Hormesis – What doesn’t kill you, makes you stronger.
If a little of something is good for you, more is not necessarily better, and might be worse.
Smoking more than ten modern tobacco cigarettes daily is the single biggest risk factor for progressive
periodontal disease as well as the stressed metabolism of syndrome X which includes diabetes, arthritis,
depression, heart and artery disease, stroke and cancer.
Even low levels of secondhand smoke are harmful to some populations (especially developing children
and the elderly). Most modern tobacco is sugar-cured, so habit-forming nicotine is now synergized with
the alluring addictive taste of inhaled caramelized sugar while we seek our primitively programmed oral
suckling rewards.
Diabetes is by itself the second biggest risk factor for modern society’s primary killer diseases. Diabetes
is controlled by eliminating addictive foods with high glycemic load such as boxed breakfast cereals,
breads, cakes, pancakes, waffles, pop-tarts, donuts, cookies, pretzels, French fries and chips of all
varieties.
Like modern corporatized tobacco, these favorite foods that trigger high blood sugar responses also
feature the tempting taste of caramelized sugar. Repeated high blood sugar response to these heated
and deformed food molecules creates a stressed metabolism with loss of homeostatic controls while
enhancing enzymatic caramelization and stiffening of our own tissues.
Toasted sugars become browned and rigidly shaped when glycated by heat. When our own tissues
stiffen and harden enzymatically due to high availability of sugar, it is called glycosylation. In industry
these AGEs (advanced glycation end-products) are also called acrylamides or polyacrylamides and they
are well known carcinogens.
Collecting increased AGEs in one’s body causes cataracts, wrinkles and age spots in the skin as well as
the rigidity, brittleness and neuropathy of old age. AGEs mimic heat shock protein in our bodies,
mimicking stress messenger-molecules created in response to burns or bacterial infection.
If AGEs are so bad for us, why do we love the taste of caramel so much? The controlled caramelization
of the sugars, starches and proteins in foods creating pleasing flavor nuances is the basis of most
modern cooking. Surprisingly, a little bit of such food derived stress is good for us, making us stronger
and able to handle bigger strains. It is just too cheap and easy for modern man to toast things, thus we
too frequently send these tasty but overwhelming biochemical stress-signals of ‘forest fire’ to our
primitive genes.
The challenging and controversial concept that poisons can heal when given in low doses is explored in
“Sipping from a Poisoned Chalice” (Science - Oct 17, 2003, Vol. 302). Organisms can respond with a
great variety of responses after exposure to a stimulus or chemical, be it beneficial, adaptive, or early
manifestations on a range to toxicity, overt toxicity as well as several of these in combination. For ages,
a small minority of people (mostly homeopaths) have also known through ‘provings’ that small doses of
poisons can paradoxically produce beneficial effects.
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Usually one expects a graded linear response to a stimulus from low to medium to high. Hormesis
describes the unexpected finding that in an organism, often a specific stressor or chemical is able to
induce biologically opposite effects at different doses; often there is a stimulatory or beneficial effect at
very low doses and an inhibitory or toxic effect at higher doses.
The wide range of hormetic effects (stress resistance, altered metabolism with increased growth,
fecundity, genetic stability and longevity, immune-regulation as well as decreased disease incidence)
indicates that these changes are fundamental endurance responses of the organism that affect
thousands of genes. Although there is no single specific hormetic pathway, there seems to be a
common biological continued existence strategy underlying such beneficial observations.
Hormesis defines the capacity of a chemical or physical agent to condition the physiological state of an
organism to tolerate higher stress with very low doses of otherwise harmful agents. Evolutionary
evidence demonstrates that the continued existence and longevity of species hinge on their optimal
ability to resist stress challenge. Hormesis is a potent survival strategy to stimulate latent repair
processes to enhance overall tolerance to challenge.
It is common wisdom that an infant benefits from earlier rather than later exposure to the world at large
and that without such challenges is unlikely to cope as well with sudden delayed exposure. This
hormetic principle extends into adulthood and fades with senescence.
Brief whole-body exposure to cold water increases both activity and numbers of peripheral natural
killer (NK) cells and CD8+ T lymphocytes. Likely transient activation of the sympathetic nervous system,
the hypothalamic-pituitary-adrenal axis as well as the hypothalamic-pituitary-thyroid axis results in a
brief action of norepinephrine, adrenocorticotropic hormone (ACTH), beta-endorphin as well as thyroid
hormones {triiodothyronine (T3) and thyroxine (T4)} on cytotoxic T lymphocytes and NK cells.
Cold water stress enhances survival with its analgesic effect and by encouraging cellular immunity while
reducing tumor formation and autoimmunity.
A wide variety of physical, chemical and biological agents exhibit hormetic effects, including heavy
metals, pesticides, antibiotics, chemotherapeutic agents, vitamins, hormones and hormone mimics like
plasticizers, ethanol, aldehydes, chloroform, pro-oxidants, hypergravity and ionizing radiation.
Glucose and oxidation-mediated protein and DNA damage are common underlying causes of many agerelated diseases. Physiological hormetic conditioning may trigger: 1) activation of latent stress
resistance pathways of youthful DNA repair; 2) increased resistance to oxidizing pollutants; 3)
improved protein structure and function; 4) improved immunity; 5) damaged tissue remodeling; 6)
adjustments in central and peripheral nervous systems; 7) altered metabolism; and 8) delay or breaking
of inappropriate protein cross-links.
The hormetic dose–response challenges long-standing beliefs about the nature of the dose–response in
a low dose zone and has the potential to affect significantly the design of pre-clinical studies and clinical
trials as well as strategies for optimal patient dosing in the treatment of numerous diseases.
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Hormetic messengers or mimetics may help prevent cancer, diabetes, age-related diseases, infectious
diseases, heart and kidney failure, cardiovascular diseases and Alzheimer’s disease. Small nucleotide
SOS signals, dipeptides, ethanol, thiols and metals as well as conserved peptide sequences found in
sharks, frogs, woodchucks and bears, can regulate cytokines, cellular immunity as well as central and
peripheral neuronal regulatory pathways to promote healthy blood pressure maintenance, heart rate
and metabolic pathways, reducing disease sensitivity.
Stress mimetics rejuvenate DNA as well as enhance repair of proteins and thus may intervene in aging,
disease and trauma. Deltorphins (stress-induced hibernation-induction trigger mimetics which fit delta
endorphin receptors), come to light as new hormetic agents, effective both as pre and post exposure to
physiological conditioners to tolerate trauma as well as prevent damage, and possibly delay aging.
Botulinum
Botulinum is one of the most poisonous substances known. A gram of botulinum toxin, if dispersed and
ingested could kill 20 million people. Yet, Botox treatment to remove wrinkles is botulinum in
extremely dilute form.
Other applications include relief of migraines, a cure for crossed eyes as well as a treatment for the
spastic conditions of multiple sclerosis and cerebral palsy. A combination of botulinum and a protein
from the Mediterranean coral tree could provide a treatment for the chronic pain that afflicts millions of
people, including cancer patients.
Treatments with botulinum toxin can often help focal dystonia, a misfiring of the brain that causes
muscles to contract into abnormal and sometimes painful positions. This career threatening disorder
often strikes those who depend on small motor skills: musicians, writers and surgeons.
Hydrogen sulfide (H2S)
According to the OSHA fact sheet, hydrogen sulfide is a colorless, flammable, extremely hazardous gas
with a “rotten egg” smell. Hydrogen sulfide is heavier than air and may travel along the ground. It
collects in low-lying and enclosed, poorly-ventilated areas. Hydrogen sulfide is both an irritant and a
chemical asphyxiant with effects on both oxygen utilization and the central nervous system.
Its health effects can vary depending on the level and duration of exposure. Repeated exposure can
result in health effects occurring at levels that were previously tolerated without any effect.
Low concentrations irritate the eyes, nose, throat and respiratory system (e.g., burning/tearing of eyes,
cough, shortness of breath). Asthmatics may experience breathing difficulties. The effects can be
delayed for several hours, or sometimes several days, when working in low-level concentrations.
Repeated or prolonged exposures may cause eye inflammation, headache, fatigue, irritability, insomnia,
digestive disturbances and weight loss.
Moderate concentrations can cause more severe eye and respiratory irritation (including coughing,
difficulty breathing, and accumulation of fluid in the lungs), headache, dizziness, nausea, vomiting,
staggering and excitability.
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High concentrations can cause shock, convulsions, inability to breathe, extremely rapid
unconsciousness, coma and death. Effects can occur within a few breaths, and possibly a single breath.
Hydrogen sulfide is considered a broad-spectrum poison, meaning that it can poison several different
systems in the body, although the nervous system is most affected. The toxicity of H2S is comparable
with that of hydrogen cyanide. It forms a complex bond with iron in the mitochondrial cytochrome
enzymes, thereby blocking oxygen from binding and stopping cellular respiration.
Since hydrogen sulfide occurs naturally in the environment and the gut, enzymes exist in the body
capable of detoxifying it by oxidation to (harmless) sulfate. Hence, low levels of sulfide may be tolerated
indefinitely. However, at some threshold level, the oxidative enzymes will be overwhelmed.
Hydrogen sulfide is produced in small amounts by some cells in mammals and has a number of biological
functions. It is enzymatically produced from cysteine. It acts as a vasodilator and is also active in the
central nervous system, where it increases the response of the NMDA receptor and facilitates memory.
Eventually the gas is converted to sulfites and further oxidized to thiosulfate and sulfate. Due to its
effects similar to NO (without its potential to form free radicals by interacting with superoxide),
hydrogen sulfide is now recognized as a potential cardioprotective agent. Vasoactivity of garlic is partly
caused by catabolism of the polysulfide group in allicin to H2S, a reaction which likely depends on
reduction mediated by glutathione (which the other parts of garlic help recycle).
Hydrogen sulfide binds to cytochrome oxidase and thereby prevents oxygen from binding, which leads
to the dramatic slowdown of metabolism. Animals and humans naturally produce some hydrogen
sulfide in their body, perhaps to regulate metabolic activity and body temperature.
Mice can be put into a state of suspended animation like hypothermia by applying a low dosage of
hydrogen sulfide (81 ppm H2S) in the air, roughly the amount that will cause eye damage to humans at
work. If the H2S-induced hibernation can be made to work in humans, it could be useful in the
emergency management of severely injured patients and in the conservation of donated organs.
Several interrelated cellular signaling molecules are involved in the process of hormesis. Examples
include the gases oxygen, carbon monoxide and nitric oxide, the neurotransmitter glutamate, the
calcium ion and tumor necrosis factor.
In each case low levels of these signaling molecules are beneficial and protect against disease, whereas
high levels can cause the dysfunction and/or death of cells. Hormesis conditioning offers powerful
survival strategies. Combinations of several mimetics may more closely imitate environmental
challenges.
Oxygen
Hormesis may be induced by endogenously produced, potentially toxic agents. For example,
mitochondria consume oxygen which generates free radicals (reactive oxygen species) as an inevitable
by-product.
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The biochemical basis for the toxicity of oxygen is the partial reduction of oxygen by one or two
electrons to form reactive oxygen species, which are natural by-products of the normal metabolism of
oxygen and have important roles in cell signaling. One species produced by the body, the superoxide
anion (O2–), is likely involved in iron acquisition.
The superoxide radical serves as both an initiator and a terminator of the free radical-mediated chain
reaction resulting in lipid peroxidation. Lipid peroxidation is a universal feature of oxidative stress,
causing loss of cellular structure and function. Under any given conditions, the optimal concentration of
SOD is that which decreases chain initiation without elimination of the chain termination properties of
the radical, resulting in a minimum of net lipid peroxidation.
Higher than normal concentrations of oxygen lead to increased levels of reactive oxygen species.
Oxygen is necessary for cell metabolism, and the blood supplies it to all parts of the body. When oxygen
is breathed at high partial pressures, a hyperoxic condition will rapidly spread, with the most
vascularized tissues being most vulnerable. During times of environmental stress, levels of reactive
oxygen species can increase dramatically, which can damage cell structures and produce oxidative
stress.
While all the reaction mechanisms of these species within the body are not yet fully understood, one of
the most reactive products of oxidative stress is the hydroxyl radical (·OH), which can initiate a damaging
chain reaction of lipid peroxidation of the unsaturated lipids within cell membranes.
High concentrations of oxygen also increase the formation of other free radicals, such as nitric oxide,
peroxynitrite and trioxidane, which harm DNA and other biomolecules. Although the body has many
antioxidant systems such as glutathione that guard against oxidative stress, these systems are eventually
overwhelmed at very high concentrations of free oxygen, and the rate of cell damage exceeds the
capacity of the systems that prevent or repair it. Cell damage and cell death can then result.
Free radicals may induce an endogenous response cumulating in increased defense capacity against
exogenous radicals (and possibly other toxic compounds). Indeed, such induction of endogenous free
radical production through exercise extends life span of a model organism. Interestingly, this induction
of life span is prevented by antioxidants, providing direct evidence those toxic radicals may hormetically
influence the mitochondria and exert life extending and health promoting effects.
Since mitochondrial activity was found to be increased in the before-mentioned studies, this effect
cannot be explained by an excess of free radicals that might mark mitochondria for destruction by
lysosomes, and that the free radicals act as an apoptotic signal within the cell indicating which
mitochondria are ready for destruction.
Carbon Monoxide
Carbon monoxide is an example of a ‘pollutant’ that is important for human existence. This deadly gas
that kills thousands each year offers potential help for a number of medical conditions.
There are pathogenic implications for conditions that substantially raise the tissue CO content and
produce oxidative stress, such as smoking, air pollution and CO poisoning as well as hemolytic or
inflammatory states that accelerate heme turnover. Although carbon monoxide inhalation can be lethal,
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our bodies make CO molecules naturally in small amounts when an enzyme called heme-oxygenase-1
(HO-1) breaks down a portion of the blood protein hemoglobin.
Ventilator-induced lung injury (VILI) is a major cause of morbidity and mortality in intensive care units.
The stress-inducible gene product, HO-1 and carbon monoxide, a major by product of the oxygenase
catalysis of heme, have been shown to confer potent anti-inflammatory effects in models of tissue and
cellular injury. Inhaled low-dose CO might be useful in minimizing VILI.
Small amounts of carbon monoxide might alleviate symptoms of multiple sclerosis, a study in mice
suggests. Other studies of laboratory animals suggest that carbon monoxide in small doses can prevent
injury to blood vessels caused by surgery. In this study, rats that inhaled carbon monoxide-laced air for 1
hour before angioplasty had much less subsequent artery blockage than did rats not receiving the gas.
Rats that underwent a vessel transplant also fared significantly better if given carbon monoxide before
and after the surgery.
Low concentrations of CO act very rapidly on the macrophage and induce stabilization of the
transcription factor hypoxia inducible factor 1α (HIF1α), a potent oxidant stress response gene
responsible for regulating gene expression involved in angiogenesis, metabolism and survival. The
ability of CO to increase HIF1α activity is mediated in part by a highly significant and transient burst
of reactive oxygen species (ROS) arising from the mitochondria.
CO-mediated HIF1α activity then leads to the induction and secretion of TGFβ, a potent antiinflammatory cytokine. The induction of both HIF1α and TGFβ by CO are necessary to rescue lung
macrophages from anoxia/reoxygenation-induced apoptosis and ischemia-reperfusion injury.
Modest increases in cellular CO concentration activate mitochondrial biogenesis. Mitochondrial
generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart.
Mitochondrial CO and H2O2 are activating factors in cardiac mitochondrial biogenesis. Mitochondrial
H2O2 production deriving from CO binding to cytochrome c oxidase is an activating factor in
mitochondrial biogenesis.
Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1
(NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1 , and of
mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA
(mtDNA). This is independently of nitric oxide synthase (eNOS and iNOS) or hypoxia.
Nitric oxide (NO)
Nitric oxide is an air pollutant produced by cigarette smoke, automobile engines and power plants. NO
is also an important messenger molecule involved in many physiological and pathological processes
within the mammalian body both beneficial and detrimental. Appropriate levels of NO production are
important in protecting an organ such as the liver from ischemic damage.
However sustained levels of NO production result in direct tissue toxicity and contribute to the vascular
collapse associated with septic shock, whereas chronic expression of NO is associated with various
carcinomas and inflammatory conditions including juvenile diabetes, multiple sclerosis, arthritis and
ulcerative colitis.
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The dilating mechanism is mediated by the formation of gaseous nitric oxide from nitrites. Nitric oxide
(NO) is a molecule used by the endothelial cells lining the surface of blood vessels to signal surrounding
muscle to relax, leading to a reduction in blood pressure, reduced blood clotting and protection against
myocardial infarction and strokes.
Coexpression of eNOS, VEGF (vascular endothelial growth factor) and angiopoietin-1 results in more
mature vascularization of connective tissue, and generates new arterioles as well as new capillaries.
Combining hemodynamic forces with growth factors provides a more physiological therapeutic
approach than single growth factor administration.
VEGF is part of a sub-family of cystine-knot growth factors including platelet-derived growth factor
(PDGF) and placenta growth factor. Cystine knots are the result of an unusual arrangement of six
cysteine residues.
Cystine knot structures are found in nerve growth factor, tumor growth factor-beta, chorionic
gonadotropin, luteinizing hormone, follicle stimulating hormone and thyrotrophin (thyroid stimulating
hormone or TSH) also contain subunits with a cystine knot structure. Sulfur-containing cysteine does
much more than function as the rate-limiting amino acid for the formation of critical glutathione, so
pivotally important for energy production and cellular immunity.
VEGF production is induced in cells that are not receiving enough oxygen (as in anemia induced by
nitrite-induced methemoglobin). When a cell is deficient in oxygen, it produces HIF, hypoxia inducible
factor, and a transcription factor which stimulates the release of VEGF, among other functions (including
modulation of erythropoeisis). Circulating VEGF then binds to VEGF receptors on endothelial cells,
triggering a tyrosine kinase pathway leading to angiogenesis.
Generation of contractile microvessels (arteriogenesis) is required for the development of therapeutic
angiogenic strategies. This can be achieved by combining vascular growth factors (VEGF and
angiopoietin-1) with eNOS over expression, providing extra messaging for neovascular gene therapy.
However, excessive production of NO can lead to efficiently feeding new tumors, macular degeneration,
diabetic retinopathy, hypertrophy of kidney glomeruli allowing proteinuria or the production of toxic
oxidizing peroxynitrites, causing arterial injury or neuropathy leading to ‘brain on fire’ expressed as
cognitive dysfunction, Alzheimer’s or Parkinson’s disease.
The formation of reactive nitrogen species is not the usual consequence of synthesizing NO. NO is
efficiently removed by reacting with circulating oxyhemoglobin to form nitrate, which prevents even the
highest rates of NO synthesis from directly reacting with oxygen to form significant amounts of nitrogen
dioxide.
However, the simultaneous activation of superoxide synthesis along with NO will completely transform
the biological actions of NO by forming peroxynitrite. Several enzyme complexes, such as NADPH
oxidases (NADPHox) and xanthine oxidase (from pasteurized cow’s milk protein), can be activated in
many cellular systems to actively produce large amounts of superoxide.
What happens when superoxide and NO are produced simultaneously in close proximity? Modestly
increasing superoxide and NO each at a 10-fold greater rate will increase peroxynitrite formation by
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100-fold. Under proinflammatory conditions, simultaneous production of superoxide and NO can be
strongly activated to increase production 1,000-fold, which increases peroxynitrite formation by a
1,000,000-fold.
Without superoxide, the formation of nitrogen dioxide by the reaction of NO with oxygen is miniscule
by comparison. However, NO and superoxide do not even have to be produced within the same cell to
form peroxynitrite, because NO can so readily move through membranes and between cells.
NO is mostly removed by reacting with oxyhemoglobin to form nitrate, with only a small fraction being
oxidized by heme proteins. NO is the one molecule produced in high enough concentrations and reacts
fast enough to competitively react with endogenous SOD (superoxide dismutase) for superoxide. Nitric
oxide reacts rapidly with superoxide to form the potent free radical peroxynitrite.
Cells can be activated to produce large amounts of superoxide by specific NADPH oxidases and other
enzymatic sources. Because the rate of peroxynitrite formation rises 100-fold for each 10-fold increase
in superoxide and NO production, the production of superoxide offers a dynamic mechanism to redirect
NO from being a signaling molecule to an important component of host-defense and innate immunity.
This primary peroxynitrite weapon of the immune system is usually tightly controlled within the
peroxisomes of white blood cells. Unbuffered peroxynitrites may produce a number of types of tissue
damage, including free radical damage to the mitochondria (energy producing organelles within cells)
and to cell membranes through oxidative chain reactions. Adequate recycled reduced glutathione from
precursors and fresh organic foods is the key to quickly quenching peroxynitrites.
Extreme caution must be exercised in adding nitrate or nitrite to meat, since these ingredients tend to
be toxic to humans. In using these materials never use more than called for in the recipe. A little is
enough.
Potassium nitrate can cause gastroenteritis (violent stomach ache), low blood pressure, anemia, kidney
disease as well as general weakness and torpor. It also has an alarmingly depressive effect on the heart.
Potassium nitrate and other nitrates do successfully combat high blood pressure and are used medically
to relieve angina and cold vasoconstrictive migraine. Potassium nitrate is also used in dental cements
and toothpastes to instantly desensitize hypersensitive teeth.
Nitrates themselves are relatively nontoxic. However, when swallowed, especially if one has low
stomach acid, opportunistic bacteria convert nitrates to nitrites that can react with circulating
hemoglobin, oxidizing its divalent iron to the trivalent form and creating methemoglobin.
Methemoglobin cannot bind oxygen, which decreases the capacity of the blood to transport oxygen so
less oxygen is transported from lungs to body tissues, causing methemoglobinemia.
Normal individuals have low levels (0.5-2%) of methemoglobin in their blood. When this level increases
to 10%, the skin and lips can take on a bluish tinge (cyanosis) and levels above 25% can cause weakness
and a rapid pulse. At levels above 50-60%, a person can lose consciousness, go into a coma and die.
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Infants are much more sensitive than adults to nitrates/nitrites. Essentially all deaths from
nitrate/nitrite poisoning have been in infants. Long-term exposure to nitrates and nitrites can cause
diuresis (an increase in the excretion of urine, and starchy deposits or hemorrhaging in the spleen).
Nitrates are found naturally in spinach, eggplant, beets, green lettuce, turnip greens, green beans,
carrots, radishes, celery and collards. Most babies’ liver detoxification enzyme systems are well enough
developed by 9 months of age to handle purees of these wonderful fiber-rich and nitrate-rich foods.
Nitrogen in chemical fertilizers oxidizes into nitrates that these plants absorb. These nitrates cause part
of the bitter flavor associated with some greens such as collards. Organic vegetables contain
significantly less nitrates because natural compost is used to fertilize the soil.
Organic vegetables are also richer in polyphenols, antioxidants, vitamins and minerals. Nitrate fears
should not be used as an excuse to avoid them, since their fibers safely sequester nitrites. It is,
however, one more reason to vote ‘organic’ with your food-purchasing dollar.
Homeopathy and Water
Hormesis validates homeopathy, which is controversial (mostly to conventional medical doctors whose
minds have been brutally trained to think only linearly). The homeopathic therapeutic concept believes
that extremely diluted toxicants can be beneficial to human health, relieving similar symptoms
generated by larger doses. Hormesis is truly a real biological phenomenon, supporting the homeopathic
concept of “like treating like.”
Homeopathic vaccinations actually create a balanced and modulated immune protection, creating more
regulatory or suppressor T-cells as opposed to the expected imbalances (diminished cellular immunity
and heightened autoimmunity) created by the far more toxic injected vaccines with the added immuneirritating adjuvants of corporate conventional medicine.
Most vaccinated people end up with depressed cellular immunity (since the skin trigger of cellular
immune response was bypassed with the shot) and increased humoral immunity (which means more
autoimmune disease and cancer). Even more insidious, depending on whether the injected medicine
ends up in an artery (where it becomes a major immune insult) or the planned muscle or subcutaneous
tissue, small percentages of children with weak detoxification systems are much more severely injured.
Everyone knows water. It shapes our bodies and supports life on our planet. But despite the magical
liquid’s ever presence, the molecular structure of water remains a mystery. Water exhibits a strangely
varying density, large heat capacity and high surface tension at temperatures which are relevant to life.
Compared to other liquids, water has bizarre properties that are still poorly understood. The molecular
structure of water might be compared to a crowded club with a dance floor, where participants (the
molecules) switch between dancing excitedly and sitting in orderly fashion at tables. Water molecules
can form long polymers of dipoles associated by hydrogen bonds and the electromagnetic radiations
that they emit enable them to avoid decay.
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Water molecules polymerize themselves solidly in ice, and form a less-dense tight “tetrahedral” lattice,
with each molecule binding to four others. As ice melts, water’s tetrahedral structures theoretically
loosen their grip globally, breaking apart consistently as the temperature rises, but all still striving to remain as tetrahedral as possible, resulting in a smooth distribution around distorted, partially broken tetrahedral structures.
New X-ray studies of liquid water surprisingly found two distinct structures (either very disordered or
very tetrahedral) that exist no matter the temperature. The two types of structure are spatially separated, with the tetrahedral structures existing in clusters made of up to about 100 molecules surrounded
by disordered regions. Organized tetrahedral water is low-density and chaotic water is higher in density.
Most “normal” liquids become denser, or molecularly more packed, as they get colder. Water however,
reaches its maximum density at about 4 degrees Celsius. Above and below this temperature, water is
less dense; this is why lakes freeze from the surface down.
Water also has an unusually large capacity to store heat, which stabilizes ocean temperatures, and a
high surface tension, which allows insects to walk on water, droplets to form and trees to transport water to great heights.
Water is a fluctuating mix of the two molecular organizations at temperatures ranging from ambient to
all the way to near the boiling point. As the temperature of water increases, fewer and fewer of these
clumps exist; but they are always there to some degree, in clusters of a similar size. The disordered regions themselves become more chaotic as temperature rises.
Clusters of molecules within liquid water have been discovered, identified and characterized that form
unique stable (non-melting) ‘ice crystals’ that maintain a vibrational memory of the diluted material as a
characteristic subtle electromagnetic field. These nanometer-sized, rod-shaped water clusters (specific
aqueous nanostructures) are created when a substance is placed in distilled water, then vigorously
shaken or stirred, and then homeopathically repeatedly diluted ten times while again and again being
vigorously shaken or stirred.
Some bacterial DNA sequences induce electromagnetic waves at high aqueous dilutions (a newly
discovered energetic property of DNA). It seems to be a resonance phenomenon triggered by the
ambient electromagnetic background of very low frequency waves.
The aqueous solutions were strongly agitated and serially diluted since this step was “critical for the
generation of signals”. Pathogenic bacteria and viruses show a distinct electromagnetic signature at
water dilutions ranging from 10(-5) to 10(-12) (corresponding to 5X to 12X) and small DNA fragments
(responsible for pathogenicity) are solely accountable for the electromagnetic signal.
One experiment found significant effects from dilutions as high as 10(-18) (equivalent to 18X). The
electromagnetic signature changed with dilution levels but was unaffected by the initial concentration
and remained even after the remaining DNA fragments were destroyed by chemical agents.
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These characteristic frozen crystals of magnetically organized clusters of harmonically vibrating water
molecules remain stable at high temperatures, and its intriguing that the ice crystals seem to still exist
with varying fluctuation even after 23 repeated dilutions (which is beyond Avogadro’s number, meaning
no original molecules of the formerly potent or dangerous diluted substance seem to remain in the
diluted and shaken water, only traces of its stored electromagnetic vibrational memory).
The phenomena of hormesis and toxicity thresholds are likely related to activation of allostatic
adaptive pathways responsible for cellular and physiological homeostasis (our ‘steady state’).
Disruption of homeostasis triggers modest overcompensation and the reestablishment of harmonic
homeostasis via the adaptive nature of this process.
Thus, fasting, heat shock or hot and cold hydrotherapy, pro-oxidants like mega-dose vitamin C, one or
two alcoholic drinks per day, plant polyphenols and aldehydes, moderate exercise as well as mild
irradiation or sunshine can all be interpreted by our genes as gentle beneficent stressors.
The key factor in the hormesis concept is not the irritant or chemical, but the organism’s response of
overcompensation to a disruption in homeostasis. Therefore, any agent or stressor can induce a
hormetic response, depending on dose.
Homeostasis is defined as the maintenance of a constant internal environmental state for efficient
functioning and performance of the organism. However, convincing arguments have been put forward
to replace the term homeostasis with homeodynamics, taking into account the harmonic dynamic
rhythmic nature of living processes within the ever-changing parabolic wave of life.
The harmonic vibrational pattern of these internal rhythms inherently resists perturbation. A critical
part of the homeodynamic character of living systems is their capacity to respond and adapt to
environmental stress. In this context, the term "stress" is defined as a signal generated by any physical,
chemical or biological factor (stressor), which, in a living system, initiates a series of biochemical events
in order to counteract, change and survive by maintaining allostasis (the compensatory steady state).
Thermoregulation, detoxification, cell proliferation or reduction through apoptosis, DNA repair, heat
shock protein synthesis, protein turnover and antioxidative responses are some of the crucial
homeodynamic responses. Often, these survival mechanisms are common to several stresses as well as
different species, and have been given a collective term "the general-adaptive syndrome."
Relatively small individual hormetic effects can become biologically amplified resulting in the collective
significant improvement of cellular, tissue and organ functions enhancing survival of the whole
organism. Higher exposure switches cells to a stressed state when allostatic load reaches the limit of
homeostatic control. In the highly stressed state of exhaustion, the immune system typically becomes
activated leading to inflammatory responses.
Cells in adaptive or stressed state can still return to normal, unstressed state after removal of the
stressor, depending on duration. However, very high doses of stressors for too long are likely to drive
cells irreversibly to a toxic state, where cells die by apoptosis or necrosis.
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Apoptosis is an active, programmed self-terminating process of the cell in the event that the cellular
damage is too large to be repaired or worth repairing, or the cell’s continued survival no longer benefits
the organism as a whole. As opposed to overwhelming toxicity or excessive inflammation inciting
explosive cellular death by necrosis, quiet apoptosis eliminates only damaged parts, while prepackaging
cellular components for efficient reclamation and reuse by associated phagocytic white blood cells.
As early as 1898, studies in radiobiology found that irradiated algae grew more quickly than nonirradiated controls. Physicians, the public and research scientists showed much interest in the possible
beneficial effects of low levels of radiation.
Such enthusiasms were soon dampened by reports of deaths and severe injury from large amounts of
radiation. After Herman Muller's 1928 publication on genetic damage in fruit flies, radiation became
associated with chromosome damage. Data published in the 1930s-1950s again showed small amounts
of radiation to be beneficial to biofilm cellular growth and repair, explained by hormetic concepts.
Considerable money and effort has been spent to reduce radiation doses to the lowest possible level,
since most people have come to believe there is no safe level of radiation. Some of these efforts may be
misplaced, since the radiation fear is based on the incomplete linear ‘no-threshold theory’ of
carcinogenesis, which theorizes that "if 1 Gy (100 rad) of exposure gives a cancer risk R, then the risk
from 0.01 Gy (1 rad) of exposure is R/100, the risk from 0.00001 Gy (1 mrad) is R/100,000, straight on to
infinity.
According to the errant no-threshold theory, the cancer risk is not zero regardless of how low the
exposure (since we are surrounded by ambient radiation). In terms of imaging exams, a hormetically
beneficial back-to-front chest x-ray delivers a surface entrance dose of about 0.02 cGy (rad), at least 100
times lower than the moderately risky dose of 2-5 cGy (rads) of a standard chest CT.
According to the no-threshold theory, "a single particle of radiation hitting a single DNA molecule in the
nucleus of a single cell of the human body can initiate a cancer." "The probability of such a cancer
initiation is theoretically proportional to the number of such hits, which is proportional to the number of
particles of radiation, which is proportional to the dose. Thus risk is proportional to the dose."
But real-world experience does not jibe with this theory. Working to prevent most cancers are the
body's defense mechanisms. The body produces enzymes that repair 99.99% of cell damage, and lowlevel radiation is now known to hormetically stimulate apoptosis, by which damaged or defective cells
"commit cell suicide" quietly eliminating themselves before they become tumors.
Cancer mortality rates actually decrease following exposure to low dose irradiation. Hormesis (Greek
HORMO = I excite) strictly speaking is the beneficial stimulation of any system by low doses of any agent.
Ultra low doses of many agents evoke a biologically positive effect; whereas large doses may produce a
harmful effect. The message is simple: small and large doses often induce opposite physiologic results.
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Radiation hormesis implies beneficial stimulation by small doses of ionizing radiation. Cancer induction
is the most feared action of large doses of ionizing radiation. Cancer mortality rates illustrate radiation
hormesis in humans. Large doses of ionizing radiation harmfully increase cancer mortality rates.
Since small doses decrease cancer mortality rates, low dose irradiation is surprisingly beneficial.
Although small doses of radiation or dietary stressors like plant polyphenols can stimulate cell and
cancer growth, the stimulation of different components of our complex immune system more than
compensates for simple cellular effects. The net effect is decreased cancer mortality.
Radiation-induced genomic instability, in which the progeny of irradiated cells display a high frequency
of nonclonal genomic damage, occurs at a frequency inconsistent with mutation. In human mammary
epithelial cells (HMEC) exposed to low doses of radiation, centrosome deregulation occurs in the first
cell cycle after irradiation, is dose dependent, and that viable daughters of these cells are genomically
unstable as evidenced by spontaneous DNA damage, tetraploidy and aneuploidy.
TGFbeta inhibition significantly increases centrosome aberration frequency, tetraploidy and aneuploidy
in nonirradiated HMEC. Rather than preventing radiation-induced or spontaneous centrosome
aberrations, TGFbeta selectively deletes unstable cells (which might become cancer) via p53-dependent
apoptosis. Radiation deregulates centrosome stability, which underlies genomic instability in normal
human epithelial cells, and that is opposed by low-dose radiation-induced TGFbeta signaling.
A study of naval shipyard workers who serviced nuclear-propelled ships compared workers who were
and those who were not occupationally exposed to radiation. Workers exposed to the highest levels of
radiation (> 0.5 cSv) had cancer mortality rate that was only 85% of the rate experienced by workers
who were not exposed. The most convincing finding was the very significant decrease of 24% in deaths
from all causes among workers exposed to the highest doses (U.S. Dept of Energy, 1991).
A study of lung cancer rates among women exposed to fluoroscopic examinations for TB came to similar
conclusions. Lung cancer rates among these Canadian women, as well as a one-point study of 10,000
tuberculosis patients in Massachusetts, showed a protective effect up to 20 cSv and 100 cSv (Radiation
Research, June 1995, Vol. 142:3, pp. 295-304; and Cancer Research, November 1989).
Radiation-induced noncancer health effects are not detectable for fetal doses below about 50 mGy (1
mGy =100 milli rad). Noncancer health effects may be expected after fetal doses >=100mGy and appear
to have the most significant effects between the gestational ages of 8-25 weeks. Dental x-rays barely
reach the fetus (except in a hormetic way) at .001 rads.
An average chest x-ray delivers only .00007 rads. A single mammogram film, on the other hand,
delivers .1-.2 rads. If two mammogram films are taken of each breast, then that means that a breast
would receive about .001 rads during a chest x-ray as opposed to about .2-.4 rads with a mammogram.
This means that a mammogram procedure can be 250-500 times more intense than a chest x-ray, if no
extra films are requested for clarification.
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Repeated mammograms do not improve survival rates and are associated with an increased risk to
cancer. Perhaps it is not the radiation. Some believe that the compression force used may rupture
existing cancer cells that are contained in a localized mass, and cause malignant cells to be released into
the bloodstream, thereby promoting metastatic cancer. Thermograms are a safer alternative and make
more sense because they can pick up an area that is cold or hot, before it has actually turned into
cancer. Mammograms farm for industry and find established cancers. Thermograms can prevent them.
Summary of the effects of chronic, whole body radiation exposures on four physiologic functions:
Beneficial radiation hormesis rises with up to a 100 fold increase in ambient levels of radiation. Positive
effects are represented by the defined area above the horizontal line. When compared with controls,
represented by the
horizontal line, larger dose
rates exert a negative
effect. Conclusion: “The
linear no-threshold theory
fails badly in the low-dose
region, because it grossly
overestimates risk from
low-level radiation. This
means that cancer risk
from diagnostic X-rays is
much lower than is usually
estimated, maybe zero."
This curve represents the classic hormetic response to stressors, the most common form of the
hormetic dose-response curve depicting low-dose stimulatory and high-dose inhibitory responses, the or inverted U-shaped curve. Just the opposite may occur with the hormetic dose-response curve
depicting low-dose reduction and high-dose enhancement of adverse effects, the J- or U-shaped curve.
Minimal dose detectable by chromosome analysis is 5-25 rads. Typical chest X-ray with two views is
1/20 rad. A cervical or thoracic spine study with multiple views is about ½ rad. Lumbar spine views
dose us with 2 rads and a routine GI study with fluoroscopy is 5-10 rads. Head CT (measured at the
center of a phantom) is 6rads; body CT (measured at the periphery of a phantom, 1 cm beneath the
surface) is 4 rads.
As reported in Natural News, a study in the medical journal Radiology found that people who had
numerous CT scans over their lifetime had a significantly increased risk of cancer. In fact, many CT scans
increased the risk to cancer by 2.7-12%.
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Many medical imaging techniques, including cardiac angiography and CT scans, often involve the use of
contrast agents, substances that contain iodine (like iopamidol and iodixanol) and barium, because they
enhance the contrast between body structures or fluids within the body. This allows blood vessels and
changes in tissues to be more clearly visualized.
Exposure to contrast agents can cause damage even in seemingly healthy kidneys, but patients are
typically assured this is just a temporary side effect that will resolve on its own. If followed a year or two
after imaging with contrast however, 13% of patients experience a major event, such as death, stroke,
heart attack or end-stage renal disease. Those who developed contrast-induced kidney injuries had
twice as many long-term negative health effects as compared with patients who did not suffer kidney
damage.
The average total background radiation of about 1/3 rem per year roughly compares to having 7 (2
view) chest x-rays! (Another example of how low the exposures are for many diagnostic x-rays!)
Intra-oral (cavity-detecting dental bite-wings using film) measured exposure at skin entrance averages
250 milli rads. If skin doses are compared, many medical offices could produce all 7 cervical spine films
in a comprehensive study for less skin dose radiation than one or two traditional bite wing films! Intraoral (digital) average is about ¼ less, at around 70 milli rads.
Cephalometric (film) skin entrance is usually just 15 milli rads, similar to the chest. Literature reports
that the effective dose of a panoramic slitted view is but 0.3-1 milli rads. Jet flight exposes us to ½-1
mrem / hour in the air and luggage inspection 0.002 mrem.
Endogenous ligands for many receptors exhibit similar parabolic or biphasic dose-response curves, with
high doses being toxic. A prime example is glutamate, the major excitatory neurotransmitter in the
brain. In low to moderate amounts that are released from presynaptic terminals during the normal
activity of nerve cell networks, glutamate mediates processes such as learning and memory and sensorymotor behaviors.
Binding of glutamate to its receptors causes membrane depolarization and calcium influx through
ligand-gated and voltage-dependent calcium channels. The beneficial effects of low to moderate levels
of glutamate receptor activation result from calcium-mediated activation of transcription factors such as
nuclear factor (NF)-κB and CREB (cyclic AMP response element binding protein) that induce the
expression of genes that encode proteins that promote the survival and plasticity of neurons including
brain-derived neurotrophic factor (BDNF) and the anti-apoptotic protein Bcl-2.
However, excessively high levels of glutamate can overwhelm any hormetic pathways and kill neurons
by a process called excitotoxicity.
Mercury
Mercury deserves special mention since it is the most toxic non-radioactive substance in our
environment. At low micromolar concentrations, mercury uncouples tubulin, a structural protein
necessary for nerve formation and synapses as well as chromosomal reorganization during reproductive
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meiosis and mitosis. There seems to be almost no safe level (smallest micromolar amounts are
hormetic, less than ten millionths) of elemental mercury. Only very high homeopathic dilutions have
clinical use, usually to calm irritability and combativeness, relieve pain or aid detoxification of mercury.
Bacteria are even more vulnerable to damage from mercury than us. Before the age of antibiotics,
mercury was often used to treat syphilis. Doctors of the day noted initial salutary effects before toxicity
took over. People who were dull and phlegmatic became passionate about the issues of life, even to the
point of becoming combative. Now that we understand how dangerous elemental mercury is,
background exposure is already higher than beneficial hormetic levels (just like fluoride). However, at
the homeopathic vibrational level, benefit can be created just from the energetic imprint of mercury left
in the electromagnetic memory of water.
Fluoride
The range of fluorine-containing compounds is considerable as fluorine is capable of forming
compounds with all the elements except helium and neon. Structurally, and to some extent chemically,
the fluoride ion resembles the hydroxide ion. In biochemistry, fluoride salts are commonly used to
inhibit the activity of phosphatases, such as serine/threonine phosphatases. It may do this by replacing
the nucleophilic hydroxyl ion in these enzymes' active sites.
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The mechanism of toxicity involves the combination of the fluoride anion with the calcium ions in the
blood to form insoluble calcium fluoride, resulting in hypocalcemia; calcium is indispensable for the
function of the nervous system, and the condition can be fatal.
Fluoride-containing compounds are used in topical and systemic fluoride therapy for preventing tooth
decay. They are used for water fluoridation and in many oral hygiene products. Originally, sodium
fluoride was used to fluoridate water; however, the waste-product hexafluorosilic acid and its salt
sodium hexafluorosilicate are more commonly used additives, especially in the U.S. Public health
officials worsened the situation by adding fluoride (its current industrial waste source also increases the
amount and absorptive availability of lead, arsenic and aluminum) in our water. Fluoride ingestion or
absorption/inhalation greatly enhances uptake of radioactive elements, including iodine 131 and
strontium 90.
The fluoridation of water has been ‘scientifically proven’ (with the backing of the biggest fluoride
polluters) to prevent tooth decay and is considered by the U.S. Centers for Disease Control and
Prevention as "one of 10 great public health achievements of the 20th century".
It is a common theory that the reason fluoride was proven to reduce tooth decay in Michigan (a
glaciated area low in soil iodine, where hypothyroidism is endemic) was through a statistical trick. The
key statistical dental parameter improved (in Michigan) by adding one part per million fluoride in
community water was decayed, extracted or filled 6 year molars. Degrees of hypothyroidism
progressively delay the eruption of teeth. Fewer teeth results in fewer cavities.
The amount of fluoride a modern American gets from fluoridated water and contaminated foods is the
amount German physicians sometimes still use today to poison the thyroid to treat hyperthyroidism.
Further fluoride competition (with already low iodine) accentuated subclinical hypothyroidism and
delayed eruption of studied ‘6 year’ molars (perhaps slowed as much as a year) and accounted for
statistical improvement of decay scores. Delayed eruption of teeth was interpreted as a "benefit" in
fluoridated areas when same-age children's teeth were compared.
Fluoridation of water is however (especially since there is now so much in the environment), not
without critics. Russell L Blaylock, MD notes that fluoride is strongly associated with damaging DNA,
interfering with thyroid function leading to hypothyroidism, creating problems with fluoridated organic
molecules (Paxil, Prozac and some antibiotics), significantly increasing many types of cancer, increasing
heart disease, increasing oral cancer and even periodontal disease, reducing zinc in body tissues
(including the brain), increasing Down's Syndrome, reducing testosterone and sperm count, increasing
Alzheimer's and lowering IQ.
Perfluorinated chemicals, (pervasive in food packaging, pesticides, clothing, upholstery, carpets and
personal care products), may delay pregnancy. These chemicals are also commonly used in non-stick
cookware. Using non-stick cookware encourages ingesting perfluorinates, which are being phased out
in the U.S. because of their toxicity. However, they remain in the environment and in the body for
decades, and are linked to developmental problems. Danish women with high levels of
perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) take longer to get pregnant.
Women in the three groups with the highest levels of PFOS took from 70-134% longer to get pregnant
than women in the lowest quartile with the lowest PFOS levels. Women with the highest PFOA levels
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took 60-154% longer to get pregnant compared with women with lowest levels. In animals, these
chemicals have a variety of toxic effects on liver, immune system and developmental as well as
reproductive organs, also inducing impaired fetal growth.
Environmental contaminants such as PCBs, PBDEs, and mercury can alter brain neuron functioning even
before a child is born. These changes to the brain can be long-lasting. Stain-resistant chemicals, found in
up to 98% of Americans sampled in the late 1990s, are found in clothing, carpeting, upholstery, and
even the lining of food containers.
Hormone-like vitamin A also has hormetic effects. Vitamin A in relatively low amounts is essential for
normal development, immunity and eye function, but in high amounts can cause anorexia, dry skin,
headaches, drowsiness, altered mental states and immune suppression.
Studies on the use of the stressor alcohol have shown hormetic protective effects against coronary
heart disease. These studies show that one or two alcoholic drinks per day increases high-density
lipoproteins. Also, moderate alcohol consumption decreases low-density lipoprotein (LDL) cholesterol
and triglycerides. Finally, alcohol consumption decreases platelet aggregation.
Red wine has benefits that other sources of alcohol do not have. Red wine reduces C-reactive protein,
a marker of inflammation related to atherosclerosis and cancer. Red wine has higher concentrations of
antioxidant molecules, called polyphenols, than other alcoholic drinks, which protect against coronary
heart disease by reducing oxidation of LDL cholesterol. The polyphenols in red wine include
anthocyanins, proanthocyanidins and resveratrol, as well as flavonoids, including catechins, kaempferol
and quercitin.
Twelve healthy subjects imbibed either a vitamin-enriched beverage twice daily or the same vitaminenriched beverage supplemented with an additional 500 mg of the plant-based flavonoid quercitin.
Over a week-long period, participants were monitored to assess the amount of time it took to show
fatigue during a stationary bike riding session, as measured by VO2max (also known as maximal oxygen
consumption), a marker of physical fitness that measures maximal capacity of the body to use and
transport oxygen during exercise.
Supplementing with quercitin mimics exercise training in that it increased VO2max by 3.9% compared
to placebo, a marginal improvement. However, fatigue times told a very different story. Those who
received a quercitin boost showed a significantly higher 13.9% increase in physical stamina during bikeriding exercise.
Red wine tends to reduce mutagenic DNA damage and improve endothelial function when included in a
high fat diet. Wine can stimulate gastric acid secretion and gastrin release. Perhaps this is why
moderate to high wine intake seems to prevent Helicobacter pylori infection. Red wine may help to
prevent noise-induced hearing loss, reduce the risk of developing age-related macular degeneration,
may help to prevent cataracts and may help prevent rheumatoid arthritis.
Many studies suggest salutary roles of dietary phytochemicals produced in survival response to stress
in protecting against chronic disorders. Several dietary phytochemicals also benefit the nervous system
18
and, when consumed regularly, reduce the risk of disorders such as Alzheimer’s and Parkinson’s
diseases. Not all grapes (nor red wines) contain the same amount of resveratrol. Because resveratrol is
created by the grape plant primarily in response to fungus, grapes that are sprayed with fungicides
produce virtually no resveratrol. Only organically-grown plants produce the highest levels of resveratrol.
One general mechanism of action of phytochemicals is that they activate hormetic adaptive cellular
stress-response pathways. From an evolutionary perspective, the noxious properties of such
phytochemicals play an important role in dissuading insects and other pests from eating plants.
However at the relatively small doses in plants ingested by humans, the phytochemicals are not toxic
and instead induce beneficial strengthening through mild cellular stress responses.
Hormesis has been widely observed in biology and medicine, and has been described as
‘preconditioning’. Hormetic pathways activated by pigmented phytochemicals may involve kinases and
transcription factors that induce the expression of genes that encode antioxidant enzymes, protein
chaperones, phase-2 detoxifying enzymes, neurotrophic factors as well as other protective proteins. A
family of histone deacetylases called sirtuins has played pivotal roles in stress resistance through a vast
expanse of evolutionary history.
Specific examples of such pathways include the life-extending sirtuin–FOXO pathway triggered also by
calorie restriction or resveratrol, the protective (when tethered) proinflammatory NF-κB pathway and
the Nrf-2/ARE pathway, which upregulates expression of phase II detoxifying enzymes and antioxidants,
thus enhancing elimination of noxious stimuli. Hormetic phytochemical actions of the Nrf-2/ARE
signaling pathway are a classical expression of a neuroprotective mode of action of many specific dietary
phytochemicals.
The term hormesis is commonly used by toxicologists to describe the parabolic or biphasic dose
response curve where a chemical may have a beneficial stimulatory effect at ultra low doses, but
become harmfully toxic at high doses. This has led some to argue that environmental health standards
can be relaxed because if low doses are beneficial, then there is no need to achieve stringent cleanup
standards. However, low doses can sometimes have surprising impacts that cannot be predicted from
high dose experiments.
Hormesis as a programming modifier
Bisphenol A is moderately toxic at high doses and at ultra-low doses has even more problematic
hormone-like effects, (literally changing gene expression, sometimes at critical developmental phases).
Higher toxicological doses of estrogenic compounds like estradiol and bisphenol A act as a hormone
mimic through estrogen receptors, and can actually turn off genes turned on by lower doses.
Traditional high dose testing misses many low dose adverse effects. Current testing procedures are
vulnerable to dramatic under-estimations of health risks because of lack of knowledge of molecular
details of just how endocrine disruption of estrogenic signaling actually works.
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High doses of the estrogenic drug diethylstilbestrol cause weight loss in adults following exposure in the
womb. Lower doses (within the range that lead to a wide array of adult disorders of the reproductive
tract) have no effect on adult weight. But doses far lower than those (1 ppb) cause grotesque obesity.
Atrazine
For decades, farmers, lawn care workers and professional green thumbs have relied on the popular
weed killer atrazine to protect their crops, golf courses and manicured lawns. But atrazine often washes
into water supplies and has become among the most common contaminants in American reservoirs and
other sources of drinking water.
At high doses, atrazine is a neurological poison that can lead to Parkinson’s disease and is detoxified by
the cytochrome P450 enzymes (which have great individual variability), specifically CYP1A2. Caffeine,
melatonin, diflucan, clozapine and many other drugs are oxidized for detoxification by this enzyme, and
may overload the system.
Drugs like artemisinin or ethynil estradiol that inhibit CYP1A2 will predictably increase the plasma
concentrations of atrazine and many medications and in some cases adverse outcomes will occur. Of
particular note is fluvoxamine, which is a potent CYP1A2 inhibitor and also inhibits other CYP450
enzymes, such as CYP2C19, the most important CYP3A4, and to some extent CYP2C9. Thus, fluvoxamine
may prevent other metabolic pathways from compensating for the CYP1A2 inhibition. The
fluoroquinolone antibiotics, enoxacin and ciprofloxacin, also substantially inhibit CYP1A2.
Cigarette smoking upregulates and induces CYP1A2 enhancing detoxification of atrazine or reducing
beneficial levels of theophylline. Smoking, grilled meat and cruciferous vegetables or barbiturates also
reduce the serum concentrations and efficacy of the atypical antipsychotics, clozapine and olanzapine.
In recent years, five epidemiological studies published in peer-reviewed journals have found evidence
suggesting that small amounts of atrazine in drinking water, including levels considered safe by federal
standards, may be associated with birth defects — including skull and facial malformations and
misshapen limbs — as well as low birth weights in newborns and premature births. Such defects and
premature births are leading causes of infant deaths.
Some studies note that as atrazine concentrations rise, the incidence of birth defects grows. One study
done at Purdue University, published in the journal Environmental Health Perspectives — suggests that
concentrations as small as 0.1 parts per billion may be associated with low birth weights.
Atrazine may be safe during many periods of life but dangerous during brief windows of development,
like when a fetus is growing and pregnant women are told to drink lots of water. There are short, critical
times (like when a fetus’s brain is developing), when chemicals can have disastrous impacts, even in very
small concentrations.
The E.P.A. generally does not require water systems to notify residents unless the yearly average of
atrazine in drinking water exceeds 3 parts per billion, and under a determination made earlier this
decade, the agency considers one-day exposures of up to 297 parts per billion safe.
Another study suggests that concentrations of atrazine in drinking water below the E.P.A. thresholds
may disrupt menstrual cycles. Many of those studies examined large populations already exposed to
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atrazine and sought to exclude the effects of other contaminants and environmental or health factors.
However, such epidemiological studies cannot prove that atrazine causes specific diseases.
The concept of hormesis has been adopted in the fields of biology and medicine to describe the
adaptive response of cells and organisms to moderate stress. Mild stress induces the activation of
signaling pathways, leading to intrinsic changes conferring resistance to more severe stresses. Usually,
the stressor elicits molecular responses that not only protect the cell against higher doses of the same
agent, but also against other agents or even less specific stressors including oxidative, metabolic and
thermal stress.
Major components of the hormetic response include various stress resistance proteins such as heatshock proteins (which AGEs mimic), antioxidants and growth factors. Besides AGEs in caramels or toast,
classic examples of hormetic stress are hot and cold hydrotherapy, exercise and calorie restriction.
Studies have consistently demonstrated that moderate levels of exercise and calorie restriction
promotes good health, where higher levels are harmful.
Growing plants need protection against radiation, bacteria, fungi, viruses and hazardous environmental
changes. Plants concentrate defensive chemicals in their most vulnerable parts: leaves, flowers and
roots. Like the mild stress of a cold shower, an alcoholic beverage or two, moderate exercise or fasting,
many of these plant ‘poisons’ also exhibit hormetic properties, being harmful at high individual doses
yet being especially beneficial at harmonic combinations at dietarily relevant low doses from herbs,
vegetables and fruit as well as soaked seeds, beans, nuts and grains.
The hormetic non-linear biphasic dose-response exhibits a parabolic curve. A hormetic response is a
special case of a larger set of dose-response curves called ‘non-monotonic dose-response curves’,
because the slope of the curve changes direction somewhere along the curve. Thus, J-shaped or Ushaped or inverted-U shaped parabolic curves are all non-monotonic.
Curves contrast with linear monotonic responses (where an incomplete range of dilutions are tested,
creating a small linear section of a larger parabolic curvilinear response) in which the slope never
changes sign (in other words, if the curve or line is upward it always remains upward (although it can
change slope and flatten out).
Hormesis can be initiated by exposure to various environmental stressors including ingestion of
phytochemicals. Such exposures typically result in mild cellular stress involving free radical production,
ion fluxes and increased energy demand.
As a result, adaptive stress response pathways are activated leading to the synthesis of proteins that
protect the organism against more severe stress. Examples of stress resistance proteins include
antioxidants, protein chaperones, growth factors and proteins involved in the regulation of energy
metabolism as well as cellular calcium homeostasis.
The amounts of stress-inducing phytochemicals found in the fruits and vegetables usually consumed by
humans fall within the low-dose beneficial stimulatory range of concentrations. However, it is well21
known that some plants and fungi produce and concentrate toxins in amounts great enough to cause
sickness or death in humans.
Consumption of plant phytochemicals in form of concentrated supplements has the potential for
negative health consequences if the doses consumed exceed toxic threshold. Each individual
phytochemical would best be extensively evaluated (and then in combinations), including detailed doseresponse studies that reveal safety and effectiveness in regard to disease prevention. Low-dose
extrapolations employed in risk assessments will have to stay wedded to the low-dose linear and
threshold methodologies that are now favored until much more research is done.
Combinations of stimuli can have unpredictable outcomes. Mild to moderate exercise derives its
hormetic effect from the production of stressful reactive oxygen species. Moderate doses of antioxidant
vitamins can ‘mop up’ these mildly stressful oxidants, cancelling the benefit of exercise. Paradoxically,
large doses of antioxidant supplements increase oxidative stress, hormetically increasing tolerance to
other stressors.
UV hormesis can be thought of as an induced effect that occurs over intervals of time measured in
hours or days, in contrast to the virtually instantaneous damaging effects of UV on DNA. It relies on
eliciting a metabolic response by the plant tissue in countering what it perceives as an applied stress.
The response is chemical. For certain types of fruit, the compounds produced as a result of low-dose UV
treatment have been identified, including a wide range of phytochemicals and enzymes.
The critical factor is that these compounds confer resistance to attack by many different types of
microorganisms, and molds in particular. More importantly, these naturally occurring compounds and
microbial inhibition can be achieved without the use of exogenous biocides. Many species of fruits and
vegetables have been shown to respond to this form of treatment.
In commercial terms, this stress response offers a way to extend the shelf life of fresh commodities.
Hormetic treatments also have the potential to reduce waste through decreasing the rate of
senescence. However, much work remains to be done in scaling up laboratory studies to enable
hormetic treatments to be applied commercially.
There is another benefit of hormetic treatment, and that is that many of the compounds produced by
the plant in response to UV are actually beneficial to human health. The best studied example is
resveratrol in grapes (where recent work has shown that the levels of this cardio-protectant may be
increased many fold by treating grapes with low doses of UV).
The lethal effects of UV used as a germicide may be increased by combining UV treatment with the use
of powerful oxidants, such as hydrogen peroxide and/or ozone. Although both of these compounds are
moderately bactericidal in their own right, the added effect of UV is to bring about a synergistic
inactivation through the enhanced generation of highly reactive free radical species.
Ozone has been assigned the classification “generally recognized as safe” (GRAS), but hydrogen
peroxide residuals can persist in foods for considerable periods of time. This may prove problematic in
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the treatment of foods, as opposed to food processing equipment, or even the fabric of food processing
facilities. Careful control of peroxide concentration and UV dose is required to ensure total photolysis of
peroxide.
The evidence supporting health benefits of vegetables and fruits provides grounds for identification of
the specific phytochemicals responsible, and for investigation of their molecular and cellular
mechanisms of action. Practically all plants provide felicitous phytochemicals, here are a few:
The primary polyphenol found in flesh of grapes and concentrated in white grape juice,
hydroxycinnamic acids (also major phenolic acids in blueberries and blackberries) are a superset of
phenolic acids which includes p-coumaric, caffeic and ferulic acid (major phenolic acids in blueberries
and blackberries). Ferulic acid is abundant in cell walls of seeds of brown rice, whole wheat and oats
and rich in apple, artichoke, orange, peanut and pineapple.
Ferulic acid is precursor to vanillin and is antioxidant and anticancer, exhibiting antitumor activity in
breast and liver cancer. Vanillin (primary extract from vanilla bean) is antimutagenic and antioxidant,
inhibits carcinogenesis, is anti-inflammatory (inhibits peroxynitrite) and inhibits double-strand DNA
breaks. Cinnamic acid (phenyl acrylic acid) provides oil of cinnamon's characteristic odor and flavor. It
has antibacterial, antifungal and antiparasitic properties. Cinnamic acid is building block for lignans.
Ferulic acid is found in the leaves and seeds of many plants, but especially in cereals such as brown rice,
whole wheat and oats. Ferulic acid is also present in tomatoes, sweet corn, coffee, apple, artichoke,
peanut, orange and pineapple. Ferulic acid decreases the levels of inflammatory mediators
(prostaglandin E2 and TNF-α and nitric oxide synthase expression and function. Ferulic acid and its
esters are potentially powerful anti-inflammatory drugs. Ferulic acid belongs to the family of
hydroxycinnamic acid. The chemical structure of ferulic acid is very similar to that of curcurmin.
Curcumin (diferuloylmethane) is a component of the yellow powder prepared from the roots of
Curcuma longa (Zingiberaceae), also known as tumeric or turmeric. It is widely cultivated and used as a
food ingredient in tropical areas of Asia and Central America.
Treatment of mid-passage human epidermal keratinocytes with curcumin resulted in a biphasic
hormetic dose–response with respect to proteasome activity. Curcumin treatment (up to 1 μM for 24 h)
increased chymotrypsin-like activity by 46% compared to that in untreated keratinocytes. However,
higher concentrations of curcumin were inhibitory, and at 10 μM the proteasome activity decreased to
46% of its initial value.
Furthermore, the preincubation of human keratinocytes at 43°C for 1 h, followed by 24-h treatment
with 3 μM curcumin, led to an increase in heat-shock protein (hsp70 and hsp90) levels by 24% and 19%,
respectively, and the effect was sustained at concentrations up to 10 μM. On the other hand, the level
of the small hsp27 was unaffected by curcumin concentrations of 0.3–1 μM, while it decreased by 34%
at 10 μM.
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Chalcone is an α, β-unsaturated aromatic ketone present in ashitaba (Angelica keiskei Koidzumi), a
white turmeric traditionally used in Japanese’s cuisine. Chalcone has antibacterial, anti-fungal, antitumor and anti-inflammatory activities. The anti-inflammatory effects of chalcones rely on their ability
to regulate nitric oxide and cytokine production in macrophages, as well as to prevent tumor necrosis
factor-α and lipopolysaccharide-induced neutrophil adhesion. Chalcone also suppresses the activity of
cycloxygenase-2 and 5-lipoxygenase. Blood sugar leveler methyl hydroxychalcone is found in cinnamon.
Hops contain chalcones, xanthohumol and dehydrocycloxanthohumol hydrate.
Polyphenol compounds found in green tea include epigallocatechin-3-gallate (EGCG), epicatechin-3gallate (ECG), epigallocatechin (EGC) and epicatechin (EC), and their intake has been associated with
reduced risk of coronary artery disease. EGCG is the most abundant and active catechin derivative, and
has been shown to possess both anti-inflammatory and anti-atherogenic properties. EGCG up-regulates
hemeoxygenase-1 (HO-1) expression by hormetically activating the Nrf2/ARE pathway in endothelial
cells, conferring resistance against H2O2-induced cell death.
Luteolin is a widespread citrus flavonoid aglycon structurally related to quercitin. Most often found in
leaves, but it is also seen in dandelion, rinds, barks and clover blossom and ragweed pollen. Dietary
sources include celery, green pepper, thyme, as well as perilla and chamomile tea. Topical application of
luteolin causes significant reduction of skin tumor incidence and multiplicity in a mouse model. In cell
culture studies, luteolin has been shown to be a potent inhibitor of cyclin-dependent kinases, to induce
cell cycle arrest in human melanoma cells and apoptotic cell death in human myeloid leukemia cells.
Luteolin also sensitizes cancer cell lines to TNFα-dependent apoptosis by inhibiting the NF-κB pathway.
In addition to anticancer properties luteolin has also shown to protect neuronal cell lines against H2O2
induced oxidative damage.
Phenethyl isothiocyanate occurs naturally in cruciferous vegetables such as Chinese cabbage, turnips,
rutabagas, watercress and radishes. Isothiocyanate is liberated from its glucosinolate precursor
gluconasturtiin by hydrolysis following disruption (crushing, shredding and chewing) of the plant tissue
and liberation of the plant enzyme myrosinase. Glucosinolates have been shown to inhibit the tumor
causing effects of various carcinogens. Sulforaphane is a related phytochemical present in high amounts
in broccoli sprouts and cruciferous vegetables.
Piceatannol isolated from the seeds of Euphorbia lagascae, is a structural homolog of resveratrol and
both are found in red wine. Piceatannol is an anti-inflammatory, immune modulatory and antiproliferative compound. Piceatannol inhibits the release of nitric oxide, PGE2 and pro-inflammatory
cytokines in a dose-dependent manner. The protective effect afforded by piceatannol is reportedly
stronger than the effect of resveratrol.
Life extension and neuroprotective effects of resveratrol have been reported by many different
researchers. It protected cultured PC12 neural cells against Aβ toxicity and dopaminergic neurons in
midbrain slice cultures against several different insults. Resveratrol also protected hippocampal
neurons against nitric oxide-mediated death, prevented axon degeneration and protected nematode
and mammalian neurons against mutant polyglutamine toxicity.
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Resveratrol was found in varying amounts between 7- 5800 ng/g dry sample in bilberry, cranberry,
deerberry, Elliott's blueberry, highbush blueberry, lingonberry, lowbush blueberry, rabbiteye blueberry,
sparkleberry and Partridgeberry. Lingonberry was found to have the highest content comparable to that
found in grapes, 6500 ng/g dry sample.
Seanol is a unique patented polyphenol/phlorotannin extract from Ecklonia cava marine red/brown
algae grown off the coasts of Korea and Japan. Polyphenols, which are antioxidants found in many landbased products such as berries, tea leaves, grapes, pomegranates, fruits, and vegetables (and in Seanol),
have a molecular structure of two to four connected rings. These rings “trap” damaging free radicals.
Trans-resveratrol from red grapes has a two-ring molecular structure and, green tea has a four-ring
molecular structure. However, Seanol has similar polyphenols and phlorotannins, which have a more
sophisticated molecular structure of eight rings, which allows it to trap many more free radicals.
Seanol is both water and fat soluble, so it can easily penetrate phospholipid membranes, working inside
of cells for maximum protection. Even better, it easily crosses the blood/brain barrier to give the brain
extra antioxidant protection. Since Seanol is fat soluble, it stays in the body longer, as much as 12 hours,
compared to water soluble antioxidants which are excreted in the urine in roughly 30 minutes.
Seanol helps increase brain alpha waves, a good indication of relaxing blood vessels to the central
nervous system and increasing blood flow, promoting brain activity as well as increasing energy and
endurance. Seanol also helps stimulate the production of acetylcholine, the brain chemical of learning
and memory as well as the neurotransmitter that modulates and reduces immune inflammatory
response in the digestive system, joints and arteries via the vagus nerve.
Blueberry supplementation prevented learning and memory deficits in a mouse model of Alzheimer’s
disease. Dietary supplementation with blueberry extract increased the survival of dopamine-producing
neurons in a model relevant to Parkinson’s disease. Blueberries extract increased thermal stress
resistance and increased lifespan in the nematode, suggesting an evolutionary conservation of
phytochemical hormetic response pathways. Supplementation of the diet of 19 month-old rats with
strawberry, blueberry or spinach extracts for 8 weeks resulted in the reversal of age-related deficits in
several neuronal and behavioral parameters.
In an animal model of stroke, curcurmin (from turmeric) protected neurons against ischemic cell death
and ameliorated behavioral deficits. In a rat model of Parkinson’s disease, curcurmin protected
dopaminergic neurons against 6-hydroxydopamine toxicity. A hormetic mechanism of action of
curcurmin is likely since levels of expression of the stress response protein HO-1 were increased in
cultured hippocampal neurons treated with curcurmin. Curcurmin also has been shown to reverse
chronic stress-induced impairment of hippocampal neurogenesis and increase expression of brainderived neurotrophic factor in an animal model of depression. Wild ginger is also a likely candidate for
a hormesis effect.
The radium pad (low dosage radiation) is an example of hormesis from the Edgar Cayce readings.
The Cayce readings often extolled the healing properties of olive oil. The following story illustrates an
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unusual application involving very small amounts of olive oil taken orally for acid reflux (often caused by
large amounts of fat or oil):
"Seven years ago I had my gallbladder removed because of gallstones, and within a few months I
began to have acid reflux (heartburn). TUMS relieved it, but within a couple years I was up to four of the
largest size TUMS a day. Preferring to interfere with my digestive physiology as little as possible, I didn't
want to take any of the acid blocker medicines that are now available.
Instead, I recalled that the Cayce readings had said that olive oil taken in very small doses would be
soothing and healing to the digestive system, along its entire length. For example, reading 5422-2, given
for ulcers, said to take a half teaspoonful every few hours. Another reading, 760-7, for impacted colon,
explained that, "This character of oil, as seen, is food value for tissue that is deadened by inactivity
through the form of conditions existent in system." The readings were clear that small doses would be
the most effective, no more than a half a teaspoonful taken every few hours.
"I began to take very small doses of extra virgin olive oil (no more than a quarter or half of a teaspoon
about 4- 5 times a day), based on the most common recommendation in the readings. Within a couple
weeks I noticed that I had less need of TUMS. After a few months, I was down to needing at most one
TUMS a day, and most days no medicine at all. My overall digestion felt a lot better, too.
Aging is primarily the result of a failure of maintenance and repair mechanisms. Hormesis is a
promising approach for modulating aging and age-related diseases via modest stimulation of various
cellular and biochemical functional characteristics of human skin fibroblasts.
Beneficial effects include the maintenance of a favorable stress protein profile, reduction in the
accumulation of oxidatively and glyco-oxidatively misfolded damaged proteins (AGEs), stimulation of the
proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other
stresses and enhanced levels of cellular and mitochondrial antioxidant ability.
The progression of cellular aging can be slowed without upsetting the regulatory mechanisms of the
cell cycle by using the body’s intrinsic capacity for self-maintenance and repair, where through
protective low-dose toxin hormetic effects, the quality of life of cells in terms of their structural and
functional integrity can be improved without pushing them into a potentially carcinogenic hyperproliferative mode.
Progressive accumulation of molecular damage to human skin fibroblasts and keratinocytes, a hallmark
of cellular aging, is thus treatable by targeted biological hormetic interventions and preventions.
Application of hormesis as an anti-aging approach is gaining wide recognition and acceptance. Various
chemical stressors, including oxidants, both synthetic and natural (such as hydrogen peroxide and 1,4dioxane) are reported to delay aging and prolong life in various systems, when they act as hormetins.
Almost all antioxidants show hormetic dose response and become pro-oxidants above certain doses.
Furthermore, in some cases such as alpha lipoic acid and coenzyme Q10, it is their pro-oxidant activity in
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producing hydrogen peroxide (which induces defensive responses), which is the sources of their overall
beneficial effects.
Hormesis is a common phenomenon in dermatology. Skin is an excellent hormesis candidate due to its
repertoire of inflammatory and immune-modulating cytokines, hormones and vitamins, as well as its
unique responses to ultraviolet light, toxins and injury. More focus could be redirected from looking
only at adverse effects at high levels of exposure to characterizing the complex beneficial biological
effects that occur at low and ultra low levels of exposure.
Molecular mechanisms facilitating hormetic effects comprise of a cascade of stress response
maintenance and repair pathways. Although the extent of immediate hormetic effects after exposure to
a particular stress may only be moderate, chains of events following initial hormesis can lead to
biologically amplified effects that may be much larger, synergistic and pleotropic.
The consequence of hormetic amplification is increased overall cellular and systemic defense capacity
of the organism. Exposure to low doses of potentially harmful agents can have a variety of beneficial
anti-aging and longevity-extending hormetic effects. Too much stress can overwhelm and exhaust, but
the right amount can increase strength and endurance, prolong life and bring other benefits.
Just about any stimulus can be beneficial or harmful,
depending on dose, duration, perception and individual response.
Steven N. Green, DDS, 10261 SW 72 St., #106, Miami, FL, 33173, 305-273-7779
ddsgreen@bellsouth.net antiagingdentist.com
September 26, 2009
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