Toxic Heavy Metals and Undeclared Drugs in Asian Herbal Medicines by Edzard Ernst This article will also appear in Trends in Pharmacological Sciences. Issue 120 Abstract Asian herbal medicines are currently used by large sections of the population. Because they are not regulated as medicines and are freely available to everyone, serious safety concerns might be associated with these herbal medicines. In this article, evidence suggesting that some Asian herbal medicines contain toxic heavy metals or undeclared prescription drugs is reviewed. In particular, Indian and Chinese preparations have been implicated. Although adulteration with drugs is by definition fraudulent, the inclusion of heavy metals could be either intentional for alleged medicinal purposes or accidental. Evidence from various countries implies that toxic heavy metals and undeclared prescription drugs in Asian herbal medicines might constitute a serious health problem. However, the majority of the data is anecdotal and insufficient to define prevalence figures. Ways ought to be found to maximize consumer safety. In most developed countries, Asian herbal medicines (AHMs) are becoming more and more popular [1]. However, usually AHMs are not regulated as medicines. Problems might arise as a result of the lack of adequate regulations, the pharmacological complexity of herbal products, and the paucity of information on the pharmacology and toxicity of these compounds. AHMs can be purchased from outlets ranging from health-food stores to Internet sites, and thus a crucial evaluation of their safety is relevant and important. One obvious safety issue relates to the possibility that some AHMs contain heavy metals or undeclared drugs [2]. Based on a review of the recent medical literature (Medline, Embase 1990-2001), this article aims to summarize the recent evidence pertaining to this subject. Indian Remedies Indian medical systems (e.g. Ayurveda and Unani) have a long and rich history of herbal medicine, and heavy metals have been a regular and deliberate constituent of traditional Indian remedies [3]. Thus, to use the term "contamination" with respect to the presence of heavy metals in such remedies might be misleading (see below). A London-based toxicology unit published a case series of adverse events associated with traditional medicines that were reported to them between 1991 and 1995 [4]. Of 12 cases of poisoning with lead, arsenic or mercury, nine cases were associated with herbal remedies from India and the remainder was due to traditional Indian cosmetics (e.g., "surma.") A recent exemplary case report from Italy [5] (box 1) exhibits many hallmarks of such cases: desperate parents, non-medically qualified healers, lack of product standards, undeclared ingredients, nondisclosure of usage and long-term medication, in addition to delay of diagnosis of poisoning and hence delay of effective therapy. Indian authors recently analyzed 31 Ayurvedic formulations obtained in India for their mercury content [6]. With the exception of one remedy, all exceeded the legal limits of 1 ppm mercury and 16 preparations exceeded the limits by more than two orders of magnitude. These authors also noted that huge variability of mercury content existed within one allegedly identical remedy manufactured by different companies. No recent systematic investigations are available about the prevalence of heavy metal content of traditional Indian remedies on sale in developed countries. Thus, a considerable degree of uncertainty continues to surround this area. Chinese Remedies Numerous case reports and case series of heavy metal poisoning associated with the use of traditional Chinese medicines (TCMs) have been published [7]; lead has relatively often been implicated as the cause of such poisoning but mercury, cadmium, arsenic, copper, and thallium have also been found in TCMs [7]. Californian officials have screened for undeclared pharmaceuticals and heavy metals in imported Chinese remedies on sale in Californian herbal retail stores [8]. Seven percent of the 251 products tested contained undeclared pharmaceuticals (e.g., ephedrine, chlorpheniramine, methyltestosterone, and phenacetin). Twenty-four products contained at least 10 ppm lead, 36 contained an average of 14.6 ppm arsenic, 35 contained an average of 1,046 ppm mercury, and 23 had more than one contaminant and/or adulterant. Koh and Woo [9] reported the detection of toxic heavy metals that exceeded Singapore's legal limits in 42 Chinese proprietary medicines. They collected 2,080 samples of such medicines in Singapore and tested them for heavy metal content. Forty-two different medicines were found to contain metals in amounts exceeding the legal limits. Mercury was found in 28 products, lead in eight, arsenic in six, and copper in one. One product contained both mercury and lead and another product contained both mercury and arsenic. Melchart et al. [10] analyzed all 317 batches of dried Chinese herbs delivered to a German hospital of Chinese medicine. Heavy metal content beyond the legal limits was detected in 3.5% of these samples. Obviously, heavy metals are not the only possible toxic ingredients in herbal remedies; contamination with herbicides, pesticides, microorganisms; or mycotoxins, insects, or undeclared herbal constituents are other relevant possibilities [2,11-13]. Moreover, contamination with toxic herbal constituents (e.g., through misidentification of the herbal ingredients) can be a serious problem. In Belgium, the use of a TCM contaminated with plants from the Aristolochia species resulted in an epidemic of subacute intestinal nephropathy. Many of the affected patients required kidney transplantation. When 19 kidneys and urethras removed from ten such patients were examined histologically, there were conclusive signs of neoplasms in 40% of cases [14]. Numerous case reports originating from countries such as Australia, Belgium, China, the Netherlands, New Zealand, United Kingdom, and United States demonstrate the adulteration of TCMs with synthetic drugs and associate the use of adultered remedies with health problems of the user [15]. The adulterants include a wide range of pharmaceuticals (box 2). The resulting clinical consequences are often serious and sometimes life threatening: agranulocytosis, Cushing's syndrome, coma, the excessive increase of the international normalized ratio (INR) have all been reported. In other cases, the adulterants caused no symptoms at all and the problem was discovered only through routine check-ups or through the remarkably good clinical response, which turned out to be due not to the TCM but to the undeclared prescription drug. Analyses are available of Chinese herbal medicines collected in Australia [16], Taiwan [17] and UK [18]. The largest of these studies is that of Huang and colleagues from Taiwan [17], who showed that 24% of all 2,609 samples collected contained at least one adulterant. This high prevalence was due to the fact that the samples were associated with reports of adverse effects and poisoning, and possibly included low-grade folk remedies. Examples of recent case reports [19,20] are illustrated in boxes 3 and 4. Concerns About the Safety of Asian Herbal Medicines These data raise concerns about the safety of consumers using AHMs. Both toxic heavy metal content and adulteration with prescription drugs have been reported. To date, few data are available to calculate the prevalence of these problems reliably in developed countries. A recent press release [21] of the British "Medicines Control Agency" stated that this regulatory body "continues to find potentially dangerous and illegal ingredients in TCMs. Recently TCMs have been found to include . . . mercury and arsenic . . . [and] prescription only steroids." It is notable that the majority of clinical problems occur with self-prescription of AHMs. One could therefore argue that consulting an experienced herbal practitioner might avert adverse events; however, evidence is required to support this claim. Several possibilities exist to explain the presence of heavy metals in AHMs. First, heavy metals could be included intentionally for alleged medicinal properties. Some Indian schools of medicine emphasize the importance of metals such as lead, copper, gold, iron, mercury, silver, tin and zinc for the proper function of the human body [22]. Ayurvedic textbooks, for example, take note of the toxicity of heavy metals and recommend special physicochemical processes that, according to ancient Indian belief, "detoxify" such toxic heavy metals (e.g. by heating them until they glow [23]). In traditional Chinese medicine, mercury is part of some preparations under the terminology of "cinnabaris" (mercury sulfide), "calomel" (mercury chloride) or "hydrargyri oxydum rubrum" (mercury oxide). Such products are used for a variety of indications including, for example, as a tranquilliser, an anti-epileptic, for ulcers or to treat insomnia [9]. Lead is used as "Mi Tuo Seng" (Lithargyrum) [24] and arsenic as "Xiong Huang" (Realgar) [25] in the manufacture of several TCMs. Strictly speaking, these constituents are thus not contaminants but ingredients deliberately included for a specific curative purpose. Second, the presence of heavy metals might be the result of contamination during manufacture, for example, from grinding weights or lead-increasing containers or other manufacturing utensils [9]. Third, AHMs might contain heavy metals when grown on seriously polluted soil [26]. In this context it is relevant to note that TCMs might also contain animal and mineral products and that these too might be contaminated with heavy metals [27]. Although contamination can be accidental, adulteration is, by definition, fraudulent. The reasons why some AHMs contain prescription drugs are speculative. I suspect that some manufacturers include such ingredients to render their products more clinically effective. If this is the case, it seems obvious that the inclusion of prescription drugs is fraudulent and illegal. Many consumers are motivated to try AHMs through a misconception that these remedies are inherently safe [28], and there is evidence that the (UK) daily press have their share in perpetuating this myth [29]. Approximately half of the individuals using herbal medicines do not tell their physician [30]. This level of non-communication further increases the risk to the consumer because doctors might fail to diagnose adverse effects caused by treatments of which they are not aware. The majority of people taking herbal remedies combine them with conventional drugs [30]. This opens the possibility of herb-drug interactions [31,32], which, in turn, further raises concern about consumer safety. Recent evidence suggests that consumers are beginning to become concerned about the risks of under-regulation of dietary supplements, and the majority of US consumers now seem to support [33]: (1) the requirement that the Food and Drug Administration (FDA) review the safety of new dietary supplements before their sale; (2) increased authority to remove from sale those products shown to be unsafe; and (3) increased government regulation to ensure that advertising claims about the health benefits of dietary supplements are true. How can the risk to patients be minimized? An appropriate strategy [34,35] (box 5) should follow several avenues. The consumer should be informed that "natural" does not necessarily mean 'free from risk' and that adverse effects as a result of AHMs are an undeniable reality. Patients and physicians should be encouraged to talk about the use of AHMs and other complementary/alternative treatments [34] and the possibility of interactions of herbal medicines with prescribed drugs [31,32]. Regulators should consider measures to control this sector of healthcare more effectively. It is concluded that toxic herbal metals and undeclared drugs in AHM represent a potentially serious problem that puts consumers at risk. Means of minimizing this risk must be found and implemented. Wang, Ang, b. 1615; Hu, Tsung-wen Shen-nung pen ts'ao pei yao i fang ho pien (Herbal and Prescriptions) China, 1740. 6 vols. from The National Library of Medicine. ================================================================== Breast Cancer News is brought to you by the The MID HUDSON OPTIONS PROJECT, INC a grassroots Breast Cancer Health Advocacy, Support and Activist Group. Remember we are NOT Doctors and have NO medical training. 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