Shifting Perspective
We must learn to embrace a fundamental shift in thinking about how our bodies work. A body is an ecosystem. It is a complex system of interacting parts that are tightly regulated for homeostasis through layers of "conversations" happening together with the surrounding environment. The reality isn't black-or-white; physiological processes can and do have degrees of function or dysfunction, degrees of expression or suppression.
The Law of Hormesis exists for biological organisms like you and I and states that a substance in a small dose may have beneficial effect, but in a large dose may be harmful or even lethal. Similarly, the beneficial and detrimental effects of nutrients such as vitamins and minerals follows a "U-shaped" or "J-shaped" curve - where both deficiency and excess can cause similar negative effects, including death (1, 2, 3). Sodium intake is a great illustration of this principle. In very high amounts (>5000 mg/d) or very low amounts (<3000 mg/d), we see the same detrimental effect (2). In fact, we see this phenomenon in almost all areas of nutrition science (3).
"the requirement of a given nutrient can best be said to be the intake that calls for the least adaptation or compensation by the intact organism." (2)
Avoid Pitfalls in Thinking
Science is a systematic pursuit of knowledge and understanding. When old models of the world no longer map accurately onto the new data, we build new models. In this way, science in not a static practice, but a very dynamic one. Science has traditionally thrived, and in many ways still thrives, on reductionistic linear models that break down a bigger picture into smaller isolated components. This is a very effective method for studying the world in many ways. However, as science advances, scientists evolve their approach and are challenged to develop experimental models for understanding integrated systems. These systems have often failed to be adequately understood through reductionistic models alone.
Isolated elements do not behave the same way as they might when placed inside a system with multiple variables and moving parts. This is why in vitro studies are very rarely if ever equated with in vivo ones. In the former, an element of interest (enzyme, pathogen, carcinogen, antioxidant) is isolated in a test tube, petri dish, or other simplified media; context removed. In the latter, we examine how the element of interest interacts with the whole body - often drastically altering its effect (4, 5, 6).
Antioxidants: An Example
Relating this more directly to nutrition science, we look at antioxidants. This example helps us not only to see how in vitro and in vivo study designs differ, but also nicely illustrates the principle of hormesis.
Antioxidants are compounds that neutralize reactive free radical molecules. Free radicals, or reactive oxygen or nitrogen species (ROS, RNS), respectively, as they are often known, are generated by normal metabolic processes, exposure to radiation, present in normal cellular inflammatory response, and in air pollution. Some amount of free radicals are necessary to keep us alive, as the immune system relies on free radicals for attacking pathogens. Unhindered, however, free radicals will cause tissue and DNA damage. The body has ways of combating this risk and keeping the system stabilized through the use of antioxidants. Though there are many endogenous antioxidants, the main ones include glutathione (including specifically glutathione peroxidase), superoxide dismutase, and catalase (9). Exogenous antioxidants, or antioxidants we acquire through food, include vitamin C, vitamin E, selenium, carotenoids, and polyphenols, among others (10).
In appropriate doses, most exogenous antioxidants can help support overall antioxidant status. However, many polyphenolic antioxidants, or phytochemicals, found in plants, may cause toxicity in high doses, as the body treats them like xenobiotics (for an in-depth discussion on xenobiotics, see the following series, Understanding Detoxification). Additionally, these phytochemicals themselves offer minimal to no appreciable contribution to endogenous antioxidant status (10). This means that the polyphenol "antioxidants" found in your blueberries, tea, chocolate, or so-called "superfruits" don't contribute much to your overall antioxidant status.
If this is true, then why are companies marketing these foods and food products as containing antioxidants? The answer is that they do contain antioxidants. However, people have made false equivalencies between in vitro and in vivo studies looking at these phytonutrients. When these compounds were investigated in vitro (in test tubes, petri dishes), antioxidant activity was measured with an oxygen radical absorbance test (ORAC) and found to be high, signifying high antioxidant activity. You could place a blueberry in a test tube and apply the ORAC test and behold, a number was generated denoting the elevated antioxidant capacity of the blueberry. The problem with this method is that it wholly fails to mimic what actually happens in the body. In the body, these polyphenolic compounds are whisked away quite quickly to the liver biotransformation pathways (for a more complete discussion on liver biotransformation pathways, read the subsequent Understanding Detoxification series of blog posts), exerting negligible antioxidant effect (10).
So, should we stop eating foods rich in phytonutrients such as fruits and vegetables? Of course not! There are so many ways that these foods contribute to overall health and there is no shortage of evidence to support their regular consumption (11). And while it is true that we may not be getting much antioxidant bang from our phytonutrient buck, these compounds are thought to have other important inhibitory effects on some inflammatory compounds and can regulate other important cellular processes (10). Not to mention that fruits and vegetables contain vitamins, minerals, and fiber that so many Americans are direly lacking (11).
Putting it all Together
Nutrition science and the science of understanding how complex whole foods or diets interact with intricate and unique bodies-as-a-whole is a relatively new endeavor. When we try to study how complex systems interact with other complex systems and are seeking to avoid overly-reductionistic models - which may fail to accurately depict what is actually going on in a system as a whole - mistakes are unavoidable. We must be patient and persistent with our research.
How do we avoid falling into the trap of overly-reductionistic thinking when it comes to our own bodies or when choosing a doctor or other healthcare practitioner?
Even the most so-called "holistic" or "alternative" -minded practitioners are not immune to implementing overly-reductionistic and incomplete models of physiology, diagnostics, and clinical treatment. This is the legacy of a very old dualistic ideological/philosophical tradition that continues to inform our medical paradigm (traditional and alternative alike).
I recommend that all individuals begin by questioning their own beliefs about their bodies, as well as questioning their healthcare practitioners and become an active participant in their own care process. Don't settle for unsatisfactory explanations to your questions and be empowered to learn more about how your body works through exploring many different resources and educating yourself. I always recommend that individuals seek qualified medical experts who are versed in systems biology, can speak coherently about how different parts of the body influence other parts, and to run from all practitioners who tell them that their prospective treatment will involve only one targeted isolated area of the body.
Committing ourselves to ongoing critical evaluation of the world through the lens of science will not shrink our imagination, but encourage its development. Science is a creative endeavor at its heart, with world-changing hypotheses and theories often emerging from what many people had once historically considered "too extreme" or "unlikely" or "radical". Many of the pioneers of scientific thought were not popular at first and went against the grain with their ideas and postulates. Grounding ourselves in the language of science and then challenging science itself to expand and encompass experience more fully is the task of the true scientist and avid pursuer of knowledge and understanding. Questioning ourselves, our communities, our academic and medical institutions and refusing to accept lazy thinking or short-cut tunnel-vision solutions to systemic problems is our way forward.
(1) Chokshi DA, El-Sayed AM. J-Shaped Curves and Public Health. JAMA. 2015;314(13):1339-1340
(2) Heaney RP. Making Sense of the Science of Sodium. Nutr Today. April 2015. Vol 50 no. 2; 578S-581S
(3) Hayes DP. Adverse effects of nutritional inadequacy and excess: a hormetic model. Am J Clin Nutr August 2008. vol. 88 no. 2 578S-581S
(4) Ghallab A. In vitro test systems and their limitations. EXCLI J. 2013; Dec 12: 1024–1026
(5) Matula T. Validity of in vitro testing. Drug Metab Rev. 1990;22(6-8):777-87
(6) Emami J. In vitro - in vivo correlation: from theory to applications. J Pharm Pharm Sci. 2006;9(2):169-89
(7) Niki E. Assessment of antioxidant capacity in vitro and in vivo. Free Radic Biol Med. 2010 Aug 15;49(4):503-15
(8) Rahman K. Studies on free radicals, antioxidants, and co-factors. Clin Interv Aging. 2007 Jun; 2(2): 219–236
(9) Rizzo AM, Berselli P, Zava S, Montorfano G. Endogenous antioxidants and radical scavengers. Adv Exp Med Biol. 2010;698:52-67
(10) Bouayed J, Bohn T. Exogenous antioxidants—Double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxid Med Cell Longev. 2010 Jul-Aug; 3(4): 228–237
(11) Boeing H, Bechthold A, Bub A, Ellinger S. Critical review: vegetables and fruit in the prevention of chronic diseases. Eur J Nutr. 2012 Sep; 51(6): 637–663
About the Author
Heather Davis, MS, RDN, LDN, holds a master's degree in nutrition science and is accredited by the Academy of Nutrition and Dietetics as a registered dietitian nutritionist (RDN). She works as a clinical dietitian, educator, and medical writer specializing in neuroendocrine nutrition and advanced chronic disease medical nutrition therapy