What doesn't kill you makes you stronger

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But the real fear is about the unknownpathogens that still lurk in the wild.Indeed, “a good measure is just

knowing what we are dealing with”,Schmitz said. Shapiro pointed out that sys-tematic ways of looking for new diseasesare one preventive measure. “There are lim-ited attempts to define the sea of microor-ganisms that we swim in,” Shapiro said,such as molecular analysis of animals andtheir viruses in the Amazon basin. Otherprojects search for relatives of knownpathogens to try and analyse them on amolecular level, or investigate the deaths ofpersons who died of unknown causes. Butalthough “these settings are exampleswhere the science runs well ahead of theclinical data,” he thinks that, inevitably,finding new diseases is an impossible task.

Consequently, public health is left todeal with new outbreaks and so clearlymore awareness of zoonoses is needed.“Both veterinary public health and humanpublic health makes sense in this context,”Shapiro said. As human trade and travelcan quickly turn a local outbreak into aglobal epidemic, a better global aware-ness of the problem is needed as well. “Ithink we need to do a few things: one isthat the international boundaries in publichealth surveillance have to be recognizedas a major problem,” Shapiro said, “Youneed to have a barrier-free situation whenwe’re dealing with infectious diseases.” Inaddition, more research into new vaccinesand drugs is required, particularly tocounter the threat of viral zoonoses. Giventhat vaccine and antiviral research are nothigh priorities for the pharmaceuticalindustry, Shapiro thus pointed to public–private partnerships as a possible solutionto developing treatments against new dis-eases. Nevertheless, these partnershipsrely on the goodwill of politicians for sup-port, so a better awareness of the threat ofzoonotic diseases among public-healthofficials and politicians is certainly neces-sary. But the complexity of the problem, itsglobal extent and the many factors thathave a role in emerging diseases make italmost impossible to predict and counterthem efficiently. “We couldn’t have a strat-egy to predict all these things. We couldonly react,” Artsob said. “I don’t knowhow you can stop some of these diseasesfrom emerging.”

Holger Breithauptdoi:10.1038/sj.embor.embor949

We all know a daily glass of redwine reduces the risk of heartdisease. However, drinking sev-

eral bottles of wine a day would soon leadto liver disease, pancreatitis and other debil-itating health problems. High doses of radia-tion cause radiation sickness, cancer anddeath. But what if low doses of radiationcould reduce the risk of developing cancer?Traditional toxicological models of riskassessment assume that as the dose of aharmful substance increases, so too does therisk associated with it. In the absence ofexperimental evidence, this linear relation-ship is extrapolated to low doses. But evi-dence is growing that the relationshipbetween low doses and risk may not alwaysbe linear after all; some toxic substancesoften have unexpected effects. Recognizingthis toxicological oddity will not only haveprofound implications for toxicological andpharmacological research, but may alsohave a broad impact on the way in whichscience, regulatory agencies and the publicperceive and respond to risk.

Two models have traditionally been usedto describe the dose–response relationship.When assessing the risk of non-carcinogens,toxicologists use a model that assumes a lin-ear relationship between dose and risk,which holds true down to a certain thresh-old. Below this threshold, no more adverseaffects are observed, indicating that theexposure level is safe (threshold model, Fig. 1A). When assessing the risk of carcino-gens, a more cautious model is used. Thelinear non-threshold (LNT) model assumesthat some level of risk is always present,even at the lowest possible dose (Fig. 1B).Under this assumption, even one X-ray hasthe potential to cause cancer. These two

models constitute the backbone of riskassessment, and form the basis for evaluat-ing chemicals and drugs, estimating risk,establishing risk-communication practicesand setting environmental and occupationalhealth standards.

A third model rejects the standardassumption that effects at low doses canbe extrapolated from data obtained fromhigh doses, and instead describes the rela-tionship as an inverted U- or J-shapedcurve, depending on whether the sub-stance causes a decrease in risk (as ingrowth or survival, Fig. 1C) or an increase(as in disease incidence, Fig. 1D). Thiscombination of low-dose stimulation fol-lowed by high-dose inhibition is com-monly termed ‘hormesis’, from the Greekword ‘hormo’ meaning ‘to excite’. EdwardCalabrese, Professor of Toxicology andEnvironmental Health Sciences at theUniversity of Massachusetts (Amherst,MA, USA) and a strong advocate of the U-shaped dose–response curve, said, “Iactually think there should be a paradigmshift and that the hormetic model shouldbe the default model.”

Many common examples of horme-sis can be found in our everydaylives. A modest intake of many vit-

amins and minerals is essential to ourhealth, whereas excessively high doses canbe damaging. Moderate alcohol consump-tion is now advocated, as is a moderatelevel of regular exercise; too much of either can cause harm to one’s health.Psychologists have long recognized thatmild forms of stress can promote mentaland physical function, whereas extremestress is more likely to cause mentalanguish and physical ailments. However,the effects of low doses are not always ben-eficial; studies have shown that low dosesof a tumour suppressor can actually pro-mote tumour growth, and small amounts ofvarious bactericides can promote bacterial

What doesn’t kill youmakes you strongerA new model for risk assessment may not only revolutionize the field of

toxicology, but also have vast implications for risk assessment

…hormesis was effectivelyignored by the toxicologycommunity until relativelyrecently

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colony growth. Contrary to the dose-responsemodels now in place, risk is clearly notalways linearly correlated to dose. As theSwiss physician Paracelsus noted more than450 years ago, “the right dose differentiates apoison from a remedy.”

The concept of hormesis is not new andhas been embraced by those studying epi-demiology and molecular pharmacology,who were already aware of many chemi-cals that stimulate at low doses but inhibitat high doses (for example, aspirin andparacetamol). However, hormesis was

effectively ignored by the toxicology com-munity until relatively recently. As early asthe late nineteenth century, severaldose–response studies described low-dose stimulation followed by high-doseinhibition. But over the subsequent decades,a combination of factors relegated thehormetic model to scientific obscurity, tobe replaced by the current risk-assessmentmodels that are based on linear curves. In addition to having no strong advocates for hormesis, toxicologists were moreinterested in the upper end of thedose–response curves, where dose andrisk are at their highest. Hormetic effectsare difficult to measure and quantify with-out extensive studies using many animals,and so were not easily or frequently seenin experiments designed primarily to mea-sure high-dose inhibition. To compoundthe problem, hormesis suffered from anassociation with the practice of homeopa-thy, whereby a disease is treated byadministering remedies in doses so dilutedthat they might no longer contain evenone molecule of the active ingredient.When no clear molecular mechanismcould be found to support the concept ofhormesis, the collective force of theseobstacles led to its marginalization.Calabrese admits, “I think, in the beginning,people thought this was the toxicologicalversion of cold fusion.”

Unlike the toxicology community,molecular pharmacologists havespent considerable time studying

various dose responses, and have identifiedmore than 30 receptor systems that showhormesis (see sidebar for a selected list ofreceptor systems displaying the hormeticbiphasic response). The disparity betweenthe two fields can be explained by their dif-fering approaches to dose–response relation-ships: toxicology is concerned with the toxiceffects of substances (commonly displayedat high dose), whereas pharmacology is primarily concerned with the therapeuticvalue of substances (often seen at smalldoses). John Doull, Professor Emeritus ofPharmacology and Toxicology at theUniversity of Kansas Medical School (KS,USA) and one of the original authors of theleading toxicology textbook, Casarett &Doull’s Toxicology: The Basic Science ofPoisons (Klaassen, McGraw-Hill Professional,New York, USA; 2001), admits, “It is partlysemantics and our reluctance to adopt newwords” that have excluded hormesis from

mainstream toxicology, and Toxicology, untilonly recently.

Molecular biology goes one step fur-ther than both toxicology and pharmacol-ogy by not only identifying the biologicaleffect, but also investigating its fundamen-tal causes. As Tony Stebbing, HonoraryFellow at the Plymouth Marine Laboratory(Plymouth, UK) said, “hormesis has muchmore to do with the underlying mecha-nism than the toxicant.” The discovery ofmolecular mechanisms to explain horme-sis may encourage its more widespreadacceptance. In the ‘survival of the fittest’,it follows that organisms should be bestadapted to cope with optimal levels ofdietary requirements (such as vitamins)and background levels of toxic substances(such as ionizing radiation or other car-cinogens). Molecular biology has estab-lished that cells have sophisticated repairsystems to cope with various types ofdamage. “Ecological criteria ultimatelydetermine evolutionary change,” explainedPeter Parsons, Emeritus Professor at theSchool of Genetics and Human Variationat La Trobe University (Victoria, Australia).“Organisms should evolve to survive bestand live longest, or show highest fitness,in the habitats in which they most com-monly occur.” This implies that the LNTmodel is invalid for all environmentalagents, because organisms will havealready developed a mechanism to copewith their effects.

The process of adaptive evolutionexplains how a similar hormetic reactioncan be observed for such a wide range ofagents that have no apparent sharedphysico-chemical properties. As hormeticeffects have been observed for a broadrange of species, substances and biologi-cal endpoints (such as growth, longevity,reproduction, immune response and manyphysiological and metabolic responses),there is no longer the expectation that onemolecular mechanism can provide theexplanation. As Calabrese pointed out,

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Fig. 1 | Dose–response relationships. (A) The

threshold model, (B) the linear non-threshold

(LNT) model, (C) the inverted U-shaped hormetic

model and (D) the J-shaped hormetic model.

If regulatory agencies can beconvinced that hormetic effectsneed to be taken into accountwhen establishing standards forhealth and the environment, thishas the potential to alterdramatically the way in whichrisk is assessed and controlled

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“There may be an overall strategy thatcells have adopted that is played outthrough different tactics, and I think thatthe tactics are really the mechanisms that people are looking for.”

More than 20 years ago, Stebbing pro-posed that the disturbance of homeostasiswas the driving force behind the hormeticresponse. Organisms have homeostaticsystems of biochemical and physiologicalcontrol mechanisms that regulate internalprocesses and respond to external distur-bances. These systems maintain metabolicequilibrium by over-compensating for anydisruptions, such as those caused byexternal stress or damage. After the com-pensatory response neutralizes the prob-lem and restores equilibrium, the fitnessof the individual is optimized to respondto subsequent, more serious, challenges.However, high levels of stress or damagedisrupt the organism beyond its limits of recovery, causing irreparable damage.Although the specific details of the

mechanism may differ depending on howthe organism is being challenged, theoverall strategy is the same. “The underly-ing evolutionary process is selection formetabolic efficiency,” Parsons said.

The difficulty in identifying examplesof and explanations for hormesis isdue to the modest nature of the

response, and the fundamental way inwhich dose–response relationships aremeasured. Studies now concentrate on theupper end of the dose scale, and aim todetermine the level below which no moreadverse effects are observed (the ‘noobserved adverse effects level’, or NOAEL).For hormetic effects to be observed, stud-ies need to be designed to include an ade-quate number of doses below this level.These doses need to be spaced sufficiently,and temporal measurements are requiredto distinguish between the initial disrup-tion of homeostasis, the subsequent over-compensation response, and the re-establishment of homeostasis. Mostimportantly, animal models need to have asufficiently high background level of thedisease or condition being studied, so thatthe hormetic reduction of incidence canbe quantified. These requirements, plusthe need for reproducibility, make it muchmore difficult for hormetic effects to bestudied and understood by classical toxi-cology experiments, and call for a signifi-cant change in the way these experimentsare conducted.

Although, as Calabrese said, “Thedose-response is the basic founda-tion of toxicology,” the study of

hormetic behaviour is not a primary con-cern of toxicologists, who are more inter-ested in the study of the toxic effects ofsubstances. As the search for the physio-logical and biochemical basis for horme-sis becomes more important, engagingother fields in the study of hormesis is cru-cial. Calabrese believes “Broad accep-tance is going to come from the molecularcommunity.” Like Doull, he admits thatdifferent fields “use different terminology”to describe similar phenomena. “Theremay be some synergism by people whoare studying how organisms respond tolow-level stressor agents that normallynever see each other’s work.” Inviting awider scientific audience to examinehormesis might also encourage furtherdiscussion on its extensive implications. If

regulatory agencies can be convincedthat hormetic effects need to be taken intoaccount when establishing standards forhealth and the environment, this has thepotential to alter dramatically the way inwhich risk is assessed and controlled. Itmay be that the LNT model is discardedfor cancer risk assessment, and a thresh-old is introduced, meaning that low levelsof carcinogens would be considered non-harmful. This could then have repercus-sions on the levels of permissible waterand air contaminants, and the extent towhich hazardous wastes or chemicalspills are cleaned up. Risk communica-tion practices would have to change,which would then influence policy mak-ing and the legal definition of risk. Mostlikely, the public’s perception of the dan-gers of chemicals is the biggest obstacle toovercome. Calabrese admits that peoplehave “basically been afraid of this thingbecause of what they perceive are itsimplications.”

But the news is not all bad. Althoughthe way in which chemicals and drugs areevaluated would have to change, thiswould hopefully improve human healthand longevity. Understanding hormesiscould improve the understanding of otherbiological phenomena, such as the ageingprocess, the course of bacterial infesta-tions and insect outbreaks, or the relationshipbetween stress and human performance.Ultimately, understanding hormesis shouldenhance the quality of life. “The only waythere can be a paradigm shift is if you […]show overwhelming evidence that yourconcept is actually superior,” Calabresesaid. “If people think that the hormesisidea actually helps them explain thingsbetter than the current model, then it’ll be successful.”

Caroline Hadleydoi:10.1038/sj.embor.embor953

Understanding hormesis couldimprove the understanding ofother biological phenomena,such as the ageing process, thecourse of bacterial infestationsand insect outbreaks, or therelationship between stress andhuman performance

RECEPTOR SYSTEMSDISPLAYING HORMETICDOSE–RESPONSERELATIONSHIPS

AdenosineAdrenoreceptorBradykininCholecystokinin (CCK)CorticosteroneDopamineEndothelinEpidermal growth factor5-Hydroxytryptamine (5-HT)Human chorionic gonadotropinMuscarinic acetylcholineNeuropeptides (for example, vasopressin)Nitric oxideN-methyl-D-aspartate (NMDA)OestrogenOpioidPlatelet-derived growth factorProlactinProstaglandinSomatostatinSpermineTestosteroneTransforming growth factor-βTumour necrosis factor-α

Adapted from Calabrese & Baldwin, Annu. Rev.Pharmacol. Toxicol., 43, 175–197; 2003