Nutritional Hormesis

REVIEW Nutritional hormesis

DP Hayes

New York City Department of Health and Mental Hygiene, New York, NY, USA

Objective: Hormesis, the biological and toxicological concept that small quantities have opposite effects from large quantities, is reviewed with emphasis on its relevance to nutrition. Results: Hormetic and other dose–response relationships are categorized, depicted, and discussed. Evidence for nutritional hormesis is presented for essential vitamin and mineral nutrients, dietary restriction, alcohol (ethanol), natural dietary and some synthetic pesticides, some herbicides, and acrylamide. Some of the different hormetic mechanisms that have been proposed are reviewed. Conclusions: The credence and relevance of hormesis to nutrition are considered to be established. The roles of hormesis in nutritional research and in formulating nutritional guidelines are discussed. Sponsorship: The New York City Department of Health and Mental Hygiene. European Journal of Clinical Nutrition (2007) 61, 147–159. doi:10.1038/sj.ejcn.1602507; published online 2 August 2006

Keywords: hormesis; dose–response relationships; dietary restriction; alcohol/ethanol; pesticides; acrylamide

Introduction opposite response. Hormesis proponents believe it to be commonly manifested in both biology and toxicology, and Moderate levels of exercise promote good health, whereas highly generalizable according to biological model tested, excessive levels are debilitating (Melzer et al., 2004). In end point measured, and chemical class/physical agent molecular pharmacology, many chemicals are known to employed. This review will discuss evidence for hormesis have opposite effects as a function of dosage (e.g., the in human nutrition, the possible relevance of hormesis to antibiotics penicillin, erythromycin and streptomycin pro- nutritional research, and the formulation of hormetic mote bacterial growth at low doses, contrary to effects at nutritional guidelines. higher doses). It has long been recognized that mild forms of stress can promote mental and physical function whereas extreme stress is more likely to cause mental anguish and Hormesis – definition and dose–response forms physical ailments, the Yerkes-Dodson Law in experimental psychology (Yerkes and Dodson, 1908). In stating that only Figure 1 (adapted from Davis and Svendsgaard, 1990) the dose makes a thing not a poison, Paracelsus (the provides some representative dose–response forms. Dose– supposed model for Goethe’s Dr Faustus) recognized some response relationships have usually been characterized by six centuries ago that in medicine the efficacy of toxic either the threshold model (Figure 1a) or the linear non- chemicals depends on dosage. These examples of small threshold (LNT) model (Figure 1b). Since the consolidation quantities having effects opposite from that of large of toxicological and pharmacological conceptual thinking, quantities are commonly termed hormesis. The hormesis the most accepted dose response model in these disciplines concept claims that as the dose of an agent being studied is has been the threshold model, which assumes that dose reduced, the response of the end point being measured does has no effect until a threshold is reached, at which point not simply get smaller and smaller, drifting into background response increases linearly with dose. According to the LNT noise, but may actually reverse course and change to an model, response is directly proportional to dose without any threshold, so that some level of response is always present, Correspondence: Dr DP Hayes, New York City Department of Health and even at the lowest possible dose level. The LNT model has Mental Hygiene, 2 Lafayette Street, New York, NY 10007, USA. become the standard model for assessing the health risk of E-mail: [email protected] Received 2 January 2006; revised 31 May 2006; accepted 9 June 2006; chemical carcinogens and radiation by regulatory agencies published online 2 August 2006 in many countries; while for non-carcinogens, the same Nutritional hormesis DP Hayes 148 a regulatory agencies assume that there is a threshold dose, below which there is no health risk. Hormesis is characterized by dose–response relationships having two distinct phases (i.e., biphasic, non-monotonic) whose forms depend on end points measured. Examples include inverted U-shaped curves (Figure 1c) showing low- dose enhancement when reduction is expected (normal function end points displaying this type curve include Control growth, fecundity, longevity and cognitive function);

Response J-shaped curves (Figure 1d), which are allied to U-shaped curves, showing low-dose reduction when enhancement is Dose expected (adverse dysfunction end points displaying this b type curve include carcinogenesis, mutagenesis and disease incidence). Note that hormesis not only challenges the threshold and LNT models but also more importantly suggests that as dose decreases there are not only quantitative changes in measured responses but also qualitative changes vis-a`-vis both control (background) and high-dose levels. Figure 2 (adapted from Eaton and Klaassen, 2001) is a Control depiction of hypothetical dose–response relationships con- tributing to a postulated hormetic effect, in this case a U- Response shaped dose–response curve. Low doses produce a response Dose demarked Protective in Figure 2b. Increased doses produce an oppositely postulated response demarked Adverse in c Figure 2a. The combined effect curve (Figure 2c) shows a hormetic U-shaped dose–response. The definition of hormesis adopted here is that of adaptive nonlinear biphasic dose–response relationships character- Control ized by small quantities having opposite effects from large quantities, that is, small doses elicit opposite responses to that seen at high doses. This definition purposefully side-

Response steps the potentially vexing issue of beneficial/harmful

(normal function) effects, which should be deferred to subsequent evaluation of the biological and ecological content of the response.

Dose Hormesis – current background d There is a great deal of current interest in the topics of hormesis and hormetic-like responses. The most effective current proponents of hormesis are Edward Calabrese’s group at the University of Massachusetts who have system- Control atically developed methodologies for evaluating dose–response relationships (Calabrese, 2005a). They have reported hormetic-like biphasic dose/concentration responses for Response

(dysfunction) numerous endogenous agonists, including NO, adenosine,

Figure 1 Stylized curves representing some dose–response relationships. (a) The threshold model. (b) The LNT model. (c) The Dose inverted U-shaped hormetic model depicting low-dose enhancement and high-dose reduction of normal function effects. (d) The J-shaped hormetic model depicting low-dose reduction and high- dose enhancement of adverse dysfunction effects. See text for further discussion. Adapted from Davis and Svendsgaard (1990).

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 149 a nists and phyto-compounds (Calabrese, 2005b). Extensive hormetic-like biphasic dose–response relationships have Effect A- Adverse been reported in immunology, with over 90 different immune response-related end points induced by over 70 endogenous agonists, over 200 drugs, over 40 environmental contaminants, and over 30 animal models spanning over a dozen mammalian and human cell lines (Calabrese, 2005c). The clinical implications for hormesis in humans are presently essentially unknown, although numerous investi- gators have raised some important concerns. For example, b Brandes (2005) reports that certain antidepressant drugs in Effect B- Protective addition to producing biphasic growth responses in in vitro cancer cells and stimulating cancer growth in rodents also correlates with an increased risk of breast and other cancers in some, but not all, patients on these drugs. Methodologies developed by Calabrese’s group have been used to generate two separate intensive and extensive hormetic databases. The more recent and complete database, The Relational Hormesis Database (a.k.a. The Hormesis Data- base), culled some 1450 publications to report 46000 cases of hormetic dose–response relationships for some 900 c broadly diversified chemical and physical agents (Calabrese Combined Effect and Blain, 2004). The hormetic dose–responses satisfied rigorous a prior evaluative criteria (including to varying degrees: strength of study design, magnitude of stimulation, statistical significance and reproducibility of findings). With stimulation used in the context of Calabrese and Baldwin’s

Over Effect Response B Response A (2002) definition, that is, a response opposite to that observed at higher (i.e., greater than threshold) doses, the maximum stimulatory responses were typically only approximately 30–60% greater than the concurrent control, with nearly 80% of the maximum responses being less than Dose (mg/kg/day) twice the control value. In general, the widths of the Figure 2 Hypothetical dose–response relationships depicting stimulatory responses were also modest, typically extending hormesis characteristics with dose denominated (mg/kg/day). over a dose range of 20-fold (i.e., 1/20) or less immediately Low-doses produce a postulated Protective response (b). In- creased-doses produce an oppositely postulated Adverse response below the NOAEL (No Observed Adverse Effect Level – the (a). The Combined Effect curve (c) shows a hormetic U-shaped highest dose not differing in a statistically significant dose–response. See text for further discussion. Adapted from Eaton manner from the control group, which serves as a toxicolo- and Klaassen (2001). gical quasi-threshold), and often less than 10-fold (i.e., 1/10). To reiterate, hormetic responses in the vast majority of cases within The Relational Hormesis Database were typically quite opioids, adrenergic agents, prostaglandins, estrogens, andro- modest in both magnitude and width. gens, 5-hydroxytryptamine and dopamine (Calabrese and The analyses of Calabrese’s group revealed the uncovered Baldwin, 2001a); inorganic agents including numerous toxic biphasic dose–response relationships to be quite common substances such as arsenic, cadmium, lead, mercury, etc., and and broadly generalizable; that is such responses do not chemotherapeutic agents, peptides and ethanol (Calabrese appear to be restricted to biological model, end point and Baldwin, 2003a); as well as processes such as apoptosis measured, or stressor agent, and appear to represent a basic (Calabrese, 2001). The hormetic chemotherapeutic agents feature of biological responsiveness to chemical and physical studied included antibacterial, antiviral, antitumor and anti- stressors. Furthermore, the quantitative features of the angiogenesis agents, with their quantitative and temporal hormetic-like dose responses are remarkably similar with dose responses being similar to that reported for both respect of response amplitude and width, and the relation- chemicals and radiation (Calabrese and Baldwin, 2003b). ship of the maximum response to the ‘quasi-threshold’ Hormetic-like biphasic dose–responses have been reported in NOEL. Such similarities across models, end points and over 130 human tumor cell lines from a wide range of agents, stressor agents suggest a similar type of adaptive strategy including antineoplastics, toxic substances (i.e., environ- possibly related to resource allocation. In addition, the mental pollutants), non-neoplastic drugs, endogenous ago- biphasic dose–response was also found to be more common

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 150 Death individual dose–response relationship for an essential sub- stance required for normal physiologic function and survival Threshold for adverse response such as a vitamin or trace element as being U-shaped (Figure 3). At very low doses there is a high adverse effect, which decreases with increasing dose. This is the deficiency region of the dose–response relationship for essential

Response nutrients. As the dose is increased to a point where the Region of Homeostasis deficiency no longer exists, no adverse response is detected; the organism is then in a state of homeostasis, defined as the maintenance of constant internal state for an organism’s efficient function and performance to ensure that a stable physiological milieu is maintained in the face of perturba- tions. (Homeostasis is operationally defined as the dose Deficiency Toxicity range that results in neither deficiency nor toxicity.) However, as the dose is increased to higher levels, a toxicity Dose adverse response (usually qualitatively different from that Figure 3 Depiction of dose–response relationships for essential observed at deficient doses) appears and increases in vitamin or mineral nutrients. The U-shaped hormetic response is magnitude with increasing dose, just as with other toxic shown with a Region of Homeostasis (the dose range with neither nutrient deficiency nor toxicity) being contiguous to both the low- substances. Thus, the biphasic nature of the U-shaped dose Deficiency region and the high-dose Toxicity region. See text response can, practically speaking, be subdivided into low- for further discussion. Adapted from Eaton and Klaassen (2001). and high-dose regions where the toxicity response differen- tially occurs (the arms of the U), plus a region of no toxic effect (the trough of the U). As specifically cited by Eaton and than other competing models, even the long-pre-eminent Klaassen, Vitamin A deficiency can have harmful vision toxicological threshold model (Calabrese and Baldwin, effects while excessive Vitamin A can damage the liver or 2001b, 2003a). cause birth defects; and high doses of selenium can affect the brain while high doses of estrogens may increase the risk of breast cancer. Nevertheless, all three of these substances are Examples of hormetic nutrition essential for life and their deficiencies will cause harm. It is important to note that while Eaton and Klaassen have not The following subsections will review manifestations of explicitly claimed Figure 3 to be an example of hormesis, nutrition hormesis in the following areas: essential nutrients they have come very close to doing so in noting it to be (vitamins and minerals), dietary restriction, alcohol (ethanol), conceptually similar to the hypothetical hormetic dose– natural dietary and some synthetic pesticides, some herbi- response relationship that they had depicted in Figure 2. In cides and acrylamide. addition, Mertz (1981) has cited many examples of essential trace elements exerting a U-shaped dose–response on physiological functioning, ranging from impairment at Hormetic essential vitamin and mineral nutrients levels of deficient intake, to optimal function at intermediate levels, to toxicity at excessive intake levels. Vitamins and minerals are hormetic essential nutrients that are necessary to maintain human health. Small daily levels of these substances are both required and beneficial, while excessive dietary levels can lead to hypervitaminosis, tissue Hormetic dietary restriction mineralization, or electrolyte imbalance. For example, the Seventeenth Edition of The Merck Manual of Diagnosis and Owing to its ability to intervene in both biological aging and Therapy published in 1999 discusses deficiency, dependence life-shortening pathogenesis, dietary modification in the

and toxicity in vitamins A, D, E, K, B6; deficiency and form of dietary restriction (DR) is the most effective and toxicity in the macrominerals sodium, potassium, calcium, reproducible laboratory intervention for extending lifetime magnesium, phosphate and chloride, and in the micromin- survival (both mean and maximum lifespan) in a variety of erals iron, iodine, fluorine, selenium and copper. All trace diverse organisms. The two DR protocols most commonly elements (i.e., microminerals) are toxic at high levels, and used in animal studies are: (1) every-day caloric restriction some (e.g., arsenic, nickel, and chromium) have been (CR) with the restricted animals being typically being given implicated in carcinogenesis. 20–40% fewer calories than the ad libitum (AL) fed control Eaton and Klaassen (2001) in their ‘Principles of Toxico- animals, and (2) intermittent fasting (IF) with the restricted logy’ chapter of the major toxicological reference Casarett animals typically going a whole day without food and then and Doull’s Toxicology: The Basic Science of Poisons depict the permitted to eat AL on the following day.

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 151 Both the CR and IF laboratory DR regimens provide Japanese islands, display lower death rates from cerebrovas- essential nutrients and vitamins, thereby avoiding con- cular disease, cancer, and heart disease. Food shortages in founding effects of malnutrition. In fact, CR and IF animals some North European countries during World War II led to a are almost always healthier, sleeker, and more active than sharp fall in mortality from coronary artery disease followed their AL counterparts, who tend to develop obesity in mid- by sharp rise in mortality with the war’s end, although these life. While the CR laboratory regimen administered through- observations are difficult to interpret because of confound- out life is generally more protective than adult-onset CR, ing factors such as malnutrition (Strom and Jensen, 1951). both prevent adult-onset obesity, significantly extend life- There are some other more controlled human demonstra- span and suppress tumorgenesis. Laboratory caloric re- tions, such as the Biosphere 2 studies (Verdery and Walford, stricted diets, which as noted are designed to provide 1998), which also suggest positive effects but which adequate micronutrient coverage, have been found to unfortunately suffer from a dearth of subjects and non- produce reduced oxidative DNA damage (Haley-Zitlin and optimum controls. On a more encouraging note, emerging Richardson, 1993). Contrast this result with laboratory evidence from human population studies (as well as reports that micronutrient deficiencies produce DNA da- laboratory experimental data) indicate that low calorie mage both through oxidative lesions and single- and double- intake can reduce risk of Alzheimer’s disease, Parkinson’s strand breaks (Ames, 1998). disease and stroke, three of the most devastating neurode- DR by either the CR or IF regimen can significantly extend generative conditions in the elderly (Roth et al., 1999; the life span of rodents by some 30–40% (Mattson et al., Mattson et al., 2002). In addition, some as of yet small-scale 2002). Life-extending CR effects have been observed in, clinical studies have reported that long-term CR ameliorates amongst others, protozoa, yeast, nematode, several insect diastolic function and reduces atherosclerosis (Fontana et al., species including fruitfly, mouse, rat, hamster, guinea-pig, 2004; Meyer et al., 2006). dog, cow and in several non-human primate species. CR is a Anti-aging and life-prolonging effects of laboratory CR potent and broadly acting cancer-prevention regimen in studies are accompanied by stimulation of various main- laboratory experimental carcinogenic models, being effective tenance mechanisms, including increased efficiency of DNA in several species, for a variety of tumor types, and for repair, increased fidelity of genetic information transfer, spontaneous and chemically induced neoplasias. For exam- more efficient protein synthesis, more efficient protein ple, CR inhibits spontaneous neoplasias in several knockout degradation, more efficient cell replacement and regenera- and transgenic mouse models, it suppresses the carcinogenic tion, improved cellular responsiveness, as well as fortifica- action of several classes of chemicals in rodents, and also tion of the immune system. Among the specific mechanisms inhibits several forms of radiation-induced cancer. CR in proposed to account for the antiaging and life-prolonging animal models also reduces age-associated neurodegenerative actions of CR are oxidative damage attenuation, alteration disorders, prevents age-assisted declines in psychomotor and of the glucose–insulin system and alteration of the IGF-1, spatial memory tasks, improves the brain’s plasticity and which ubiquitously acts on tissues to regulate growth, cell ability for self-repair, as well as retarding age-associated death, and development (Hursting et al., 2003; Masoro, physiological deterioration and delaying and, in some cases, 2003). As an additional and more general explanation, preventing age-assisted diseases. These salutary effects have Masoro (1998) has proposed hormesis as the beneficial been found to arise from either CR (i.e., energy) or meal action(s) resulting from the response of an organism to frequency rather than from restriction of specific toxic dietary low-intensity stress. In this context, ‘stress’ is operationally contaminants or specific macro- or micronutrients (Yu, 1994). defined as a signal generated by a physical or chemical factor, They occur without a reduction of mass-specific metabolic the stressor, which in a living system initiates a series of rate or level of physical activity (Hursting et al., 2003). events in order to counteract, adapt and survive. Some Observational studies suggest that dietary restriction has moderate intensity long-term stressors have been reported to beneficial effects on human morbidity and mortality. delay aging and prolong life and include temperature shock Participants in the Harvard Alumni Health Study and the (heat and cold), irradiation (UV-, gamma- and X-rays), heavy Nurse’s Health Study with body mass indexes (a possible metals, prooxidants, alcohol, exercise, as well as CR (Rattan, biological marker of CR) some 15–20% below the national 2004). Stress exposure induces various regulatory stress average (a hallmark of ‘chronic but mild undernutrition’) response proteins (e.g., glucocorticoids glucose-regulated had reduced mortality. Their peripheral blood lymphocytes stress proteins and/or hsps heat shock proteins) that protect had higher DNA repair capacity and exhibited no appreci- cellular components as well as allow a better degradation of able age-dependent decline in DNA-repair potential vis-a`-vis damaged proteins during stress. The heat shock protein normal subjects (Raji et al., 1998). Moreover, physiological system is known to protect cells against the damaging action changes analogous to those observed in CR monkeys, of a broad spectrum of physiological stresses in addition to including high-density lipoprotein (HDL) cholesterol in- heat and CR, for example, cold, amino acid analogues, heavy creases, are reported in Muslims who fast during the holy metals, free radicals, exercise activity, etc. (Lindquist, 1986). month of Ramzan. Residents of Okinawa, Japan, who are These stress response proteins repair exposure-caused cellular known to consume fewer calories than residents of the main damages and potentially even the damages present before

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 152 the stress, so that organisms may be in better conditions after hormetic responses to a wide range of toxic chemical agents the stress and live longer. Other stress response mechanisms that they had previously reported (Calabrese and Baldwin, that have been proposed include induction of detoxification 1997). enzymes, cell proliferation/apoptosis, DNA repair, protein While there are a considerable number of published turnover and antioxidative response (Yu and Chung, 2001; investigations suggesting that chronic alcoholics have an Klaunig, 2005). increased susceptibility to infectious diseases (in particular In support for the hormesis hypothesis, Masoro (2003) has pneumonia), Hallengren and Forsgren (1978) have presented cited findings that single-gene mutations that extend the evidence that at low to moderate blood alcohol concentra- life of invertebrate species also increase the ability of these tions there is an increased adherence, phagocytosis and organisms to cope with damaging agents. Recent neurode- chemotaxis of human polypmorphonuclear leucocytes. The generative laboratory studies lend additional strong support magnitude of the detected response is consistent with that to hormetic stress mechanisms (Mattson et al., 2002; Anson seen for hormetic responses, with the hormetic concentra- et al., 2003). It was found that stress induced by every-other- tion range being about four-fold. It would appear that day feeding (IF, with the laboratory animals going a whole these results have important ramifications for biomedical day without food and then eating AL on the next day) researchers and clinicians. sometimes produced even more positive results than CR Human health benefits of regular light-to-moderate feeding every day. The observed reductions in neurode- alcohol consumption vis-a`-vis abstinence include decreased generative disorders were attributed to activation at the risks of dementia, diabetes, osteoporosis, and cardiovascular cellular and molecular levels of hormetic responses in which disease and death (Standridge et al., 2004). Both case–control neurons increased production of neurotropic factors and and cohort epidemiological studies have consistently shown stress proteins (specifically hsps heat shock proteins and that light-to-moderate drinkers are at lower risk of cardio- glucose-regulated stress proteins). The intriguing possibility vascular disease and death than nondrinkers, although that the beneficial effects of IF can at least in part be heavier alcohol consumption can negatively affect the dissociated from caloric intake is further supported by the neurologic, gastrointestinal, hematologic, immune, psychia- finding that targeted deletion of the insulin receptor in tric and musculoskeletal organ systems. The hormetic adipose cells results in increased longevity without a biphasic effects of alcohol consumption on total human reduction in caloric intake (Bluher et al., 2003). mortality is a well studied and documented phenomenon with the basic J-shape of the dose–response curve confirmed in the vast majority of studies and being remarkably stable Hormetic alcohol (ethanol) and independent of assessment measure (Gaziano and Buring, 1998; Rehm, 2000). For example, Gronbaek (2004) The review of Pohorecky (1977) provides strong psychological, cited 19 separate epidemiological studies conducted over the behavioral and biochemical evidence for alcohol (ethanol) last three decades that describe the impact of alcohol on affecting the experimental behavior of animals and humans total mortality as J-shaped, with a beneficial effect of regular in a biphasic dose–dependent manner, with low-doses being light-to-moderate intake (10–40 g per day, or one to three excitory and high-doses depressant. For non-human mamma- alcoholic beverages), and a detrimental effect of both lower lian biological end points (including, amongst others, the and higher intake. These studies have been reported by a liver, kidney, heart, spleen, endocrine, embryonic develop- large number of different research teams, with the effects ment and birth weight), Calabrese and Baldwin’s (2003c) observed in populations of different genders, races and assessment of the toxicological and pharmacological literature nationalities. The total mortality risk reduction at light-to- demonstrated ethanol-induced biphasic dose responses over a moderate levels is likely due to lower risk of fatal cardio- wide range. In most cases, the low-dose hormetic responses vascular disease without dramatic increases in other causes were judged to be statistically significant and reliable. They of death. Rehm (2000) notes that the J-shape results mainly observed striking similarities across studies in both hormetic from the beneficial effect of moderate alcohol consumption dose-ranges and hormetic dose–response magnitudes, with on ischemic cardiovascular conditions coupled with the the maximum hormetic response approaching two-fold but detrimental effects of drinking on other health conditions. was usually 25–40% greater than the control value. Further- While the risk curves of detrimental effects may vary more, the maximum hormetic response was generally within between linear, exponential or threshold effects, they always a factor of 2–4 of the estimated NOAEL. They argued against a seem to be monotonic: the more consumption, the higher common explanatory mechanism, and for a diverse plethora the disease-specific mortality risk. Rehm further notes that of underlying mechanisms. They also stated that regardless of this means that the J-shaped curve should not be expected actual response mechanisms, the similarity of dose–response and cannot be found in populations with no or few coronary characteristics likely reflected an important overall regulatory heart disease (CHD) deaths, for example, in some developing strategy built into the framework of a homeostatic control countries or in younger age groups. system. Calabrese and Baldwin (2003c) further noted that Epidemiological studies indicate that all types of alcoholic these collective findings closely resembled the biphasic beverages are associated with increased cancer risk at higher

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 153 drinking levels, suggesting that ethanol itself causes the reduction in tumor incidence at lower doses. For example, detrimental effect rather than any particular type of initial studies of DDT (1,1-bis(p-chlorophenyl)-2,2,2-trichloro- beverage. A great deal of recent research has focused on the ethane) with the rat model used by the United States National possible benefits of specific alcoholic beverages. Some have Toxicology Program suggested a hormetic response at low postulated that wine’s polyphenolic antioxidants including doses and carcinogenicity at higher doses, ‘showing a U- resveratrol and proanthocyanidin reduce risk of cardio- shaped curve at very low doses’ (Sukata et al., 2002). A later vascular disease. Resveratrol has been shown to exert its follow-up study reported that a low dose of DDT can inhibit effects on cells by inducing a stress response mediated by the the formation of both preneoplastic and neoplastic lesions sirtuin protein family (Tissenbaum and Guarente, 2001; in the rat liver in an initiation-promotion model, with the Howitz et al., 2003). At this point in time the totality of dose–response curve showing a J-shape hormetic pheno- evidence suggests that the major beneficial component of menon (Kushida et al., 2005). DDT and similar organochloride alcoholic beverages on cardiovascular mortality is in fact insecticides have been of concern because of their unusual ethanol per se rather than some other component (Rimm lipophilicity, persistence because of their chlorine substituents et al., 1996). Gronbaek (2004) states that it is likely that any and concentration in adipose tissue. However, many thou- apparent additional beneficial effect of wine on health in sands of chlorinated chemicals are produced in nature and addition to the effect of ethanol itself is a consequence of natural pesticides can also bioconcentrate if they are fat- confounding. soluble. Furthermore, there is no convincing epidemiological Several plausible mechanisms for the cardioprotective evidence of a carcinogenic hazard of DDT to humans (Key and effect of light-to-moderate alcohol intake have been sug- Reeves, 1994). Specifically, ‘the literature does not contain gested (Korthuis, 2004; Standridge et al., 2004). One is its role even one peer-reviewed independently replicated study link- in increasing plasma HDL cholesterol concentrations and in ing DDT exposure to any adverse health outcome’ (Attaran reducing low-density lipoprotein (LDL) cholesterol concen- and Maharaj, 2000). In support of laboratory studies reporting trations. Such changes have been suggested to account for hormetic effects is the confirmatory speculation of Morse approximately half of alcohol’s protective effect against (1998) that low doses of pesticides may be responsible for a CHD. (Commonly referred to as the good cholesterol, HDL hormetically induced resurgence of insects and mites in binds with cholesterol and brings it back to the liver for secondary pest outbreaks following pesticide applications on elimination or reprocessing, thereby lowering total choles- agricultural commodities. A major impact of this hormesis terol levels in body tissues and its build-up on arterial walls, effect would be its leading to the need for additional pesticide and in a sense reversing the atherosclerotic process.) Free treatments resulting in a spiraling increase in pesticide usage, radical scavenging and inhibition of LDL oxidation by free termed the ‘pesticide syndrome’ in the entomological litera- radicals have also been proposed as mechanisms; as well as ture. reduction/inhibition of platelet adhesion and aggregation, As opposed to synthetic chemical pesticides, Ames and clotting factor concentrations, vascular smooth muscle cell Gold (2000) and Gold et al. (2003) have reported the proliferation and migration, and inflammation involving ubiquitous presence of natural pesticides in foods. About monocytes and T lymphocytes. Of particular interest in light 99.9% of all chemicals to which humans are exposed (mainly of previous reference to hsps heat shock proteins are animal through food) are of natural origin. The amounts of studies showing that oxidative stress from low dose alcohol synthetic chemical pesticide residues in plant foods, for consumption induces several heat shock and antioxidant example, are extremely low compared to the amounts of proteins, which may serve as cardioprotective proteins in natural ‘pesticides’ produced by plants themselves. Of all hearts subsequently exposed to ischemia/reperfusion (I/R) dietary pesticides that humans eat, 99.99% are natural: these injury (Sato et al., 2004). Also of interest is the surprising are chemicals produced by plants to defend themselves finding that alcoholics had significantly less DNA damage against fungi, insects and other animal predators. Each plant than controls and demonstrated higher capacity for DNA produces a different array of such chemicals. On average, the repair, possibly because excessive ethanol rather than Western diet includes roughly 5000–10 000 different natural damaging DNA (it is not genotoxic) induces antioxidant pesticides and their breakdown products. Americans eat and repair enzymes (Pool-Zobel et al., 2004). about 1500 mg of natural pesticides per person per day, which is about 10 000 times more than they consume of synthetic pesticide residues. Even though only a small Hormetic synthetic and natural dietary pesticides proportion of natural pesticides have been tested for carcinogenicity, circa year 2003 half of those tested (38/72) Pesticides are substances that prevent, destroy or repel pests. have been found to be rodent carcinogens. For example, While most intended pesticides are synthetic chemicals, more than 1000 naturally occurring chemicals have been some are plant derivatives, organic dusts or biological described in coffee: 30 have been tested and 21 have been agents/products such as bacteria or their toxins. There is found to be rodent carcinogens in high-dose tests. In a single evidence that some synthetic chemical pesticides that cup of coffee, the natural chemicals that are rodent enhance tumor formation at high doses may affect a carcinogens are about equal in weight to an entire year’s

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 154 worth of synthetic pesticide residues that are rodent including allium compounds, carotenoids, coumarins, diet- carcinogens, even though only 3% of the natural chemicals ary fiber, dithiolthiones, flavonoids, folate, glucosinolates, in roasted coffee have been adequately tested for carcino- indoles, inositol hexaphosphate, isoflavones, isothiocya- genicity. Cooking of foods produces burnt materials – about nates, limonene, plant sterols, phytosterois, protease inhibi- 2000 mg per person per day – that also contain many rodent tors, saponins, selenium, and Vitamins C (ascorbate) and E carcinogens. In contrast, the residues of 200 synthetic (tocopherols) (Potter and Steinmetz, 1996; Safe et al., 1999; chemicals measured by the United States Federal Drug Milner, 2002). Some of the specific mechanisms by which Administration, including the synthetic pesticides thought nutrients may suppress the cancer process include the to be of greatest importance, average only about 0.09 mg per following: inhibiting genetic damage caused by exogenous person per day. Naturally occurring pesticides that are rodent agents by inhibiting carcinogen uptake, retarding activation, carcinogens are ubiquitous in fruits, vegetables, herbs, and enhancing detoxification, scavenging oxygen radicals, and spices. In summation, it is probable that almost every fruit preventing DNA binding; influencing the repair of structural/ and vegetable in the supermarket contains natural pesticides functional genetic defects by enhancing endogenous repair that are rodent carcinogens, that no diet can be free of and restoring proper methylation; eliminating damaged cells chemicals identified as carcinogens in high-dose rodent or clones by inducing apoptosis, promoting differentiation tests, and that exposure to synthetic rodent carcinogens is and enhancing immunosurveillance; and, suppressing growth small compared to the natural background of rodent and clonal evolution by slowing or stopping proliferation, carcinogens. retarding angiogenesis and inhibiting invasion (Potter and There are numerous epidemiological studies supporting Steinmetz, 1996; Steinmetz and Potter, 1996; Milner, 2002). the likelihood that nutritional preemption is a useful strategy to reduce cancer risk at multiple body sites, with the greatest protection attributable to greater fruit and Hormetic herbicides: dioxin and phosfon vegetable consumption. For example, both the international review panel of the World Cancer Research Fund – American Seventy-five phenoxy acid compounds constitute the group Institute for Cancer Research (1997), and the Chief Medical labeled dioxins (polychlorinated dibenzo-p-dioxins). The Officer’s Committee on Medical Aspects of Food and most acutely toxic of the polychlorinated dioxin isomers Nutrition Policy (COMA), British Department of Health is considered to be 2,3,7,8-tetrachlorodibenzo-p-dioxin, or (1998) recommend fruit and vegetable consumption to TCDD. A stable compound, dioxin breaks down slowly in the combat cancer. Epidemiological and other studies support- environment when protected from the ultraviolet rays of the ing the protective role of fruits and vegetables against cancer sun, but once it finds its way into the soil it persists for a long have been reviewed by Hayes (2005), including prospective time, remaining tightly bound to soil particles. Since dioxin epidemiological studies of atomic-bomb survivors that is highly insoluble in water, it tends not to migrate very fast show significant and convincing protection against various in soil. Dioxins are not manufactured directly for use in any cancers (Sauvaget et al., 2003, 2004). product. Rather, they are formed as unwanted byproducts in What accounts for the paradox that plant foods contain the production of herbicides such as 2,4,5-T, in wood carcinogens and also protect against cancer? Hormesis has preservatives made from chlorophenols, in the incomplete been alluded to as an explanation by Parsons (2000), Rico combustion of wood products and industrial and municipal (2002), and Johnson and Bruunsgaard (1998). It has been wastes, and in the combustion of diesel fuel (Kociba and suggested that the plant diet brings together many different Schwetz, 1982). toxic chemicals which when ingested at low doses stimulate Dioxin is highly toxic to some species of animals (while the chemo-defense system and enhance host resistance, less so to others), and at high doses an animal carcinogen. while the chemo-defense system is overwhelmed at higher The largest, longest, and most detailed laboratory dioxin doses. It has been further proposed that the toxic phyto- experiment entailed a 2-year TCDD study of 485 white rats chemicals in fruits and vegetables that protect against insects carried by Kociba et al. (1978). This study formed the basis and other predators may induce a mild hormetic stress of the United States Environmental Protection Agency (EPA) response in cells (Mattson, 2005). Induction of mild cellular declaring dioxin a human carcinogen, with aspects of this responses have been cursorily invoked to explain the study having been criticized by Keenan et al. (1991) and hormetic actions of the phytochemicals isothiocyanates, Paustenbach et al. (1991). But the Kociba study also showed present in broccoli, and quercetin, present in red grape seeds that dioxin has an anticancer effect at low doses, reducing (Faulkner et al., 1998; Blardi et al., 1999). tumor incidences of the pituary, uterus, mammary glands, As of this date little detailed explanations of the hormetic pancreas and adrenals. At these dioxin levels striking U- effects of natural dietary pesticides have been offered, shaped dose–response relationships were shown when all although there is a wealth of available information regarding tumors were combined; and at the lowest dose the females the efficacy of dietary nutrients as anticarcinogenic agents. displayed a modest decrease in liver tumors, the critical Circa year 2002, more than 500 dietary compounds have target organ for the EPA cancer risk assessment (Cook, 1994). been identified as potential modifiers of the cancer process, Complementary laboratory evidence for hormesis is

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 155 provided by the report that TCDD in Sprague–Dawley rats from dietary intake (whereas Crump et al. (2003) from affected cell-mediated immunity by producing a striking analyses of essentially the same data concluded that dioxin inverted U-shaped response curve, in that low doses toxic equivalent exposures within roughly three-fold of enhanced and high doses suppressed this immune function current background levels may be carcinogenic). Chemical and that humoral-mediated immunity might also be stimu- plant worker mortality data underlying the 1990 National lated by TCDD (Fan et al., 1996). Institute of Occupational Safety and Health (NIOSH) Report Since dioxin is found in trace amounts in some herbicides, on Dioxin has been used by Kayajanian (1999) to identify autoexhaust and the incineration process, people could be tissue/organ/system sites at which dioxin exposure caused or exposed to it just by eating meat, fish, eggs or diary products. was associated with a reduction in mortality. Kayajanian There is strong epidemiological evidence supporting (2002) reported that the NIOSH data showed a hormetic hormetic effects. The herbicide 2,4,5-T contains the potent J-shaped dioxin dose–response curve, and also cited evidence dioxin toxin TCDD. In the Vietnam War, Agent Orange was that the Saveso cancer data showed hormetic J-shaped the military code name for a mixture of the dioxin herbicide responses. 2,4,5-T and the nondioxin herbicide 2,4-D (which itself The synthetic plant growth inhibitor phosfon (2,4- evinces hormesis in oyster growth (Davis and Hidu, 1969)). dichlorobenzyl tributyl phosphonium chloride) exhibits a There were some 1200 United States servicemen who as hormetic inverted U-shaped dose–response relationship on members of the ‘Ranch Hand’ team were heavily exposed to the growth of peppermint, Mentha piperita (Calabrese, 1999; Agent Orange, mixing and loading it, spending hours in its Calabrese and Baldwin, 2003b; Kaiser, 2003). Growth spray mist and accumulating it on their clothing. Those stimulation occurred at lower phosfon doses with diminu- servicemen exposed to both the Southeast Asia environment tion of the stimulatory response at higher doses, leading to and dioxin were found to have significant reductions of marked inhibitory growth depending on the specific range elevated systemic cancer and total skin cancers compared to of doses employed. This growth-pattern hormesis was their colleagues only exposed to the Southeast Asia environ- attributed to overcompensation to an initial disruption in ment (termed Comparisons) who showed increases in homeostasis. systemic, melanoma and total skin cancers (Kayajanian, 2000). For Ranch Hand veterans there is a significant 50% reduction in total cancers at the highest dioxin body burden Hormetic acrylamide levels compared to low-level background body burden (Kayajanian, 2001). These results are consistent with the Acrylamide is an industrial chemical also found in cigarette failure to detect prostate cancer increase of the Ranch Hand smoke. Acrylamide also occurs as a natural product of group vis-a`-vis Comparisons in association with either cooking, rather than as a food contaminant, as a result of a monitored TCDD levels or time served in Southeast Asia Maillard chemical reaction between reducing sugars and (Pavuk et al., 2006). The latter study suggested that a longer specific amino acids (e.g., asparagines within foods upon service in the Southeast Asia environment and exposures exposure to high heat). Recently, relatively high levels of other than TCDD may have increased the risk of prostate acrylamide were unexpectedly detected in widely consumed cancer in Comparison veterans. food items, notably French fries, potato chips and bread. Other epidemiological studies are also pertinent. Of Acrylamide is a known human neurotoxin. It has been especial interest are some recent case–control studies that classified as a group 2A carcinogen (‘probably carcinogenic report J-shaped soft tissue sarcoma dose–response curves for to humans’) by the International Agency for Research on low body burdens of dioxin and three polychlorinated Cancer (although the data suggesting that acrylamide may biphenyl compounds (Tuomisto et al., 2004, 2005). These cause cancer in humans is derived from only one strain of results were reported to support similar J-shaped dose– one animal species). This has sparked intensive investiga- responses in animal studies, and were cited as possible tions regarding its occurrence, chemistry and toxicology/ examples of hormesis. Long-term monitoring of victims of potential health risk in the human diet. major dioxin industrial accidents at Saveso, Italy in 1976 and Retrospective studies on the association of cancer inci- at Monsanto Chemical’s Nitro, West Virginia plant in 1949 dence and dietary acrylamide in Sweden (Mucci et al., failed to reveal any deleterious effects other than temporary 2003a, b, 2004, 2005) and in Italy/Switzerland (Pelucchi chloracne (a severe acnelike skin disorder), and short-term et al., 2003, 2006) could not provide evidence for an reversible nerve dysfunction (Cole et al., 2003). A long-term association between high and low acrylamide intake and mortality study of a cohort of some 2000 male chemical cancer incidence of various organs. A hormetic effect was production workers previously exposed to substantial dioxin reported by Mucci et al. (2003a): ‘unexpectedly, an inverse levels (some substantial enough to result in chloracne) found trend was found for large bowel cancer with a 40% reduced no coherent evidence of increased cancer (Bodner et al., risk in the highest compared to lowest quartiles of known 2003). From analyses of three occupational cohorts, Starr acrylamide intake,’ while Mucci et al. (2003b) reported (2003) reported zero additional cancer deaths from all decreased risk of colorectal and kidney cancers with increas- exposures to dioxin-like compounds including those arising ing acrylamide dose. Pelucchi et al. (2003) found no evidence

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 156 of an increased risk of cancer with higher fried potatoes or damage (Stebbing, 1982, 2003). After the homeostasis consumption, an important source of dietary acrylamide, compensatory response neutralizes the disturbance and and also confirmed the inverse association with large bowel restores equilibrium, the fitness of the individual is opti- cancer. A large prospective study found no evidence that mized to respond to subsequent, more serious, challenges. dietary intake of acrylamide is associated with cancers of the However, high levels of stress or damage disrupt the colon or rectum (Mucci et al., 2006). In addition, a study of organism beyond its limits of recovery, causing irreparable some 9000 workers exposed to acrylamide between the years damage. Although the specific details of the hormetic 1925 and 1976 found a statistically significant decrease in mechanism may differ depending on how the organism is deaths from all causes (Collins et al., 1989). A follow-up being challenged; the overall strategy is the same, the study of these workers through year 1994 corroborated many maintenance of constant internal state to ensure an organ- of the initial findings (Marsh et al., 1999). ism’s efficient functioning and performance (i.e., homeostasis) that in turn produces biphasic dose–response relationships. Hormetic mechanism(s) An alternative explanation involves direct response to stress in the receptor systems that control the broad range As already noted, stress has been suggested as a hormesis- of critical processes underlying most organismal activities. inducing agent and has been invoked to explain hormesis Hormetic biphasic dose–response relationships acting via the arising from dietary restriction, natural dietary pesticides receptor-based mechanism have been explained from having and ethanol consumption. While specific hormetic inducing two receptor subtypes with markedly different agonist mechanisms have been advanced, prominent among them affinities, with different receptor subtypes existing in being stress protein induction; there is now less expectation different quantities, having different affinities for binding that any one single molecular mechanism can explain an agonist, and having different effects that lead to either a hormetic effects. This judgment arises from the fact that stimulatory or inhibitory pathway (Calabrese, 2004). At low hormetic effects have been observed for a broad range of concentrations with small amounts of the agonist present, a species, substances and biological end points (such as high-affinity receptor would be responsible for the dominant growth, longevity, reproduction, immune response, and response. However, it is postulated that low-affinity recep- many physiological and metabolic responses). In fact, there tors exist in greater quantities. So as the concentration appear to be numerous ways in which biological systems can increases, the number of occupied low-affinity receptors will manifest hormetic biphasic dose–response relationships. eventually outnumber occupied high-affinity receptors and What is seen among the array of particular hormetic begin to dominate the response. Thus, low levels of a mechanisms is a general commonality in quantitative compound can have the opposite effect of high levels of the features of hormetic dose–responses. The usual modest same compound. As a result of the combined presence of amplitudes of hormetic responses suggest that hormesis both receptor subtypes, it would then be possible to account operates within a framework designed to conserve resources. for hormetic biphasic dose–response relationships. Such a limited, yet efficient, use of resources is consistent with the hypothesis that hormesis is a modest overcompensation to the disruption of homeostasis, a concept proposed Discussion more than a century ago by Townsend (1899) and later experimentally supported by Branham (1929). (Arguments This review has considered the current and historical back- have been advanced by Rattan (2001) to replace the term ground of hormesis, the concept that small quantities have homeostasis with the term homeodynamics to reflect the opposite effects from large quantities. Hormetic dose– dynamic nature of living processes in an ever-changing response relationships were reviewed, categorized, and lifeline.) This overcompensation (other terms in the litera- depicted vis-a`-vis other dose–response relationships. Evi- ture being over-shoot and rebound) is believed to be the dence for biphasic dose responses was presented for essential manifestation of a broad biological strategy, with the specific vitamin and mineral nutrients, dietary restriction, ethanol mechanisms unique to each system being simply biological consumption, natural dietary and some synthetic pesticides, tactics. Linked in this way to a control system designed to some herbicides and acrylamide. Some of the evidence is restore homeostasis, only modest overcompensation would quite extensive. For example, there are at least 19 separate be predicted, and this has proven to be the case. This reports of alcohol’s impact on mortality being biphasic overcompensation not only negates the negative effects, but J-shaped; while the evidence for the paradoxical effects also offers protection against its later recurrence. of fruits and vegetables are also compelling. The hormesis Stebbing had proposed that the disturbance of homeo- paradigm appears to account for and explain many para- stasis is the driving force behind hormetic response, with doxical nutritional effects in a logical and consistent organisms having biochemical and physiological control manner. mechanisms that regulate internal processes and respond to Those engaged in nutritional research and in formulating external disturbances such as that caused by external stress nutritional guidelines should be cognizant of the following

European Journal of Clinical Nutrition Nutritional hormesis DP Hayes 157 facts. As discussed, hormetic effects are relatively modest. Ames BN, Gold LS (2000). Paracelsus to parascience: the environ- Although modest, such effects can be quite important, for mental cancer distraction. Mutat Res 447, 3–13. example, in molecular pharmacology where concerted low- Anson RM, Guo Z, de Cabo R, Iyun T, Rios M, Hagepanos A et al. (2003). Intermittent fasting dissociates beneficial effects of level measurements have yielded a treasure trove of hormetic dietary restriction on glucose metabolism and neuronal resistance effects (Calabrese, 2005c). Any consideration of hormesis to injury from caloric intake. Proc Natl Acad Sci USA 100, should also take into account that it may be a two-edged 6216–6220. sword. To wit, hormetic effects with reduction of dose do Attaran A, Maharaj R (2000). DDT for malaria control should not be banned. Br Med J 321, 1403–1404. not necessarily induce subjectively salutary changes. On the Blardi P, De Lalla A, Volpi L, Di Perri T (1999). Stimulation of contrary, account must be taken of the fact that hormesis, endogenous adenosine release of oral administration of quercetin if present, could induce subjectively negative effects. For and resveratrol in man. Drugs Exp Clin Res 25, 105–110. example, some chemotherapeutics used to treat tumors at Bluher M, Kahn BB, Kahn CR (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572– high concentrations enhance tumor growth at lower con- 574. centrations. Calabrese et al. (2006) have detailed this Bodner KM, Collins JJ, Bloemen LJ, Carson ML (2003). Cancer risk for potential problem in the field of drug development – one chemical workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin. scenario the case where low-dosage represents an adverse/ Occup Environ Med 60, 672–675. Brandes LJ (2005). 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