UNDER THE MICROSCOPE:While high levels of toxins are bad for you, low levels can be beneficial, writes Dr William Reville
THE WORD HORMESIS (from the Greek "to excite") was coined in 1943 to describe the phenomenon whereby high doses of a substance are toxic but low doses have a beneficial effect. This basic notion was first recognised by the Swiss alchemist and physician Paracelsus (1493-1541, the "father of toxicology") who wrote "all things are poison and nothing is without poison, only the dose permits something not to be poisonous".
The theory of hormesis was long treated with scepticism, but biochemists have now deciphered how it works. Hormesis is now accepted as a basic principle of biology and biomedicine and research is under way to elucidate how to apply it to improve our health.
The current situation was nicely summarised by Mark Mattson and Edward Calalese in New Scientist, on August 9th.
Two standard approaches are used in toxicology to describe the relationship between toxicity and dose. With some toxic agents, eg ionising radiation, it is assumed that there is no low threshold dose below which the agent is harmless. It is assumed that the only safe level of the agent is zero dose and above this level there is a linear relationship between dose and risk/effect - if you double the dose you double the effect.
With other substances it is assumed (based on evidence, of course) that they are neutral up to a certain threshold level, above which a linear relationship kicks in between dose and effect. In hormesis, in contrast, the dose-effect response is "biphasic" - low doses are beneficial, higher doses are toxic.
The majority of toxins exhibit hormesis, according to Mattson and Calalese. Ionising radiation has been well studied - low doses invigorate plants and extend the lifespan of mice, but high doses are lethal. Cadmium, arsenic and pesticides and some carcinogenic chemicals also display hormesis, and several vitamins (A, B6 and C) that improve health at low doses are toxic at high doses. Hormetic behaviour also applies to many biochemicals naturally present in cells. For example, glutamate facilitates nerve signal transmission in the brain. At low levels it stimulates nerve growth and survival, but glutamate is highly toxic at high levels such as can occur after brain injury.
Biochemists now understand the molecular mechanisms that underpin hormesis. Low levels of hormetic toxins in cells cause low-level stress that stimulates production of defence molecules to deal with the threat. These defence molecules deal not only with the immediate threat but also provide resistance to other threats.
One such class of defence molecules are the heat-shock proteins. They are released when cells are exposed to high temperatures, inflammation or toxins, and they protect other proteins in the cell from damage by binding to them. Other bodyguard molecules released by mild stress stimulate the production of protective proteins such as antioxidants, or act as messengers to alert other cells of danger, and they may also enhance the function of cells.
These natural bodyguards can also be activated deliberately, for example by eating fruit and vegetables. Diets rich in plant material reduce the risk of heart disease, cancer and neurodegenerative disorders. It was thought that this effect is mediated through the high level of antioxidants in plants that neutralise dangerous naturally occurring chemicals in the cells. However, it seems that eating ordinary amounts of plants will not provide enough antioxidants to make much difference. But, as Mattson and Calalese point out, since plant antioxidants are probably natural pesticides evolved to deter herbivores, it is likely that at low concentrations in our bodies they will activate our molecular stress response - hormesis.
Exercise and reduced calorie intake are good for the health. At least some of this effect is due to hormesis. Exercise and dieting cause mild metabolic stress and cells respond by activating protective mechanisms and this helps to prevent diabetes, reduce blood pressure, reduce risk of heart disease, stroke, colon cancer, and Alzheimer's and Parkinson's diseases. Indeed, feeding rats and mice only half rations increases life span by 30 per cent. Regular exercise and low-calorie diets also improve human cognitive function, as do intellectually challenging exercises.
Some commonly prescribed drugs seem to work through hormesis - effective at low doses but toxic at higher doses. Such drugs are best administered intermittently in order to allow cells time to recover and heal any damage caused by the low stress. Rest is also required to benefit from exercise. However the standard approach in pharmacology and dietary supplementation is to keep the drug at a constant concentration in the body.
Much work is now going on to identify hormetic agents and how they affect health. It has long been assumed that all types of stress are bad, but this is not true. Low levels of stress are very important. We should look again at the old saying: What doesn't kill you, makes you stronger.
• William Reville is associate professor of biochemistry and public awareness of science officer at UCC - www.understandingscience.ucc.ie