Exposures to fine particulate matter (PM2.5) in air (C) have been suspected of contributing causally to increased acute (e.g., same-day or next-day) human mortality rates (R). We tested this causal hypothesis in 100 United States cities using the publicly available NMMAPS database. Although a significant, approximately linear, statistical C-R association exists in simple statistical models, closer analysis suggests that it is not causal. Surprisingly, conditioning on other variables that have been extensively considered in previous analyses (usually using splines or other smoothers to approximate their effects), such as month of the year and mean daily temperature, suggests that they create strong, nonlinear confounding that explains the statistical association between PM2.5 and mortality rates in this data set. As this finding disagrees with conventional wisdom, we apply several different techniques to examine it. Conditional independence tests for potential causation, non-parametric classification tree analysis, Bayesian Model Averaging (BMA), and Granger-Sims causality testing, show no evidence that PM2.5 concentrations have any causal impact on increasing mortality rates. This apparent absence of a causal C-R relation, despite their statistical association, has potentially important implications for managing and communicating the uncertain health risks associated with, but not necessarily caused by, PM2.5 exposures.
Air pollution health effects; PM2.5; time series; mortality rates; cardiovascular disease; causality; Granger-Sims; conditional independence tests; J-shaped dose-response curve
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
The hormesis phenomena or J-shaped dose response have been accepted as a common phenomenon regardless of the involved biological model, endpoint measured and chemical class/physical stressor. This paper first introduced a mathematical dose response model based on systems biology approach. It links molecular-level cell cycle checkpoint control information to clonal growth cancer model to predict the possible shapes of the dose response curves of Ionizing Radiation (IR) induced tumor transformation frequency. J-shaped dose response curves have been captured with consideration of cell cycle checkpoint control mechanisms. The simulation results indicate the shape of the dose response curve relates to the behavior of the saddle-node points of the model in the bifurcation diagram. A simplified version of the model in previous work of the authors was used mathematically to analyze behaviors relating to the saddle-node points for the J-shaped dose response curve. It indicates that low-linear energy transfer (LET) is more likely to have a J-shaped dose response curve. This result emphasizes the significance of systems biology approach, which encourages collaboration of multidiscipline of biologists, toxicologists and mathematicians, to illustrate complex cancer-related events, and confirm the biphasic dose-response at low doses.
hormesis; bi-phasic behavior; systems biology approach; ionizing radiation; cell cycle control
Understanding the effects to human health resulting from exposure to low doses of ionizing radiation is a persisting challenge. No one questions the deleterious consequences for humans following exposure to high radiation doses; however, in the low dose range, the complex and to some extent unknown cellular responses raise important misgivings about the resulting protective or potentially detrimental effects. Bystander effects are involved in low dose exposures, being characterized by the appearance in unirradiated cells of a cellular damage associated with direct radiation exposure. The purpose of our work was to assess, by using clonogenic and micronuclei assays, the dose and time dependence of the bystander response after cells exposure to very low doses of α-particles and to evaluate its importance in the overall induced damage. The study includes an irradiated cells culture, a medium transfer culture with non-irradiated cells and a culture with irradiated cells after centrifugation. We observed a non-negligible contribution of the bystander effects in the overall cellular damage. Low-dose hyper-sensitivity was observed for medium transfer and irradiated cells after centrifugation cultures. Delayed and earlier cellular damage were similar in almost all experiments, suggesting an effectiveness of irradiated medium to induce a bystander response soon after irradiation.
bystander effects; very low doses; MN assay; early and delayed cellular damage
Radiations may trigger protective response within a threshold of doses applied. Exposures above an upper threshold are generally detrimental, while exposures below a lower threshold may or may not increase risks for health. We recently reported that a cellular protective response occurs in interventional cardiologists to counteract the oxidative damage caused by radiation. Here, we demonstrated in an in vitro model represented by whole blood of healthy donors γ-irradiated with 220–440 mGy, that haemolysis of erythrocytes induced by hypochlorous acid was reduced by 40%. The protection triggered by γ-radiations made erythrocytes more resistant to oxidative insult caused by hypochlorous acid which was induced 3 h after irradiation and involved biochemical changes in the synthesis and turnover of glutathione. Overall, the biochemical remodelling induced by exposure to γ-radiations might contribute to generate new guidelines in professionally exposed workers.
ionizing radiation; reactive oxygen species; GSH; hypochlorous acid; human erythrocytes
In contrast to the detrimental action of severe stress conditions, the beneficial effects of mild stress, known as hormesis, is increasingly discussed and studied. A variety of applications for hormesis in risk assessment processes, anti-ageing strategies and clinical therapies have been proposed. The molecular mechanisms underlying the phenomenon of hormesis, however, are not yet fully understood. A possible mechanism that has been proposed for hormesis, the homoeostasis overshoot hypothesis, assumes that an overshoot of repair- and self-recovery mechanisms in response to mild damage can be held responsible for the beneficial effects of hormesis. The present paper proposes ‘cellular quality control’ as a further explanation of the molecular mechanisms underlying the benefits observed after exposure to mild stress. The most important quality control mechanisms are outlined and their known and hypothesised actions in hormesis are discussed. As an example, different aspects of protein quality control will be described in more detail, which includes the reaction of the cell upon stress-induced protein damage and –aggregation. The regulation of Heat Shock Proteins and components from the ubiquitin proteasome system as part of cellular quality control is described in relation to its beneficial role in hormesis.
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
In our contribution we concisely question and answer some basic notions on food, health, and safety. We show that for some food components such as flavonoids, a whole range of small toxicological effects that have been uncovered the last decade on the whole confer benefits to human health. This development underlines the notion that health is adaptation with respect to the exposures humans experience when consuming food.
Obstructive sleep apnea causes cardiovascular disease via chronic intermittent hypoxia (IH), which may be related to oxidative stress. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is an important cellular defense mechanism against oxidative stress by regulating its down-stream multiple antioxidants. The present study was to define whether IH can induce renal pathogenic damage and if so, whether Nrf2 and its down-stream antioxidants are involved in IH-induced pathogenic changes. Mice were culled for exposure to intermittent air as control or IH that consisted of 20.9% O2/ 8% O2 FIO2 alternation cycles (30 episodes per h) with 20 seconds at the nadir FIO2 for 12 h a day during daylight. Short-term IH exposure (3 – 7 days) induced significant increases in renal inflammatory response and antioxidant levels along with a reduction of the spontaneous content of malondialdehyde while long-term IH exposure (8 weeks) induced a significant decrease of antioxidant levels and significant increases of renal inflammation, oxidative damage, cell death, and fibrosis. This study suggests that IH induces a hormetic response, i.e.: short-term IH exposure is able to induce a protective response to protect the kidney from oxidative damage while long-term IH exposure is able to induce a damage effect on the kidney.
Intermittent hypoxia; kidney hypoxic damage; Nrf2; metallothionein
Herbicide phosphinothricin (PPT) inhibits glutamine synthetase (GS), a key enzyme in nitrogen assimilation, thus causing ammonia accumulation, glutamine depletion and eventually plant death. However, the growth response of Lotus corniculatus L. plants immersed in solutions with a broad range of PPT concentrations is biphasic, with pronounced stimulating effect on biomass production at concentrations ≤ 50 μM and growth inhibition at higher concentrations. The growth stimulation at low PPT concentrations is a result of activation of chloroplastic isoform GS2, while the growth suppression is caused by inhibition of both cytosolic GS1 and GS2 at higher PPT concentrations. Since the results are obtained in cell-free system (e.g. protein extracts), to which the principles of homeostasis are not applicable, this PPT effect is an unambiguous example of direct stimulation hormesis. A detailed molecular mechanism of concentration-dependent interaction of both PPT and a related GS inhibitor, methionine sulfoximine, with GS holoenzymes is proposed. The mechanism is in concurrence with all experimental and literature data.
Glufosinate; Glutamine synthetase; Hormesis; Lotus corniculatus L.; Phosphinothricin; Methionine sulfoximine
Although plant diseases can be caused by bacteria, viruses, and protists, most are caused by fungi and fungus-like oomycetes. Intensive use of fungicides with the same mode of action can lead to selection of resistant strains increasing the risk of unmanageable epidemics. In spite of the integrated use of nonchemical plant disease management strategies, agricultural productivity relies heavily on the use of chemical pesticides and biocides for disease prevention and treatment and sanitation of tools and substrates. Despite the prominent use of fungi in early hormesis studies and the continuous use of yeast as a research model, the relevance of hormesis in agricultural systems has not been investigated by plant pathologists, until recently. A protocol was standardized for detection and assessment of chemical hormesis in fungi and oomycetes using radial growth as endpoint. Biphasic dose-responses were observed in Pythium aphanidermatum exposed to sub-inhibitory doses of ethanol, cyazofamid, and propamocarb, and in Rhizoctonia zeae exposed to ethanol. This report provides an update on chemical hormesis in fungal plant pathogens and a perspective on the potential risks it poses to crop productivity and global food supply.
chemical hormesis; oomycetes; fungi; low-dose; biphasic; growth stimulation; plant pathogen
Low dose radiation has been shown to be beneficial to living organisms using several biological systems, including immune and hematopoietic systems. Chronic low dose radiation was shown to stimulate immune systems, resulting in controlling the proliferation of cancer cells, maintain immune balance and induce hematopoietic hormesis. Since dendritic cells are differentiated from bone marrow cells and are key players in maintaining the balance between immune activation and tolerance, it may be important to further characterize whether low dose radiation can influence the capacity of bone marrow cells to differentiate into dendritic cells. We have shown that bone marrow cells from low dose-irradiated (γ-radiation, 0.2Gy, 15.44mGy/h) mice can differentiate into dendritic cells that have several different characteristics, such as expression of surface molecules, cytokine secretion and antigen uptake capacity, when compared to dentritic cells differentiated from the control bone marrow cells. These differences observed in the low dose radiation group can be beneficial to living organisms either by activation of immune responses to foreign antigens or tumors, or maintenance of self-tolerance. To the best of our knowledge, this is the first report showing that total-body low dose radiation can modulate the capacity of bone marrow cells to differentiate into dendritic cells.
Low dose radiation; Dendritic cells; Immune system; Hematopoietic system; Hormesis
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
The present study proposed a QSAR model to predict joint effects at non-equitoxic ratios for binary mixtures containing reactive toxicants, cyanogenic compounds and aldehydes. Toxicity of single and binary mixtures was measured by quantifying the decrease in light emission from the Photobacterium phosphoreum for 15 min. The joint effects of binary mixtures (TUsum) can thus be obtained. The results showed that the relationships between toxic ratios of the individual chemicals and their joint effects can be described by normal distribution function. Based on normal distribution equations, the joint effects of binary mixtures at non-equitoxic ratios (
TUsumn:m) can be predicted quantitatively using the joint effects at equitoxic ratios (
TUsum1:1). Combined with a QSAR model of
TUsum1:1in our previous work, a novel QSAR model can be proposed to predict the joint effects of mixtures at non-equitoxic ratios (
TUsumn:m). The proposed model has been validated using additional mixtures other than the one used for the development of the model. Predicted and observed results were similar (p>0.05). This study provides an approach to the prediction of joint effects for binary mixtures at non-equitoxic ratios.
joint effect; binary mixture; non-equitoxic; QSAR; toxic ratio-effect curve
USEPA assessed whether epidemiology data suggest that fetal or early-life chlorpyrifos exposure causes neurodevelopmental effects and, if so, whether they occur at exposures below those causing the current most sensitive endpoint, 10% inhibition of blood acetylcholinesterase (AChE). We previously conducted a hypothesis-based weight-of-evidence analysis and found that a proposed causal association between chlorpyrifos exposure and neurodevelopmental effects in the absence of AChE inhibition does not have a substantial basis in existing animal or in vitro studies, and there is no plausible basis for invoking such effects in humans at their far lower exposure levels. The epidemiology studies fail to show consistent patterns; the few associations are likely attributable to alternative explanations. Human data are inappropriate for a dose-response assessment because biomarkers were only measured at one time point, may reflect exposure to other pesticides, and many values are at or below limits of quantification. When considered with pharmacokinetic data, however, these biomarkers provide information on exposure levels relative to those in experimental studies and indicate a margin of exposure of at least 1,000. Because animal data take into account the most sensitive lifestages, the use of AChE inhibition as a regulatory endpoint is protective of adverse effects in sensitive populations.
chlorpyrifos; neurodevelopment; risk assessment; epidemiology; acetylcholinesterase
The effect of bilirubin on renal pathophysiology is controversial. This study aimed to observe the effects of bilirubin on the proliferation of normal rat renal tubular epithelial cell line (NRK52E) and its potential interplay with gap junction function.
Cultured NRK52E cells, seeded respectively at high- or low- densities, were treated with varying concentrations of bilirubin for 24 hours. Cell injury was assessed by measuring cell viability and proliferation, and gap junction function was assessed by Parachute dye-coupling assay. Connexin 43 protein was assessed by Western blotting.
At doses from 17.1 to 513μmol/L, bilirubin dose-dependently enhanced cell viability and colony-formation rates when cells were seeded at either high- or low- densities (all p<0.05 vs. solvent group) accompanied with enhanced intercellular fluorescence transmission and increased Cx43 protein expression in high-density cells. However, the above effects of BR were gradually reversed when its concentration increased from 684 to 1026μmol/L. In high-density cells, gap junction inhibitor 12-O-tetradecanoylphorbol 13-acetate attenuated bilirubin-induced enhancement of colony-formation and fluorescence transmission. However, in the presence of high concentration bilirubin (1026μmol/L), activation of gap junction with retinoid acid decreased colony-formation rates.
Bilirubin can confer biphasic effects on renal NRK52E cell proliferation potentially by differentially affecting gap junction functions.
Bilirubin; NRK52E cells; gap junction; connexin; cell proliferation; kidney injury
Hormetic morphogens are morphogens such as transforming growth factor beta (TGF-β) in mammals and auxin in plants that induce hormetic responses. For example, in vitro, TGF-β stimulates and inhibits cell proliferation at low and high concentrations respectively. I developed a model of hormetic morphogen gradient control of the morphogenesis of the fusion of bilateral aortic precursors (Anlagen) that form the aorta during development; and validated the model with findings obtained by Daucus Carota fusion experiments. Theoretically, radial concentration gradients of a hormetic morphogen can form hollow (vessels) or solid (Carota) tubular structures. In arteries, blood flow and pressure can shape mural gradients and determine wall curvature and thereby vessel diameter. As Anlagen grow they form a temporary common wall that is subsequently removed, which results in fusion of the Anlagen lumina and an aorta with a lumen diameter that accommodates the combined blood flow to the iliac arteries. Carota seedlings grown close together exhibited proximally fused root cones, serial cross-sections of which exhibited coaxial fusion patterns that closely resembled the predicted vascular fusion patterns, thus validating a role for hormesis and hormetic morphogens in the morphogenesis of the aorta and possibly the morphogenesis of other human midline structures.
Hormesis; hormetic morphogen; gradient; pattern formation; hormetic fusion; fusion tubulogenesis
Although the adult human brain has a small number of neural stem cells, they are insufficient to repair the damaged brain to achieve significant functional recovery for neurodegenerative diseases and stroke. Stem cell therapy, by either enhancing endogenous neurogenesis, or transplanting stem cells, has been regarded as a promising solution. However, the harsh environment of the diseased brain posts a severe threat to the survival and correct differentiation of those new stem cells. Hormesis (or preconditioning, stress adaptation) is an adaptation mechanism by which cells or organisms are potentiated to survive an otherwise lethal condition, such as the harsh oxidative stress in the stroke brain. Stem cells treated by low levels of chemical, physical, or pharmacological stimuli have been shown to survive better in the neurodegenerative brain. Thus combining hormesis and stem cell therapy might improve the outcome for treatment of these diseases. In addition, since the cell death patterns and their underlying molecular mechanism may vary in different neurodegenerative diseases, even in different progression stages of the same disease, it is essential to design a suitable and optimum hormetic strategy that is tailored to the individual patient.
hormesis; preconditioning; regenerative medicine; stem cells; cell death; apoptosis; necrosis; autophagy; molecular chaperone; Hsp90 inhibitors
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