Public Health

The Dose Makes the Cure

Toxicologist Edward Calabrese finds that what does not kill you can make you stronger.

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"All things are poison and nothing is without poison. It is the dose that makes a thing a poison," declared the wandering Renaissance physician-surgeon Paracelsus. Now after reviewing more than 5,000 toxicological studies, University of Massachusetts toxicologist Edward Calabrese has a possible amendment to Paracelsus' dictum: Low doses of poisons may be good for you.

Calabrese speculates that evolution has given our bodies and cells the ability to repair themselves. Low exposures to toxins stimulate these biological repair mechanisms and lead them to fix the damage caused by the toxin—and even to repair some of the normal background damage as well. In other words, exposure to low levels of toxins provides "a very modest overcompensation to a little damage." Calabrese and his colleagues have organized an interdisciplinary group called BELLE (Biological Effects of Low Level Exposures) to study this "hormesis" effect. Hormesis is an effect where a toxic substance acts like a stimulant in small doses.

Calabrese points out that some animal-model studies have shown that exposure to small quantities of toxins like dioxin, cadmium, and some petrochemical exhaust products seems to protect against various cancers. Low levels of gamma rays also seem to protect mice against malignant tumors. There is even a forthcoming study that shows that exposure to low levels of arsenic protects against cancer. However, hormesis could be a double-edged sword. Hormesis is about stimulation and it turns out in a number of in vitro cell cultures that exposures to low levels of toxins can stimulate cancer cell growth.

Calabrese's arguments are more than just a scientific curiosity. They have political relevance as well. Modern toxicology has generally assumed that there is no safe dose for carcinogens. The regulations based on this belief assume a linear dose/response relationship for toxins—that is, if a lot of something is bad for you, even a little bit is bad for you.

This faith in a linear dose/response relationship has been codified in various federal regulations such as those promulgated by the Environmental Protection Agency (EPA). The result has been a relentless and costly effort to reduce our exposure to even the smallest quantities of allegedly toxic molecules in the hopes of reducing rates of cancer and birth defects.

"The real significance of the hormetic model in the conflict over threshold versus linear response models is of course that if hormesis could be unequivocally demonstrated as universal then it would establish a bona fide threshold for carcinogenic effects," writes Calabrese in the journal Mutation Research. "This would immediately discredit the many uses of linearity models to estimate cancer risk." In other words, it would mean that federal regulations are wasting lots of money trying to solve a non-existent problem—and even stifling possible positive effects.

Hormetic effects generally occur at doses five times lower than the threshold for toxicity, known as the No Observed Adverse Effects Level (NOAEL). However, the ever-cautious EPA usually sets its exposure limits by a factor of 100 below the NOAEL. If exposure to low levels of carcinogens does not cause cancer, that may explain why so many studies over the years have failed to find that low levels of synthetic chemicals are an appreciable source of cancer.

Calabrese believes that is time for the EPA and Food and Drug Administration (FDA) to commission the National Academy of Sciences (NAS) and/or the Institute of Medicine to evaluate hormesis and its application to regulatory science. If the NAS agrees that hormesis is a universal effect, incorporating it into EPA and FDA standards would improve how cancer risk assessment is done and reduce the costs of regulation.

Who knows? Perhaps one day you'll be popping an arsenic pill to ward off skin cancer.

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