Cancer Complementary and alternative medicine Medicine

Yet more evidence that “natural” doesn’t necessarily mean “safer”

Repeat after me one more time: Just because something is natural does not necessarily mean it’s effective or, more importantly, safe. If there’s one thing common among virtually all purveyors of “alternative” medicine, it’s that they fetishize anything they consider “natural.” To them, “natural” is always better. At the very least it’s better than those evil big pharma-produced purified drugs that they so distrust. Of course, often forgotten in all of this is that any herbal remedy that does anything at all from a physiological standpoint to reverse disease or make you feel better does so because it contains chemical compounds that are responsible for that aforementioned physiological effect. That is, I must remind you, the very definition of a drug. Yes, herbs can be drugs. They’re impure drugs with highly variable content of the active ingredient, but they’re drugs nonetheless.

And drugs can have side effects. Sometimes those side effects are long term.

I was reminded of this yet again (as if I need to be reminded) by a story that I saw coming across the wires yesterday entitled Herbal remedy blamed for high cancer rate in Taiwan: study:

A toxic ingredient in a popular herbal remedy is linked to more than half of all cases of urinary tract cancer in Taiwan where use of traditional medicine is widespread, said a US study Monday.

Aristolochic acid (AA) is a potent human carcinogen that is found naturally in Aristolochia plants, an ingredient common in botanical Asian remedies for aiding weight loss, easing joint pain and improving stomach ailments.

The ancient herb has been touted around the world for thousands of years for everything from gout to childbirth, but scientists now know it carries serious risks of causing kidney disease and urinary cancers.

The latest research found it can interact with a person’s DNA and form unique biomarkers of exposure, as well as creating signals within tumor suppressing genes that indicate the carcinogen has been ingested.

What amazes me about this is that AA was known to be a powerful nephrotoxin; i.e., it’s toxic to the kidney. It’s the cause of a kidney ailment known as Balkan endemic nephropathy (EN). This was discovered back in the 1950s when it was first described in rural farmers in Bosnia and Herzegovina, Bulgaria, Croatia, Romania and Serbia. Later, in the 1990s, otherwise healthy Belgian women developed renal failure after ingesting Aristolochia herbs as part of a weight loss regime. More reports of kidney toxicity associated with this particular herb kept cropping up, such that the syndrome is now known as aristolochic acid nephropathy (AAN), after the substance from the Aristolochia herb believed to be responsible for the problems.

Naturally, when I started to see news reports about this herb, there was only one thing for me to do. That’s right. I had to go to the original study and find out what the skinny is about this herb. It turns out that the specific cancer associated with AA is known as urothelial carcinoma of the upper urinary tract (UUC). Basically, its a cancer of the epithelial lining of the kidney and upper ureter. The authors took advantage of the observation that the place with the highest incidence of UUC in the world is Taiwan. Making the link between such a high incidence of UUC and high usage of AA by the population, the authors were able to test the hypothesis that it is AA that is driving the high levels of UUC in Taiwan. As the authors note, it’s not an unreasonable hypothesis at all:

In Taiwan, the remarkably high incidence ofUUC(13), coupled with widespread use of Aristolochia herbal remedies, suggested that AA might play a central role in the etiology of this disease. The high level of exposure to AA in Taiwan has been documented by a systematic analysis of prescriptions filled by a 200,000 person random sample of the entire insured population of Taiwan between 1997 and 2003, revealing that approximately one-third of these individuals consumed herbs containing, or likely to contain, AA (14). Moreover, consumption of AA is associated, in a dosedependent manner, with an increased risk of developing end-stage renal disease or urothelial carcinoma (13, 15).

That’s one popular herbal remedy there.

So how do we put the two together? How do we make the link between AA and UUC in such a way that we can infer causation. Obviously, we can’t do a randomized controlled study in which half the subjects are given AA and the other half a placebo and then wait a decade or so for AA-caused cancers to start to crop up so that we can see if there is an increased incidence of them in subjects in the AA group. Damn ethics! We can, however, infer the likelihood of causation from epidemiological evidence, which is what the authors did. They undertook a molecular epidemiological study.

It turns out that there are good biomarkers for AA exposure. These include aristolactam-DNA (AL-DNA) adducts are due to the binding of AA to DNA and are a sensitive biomarker for AA exposure, particularly given that they concentrate in part of the kidney known as the renal cortex. They also persist for a long time, making them fantastic markers for past exposue. These lesions also lead to a specific mutational signature in the TP53 tumor suppressor gene. This particular mutational signature is characteristic because it is so unusual. Using this mutational signature as a biomarker, the investigators examined 151 Taiwanese patients with UUC. Twenty-five patients with renal cell carcinoma were used as controls. Basically, the authors found that 60% of these patients had mutations that could be due to AA exposure. Everything else fit, as well. Epidemiologically, the incidence of UUC correlated strongly with AA exposure. Biomarkers pinpointed the types of mutations induced by AA. The timing fit, too, in that the increase in UUC in Taiwan was the right length of time after major importation of AA-containing herbal remedies, and the molecular epidemiology fit. All of this led the authors to conclude:

We attribute the progressive increase in the incidence of UUC in Taiwan over the past 25 y, especially among women (Fig. 4), in part to the systematic replacement of traditionally used Mutong and Fangchi herbs with Aristolochia manchuriensis and Aristolochia fangchi, respectively (35, 36). In mainland China, this practice appears to have begun in the 1930s, becoming universal by 1950 and continuing until 2003, when these substitutions were prohibited by the Chinese government (37). The presence of AA in Mutong and Fangchi exported to Taiwan between 1995 and 2003, as well as to other Asian countries, Great Britain, and the Netherlands, has been documented by chemical analysis (38, 39). Thus, assuming a latency period of 20-40 y, an estimate based on the development of AA-associated urothelial carcinomas in Balkan countries (8, 9), the carcinogenic effects of AA would be expected to have become increasingly manifest in Taiwan by 1985 (Fig. 4).

In conclusion, this study provides compelling evidence for the primary role of AA in the etiology of UUC in Taiwan. Importantly, the traditional practice of Chinese herbal medicine in Taiwan mirrors that in China and other Asian countries. Thus, it appears likely that UUC and its attendant AAN also are prevalent in these and in other countries where Aristolochia herbs have long been used for treatment and prevention of disease (1, 5). Because of the lifelong persistence of mutagenic DNA-AL-I adducts in target tissues and irreversible damage to the proximal renal tubules caused by AA, persons treated with Aristolochia herbal preparations at any time in their life are at significant risk of developing UUC or chronic renal disease, thereby creating an international public health problem of considerable magnitude.

Once again, as is often the case, the herbs used in Taiwan come from China. We’ve read time and time again about herbal remedies from China containing mercury and all sorts of toxic metals. This time around it’s a bit different. AA from China isn’t adulterated. Its toxicity is not due to anything external but rather due to chemicals that are naturally part of the plant.

Nature’s a bitch, isn’t she?

It’s hard for me not to repeat this once again; so I won’t even try not to. Instead, I’ll simply reiterate: “Natural” doesn’t mean “good” or “safe,” and herbs can be just as toxic as any medication, even to the point of causing cancer.

By Orac

Orac is the nom de blog of a humble surgeon/scientist who has an ego just big enough to delude himself that someone, somewhere might actually give a rodent's posterior about his copious verbal meanderings, but just barely small enough to admit to himself that few probably will. That surgeon is otherwise known as David Gorski.

That this particular surgeon has chosen his nom de blog based on a rather cranky and arrogant computer shaped like a clear box of blinking lights that he originally encountered when he became a fan of a 35 year old British SF television show whose special effects were renowned for their BBC/Doctor Who-style low budget look, but whose stories nonetheless resulted in some of the best, most innovative science fiction ever televised, should tell you nearly all that you need to know about Orac. (That, and the length of the preceding sentence.)

DISCLAIMER:: The various written meanderings here are the opinions of Orac and Orac alone, written on his own time. They should never be construed as representing the opinions of any other person or entity, especially Orac's cancer center, department of surgery, medical school, or university. Also note that Orac is nonpartisan; he is more than willing to criticize the statements of anyone, regardless of of political leanings, if that anyone advocates pseudoscience or quackery. Finally, medical commentary is not to be construed in any way as medical advice.

To contact Orac: [email protected]

4 replies on “Yet more evidence that “natural” doesn’t necessarily mean “safer””

I would recommend to Tabby reading the work of Dr. David Burns, in particular the best-selling of his books. It would contain a lot of helpful advice that I think she could use to minimize conflict in future discussions such as this.

@Tabby: In addition to Todd, composer99 and chris’ advice, I’d like to add that if you need to use the ‘f-word’ to punctuate every sentence of yours, it does not speak very highly of your intentions behind being here.
If you want to prove a point, logic, reason and (where required) citations are all that you need. Insults and profanity are nothing more than fluff which you only need to add if there is nothing much in what you have to say.


Also, some general advice that goes back to Usenet: lurk before posting. In the case of a blog like this, that would mean reading more than one of Orac’s posts, and looking at the comment threads. You can get a handle on the local customs (for example, some of the language thrown around at Pharyngula wouldn’t fly here, and might well get someone banned at Making Light, but someone complaining about it at Pharyngula would probably be mocked) and range of discussion. You can also get an idea of which commenters are worth your time to read and maybe engage with.

WPoPZn Steve: When I move to Canada, remind me to display you how everything functions.Steve: Cynical, I participate in these programs – I am a customer!,

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