Evidence-based toxicity evaluation and scheduling of Chinese herbal medicines

Abstract

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.

Introduction

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.

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 (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.

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.

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.