D
Hormesis

Hormesis has been defined as “the stimulating effect of small doses of substances which in larger doses are inhibitory.” As stated by Wolff (1989) the meaning has been modified in recent times to refer not only to a stimulatory effect but also to a beneficial effect. In other words, hormesis now connotes a value judgment whereby a low dose of a noxious substance is considered beneficial to an organism.

The committee has reviewed evidence for “hormetic effects” after radiation exposure, with emphasis on material published since the previous BEIR study on the health effects of exposure to low levels of ionizing radiation. Historical material relating to this subject has been reviewed by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR 1994), and a special edition of Health Physics on hormesis is available (Sagan 1987). A recent publication reviews data for and against the concept of hormesis (Upton 2000), while noting that further research needs to be done at low-dose and low-dose-rate exposures to resolve the issue. Another recent review argues against the validity of a linear no-threshold model in the low-dose region (Cohen 2002). The committee also reviewed a compilation of materials submitted by Radiation, Science, and Health Inc., entitled Low Level Radiation Health Effects: Compiling the Data and materials provided by Dr. Edward J. Calabrese including the Belle Newsletter Vol. 8, no. 2, December 1999 and the article; Hormesis: a highly generalizable and reproducible phenomenon with important implications for risk assessment (Calabrese and coworkers 1999).

Much of the historical material on radiation hormesis relates to plants, fungi, algae, protozoans, insects, and nonmammalian vertebrates (Calabrese and Baldwin 2000). For the purposes of this report on human health effects, the committee focused on recent information from mammalian cell and animal biology and from human epidemiology. In this context, some investigators have suggested that radiation exposure may enhance immune response (Luckey 1996; Liu 1997) or DNA repair processes (see “Adaptive Response” below). It has been postulated that such stimulation might result in a net health benefit after exposure, and these observations are sometimes offered as mechanisms for hormesis.

Theoretical Considerations

Pollycove and Feinendegen have made a theoretical argument that the hazards of radiation exposure are negligible in comparison to DNA damage that results from oxidative processes during normal metabolism. They argue that endogenous processes, autoxidation, depurination, and/or deamination can lead to cellular DNA damage resembling that produced by ionizing radiation. Oxidative damage is much more complex than they appreciate and involves predominantly proteins and mitochondrial targets associated with transcription, protein trafficking, and vacuolar functions (Thorpe and others 2004). The identity of the particular radical species generated endogenously in undamaged cells is unknown, and therefore yields of endogenous single-strand breaks (SSBs) and double-strand breaks (DSBs) cannot be estimated reliably a priori. Direct measurements of SSBs in unirradiated cells indicate levels several orders of magnitude less than that estimated by Pollycove and Feinendegen. The authors’ hypothesis that endogenous processes within cells give rise to significant levels of DSBs from SSBs in close proximity is speculative and not supported by current experimental information. Exposure of cells to high levels of hydrogen peroxide, for example, produces high frequencies of SSBs but no DSBs, suggesting that overlap of SSBs does not occur to a significant extent experimentally (Ward and others 1985). They also hypothesize that low-dose radiation induces a specific repair mechanism that then acts to reduce both spontaneous and radiation-induced damage to below spontaneous levels, thus causing a hormetic effect. The evidence for such a repair mechanism is weak and indirect and is contradicted by direct measures of DSB repair foci at low doses (Rothkamm and Lobrich 2003).



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D Hormesis Hormesis has been defined as “the stimulating effect of might result in a net health benefit after exposure, and these small doses of substances which in larger doses are inhibi- observations are sometimes offered as mechanisms for tory.” As stated by Wolff (1989) the meaning has been modi- hormesis. fied in recent times to refer not only to a stimulatory effect but also to a beneficial effect. In other words, hormesis now Theoretical Considerations connotes a value judgment whereby a low dose of a noxious substance is considered beneficial to an organism. Pollycove and Feinendegen have made a theoretical ar- The committee has reviewed evidence for “hormetic ef- gument that the hazards of radiation exposure are negligible fects” after radiation exposure, with emphasis on material in comparison to DNA damage that results from oxidative published since the previous BEIR study on the health ef- processes during normal metabolism. They argue that en- fects of exposure to low levels of ionizing radiation. Histori- dogenous processes, autoxidation, depurination, and/or cal material relating to this subject has been reviewed by the deamination can lead to cellular DNA damage resembling United Nations Scientific Committee on the Effects of that produced by ionizing radiation. Oxidative damage is Atomic Radiation (UNSCEAR 1994), and a special edition much more complex than they appreciate and involves pre- of Health Physics on hormesis is available (Sagan 1987). A dominantly proteins and mitochondrial targets associated recent publication reviews data for and against the concept with transcription, protein trafficking, and vacuolar functions of hormesis (Upton 2000), while noting that further research (Thorpe and others 2004). The identity of the particular radi- needs to be done at low-dose and low-dose-rate exposures to cal species generated endogenously in undamaged cells is resolve the issue. Another recent review argues against the unknown, and therefore yields of endogenous single-strand validity of a linear no-threshold model in the low-dose re- breaks (SSBs) and double-strand breaks (DSBs) cannot be gion (Cohen 2002). The committee also reviewed a compila- estimated reliably a priori. Direct measurements of SSBs in tion of materials submitted by Radiation, Science, and Health unirradiated cells indicate levels several orders of magni- Inc., entitled Low Level Radiation Health Effects: Compil- tude less than that estimated by Pollycove and Feinendegen. ing the Data and materials provided by Dr. Edward J. The authors’ hypothesis that endogenous processes within Calabrese including the Belle Newsletter Vol. 8, no. 2, De- cells give rise to significant levels of DSBs from SSBs in cember 1999 and the article; Hormesis: a highly generaliz- close proximity is speculative and not supported by current able and reproducible phenomenon with important implica- experimental information. Exposure of cells to high levels of tions for risk assessment (Calabrese and coworkers 1999). hydrogen peroxide, for example, produces high frequencies Much of the historical material on radiation hormesis re- of SSBs but no DSBs, suggesting that overlap of SSBs does lates to plants, fungi, algae, protozoans, insects, and not occur to a significant extent experimentally (Ward and nonmammalian vertebrates (Calabrese and Baldwin 2000). others 1985). They also hypothesize that low-dose radiation For the purposes of this report on human health effects, the induces a specific repair mechanism that then acts to reduce committee focused on recent information from mammalian both spontaneous and radiation-induced damage to below cell and animal biology and from human epidemiology. In spontaneous levels, thus causing a hormetic effect. The evi- this context, some investigators have suggested that radia- dence for such a repair mechanism is weak and indirect and tion exposure may enhance immune response (Luckey 1996; is contradicted by direct measures of DSB repair foci at low Liu 1997) or DNA repair processes (see “Adaptive Re- doses (Rothkamm and Lobrich 2003). sponse” below). It has been postulated that such stimulation 332

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APPENDIX D 333 Evidence from Cell Biology synthesis of proteins are involved in the adaptive response in lymphocytes, no specific signal transduction or repair path- Possible stimulatory effects have been reported for radia- ways have been identified. A recent study (Barquinero and tion exposure, such as mobilization of intracellular calcium others 1995), which reported that chronic average occupa- (Liu 1994), gene activation (Boothman and others 1993), tional exposure of about 2.5 mSv per year over 7 to 21 years activation of signal transduction pathways (Liu 1994; Ishii induced an adaptive response for radiation-induced chromo- and others 1997), increase in antioxidants such as reduced somal aberrations in human lymphocytes, also reported that glutathione (GSH; Kojima and others 1997), increase in the spontaneous level of aberrations was elevated signifi- lipoperoxide levels (Petcu and others 1997), and increase in cantly, presumably by the occupational exposure. (See circulating lymphocytes (Luckey 1991). The general thesis Barquinero and others [1995] for references to six other re- presented is that stress responses activated by low doses of ports that basal levels of chromosome abnormalities are in radiation, particularly those that would increase immuno- general higher in exposed human populations.) These results logical responses, are more beneficial than any deleterious suggest that occupational exposure may have induced chro- effects that might result from the low doses of ionizing ra- mosomal damage in the worker population while protecting diation. Although evidence for stimulatory effects from low lymphocytes from a subsequent experimental radiation ex- doses has been presented, little if any evidence is offered posure administered years after initiation of the chronic ex- concerning the ultimate deleterious effects that may occur. posure. It is unclear whether such competing events would In the section of this report on observed dose-response rela- result in a net gain, net loss, or no change in health status. tionships at low doses, bystander effects and hyper radiation In general, to observe hormetic effects the spontaneous sensitivity for low-dose deleterious effects in mammalian levels of these effects have to be rather high. The committee cells have been observed for doses in the 10–100 mGy range. notes in the Biology section that a very low radiation dose End points for these deleterious effects include mutations, was reported to cause a reduction in transformation in vitro chromosomal aberrations, oncogenic transformation, ge- below a relatively high spontaneous transformation fre- nomic instability, and cell lethality. These deleterious effects quency. However, problems and possible artifacts of the have been observed for cells irradiated in vivo as well as assay system employed are also discussed. When radioresis- in vitro. tance is observed after doses that cause some cell lethality— for example, after chronic doses that continually eliminate Adaptive Response cells from the population—the radioresistance that emerges may be caused either (1) by some inductive phenomenon or The radiation-adaptive response in mammalian cells was (2) by selecting for cells that are intrinsically radioresistant. demonstrated initially in human lymphocyte experiments Either process 1 or process 2 could occur as the radiosensi- (Olivieri and others 1984) and has been associated in recent tive cells are selectively killed and thus eliminated from the years with the older concept of radiation hormesis. A more population as the chronic irradiation is delivered. In the end, extensive treatment of adaptive effects is discussed in an- an adaptive or hormetic response in the population may ap- other section of this report. Radiation adaptation, as it was pear to have occurred, but this would be at the expense of initially observed in human lymphocytes, is a transient phe- eliminating the sensitive or weak components in the popula- nomenon that occurs in some (but not all) individuals when tion. a conditioning radiation dose lowers the biological effect of In chronic low-dose experiments with dogs (75 mGy/d a subsequent (usually higher) radiation exposure. In lym- for the duration of life), vital hematopoietic progenitors phocyte experiments, this reduction occurs under defined showed increased radioresistance along with renewed pro- temporal conditions and at specific radiation dose levels and liferative capacity (Seed and Kaspar 1992). Under the same dose rates (Shadley and others 1987; Shadley and Wiencke conditions, a subset of animals showed an increased repair 1989). However, priming doses less than 5 mGy or greater capacity as judged by the unscheduled DNA synthesis assay than ~200 mGy generally result in very little if any adapta- (Seed and Meyers 1993). Although one might interpret these tion, and adaptation has not been reported for challenge doses observations as an adaptive effect at the cellular level, the of less than about 1000 mGy. Furthermore, the induction exposed animal population experienced a high incidence of and magnitude of the adaptive response in human lympho- myeloid leukemia and related myeloproliferative disorders. cytes is highly variable (Bose and Olivieri 1989; Hain and The authors concluded that “the acquisition of radioresis- others 1992; Vijayalaxmi and others 1995), with a great deal tance and associated repair functions under the strong selec- of heterogeneity demonstrated between different individuals tive and mutagenic pressure of chronic radiation is tied tem- (Upton 2000). Also, the adaptive response could not be in- porally and causally to leukemogenic transformation by the duced when the lymphocytes were given the priming dose radiation exposure” (Seed and Kaspar 1992). during G0. Although inhibitor and electrophoretic studies suggest that alterations in transcribing messenger RNA and

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334 APPENDIX D Evidence from Animal Experiments In a study by Covelli and colleagues (1989), a decrease in incidence of malignant lymphoma at low doses of radiation Life Span Data (46 and 52% age-adjusted incidence at X-ray exposures of 500 and 1000 mGy versus 57% incidence in control ani- In contrast to experiments showing that radiation short- mals) shows a reduction in tumor incidence relative to the ens the life span, some early publications reported apparent control frequency. After peaking at 60% lymphoma inci- radiation-induced life lengthening following exposure to low dence (3000 mGy), the frequencies decline, “possibly due to levels of single or protracted doses of radiation (Lorenz cell inactivation becoming predominant at higher doses over 1950; Lorenz and others 1954). Statistical analyses of the the initial transforming events.” distribution of deaths in these studies indicate control ani- The reduction in spontaneous tumors noted in the previ- mals usually show a greater variance around the mean sur- ous two studies may in some way be related to the high spon- vival time than groups exposed to low doses of radiation. In taneous lymphoma incidence in this mouse strain. In the Ishii addition, the longer-living irradiated animals generally have study, the authors speculate that possible mechanisms may a reduced rate of intercurrent mortality from nonspecific and include augmentation of the immune system or initiation of infectious diseases during their early adult life, followed by an “adaptive response.” One might also consider that the a greater mortality rate later in life. Since these investiga- substantial doses delivered to the animals in this study (6000 tions were conducted under conditions in which infectious and 12,000 mGy) are effectively acting as radiotherapy in diseases made a significant contribution to overall mortality, the reduction of spontaneous tumor incidence. Human popu- the interpretation of these studies with respect to radiation- lations, which have a wider spectrum of “spontaneous” tu- induced cancer or other chronic diseases in human popula- mors occurring at a lower incidence, may not be expected to tions must be viewed with caution. respond to radiation in the same way as mouse strains with Problems with variability in controls was a major diffi- high lymphoma incidence. culty in the early studies before animal maintenance and heath care issues were dealt with by transitioning to the use of specific pathogen-free (SPF) facilities; this change to SPF HORMESIS AND EPIDEMIOLOGY facilities substantially reduced interexperimental variability. The term hormesis is not commonly used in the epide- For example, the cited data of Lorenz (1950) show a small miologic literature. Rather, epidemiologists discuss associa- difference in life span in mice exposed to 0.11 r/d compared tions between exposure and disease. A positive association to controls; the irradiated group lived somewhat longer than is one in which the rate of disease is higher among a group the unirradiated group, but the difference was not signifi- exposed to some substance or condition than among those cant. A French study (Caratero and others 1998) shows life not exposed, and a negative (or inverse) association is one in lengthening in irradiated mice compared to controls; unfor- which the rate of disease is lower among the exposed group. tunately, the control life spans were significantly shorter by If an association is judged to be causal, a positive association 100–150 d than any in other published data for this mouse may be termed a causal effect and a negative association strain (Sacher 1955; Congdon 1987). could be termed a protective effect. One type of epidemiologic study that has been used to Tumor Incidence Data evaluate the association between exposure to radiation and disease is the “ecologic” study in which data on populations, Two studies have reported a significant reduction in tu- rather than data on individuals, are compared. These data mor incidence of lymphoma in animals that have a high spon- have been used to argue for the existence of radiation taneous tumor incidence (>40%; Covelli and others 1989; hormesis. Ishii and others 1996). A paper by Ishii and colleagues Another example of an ecologic study is the evaluation of (1996) describes a reduction in lymphoma incidence after geographic areas with high background levels of radiation chronic, fractionated, low-dose total-body irradiation of compared to areas with “normal” background levels. The AKR mice with a spontaneous lymphoma incidence of fact that cancer rates in these high-background-radiation geo- 80.5%. The spontaneous lymphoma incidence was decreased graphic regions are not elevated is sometimes cited as evi- significantly (to 48.6%) by 150 mGy X-irradiation delivered dence against a linear no-threshold model (Jaworowowski twice a week for 40 weeks. A protocol of 50 mGy three 1995). times a week gave a smaller (not statistically significant) It is also true that certain populations residing in high- decrease to 67.5% lymphoma incidence. The mean survival background areas, such as occur at high altitudes, have lower time was significantly prolonged from 283 d for the control levels of health problems than those residing at lower alti- animals to 309 d with the three-exposure-per-week protocol tudes. This observation has been interpreted by some as evi- and to 316 d with the twice-a-week protocol. dence for a hormetic effect of radiation. BEIR V discussed

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APPENDIX D 335 the effect of confounders and the ecological fallacy2 in the It is common in cohort studies of occupational popula- evaluation of high-background-radiation areas and con- tions to observe that the overall mortality rate is lower than cluded that “these two problems alone are enough to make that of the general population, commonly about 15%. This is such studies essentially meaningless” (NRC 1990). not interpreted to mean that work per se reduces the risk of Another important consideration is the expected magni- mortality, but rather that healthy persons start to work more tude of the increase in health effect induced by excess back- often than unhealthy persons (Monson 1990). The term ground radiation. If one assumes a linear no-threshold re- “healthy worker effect” (HWE) is commonly used to de- sponse, a calculation can be made for expected cancers scribe this observation. Diseases such as cancer that develop induced by excess radiation in a high-background-radiation in later life ordinarily have less of an HWE than noncancer- area. As an example, consider the elevated levels of gamma ous diseases. The HWE is observed in most occupational radiation in Guodong Province, Peoples’ Republic of China studies, including those of radiation workers, and should not (PRC). In this study, a population receiving 3–4 mGy per be interpreted to mean that low doses of radiation prevent year was compared to an adjacent control population receiv- death from cancer or other causes. ing 1 mGy per year. No difference in cancers was noted be- A third type of epidemiologic study that has been used to tween the high-background area and the control area (NRC evaluate the association between exposure to radiation and 1990). One can estimate the expected excess percentage of disease is the case-control study. Persons with a specific dis- cancers resulting from the 2–3 mGy difference in exposure ease are compared to a control group of persons without the per year using a linear nonthreshold model and the lifetime disease with respect to their past exposure to radiation. This risk estimates developed in this report. A calculation by this type of study is unusual in radiation epidemiology, in that committee indicated that the expected percentage of cancers most general populations have relatively low exposure to induced by the excess background radiation would be 1–2% radiation. above the cancers occurring from all other causes in a life- While no phenomenon similar to the HWE is observed in time. Even if all confounding factors were accounted for, it case-control studies, the play of chance is always operative, is questionable whether one could detect an excess cancer as it is in cohort studies. Thus, if some exposure does not rate of 1–2%. Excess cancers may indeed be induced by el- cause cancer and if a number of case-control studies are con- evated radiation exposure in high-background areas, but the ducted, there will be a normal distribution observed in the excess may not be detectable given the high lifetime occur- odds ratios that describe the association between exposure rence of cancer from all causes. and disease. Some studies will have an odds ratio that is less Ordinarily, epidemiologists do not consider ecologic data than 1.0; others will have an odds ratio greater than 1.0. In such as this as being sufficient for causal interpretations. interpreting these studies, it is inappropriate to select only Since the data are based on populations, no information is those that are consistent with an excess or deficit of disease. available on the exposure and disease status of individuals. Rather, the entire distribution must be examined to assess Such data cannot be controlled adequately for confounding the likely relationship between exposure and disease. factors or for selection bias. Although ecologic data may be The studies discussed here illustrate the variability that is consistent with an inverse association between radiation and inherent in all epidemiologic studies and the need to evalu- cancer, they may not be used to make causal inferences. ate the entire body of relevant literature in order to assess A second type of epidemiologic study that has been used possible associations between radiation and disease, be they to evaluate the association between exposure to radiation and positive or negative. In its evaluation of the literature and in disease is the retrospective cohort study. Persons who have its discussions, the committee has found no consistent evi- had past exposure to radiation are followed forward in time, dence in the epidemiologic literature that low doses of ioniz- and the rate of disease is compared between exposed and ing radiation lower the risk of disease or death. Some studies nonexposed subjects or between exposed subjects and the show isolated positive associations between radiation expo- general population. Especially valuable are occupational sure and disease, and some show isolated negative associa- studies that include both unexposed and exposed subjects, tions. However, the weight of the evidence does not lead to so that a dose-response evaluation can be made of the rela- the interpretation that low doses of radiation exert what in tion between radiation exposure and health outcome. Typi- biological terms is called hormesis. cally, study populations in retrospective cohort studies in- clude persons who have worked with radiation in medical Summary facilities or in the nuclear industry or patients with cancer or other disease who have been treated with radiation. The committee concludes that the assumption that any stimulatory hormetic effects from low doses of ionizing ra- 2Ecological fallacy: two populations differ in many factors other than diation will have a significant health benefit to humans that those being evaluated, and one or more of these may be the underlying exceeds potential detrimental effects from the radiation ex- reason for any difference noted in their morbidity or mortality experience posure is unwarranted at this time. (Lilienfeld and Stolley 1994).