HORMESIS

Hormesis is a dose-response phenomenon in which a low dose of a toxin has the opposite effect on a biological system than a high dose of the same toxin. It is generally characterized as toxic effects that are beneficial at low doses and harmful at high doses. There is some ambiguity in the more precise definition of the term, however, because some speak strictly of low-dose stimulation of biological endpoints (for example, immune system strengthening), whereas others also use it to refer to low-dose inhibition of biological endpoints (such as tumor formation). Hormesis has long been marginalized in medical and environmental fields. A growing body of evidence suggesting hormetic effects across a wide range of biological organisms and systems, however, has brought increased credibility to the topic. The implications of hormesis are potentially huge, especially in terms of risk assessment policies and research paradigms. Skepticism and controversy persist surrounding the future status and impacts of hormesis as new research, aided by advanced technologies, yields uncertainty and more questions than answers.

History

Ideas similar to hormesis have been vaguely formulated for centuries, including Hippocrates' saying that "likes are cured by likes," Paracelsus's notion that "the dose makes the poison," and Friedrich Nietzsche's famous remark that "what does not destroy me makes me stronger." Hugo Schulz, a German pharmacologist who observed that small doses of poisons stimulated the growth of yeast, was the first to systematically describe hormesis in 1888. Rudolph Arndt, a German physician, found similar results in his research on the effects of low doses of drugs on animals. Arndt claimed that toxins in general produced stimulation of biological endpoints such as growth or fertility at low doses, which became known as the Arndt-Schulz law. It lost credibility in the 1920s and 1930s, however, because Arndt was an adherent of homeopathy (Kaiser 2003). Founded by Samuel Hahnemann (1755–1843), homeopathy parallels hormesis in two respects, namely the idea that likes cure likes (symptoms produced by toxic doses can be cured by a remedy prepared from the same substance) and the theory of infinitesimals, which stated that the more dilute a substance is the more potent it can become. The marginalization of Arndt's work meant that hormesis research did not receive federal funding during the formative years of toxicological development.

C. M. Southam and J. Erlich first coined the term hormesis in 1943 in research that showed an antifungal substance had stimulatory effects on fungi when administered in low doses. The term derives from a Greek root meaning to excite, indicating the ability of small amounts of dangerous substances to excite an organism's defense systems, thereby making it healthier than it would be otherwise. Hormetic effects have since been observed in organisms ranging from humans and rats to water fleas and various plants. Yet outside of low-level ionizing radiation studies (the field in which the concept of hormesis is best developed), these observations went largely unexamined and were usually treated as aberrant data.

Edward Calabrese and Linda Baldwin (2001) synthesized these disparate findings in the toxicology literature. They also found that hormetic dose-response curves outnumbered curves showing no effect at the lowest doses by
2.5 to 1 (2003). This coupled with older, extensive literature on the beneficial effects of minute doses of ionizing radiation for animals (Luckey 1980, 1991) sparked increased interest in hormesis. In 1990 a group of scientists representing several federal agencies, the private sector, and academia launched a program of analyses and workshops called Biological Effects of Low Level Exposure (BELLE) and a newsletter devoted to low-dose toxicology. The U.S. National Research Council (NRC) has sponsored research on radiation hormesis. Researchers in Japan note that victims from the World War II nuclear attacks, if they were sufficiently distant from the blast site, have lower death rates than peers not exposed to the radiation. Researchers at Johns Hopkins University found that tens of thousands of U.S. Navy shipyard workers exposed to radiation in the 1960s and 1970s have fewer cancers than nonexposed workers (Boice 2001). Others have found evidence that lung cancer rates are lowest in areas with the highest levels of radon.

Explanation and Implications

The biological mechanisms underlying the details of hormesis are still poorly understood. In general hormesis is a manifestation of homeostasis, the fundamental property of living organisms to maintain internal conditions that are in a state of (dynamic) equilibrium. Biological systems, even at the molecular level, have adaptive responses to stress that can trigger a variety of effects including increased cellular repair, beneficial apoptosis (programmed cell death), and increased immunological strength (Stebbing 1982). For example, the cellular damage caused by exercise in the short-term stimulates beneficial long-term effects because certain physiological mechanisms overcompensate, thus making the body stronger. Caloric restriction has also been proposed as a hormetic phenomenon. Some researchers have found that low levels of dioxin reduce the occurrence of tumors in rats, low levels of cadmium increase water flea fecundity, and low levels of phosfon (a herbicide) stimulate peppermint plant growth (Kaiser 2003). These results show up as biphasic dose-response curves shaped like a J or an inverted U (see Figure 1). Such dose-response curves are not unique to hormesis, however, because they are found especially in studies of endocrine disruptors that have no beneficial effects at any dose.

When referring to nutrients, hormesis is rather straightforward. Iron, for example, is necessary for transporting oxygen throughout the body, but too much iron is poisonous. The largest scientific and political implications from hormesis come from research that shows beneficial effects from small doses of chemicals long believed to be toxic at any level, such as dioxin and certain pesticides. For example, heavy metals such as mercury spur synthesis of proteins that remove toxic metals from circulation and may prevent some DNA damage caused by free radicals. Because the relationship between dose and effect is the fundamental concept of toxicology, these kinds of results may bring about radical changes in environmental and medical sciences and regulatory practices.

Indeed some suggest that hormesis marks a revolution in toxicology, pharmacology, and risk assessment. The dominant environmental risk assessment model is twofold. For carcinogens, regulatory agencies use a linear, nonthreshold dose-response model that assumes no safe level of exposure. For noncarcinogens, regulatory agencies assume there is a threshold dose, below which there is no risk of harm. Both risk assessment models are riddled with assumptions due to extrapolations from high-dose laboratory experiments to the low doses characteristic of human exposure. Calabrese (2004) argues that the resulting uncertainty has led to a protectionist public health paradigm with stringent environmental standards that often come at high costs.

He claims that these two dose-response models erroneously calculate public health standards, poorly communicate risks to the public, lead to exorbitant cleanup costs, and provide the wrong cues about how to prioritize investments in the environment. Hormesis provides an alternative risk assessment model that harmonizes policies on carcinogens and noncarcinogens, eliminates the need to extrapolate data, and places environmental risk assessment on the same solid empirical grounding as health insurance and other forms of risk estimates. He also claims that hormesis has important implications for clinical medicine. It can improve the selection of dosages and help medical researchers avoid situations in which declining concentrations of drugs in the body (toward the end of treatment, for example) may actually stimulate the microbes or tumors they are intended to eliminate.

Clearly hormesis could radically alter environmental and biomedical practices. For certain carcinogens, for example, the benefits of hormesis may occur at levels higher than the recommended safe doses for humans. It could also change the way scientists perceive and measure risk. But major changes are not likely to occur swiftly. Beneficial hormetic effects differ by individual and are still poorly characterized, and military or industrial interests may compromise the integrity of some hormesis research. Furthermore much of the research done on hormesis has focused too narrowly on single endpoints such as cancer while ignoring others. This may mean that harmful effects at low doses are not registered. Regulators must understand complex interactive effects, which greatly increase the costs of research (Renner 2003). Most importantly Calabrese fails to consider the price paid for eliminating unverifiable extrapolations. Low-dose testing requires long-term experiments with much larger sample sizes than current risk assessment models, because at low doses small signal-to-noise ratios require researchers to collect more data in order to obtain acceptable confidence intervals. The long time periods required for such research are not suited to the needs of decision makers.

As Gary Marchant (2001) argues, the refusal by U.S. Environmental Protection Agency (EPA) regulators to consider the health benefits of ozone in their 1997 revision of air quality standards provides lessons for the regulatory implications of hormesis. First, regulatory agencies are highly resistant to considering hormesis because it is a nonintuitive phenomenon that departs from traditional toxicology assumptions. Second, scientific evidence for hormesis is severely scrutinized, which makes credibility difficult to achieve. Third, judicial review may be an effective mechanism for forcing regulatory agencies to consider hormesis.

The accumulation of scientific data and advances in the techniques of molecular biology have brought the phenomenon of hormesis and the attendant controversies once again to the forefront of science and society. Hormesis carries great economic, environmental, and public health implications, but conclusive data are hard to obtain because of the large sample sizes needed and ethical restrictions on human subjects research. Hormesis supports the argument put forth by Bruno Latour (1998) that science, rather than clearing away societal controversies, actually increases uncertainty. Continued research may resolve conflicts but it may just as well add new uncertainties to those currently generated by extrapolation in risk assessment models.

ADAM BRIGGLE

SEE ALSO Dose Response Ratios;Radiation;Regulatory Toxicology.

BIBLIOGRAPHY

Boice Jr., John D. (2001). "Study of Health Effects of Low-Level Radiation in USA Nuclear Shipyard Workers." Journal of Radiological Protection 21(4): 400–403.

Calabrese, Edward J. (2004). "Hormesis: A Revolution in Toxicology, Risk Assessment and Medicine." European Molecular Biology Organization 5: S37–S40. Proposes a new risk assessment model based on hormetic dose-response curves rather than linear or threshold models.

Calabrese, Edward J., and Baldwin, Linda A. (2001). "The Frequency of U-Shaped Dose Responses in the Toxicological Literature." Toxicological Sciences 62(2): 330–338. Surveys the toxicological literature and finds significant evidence that hormetic effects are widespread.

Calabrese, Edward J., and Baldwin, Linda A. (2003). "The Hormetic Dose-Response Model is More Common than the Threshold Model in Toxicology." Toxicological Sciences 71(2): 246–250. Tests the validity of dominant dose-response models in toxicology and argues that hormetic models fit the evidence more closely.

Kaiser, Jocelyn. (2003). "Sipping from a Poisoned Chalice." Science 302(5644): 376–379.

Latour, Bruno. (1998). "From the World of Science to the World of Research?" Science 280(5361): 208–209.

Luckey, Thomas D. (1980). Hormesis with Ionizing Radiation. Boca Raton, FL: CRC Press. Reviews the literature pertaining to radiation hormesis.

Luckey, Thomas D. (1991). Radiation Hormesis. Boca Raton, FL: CRC Press. The first complete report on radiation hormesis. Shows that many biological functions are stimulated by low doses of ionizing radiation.

Renner, Rebecca. (2003). "Nietzsche's Toxicology." Scientific American (September): 28–30.

Southam, C. M., and J. Erlich. (1943). "Effects of Extract of Western Red-Cedar Heartwood on Certain Wood Decaying Fungi in Culture." Phytopathology 33: 517–524. First study to coin the term hormesis.

Stebbing, A. (1982). "Hormesis—The Stimulation of Growth by Low Levels of Inhibitors." Science of the Total Environment 22(3): 213–234.

INTERNET RESOURCE

Marchant, Gary E. (2001). "A Regulatory Precedent for Hormesis." Biological Effects of Low Level Exposures. Available from http://www.belleonline.com/n8v92.html.