:
TM, Traditional medicine; CYP, Cytochrome P450; AAs, Aristolochic acids.
Competing interests:
There are no conflicts of interest to declare.
Citation:
Shu-Li Man, Gen-Bei Wang, Chang-Xiao Liu, et al. Annual advances of traditional medicine toxicity in 2018.
Traditional Medicine Research, 2019, 4(3): 111-117.
Executive Editor: Cui-Hong Zhu, Submitted: 12 April 2019, Accepted: 23 April 2019, Online: 26 April 2019

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Background
During 2018, there were a number of papers referred to
the toxicity advance of traditional medicine (TM) such
as Bergenia ciliate [1], Rhododendron Molle
(Ericaceae) [2], Arecae semen aqueous extract [3],
Tithonia diversifolia (Hemsl.) A. Gray [4],
Lambda-cyhalothrin [5], traditional Chinese patent
medicine for hyperthyroid heart disease [6],
phototoxicity of TM [7] and so forth. Meanwhile,
multiple theories have been applied. For example,
effect-toxicity-chemical study was used in the toxicity
of radix Wikstroemia indica [8]. Toxicokinetic-toxicity
correlation was applied for better understanding the
toxic mechanisms of Radix Aconiti Lateralis Preparata
[9], while pharmacokinetic study for the health risk
assessment of arsenic in realgar and Chinese medicine
compound preparation Niuhuang Jiedu tablets (which
is a widely used traditional Chinese medicine
containing realgar) [10]. For China had a long history
and widely uses of TM in clinic, the number of its
toxicology paper from Chinese researchers was the
largest in the world. Therefore, China promoted a rapid
upsurge in this field. Statistical analysis of annual
publications of toxicological studies on TM by relative
percentages on different countries was showed in
Figure 1A. China, India [11-16], USA [17-19] and
Morocco [20, 21] were ranked from the first to fourth
important countries researching the toxicology of TM.
Furthermore, establishment of toxicology database of
TM is very important for their rational application.
Organ toxicity
Liver was regarded as the top one toxic target
organ of TM
As we known, drug-induced hepatotoxicity is one of
the main causes inducing drug non-approval and drug
withdrawal by Food and Drug Administration. During
2018, a large amount of researches have been reported
to focus on liver toxicity. For example, Cortex
Dictamni extracts displayed potential hepatotoxicity in
mice which was associated with cell apoptosis [22] and
metabolic activation primarily by CYP (cytochrome
P450) 3A4 [23]. CYP3A induction and glutathione
depletion were involved in hepatotoxicity induced by
emodin [24]. Pyrrolizidine alkaloids as phytotoxins
identified in over 6000 plant species worldwide, like
ethnomedicine Arnebia benthamii [25], whose
hepatotoxicity was induced by pyrrole-protein adducts
[26]. Polygonum multiflorum Thunb and its processed
products have been used in China for centuries due to
their multiple beneficial effects to human body. In
2018, researchers focoused on its liver injuries
associated with potential toxic ingredients, metabolite
identification, metabolomics studies and exogenous
contaminant determination [27]. Dioscorea bulbifera
rhizome causing liver injury also mainly linked to its
metabolites such as amino acid, lipid, purine,
pyrimidine, bile acid, gut microflora, and energy
metabolisms [28]. Bavachinin as a natural product
derived from the fruit of the traditional Chinese herb
Fructus Psoraleae induced liver oxidative damage via
reactive oxygen species and the JNK/p38 signaling
pathways [29]. Interestingly, a paper reported that
Kansui fry-baked with vinegar displayed protective
effect in hepatic and gastrointestinal damage model,
but caused the same damage to the normal animals in
2018, which was consistent with the traditional
Chinese medicine application principle that traditional
Chinese medicine shows different toxicity to patients
and normal people [30].
Figure 1 Statistical analysis of annual publications on toxicological studies on traditional medicine by
relative percentages on different countries and toxic target organs
A B

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Kidney was considered as the second toxic target
organ of TM
In the year of 2018, researchers identified a new
compound in Euphorbia pekinensis and described that
it could disturb metabolic pathways of purine, amino
acid, phospholipids and sphingolipids inducing
nephrotoxicity in rats [31]. Aristolochic acids (AAs)
induced nephrotoxicity through the proapoptosis and
oxidative stress of renal tubular cells, and inhibition of
aquaporins. Furthermore, it promoted renal fibrosis by
activating TGF-β-Smad signaling and the migration of
macrophages, induced carcinogenesis based on the
formation of covalent adducts with DNA and so forth
[32]. Previous study discovered that the carcinogenic
mechanism of AAs involved in their promotion of A to
T mutations in the TP53 tumour suppressor gene
(Figure 2) [33]. Gene mutations caused by different
factors are different; the mutational signatures are
different [34]. The construction of mutational
signatures database of TM will greatly deepen our
understanding and monitoring of teratogenic and
carcinogenic toxicity of TM. Cinnabar and realgar
induced hepatorenal injury through the oxidative stress
and inflammatory damage in mice [35]. Terminalia
chebula fruits rich in hydrolysable tannins were used
in the treatment of various chronic ailments. Following
their 28 days repeated dose oral administration, they
caused mild disturbances in liver and kidney function
which was indicated by reduced body weight, food and
water intake, increase of serum urea, glucose and
aspartate aminotransferase levels and a mild
granulomatous inflammation in the liver [36].
Other toxic target organs of TM
As 2018 reported, the intestinal toxicity of Kansui was
highly correlated with its regulation of Lactobacillus
and Blautia genera. Its fry-baked with vinegar
significantly relieved side effects of Kansui.
Meanwhile, Kansui fry-baked with vinegar increased
the production of short-chain fatty acids, which were
regulated by gut microbiota [37]. It was used as an
example for explaining the reason that process should
be applied in reducing toxicity of TM.
In 2018, a review listed several herbs such as
Angelica sinensis, Tripterygium wilfordii Hook F,
Lycopodium serratum, Erycibe henryi prain, Withania
somnifera, Caulophyllum thalictroides, Pausinystalia
johimbe, Aconitum and Ephedra species associated
with heart related problems. Paper emphasized that
phase IV post marketing surveillance should be used to
diminish adverse events [18]. Semen Strychni inducing
neurotoxicity could be characterized by metabonomics
approach [38]. Psammosilene tunicoides caused
damages to heart, lung and kidney in rats [39].
Alkenylbenzenes in botanical containing products
induced genotoxic and carcinogen [40]. These extracts
should be used with caution. Taken together, statistical
analysis of annual publication referred to different
toxic target organs induced by TM was summarized in
Figure 1B.
Current advances
Zebrafish embryoes were popular for evaluating
the safety of TM
Right now, the safety evaluation has been applied in
cellular, organ & individual levels. Rodents were
regarded as the common individual models to analyze
the safety of TM or natural products. For example, the
acute and chronic toxicity of aqueous extract of the
seeds of Calycotome villosa (Poiret) Link (subsp.
intermedia) were evaluated in rodents [21], and
embryo-fetal development toxicity study with
dimethylaminoethyl ginkgolide B in rats and rabbits
[41]. Meanwhile, a zebrafish model was increasingly
considered to be a reliable model for the evaluation of
embryo toxicity and a rapid, medium throughput,
cost-effective method scince 2018. It was used in the
toxicity evaluation of Sutherlandia frutescens (L.) R.Br.
[42], Trapa natans leaf extracts [43], motherwort
essential oil [44], detoxified Radix Aconiti Lateralis
Preparata (lateral root of Aconitum carmichaeli) [45],
saponin-rich plant extracts [46] and so forth. Although
Caenorhabditis elegans [47] and Drosophila [48] were
popular in the safety evaluation of various chemical
compounds recently, there were no research on that in
TM. In the future, the application of these models can
be focused on.
New toxicology study technology
Recently, multiple theories have been applied. For
example, researchers set up an organ-on-a-Chip, a
GelMA-based 3D culture platform, to mimic the
microenvironment and basic functions of the kidney
screening main compounds associated with
nephrotoxicity in spearmint (Mentha spicata L.) [49].
Meanwhile, effect-toxicity-chemical study was used in
the toxicity of Radix Wikstroemia indica [8].
Toxicokinetic-toxicity correlation was applied for
better understanding the toxic mechanisms of Radix
Aconiti Lateralis Preparata [9], while pharmacokinetic
study for the health risk assessment of arsenic in
realgar and Chinese medicine compound preparation
Niuhuang Jiedu tablets [10]. The changes in gut
microbiota were also used to explain the reason why
processing technology should be applied in reducing
Figure 2 Examples of gene mutations induced by
aristolochic acid

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toxicity of TM [37].
Other hot issues in 2018
Adverse reaction of TM injection was always the key
point for preclinical study and clinical utility. In
addition, the safety assessment of Aconitum,
Tripterygium, Strychnine, etc. was still hot issue.
Although Radix Aconiti Lateralis Preparata has
promising therapeutic effects, its toxicities were
frequently observed. Aconitum alkaloids were
responsible for its pharmacological activity and
toxicity [50]. In 2018, researchers focused on the
toxicokinetics-toxicity relationship of its main
diester-diterpenoid alkaloids [9], the in vivo acute
toxicity of detoxified Radix Aconiti Lateralis
Preparata [45], heart toxicity related to Radix Aconiti
Lateralis Preparata [18], and safety of its stems and
leaves [51]. Tripterygium Wilfordii Hook F could be
used on psoriasis vulgaris. Recently, pharmacokinetic,
toxicological characteristics [52] and randomized
controlled trials [53] of Tripterigium glycosides and
their derivatives have been reviewed in 2018.
Meanwhile, detoxification was also a research
hotspot in 2018. It’s reported that ginger extract could
ameliorate the toxicity of Lambda-cyhalothrin on the
rat thyroid through the inhibition of oxidative stress [5].
Total glucosides of Paeoniae Radix Alba protected
against Semen Strychni-induced neurotoxicity in rats
through suppressing oxidative stress and reducing the
absorption of toxic components [54]. Chinese medicine
compound preparation Angong-Niuhuang Pill
displayed hepatorenal protective effects against
cinnabar and realgar induced oxidative stress and
inflammatory damage in mice [35].
Conclusion
Taken together, the annual researches showed that the
methods of effect-toxicity-chemical study,
toxicokinetics, gut microbiota, metabolism and
organ-on-a-Chip were used in toxicology research
since 2018. Besides rodents, zebrafish embryoes have
been regarded as common models to evaluate the
safety of TM. 2018 toxicology research indicated that
liver and kidney were the mainly toxic target organs of
TM. Their toxic mechanisms included cell apoptosis,
metabolic disorder, oxidative stress, inflammatory
damage, liver and renal fibrosis and even inducing
carcinogenesis. In addition, the safety assessment of
Aconitum, Tripterygium, Strychnine, and detoxification
methods were still hot issue. Therefore, the herbs
mentioned in this paper should be used with caution.
Combination of TM, processing drugs, quality control
and dose control should be used in the prevention of
TM toxicology in the future.
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