Low-dose ionizing radiation (LDR) may lead to suppression of smoking-related lung cancer. We examined the effects of a known cigarette smoke carcinogen Benzo[a]pyrene (B[a]P) alone or in combination with fractionated low-dose gamma radiation (60 – 600 mGy total dose) on the induction of lung neoplasms in the A/J mouse. Our results show that 600 mGy of gamma radiation delivered in six biweekly fractions of 100 mGy starting 1 month after B[a]P injection significantly inhibits the development of lung adenomas per animal induced by B[a]P. Our data also indicated that the six biweekly doses suppressed the occurrence of spontaneous hyperplastic foci in the lung, although this suppression failed to reach statistical significance when analyzed as average foci per lung possibly related to the small sample sizes used for the control and test groups.
Low-dose gamma-radiation; Benzo[a]pyrene; lung cancer
Radiological and nuclear devices may be used by terrorists or may be the source of accidental exposure. A tiered approach has been recommended for response to a terrorist event wherein local, regional, state and federal assets become involved sequentially, as the magnitude in severity of the incident increases. State-wide hospital plans have been developed and published for Connecticut, New York and California. These plans address delineation of responsibilities of various categories of health professionals, protection of healthcare providers, identification and classification of individuals who might have been exposed to and/or contaminated by radiation and, in the case of Connecticut response plan, early management of victims. Regional response programs such as the New England Regional Health Compact (consisting of 6 member states) have been developed to manage consequences of radiation injury. The Department of Homeland Security is ultimately responsible for managing both health consequences and the crisis. Multiple US national response assets may be called upon for use in radiological incidents. These include agencies and programs that have been developed by the Department of Energy, the Environmental Protection Agency and the Department of Defense. Coordination of national, regional and state assets with local response efforts is necessary to provide a timely and efficient response.
We show evidence for low doses of γ rays preventing spontaneous hyperplastic foci and adenomas in the lungs of mice, presumably via activating natural anticancer defenses. The evidence partly relates to a new study we conducted whereby a small number of female A/J mice received 6 biweekly dose fractions (100 mGy per fraction) of γ rays to the total body which prevented the occurrence of spontaneous hyperplastic foci in the lung. We also analyzed data from a much earlier Oak Ridge National Laboratory study involving more than 10,000 female RFMf/Un mice whereby single γ-ray doses from 100 to 1,000 mGy prevented spontaneous lung adenomas. We point out the possibility that the decrease in lung cancer mortality observed in The National Lung Screening Trial Research Team study involving lung tumor screening using low-dose computed tomography (CT) may relate at least in part to low-dose X-rays activating the body’s natural anticancer defenses (i.e., radiation hormesis). This possibility was apparently not recognized by the indicated research team.
low-dose radiation; lung tumor prevention; hormesis
Ultra-low doses and dose- rates of ionizing radiation are effective in preventing disease which suggests that they also may be effective in treating disease. Limited experimental and anecdotal evidence indicates that low radiation doses from radon in mines and spas, thorium-bearing monazite sands and enhanced radioactive uranium ore obtained from a natural geological reactor may be useful in treating many inflammatory conditions and proliferative disorders, including cancer. Optimal therapeutic applications were identified via a literature survey as dose-rates ranging from 7 to 11μGy/hr or 28 to 44 times world average background rates. Rocks from an abandoned uranium mine in Utah were considered for therapeutic application and were examined by γ-ray and laser-induced breakdown fluorescence spectroscopy. The rocks showed the presence of transuranics and fission products with a γ-ray energy profile similar to aged spent uranium nuclear fuel (93% dose due to β particles and 7% due to γ rays). Mud packs of pulverized uranium ore rock dust in sealed plastic bags delivering bag surface β,γ dose-rates of 10–450 μGy/h were used with apparent success to treat several inflammatory and proliferative conditions in humans.
Hormesis; Therapy; Radioactive; Rocks
Chronic exposure of mammals to low dose-rates of ionizing radiation affects proliferating cell systems as a function of both dose-rate and the total dose accumulated. The lower the dose-rate the higher needs to be the total dose for a deterministic effect, i.e., tissue reaction to appear. Stem cells provide for proliferating, maturing and functional cells. Stem cells usually are particularly radiosensitive and damage to them may propagate to cause failure of functional cells. The paper revisits 1) medical histories with emphasis on the hemopoietic system of the victims of ten accidental chronic radiation exposures, 2) published hematological findings of long-term chronically gamma-irradiated rodents, and 3) such findings in dogs chronically exposed in large life-span studies. The data are consistent with the hypothesis that hemopoietic stem and early progenitor cells have the capacity to tolerate and adapt to being repetitively hit by energy deposition events. The data are compatible with the “injured stem cell hypothesis”, stating that radiation–injured stem cells, depending on dose-rate, may continue to deliver clones of functional cells that maintain homeostasis of hemopoiesis throughout life. Further studies perhaps on separated hemopoietic stem cells may unravel the molecular-biology mechanisms causing radiation tolerance and adaptation.
chronic irradiation; hemopoietic tolerance; stem cell adaptation
BALB/c and C57BL/6 mice differ in their Th1/Th2 lymphocyte and M1/M2 macrophage phenotypes, radiosensitivity, and post-irradiation tumor incidence. In this study we evaluated the effects of repeated low-level exposures to X-rays on the development of artificial tumor colonies in the lungs of animals from the two strains and cytotoxic activities of natural killer (NK) cells and macrophages obtained from these mice. After ten daily irradiations of BALB/c or C57BL/6 mice with 0.01, 0.02, and 0.1 Gy X-rays NK cell-enriched splenocytes collected from the animals demonstrated significant and comparable up-regulation of their anti-tumor cytotoxic function. Likewise, peritoneal macrophages collected from the two irradiated strains of mice exhibited the similarly stimulated cytotoxicities against susceptible tumor cells and produced significantly more nitric oxide. These results were accompanied by the significantly reduced numbers of the neoplastic colonies induced in the lungs by intravenous injection of syngeneic tumor cells. The obtained results indicate that ten low-level irradiations with X-rays stimulate the generally similar anti-tumor reactions in BALB/c and C57BL/6 mice.
low fractionated doses of X-rays; radiosensitivity; NK cells; macrophages; tumor colonies; anti-neoplastic activity
In 2005, two expert advisory bodies examined the evidence on the effects of low doses of ionizing radiation. The U.S. National Research Council concluded that current scientific evidence is consistent with the linear no-threshold dose-response relationship (NRCNA 2005) while the French National Academies of Science and Medicine concluded the opposite (Aurengo et al. 2005). These contradictory conclusions may stem in part from an emphasis on epidemiological data (a “top down” approach) versus an emphasis on biological mechanisms (a “bottom up” approach). In this paper, the strengths and limitations of the top down and bottom up approaches are discussed, and proposals for strengthening and reconciling them are suggested. The past seven years since these two reports were published have yielded increasing evidence of nonlinear responses of biological systems to low radiation doses delivered at low dose-rates. This growing body of evidence is casting ever more doubt on the extrapolation of risks observed at high doses and dose-rates to estimate risks associated with typical environmental and occupational exposures. This paper compares current evidence on low dose, low dose-rate effects against objective criteria of causation. Finally, some questions for a post-LNT world are posed.
linear no-threshold hypothesis; hormesis; cancer
A recent update on the atomic bomb survivor cancer mortality data has concluded that excess relative risk (ERR) for solid cancers increases linearly with dose and that zero dose is the best estimate for the threshold, apparently validating the present use of the linear no threshold (LNT) model for estimating the cancer risk from low dose radiation. A major flaw in the standard ERR formalism for estimating cancer risk from radiation (and other carcinogens) is that it ignores the potential for a large systematic bias in the measured baseline cancer mortality rate, which can have a major effect on the ERR values. Cancer rates are highly variable from year to year and between adjacent regions and so the likelihood of such a bias is high. Calculations show that a correction for such a bias can lower the ERRs in the atomic bomb survivor data to negative values for intermediate doses. This is consistent with the phenomenon of radiation hormesis, providing a rational explanation for the decreased risk of cancer observed at intermediate doses for which there is no explanation based on the LNT model. The recent atomic bomb survivor data provides additional evidence for radiation hormesis in humans.
Radiation Hormesis; Atomic Bomb Survivors; Cancer Mortality; LNT Model; Systematic bias
The term hormesis describes a dose-response relationship that is characterized by a response that is opposite above and below the toxicological or pharmacological threshold. Previous reports have shown that this relationship is ubiquitous in the response of pharmaceuticals, metals, organic chemicals, radiation, and physical stressor agents. Recent reports have also indicated that certain nanoparticles (NPs) may also exhibit a hormetic dose-response. We describe the application of three previously described methods to quantify the magnitude of the hormetic biphasic dose-responses in nanotoxicology studies. This methodology is useful in screening assays that attempt to parse the observed toxicological dose-response data into categories based on the magnitude of hormesis in the evaluation of NPs. For example, these methods may be used to quickly identify NP induced hormetic responses that are either desirably enhanced (e.g., neuronal cell viability) or undesirably stimulated (e.g., low dose stimulation of tumor cells).
hormesis; nanoparticles; toxicology; high-throughput; biphasic
While the use of x-rays to treat patients with gas gangrene ended in the early 1940’s with the advent of antibiotics, x-ray had been widely accepted as a useful and highly effective treatment for this condition. The present paper re-assesses the historical foundations of this belief, the quality of the data, use of confirmatory animal models, and underlying mechanisms that might account for the therapeutic role of x-rays in the treatment of gas gangrene.
x-ray; gas gangrene; dose-response; history of medicine; hormesis
This commentary reviews the international radiation protection policy that resulted in the evacuation of more than 90,000 residents from areas near the Fukushima Daiichi NPS and the enormous expenditures to protect them against a hypothetical risk of cancer. The basis for the precautionary measures is shown to be invalid; the radiation level chosen for evacuation is not conservative. The actions caused unnecessary fear and suffering. An appropriate level for evacuation is recommended. Radical changes to the ICRP recommendations are long overdue.
radiation protection; evacuation; nuclear accident; spontaneous DNA damage; stimulated biodefences
In any decision involving radiation a risk-risk or risk-benefit comparison should be done. This can be either explicit or implicit. When the adverse effect of an alternate action is less than the planned action, such as medical use of X rays or nuclear power in ordinary operation, the comparison is simple. But in this paper I argue that with the situation faced by the Japanese in Fukushima, the assumption that the risk of an alternate action is small is false. The risks of unnecessary evacuation exceeded the risk of radiation cancers hypothetically produced by staying in place. This was not realized by those that had to make a decision within hours. This realization suggests important changes, worldwide, in the guidelines for radiation protection in accident situations.
Evacuation; Nuclear; accident; radiation; risk
The current radiation safety paradigm using the linear no-threshold (LNT) model is based on the premise that even the smallest amount of radiation may cause mutations increasing the risk of cancer. Autopsy studies have shown that the presence of cancer cells is not a decisive factor in the occurrence of clinical cancer. On the other hand, suppression of immune system more than doubles the cancer risk in organ transplant patients, indicating its key role in keeping occult cancers in check. Low dose radiation (LDR) elevates immune response, and so it may reduce rather than increase the risk of cancer. LNT model pays exclusive attention to DNA damage, which is not a decisive factor, and completely ignores immune system response, which is an important factor, and so is not scientifically justifiable. By not recognizing the importance of the immune system in cancer, and not exploring exercise intervention, the current paradigm may have missed an opportunity to reduce cancer deaths among atomic bomb survivors. Increased antioxidants from LDR may reduce aging-related non-cancer diseases since oxidative damage is implicated in these. A paradigm shift is warranted to reduce further casualties, reduce fear of LDR, and enable investigation of potential beneficial applications of LDR.
Radiation safety; Low dose radiation; LNT model; Immune system; Antioxidant stimulation; Aging-related diseases
This study aims to explore the expression of GRP78, a marker of endoplasmic reticulum (ER) stress, in the cortex of rat brains acutely exposed to methylmercury (MeHg). Thirty Sprague-Dawley (SD) rats were randomly divided into six groups, and decapitated 6 hours (h) after intraperitoneal (i.p.) injection of MeHg (2, 4, 6, 8 or 10 mg/kg body weight) or normal saline. Protein and mRNA expression of Grp78 were detected by western blotting and real-time PCR, respectively. The results showed that a gradual increase in GRP78 protein expression was observed in the cortex of rats acutely exposed to MeHg (2, 4 or 6 mg/kg). Protein levels peaked in the 6 mg/kg group (p < 0.05 vs. controls), decreased in the 8 mg/kg group, and bottomed below the control level in the 10 mg/kg group. Parallel changes were noted for Grp78 mRNA expression. It may be implied that acute exposure to MeHg induced hormetic dose-dependent changes in Grp78 mRNA and protein expression, suggesting that activation of ER stress is involved in MeHg-induced neurotoxicity. Low level MeHg exposure may induce GRP78 protein expression to stimulate endogenous cytoprotective mechanisms.
Methylmercury; endoplasmic reticulum stress; GRP78; rat; cortex
Many so-called “alternative medicine” techniques such as Reiki and acupuncture produce very good outcomes for intractable pain and other chronic illnesses but the efficacy is often dismissed as being psychosomatic. However a plausible mechanism does exist i.e. that the treatments alter the electromagnetic fields in living organisms and thereby prevent or reduce activity of neurons which lead to the pain. Low doses of ionising radiation have similar effects on electromagnetic fields and are known to induce signaling cascades in tissues due to ion gradients. To test this hypothesis cell cultures were exposed to Reiki – like and to acupuncture – like treatments, both performed by qualified practitioners. The cells were exposed either before or after the treatment to x-rays and were monitored for production of direct damage or bystander signals. The data suggest that the alternative techniques altered the response of cells to direct irradiation and altered bystander signal mechanisms. We conclude that alternative medicine techniques involving electromagnetic perturbations may modify the response of cells to ionizing radiation. In addition to the obvious implications for mechanistic studies of low dose effects, this could provide a novel target to exploit in radiation protection and in optimizing therapeutic gain during radiotherapy.
radiation-induced bystander effects; complementary and alternative medicine; Reiki; acupuncture; non-linear dose response; bioenergy
Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure.
Iridium; Sub-chronic exposure; Rats; Distribution; Excretion
The cancer mortality ratios (CMRs) in Poland in high and low level radiation areas were analyzed based on information from national cancer registry. Presented ecological study concerned six regions, extending from the largest administration areas (a group of voivodeships), to the smallest regions (single counties). The data show that the relative risk of cancer deaths is lower in the higher radiation level areas. The decrease by 1.17%/mSv/year (p = 0.02) of all cancer deaths and by 0.82%/mSv/year (p = 0.2) of lung cancers only are observed.
Tribute to Prof. Zbigniew Jaworowski (1927–2011)
ecological study; epidemiology; low dose; hormesis; Poland; residential
Application of hormesis in aging research and interventions is becoming increasingly attractive and successful. The reason for this is the realization that mild stress-induced activation of one or more stress response (SR) pathways, and its consequent stimulation of repair mechanisms, is effective in reducing the age-related accumulation of molecular damage. For example, repeated heat stress-induced synthesis of heat shock proteins has been shown to have a variety of anti-aging effects on growth and other cellular and biochemical characteristics of normal human skin fibroblasts, keratinocytes and endothelial cells undergoing aging in vitro. Therefore, searching for potential hormetins – conditions and compounds eliciting SR-mediated hormesis – is drawing attention of not only the researchers but also the industry involved in developing healthcare products, including nutriceuticals, functional foods and cosmeceuticals. Here we present the example of a skin care cosmetic as one of the first successful product developments incorporating the ideas of hormesis. This was based on the studies to analyse the molecular effects of active ingredients extracted from the roots of the Chinese herb Sanchi (Panax notoginseng) on gene expression at the level of mRNAs and proteins in human skin cells. The results showed that the ginsenosides extracted from Sanchi induced the transcription of stress genes and increased the synthesis of stress proteins, especially the heat shock protein HSP1A1 or Hsp70, in normal human keratinocytes and dermal fibroblasts. Furthermore, this extract also has significant positive effects against facial wrinkles and other symptoms of facial skin aging as tested clinically, which may be due to its hormetic mode of action by stress-induced synthesis of chaperones involved in protein repair and removal of abnormal proteins. Acceptance of such a hormesis-based product by the wider public could be instrumental in the social recognition of the concept of hormesis as the beneficial effects of mild stress of choice, and will encourage the development of novel health care products with physical, nutritional and mental hormetins.
anti-aging; hormesis; hormetin; proteasome; stress
There is no doubt that prudence and risk aversion must guide public decisions when the associated adverse outcomes are either serious or irreversible. With any carcinogen, the levels of risk and needed protection before and after an event occurs, are determined by dose-response models. Regulatory law should not crowd out the actual beneficial effects from low dose exposures—when demonstrable—that are inevitably lost when it adopts the linear non-threshold (LNT) as its causal model. Because regulating exposures requires planning and developing protective measures for future acute and chronic exposures, public management decisions should be based on minimizing costs and harmful exposures. We address the direct and indirect effects of causation when the danger consists of exposure to very low levels of carcinogens and toxicants. The societal consequences of a policy can be deleterious when that policy is based on a risk assumed by the LNT, in cases where low exposures are actually beneficial. Our work develops the science and the law of causal risk modeling: both are interwoven. We suggest how their relevant characteristics differ, but do not attempt to keep them separated; as we demonstrate, this union, however unsatisfactory, cannot be severed.
Cancer; dose-response models; hormesis; biphasic response; ionizing radiation; chemical exposures
Cadmium (Cd) is an important nephrotoxic pollutant. To examine late effects on the kidney of individuals previously exposed to chronic Cd at very low levels, male Wistar rats were given 20 nmol/kg i.p. injections of Cd every other day for 4 weeks. At the 20th, 28th, 36th, 44th and 52nd week of the study, renal metal accumulation, morphology and function were examined. Immunochemical staining was performed to detect renal 3-nitrotyrosine (3-NT) accumulation, metallothionein (MT) expression, cell proliferation and global DNA methylation. Results showed that renal Cd concentration and MT expression along with 3-NT accumulation were significantly higher in the Cd group than that in the control. Histopathologically renal tubule damage at the early stage and hyperplasia at the late stage were observed in the Cd group. Renal fibrosis in glomeruli was evident in the Cd group, particularly at the late stage of the study. Immunoreactivity of global DNA methylation was markedly diminished in the Cd group at both 20th and 52nd weeks. These results suggest that previous exposure to chronic Cd at very low level induced persistent damaging effects on the kidney along with increases in cell proliferation and global DNA hypomethylation.
Cadmium; renal toxicity; persistent effect; renal dysfunction; methylation
Acrylonitrile(AN) is a neurotoxin both in animals and humans, but its effects on acetylcholinesterase (AChE) activity remain controversial. This study aimed to determine the dose-response effects of AN on AChE activity and the modulatory role of ethanol pre-treatment. A total of 144 Kunming mice were randomly divided into 18 groups: nine groups received 5% ethanol in their drinking water, and the remaining nine groups received regular tap water. One week later, both the ethanol and tap water only groups were given an intraperitoneal injection of AN at the following doses: 0 (control), 0.156, 0.3125, 0.625, 1.25, 2.5, 5, 10 or 20 mg AN/kg body weight. AChE activity was determined on whole blood and brain 24 h later. Blood AChE activity was higher in AN-injected mice than in controls at all doses. AChE activity in blood increased in a dose-dependent manner, peaking at 0.156 mg/kg, after which a gradual decrease ensued, displaying a β-typed dose-response relationship. In contrast, brain AChE activity, following a single AN injection, was consistently lower than in control mice, and continued to fall up to a dose of 0.313 mg/kg, and thereafter increased gradually with higher doses. Mice receiving a 20 mg/kg dose of AN exhibited AChE brain activity indistinguishable from that of control mice, demonstrating a typical U-typed dose-response relationship. The activity of AChE in the blood and brain of the AN + ethanol-treated groups displayed a shift to the right, and the magnitude of the decrease in AChE activity induced by AN was attenuated relative to the AN-only group. These results suggest that AN affects AChE activity in both mouse blood and brain in a hormetic manner. Pretreatment with ethanol modifies the effect of AN on AChE, indicating that parent AN has a more prominent role than its metabolites in modulating enzyme activity.
acrylonitrile; acetylcholinesterase; biphasic effects; hormesis