Open Journal of Safety Science and Technology, 2012, 2, 32-39
http://dx.doi.org/10.4236/ojsst.2012.21005 Published Online March 2012 (http://www.SciRP.org/journal/ojsst)
Safety in Chinese Medicine Research
King-Fai Cheng, Ping-Chung Leung*
Institute of Chinese Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
Received November 14, 2011; revised December 8, 2011; accepted December 22, 2011
ABSTRACT
Safety of drugs is a common concern, regardless of traditional Chinese medicine or Western medicine. Historical ex-
periences tell us that ignored drug safety evaluation would lead to serious consequences. Although Chinese medicine
has been used for thousands of years, re-evaluation of the safety is still very important. The criteria for safety of Chi-
nese herbal medicines should be the same as those for chemical drugs. Many Chinese herbal medicines have a long his-
tory of traditional use. However, many of them do not possess proven safety and efficacy by today’s standards. Well-
designed randomized controlled trials and comprehensiv e pre-clinical toxicological stud ies were not done. Although the
lack of such evidence does not absolutely count against the efficacy and safety of Chinese herbs, laboratory and clinical
investigation s are still needed before th e herbs cou ld be considered safe. This paper reviews the evaluation on the safety
of Traditional Chinese Medicine.
Keywords: Traditional Chinese Med icine; Safety Evaluation; Toxic Chinese Herbs; Adverse Reactions
1. Introduction
The Need for Safety Evaluation
In the last century, more than 40 major drug disasters
happened in the world. Such incidents alerted people of
all levels about the importance of drug safety. For exam-
ple, the “thalidomide” event that occurred in the 1960s of
the last century might be the most tragic and dramatic
drug disaster. Thalidomide was used to treat ailments of
pregnant women. Teratogenicity of thalidomide was not
consider ed important. Th e result was 8000 to 10,000 bab ies
were born with congenital malformations [1-3]. Such d isas-
ters caused by chemical drugs made clinicians and authori-
ties realize the importance of drug safety before promo-
tion. In the situations of traditional Chinese medicine,
although the history has been over 3000 years, and has
been generally considered safe; the safety data derived from
scientific tests remain very limited. We do not have es-
sential data of many commonly used traditional Chinese
medications such as maximum safe dose and duration of
treatment that is considered safe.
In actual fact, many commonly used Chinese herbs are
already known to be high ly toxic, such as Strychnos, Radix
Aconiti, Radix Aconiti Kusnezoffii, Fructus Crotonis,
Sheeploitered Azalea etc. Others such as Rhizoma Ari-
saematis, Rhizo ma Pinelliae, Realgar, Rhizo ma Polygoni
Cuspidati, and Radix Sophorae Tonkinensis are moder-
ately toxic; while many others are mildly toxic. Tradi-
tionally, the principles of prescription in Chinese medi-
cine include the theories of “nineteen avoidances (十九
畏)” and “eighteen clashes (十八反)” which lay down
the recommendations on the avoidance of certain herbs
with regard to either solitary use or in combination. Al-
though the toxicity effects of medicinal herbs could be
infrequen t, s low, and mo d er ate, wh en co mp ar ed with ch e mi-
cal drugs, however herbal toxicity could also be more
complex, and more obscure.
The compositions of Traditional Chinese medicine are
derived not only from plants, but also consist of minerals,
and animal products. The degree of toxicity of toxic herbs
may be affected by the soil, water, and breeding condi-
tions. All of which are vulnerable to different forms of
pollutions like pesticides, fertilizers and other toxic sub-
stances. The more over authentications of the herbs could
be defective and counterfeit herbs mixed with genuine
supplies are not uncommon, thus giving more threat to
safety. Processing of medicinal herbs, their storage, and
transports, further complicated the safety issue. With regard
to proprietary herbal medicinal products, the situation is
more complicated. There could be adulterations of chemi-
cals or pharmaceuticals, incompatible combination s, and/
or dangerous dosages. On the whole, due to the limited in-
formation available, misunderstanding and negligence tend
to be common. Therefore, when using Chinese medicine,
we cannot rely only on traditional beliefs from either classi-
cal documents or experience. A comprehensive evaluation
on the safety of the medicine we intend to use is manda-
tory on both clinical and research levels.
*Corresponding author.
C
opyright © 2012 SciRes. OJSST

K.-F. CHENG ET AL. 33
2. Current Status of Safety Evaluation in
Chinese Medicine Research
2.1. Toxicity Studies Basing on the Traditional
Herbal Classification
As the chemical compositions of medicinal herbs are ex-
tremely complex, the study on their toxicology is difficult.
The traditional principles of “nineteen avoidances” and
“eighteen clashes” could be helpful but are obviously
insufficient. There have been no systematic studies on
the safety and compatibility of the pairs of herbs referred
within the framework of the principles.
The Traditional classification of “toxic Chinese herbs”
was mostly based on the ancient clinicians’ experiences
and records. “Shen Nong Ben Cao Jing” <神農本草經>
divided traditional Chinese herbs into toxic and non-toxic
types, without reference to their degree of toxicity.
“Compendium of Materia Medica” <本草綱目> classi-
fied the toxic herbs into four grades i.e. extremely toxic,
highly toxic, moderately toxic, and sligh tly toxic without
providing useful objective data to support the classifica-
tion. Today, the pharmaceutical classification of toxicity
is based on experimental data using animals which are
fed with the drug until poisoning or death. Toxicity is
therefore described quantitatively as the median lethal
dose (LD50). When the oral lethal dose is less than 5 g/kg,
the drug is classified as extremely toxic; the lethal doses
between 5 - 15 g/kg and 16 - 50 g/kg are classified as
moderately and slightly toxic. Non toxic drug refers to
those producing mortality with doses of over 50 g/kg
(Table 1) [4]. The modern pharmacological concepts of
toxicity also include acute toxicity, subacute and chronic
toxicity, special toxicity (mutagenicity, teratogenicity,
carcinogenicity, abortion, and addiction toxicity etc).
None of these modern methods of safety evaluation has
been systematically applied in the evaluation of tradi-
tional Chinese medicine. The defective guarantee on
safety has certainly hindered the globalization of tradi-
tional Chinese medicine.
Table 1. Toxic classification of Chinese medicine.
Item Highly toxic
Moderately
toxic Slightly toxic
Symptom Very severe Severe Common side effect
Organs damage d Key organs Key organs Rare organ damage
High dose Death Death Rare death
LD50 (oral) <5 g/kg 5 - 15 g/kg 16 - 50 g/kg
Treat dose
and toxic dose Very close Close Not close
Toxic dose
for adult <3 g 3 - 12 g 13 - 20 g
Poisoning
incubation <10 min 10 - 30 min >30 min or accumulation
Our literature reviews indicated that scholars in the
Chinese medicine field have actually done much work on
the toxicity of traditional medicinal herbs. Interesting areas
include:
1) The study of “eighteen clashes”—the reasons be-
hind incompatible herbs: e.g. toxicity increases when
Euphorbia kansui is used with Radix Glycyrrhiza; Adix
aconiti lateralis p reparata with Rhizoma Bletillae; Vera-
trum nigrum L. with Schizophyllumcommuneh or White
Paeony Root [5]. Efficacy might also be affected because
of incompatibility. Modern laboratory studies have shown
that Yougui drink with ginseng lengthened th e swimming
time of mice. However, if Veratrum nigrum L. is added,
the effects on swimming rat became worse compared
even without ginseng [6].
2) Researches on medicinal herbs con taining aristolochic
acid were plentiful because of many reports of serious
toxicity [7-9].
3) Other areas of extensive research work include:
Berberine-induced neonatal jaundice [10], Cinnabar and
arsenic contained herbs [11,12] and heavy metals related
to medicinal herbs [13,14].
2.2. Herb-Drug Interactions
TCM medications could affect the metabolism of chemi-
cal drugs which are being taken while their toxicities
might also be significantly altered by the chemical drugs
[15-18].
Synergistic or additive therapeutic effects may lead to
unfavorable adverse events related to over-dosage. On the
other hand antagonistic interactions could result in defi-
cient efficacy and therapeutic failure. The potential inter-
action of herbal medicines with chemical drugs is a major
safety concern, which must not be underestimated because
the use of herbal medicines is gaining populari ty.
A distinguished herbal expert of the Yuan Dynasty
(about 1300 AD) Zhang Zhi-he wrote in his collection of
clinical cases (儒門事親) [19]. “Toxicity is a property of
all drugs not just that poisons are toxic. One must not
forget that herbs as popular as Liquorice (Radix Glycyr-
rhizae) and Radix Sophorae Flavescentis could also be
toxic. Undesirable outcomes follow over dosages.” Cura-
tive and toxic potentials are properties of all drugs. The
key to successful treatment is to select the righ t drug, the
right dosage and the right channel of administration. The
simultaneous administration of Chinese medicine and
pharmaceuticals must be arranged with care. It has alread y
been reported that when herbal medicine is used together
with insulin injection or oral anti-diabetics for diabetic
control, hypoglycemia frequently result [20].
The interactions between Chinese herbs and modern
drugs should be common issues, yet reports are fewer.
Likewise medicinal herbs are getting popular in the US,
yet toxicities and interactions related are not thoroughly

K.-F. CHENG ET AL.
34
known. According to a survey in the US on 1000 patien ts
attending the accident and emergency departments, 538
of them were using over 1087 types of various forms of
drugs, and 30 of them have already shown unfavorable
side-effects [21].
Drug interactions could be investigated by in vitro and
in vivo experiments, but the results obtained could be
inconsistent. For example, St. John’s wort, an herb com-
monly used in America was shown to suppress monoam-
ine oxides in vitro, but such observations could not be
demonstrated in vivo studies.
When used appropriately herbal medicine used together
with modern medicine may produce better outcomes. For
example, in the case of sore throat and tonsillitis, co-
administration of Radi x Isatidis (板蘭根) with Trimethoprin
has been found to significantly strengthen the immune
system, w hich m ight b e respo nsibl e for t he bett er outc ome.
On the contrary, disastrous outcomes may follow the
inappropriate use of Chinese medicine together with modern
medicine. For example, co-administration of digoxin and
Liu Shen Pill (六神丸) had led to repeated ventricular
extrasystoles; and mixing Cinnabaris (硃砂) containing
Chinese Medicine with halogen compounds could pro-
duce disastrous toxic outcome [22].
Some herbal medicine, apparently safe, could become
toxic with overdose. Aloe vera is a good example. In
high doses, Aloe vera led to hypersensitive reactions of
erythema, urticaria, even nausea and diarrhoea in chil-
dren; uterine bleeding in pregnant women, and bleeding
among t hose s ufferi ng fr om ha emorr hoids or epi staxi s [23] .
3. Study of Safety Dosages of Chinese
Medicinal Herbs
Each drug should have its unique proper dose range. How-
ever, for Chinese medicinal herbs unlike chemical drugs,
they have not been pharmaceutically tested to define its
effective dose, maximal dose and toxic dose. Only clas-
sic clinical experiences are available. Obviously, unduly
increased doses or long administrations could induce
adverse reactions. Even herbs believed to be “mild” such
as licorice could induce toxic effects if improperly used
[24].
For any drug, its toxicity is closely related to its do s age,
and when excessive dose is given, even non-toxic drug
should produce adverse effects. Cancer drugs are well
known toxic agents and yet could be used cleverly for
cancer treatment [25]. A Chinese herb Guanmutong, is
usually administered in dose of 3 - 6 grams. However it
readily produces acute renal failure and anaphylactoid
purpura while higher doses are used [26]. Tripterygium
wilfordii and its preparations are commonly used in China
for the treatment of rheumatoid arthritis. However since
its therapeutic do se is very close to its toxic dose, it may
lead to gastrointestinal bleeding, even visceral necrosis
and renal failure [27,28]. Overdose of another medicinal
herb, viz. Vietnamese Sophora Root could cause cardiac
failure, shock and even death [29,30]. In addition, Pro-
prietor Chinese medicine has also been reported for severe
adverse events. For example, cinnabar sedative pills and
Tianwangbuxin Dan (both preparations containing cin-
nabar) when used together, have been reported to be
dangerous [31].
The safety duration of administration of Chinese medi-
cine is another current problem in Chinese medicine re-
search. As the desirable efficacy of Chinese medicine is
expected to be slow, the duration of administration can-
not be shor t. Hence, the long duration wo uld invite more
adverse effects. It is therefore essential to test out the opti-
mal doses and duration of administration in the event of
maintaining both effectiveness and safety.
4. Toxicological Studies
Toxicology of Chinese medicine includes experimental
toxicology, clinical to xicology and tox icokinetics. Toxic-
ity and adverse reactions of traditiona l Chinese medicine
in the clinical application have attracted general concern
but remain insufficient.
The misconception that traditional Chinese medicines
are “natural drugs” without toxic effects is still widely
believed. In fact, some Chinese herbal medicines are not
only toxic, but also carcino genic.
The Virus Section of the China Institute of Medical
Science on Prevention has studied 1693 kinds of Chinese
herbs and plants, and found that 52 are carcinogenic [32].
According to a report of the Monitoring Center for
Adverse Drug Reactions of the Ministry of Health in
China, about 20 million people in China died of adverse
drug reactions and d rug-induced diseases every year [33].
According to a survey in China on the analysis of 382
adverse drug reaction cases in China in 2006, the propor-
tion of adverse reactions induced by Traditional Chinese
Medicine was as high as 25.1%, only second to that of
induced by antibiotics [34 ]. Since the chemical composi-
tion of chemical medicine is clear, and the research be-
fore marketing is well regulated, the mechanisms of ad-
verse reactions are known. On the other hand, the researches
of adverse effects and toxic itie s of trad ition al Ch in es e medi-
cine are not well developed, for example, the study of
clinical pharmacology, toxicology and drug metabolism
of traditional Chinese medicine are started late and de-
veloped slowly, many people are lack of knowledge of
side effects or adverse effects of traditional Chinese medi-
cine. In fact, the adverse effects of traditional Chinese
medicine are not uncommon.
About 90% traditional Chinese medicine their toxico-
logical data are still unknown, such as their classification,
the toxic ingredients, the tox ic reactions, their prevention,
treatment and rescue etc.

K.-F. CHENG ET AL. 35
4.1. Systematic Study and Safety Evaluation
Investigators reviewed the reports of toxic and adverse
reactions related to TCM from 110 medical journals from
1915 to 1994. They found that there were totally 6061
cases of adverse reactions reported. Before 1950 s only 26
adverse reactions were reported. The number increased in
1960s to 147 reported in 1970s to 398, and in 1980s to
2217. From the four years of 1991 to 1994 there were
already 3273 cases, which sharp rising trend is therefore
obvious [35]. Liver and kidney toxicities are related to
Chinese medicinal herbs, and systematic studies and safety
evaluation, should accordingly set the priorities.
4.2. Pre-Clinical Safety Evaluation
Pre-clinical safety evaluation is intended to provide the
scientific evidences to predict the toxicity of a new drug
through toxicology tests before it is clinically used. The
toxipathological examination is to determine the patholo-
gical damages in site, extent, nature, including the long-
term effects. Most experiments are conducted through
animal tests, which include acute toxicity, long-term toxicity,
teratogenicity, and carcinogenicity tests etc (Table 2), all
of these tests are inseparable from toxicpathology. The
longer the testing period, the more important the toxi-
pathological examination. Therefore, the toxipathology is
the most important component of preclinical safety eva-
luation.
4.2.1. Acute Toxicity Stu dy
The objective of acute toxicity study is to assess the acute
toxicity of a test item when administered as a single dose
followed by an observation period of 14 days and thereby
obtain information both about hazard assessment and for
ranking articles [36].
For chemical drugs, the toxicity can be classified into
6 levels (Table 3).
Table 2. Content of preclinical safety evaluation of traditional
Chinese medicine.
Acute toxicity test (oral)
Long-term toxicity test (oral)
Acute toxicity test (skin)
Long-term toxicity test (s kin)
Skin/Mucosal irritation test
Skin sensitization test
Genetic toxicity tests
Reproductive toxicity test
Carcinogenicity test
Drug dependence test
However, for most herbal medicines, the value of median
lethal dose (LD50) is not obtainable with practical measures
because of the limits on concentration or volume of the
medicine, the acute toxicity can be represented by its
maximum tolerable dose (MTD).
4.2.2. Repeated Dose Toxicity Study
Acute toxicity test does not fully reflect the safety of
Chinese medicine. As traditional Chinese medicine usually
requires long periods of administration, a long-term toxicity
test could better reflect the safety.
The study provided information on the major toxic effects,
indicated target organs and the possibility of accumulation,
and would provide an estimate of adverse-effects related
to certain dose levels which could be used for chronic
studies and for establishing safety criteria for human
exposure [36].
Long-term toxicity test is one of the key components
of the pre-clinical safety evaluation, and it is the fun-
damental basis for the approval of the new drug for cli-
nical trial.
The purposes of the repeated dose toxicity tests in-
clude:
1) To determine whether the test article is suitable for
clinical trial;
2) To predict the po ssible toxicity and the safety range
for the human clinical applicatio n;
3) To provide an importan t reference of th e initial d ose
selected for clinical trial;
4) To determine the key observations and reveal pre-
ventive measures in clinical trials.
In short, the data of long-term toxicity test supply
evidences to determine whether a drug could be further
developed.
The duration of long-term toxicology studies would
depend on the nature of the herbal preparation and the
actual time of clinical trial application. In general, if the
herbal medicine is indicated for single dose administra-
tion or for repetitive administrations spanning less th an a
week, the administration period of long-term test should
be 2 weeks to a month; if the herbal medicine is for re-
Table 3. Classification of chemical toxicity (oral) from GB
15193.3-94.
Category LD50 (mg/Kg)
Extremely toxic 1.0 or less
Highly toxic 1.0 - 50.0
Moderately toxic 51.0 - 500.0
Slightly toxic 501.0 - 5000.0
Practically non-toxic 5001.0 - 15,000.0
Non-toxic >15,000

K.-F. CHENG ET AL.
36
petitive administration spannin g over a week, the test ad-
ministration term should be 3 - 4 times the period of clinical
treatment (the maximal period is 6 months for rodents, 9
months for non-rodents) (Table 4) [36].
Animal species: The test animals include at least two
species (includ i ng both rodent and non-rodent).
Rodent: White rats are the most commonly used animals.
Non-rodent: Dogs and monkeys are most commonly
used animals.
Dose Levels: 3 different dose levels and 1 control group.
Observation:
General observation: physical signs, weights, appearance.
Hematology: blood test.
Blood chemistry: livers, kidneys.
Pathology: pathological di agnosis.
There was research reported that some herbs could in-
duce pathological damages if repeated doses were given
(Table 5) [37].
Special toxicity studies include:
Mutagenicity Test;
Teratogenicity Test;
Carcinogenicity Test.
Table 4. Clinical treatment course and experimental administration period.
Clinical treatment course Experimental administration
Single dose or less than 1 week 2 weeks to a month
over a week 3 - 4 times of the period of clinical tr eat ment (Not over 6 months in maximum
for rodents, Not over 9 months for non-rodents)
Table 5. 44 herbs that induce pathological damages through long-term toxicity test.
Superficies-resolving h e rbs (解表藥) 桑葉 (Folium mori)
Heat-clearing herbs (清熱藥)
天花粉 (Radix Trichosanthis), 青黛 (Indigo Naturalis),
青蒿 (Artemisia annua L.), 蒲公英 (Herba Taraxaci),
千里光 (Herba Senecionis Scandentis), 半邊蓮 (Lobelia chinensis),
虎杖 (Rhizoma Polygoni Cuspidati), 野菊花 (Chrysanthemum Indici Flos)
Expelling phlegm herbs (化痰止咳藥) 半夏 (Pinellia Tuber), 馬兜鈴 (Aristolochia debilis), 啤酒花 (Humulus lupulus)
Herbs for purgation (瀉下藥) 大黃 (Rheum palmatum L.), 蓖麻子 (Semen ricini)
Herbs for eliminating dampness and
diuresis (滲濕利水藥) 澤瀉 (Rhizoma Alismatis), 木通 (Akebia Stem)
Herbs for dispelling pathogenic wind and removing
dampness (祛風濕藥)
獨活 (Radix Angelicae Biseratae), 秦艽 (Radix gentianae macrophyllae),
蒼耳子 (Fructus Xanthii), 八角楓 (Alangium chinense),
松蘿 (Chinese Usnea), 雷公藤 (Common Threewingnut Root)
Herbs for promoting b lood circulation and
removing blood stasis (活血化瘀藥) 莪術 (Rhizoma Curcumae Aeruginosae), 延胡索 (Rhizoma corydalis)
Supplementing and boosting her bs (補益藥) 甘草 (Radix Glycyrrhiza), 補骨脂 (Psoralea corylifolia L.),
白術 (Rhizoma Atractylodis Macrocephalae)
Anti-helminthic herbs (驅蟲藥) 苦楝皮 (Cortex meliae), 常山 (Antifeverile Dichroa Root)
Anti-cancer herbs (抗腫瘤藥)
長春花 (Herba Catharanthi rosei), 喜樹 (Camptotheca acuminata),
野百合 (Crotalaria sessiliflora L.), 大豬屎豆 (C rot ala ria assa mic a),
龍葵 (Solanum nigrum L.), 三尖杉 (Cephalotaxus fortunei Hook. f.),
斑蝥 (Spanish fly), 山慈菇 (Pleione bulboc odioides)
Others (其他)
甜瓜蒂 (Cucumis melo L), 蟾酥 (Venenum bufonis), 棉籽 (Cottonseed),
鉤藤 (Gambir Plant), 銀杏 (Ginkgo biloba),
博落回 (Macle a ya corda ta), 馬桑 (Coriaria sinica Maxim)

K.-F. CHENG ET AL. 37
4.2.3. Reproductive Toxicity Study
The objective is to examine whether the test medicine
has toxic effects on animal’s reproductivity and whether
it has teratogenic effects on their offspring.
The herbal drugs intended for contraceptives, preventing
miscarriage, prolactin, pregnancy-related drugs, and those
affecting fetal development, the reproductive toxicity testing
is required.
Local toxicity stud y:
The objective of local toxicity test is to examine whe-
ther local-applied medicines will cause any irritation or
allergic reaction, which includes:
Skin irritation;
Skin sensitization;
Eye irritation.
4.2.4. Drug De pendence Test
When the medication is used for analgesic and sedative-
hypnotics, the drug dependency test is required .
4.3. Clinical Safety Evaluation
Olsen conducted a review looking at the toxicity of
pharmaceuticals observed in humans compared with those
earlier observed in experimental animals. This survey in-
cluded input from 12 pharmaceutical companies with data
compiled from 150 compounds. A total of 221 human
toxicity (HT) events were reported. The results showed a
positive HT concordance rate of 71% for rodent and
non-rodent species. For non-rodents alone the predictive
rate was 63% of HTs and for rodents alone, it was 43%.
The results also showed that 94% HT were first observed
in studies of 1 month or less in duration [38]. Most human
toxicity could be found in single dose toxicity test. On
the whole, 25% of human toxicity are observed in safety
and pharmacology experiments. Using animals China
scholars observed embryonic toxicity in animal experiments
using Artemisinin. However, in clinical studies pregnant
women taking this drug have no t produced abnor mal babies
[39]. In spite of the weak correlation, animal studies are
still important. In vivo studies are more reliable than in
vitro experiments. This is particularly important for tra-
ditional Chinese medicine, because most Chinese herbal
medicines are tested with their gross extracts, with unclear
chemicals, impurities, and other variable physical factors
might all affect the in vitro resu lts. Therefore, toxicology
studies of Chinese medicine must be based on in vivo
tests, rather than in vitro studies alone.
Herbal poisoning must be differentiated from adverse
reactions. Poisoning refers to tissue and organ damages
caused by toxic chemicals in the medicinal herb. Adverse
reaction is a response to the herbal item which is noxious
and unexpected and which occurs at doses normally used
in humans for prophylaxis, diagnosis, or therapy of dis-
ease or for the modification of physiologic function. Ad-
verse drug reactio n is harm directly caused by th e drug at
normal doses, during normal use. When conducting a
clinical trial of Chinese medicine, it is important not only
to observe the clinical efficacy, but also to observe the
clinical safety. Clinical safety evaluation of traditional Chi-
nese medicine therefore includes toxicity of the drug, ad-
verse reaction monitoring, and the interactions between
traditional Chinese medicine and chemical medicine.
4.4. Adverse Reactions of Chinese Medicine and
Post-Marketing Re-Evaluation
Animal toxicology study has its limitations, but the clinical
study alone is unable to find ou t all toxicities of the drug.
As the number of subjects (sample size) for the clinical
study of new drug is limited and the inclusion/exclusion
criteria are stringent, some adverse reactions cannot be
found during the clinical trial period. According to sta-
tistical data, if the incidence of adverse reactions is less
than ten thousandth, the adverse reactions cannot be found
during pre-marketing clinical trials [40]. Therefore, the
toxicology studies of Chinese medicine should be extended
to post-marketing evaluation i.e. post-marketing adverse
events monitoring .
Adverse reactions for herbal administration might be
due to the processing of the herbs duration of its admi-
nistration, contaminations, individual differences, medi-
cine incompatibility, etc.
Most Chinese decoction or proprietary compound con-
sist of a number of herbs, and each herb contains many
chemical ingredients. Once adverse reaction occurred, it
is most difficult to identify the causes; and the respon-
sable chemical component.
As pre-market clinical trials of Chinese medicine are
usually conducted in specific population groups with spe-
cial age ranges, unique health conditions and the obser-
vational times are limited. Observations on adverse effects,
mortalities and quality of life would not have universal
value. This gives a post-market evaluation extra values.
Toxicology study of the Chinese Medicine should also
make use of new knowledge and new techniques of toxi-
cology, which apply to chemical drug development for its
healthy development.
5. Conclusion
Chinese herbal medicine is the most important part of
Traditional Chinese medicine; their safety issues directly
affect the clinical efficacy and drug development, as well
as its globalization. The reasons that induce adverse re-
actions of traditional Chinese medicine are complex and
divergent, and require systematic studies. Worries about
TCM safety have come up many times because of senti-
mental reports about mass toxicities. It is therefore timely

K.-F. CHENG ET AL.
38
to look for practical, systematic ways to ensure TCM
safety through proper evaluations, and tests.
6. Acknowledgements
The authors would like to acknowledge the Ming Lai
Foundation and The International Association of Lions
Clubs District 303-Hong Kong and Macau Tam Wah
Ching Chinese Medicine Resource Centre for the support
given to the Institute of Chinese Medicine, CUHK.
REFERENCES
[1] W. Lenz, “Thalidomide and Congenital Abnormalities,”
The Lancet, Vol. 2, 1962, p. 45.
[2] W. Lenz, “A Short History of Thalidomide Embryopathy,”
Teratology, Vol. 38, No. 3, 1988, pp. 203-215.
doi:10.1002/tera.1420380303
[3] B. J. Yuan and Z. Q. Wang, “The Purpose and the Sig-
nificance of Preclinical Safety Evaluation,” Military
Medical Science Press, Beijing, 1997.
[4] L. Y. Xia, “Modern Toxicology of Chinese Medicine,”
Tianjin Science and Technology Translation and Pub-
lishing Corporation, Tianjin, 2005.
[5] J. L. Li, “Animal Experimental Studies of ‘Eighteen
Clashes’ of Chinese Medicinal Herbs,” Journal of Chang-
chun College of Traditional Chinese Medicine, Vol. 2, No.
3, 1988, p. 89.
[6] X. S. Gao, “Eighteen Clashes Research of Chinese Me-
dicinal Herbs,” Chinese Ancient Books Publishing House,
Beijing, 1991.
[7] J. Lu, “Studies on the Aristolochic Acid Related Crude
Traditional Chinese Medicine,” Drug Standards of China,
Vol. 3, No. 2, 2002, pp. 49-50.
[8] L. S. Wang, “Toxic Effects of Aristolochic Acid,” Tradi-
tional Chinese Drug Research & Clinical Pharmacology,
Vol. 12, No. 6, 2001, pp. 394-395.
[9] G. Z. Jiang and L. Chen, “New Research Progress of
Toxicity of Aristolochic Acid in Traditional Chinese Medi-
cine,” Chinese Agricultural Science Bulletin, Vol. 24, No.
9, 2008, pp. 84-87.
[10] N. K. Ho, “Traditional Chinese Medicine and Treatment
of Neonatal Jaundice,” Singapore Medical Journal, Vol.
37, No. 6, 1996, pp. 645-651.
[11] L. Zhang, S. H. Gao, C. F. Zhou, et al., “Safety Issues of
Traditional Chinese Medical Preparations Containing Ar-
senic Substances: Review Starting from Niuhuang Jiedu
Pian (Wan),” China Journal of Chinese Materia Medica,
Vol. 31, No. 23, 2006, pp. 2010-2012.
[12] P. Li, “Research Status of Traditional Medicine Cinna-
bar,” West China Journal of Pharmaceutical Sciences,
Vol. 25, No. 5, 2010, pp. 622-624.
[13] K. Yang, X. F. Li, Q. H. Li and G. H. Ding, “Overview of
Adverse Reactions of Chinese Medicine Containing Heavy
Metals and Arsenic,” Chinese Journal of Hospital Phar-
macy, Vol. 28, No. 4, 2008, pp. 301-304.
[14] D. X. Wang and X. L. Zhu, “Poisoning of Traditional
Chinese Mineral Medicines Containing Heavy Metal:
Clinical Presentation and Management,” Adverse Drug
Reactions Journal, Vol. 9, No. 1, 2007, pp. 43-45.
[15] R. L. Page and J. D. Lawrence, “Potentiation of Warfarin
by Dong Quai,” Pharmacotherapy, Vol. 19, No. 7, 1999,
pp. 870-876. doi:10.1592/phco.19.10.870.31558
[16] B. Cheng, C. T. Hung and W. Chiu, “Herbal Medicine
and Anaesthesia,” Hong Kong Medical Journal, Vol. 8,
No. 2, 2002, pp. 123-130.
[17] A. A. Izzo and E. Ernst, “Interactions between Herbal
Medicines and Prescribed Drugs: A Systematic Review,”
Drugs, Vol. 61, No. 15, 2001, pp. 2163-2175.
doi:10.2165/00003495-200161150-00002
[18] A. Fugh-Berman, “Herb-Drug Interactions,” The Lancet,
Vol. 355, No. 9198, 2000, pp. 134-138.
doi:10.1016/S0140-6736(99)06457-0
[19] Z. H. Zhang, “Ru Men Shi Qing,” The Yuan Dynasty,
AD1300.
[20] The American Society of Anesthesiologists, “Anesthesi-
ologists Warn: If You’re Taking Herbal Products, Tell
Your Doctor before Surgery,” 2001.
http://anestit.unipa.it/mirror/asa2/PublicEducation/herbal.
html
[21] J. Doucet, P. Chassagne, C. Trivalle, I. Landrin, M. D.
Panty, N. Kadri, J. F. Menard and E. Bercoff, “Drug-Drug
Interactions Related to Hospital Administrations in Older
Adults: A Prospective Study of 1000 Patients,” Journal of
American Geriatric Society, Vol. 44, No. 8, 1996, pp.
944-948.
[22] X. A. Zhang, “Drug Induced Diseases,” China Medical
Technology Publishing House, Beijing, 1997.
[23] D. M. Tan, “Abuse of Aloe Vera ,” Science Daily, Vol. 30,
2001.
[24] J. M. Zhang, “Excessive Intake of Licorice can Cause
Potassium Loss,” International Journal of Traditional
Chinese Medicine, Vol. 14, No. 6, 1992, p. 14.
[25] J. Hu, Ji. Fang, Y. Dong, S. J. Chen and Z. Chen, “Arse-
nic in Cancer Therapy,” Anticancer Drugs, Vol. 16, No. 2,
2005, pp. 119-127.
doi:10.1097/00001813-200502000-00002
[26] Q. L. Li, “One Case of Allergic Purpura Caused by Ex-
cessive Aristolochia Manshuriensis Decoction,” China
Journal of Chinese Materia Medica, Vol. 25, No. 2, 2000,
p. 124.
[27] K. B. Bi and Y. L. Jia, “1 Case of Acute Renal Failure
Induced by Overdose of Tripterygium Decoction,” China
Journal of Chinese Materia Medica, Vol. 25, No. 3, 2000,
p. 191.
[28] Z. Y. Cau, “Clinical Analysis of 72 Cases of Acute Poi-
soning after Oral Tripterygium,” Hunan Journal of Tradi-
tional Chinese Medicine, Vol. 8, No. 2, 1981, p. 17-19.
[29] J. Z. Wang, “3 Cases of Tonkinensis Poisoning Report,”
Clinical Medicine, Vol. 8, No. 6, 1988, p. 279.
[30] Y. M. Wen, “One Death Case of Poisoning after Oral
Taking Radix Sophorae Tonkinensis,” Chinese Journal of
Hospital Pharmacy, Vol. 11, No. 6, 1991, p. 271.
[31] G. T. Zhang and A. Y. Zhao, “Improper Combination of

K.-F. CHENG ET AL.
39
Proprietary Chinese Medicine in Clinical Practice,” Chi-
nese Journal of Hospital Pharmacy, Vol. 191, No. 10,
1999, p. 621.
[32] “52 Kinds of Hospital Inhibited Plants Which Contain
‘Epsteln-Barr Virus Early Antigen-Inducer’ Have Cancer-
promoting Effects,” Chinese Hospital Architecture &
Equipment, Vol. 4, 2003, p. 11.
[33] W. L. Xue, “From the Safety of Traditional Chinese
Medicine to Its Internationalization,” Information on
Traditional Chinese Medicine, Vol. 22, No. 2, 2005, pp.
6-7.
[34] Y. P. Xiao, X. H. Ren and Y. X. Wu, “Lianyuan City
Drug Adverse Reaction Analysis Report,” Journal of
Clinical and Experimental Medicine, Vol. 6, No. 5, 2007,
pp. 172-173.
[35] S. T. Yuan, “Consideration on the Problem of Ascension
of the Case Poisoned by Chinese Traditional Medicines,”
China Journal of Chinese Materia Medica, Vol. 25, No. 1,
2000, p. 56.
[36] Chinese Medicine Council of Hong Kong, “Registration
of Proprietary Chinese Medicine (Application Hand-
book),” 2004.
http://www.cmchk.org.hk/pcm/pdf/reg_handbook_e.pdf
[37] J. Ma, “The Relationship between Drug Toxicology and
Other Disciplines,” Shanghai National Center for New
Drug Safety Evaluation GLP Training Seminars, Cheng-
du, 6 March 2011.
[38] H. Olson, G. Betton, D. Robjnson, et al., “Concordance
of the Toxicity of Pharmaceuticals in Humans and Ani-
mals,” Regulatory Toxicology and Pharmacology, Vol.
32, No. 1, 2000, pp. 56-67. doi:10.1006/rtph.2000.1399
[39] L. X. Yang, “Toxicology Studies of Artemisinin and Its
Derivatives,” Journal of Traditional Chinese Medicine,
Vol. 1, No. 1, 1982, pp. 3-6.
[40] Center for Evaluation and Research, “Annual Report of
2001 to Nation,” 2001.
http://www.fda.gov/eder/reports/rtn/2001