All things are poison and nothing is without poison, only the dose permits something not to be poisonous.

–Paracelsus

rees which grow amidst harsh winds, and which are continually forced to flex and sway, are known to develop particularly strong trunks and branches as a result.  Botanists call this phenomenon wind firmness, and this protective response to stress is what's largely responsible for the hardness of different types of lumber.

As a group, members of the plant kingdom are capable of exhibiting many such protective adaptations in response to threats from their environment. Numerous phytochemicals, for example, are thought to have evolved specifically as toxins to protect plants from harmful organisms like insects, bacteria, and fungi.

But many of these protective plant chemicals which are toxic to microbes and insects may ultimately be beneficial to humans. Small doses of these subtly harmful plant components may be able to gently “nudge” our body’s defense mechanisms into action. The well–known health benefits of a diet rich in fruits and vegetables, as well as the rich history of herbal medicine are both testament to the adaptive response of the human body when small doses of plant–based toxins are ingested.

In recent decades, scientists have increasingly identified and isolated many of the plant–defense chemicals which may be responsible for the health–promoting effects of certain herbs and plant–based foods. But in our modern world, the forces of commerce have served to perpetuate a distorted view of our nature, and the nature of the ecosystem to which we belong. As a result, a startling number of these plant extracts have become available as dietary supplements, allowing any person so inclined to consume these plant–based “toxins” in doses hundreds or even thousand of times higher than could ever be obtained through any sort of rational diet.

The pages of health magazines and internet websites often extol the virtues of things such as green tea extracts, exotic berry extracts, and, most recently, the plant–hormone anti–microbial, known as resveratrol. The fact that these extracts are “natural,” “derived from food,” and “extensively researched” is often touted, but this gives the health–conscious consumer a false sense of security regarding the long–term safety of ingesting artificially high amounts of these metabolically–active substances.

By examining exactly how our bodies respond to these chemicals when ingested, it’s easy to see that ingesting unprecedented doses of such plant components may pose a serious risk to human health. Ironically, those most apt to be harmed are those who have unquestioningly accepted the dominant trends of the “health food” and nutritional supplement industries.

The Myth of Antioxidants

In a sense, aging can be very simply defined as the accumulated cellular damage that occurs to our body over a lifetime. It’s a slow process, of course, but the outward manifestations of aging can be obvious at advanced stages: our skin wrinkles and loses the suppleness of youth, the muscles that we’ve worked so hard to build begin to atrophy, and our joints become stiff, inflexible, and often, painful.

For decades, plant foods containing certain phytonutrients like carotenoids, polyphenols, flavonoids, and isothiocyanates have been suspected of exerting protective benefits against some aspects of the aging process – and against some age–related diseases such as heart disease and cancer. As research into the biology of aging deepened, scientists began to see that the cellular damage characteristic of aging and age–related disease was linked to chemically destructive compounds, called free radicals.

Oxidative stress (i.e., a chronic excess of free radicals) is a sign of increasingly inefficient cellular energy production and was found to be a common thread running through most, if not all age–related diseases and the aging process in general. It just so happened that most of the protective plant chemicals studied were found (at least in certain contexts) to possess antioxidant activity (i.e., they were able to disrupt the chemical chain reaction of free radical production).

Knowing that many phytonutrients may possess antioxidant activity, and knowing that the consumption of these phytonutrients was associated with reduced levels of oxidative stress and degenerative disease, the logical conclusion seemed clear: phytonutrients from fruits and vegetables exert antioxidant activity when consumed, by quenching free radicals in the body, thus reducing oxidative stress.

This simple hypothesis found its way into the public consciousness largely via the promotion of antioxidant supplements. Even the casual supplement user these days knows that antioxidants, like vitamins E, C, and beta carotene neutralize free radicals; and in recent decades the use of antioxidant nutritional supplements has increased greatly. But for all the fanfare and promotion, antioxidants have largely failed to live up to the initial expectations of halting the aging process or preventing age–related disease. In fact, more than a few studies have shown that the relatively indiscriminate use of isolated antioxidants may sometimes stimulate free radical damage – doing more harm than good.

Study Link – A review of the epidemiological evidence for the 'antioxidant hypothesis'.

Quote from the above study:

Although scientific rationale and observational studies have been convincing, randomised primary and secondary intervention trials have failed to show any consistent benefit from the use of antioxidant supplements on cardiovascular disease or cancer risk, with some trials even suggesting possible harm in certain subgroups…The most prudent public health advice remains to increase the consumption of plant foods, as such dietary patterns are associated with reduced risk of chronic disease.

As in the study above, researchers often note that while a diet full of antioxidant–rich foods is well–documented to help prevent disease, the effects of isolated antioxidant supplements have been more than a bit discouraging.

But exactly why do antioxidant–rich foods work to stall the aging process while those from isolated supplements fall short in study after study?

One current theory is that the chronic low doses of phytonutrient antioxidants we ingest through foods may actually stimulate our bodies’ own antioxidant systems. In other words, it may actually be the chronic and subtly harmful nature of antioxidants which causes our body to increase its production of substances to protect us. Many substances which are antioxidants in some circumstances may easily convert to pro–oxidants within the dynamic milieu of the human body. Knowing this, we can see that high–dose antioxidants from supplements, when taken in isolated form, may actually overwhelm our body’s protective mechanisms and do more harm than good.

Dose Is Everything

In biology, it’s often been found that low–level exposure to a compound or external “stress” stimulates our bodies’ protective mechanisms – often conferring long–term health benefits. Conversely, high levels of exposure to the same compound or stress often prove to be decidedly harmful.

And this sort of dose–response relationship isn’t merely limited to substances we ingest. Exercise is a perfect example. Exercise actually increases our level of oxidative stress markers in the short term, but by adapting to this stress, our body is ideally able to up–regulate its own production of very powerfully protective enzymes and proteins.

Another common example would be the skin’s exposure to ultraviolet light. A certain amount of UV exposure is undoubtedly beneficial as a source of vitamin D, and a suntan, itself, can be seen as a protective defense against damaging UV rays.

It’s important to remember, however, that excessive exercise or UV exposure can overwhelm our bodies’ ability to adapt, and can actually hasten the degenerative process. Similarly, an excessive intake of plant–based “antioxidant” substances may prove harmful as well.

Green Tea Extract

The green tea polyphenol known as epigallocatechin–3–gallate (EGCG) offers a good example. As one of the most extensively researched dietary polyphenols, and one of the most widely consumed dietary supplements, EGCG offers us clues as to how and why negative effects may manifest when such “antioxidants” are consumed in artificially–high doses.

Recently, for example, a popular dietary supplement sold for weight loss was pulled from the supplement market in the United States amidst concerns associated with its possible liver toxicity. Common over–the–counter weight loss supplements often contain several ingredients which may be liver–toxic, but the most well–documented liver toxin in these formulas is green tea extract:

Study Link – Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements.

Quote from the above study:

Acute hepatotoxicity from C. Sinensis (green tea) is well–described, and may range from acute hepatitis to acute liver failure. Based on 17 published cases in the literature, most cases appear to occur following large ingestions of green tea, with resolution following withdrawal, and recurrence with re–challenge.

Considering that green tea is a dietary staple of many Asian cultures, and that green tea consumption has been associated with possible health benefits, most people simply assume that high–potency green tea extracts are safe to consume. But polyphenols, by their very nature, are hormonally active substances. When ingested in high amounts, these foreign plant “hormones” often burden the liver and other detoxifying organs of the body. It’s worth noting too, according to the case reports in the scientific literature, liver toxicity often manifests when green tea–containing supplements are taken at or near the recommended doses.

Study Link – Acute liver failure induced by green tea extracts: case report and review of the literature.

Quote from the above study:

In industrialized countries, over–the–counter dietary supplements have become popular in preventing and treating an expanding list of medical conditions. Although most commercially available supplements have not been rigorously tested for safety and efficacy, they have found an enlarging market because they are considered natural. Oral supplements containing green tea extract have been marketed as effective for weight loss and to prevent and cure some solid tumors. Although there is little scientific evidence of the effectiveness of green tea extracts to improve the quality of health of regular consumers, there is an increasing body of medical literature supporting the hypothesis that they can cause serious side effects. Our experience adds to previous reports of acute liver toxicity observed in individuals consuming supplements containing green tea extract. We highlight the importance of obtaining a detailed history of dietary supplement consumption when evaluating a patient presenting with acute liver dysfunction.

Inhibiting Detoxification

Adding a layer of complexity to the toxicity of green tea extracts, is the fact that the ingestion of these, and other plant components, may alter the metabolism of drugs and dietary substances – possibly making the combination of substances all the more toxic. There exists a well–known phenomenon in pharmacology known as the grapefruit effect, by which the ingestion of grapefruit (or grapefruit juice) can drastically increase the levels of certain medications taken at the same time. After puzzling over the issue for some time, researchers have recently implicated furanocoumarins from grapefruit as the causative elements:

Study Link – A furanocoumarin–free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice–felodipine interaction.

Quote from the above study:

Furanocoumarins are the active ingredients in [grapefruit juice] responsible for enhancing the systemic exposure of felodipine and probably other CYP3A4 substrates that undergo extensive intestinal first–pass metabolism.

It seems that even small amounts of furanocoumarins are able to inhibit drug–detoxifying enzymes in intestinal cells. When these enzymes are inhibited, ingested drugs may reach dangerously high levels in the bloodstream.

As relates to the polyphenols from green tea, evidence from animal studies is beginning to suggest that EGCG may exhibit a similar inhibitory action upon the enzymes used to properly metabolize orally ingested drugs.

Study Link – Effects of epigallocatechin gallate on the oral bioavailability and pharmacokinetics of tamoxifen and its main metabolite, 4–hydroxytamoxifen, in rats.

Quote from the above study:

The increase in bioavailability of tamoxifen is likely to be due to the decrease in first–pass metabolism in the intestine and liver by inhibition of P–glycoprotein and CYP3A by EGCG. The increase in oral bioavailability of tamoxifen in the presence of EGCG should be taken into consideration of potential drug interactions between tamoxifen and EGCG.

The above study shows that EGCG, like many other potentially toxic substances, is able to inhibit the detoxifying effects of substances known as P–glycoprotein and CYP3A. This effect opens the door for many potentially negative drug interactions when green tea or other herbal supplements are consumed together.

Within the realm of nutritional supplements, an extract of black pepper, called piperine (or, called by various trade names) is often added to nutritional supplements “to improve absorption” or “to improve bioavailability.” But the research which exists on piperine shows that this substance similarly inhibits the detoxifying mechanisms of P–glycoprotein and CYP3A4.

Study Link – Piperine, a Major Constituent of Black Pepper, Inhibits Human P–glycoprotein and CYP3A4.

Quote from the above study:

In summary, we showed that piperine inhibits both the drug transporter P–glycoprotein and the major drug–metabolizing enzyme CYP3A4. Because both proteins are expressed in enterocytes and hepatocytes and contribute to a major extent to first–pass elimination of many drugs, our data indicate that dietary piperine could affect plasma concentrations of P–glycoprotein and CYP3A4 substrates in humans, in particular if these drugs are administered orally.

In some limited contexts (usually the context of marketing), “improving the bioavailability” of substances may seem beneficial. But in any truly meaningful biological context it’s likely that we’ll want to avoid substances like pepper extracts which achieve this end by inhibiting our body’s detoxifying mechanisms.

Plant Toxins and Cancer

Numerous plant substances (including the EGCG from green tea) have repeatedly been shown to trigger apoptosis in various types of cancerous cells. Apoptosis is a controlled type of self–destruction which is lost by “immortalized” cancer cells, so at first glance, any substance which can trigger apoptosis in these cells is sure to raise interest as a potential cancer therapy.

But first and foremost, it’s important to realize that most of the studies conducted on the apoptotic effects of plant chemicals are conducted in vitro – literally, “in glass,” that is, in a test tube or Petri dish. These studies can give us meaningful clues as to the nature of a substance, but because they don’t take into account the complexities of living organisms (e.g. the effects of an orally ingested substance on our detoxifying mechanisms, as we have just seen) in vitro studies are not, in and of themselves, sufficient to justify that we actually ingest unprecedented amounts of these plant–based chemicals.

Within the nutritional supplement industry, however, in vitro studies are often used as the predominant justification for selling and promoting high–potency plant–based “nutritional supplements”.

But some in vitro studies show that EGCG, for example, is toxic to both normal and cancerous cells:

Study Link – In vitro cytotoxicity of epigallocatechin gallate and tea extracts to cancerous and normal cells from the human oral cavity.

Quote from the above study:

The results presented herein are consistent with EGCG acting as a prooxidant, with the cancerous cells more sensitive to oxidative stress than the normal cells.

In the above study, EGCG acted as a pro–oxidant, the exact opposite of the antioxidant we’re often promised in the marketing of nutritional supplements. And while EGCG was more toxic to cancerous cells than normal cells, studies like this one should give any healthy person reason to think twice before consuming high–dose green tea extracts for general health benefits.

Even if plant chemicals such as EGCG turn out to sometimes be useful treatments (or adjunctive treatments) for cancer therapy, this would not necessarily justify the consumption of high–dose “phytotherapy” as a preventative against cancer in healthy individuals.

Again, the take–home lesson is that these plant substances, while sometimes beneficial, are fundamentally, toxic. It may be that in some circumstances their toxic nature is able to be directed towards cancerous cells, or it may be that the subtle harm they cause in low amounts is actually able to make our body more resilient in the long–run. But their toxic nature is often easy to miss when these substances are sold under the overly broad designation of “antioxidants.”

It’s intuitively obvious that exposing healthy people to pharmacologic chemotherapy drugs would not be a viable way to prevent cancer – although chemotherapy drugs may be useful in certain contexts, their toxicity is far too great of a risk for healthy individuals, and the type of metabolic disruption they cause would almost certainly be more likely to cause cancer than to prevent it.

But outside of the pharmaceutical realm, in the “natural” realm of dietary supplements, similarly potent disruptors of human metabolism are often not identified as such simply because they’re “natural” and they “come from food.” In the modern environment of dietary supplements and functional foods, we’ll be well–served to always remember (to paraphrase Paracelsus) that it’s the dose that makes the poison.

In practice, dietary staples such as green tea, chocolate, berries, and red wine are likely to play an important role in supporting our health. But the amounts of “active” plant chemicals in the actual foods, themselves, are sure to be infinitely safer than the high–potency extracts currently being sold as nutritional supplements. Once we realize that there’s a depth of complexity to the actions of these plant chemicals in the human body that goes beyond the simplistic notion of antioxidant activity, only then are we poised to reap their full benefit in the amounts that Nature has deemed appropriate.