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Evidence-based toxicity evaluation
and scheduling of Chinese herbal
medicines
Meicun Yao
Journal of Ethnopharmacology
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Journal of Ethnopharmacology 146 (2013) 40–61
Contents lists available at SciVerse ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
Evidence-based toxicity evaluation and scheduling of Chinese
herbal medicines
Ellie J.Y. Kim a, Yuling Chen a, Johnson Q. Huang a, Kong M. Li b, Valentina Razmovski-Naumovski a,c,
Josiah Poon d, Kelvin Chan a,c, Basil D. Roufogalis a, Andrew J. McLachlan a, Sui-Lin Mo e, Depo Yang f,
Meicun Yao f, Zhaolan Liu a,g, Jianping Liu g, George Q. Li a,n
a
Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia
Discipline of Pharmacology, Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
c
Centre for Complementary Medicine Research, University of Western Sydney, Sydney, NSW 2560, Australia
d
School of Information Technology, The University of Sydney, Sydney, NSW 2006, Australia
e
First Affiliate Hospital, Sun Yat-sen University, Guangzhou 510080, China
f
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510080, China
g
Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2012
Received in revised form
19 December 2012
Accepted 19 December 2012
Available online 31 December 2012
Ethnopharmacological relevance: While there is an increasing number of toxicity report cases and
toxicological studies on Chinese herbal medicines, the guidelines for toxicity evaluation and scheduling
of Chinese herbal medicines are lacking.
Aim: The aim of this study was to review the current literature on potentially toxic Chinese herbal
medicines, and to develop a scheduling platform which will inform an evidence-based regulatory
framework for these medicines in the community.
Materials and methods: The Australian and Chinese regulations were used as a starting point to compile
a list of potentially toxic herbs. Systematic literature searches of botanical and pharmaceutical Latin
name, English and Chinese names and suspected toxic chemicals were conducted on Medline, PubMed
and Chinese CNKI databases.
Results: Seventy-four Chinese herbal medicines were identified and five of them were selected for
detailed study. Preclinical and clinical data were summarised at six levels. Based on the evaluation
criteria, which included risk–benefit analysis, severity of toxic effects and clinical and preclinical data,
four regulatory classes were proposed: Prohibited for medicinal usage, which are those with high
toxicity and can lead to injury or death, e.g., aristolochia; Restricted for medicinal usage, e.g., aconite,
asarum, and ephedra; Required warning label, e.g., coltsfoot; and Over-the-counter herbs for those
herbs with a safe toxicity profile.
Conclusion: Chinese herbal medicines should be scheduled based on a set of evaluation criteria, to
ensure their safe use and to satisfy the need for access to the herbs. The current Chinese and Australian
regulation of Chinese herbal medicines should be updated to restrict the access of some potentially
toxic herbs to Chinese medicine practitioners who are qualified through registration.
& 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords:
Evaluation criteria
Toxicity
Scheduling
Chinese herbal medicines
Aristolochia
Aconite
Abbreviations: TCM, Traditional Chinese medicine; CAM, Complementary and alternative medicine; NRAS, National Registration Accreditation Scheme; AHPRA,
Australian Health Practitioner Regulation Agency; SUSMP, Standard for the Uniform Scheduling of Medicines and Poisons; AAPCC, American Association of Poison Control
Centers; TESS, Toxic Exposure Surveillance System; TGA, Therapeutic Goods Administration; FDA, Food and Drug Administration; EU, European Union; CNKI, China
National Knowledge Infrastructure; CN, Chinese literature; EN, English literature; S2, Schedule 2; S4, Schedule 4; PRC, People’s Republic of China; S6, Schedule 6; S8,
Schedule 8; S9, Schedule 9; S5, Schedule 5; LD50, Lethal dose in 50% of the population; ED50, Effective dose in 50% of the population; TD50, Toxic dose in 50% of the
population; HED, Human equivalent dose; p.o., Oral administration; s.c., Subcutaneous injection; i.v., Intravenous injection; i.p., Intraperitoneal injection; CMC,
Carboxymethylated cellulose; ADRs, Adverse drug reactions; NHMRC, National Health and Medical Research Council; RCTs, Randomised controlled trials; HK-2, Human
kidney proximal tubule immortalised cells; HUVECs, Human umbilical vein endothelial cells; LLC-PK1, Renal tubular cells; AA-A, Aristolochic acid A; AA-B, Aristolochic
acid B; AAs, Aristolochic acids; DNA, Deoxyribonucleic acid; MTT, 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide; LDH, Lactatedehydrogenase; ESRD,
End stage renal disease; NOAELs, No observed adverse effect levels; SD rats, Sprague Dawley rats; DHP-derived, 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizinederived; GPT, Glutamic-pyruvic transaminase; GOT, Glutamic-oxaloacetic transaminase
n
Corresponding author. Tel.: þ61 2 9351 4435; fax: þ 61 2 9351 4391.
E-mail address: george.li@sydney.edu.au (G.Q. Li).
0378-8741/$ - see front matter & 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jep.2012.12.027
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
41
Contents
1.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1.1.
The need for evidence-based toxicological review on Chinese herbal medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1.2.
Current herbal medicines regulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1.3.
Evaluation systems of toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
1.4.
Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3. Results and discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.1.
List of scheduled and toxic herbs in Australia, China and Hong Kong. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
3.2.
Evaluation criteria according to toxicity data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.2.1.
Risk–benefit analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.2.2.
Severity of toxic effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.2.3.
Preclinical and clinical data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.3.
Toxicity data of the priority herbs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.3.1.
Aristolochia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.3.2.
Asarum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.3.3.
Aconite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.3.4.
Ephedra. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
3.3.5.
Tussilago farfara . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
3.4.
Scheduling of Chinese herbal medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
1. Introduction
1.1. The need for evidence-based toxicological review on Chinese
herbal medicine
Traditional Chinese medicine (TCM) has been widely used
throughout the world as a primary treatment strategy and as a
complementary and alternative medicine (CAM). The popularity and
demand of TCM is growing rapidly (Bensoussan and Lewith, 2004;
Chau et al., 2011), along with the concerns for the quality and safety
of the Chinese herbs used in therapeutic treatment (State
Administration of TCM Chinese Materia Medica Editorial
Committee, 1998; Hu et al., 2003). From 1 July 2012, Chinese
medicine practitioners have been part of the National Registration
Accreditation Scheme (NRAS) under the Australian Health Practitioner Regulation Agency (AHPRA), Health Practitioner Regulation
National Law Act (the National Law). It is imperative for the
practitioners to continuously monitor and improve their practice
standards, and to provide quality and safe healthcare services to the
public under the NRAS. This is particularly important in relation to
the prescription of herbal materials in treatments, as the recommendations for the use of herbal products and dietary supplements
accounts for a significant part of the lifestyle in modern Australian
society (MacLennan et al., 2006; Adams et al., 2011).
However, with the development of online markets and global
transportations, some potentially toxic herb medicines products are
readily accessed by individuals from overseas, avoiding restrictions
imposed by the regulatory measures in Australia. This was highlighted recently with the death of a 75 year old male from kidney
failure which was reportedly associated with the toxic preparation
containing the root of Aristolochia fangchi purchased over the
internet for psoriasis (Chau et al., 2011). The Australian Standard
for the Uniform Scheduling of Medicines and Poisons (SUSMP),
legally referred to as the Poisons Standard, (Department of Health
and Aging Therapeutic Goods Administration, 2011b) states that the
Aristolochia species are prohibited for use in Australia. Ephedra is
another well-known herb with debate surrounding its use. Ephedra
has long been prescribed by herbalists to relieve nasal congestion,
symptoms of respiratory infections and asthma. However, it has
been marketed as a weight-loss dietary supplement in USA, and has
been associated with a number of serious adverse effects on the
cardiovascular (Hallas et al., 2008) and nervous system (Verduin and
Labbate, 2002). These issues have called for a more structured and
controlled regulation of Chinese herbal medicine use in Australia,
and highlights the need to review the toxicological evidence of
Chinese herbal medicines. This revision will support the regulation of toxic herbs for patients’ safety and the practitioner’s
right to prescribe the most efficacious, yet safe Chinese herbs
and products.
1.2. Current herbal medicines regulations
In Australia, commercial herbal products are regulated by the
Therapeutic Goods Administration (TGA) and potentially toxic
herbal medicines are further regulated by the Australian SUSMP.
The evidence for inclusion of herbal medicines in the SUSMP is
not clear, and the list has not been updated in the last few
decades. The implementation of the SUSMP as the regulatory
measure for Chinese herbal medicines is controversial to Chinese
medicine professionals as some herbs such as ephedra (included
in the SUSMP) are available only through to pharmacists and
medical doctors, and not to Chinese medicine practitioners.
Consequently, the Victoria Chinese Medicine Registration Board
has requested revision of the scheduling (Chinese Medicine
Registration Board of Victoria, 2009). In Europe, the main regulatory body is the European Medicines Agency (EMA) but each
Member State also has their own regulatory agency, for example,
The Medicines and Healthcare products Regulatory Agency
(MHRA) in the UK, and The Federal Institute for Drugs and
Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM) in Germany (Fan et al., 2012; Quintus and
Schweim, 2012). To date, there is no separate regulation for the
registration of TCM. In China, a national regulation, Medicinal
Toxic Drugs Control Regulations, has set procedures for the
prescription of extremely toxic drugs and 16 raw herbs such as
raw aconite (The State Council of the People’s Republic of China,
1988). A similar list of toxic Chinese medicinal materials has been
issued in the Hong Kong Chinese Medicine Ordinance Schedule 1
42
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
(The Hong Kong Government, 1999). The standard and toxicity
ranking of Chinese medicines are set in the Chinese Pharmacopoeia, including highly toxic, toxic and non-toxic. However, the
toxicity ranking criteria are not well defined in the Chinese
Pharmacopoeia (Chinese Pharmacopoeia Commission, 2010).
With the regulation of Chinese medicine practitioners in Australia
from July 2012, and new reports on the toxicology of Chinese
medicines available, there is a strong need to review the regulation of toxic Chinese herbs in Australia and China.
1.3. Evaluation systems of toxicity
In Australia, the Scheduling Policy Framework sets out the
scheduling process, a guidance for amending the Poisons Standard SUSMP. The scheduling decision involves consideration of a
number of factors such as the toxicity of the substance, diagnosis
and the purpose of use, potential for abuse, safety in use and the
need for access to the substance. The factors are considered as a
whole in determining the public health risk for the proposal, not
applying any particular order of consideration or weight to any
one factor. This will allow the objective assessment of the risk/
benefit balance for the consumer at different levels of access and
therefore optimal public availability. For example, the Prescription Only Medicines (Schedule 4) apply if the ailments or
symptoms that the substance is used for and the use of the
substance require medical intervention, and if the seriousness,
severity and frequency of adverse effects, the margin of safety
between the therapeutic and toxic dose of the substance, the
seriousness or severity and frequency of the interactions of the
substance, are such that they require medical intervention to
minimise the risk of using the substance (The National
Coordinating Committee on Therapeutic Goods, 2010).
In the United States, the study by Woolf et al. (2005) has
effectively used the Toxic Exposure Surveillance System (TESS)
Medical Outcome Severity Codes from the American Association
of Poison Control Centers (AAPCC) to code and grade the medical
outcomes of botanical poisonings and other toxic exposures. The
standardised TESS codes definitions include ‘no effect’, ‘mild
effect’, ‘moderate effect’, ‘major effect’, ‘death’, ‘not followed
nontoxic’, ‘not followed minimal toxicity expected’, ‘not followed
potential toxicity’, ‘confirmed non-exposure’, or ‘unrelated effect’,
and the trained healthcare professionals working in the poison
centres determine the outcome based on predefined AAPCC
criteria corresponding to each code. Bensoussan et al. (2002)
developed a criteria for grading the potential toxicity of herbs in
therapeutic use or in overdose and inappropriate use, based on
the clinical and laboratory evidence collected from case reports,
clinical trials, in vitro and animal studies. The herbs are graded
based on the analysis and evaluation of the data, and the herbs
with insufficient data are left ungraded (Drew et al., 2002).
The safety of herbal medicines is a major concern for herbal
medicine practitioners, pharmacists, doctors and other healthcare
professionals (Livingstone et al., 2010). The review of the regulation of scheduled and toxic Chinese herbs and the development of
control measures are necessary to protect both the practitioners
and the patients. An evidence-based grading system is needed to
form the foundation for the appropriate scheduling of the
toxic herbs.
1.4. Objectives
The aim of this study was to review the current literature on
scheduled and potentially toxic Chinese herbal medicines, evaluate
the evidence of their toxicity, and provide a framework for the
toxicity classification of these herbs. This will provide a foundation
for the further development of an evidence-based approach to
regulate all Chinese herbal medicines.
2. Methods
By comparing the current medicine regulations (relevant to
herbal medicines and related products) from the SUSMP of
Australia, the Medicinal Toxic Drugs Control Regulations of China,
and Chinese Medicine Ordinance of Hong Kong, 74 Chinese herbal
medicines were included in the current study. Five herbal
medicines, aristolochia (Arisolochia species), asarum (Asarum
species), aconite (Aconitum species), ephedra (Ephedra species)
and coltsfoot (Tussilago farfara) which highlighted differences in
the Chinese and Australian regulations, were selected as the
priority herbs for detailed review. The English edition of the
Chinese Pharmacopoeia (Chinese Pharmacopoeia Commission,
2010), Chinese Herbal Medicine: Materia Medica (Bensky et al.,
2004), and Pharmacology and Applications of Chinese Materia
Medica (Chang and But, 1996) were used to collect general
information on the 74 herbs.
A detailed literature search was carried out for the 74 herbs.
Medline, PubMed was searched up to December 2011 and China
National Knowledge Infrastructure (CNKI) database was searched
up to February 2012. For each herb, the search comprised of a
combination of the names of the herbs and the terms reflecting
‘‘toxicity’’. The names of the herbs were botanical Latin name,
pharmaceutical Latin name, English common name, Chinese
Pinyin name, or their suspected toxic chemicals. Toxicity terms
included: Toxic, Toxicity, Intoxication, Poisoning and Adverse.
In CNKI, search terms were explored as either key word combinations or words in the abstract and full text. Only the citations
relevant to the potential toxicity of the herbal material or the
potentially toxic phytochemical constituents were retrieved.
3. Results and discussion
3.1. List of scheduled and toxic herbs in Australia, China and Hong
Kong
Table 1 shows the list of 74 Chinese herbal medicines with
nomenclature, their current schedules in the Australian SUSMP,
and the status in the Medicinal Toxic Drugs Control Regulations of
China and Chinese Medicine Ordinance of Hong Kong. The toxicity
grading of the herbs in the Pharmacopoeia of the People’s
Republic of China was entered in Table 1.
Of the 74 Chinese herbal medicines, 67 were included in the
SUSMP and most of them were either under Schedule 4 (prescription only medicine or prescription animal remedy), or
Appendix C, the substances other than those included in Schedule
9 (danger to health as to warrant prohibition of sale, supply and
use) (Department of Health and Aging Therapeutic Goods
Administration, 2011b). Sixteen Chinese herbal medicines were
from the Chinese regulation: Aconitum brachypodum Diels (Raw,
Sheng Xueshangyizhihao), Aconitum carmichaeli Debx. (Raw,
Sheng Chuanwu, Sheng Fuzi), Aconitum kusnezoffii Reichb. (Raw,
Sheng Caowu), Arisaema erubescens (Wall.) Schott./Arisaema
heterophyllum Bl./Arisaema amurense Maxim. (Raw, Sheng Nanxing), Croton tiglium L. (Raw, Sheng Badou), Datura metel L. (Raw,
Sheng Yangjinhua), Euphorbia fischeriana Steud/Euphorbia ebracteolata Hayata (Raw, Sheng Landu), Euphorbia kansui Lou (Raw,
Sheng Gansui), Euphorbia lathyris L. (Raw, Sheng Qianjinzi),
Garcinia morella Desv. (Raw, Sheng Tenghuang), Hyoscyamus niger
L. (Raw, Sheng Tianxianzi), Pinellia ternate (Thunb.) Breit. (Raw,
Sheng Banxia), Rhododendron molle (Bl.) G. Don (Raw, Sheng
Table 1
List of 74 toxic and scheduled Chinese herbal medicines.
Family
Pharmaceutical Latin
Chinese Pinyin
English common
name
SUSMP in
Australia
Medicinal Toxic Drugs
Control Regulations
(PRC)
Hong Kong
Ordinance
Schedule 1
Chinese
Pharmacopoeia
1
2
Acorus calamus L.
Abrus precatorius L.
Acoraceae
Fabaceae
Baichang/Changpu
Xiangsizi/Xiangsizigen
Ranunculaceae
Appendix C
Appendix C,
Appendix G
S2 or S4
Aconitum brachypodum Diels
þ
þ
4
Aconitum bullatifolium Levl.
Ranunculaceae
S2 or S4
5
Aconitum carmichaeli Debx.
Ranunculaceae
S2 or S4
þ
þ
Highly Toxic
6
Aconitum carmichaeli Debx.
Ranunculaceae
S2 or S4
þ
þ
Toxic
7
Aconitum coreanum (Levl.) Rapaics
Ranunculaceae
S2 or S4
8
Aconitum kusnezoffii Reichb.
Ranunculaceae
Sweetflag Rhizome
Coralhead Plant
Seed/Root
Monkshood Root/
Pendulous
Heterohariy
Monkshood Root
Monkshood Mother
Root
Common
Monkshood
Korean Monkshood
Root
Kusnezoff’s
Monkshood Root
Dogbane Leaf
Jack-in-the-pulpit
Rhizome
Fangchi Root/
Southern Fangji
Root
Root of Kaempfer
Dutchmanspipe
Dutchmanspipe
Root
Vine/Northern
Dutchmanspipe
Dutchmanspipe
Fruit
Dutchmanspipe
Root
Dutchmanspipe
Stem
Wooly
Dutchmanspipe
Herb
3
Acori Calami Rhizoma
Abri precatorii Semen/
Radix
Aconiti Brachypodi/
Radix
Aconiti Heterotrichi
Radix
Aconiti Radix
S2 or S4
þ
þ
Highly Toxic
S4
S6
þ
þ
Non toxic
Toxic
Appendix C
Appendix C
Appendix C
Appendix C
Appendix C
Appendix C
Precautions and
Warnings
Precautions and
Warnings
Appendix C
Appendix C
Appendix C
Manchurian Wild
Ginger
Appendix C
Non Toxic
S2 or S4
Non Toxic
Appendix C
Non toxic
Precautions and
Warnings
–
Aconiti Lateralis
Praeparata Radix
Aconiti Coreani Radix
Aconiti Kusnezoffii
Radix
Apocyni Veneti Folium
Arisaematis Rhizoma
Xueshangyizhihao
Xiaobaicheng
Chuanwu/Wutou
Fuzi
Guanbaifu
Caowu
9 Apocynum venetum L.
10 Arisaema erubescens (Wall.) Schott./Arisaema
heterophyllum Bl./Arisaema amurense Maxim.
11 Aristolochia fangchi Y.C. Wu ex L.D. Chou & S.M.
Hwang
Apocynaceae
Araceae
Luobuma
Tiannanxing
Aristolochiaceae
Aristolochiae Fangchi
Radix
Guangfangji
12 Aristolochia cinnabarina C.Y. Cheng et J.L. Wu/A.
kaempferi Willd.
13 Aristolochia debilis Sieb.et Zucc.
Aristolochiaceae
Zhushalian
Aristolochiaceae
Aristolochiae
Kaempferie Radix
Aristolochiae Radix
Qingmuxiang
Aristolochiaceae
Aristolochiae Herb
Tianxianteng
Madouling
(Beimadouling)
Hanzhongfangji
Aristolochiaceae
Aristolochiae Fructus
Aristolochiaceae
17 Aristolochia manshuriensis Kom.
Aristolochiaceae
18 Aristolochia mollissima Hance
Aristolochiaceae
Aristolochiae
Heterophyllae Radix
Aristolochiae
Manshuriensis Caulis
Aristolochiae
Mollissimae Herba
19 Aristolochia yunnanensis Franch./A. calcicola C. Y.
Wu
Aristolochiaceae
20 Asarum heterotropoides Fr.
Schmidt.var.mandshuricum (Maxim.) Kitag./
Asarum sieboldii Miq.var. seoulense
Nakai/Asarum sieboldii Miq.
21 Atropa belladonna L.
Aristolochiaceae
Mianmaomadouling/
Qinggufeng /
Xungufeng
Aristolochiae Calcicolae Nanmuxiang/
Qingxiangteng
Radix et Rhizoma et
Caulis
Asari Radix et Rhizoma Xixin
Solanaceae
Belladonnae Herba
Dianqiecao
22 Cacalia ainsliaefora (Franch.) Hand.- Mazz.
Asteraceae
Bajiaoxiang
23 Cannabis sativa L.
24 Carthamus tinctorius L.
Moraceae
Compositae
Cacaliae Ainsliaeforae
Rhizoma
Cannabis Semen
Carthami Flos
Belladonna Herb /
Deadly Nightshade
Star Anise
Huomaren
Honghua
Hemp seed
Safflower
S8, S9
25 Cinnamomum camphora (L.) Presl.
26 Claviceps purpurea (Fr.) Tul/C. microcephala
(Wallr.) Tul.
Lauraceae
Clavicepitaceae
Camphora
Ergota
Zhangnao
Maijiao
Camphor
Ergot
S4
S4
Guanmutong
43
14 Aristolochia debilis Sieb.et Zucc./Aristolochia
contorta Bge.
15 Aristolochia debilis Sieb.et Zucc./Aristolochia
contorta Bge.
16 Aristolochia heterophylla Hemsl.
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Botanical Latin
44
Table 1 (continued )
Botanical Latin
Family
Pharmaceutical Latin
Chinese Pinyin
English common
name
SUSMP in
Australia
Medicinal Toxic Drugs
Control Regulations
(PRC)
Hong Kong
Ordinance
Schedule 1
Chinese
Pharmacopoeia
Appendix C
–
–
–
S4
–
–
–
Menispermaceae Cocculi Trilobi Radix
Mufangji
Ruscaceae
Linglan
Japanese Snailseed
Root
Lily of the valley
29 Crocus sativus L.
Iridaceae
Xihonghua
Saffron
–
–
–
30 Crotalaria albida Heyne ex Roth
Papilionaceae
Huanghuadiding
Crotalaria herb
Appendix C
–
–
Precautions and
Warnings
–
31 Crotalaria pallida Ait.
Papilionaceae
Appendix C
–
–
–
Appendix C
–
–
–
Appendix C
þ
þ
Highly Toxic
Appendix C
–
–
–
Appendix C
–
–
–
S2 or S4
þ
þ
Toxic
S2 or S4
–
–
–
S2 or S4
S4
–
–
–
–
–
–
S4
–
–
–
S4
–
–
Non toxic
S4
–
–
–
S4
þ
þ
Toxic
S4
þ
þ
Toxic
S4
þ
þ
Toxic
Appendix C
–
–
–
–
þ
þ
–
32 Crotalaria sessiliflora L.
33 Croton tiglium L.
34 Cynoglossum amabile Stapf et J. R. Drumm.
35 Cynoglossum officinale L.
36 Datura metel L.
37 Datura stramonium L.
38 Datura tatula L.
39 Digitalis lanata Ehrh
40 Digitalis purpurea Linn.
41 Ephedra sinica Stapf/Ephedra intermedia Schrenk
et C.A. Mey./E. equisetina Bae.
42 Erysimum bungei (Kitag.) Kitag./Erysimum
amurense Kitag./Erysimum perofskianum Fisch. &
C.A. Mey.
43 Euphorbia fischeriana Steud/Euphorbia
ebracteolata Hayata
44 Euphorbia kansui T.N. Liou ex T.P. Wang
Convallariae Majalis
Herba Seu Radix
Croci Stigma
Crotalriae Albidae
Herba et Radix
Crotalariae Pallidae
Semen
Crotalariae Sessiliflorae
Herba
Crotonis Fructus
Striped Crotalaria
Herb
Papilionaceae
Yebaihe
Purple Flower
Crotalarla Herb
Euphorbiaceae
Badou/Badoushuang
Croton Seed/Croton
Cream
Boraginaceae
Cynoglossi Amabillis
Daotihu/Goushihua
Chinese hound’sHerba et Radix
tongue
Boraginaceae
Cynoglossi Officinalis
Yaoyongdaotihu
Root of Common
Radix
Houndstongue
Solanaceae
Daturae Flos
Yangjinhua
Flower/Hairy
Datura Flower
Solanaceae
Daturae Stanmonii Flos Mantuoluo
Jimson weed/
Devil’s trumpet
Solanaceae
Daturae Tatulae Flos
Fengqiehua
Thorn apple
Scrophulariaceae Digitalis lanatae Folium Maohuayangdihuangye Digitalis Lanata
Leaf
Scrophulariaceae Digitalis Purpureae
Yangdihuangye
Common Foxglove
Folium
Leaf
Ephedraceae
Ephedrae Herba/Radix
Mahuang /
Ephedra Herb/Root
Mahuanggen
Brassicaceae
Erysimi Semen
Tangjie
Wallflowers seeds
Euphorbiaceae
Euphorbiaceae
Euphorbiae
Ebracteolatae Radix
Kansui Radix
45 Euphorbia lathyris L.
Euphorbiaceae
Euphorbiae Semen
46 Farfugium japonicum (L.) Kitam.
Asteraceae
Farfugii Japonica Herba
47 Garcinia morella Desv.
Clusiaceae
Garciniae Morellae
Resina
48 Heliotropium indicum L.
Boraginaceae
Heliotropi Herba
49 Hyoscyamus niger L.
Solanaceae
50 Illicium verum Hook. f.
51 Ligularia dentata (A. Gray) Hara
Schisandraceae
Asteraceae
52 Lobelia chinensis Lour.
Lobeliaceae
53 Melia azedarach L./M. toosendan Sieb. et Zucc.
Meliaceae
Hyoscyami Folium /
Semen
Anisi Stellati Oleum
Ligulariae Dentatae
Radix
Lobeliae Chinensis
Herba
Meliae Cortex / Meliae
Flos
Zhushidou
Shenglandu
Unprocessed
Langdu Root
Shenggansui
Unprocessed
Gansui Root
Shengqianjinzi
Unprocessed Caper
Euphorbia Seed
Lianpengcao
Herb of Japanese
Farfugium
Shengtenghuang
Unprocessed gunresin of Garcinia
morella
Daweiyao
Herb of Indian
Heliotrope
Langdangye/Tianxianzi Henbane Leaf/
Henbane Seed
Bajiaohuixiangyou
Anise Star Oil
Huluqi/chiyetuowu
Summer ragwort
Appendix C
–
–
–
S2 or S4 or
Appendix G
S5
Appendix C
þ
þ
Highly Toxic
–
–
–
–
Non Toxic
–
Banbianlian
S2
–
–
Non toxic
Appendix C
–
–
Toxic
Kulianpi/Lianhua
Chinese Lobelia
Herb
Chinaberry Bark/
Chinaberry Flower
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
27 Cocculus orbiculatus (L.) D.C./C. trilobus (Thunb.)
D.C.
28 Convallaria majalis L.
Apocynaceae
Nerii Folium
Jiazhutaoye
55 Papaver somniferum L.
Papaveraceae
Papaveris Pericarpium
Yingsuke
56 Petasites japonicus (Sieb. et Zucc.) F. Schmidt
Asteraceae
Fengdoucai
57 Pinellia ternata (Thunb.) Breit.
58 Podophyllum peltatum
Araceae
Berberidaceae
59 Prunus armeniaca L.
Rosaceae
60 Rauvolfia serpentine (L.) Benth. ex Kurz
Apocynaceae
61 Rauvolfia verticillata (Lour.) Baill.
Apocynaceae
Petasiti Japonica Herba
et Rhizoma
Pinelliae Rhizoma
Podophylli Peltati
Rhizoma
Armeniacae Semen
Amarum
Rauvolfiae Serpentinae
Radix/Caulis/Folium
Rauvolfiae Radix
62 Rauvolfia vomitoria Afzel. ex Spreng.
Apocynaceae
63 Rhododendron molle G.Don
Ericaceae
64 Senecio campestris (Retz.) DC. ssp. kirilowii
(Turcz.) Kitag.
65 Senecio scandens Buch.-Ham.
Asteraceae
Asteraceae
66 Podophyllum emodii Wall.
Berberidaceae
67 Sophora tonkinensis Gagnep.
Fabaceae
68 Strophanthus divaricatus Hook & Arn.
69 Strychnos nux-vomica L.
70 Symphytum officinale Linn.
Apocynaceae
Loganiaceae
Boraginaceae
71 Thevetia peruviana (Pers.) K.Schum
Banxia
Dunyeguijiu
Kuxingren
Shegengmu
Luofumu
Rauvolfiae Vomitariae
Cuituluofumu
Radix/Cortex
Rhododendri Mollis Flos Naoyanghua
Senecionis Campestris
Herba
Senecionis Scandentis
Herba
Podophylli Radix et
Rhizoma
Goushecao
Shandougen
Yangjiaoniuzi
Maqianzi
Juhecao
Apocynaceae
Sophorae Tonkinensis
Radix et Rhizoma
Strophanthi Divaricati
Strychni Semen
Symphyti Officinalis
Radix
Thevetiae Semen
72 Tussilago farfara L.
Asteraceae
Farfarae Flos
Kuandonghua
73 Typhonium giganteum Engl.
Apocynaceae
Baifuzi
74 Veratrum nigrum L./Veratrum schindleri Loes. F.
Liliaceae
Typhonii Gigantei
Rhizoma
Veratri nigri Radix et
Rhizoma
Qianliguang
Guijiu/Taoerqi
Huanghuajiazhutao
Lilu
Sweet Scented
Oleander Leaf
Opium poppy husk
Rhizome of
Japanese Butterbur
Pinellia Tuber
Mayapple /
Mandrake root
Apricot seed or
kernel
Snakeroot
Java Devilpepper
Root
Poison devil’spepper
Chinese Azalea
Flower
Kirilow Groundsel
Herb
Climbing
Groundseal Herb
Himalayan
mayapple/Indian
may apple
Vietnamese
Sophora Root
Strophantus Seed
Nux Vomica
Common comfrey
Luckynut Thevetia
Seed
Common Coltsfoot
Flower
Giant Typhonium
Veratrum root and
rhizome
S4
–
–
–
S2 or S4 or S8 –
or Appendix K
Appendix C
–
–
Toxic
–
–
–
S2
þ
þ
Toxic
Appendix C
–
–
Slightly toxic
S4
–
–
–
S4
–
–
–
S4
–
–
–
–
þ
þ
Highly Toxic
Appendix C
–
–
–
Appendix C
–
–
Non Toxic
S2
þ
–
–
þ
Toxic
S4
S4
S5 Appendix
C
S4
–
þ
–
–
þ
–
–
Highly Toxic
–
–
–
–
Appendix C
–
–
Non toxic
–
þ
þ
Toxic
S4
–
–
–
Key: S2, Pharmacy Medicine; S4, Prescription Only Medicine or Prescription Animal Remedy; S5, Caution; S6, Poison; S8, Controlled Drug; S9, Prohibited Substance; Appendix C, Substances, other than those included in Schedule
9, of such danger to health as to warrant prohibition of sale, supply and use; Appendix G, Dilute preparations; Appendix K, Human medicines required to be labelled with a sedation warning; þ , listed in the document; –, not
listed in the document.
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
54 Nerium indicum Mill.
45
46
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Naoyanghua), Strychnos nux-vomica L. (Raw, Sheng Maqianzi),
Typhonium giganteum Engl. (Raw, Sheng Baifuzi). Euphorbia
fischeriana is not in the current edition of Chinese Pharmacopoeia.
In addition to these sixteen Chinese herbal medicines from the
Chinese regulation, two more species, Podophyllum emodii,
Sophora tonkinensis, were found to be scheduled as toxic herbs
in Hong Kong.
Therefore, there are obvious differences in the lists of the toxic
herbs from the Australian, Chinese and Hong Kong regulations.
Many of the herbs scheduled in the SUSMP for restricted or
prohibited use were not listed in China’s and Hong Kong’s
regulations. The major examples include Aristolochia species,
Asarum species, Ephedra species and Tussilago farfara. Herbs such
as Aristolochia species, Asarum species and Tussilago farfara in
Appendix C of the SUSMP have been prohibited for therapeutic
use in Australia. However, these were not included in the toxic
herb schedules in China and Hong Kong. Similarly, Ephedra
species were restricted to prescription only in Australia.
In contrast, there was no restriction to herbal practitioners for
dispensing the Ephedra herb as it was not listed as toxic herbal
medicine in China and Hong Kong.
Although the schedules from Australia, China and Hong Kong
do not agree with most of the herbs on the list of 74 Chinese
herbal medicines, Aconitum species, Croton tiglium, Datura metel
and Euphorbia species were classified as toxic for therapeutic use
by all three schedules and required restricted usage. According
to the SUSMP, Aconitum carmichaeli, Aconitum kusnezoffii and
Aconitum brachypodum are available for therapeutic use through
Pharmacy Only Medicine (S2) or Prescriptions Only Medicine (S4).
From the China and Hong Kong schedules, unprocessed forms of
these herbal species are recognised as toxic, thus requiring strict
regulation. The five most contentious Chinese herbal medicines,
aristolochia, asarum, aconite, ephedra and coltsfoot, have been
selected as the priority herbs for further in depth evaluation of
their toxicity.
3.2. Evaluation criteria according to toxicity data
The evaluation criteria was based on risk–benefit analysis, the
severity of toxic effects, clinical data and preclinical data, using
the five priority Chinese herbal medicines, aristolochia, asarum,
aconite, ephedra and coltsfoot as examples.
3.2.1. Risk–benefit analysis
Risk–benefit analysis is one of the guiding principles for
medical and pharmaceutical practice. The scheduling decision in
Australia takes into consideration a number of factors such as the
toxicity of the substance, to assess the risk–benefit balance for the
consumer at different levels of access and therefore optimal
public availability (The National Coordinating Committee on
Therapeutic Goods, 2010).
While the risk–benefit analysis is lacking for most herbal
medicines, we propose to include literature on traditional formulas, pharmacopoeia, number of commercial patent products in
the market, volume of the industry, and clinical studies as the
basis for benefit analysis. Many of the TCM classic texts such as
the Divine Husbandman’s Classic of Materia Medica (Shen Nong
Ben Cao Jing) and the Discussion of Cold Damage (Shang Han Lun)
discuss the effective therapeutic use and toxicity of herbal
medicines. The Chinese Pharmacopoeia has included 2165 most
commonly used Chinese herbal medicines, extracts, oil and
formulary preparations. The inclusion is an indication of traditional and current practice of TCM. Among the five herbs,
however, Aristolochia is less frequently used in formulary
preparations (Chinese Pharmacopoeia Commission, 2010).
Traditionally, Aristolochia debilis is indicated for cough, panting, blood in phlegm, painful haemorrhoids and the pain in the
epigastrium and abdomen. It is an ingredient in the formulary
preparations Zhisou Huatan Wan for cough and asthma (Chinese
Pharmacopoeia Commission, 2010). Aristolochia contorta and
Aristolochia debilis are interchangeably referred and used as
Aristolochiae fructus according to the Chinese Pharmacopoeia.
It has been reported that processing methods such as boiling in
limewater, liquorice juice, soda water, or black soybean decoction,
and stir-baking with talcum powder can reduce the content of
aristolochic acid in the herb and lessen the nephrotoxicity effects
(Pan et al., 2010). Other studies showed that some of the herbs
such as Salvia miltiorrhiza and Ramulus Cinnamomi have ameliorating effects on kidney toxicity from Aristolochia species when
used in combination (Cheng et al., 2006; Wang et al., 2007).
However, it is well established that aristolochic acids are associated with nephropathy (Debelle et al., 2008), genotoxicity
(Hwang et al., 2012), and urothelial cancer (Chen et al., 2012).
Further studies on their potential health risk are needed (Heinrich
et al., 2009).
Asarum species are widely used for the treatment of the
common cold, headache, toothache, sinusitis with nasal obstruction and rheumatic arthralgia in Chinese medicine (Chinese
Pharmacopoeia Commission, 2010). Its pharmacological actions
include sedative and analgesic effects, antipyretic and antiinflammatory effects, local anaesthetic effect, and effects of major
body systems such as the respiratory and cardiovascular systems.
It is an ingredient in commonly used formulary preparations such
as Chuanxiong Chatiao Wan and Xiaoqinglong Heji for common
cold (Chinese Pharmacopoeia Commission, 2010). The traditional
use of Tussilago farfara includes the treatment of cough, bronchitis
and asthmatic conditions. Recent studies have shown that tussilagone, the active constituent of Tussilago fafara, has inhibitory
activity on lung cancer cell proliferation (Liu et al., 2009a). It is
an ingredient in commonly used formulary preparations such
as Zhike Juhong Koufuye for cough (Chinese Pharmacopoeia
Commission, 2010).
Aconitum species such as Aconitum carmichaeli and Aconitum
kusnezoffii have been traditionally used for the treatment of joint
pain, cold pain in the heart and abdomen, and applied as
anaesthesia for pain relief (Chinese Pharmacopoeia Commission,
2010). The toxicity of Aconitum mainly derives from the diester
diterpene alkaloids including aconitine, mesaconitine and hypaconitine (Xu et al., 2005), thus prior processing of the herbs before
use is required to reduce any toxic effects. For example, pretreating with rice vinegar and black soya bean increased the LD50
by more than 10 times compared to the crude Aconitum
(Wu et al., 2011). Other studies have showed that various
processing methods reduced the toxicity of Aconitum species
(Ma et al., 1994; Liu et al., 2009b; Chen et al., 2010a). It is an
ingredient in commonly used formulary preparations such as Sini
Tang for stroke and heart failure, Fuzi Lizhong Wan for diarrhoea
and Guifu Dihuang Wan for diabetes (Chinese Pharmacopoeia
Commission, 2010).
Ephedra is one of the major Chinese herbs with long historical
use, and has been developed into pharmaceuticals. Traditionally,
ephedra has been used in China for bronchial asthma, coughs, colds,
flu, fever, chills, headaches and nasal congestion (Bensky et al.,
2004; Zhang et al., 1999). In modern society, the main focus of
ephedra use is its pharmacological action in stimulating the central
nervous system, and effectiveness in weight-loss and performance
enhancement (Abourashed et al., 2003). Ephedra is currently
included in the Chinese Pharmacopoeia for therapeutic use and
graded as a non-toxic herb. Its efficacy has been successfully
demonstrated in a number of randomised double blind clinical
trials (Boozer et al., 2002; Haller et al., 2005; Kim et al., 2008).
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Ephedra is an ingredient in commonly used formulary preparations
such as Xiaoqinglong Heji for common cold and Zhisou Dingchuan
Koufuye for asthma (Chinese Pharmacopoeia Commission, 2010).
Although efficacy has been established for some herbal medicines, efficacy is lacking for many other herbal medicines due to
insufficient research. Ernst (2007) has emphasised that in order to
conduct a risk–benefit analysis of herbal medicines, definitive
efficacy and safety data is required. Therapeutic index is one of
the fundamental measures used to analyse the balance between
benefit and the risk of a medicinal compound. The therapeutic
index of a drug is expressed as: Therapeutic index ¼LD50/ED50,
where LD50 is the dose that is lethal in 50% of the population, and
ED50 is the dose that is effective in 50% of the population (Rang
et al., 2003). As lethality is not determined in clinical studies, the
dose that produces a toxic effect in 50% of the population, TD50, is
used to calculate the therapeutic index. It is intended to indicate
the margin of safety of a drug by emphasising the relationship
between the effective and toxic doses. Although therapeutic index
is one of the important contributing factors in determining the
benefit of drugs, it is often not readily available for herbal
medicines. Therapeutic index values were searched for some of
the well-known toxic herbs such as aristolochia, asarum, aconite,
ephedra and coltsfoot, however, the values were not available and
only the LD50 values were found.
Since animal toxicological studies provide a foundation for
human clinical studies, we converted the animal LD50 values to
theoretical Human Equivalent Dose (HED) using the formula from
the study by Reagan-Shaw et al. (2008): HED (mg/kg)¼ animal
dose (mg/kg) animal km/human km, where animal km is 3 for
mice, human km is 37, average weight of human equals to 60 kg,
and the average weight of mice is 0.02 kg (Reagan-Shaw et al.,
2008). This conversion method is based on the use of body surface
area normalisation rather than a simple conversion based on body
weight.
LD50 values of some of the herbs and their chemical constituents have been described in a number of studies (State
Administration of TCM Chinese Materia Medica Editorial
Committee, 1998; Jiang and Chen, 2008; Singhuber et al., 2009).
These values were then converted to the theoretical HED using
the above formula and shown in Table 2. Variable factors included
the extract type, administration method, and in some cases, the
sex of mice used in the experiment.
The theoretical p.o. HED values (g/60 kg) of water extracts
were calculated for the priority herbs: asarum, 60.2–490.4,
aristolochia (Aristolochia debilis), 712.5, coltsfoot, 603.2, ephedra
379.5, and aconite (Aconitum carmichaeli—Processed Fuzi) 84.6,
indicating aconite is the most toxic herb. For extracts, the dosage
normally refers to the equivalent weight of dry herbs. The clinical
dosages of the dry herbs are: asarum, 1–3 g, aristolochia
(Aristolochia debilis), 3–9 g, coltsfoot, 5–10 g, ephedra, 2–10 g,
and aconite (Aconitum carmichaeli—Processed Fuzi), 3–15 g
(Chinese Pharmacopoeia Commission, 2010). The ratio between
HED and dosage (60.2/3) is over 20 times for asarum, and
less than 6 for aconite (84.6/15) to some extend indicating the
therapeutic window.
Water extracts are generally less toxic than ethanol extracts, and
oral administration is less toxic than i.v. and i.p. The p.o. HED value
of the water extract of coltsfoot in mice was 603.2 g/60 kg, while the
ether extract was 209.2 g/60 kg. Aconitine and mesaconitine are the
major alkaloids found in the processed roots of Aconitum (Singhuber
et al., 2009), and higher amounts are found in unprocessed aconite
roots (Ding et al., 1993). The theoretical HED was 0.0016 g for
aconitine and 0.0024 g for mesaconitine. In comparison, aristolochic
acid from the Aristolochia species showed higher theoretical HED
ranging from 0.187 g to 0.516 g, depending on the administration
method and the sex of the mice. The theoretical HED for aristolochic
47
acid was more than 100 times higher than that of aconitine and
mesaconitine, and this implies that the acute toxicity of aconite is
much higher than that of aristolochia.
The LD50 and the theoretical HED values provide valuable
scientific information for further analysis of the severity of herbal
toxicity. However, LD50 measures acute toxicity only and does not
take into account toxic effects that do not result in death but are
nonetheless serious. These doses have many variables including
data from different experiments performed by different researchers in diverse conditions. In this study, the ranking of the toxicity
of herbs is evaluated by LD50 and theoretical HED in conjunction
with other factors such as the documented severity of toxic
effects, preclinical data and clinical data.
3.2.2. Severity of toxic effects
Drug toxicology analysis has used the classification of Hodge
and Sterner which stipulates six classes of acute toxicity based on
LD50 determination in rats (single PO administration): LD50 at
o1 mg/kg is Class 1, extreme toxicity, at 1–50 mg/kg is Class 2,
high toxicity, at 50–500 mg/kg is Class 3, moderate toxicity, at
500–5000 mg/kg is Class 4, low toxicity, at 5000–15,000 mg/kg
is Class 5, practically nontoxic, at 415,000 mg/kg is Class 6,
relatively harmless (Berezovskaya, 2003). The Globally Harmonized System of Classification and Labeling of Chemicals is an
internationally agreed-upon system, created by the United
Nations. The upper limit of the LD50 determination (oral) of the
five classes are: Category 1, 5 mg/kg, Category 2, 50 mg/kg,
Category 3, 300 mg/kg, Category 4, 2000 mg/kg, Category 5,
5000 mg/kg (United Nations, 2011).
Some herbal medicines may result in undesirable effects.
These effects can range from minor symptoms such as mild
headache or abdominal discomfort, to much more serious outcomes that can cause major organ damage and even death. Thus,
the severity of toxic effects is one of the most important criteria in
determining the toxicity grade of the herbs. The criteria developed by Bensoussan et al. (2002) consisted of three levels of
toxicity grading, where ‘‘Severe’’ is indicated for herbs with
reported death or textbook data indicating death occurrence,
‘‘Moderate’’ is for herbs with reported life-threatening human
adverse drug reactions (ADRs) or textbook data indicating human
ADRs occurrence, and ‘‘Mild’’ is for herbs with reported non-lifethreatening human ADRs or textbook data indicating non-lifethreatening human ADRs occurrence.
In this study, we defined the severity of the toxic effect based
on the toxicity grading by Yang et al. (1991), who introduced five
criteria for the toxicity ranking of Chinese herbal medicines, with
the clinical severity of intoxication as the first criteria. Three
toxicity rankings, ‘‘Highly Toxic’’, ‘‘Moderate Toxic’’, and ‘‘Mild
Toxic’’, have been used to grade the clinical toxic responses to the
herbs. ‘‘Very Toxic’’ grade has been indicated for herbs, such as
raw aconite (Shengcaowu), where inappropriate use of the herbs
may lead to extremely severe symptoms and the damage of
important organs and even death. ‘‘Moderate Toxic’’ grade has
been indicated for herbs, such as processed aconite (Fuzi), where
inappropriate use of the herbs may lead to severe symptoms and
even damage of important organs, and overdose can lead to death.
For ‘‘Mild Toxic’’ grade, inappropriate use of the herbs can lead to
adverse effects, but it generally will not cause death. Asarum was
included as an example of a ‘‘Mild Toxic’’ herb. Other criteria
included: the quantitative toxicological data, the difference
between the effective dosage and the toxic dosage, the toxic
dosage and the time of toxication onset, and the source, processing and quality of the herbs. The herbs are graded as ‘‘Very Toxic’’
when LD50 for oral administration of decoction herbal medicine is
48
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Table 2
Animal LD50 values from literature and the respective theoretical human equivalent dose (HED) for the priority herbs.
Herbs
Extract/
constituent
Administration
method
Mice LD50 (g/kg, unless specified) and reference
HED (g/60 kg)
Asarum sieboldii
Water extract
p.o.
60.2
36.5
15.1 mL/kg
236.9
9.2 mL/kg
23.4
31.7 (7 5.6)
Water extract
Essential oil
p.o.
Powder
Volatile oil
Water decoction
Volatile oil
Powder
Root powder
suspension
Herb powder
suspension
Volatile oil
Aristolochic acid
p.o.
p.o.
p.o.
p.o.
p.o.
p.o.
12.4 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
0.8 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
100.8 (Wei et al., 2010)
27.0 (7 0.4) (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
7.5 (Wei et al., 2010)
3.1 mL/kg (Wei et al., 2010)
48.7 (Wei et al., 2010)
1.9 mL/kg (Wei et al., 2010)
4.8 (Fu et al., 2010)
6.5 (7 1.2) (Zhou et al., 2003)
p.o.
11.7 (74.2) (Zhou et al., 2003)
56.9 (7 20.6)
Magnoflorine
p.o.
p.o. (Male)
p.o. (Female)
i.v. (Male)
i.v. (Female)
i.v.
12.2 mL/kg
0.272
0.516
0.187
0.341
0.097
Raw root
Processed root
Ethanol extract
Ethanol extract
p.o.
p.o.
p.o.
p.o.
2.5 mL/kg (Fu et al., 2010)
0.0559 (Jiang and Chen, 2008)
0.1061 (Jiang and Chen, 2008)
0.0384 (Jiang and Chen, 2008)
0.0701 (Jiang and Chen, 2008)
0.020 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
146.5 (Jiang et al., 2006)
846.1 (Jiang et al., 2006)
25.1 (76.4) (Hu et al., 2003)
4.4 (Ding et al., 2005)
Ethanol extract
Water extract
p.o. (Female)
p.o.
Ethanol extract
i.p.
Ether extract
i.v.
Water extract
p.o.
i.v.
Asarum sieboldii var.
seoulense
Asarum heterotropoides
Aristolochia debilis
Aristolochia heterophylla
Aristolochia
manshuriensis
Aristolochia fangchi
Tussilago farfara
Ephedra sinica
i.p.
Ephedrine chloride
p.o.
i.p.
s.c.
Aconitum kusnezoffii
Pseudoephedrine
salicylate
Water extract
i.p.
p.o.
i.p.
Aconitum coreanum
Water and alcohol
extract
Guanfubase A
p.o.
712.6
4116.0
122.1 (731.1)
21.4
179.0
603.2
544.9
209.2
379.5
3.0
6.811
1.459
4.928
1.730 (1.653–
1.812)
28.1 (7 0.0)
2.1 (7 0.0)
19.6
2.052 (7 0.109)
s.c.
p.o.
p.o.
257.6 (7 0.0) (Mao et al., 1993)
1253.2 (7 0.1)
s.c.
0.0003 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.0005 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
17.4 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
0.0016
i.p.
i.v.
Aconitum
carmichaeli—processed
Fuzi
5.8 (7 0.0) (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.4 (7 0.0) (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
4.0 (Bai et al., 2009)
490.4
131.4 (71.9)
0.4217 (7 0.0225) (State Administration of TCM Chinese
Materia Medica Editorial Committee, 1998)
0.134 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.1855 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.0337 (70.0063) (State Administration of TCM Chinese
Materia Medica Editorial Committee, 1998)
15.0 (Singhuber et al., 2009)
192.4 (7 0.0) (Mao et al., 1993)
i.p.
i.v.
Guanfubase G
36.8 (Du et al., 2005)
124.0 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
112.0 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
43.0 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
78.0 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
0.6 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
1.400 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.300 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
1.013 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
0.3557 (0.3398–0.3724) (Cao et al., 2002)
3.8
Water extract
50% ethanol extract
of raw herb
50% ethanol extract
of steam-processed
herb
Aconitine
Mesaconitine
s.c.
Water extract
p.o.
0.652
0.902
0.164 (7 0.031)
73.0
936.2 (70.1)
0.0024
84.6
49
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Table 2 (continued )
Herbs
Extract/
constituent
Administration
method
Mice LD50 (g/kg, unless specified) and reference
HED (g/60 kg)
i.v.
17.1
152.0
Herb treated at
120 1C
Water/alcohol
extract
Water extract
p.o.
3.5 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
26.3 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
4100.0 (State Administration of TCM Chinese Materia
Medica Editorial Committee, 1998)
31.2 (Deng et al., 2010)
p.o.
7.2 (Chen et al., 2010a)
34.8
Water extract
p.o.
87.6
Water suspension
of raw monkshood
mother tubers
p.o.
18.0 (State Administration of TCM Chinese Materia Medica
Editorial Committee, 1998)
1.7 (Chen et al., 2011)
i.p.
Aconitum
carmichaeli—prepared
Aconitum carmichaeli Raw
Aconitum
carmichaeli—Chuanwu/Wutou
p.o.
127.9
4486.5
8.2
Key: p.o.—oral administration, i.v.—intravenous injection, i.p.—intraperitoneal injection, s.c.—subcutaneous injection. For extracts, powder of dry herbs, the dosage the
equivalent weight of dry herbs.
less than 5 g/kg; ‘‘Moderate Toxic’’ when LD50 is between 5 and
15 g/kg; ‘‘Mild Toxic’’ when LD50 is between 16 and 50 g/kg; ‘‘NonToxic’’ when LD50 values are greater than 50 g/kg herbs. These LD50
ranges for the corresponding classes are set higher than the United
Nations system since the dosage refers to the dry weight of herbal
medicines, rather than pure chemicals. This classification has
received support from recent publications in China (Sun et al.,
2012; Zhao and Ye, 2012). The mice oral LD50 of the water extracts
of five priority herbs, aristolochia, ephedra, coltsfoot, asarum,
aconite are: 146, 78, 124, 12–100, 6–18 g/kg, respectively
(Table 2). From this data, aristolochia, ephedra and coltsfoot can
be graded as ‘‘Non Toxic’’, while asarum can be graded as ‘‘Moderate
Toxic’’ to ‘‘Non Toxic’’, and aconite as ‘‘Moderate Toxic’’. These
classifications are similar to the classification in Chinese Pharmacopoeia. However, acute toxicity data from animal studies need to be
used with caution. As exemplified by aristolochia and ephedra
which are used for weight loss, new data on chronic toxicity from
preclinical studies and clinical reports must be considered to review
the classification regularly. Severe chronic nephrotoxicity has now
been well established in Aristolochia.
3.2.3. Preclinical and clinical data
Many systems are available to evaluate the level of evidence
and the impact of clinical studies, including methods used by the
Australian National Health and Medical Research Council
(NHMRC) and the TGA. The TGA system categorises clinical
evidence into ‘‘High’’, ‘‘Medium’’, ‘‘General’’ and ‘‘Supporting
Evidence’’ (Department of Health and Aging Therapeutic Goods
Administration, 2011a). The clinical evidence rankings often do
not include the preclinical studies which form the basis of clinical
studies and the dominant area of herbal medicine studies.
As clinical studies may be few or not available, it is important
to evaluate preclinical studies for their value in the efficacy and
safety of herbal medicine. Therefore, in this study, the ranking
system for the extended levels of scientific evidence based on the
TGA system proposed by Omar et al. (2010) was used to classify
published articles in English and Chinese for their toxicity
information on the 74 scheduled and toxic Chinese herbs.
Non-clinical safety testing is essential for regulatory purposes
and product development, and guidelines from the Organisation
for Economic Cooperation and Development and the International
Conference on Harmonisation and WHO have been developed and
can be applied to herbal medicines (UNICEF/UNDP/World Bank/
WHO Special Programme for Research & Training in Tropical
Diseases, 2004).
There are two main categories for the clinical data available—
published literature, such as systematic reviews, randomised
clinical trials and case reports, and the data from the government’s poison centres such as AAPCC in the United States. It is
important to take both categories into consideration for toxicity
evaluation as their data may not correspond to each other. Like
pharmaceutical drugs, preclinical studies are an essential part in
the evaluation and development of herbal medicine. Animal
studies attempt to mimic the clinical pharmacological situations,
and the cellular studies propose the efficacy and mechanism of
action of herbal medicines (Omar et al., 2010). Chemical studies,
including quality and quantitative analysis, provide information
on the composition and consistency of both pharmaceutical and
herbal preparations. Therefore, the importance of preclinical data
should not be neglected in determining the toxicity ranking of
herbs. For example, limits of toxic components, ‘not more than a
quantity’ are often included in monographs of pharmacopoeia.
Approximately 50% of the literature collected comprised of
Aristolochia, Asarum, Ephedra, Aconitum species, Tussilago farfara,
and their known toxic chemical constituents. Literature for these
herbal species was grouped according to the levels of scientific
evidence (Table 3).
It is clear that clinical evidence (level 1–3) carries more weight
than preclinical data (level 4–6). Final confirmation needs to
come from clinical evidence, particularly level 1 clinical evidence.
Most of the literature was ‘‘General’’, followed by ‘‘Animal
studies’’. ‘‘High’’ or ‘‘Medium’’ level of evidence was unavailable
for most of the species. Only two herbal medicines, Ephedra and
Asarum, showed some ‘‘High’’ and ‘‘Medium’’ level of evidence,
whereas the Ephedra species had 12 ‘‘High’’ and 4 ‘‘Medium’’ level
of evidence, and the Asarum species had 1 ‘‘Medium’’ level of
evidence. The number of actual toxicity cases counted from the
literature showed that Ephedra species, even though obvious
repeated reports and overlaps were disregarded, had the highest
frequency of the toxic responses, regardless of the actual severity
of toxicity. Toxic response to the herbal medicine or dietary
supplements containing ephedra totalling 15,423 cases were
reported from 47 literature sources dominated by reports from
USA. In contrast to the high number of ephedra toxicity reports,
no clinical toxicity was reported for Tussilago farfara.
3.3. Toxicity data of the priority herbs
The preclinical and clinical studies of Aristolochia species,
Asarum species, Ephedra species, Aconite species, Tussilago farfara,
50
Table 3
The clinical evidence and preclinical data available on the five priority herbs and representative references.
Herbs
Level 1 high (systematic
review, RCTs)
Level 2 medium
(comparative
studies)
Level 3 general (case reports
and series, traditional usage)
Level 4 animal studies (in vivo)
Level 5 cellular studies (in vitro)
Level 6 chemical
studies
Aristolochia fangchi
–
–
EN:105 cases, 1 literature
(Nortier et al., 2000)
EN: 2 studies, rats
(Liang et al., 2009)
EN: 1 study, kidney cells
(Cai and Cai, 2010)
EN: 1 study, AA
(Cai and Cai,
2010)
CN: 1 study, AA
(Jin et al., 2009)
EN:1 study, AA
Aristolochia
manshuriensis
Aristolochia debilis,
Aristolochia contorta
–
–
–
–
–
–
Aconitum carmichaeli
(Chuanwu & Fuzi)
CN: 1 systematic review
(Tang et al., 2008)
–
Aconitum kusnezoffii
Ephedra sinica, Ephedra
intermedia, Ephedra
equisetina
Asarum heterotropoides,
Asarum sieboldii
–
–
EN: 7 Systematic reviews,
5 RCTs (McBride et al.,
2004;
Pittler and Ernst, 2005)
EN: 4 Comparative
studies
(White et al., 1997)
–
EN: 1 comparative
study
(Hsieh et al., 2010)
CN: 18 cases, 2 literature
(Liu, 2010)
EN: 1case, 1 literature
(Lo et al., 2005)
CN: 1 study, mice, rats, dogs
(Wang and Zheng, 1984)
EN: 79 cases, 15 literature
(Liu et al., 2011b)
EN: 1 study, mice
(Chan et al., 1995)
CN: 510 cases, 74 literature (Cao
and Niu, 2004; He and He, 2000)
EN: 45 cases, 7 literature (Chan
et al., 1993a)
CN: 704 cases, 92 literature
(Diao et al., 2005; Fang, 2001)
EN: 15423 cases, 47 literature
(Woolf et al., 2005)
CN: 39 studies, rats, mice
(Chen et al., 2011; Han et al., 2007)
EN: 1 study, mice (Chan et al., 1995)
CN: 14 studies, rats, mice, rabbits (Bai
et al., 2009; He et al., 2007)
EN: 3 studies, rats, cats, mice
(Fields et al., 2003)
CN: 3 cases, 3 literature
(Fu, 1997; Wang and Liu, 1995)
CN: 1 study, rabbit (He et al., 2010)
EN: 1 case, 1 literature
(Yang et al., 2006)
CN: 19 studies, rats, mice, rabbit (Cai
et al., 2007; Fu et al., 2010)
CN: 1 study, calf renal fibroblast
(Ma et al., 2001)
EN: 1 study, kidney cells
(Wen et al., 2006)
CN: 1 study kidney cells
(Ma and Chen, 2007)
–
CN: 4 studies, neuron, lung cells, myocardial
cells, Caco-2 cells
(You et al., 2010)
CN: 1 study, bone marrow cells
(Cao et al., 2009b)
–
–
–
Aristolochic acids
–
–
Aconitines
–
–
Pseudoephedrine
–
–
CN: 967 cases, 33 literature
(Chen and Wang, 2001;
Dang et al., 2004)
CN: 6464 cases, 302 literature
(Luo, 2009; Luo and Xu, 2008;
Su and Yu, 2009)
–
Key: CN: Chinese language literature; EN: English language literature; AA: Aristolochic acids.
CN: 2 studies, AA
(Jin and Zhou,
2007)
EN:1 study
(Lu et al., 2010)
CN: 15 studies
(Zhu et al., 2011)
CN: 1 study
(Liu et al., 1987)
EN: 2 studies, erythrocytes, neuron cells (Lee –
et al., 2000; Ling et al., 1995)
–
CN: 9 cases, 8 literature
(Chen and Cai, 2001;
Chen, 2007)
Tussilago farfara
CN: 14 studies
(Cao et al., 2009a)
CN: 5 studies
(Liu et al., 2011a;
Xu et al., 2008)
EN: 2 studies, rats (Chou and Fu, 2006) –
CN: 1 study, mice (Zhang et al., 2008)
CN: 29 studies, rats, mice (Dong et al., CN: 13 studies, HK-2, HUVECs, LLC-PK1,
L5178Y, NRK-52E (Chen et al., 2003; Yu et al.,
2011; Wang et al., 2007)
2011)
CN: 16 studies, rats mice, dogs, rabbit, CN: 7 studies, granulose cells, myocardial cells
(Li et al., 2010c)
macaque (Lei et al., 2006; Lei et al.,
2004)
CN: 2 studies, rats, mice
–
(Cao et al., 2002; Sun et al., 2006)
EN: 1 study
(Zhao et al., 2008)
CN: 17 studies
(Chen and Wang,
2009;
Liu and Yin, 2010)
–
CN: 29 studies
(Liu et al., 2010;
Xu et al., 2008)
CN: 15 studies
(Li and Jiang,
2010)
–
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Aristolochia mollissima
EN: 52 cases, 2 literature
(Shaohua et al., 2010)
CN: 230 cases in 60 literature
(Hao et al., 2003; Mo, 2007)
EN: 1 case, 1 literature
(Levi et al., 1998)
CN: 13 studies, rats, mice
(Hu et al., 2003)
EN: 10 studies, rats, mice
(Hu et al., 2004; Liu et al., 2003)
CN: 32 studies, rats, mice
(Lin et al., 2010)
CN: 1 study, rat (Zhu et al., 2002)
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
51
Fig. 1. Chemical structures of the main toxic chemical constituents in the five priority herbs. Aristolochic acid A, aristolochic acid B from aristolochia and asarum;
ephedrine and pseudo-ephedrine from ephedra; aconitine, mesaconitine, hypaconitine from aconite, and senkirkine and senecionine from coltsfoot.
and their known toxic chemicals were evaluated below to provide
supporting information for the recommended toxicity scheduling.
The chemical structures of the main toxic chemical constituents
of selected scheduled and toxic Chinese herbs are shown in Fig. 1.
Senkirkine and senecionine are the pyrrolizidine alkaloids found in
Tussilago farfara (Jiang et al., 2009), and ephedrine and pseudoephedrine are the main active compounds in Ephedra species (Woolf
et al., 2005). These chemicals are known to be responsible for the
toxic response of the corresponding herbal species.
3.3.1. Aristolochia
3.3.1.1. Aristolochic acids. The study by Yuan et al. (2011)
compared the toxicity of aristolochic acid and tetrandrine (from
Stephania tetrandra S Moore) in mice and Madin–Darby canine
kidney (MDCK) cells. The results showed that tetrandrine is more
potent than aristolochic acid in inhibiting MDCK cell growth.
However, aristolochic acid was more nephrotoxic than tetrandrine
in mice, presenting elevated blood urea nitrogen and increased renal
tubular injuries. Other rodent (Mengs, 1987; Debelle et al., 2003,
2002; Cheng et al., 2006;; Shibutani et al., 2007; Yeh et al., 2008) and
rabbit studies (Cosyns et al., 2001; Chen et al., 2007) demonstrated
the nephrotoxic effects of aristolochic acid. Interestingly, the results
from Yeh et al. (2008) showed that aristolochic acid B (AA-B)
induced kidney and liver dysfunction, while Shibutani et al. (2007)
concluded that aristolochic acid A (AA-A) was solely responsible for
the nephrotoxicity effects. Li et al. (2010a) determined and compared
the cytotoxic effects of AA-A, and aristolactam I, the main metabolite
of AA-A, on cells of the human proximal tubular epithelial cell line.
The proliferation of cells was inhibited in a concentration and timedependent manner and apoptosis was observed, with the cytotoxic
potency of aristolactam I higher than that of AA-A. Huljic et al. (2008)
demonstrated that aristolochic acid lead to cytotoxic responses in
human, rat and porcine cells in vitro. The study by Chen et al. (2010c)
revealed oxidative DNA damage and DNA repair suppression by
aristolochic acid in human kidney proximal tubular cells, suggesting
the involvement of the down-regulation of the DNA repair gene
expression as a possible mechanism for aristolochic acid-induced
mutagenesis and carcinogenesis. The mutagenic and carcinogenic
ability of aristolochic acid has been disclosed in other studies (Arlt
et al., 2002, 2007; Kohara et al., 2002; Schmeiser et al., 1990, 2009).
The case report mentioned earlier from Australia (Chau et al.,
2011) suggested the chronic usage of aristolochic acid-containing
herbal product as the most likely cause of the patient’s death from
severe nephropathy. Laboratory investigations and renal biopsy
revealed renal failure, with a markedly increased serum creatinine
and urea levels, tubulointerstitial fibrosis and atrophy. Similar
manifestations were observed in a number of cases in Taiwan and
Japan. A case report by Hong et al. (2006) showed that a 10-year-old
boy was manifested with Fanconi’s syndrome and progressive renal
failure from chronic ingestion of Chinese herbs containing aristolochic acids. Yang et al. (2002) also reported a case of aristolochic
acid-induced Fanconi’s syndrome and nephropathy. Similar cases
52
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
were reported in Japan (Kazama et al., 2004; Fujimura et al., 2005).
A case series study (Chang et al., 2001) from a hospital in Taiwan
revealed that the renal biopsy of patients with progressive renal
failure of unknown origin shared strikingly similar histological
patterns to Chinese herb nephropathy from aristolochic acids, such
as extensive paucicellular interstitial fibrosis and tubular atrophy. A
case-control study by Lai et al. (2010) demonstrated that the
consumption of aristolochic acid-containing Chinese herbal products
is associated with an increased risk of cancer of the urinary tract in a
dose-dependent manner, and a similar result was observed in a
cohort study by Li et al. (2008). Yang et al. (2009) suggested that
Chinese herbal medicine, which often contains aristolochic acids,
could be linked to the increased risk of urological cancer in herbalists.
3.3.1.2. Aristolochia contorta. The study by Wen et al. (2006)
demonstrated the cytotoxicity of other phenanthrene derivatives
extracted from Aristolochia contorta in the human proximal tubular
epithelial cell line HK-2. AA-A 7-methoxy-aristololactam IV and
aristololactam IVa showed cytotoxic activity in HK-2 cells in both
the MTT assay and LDH leakage assay (po0.01). The cellular
morphologic assessments suggested that the interactions with cell
membrane and intracellular structures such as lysosome and
mitochondria were likely to be involved in cell injury induced by
these three compounds. The study concluded that the potency of the
cytotoxic activity of aristololactam IVa and 7-methoxyaristololactam IV was similar to or even stronger than that of AA-I.
3.3.1.3. Aristolochia debilis. The case report by Levi et al. (1998)
showed the possibility of Aristolochia debilis roots as the cause for
acute hepatitis. The patient was diagnosed with acute hepatitis
from the symptoms, presenting signs and the laboratory tests.
The patient had been taking a Chinese herbal tea consisting of
several herbal species, including Aristolochia debilis roots. The
report concluded that the acute hepatitis as described in this
patient was most likely caused by the active ingredients of the
Chinese herbal tea.
3.3.1.4. Aristolochia fangchi. Animal studies were conducted to
demonstrate the toxicity of Aristolochia fangchi on rats (Liang
et al., 2009, 2010). The metabonomic profile and the renal
histopathological changes showed that Aristolochia fangchi can
induce renal and liver lesion, and its severity dependent on its
continual administration. Cai and Cai (2010) isolated five
aristolochic acid compounds from the roots of Aristolochia
fangchi and investigated their toxicities. The results showed that
aristolochic acids from the ethanol extract of Aristolochia fangchi
roots had strong cytotoxic activity against LLC-PK1 cells, and that
AA-A had a higher toxicity level than the other aristolochic acid
compounds present in the herb.
A nested case-control study (Yang et al., 2011) was conducted
in Taiwan to show the relationship between the occupational
exposure to the aristolochic acids and the risk of developing
chronic renal disease in Chinese herbalists. The study found that
processing, selling or dispensing herbal medicines containing
Aristolochia fangchi, living in the workplace and a history of herbal
medicines containing Aristolochia fangchi was significantly associated with renal failure. Another case study carried by Martinez
et al. (2002) showed that the relationship between the cumulative dose of Aristolochia fangchi and the renal failure progression
rate confirms that the regular ingestion of the Aristolochia species
is causally involved in the onset of chronic interstitial nephropathy leading to End-Stage Renal Disease (ESRD). Other studies
(Nortier et al., 2000; Nortier and Vanherweghem, 2002) demonstrated that the histological analysis of the tissue samples from
the patient with ESRD suggested the strong relationship between
the aristolochic acid from Aristolochia fangchi and the development of renal interstitial fibrosis and urothelial cancer in human.
3.3.1.5. Aristolochia manshuriensis. The animal study by Xue et al.
(2008) showed that the mice group fed with the water extract of
Aristolochia manshuriensis for 28 days resulted in significantly
decreased body weights and obvious nephropathy at doses
higher than 0.24 g/kg per day. The study concluded that the
no-observed-adverse-effect level (NOAEL) for Aristolochia manshuriensis for mice was 0.06 g/kg per day which was equivalent to
0.25 times the normal human dose in clinical prescription.
A study using an extract containing aristolochic acid in mice,
Ding et al. (2005) demonstrated that kidney and liver toxicity was
equivalent to 4.5 mg/kg and 25 mg/kg, respectively. The results
suggested that Aristolochia manshuriensis caused renal and liver
toxicity, and the dose leading to nephrotoxicity is much lower
than hepatotoxicity. In the study by Qiu et al. (2000), rats were
administered with high doses of Aristolochia manshuriensis for
7 days and this induced acute renal failure and the development
of tumours. Ye et al. (2002) demonstrated that the rat group given
an Aristolochia manshuriensis decoction at the dose three times
higher than the recommended dosage in the Chinese
Pharmacopoeia showed higher urinalysis levels; the pathological
changes of renal mesenchyme and the degree of glomerulosclerosis were more destructive than the control group.
The animal studies suggested that low to high doses of
Aristolochia manshuriensis can result in varying degrees of renal
damage. Lin et al. (2010) also demonstrated that the long-term
use of Aristolochia manshuriensis extract resulted in renal function
and morphological changes in rats, which correlated with the
time and dose of the extract used, and may be independent to the
plasma aristolochic acid A concentration. Pan et al. (2010)
demonstrated that certain processing methods can reduce the
content of aristolochic acids in Aristolochia manshuriensis and
lessen the nephrotoxicity of aristolochic acids.
A retrospective study carried by Li et al. (2001) investigated the
clinical and pathological characteristics of Aristolochia manshuriensisinduced tubulointerstitial nephropathy, and analysed the relationship to renal function decline and clinical prognosis. The common
clinical symptoms included fatigue, polyuria and nocturia, usually
accompanied by renal tubular dysfunction with or without an
elevated serum creatinine level. The pathological analysis revealed
severe degradation, necrosis and collapse of the renal epithelial cells
leaving the basement membrane exposed. The study concluded that
Aristolochia manshuriensis-induced tubulointerstitial nephropathy
was mainly related to overdose or long-term administration of
Aristolochia manshuriensis, and should be avoided. Similarly, Yang
et al. (2005) suggested that marked peritubular capillary injury, as
seen in the histopathological evaluation of Aristolochia manshuriensis-induced acute tubular necrosis, could be one of the causes for the
continuously progression of tubulointerstitial damage. Other case
reports (Shaohua et al., 2010; Yu et al., 2003) also supported that
Aristolochia manshuriensis intake may cause renal failure.
3.3.1.6. Aristolochia mollissima. The case reported by Lo et al.
(2005) suggested that the ingestion of Aristolochia mollissima
may be the cause of nephropathy in a patient with longstanding Crohn’s disease. The biochemical analysis of the
patient’s renal biopsy resembled that of the aristolochic-acidnephropathy. Transitional cell carcinoma was diagnosed five
months after ingestion of the herb, and the patient had endstage renal failure 12 months after taking the herb.
Aristolochia species were included in the Chinese Pharmacopoeia (Chinese Pharmacopoeia Commission, 2010) up until 2003
when the prohibition was imposed on certain species such as
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
53
Aristolochia manshuriensis (State Food and Drug Administration,
2003, 2004). Although the toxicity of Aristolochia debilis and
Aristolochia contorta in the Chinese Pharmacopoeia are graded at
a ‘‘Caution’’ level, there is no prohibition of their use. Despite the
long history of usage, the evaluation of clinical and preclinical
data shows that the severity of Aristolochia toxicity outweighs its
therapeutic benefits. The cumulative toxicity caused by aristolochic acids includes irreversible life-threatening conditions such
as nephropathy. A number of aristolochic-acid-nephropathy cases
have been reported from different parts of the world, and
preclinical studies have clearly demonstrated the severe acute
and chronic toxic effects of Aristolochia. Based on the overall
evaluation of scientific research data against the toxicity criteria,
Aristolochia species should be internationally prohibited for medicinal use.
structure injury and function, energy metabolic disturbance,
internal milieu disorder and the change of neurotransmitters
release. Other cellular studies (Li et al., 2010b; Wang et al., 2008)
revealed that aconitine blocks the K þ channels, thereby causing
arrhythmias in aconitine intoxication.
Two case reports (Ohuchi et al., 2000; Yoshioka et al., 1996)
explained the accidental aconitine poisoning following the ingestion of aconite mistaken for other edible plants. Patients developed ventricular tachycardia and fibrillation, however, the former
case died from brain oedema within six days of the herb ingestion, and the patient from the latter case was saved by cardiopulmonary bypass. Ohno et al. (1992) reported a patient who died
due to ventricular fibrillation from aconite poisoning. Aconitine,
mesaconitine and hypaconitine were detected from the frozen
blood sample of the patient.
3.3.2. Asarum
3.3.3.2. Aconitum carmichaeli. Chan et al. (1995) demonstrated
that the water decoction of Aconitum carmichaeli induced dosedependent histopathological changes in the liver and kidney, but
not in the heart and gonad, in mice. While there were no
observable changes at the dose of 1 mg herb/25 g body weight,
abnormal histopathological changes and the damaging effects
were observed at 5 and 10 mg herb/25 g body weight, with the
dramatic changes at higher doses. The study by Liou et al. (2005)
compared the antinociceptive action of raw and processed
Aconitum carmichaeli roots (Fuzi) with three different methods:
salt treatment, stir-frying and sulfur treatment, at a dose range of
20–60 mg/kg on mice. Although the aconitine concentrations
were significantly lower in processed roots and the analgesic
effects were lower than those produced by raw roots at the same
dose, a higher oral LD50 was found for all of processed roots, and
the analgesic effects of salt treated roots were similar to that of
the crude Fuzi. The chemical analysis of processed Aconitum
carmichaeli roots (Lu et al., 2010) also demonstrated that the
total amount of toxic constituents, aconitine, mesaconitine and
hypaconitine were substantially reduced to as low as 3.91% of the
value in the raw sample.
A retrospective study by Liu et al. (2011b) outlined seven
forensic cases of aconite poisoning in China between 1999 and
2008, where six cases occurred after the ingestion of homemade
medicated liquor containing aconite, and one case following
ingestion of a TCM containing Aconitum carmichaeli. The study
concluded that particular attention should be paid to aconite
usage due to its powerful therapeutic and poisonous characteristics. Other cases of aconite poisoning from consumption
(Tai et al., 1992; Fujita et al., 2007; Lin et al., 2011; Dhesi et al.,
2010) reported cardiotoxicity including ventricular tachycardia
and fibrillation, with a number of deaths resulting from severe
cases. Dickens et al. (1994) reported two cases of aconitine
poisoning from the consumption of herbal preparations containing aconite roots in quantities greatly exceeding the maximum
recommended dosage from the Chinese Pharmacopoeia. Patients
experienced ventricular tachycardia and fibrillation, followed by
cardiac arrest and death within 12 h of ingestion. Tachyarrhythmia (But et al., 1994), bradycardia and hypotension (Chan, 2009)
were also reported in other cases.
3.3.2.1. Asarum heterotropoides/Asarum sieboldii. A chemical study
was undertaken by Zhao et al. (2008) to assess the levels of
aristolochic acid A using liquid chromatography–mass spectrometry
in different medicinal parts of Herba Asari (Xixin) and some patent
Chinese medicines containing it as an ingredient. The results showed
that the aerial parts of the herb contained a higher level of
aristolochic acid A than the roots, and the methanolic extracts
typically contained more aristolochic acid A compared to the water
extracts. The patent Chinese medicines containing Herba Asari had a
negligible amount of AA-A. The study concluded that the decoction of
the root portion of Herba Asari is recommended for usage.
Yang et al. (2006) reported a case of a male patient who
displayed subacute renal failure induced by ingestion of a herbal
powder containing Xixin. The report suggested that care needs to be
taken in the future to identify the aristolochic acid concentration of
different components of Xixin, and Xixin-containing aristolochic
acid should be forbidden in remedies. However, a retrospective
study by Hsieh et al. (2010) demonstrated that no renal tubular
damage, no severe incidences of adverse events and adverse drug
reactions were observed in 71 eligible patients taking a traditional
Chinese herbal formula called ‘‘Duhuo Jisheng Tang’’, which contained Xixin for four weeks. Since 1965, there have been seven cases
reported on the acute toxic reactions from the misuse of Asarum,
and the clinical manifestations featured includes heart failure
(Liu et al., 1995), heart arrhythmia (Jiang, 1965; Pan et al., 2001;
Chen, 2007), unconsciousness and high fever (Jiang, 1965), headache
and vomiting (Chen and Cai, 2001), central respiratory inhibition
and the acute liver and kidney lesions (Long et al., 1999). All the
cases were cured and death had not occurred.
Although Asarum species are in Aristolochiaceae family, the
toxicity of Asarum is much lower than that of the Aristolochia
species, and Asarum has been graded to show ‘‘No Toxicity’’
(Table 1) in the Chinese Pharmacopoeia. Asarum also contains
aristolochic acids, however, from the literature evaluation, there
has been only eight cases of Asarum-related aristolochic acid
toxicity reported over approximately 45 years, which relates to
the overdose of the herbs. Preclinical chemical study evaluation
also concluded that the amount of aristolochic acid in the patent
form of the herbs was negligible, and the decoction of the root
part of Asarum is recommended for use, which agrees with TCM
usage (Chinese Pharmacopoeia Commission, 2010).
3.3.3. Aconite
3.3.3.1. Aconitine. Peng et al. (2009) demonstrated that aconitine has
neurotoxic effects on the neuron cells of Sprague-Dawley rats, causing time-dependent pathological changes including biomembrane
3.3.3.3. Aconitum kusnezoffii. In a study by Chan et al. (1995), a
water decoction of Aconitum kusnezoffii caused dose-dependent
histopathological changes in the liver and kidney of mice. Clinical
case situations (Chan et al., 1993b, 1994; Chan and Critchley,
1994; Chan, 2002) demonstrated aconitine poisoning from Aconitum
kusnezoffii consumption. Three fatal cases of tachyarrhythmia
(But et al., 1994) were reported to be due to the poisoning from
aconites derived from the rootstocks and lateral root-tubers of
54
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Aconitum carmichaeli and the rootstocks of Aconitum kusnezoffii.
The report by Chan (2009) explained the toxic effect of the
combination of Aconitum kusnezoffii and Aconitum carmichaeli
overdose as bradycardia and hypotension. The patient had taken
11 g of the herbs while the recommended clinical dosage
is 1.5 to 3 g. The report suggested that the correct dose of
processed Aconitum kusnezoffii and Aconitum carmichaeli would
not result in bradycardia as the toxicity of aconite reduces
markedly with processing.
The toxicity of Aconitum is mainly derived from the diester
diterpene alkaloids (DDAs) including aconitine, mesaconitine
and hypaconitine. The most common toxicity is cardiotoxicity
(Li et al., 2010c), which is the main contributing cause of death.
Traditionally, aconite has been used only after it has been
processed which reduces its toxicity (Chinese Pharmacopoeia
Commission, 2010) and the raw aconite is strictly regulated
(The State Council of the People’s Republic of China, 1988; The
Hong Kong Government, 1999). From the literature evaluation, a
number of aconite-related severe toxicity or death reports have
been disclosed, and animal studies also showed that aconite
causes histopathological changes in organs. Clinical and preclinical data has shown that the toxicological risk of improper usage of
Aconitum species remains very high as the toxic dosage of raw
aconitum is very close to the therapeutic dosage. Chan (2002) also
demonstrated that the annual incidence of aconitine poisoning
showed a marked decrease with the introduction of publicity
measures from healthcare officials to the public and herbalists.
Thus, raw aconitum should be prohibited and processed aconitum
should be restricted only for medicinal usage by registered TCM
practitioners.
Quality standards of all aconite have been established in the
Chinese Pharmacopoeia (2010). The upper limit of DDAs for processed aconite main root (Aconitum carmichaeli, Chuanwu) is 0.04%,
and processed aconite lateral root (Aconitum carmichaeli, Fuzi) is
0.01% (Chinese Pharmacopoeia Commission, 2010). We recommend
that all aconite species and products undergo quality testing against
DDAs content before releasing to TCM practitioners.
3.3.4. Ephedra
3.3.4.1. Ephedra sinica and ephedrine. An animal study by Dunnick
et al. (2007) compared the cardiotoxic effects of pure ephedrine
compound to that of Ephedra sinica (Mahuang) extract. It was
demonstrated that the cardiotoxic effects of Ephedra sinica, such
as haemorrhage, necrosis and degeneration in the ventricles or
interventricular septum, was similar to that of ephedrine.
Comparable results were demonstrated by Nyska et al. (2005)
with 25 mg/kg of ephedrine. Ephedrine has been demonstrated to
inhibit platelet aggregation (Watson et al., 2010). The study by
Fields et al. (2003) showed that Ephedra sinica has significant
vasoconstrictor activity in the pulmonary vascular bed of the cat.
The study suggested that herbal supplements with Ephedra sinica
may contribute to pulmonary hypertensive pathophysiologic
states, and must be used with caution due to its capacity to
increase systemic and pulmonary vascular pressures.
The cardiotoxic effect of ephedra extract was investigated
using a rabbit model system. Ephedra altered the heart function,
showing abnormal cardiogram patterns and increased enzyme
activities, and damaged myocardial tissue structure in a dosedependent manner (He et al., 2010). Sun et al. (2006) demonstrated the toxic effects of pseudoephedrine using pregnant SD
rats. The study concluded that pseudoephedrine was considered
to have maternal toxicity, embryo toxicity and teratogenic effects
in the rats.
A number of systematic reviews (Shekelle et al., 2003; Miller,
2004; Pittler and Ernst, 2004, 2005; Pittler et al., 2005; Ulbricht
et al., 2008; Hasani-Ranjbar et al., 2009) showed that the use of
Ephedra sinica and ephedrine-containing dietary supplements
resulted in various adverse events. The adverse events ranged
from dry mouth, nervousness, insomnia and palpitations, to
cardiovascular events and, although rare, some fatalities
(Hackman et al., 2006). In a recent randomised, double-blinded,
placebo-controlled study, Chen et al. (2010b) examined the acute
effects of ephedra on autonomic nervous modulation by means of
heart rate variability analysis. The results showed that the
ingestion of Ephedra sinica dry extracts could increase the heart
rate and dose-dependently shift the sympathovagal balance
towards the enhanced sympathetic activity, while impairing
parasympathetic activity. Another randomised, double-blinded,
placebo-controlled study (Haller et al., 2005) demonstrated that
the consumption of ephedra and guarana supplements following
the instruction label resulted in persistent increases in heart rate
and blood pressure and unfavourable actions on glucose and
potassium homeostasis.
Woolf et al. (2005) compared the toxicity from botanical
products containing ephedra to non-ephedra products. This
comparative study showed that the ephedra-containing botanical
products accounted for a significant number of toxic exposures,
with severe medical outcomes reported to poison centres. Hazard
rate analysis suggested that ephedra-containing botanical products were much more likely to result in severe medical outcomes than those not containing ephedra. The review by
Mehendale et al. (2004) demonstrated the significant number of
adverse effects associated with ephedra-containing dietary supplements in various parts of the body system and organs, including nervous, digestive, endocrine, urinary and cardiovascular
systems. Similarly, a pilot study (Haller et al., 2002) showed that
young healthy adults can have significant cardiovascular
responses and central nervous system effects after a single dose
supplement labelled to contain 20 mg ephedrine.
A number of case reports suggested the use of Ephedra sinica
and ephedra-containing dietary supplements as the cause of
various adverse events. Some of the reported events included
cardiovascular events (Zaacks et al., 1999; Chen et al., 2004;
Peters et al., 2005; Flanagan et al., 2010; Martinez-Quintana et al.,
2010), hepatotoxicity (Skoulidis et al., 2005; Schoepfer et al.,
2007), gastric mucosal injury (Lillegard and Porterfield Jr, 2010),
neurotoxicity (Varlibas et al., 2009) and transient blindness
(Moawad et al., 2006). Another three cases reported the acute
toxic reactions of ephedra use caused by the overdose consumption (Wang and Liu, 1995; Fu, 1997; Dan and Sun, 2001).
The clinical manifestations featured arrhythmia, unconsciousness,
convulsion and even death.
In contrast, two randomised double-blinded clinical trials
(Boozer et al., 2002; Kim et al., 2008) suggested that there were
no significant adverse events from the ingestion of Ephedra sinica
compared to the control group at the end of 6 months study
(Boozer et al., 2002) and 8 weeks study (Kim et al., 2008),
respectively. A two-phase study by White et al. (1997) demonstrated that the effect of Ephedra sinica on blood pressure changes
were statistically insignificant. Although there were few participants whose heart rate increase met statistical significance, there
were no symptoms of tachycardia or palpitations described by the
participants.
Ephedra is one of the oldest herbs that had been used in China
for the treatment of various respiratory conditions. In Chinese
Pharmacopoeia, its toxicity grade states that it has ‘‘No Toxicity’’
and only three ephedra-related poisoning cases caused by overdose consumption were retrieved from the Chinese language
literature. The correct application of the herb for thousands of
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
years has disclosed that it is a safe medicinal herb in clinical
practice. Currently, almost all of the poisoning cases are reported
in English language journals, where the causes of the poisoning
include overdose and/or long-term consumption of the herb or
preparation containing ephedrine without the supervision of
qualified healthcare professionals. Only seven preclinical studies
demonstrated the cardiotoxic effects of ephedra. As ephedra
contains ephedrine which may cause cardiotoxicity, ephedra
should be restricted for medicinal usage and prescribed by
registered TCM practitioners.
3.3.5. Tussilago farfara
The study by Chou and Fu (2006) demonstrated that the DHPderived DNA adducts, formed by the metabolism of a series of
tumorigenic pyrrolizidine alkaloids, are formed in the liver of
female rats gavaged with Tussilago farfara extract. These DHPderived DNA adducts have been proposed as potential biomarkers
of pyrrolizidine alkaloid tumorigenicity, as well as pyrrolizidine
alkaloid exposure. An animal study carried out by Hirono et al.
(1976) also suggested that the carcinogenicity of Tussilago farfara
was most likely due to a hepatotoxic pyrrolizidine alkaloid.
Zhang et al. (2008) showed the hepatotoxic effects of total
alkaloids and senkirkine isolated from Tussilago farfara by demonstrating their ability to increase the levels of glutamic-pyruvic
transaminase (GPT), glutamic-oxaloacetic transaminase (GOT)
and total bilirubin in the serum of mice, and the histopathologic
examination of the injured liver. However, compared with the
control group, the mice group given with aqueous extract of
Tussilago farfara did not show the damage in the liver.
A recent study by Edgar et al. (2011) discussed the potential
health issues of pyrrolizidine alkaloids in human. The major
potential disease outcomes were hepatic veno-occlusive disease
and cirrhosis. With the growing pyrrolizidine alkaloid-containing
herbal remedies and supplements usage, low-level dietary exposure over an extended period could cause cancer and pulmonary
hypertension rather than liver damage. Similar health issues
regarding the pyrrolizidine alkaloid intake were raised in other
studies (Stewart and Steenkamp, 2001; Fu et al., 2004), where the
consequent hepatotoxicity from the alkaloid was shown to be
dose-dependent. The studies explained that the toxicity of different pyrrolizidine alkaloids is proportional to the fraction of
alkaloid that is converted to pyrrole, the rate of conversion, and
the chemical reactivity of the pyrrole produced. Due to the
paucity of data in human toxicity, further investigations in clinical
outcomes and the restrictions in pyrrolizidine intake were
suggested.
Tussilago farfara has been used for thousands of years for the
effective treatment of acute and chronic cough with or without
profuse sputum or haemoptysis, and is known to be ‘‘Non Toxic’’
(Chinese Pharmacopoeia Commission, 2010). There were no
Tussilago farfara-related poisoning cases retrieved from the
English and Chinese language literature in this study. Preclinical
data show that the theoretical p.o. HED value of water extract is
603.2 g/60 kg, indicating a low acute toxicity. However, the herb
contains pyrrolizidine alkaloids and the potential adverse effects
should be taken into the consideration. Therefore, the herb should
be used under the supervision of a registered TCM practitioner
and requires a warning label.
55
Sub-classification of Class 1 and Class 2 may be useful for further
detailed regulations of the herbs, for example, some herbs in Class
2.1 may be available with the registered Chinese medicine
practitioner’s prescription, while herbs in Class 2.2 and 2.3 may
be available to the Chinese herbal dispensers for sale. This system
is similar to the SUSMP scheduling of Australia, where the
medicine in S3 is ‘‘Pharmacist Only Medicine’’ and the medicine
in S4 is ‘‘Prescription Only Medicine’’. Subclasses of Class 1 can be
used to distinguish the acute and the chronic toxicities of herbs.
Class 1. Prohibited for medicinal usage, is for the most toxic herbs.
The Subclass 1.1, Not for Medicinal Usage due to chronic toxicity, is
equivalent to Schedule 9 of the SUSMP for the herbs that should
not be taken as accumulated intoxication, or poisoning may cause
irreversible life-threatening lesion. Aristolochia species are examples of the Subclass 1.2 as they have been shown to cause
cumulative irreversible toxicity. Subclass 1.2, Extremely Toxic, is
for very toxic herbs which cannot be taken internally, including
raw Aconitum species, currently strictly regulated in Australia,
China and Hong Kong.
Class 2. Restricted for medicinal usage, registered TCM practitioners
only, equivalent to SUSMP 1, is for toxic herbs with a narrow to
wide margin between the therapeutic dose and the toxic dose,
and cause different severity of clinical manifestations of intoxication. Class 2 is subdivided into 2.1, 2.2 and 2.3 for more precise
classification of the toxic herbs, based on their severity on clinical
toxicity and the degree of differences between therapeutic and
toxic doses. 2.1 Highly Toxic: Very toxic herbs. The toxic dosage is
very close to the therapeutic dosage; over-dose can cause toxic
reaction or death. 2.2 Moderate Toxic: moderate toxic herbs. The
toxic dosage is close to therapeutic dosage; over-dose can cause
toxic reaction or death. 2. 3 Mild Toxic: mild toxic herbs. The toxic
dosage is much larger than the therapeutic dosage; over-dose can
cause toxic or adverse reactions.
From the preclinical data and clinical evidence analysed above,
processed Aconitum species such as Chuanwu, Caowu and Fuzi have
been shown to cause serious toxic responses or death. The
therapeutic dose and the toxic dose is close, hence they must be
prescribed by a registered practitioner only and are recommended
to be in Subclass 2.1, and 2.2. Ephedra species can be allocated in
Subclass 2.3 as their toxic dosage is much larger than therapeutic
dosage, and misusage or overdose can cause adverse reactions.
Although Asarum sieboldii contains aristolochic acid, unlike other
Aristolochia species in Subclass 1.1, it is included in the Chinese
Pharmacopoeia (Chinese Pharmacopoeia Commission, 2010). The
amount of aristolochic acid has been demonstrated to be significantly lower in Asarum species (Zhao et al., 2008), and the toxic
dose is much higher than therapeutic dose. Furthermore, there are
no Asarum human-associated toxicity reports in China. Asarum is
graded in Subclass 2.3.
3.4. Scheduling of Chinese herbal medicines
Class 3. Required warning label, advising the usage to be supervised under a qualified expert in herbal dispensing; significant
evidence suggests over-dose or misuse can potentially cause a
mild toxic or adverse event. The following labelling is recommend: ‘‘To be used only under the supervision of an expert
qualified in the appropriate use of this substance’’. One of the
examples is Tussilago farfara which has significantly high LD50
values, with no reported clinical toxicity in China, and Tussilago
farfara has been used for thousands of years.
A scheduling system has been proposed for Chinese herbal
medicines based on the evaluation of all the levels of preclinical
data and clinical evidences. The system is composed of four
classes with subclasses for Class 1 and Class 2 (Fig. 2, Table 4).
Class 4. Over-the-counter herbs, is for the herbs that are safe
enough to be sold over the counter. For example, Panax ginseng is
one of most commonly used herbs and was the second highest
selling herbal supplement in the United States in 2000 (Coon and
56
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
Evaluation criteria
Regulatory class
1. Prohibited for medicinal
• Risk-benefit
usage: aristolochia
analysis
• Severity of toxic
Literature review
2. Restricted for medicinal
usage: aconite, asarum,
effects
ephedra
• Clinical data
3. Required warning label:
• Preclinical data
4. Over-the-counter herbs
coltsfoot
Fig. 2. A flowchart for evaluation and scheduling of Chinese herbs.
Table 4
Scheduling of Chinese herbal medicines.
Toxicity class
Toxicity subclass
Example
1.1. Not for medicinal usage due to chronic toxicity. Accumulated
Aristolochia fangchi, Aristolochia manshuriensis, Aristolochia
Class 1
Prohibited for medicinal intoxication/poisoning may cause irreversible life-threatening lesion heterophylla, Aristolochia mollissima, Aristolochia cinnabarina,
Aristolochia kaempferi, Aristolochia yunnanensis, Aristolochia calcicola,
usage
Aristolochia debilis, Aristolochia contorta
1.2 Extremely toxic: Very toxic and cannot be taken internally
Raw Aconitum species: Aconitum brachypodum, Aconitum bullatifolium,
Aconitum carmichaeli, Aconitum coreanum, Aconitum kusnezoffii
2.1 Highly toxic: Very toxic. The toxic dosage is very close to the
Processed Aconitum species: Processed Chuanwu (Aconitum
Class 2
carmichaeli), processed Caowu (Aconitum kusnezoffii)
Restricted for medicinal therapeutic dosage, over-dose can cause toxic reaction or death.
2.2 Moderate toxic: Moderate toxic, the toxic dosage is close to
Processed Aconitum species: Processed Fuzi (Aconitum carmichaeli)
usage, registered TCM
therapeutic dosage, over-dose can cause toxic reaction or death.
practitioners only.
2. 3 Mild toxic: mild toxic, the toxic dosage is much larger than the Ephedra sinica, Ephedra intermedia, Ephedra equisetina; Asarum
therapeutic dosage, over-dose can cause toxic or adverse reactions. sieboldii
Tussilago farfara
Class 3
Mild toxic, significant evidence suggest over-dose or misuse can
Required warning label potentially cause adverse event. The following labelling is
recommended: ‘‘To be used only under the supervision of an expert
qualified in the appropriate use of this substance’’
Class 4
Non-toxic
Panax ginseng
Over-the-counter herbs
Ernst, 2002). It has many significant therapeutic benefits and is
not regarded as a toxic herb in Australia and many other
countries. This aspect of Panax ginseng makes it easy to market
as an over-the-counter medicine or dietary supplement, or even
as a confectionery. A number of systematic reviews (Coon and
Ernst, 2002; Seely et al., 2008; Hasani-Ranjbar et al., 2009; Lee
and Son, 2011) analysed the efficacy and safety of Panax ginseng.
According to the clinical trial data, monopreparations of ginseng
generally has a good safety profile with low incidence of adverse
events. Even when the adverse events such as headache and
gastrointestinal disorders were observed, similar events were also
observed in the placebo group (Coon and Ernst, 2002). Seely et al.
(2008) showed that the use of ginseng in pregnancy did not result
in any adverse events; however, it was advised that Panax ginseng
should be consumed with caution during pregnancy and lactation
to prevent any risks. Therefore, for the majority of Chinese herbal
medicines currently available over-the-counter, good practice still
needs to be observed according to the principles of the quality use
of medicines and theory of Chinese medicine. Some of them will
need to be placed into Class 3 when toxicity evidence becomes
available.
4. Conclusion
Our overall strategy is to apply the principles of the quality use
of medicines to herbal medicine, which incorporates the selection
of appropriate therapeutic management options, appropriate choice
of medicines and safe use as spelled out in the Australian Scheduling Policy Framework (The National Coordinating Committee on
Therapeutic Goods, 2010). Both scheduling of medicines and
registration of Chinese medicine practitioners are required for the
quality use of herbal medicines. In countries where the regulatory
systems are not available, the potentially toxic herbs should not be
made available to the public.
Among the safety, quality and efficacy of medicines, safety is a
priority issue for the regulation of herbal medicines. However, the
Australian and Chinese regulations on toxic Chinese herbal
medicines are inconsistent and need updating. Seventy-four toxic
Chinese herbal medicines were identified from the Chinese and
Australian regulations, and five of them, aristolochia, asarum,
aconite, ephedra and coltsfoot showed inconsistency in the
regulation and were selected for detailed study.
Many studies conclude that toxicology studies are important
in understanding the side-effects of herbal medicines. There is a
huge body of clinical and preclinical data on the toxicity of
Chinese medicines. However, the current regulations were found
to be biased towards case reports, traditional practice or incomplete chemistry data. For example, Aristolochia and Asarum
species both contain aristolochic acid, but in different amounts,
therefore, phytochemicals should not be used as the single
criteria for their regulation. Therefore, we proposed that the
evaluation criteria should include: risk–benefit analysis, severity
of toxic effects, clinical evidence and preclinical data. The scheduling of herbs should be based on the comprehensive evaluation
of all available data, which can be updated when new information
becomes available. We also propose that the theoretical Human
Equivalent Dose (HED) based on animal LD50 be used to compare
the clinical dosage as an indicator of the therapeutic window
when human data is unavailable.
E.J.Y. Kim et al. / Journal of Ethnopharmacology 146 (2013) 40–61
The scientific evidence, including three levels of clinical
evidences: ‘‘High’’, ‘‘Medium’’ and ‘‘General’’; and three preclinical
data: ‘‘Animal studies’’, ‘‘Cellular studies’’, and ‘‘Chemical studies’’
were reviewed for the five priority herbs. Based on the evaluation
criteria, four regulatory classes were proposed: Prohibited for
medicinal usage, e.g., aristolochia; Restricted for medicinal usage,
e.g., aconite, asarum, and ephedra; Required warning label, e.g.,
coltsfoot; and Over-the-counter herbs for those herbs with safe
profile.
The evaluation criteria are related to the ‘‘factors’’ used in the
Australian Scheduling Policy Framework. The term ‘‘factor’’ has
been used to include the toxicity of the substance, diagnosis and
the purpose of use, potential for abuse, safety in use and the need
for access to the substance (The National Coordinating Committee
on Therapeutic Goods, 2010).
One of the major challenges associated with the toxicity
assessment of the herbs is the quality of the qualitative and
quantitative preclinical and clinical data. The association of case
reports with the herbs may not be conclusive and need further
evaluation. Since in vivo and in vitro toxicological studies have the
advantage of controlled experimental conditions, preclinical toxicology studies need to be enhanced. Toxicity data from clinical
trials of individual herbs and formulas need to be collected and
evaluated systematically. Typically, Chinese medicine has documented which part of the plant is to be used, and employs
processing methods to reduce the toxicity and enhance the effects
of herbal medicines. In addition, herbs are normally used as an
ingredient in a formula, with combinations counter-acting the
toxic effects of individual herbs. These methods have been used
for thousands of years. However, preclinical research to understand the effects of processing and formulation to reduce the
toxicity is warranted.
Chinese herbal medicines are an important part of TCM
practice both locally and internationally. The evaluation and
classification of toxic Chinese herbs will support the regulation
of Chinese medicine practitioners in Australia from 2012, thereby
ensuring the safe herbal medicine practice, and optimal treatment
strategies. We recommend that the current scheduling of toxic
Chinese herbal medicines in the SUSMP and Chinese regulations
be revised regularly to keep abreast with new studies.
The regulatory framework of Chinese medicine needs to
include the registration of Chinese medicine practitioners. The
access of some potentially toxic herbs should be restricted to the
prescription of qualified registered Chinese medicine practitioners, who meet the education standard, typically a Bachelor
degree or equivalent, and have the essential knowledge of
pharmaceutical aspects of herbal medicines. The endorsement
training of the TCM practitioner in order to have the right to
prescribe toxic herbs was proposed by the Chinese Medicine
Board of Victoria (2004).
Further studies can be conducted to include literature from
other herbs so that all common Chinese herbs will be scheduled
according to this platform. The development of a quality control
method of toxic herbal medicine is an important expansion area
of study. We are developing an online toxic herb database which
contains information on the toxicity data, scheduling and authentication of toxic Chinese herbs. The platform established will be
useful in the regulation of Chinese herbal medicines and other
herbal medicines in Australia, China and internationally.
Acknowledgements
This project was supported by the University of Sydney China
Studies Centre. ZLL acknowledges the support from the Australian
Endeavour Award Program (Award holder number 2758_2012).
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