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issn:1540-143
1.  Modeling the Effect of Density-Dependent Chemical Interference Upon Seed Germination 
A mathematical model is presented to estimate the effects of phytochemicals on seed germination. According to the model, phytochemicals tend to prevent germination at low seed densities. The model predicts that at high seed densities they may increase the probability of seed germination and the number of germinating seeds. Hence, the effects are reminiscent of the density-dependent effects of allelochemicals on plant growth, but the involved variables are germination probability and seedling number. The results imply that it should be possible to bypass inhibitory effects of allelopathy in certain agricultural practices and to increase the efficiency of nature conservation in several plant communities.
doi:10.2201/nonlin.003.02.004
PMCID: PMC2657952  PMID: 19330163
chemical interference; seed density; germination probability; seedling number
2.  Mathematical Modelling of Allelopathy: IV. Assessment of Contributions of Competition and Allelopathy to Interference by Barley 
One of the main challenges to the research on allelopathy is technically the separation of allelopathic effect from competition, and quantitatively, the assessment of the contribution of each component to overall interference. A simple mathematical model is proposed to calculate the contribution of allelopathy and competition to interference. As an example of applying the quantitative model to interference by barley (Hordeum vulgare cv. Triumph), the approach used was an addition of allelopathic effect, by an equivalent amount, to the environment of the test plant (white mustard, Sinapis alba), rather than elimination of competition. Experiments were conducted in glasshouse to determine the magnitude of the contributions of allelopathy and competition to interference by barley. The leachates of living barley roots significantly reduced the total dry weight of white mustard. The model involved the calculation of adjusted densities to an equivalent basis for modelling the contribution of allelopathy and competition to total interference. The results showed that allelopathy contributed 40%, 37% and 43% to interference by barley at 6, 12 and 18 white mustard pot−1. The consistency in magnitude of the calculated contribution of allelopathic effect by barley across various densities of receiver plant suggested that the adjusted equivalent density is effective and that the model is able to assess the contribution of each component of interference regardless of the density of receiver plant.
doi:10.2201/nonlin.003.02.003
PMCID: PMC2657951  PMID: 19330162
Allelochemical(s); plant interference; biochemical interaction; barley (Hordeum vulgare cv. Triumph); white mustard (Sinapis alba); density
4.  Whole-Range Assessment: A Simple Method for Analysing Allelopathic Dose-Response Data 
Based on the typical biological responses of an organism to allelochemicals (hormesis), concepts of whole-range assessment and inhibition index were developed for improved analysis of allelopathic data. Examples of their application are presented using data drawn from the literature. The method is concise and comprehensive, and makes data grouping and multiple comparisons simple, logical, and possible. It improves data interpretation, enhances research outcomes, and is a statistically efficient summary of the plant response profiles.
doi:10.2201/nonlin.003.02.006
PMCID: PMC2657949  PMID: 19330165
Hormesis; allelopathy; biological response; allelochemical(s); inhibition index; benzoxazinoids; phenolic compounds; mathematical modelling
5.  Dose-Response—A Challenge for Allelopathy? 
The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.
doi:10.2201/nonlin.003.02.002
PMCID: PMC2657948  PMID: 19330161
hormesis; benzoxazinoids; log-logistic model; scopoletin
6.  Implementation of Card: Curve-Fitting Allelochemical Response Data 
Bioassay techniques are essential methods used to study the effects of allelochemicals on plant processes. It is often observed that the biological processes are stimulated at low allelochemical concentrations and inhibited as the concentrations increase. Liu et al., (2003) developed a simple model to fit this type of allelochemical response data. Based on the model, CARD (curve-fitting allelochemical response data) was developed as a Windows based program that can be used to fit a stimulation-inhibition response data. An example of using CARD is given.
doi:10.2201/nonlin.003.02.005
PMCID: PMC2657947  PMID: 19330164
Allelopathy; CARD; modelling; computer software; stimulation-inhibition response
7.  The Involvement of Calcium in the Protective and Toxic (Nonlinear) Responses of Rodent and Human Astroglial Cells 
The involvement of [Ca2+]i in the reactive changes of astrocytes which accompany exposure to different chemicals were studied in cultures of C6 and 1321N1 cells. Cells were exposed to up to three serial pulses of the differentiating agent dBcAMP, which induces activation-type changes in the cells. Other cells, with or without the dBcAMP treatments, were treated with a range of concentrations of the antidepressants amitriptyline and fluoxetine and the glial toxicants acrylamide and chloroquine. In some experiments the L-type voltage calcium channel blocker Nifedipine was employed. [Ca2+]i was measured in populations of the cells using Fura-2AM and a charge coupled device (CCD) camera attached to a fluorescence microscope. dBcAMP induced both dose- and time-dependent changes in [ Ca2+]i with increases in both the [Ca2+]i oscillations and mean [Ca2+]i (e.g. in C6 cells at 18 min mean [Ca2+]i was 318 ± 20nM following the single differentiating dBcAMP pulses, 489 ± 17nM (p < 0.001) following two serial pulses, and 275 ± 30nM (not significant) following three pulses). Therapeutic doses of fluoxetine and amitriptyline caused increases in the calcium oscillations and the mean calcium concentrations ( maximum recorded mean increase was in the C6 cells at 10min by 0.02 μM fluoxetine when [Ca2+]i was 411 ± 35nM c.f. control 254 ± 25nM, p = 0.01). Higher (non-therapeutic) doses of both antidepressants caused significant reductions. Chloroquine and acrylamide also caused dose-dependent bi-phasic types of alterations in [Ca2+]i, with significant reductions at lower, sub-cytotoxic doses followed by significant increases at higher concentrations, approaching those which cause cell damage. Nifedipine treatment caused some reductions in the dBcAMP, antidepressant or toxicant-induced calcium changes, but this substance also initiated cytotoxic alterations. The findings show that both the activation-type changes (which are frequently associated with increased protective capacities) and toxic responses of C6 and 1321N1 cells to different chemical agents are associated with dose-dependent alterations in [Ca2+]i.
doi:10.2201/nonlin.003.01.005
PMCID: PMC2657843  PMID: 19330156
astrocyte bi-phasic responses; C6 glioma; 1321N1 astrocytoma; astrocyte activation; calcium; antidepressants; neurotoxicants
8.  The Inverted “U-Shaped” Dose-Effect Relationships in Learning and Memory: Modulation of Arousal and Consolidation 
In the ample field of biological non-linear relationships there is also the inverted U-shaped dose-effect. In relation to cognitive functions, this phenomenon has been widely reported for many active compounds, in several learning paradigms, in several animal species and does not depend on either administration route (systemic or endocerebral) or administration time (before or after training). This review summarizes its most interesting aspects. The hypothesized mechanisms supporting it are reported and discussed, with particular emphasis on the participation of emotional arousal levels in the modulation of memory processes. Findings on the well documented relationship between stress, emotional arousal, peripheral epinephrine levels, cerebral norepinephrine levels and memory consolidation are reported. These are discussed and the need for further research is underlined.
doi:10.2201/nonlin.003.01.002
PMCID: PMC2657842  PMID: 19330154
Non-linear dose-effect trend; arousal levels; memory consolidation; stimulus intensity; hypothalamic-pituitary-adrenocortical axis
9.  Low Dose Effects in Psychopharmacology: Ontogenetic Considerations 
Low doses of psychoactive drugs often elicit a behavioral profile opposite to that observed following administration of more substantial doses. Our laboratory has observed that these effects are often age-specific in rats. For instance, whereas moderate to high doses of the dopamine agonist apomorphine increase locomotion, suppressed locomotor activity is seen following low dose exposure, with this low dose effect not emerging consistently until adolescence. A somewhat earlier emergence of a low dose “paradoxical” effect is seen with the 5HT1a receptor agonist, 8-OH-DPAT, with late preweanling, but not neonatal, rats showing increases in ingestive behavior at low doses but suppression at higher doses. In contrast to these ontogenetic increases in expression of low dose drug effects, low dose facilitation of social behavior is seen following ethanol only in adolescent rats and not their mature counterparts, although suppression of social interactions at higher doses is seen at both ages. This hormesis-like low dose stimulation appears related in part to overcompensation, with brief social suppression preceding the subsequent stimulation response, and also bears a number of ontogenetic similarities to acute tolerance, a well characterized, rapidly emerging adaptation to ethanol. Implications of these and other ontogenetic findings for studies of hormesis are discussed.
doi:10.2201/nonlin.003.01.006
PMCID: PMC2657841  PMID: 19330157
Hormesis; ontogeny; psychopharmacology; rat; ethanol; acute tolerance
10.  Hormetic Influence of Glucocorticoids on Human Memory 
In this paper, we discuss the effects of glucocorticoids on human learning and memory using the recent model of hormesis proposed by Calabrese and collaborators. Although acute increases in glucocorticoids have been shown to impair memory function in humans, other studies report no such impairments or, in contrast, beneficial effects of acute glucocorticoid increases on human memory function. We summarize these studies and assess whether the wealth of data obtained in humans with regard to the effects of acute increase of glucocorticoids on human cognition are in line with a hormetic function. We then discuss several factors that will have to be taken into account in order to confirm the presence of a hormetic function between glucocorticoids and human cognitive performance.
doi:10.2201/nonlin.003.01.003
PMCID: PMC2657840  PMID: 19330155
Glucocorticoids; Noradrenergic Hormones; Hippocampus; Frontal; Memory; Receptors; Hormesis; Humans
12.  Nonlinear Response for Neoplastic Transformation Following Low Doses of Low Let Radiation 
There are now several independent studies that indicate that the dose-response for the endpoint of radiation-induced neoplastic transformation in vitro is non-linear for low linear energy transfer (LET) radiation. At low doses (<10 cGy) the transformation frequency drops below that seen spontaneously. Importantly, this observation has been made using fluoroscopic energy x-rays, a commonly used modality in diagnostic radiology, the practice of which is responsible for the majority of radiation exposure to the general public. Since the transformation frequency is reduced over a large dose range (0.1 to 10cGy) it is likely that multiple mechanisms are involved and that the relative contribution of these may vary with dose. These include the killing of a subpopulation of cells prone to spontaneous transformation at the lowest doses, and the induction of DNA repair at somewhat higher doses. Protective effects of low doses of low LET radiation on other cancer-relevant endpoints in vitro and in vivo have also been observed by several independent laboratories. These observations strongly suggest that the linear-nonthreshold dose-response model is unlikely to apply to the induction of cancer by low doses of low LET radiation in humans.
doi:10.2201/nonlin.003.01.007
PMCID: PMC2657837  PMID: 19330158
Low dose; radiation; neoplastic transformation; adaptive response
13.  The Search for Non-Linear Exposure-Response Relationships at Ambient Levels in Environmental Epidemiology 
Environmental exposures to ambient air particulate matter (PM), ozone (O3), environmental tobacco smoke (ETS), and to dioxin and related compounds are of considerable public health concern, and risk assessments for them have generally been based on linear, non-threshold models derived from epidemiological study data. While the epidemiological databases for PM, O3, and ETS have been sufficient to show that adverse health effects are occurring, the relative risks have been quite low, and it has not been possible, to date, to identify thresholds or non-linear relationships for them. For dioxin and related compounds, the evidence for excess cancer risks has been inadequate to establish causality, and there is suggestive evidence that hormesis may have occurred.
doi:10.2201/nonlin.003.01.008
PMCID: PMC2657836  PMID: 19330159
Particulate matter; Ozone; Environmental tobacco smoke; Dioxin; Threshold; Hormesis
14.  The Particulate Air Pollution Controversy 
Scientists, regulators, legislators, and segments of industry and the lay public are attempting to understand and respond to epidemiology findings of associations between measures of modern particulate air pollutants (PM) and adverse health outcomes in urban dwellers. The associations have been interpreted to imply that tens of thousands of Americans are killed annually by small daily increments in PM. These epidemiology studies and their interpretations have been challenged, although it is accepted that high concentrations of air pollutants have claimed many lives in the past. Although reproducible and statistically significant, the relative risks associated with modern PM are very small and confounded by many factors. Neither toxicology studies nor human clinical investigations have identified the components and/or characteristics of PM that might be causing the health-effect associations. Currently, a massive worldwide research effort is under way in an attempt to identify whom might be harmed and by what substances and mechanisms. Finding the answers is important, because control measures have the potential not only to be costly but also to limit the availability of goods and services that are important to public health.
doi:10.1080/15401420490900245
PMCID: PMC2659607  PMID: 19330148
air pollution; PM; particles; EPA standards; aerosol; inhalation toxicology
15.  An Examination of Radiation Hormesis Mechanisms Using a Multistage Carcinogenesis Model 
A multistage cancer model that describes the putative rate-limiting steps in carcinogenesis is developed and used to investigate the potential impact on cumulative lung cancer incidence of the hormesis mechanisms suggested by Feinendegen and Pollycove. In the model, radiation and endogenous processes damage the DNA of target cells in the lung. Some fraction of the misrepaired or unrepaired DNA damage induces genomic instability and, ultimately, leads to the accumulation of malignant cells. The model explicitly accounts for cell birth and death processes, the clonal expansion of initiated cells, malignant conversion, and a lag period for tumor formation. Radioprotective mechanisms are incorporated into the model by postulating dose and dose-rate-dependent radical scavenging. The accuracy of DNA damage repair also depends on dose and dose rate. As currently formulated, the model is most applicable to low-linear-energy-transfer (LET) radiation delivered at low dose rates. Sensitivity studies are conducted to identify critical model inputs and to help define the shapes of the cumulative lung cancer incidence curves that may arise when dose and dose-rate-dependent cellular defense mechanisms are incorporated into a multistage cancer model. For lung cancer, both linear no-threshold (LNT-), and non-LNT-shaped responses can be obtained. If experiments demonstrate that the effects of DNA damage repair and radical scavenging are enhanced at least three-fold under low-dose conditions, our studies would support the existence of U-shaped responses. The overall fidelity of the DNA damage repair process may have a large impact on the cumulative incidence of lung cancer. The reported studies also highlight the need to know whether or not (or to what extent) multiply damaged DNA sites are formed by endogenous processes. Model inputs that give rise to U-shaped responses are consistent with an effective cumulative lung cancer incidence threshold that may be as high as 300 mGy (4 mGy per year for 75 years) for low-LET radiation.
doi:10.1080/15401420490900263
PMCID: PMC2657508  PMID: 19330150
radioprotective mechanisms; LNT; U-shaped; threshold; hormesis; endogenous damage
16.  Enhancement of Cognitive and Electrophysiological Measures of Hippocampal Functioning in Rats by a Low, But Not High, Dose of Dehydroepiandrosterone Sulfate (DHEAS) 
Dehydroepiandrosterone sulfate (DHEAS) is a steroid hornone that is synthesized, de novo, in the brain. Endogenous DHEAS levels correlate with the quality of mental and physical health, where the highest levels of DHEAS occur in healthy young adults and reduced levels of DHEAS are found with advanced age, disease, or extreme stress. DHEAS supplementation, therefore, may serve as a therapeutic agent against a broad range of maladies. This paper summarizes laboratory findings on dose-response relationships between DHEAS and cognitive and electrophysiological measures of hippocampal functioning. It was found that a low, but not a high, dose of DHEAS enhanced hippocampal primed burst potentiation (a physiological model of memory) as well as spatial (hippocampal-dependent) memory in rats. This complex dose-response function of DHEAS effects on the brain and memory may contribute toward the inconsistent findings that have been obtained by other investigators in studies on DHEAS administration in people.
doi:10.1080/15401420490900290
PMCID: PMC2657507  PMID: 19330152
neurosteroid; dehydroepiandrosterone; DHEA; hippocampus; long-term potentiation; memory
17.  Alcohol: Friend or Foe? Alcoholic Beverage Hormesis for Cataract and Atherosclerosis is Related to Plasma Antioxidant Activity 
Objectives:
To correlate the oxidative state of postabsorptive blood plasma after consumption of one or three drinks of different beverages with known J-shaped epidemiological risk curves.
Design, interventions, and main outcome measures:
Red wine, lager beer, stout (alcoholic and alcohol-free), with antioxidant activity, and an aqueous solution of alcohol were compared for the plasma antioxidant or pro-oxidant activity in human volunteers following consumption of one or three typical drinks containing equivalent amounts of alcohol (except for an alcohol-free stout used as a control for stout).
Results:
One drink of red wine, lager beer, or stout (5% alcohol v/v, and alcohol-free) significantly increased the average antioxidant activity in plasma samples obtained from volunteers averaged over 240 min. Three drinks of red wine, lager beer, or stout (5% alcohol v/v, and alcohol-free) significantly increased the average pro-oxidant activity in plasma samples obtained from volunteers averaged over 360 min. For a solution of alcohol, three drinks resulted in pro-oxidant plasma on average, whereas while one drink did not significantly affect the plasma oxidative status. A preliminary experiment in which two volunteers showed a significantly increased time to metabolize ethanol after ingestion resulted in elevated antioxidant activity in plasma for lager beer and red wine.
Conclusions:
One drink of red wine, beer, or stout provided equivalent increases in plasma antioxidant activity. Three drinks of red wine, beer, or stout provided equivalent increases in plasma pro-oxidant activity. This may explain, at least in part, the decreased risk of cataract and atherosclerosis from daily consumption of one drink of different types of alcoholic beverages as well as the increased risk from daily consumption of three drinks of alcoholic beverages. The plasma pro-oxidant activity appears to be due to ethanol metabolism, whereas the antioxidant activity may be due to the absorption of polyphenols in the beverages.
doi:10.1080/15401420490900272
PMCID: PMC2657506  PMID: 19330151
alcoholic beverages; ingestion; plasma antioxidant activity; polyphenols; cataract; atherosclerosis; risk reduction; hormesis
18.  Radiobiological Basis for Cancer Therapy by Total or Half-Body Irradiation 
The tumor control effects by total-body irradiation (TBI) or half-body irradiation (HBI) on tumor-bearing mice and human cancer were investigated. In fundamental studies using a murine experimental system, mice that received 10 or 15 cGy of TBI showed a high value of TD50 (number of tumor cells required for successful transplantation to a half group of injected sites) compared with nonirradiated control mice. The combination of low doses of TBI and local irradiation on tumor-bearing mice demonstrated enhanced tumor cell killing compared with only local irradiation, but this tumor-cell killing effect was not observed following 10 or 15 cGy of TBI alone. However, the suppression of distant metastasis of tumor cells was observed following low doses of TBI alone. Immunological studies on these effects suggested that TBI or HBI caused immunopotentiating effects. In clinical studies, malignant lymphoma (non-Hodgkin’s lymphoma) was selected as the first disease for clinical trial. The results were promising for tumor control applications, except for advanced cases and very aged patients.
doi:10.1080/15401420490900254
PMCID: PMC2657505  PMID: 19330149
total-body irradiation; tumor immunology; murine squamous carcinoma; TD50; non-Hodgkin’s lymphoma
19.  Low Doses of Gamma-Radiation Induce Nonlinear Dose Responses in Mammalian and Plant Cells 
The percentage of cells with chromosome aberrations or micronuclei induced by low doses of acute (dose rate of 47 cGy/min) or chronic (dose rate of 0.01 cGy/min) gamma-irradiation was studied in vitro in Chinese hamster fibroblasts, human lymphocytes, and Vicia faba seeds and seedlings. The sensitivity of the indicated biological entities to low doses was greater than expected based on linear extrapolation from higher doses. The dose-response curves for cytogenetic damage that were obtained were nonlinear when evaluated over the full range of the doses used. At very low doses, the dose-response curves appeared linear, followed by a plateau region at intermediate doses. At high doses the dose response curves again appeared linear with a slope different from that for the low-dose region. There was no statistically significant difference between the yields of cells with micronuclei induced by low doses of acute versus chronic irradiation. Similar data were obtained both for human lymphocyte culture and for roots and seeds of Vicia faba. Our experiments revealed that the dose range over which the plateau occurs depends on the type of cells irradiated. We have also shown that the modifying effects of the repair inhibitor caffeine and the radioprotector mercaptoethylenamine (MEA) are absent at low doses of gamma irradiation and that caffeine increased the number of cells with cytogenetic damage when evaluated over the plateau region. In the presence of MEA, the upper end of the plateau region was extended from just above 1 Gy to about 2 Gy. We therefore provide direct evidence that a plateau exists in the dose-response curve for the indicated radiation-induced stochastic effects. Furthermore, our results suggest that, for low linear energy transfer radiation, the induction of DNA repair occurs only after a threshold level of cytogenetic damage and that the higher yield of cytogenetic damage per unit dose at low radiation doses is attributable to an insignificant contribution or the absence of DNA repair processes.
doi:10.1080/15401420490519861
PMCID: PMC2657489  PMID: 19330144
nonlinear dose response; cytogenetic damage; ionizing radiation; low doses
20.  The Bystander Effect: Recent Developments and Implications for Understanding the Dose Response 
The bystander effect refers to the biological response of a cell resulting from an event in an adjacent or nearby cell. Such effects depend on intercellular communication and amplify the consequences of the original event. These responses are of particular interest in the assessment of ionizing radiation risk because at public or occupational exposure levels not every cell receives a radiation track. Current radiation protection regulations and practices are based on the assumption of a linear increase in risk with dose, including low doses where not all cells are hit. Mechanisms that amplify biological effects are inconsistent with these assumptions. Evidence suggests that there are two different bystander effects in mammalian cells. In one type, a radiation track in one cell leads to damaging, mutagenic, and sometimes lethal events in adjacent, unhit cells. In the other type, a radiation track in one cell leads to an adaptive response in bystander cells, increasing resistance to spontaneous or radiation-induced events. This paper describes some of the data for radiation-induced bystander effects in vitro and correlates that data with in vitro and in vivo observations of risk at low doses. The data suggest that protective effects, including beneficial bystander effects, outweigh detrimental effects at doses below about 100 mGy, but that the reverse is true above this threshold.
doi:10.1080/15401420490507512
PMCID: PMC2657488  PMID: 19330142
bystander effects; ionizing radiation; Trp53; cancer; mice
21.  Low-Dose Radiation and Genotoxic Chemicals Can Protect Against Stochastic Biological Effects 
A protective apoptosis-mediated (PAM) process that is turned on in mammalian cells by low-dose photon (X and γ) radiation and appears to also be turned on by the genotoxic chemical ethylene oxide is discussed. Because of the PAM process, exposure to low-dose photon radiation (and possibly also some genotoxic chemicals) can lead to a reduction in the risk of stochastic effects such as problematic mutations, neoplastic transformation (an early step in cancer occurrence), and cancer. These findings indicate a need to revise the current low-dose risk assessment paradigm for which risk of cancer is presumed to increase linearly with dose (without a threshold) after exposure to any amount of a genotoxic agent such as ionizing radiation. These findings support a view seldom mentioned in the past, that cancer risk can actually decrease, rather than increase, after exposure to low doses of photon radiation and possibly some other genotoxic agents. The PAM process (a form of natural protection) may contribute substantially to cancer prevention in humans and other mammals. However, new research is needed to improve our understanding of the process. The new research could unlock novel strategies for optimizing cancer prevention and novel protocols for low-dose therapy for cancer. With low-dose cancer therapy, normal tissue could be spared from severe damage while possibly eliminating the cancer.
doi:10.1080/15401420490507602
PMCID: PMC2657487  PMID: 19330143
low dose; radiation; ethylene oxide; risk assessment; threshold
22.  Radiation-Induced Change in Lymphocyte Proliferation and its Neuroendocrine Regulation: Dose–Response Relationship and Pathophysiological Implications 
Cellular activities are regulated by intracellular signals initiated by stimulation from the external and internal environments. Different signal pathways are involved in the initiation of different cellular functions. In connection with cell proliferation in response to mitogenic stimulation, the dose–effect relationship of the magnitude of 3H-TdR incorporation into lymphocytes after exposure to different concentrations of concanavalin A (Con A) showed an inverted U-shaped curve in the concentration range 2–30 μg/ml. In previous studies it has been observed that the stimulatory effect of Con A (5 μg/ml) on lymphocyte proliferation was potentiated by whole-body irradiation (WBI) with low dose (0.075 Gy) and suppressed by WBI with high dose (2 Gy). When different concentrations of corticosterone, ranging from 10–12 to 10–7 M, were added to the Con A–stimulated lymphocytes, low-concentration stimulation and high-concentration suppression of lymphocyte proliferation were demonstrated. In the presence of 5 ×10 –12 M (subphysiological concentration) of corticosterone the proliferation of thymocytes and splenic T cells in response to Con A was further up-regulated after low-dose radiation. Low-dose radiation (0.075 Gy) caused lowering of serum ACTH and corticosterone concentration as well as down-regulated transcription of the hypothalamic proopiomelanocortin gene. The present paper intends to show that multiple neurohormonal factors, including the pineal gland and neurotransmitters, in addition to the hypothalamic–pituitary–adrenocortical axis, are involved in the stimulation of immune responses induced by low-dose ionizing radiation. The complex nature of the interrelationship between the intracellular signaling of lymphocytes and the neuroendocrine regulation after WBI is discussed.
doi:10.1080/15401420490507486
PMCID: PMC2657486  PMID: 19330146
lymphocyte proliferation; nonlinear dose-response curve; signal molecules; neuroendocrine regulation; pineal gland; catecholamines
23.  Responses to Low Doses of Ionizing Radiation in Biological Systems 
Biological tissues operate through cells that act together within signaling networks. These assure coordinated cell function in the face of constant exposure to an array of potentially toxic agents, externally from the environment and endogenously from metabolism. Living tissues are indeed complex adaptive systems.
To examine tissue effects specific for low-dose radiation, (1) absorbed dose in tissue is replaced by the sum of the energies deposited by each track event, or hit, in a cell-equivalent tissue micromass (1 ng) in all micromasses exposed, that is, by the mean energy delivered by all microdose hits in the exposed micromasses, with cell dose expressing the total energy per micromass from multiple microdoses; and (2) tissue effects are related to cell damage and protective cellular responses per average microdose hit from a given radiation quality for all such hits in the exposed micromasses.
The probability of immediate DNA damage per low-linear-energy-transfer (LET) average micro-dose hit is extremely small, increasing over a certain dose range in proportion to the number of hits. Delayed temporary adaptive protection (AP) involves (a) induced detoxification of reactive oxygen species, (b) enhanced rate of DNA repair, (c) induced removal of damaged cells by apoptosis followed by normal cell replacement and by cell differentiation, and (d) stimulated immune response, all with corresponding changes in gene expression. These AP categories may last from less than a day to weeks and be tested by cell responses against renewed irradiation. They operate physiologically against nonradiogenic, largely endogenous DNA damage, which occurs abundantly and continually. Background radiation damage caused by rare microdose hits per micromass is many orders of magnitude less frequent. Except for apoptosis, AP increasingly fails above about 200 mGy of low-LET radiation, corresponding to about 200 microdose hits per exposed micromass. This ratio appears to exceed approximately 1 per day for protracted exposure. The balance between damage and protection favors protection at low cell doses and damage at high cell doses. Bystander effects from high-dosed cells to nonirradiated neighboring cells appear to include both damage and protection.
Regarding oncogenesis, a model based on the aforementioned dual response pattern at low doses and dose rates is consistant with the nonlinear reponse data and contradicts the linear no-threshold dose–risk hypothesis for radiation-induced cancer. Indeed, a dose–cancer risk function should include both linear and nonlinear terms.
doi:10.1080/15401420490507431
PMCID: PMC2657485  PMID: 19330141
radiation low-dose effects; hormesis
24.  Comparison in vivo Study of Genotoxic Action of High- Versus Very Low Dose-Rate γ-Irradiation 
The aim of the present study was to compare genotoxicity induced by high- versus very low dose-rate exposure of mice to γ-radiation within a dose range of 5 to 61 cGy using the single-cell gel electrophoresis (comet) assay and the micronucleus test. CBA/lac male mice were irradiated at a dose rate of 28.2 Gy/h (high dose rate) or 0.07 mGy/h (very low dose rate). The comet assay study on spleen lymphocytes showed that very low dose-rate irradiation resulted in a statistically significant increase in nucleoid relaxation (DNA breaks), starting from a dose of 20 cGy. Further prolongation of exposure time and, hence, increase of a total dose did not, however, lead to further increase in the extent of nucleoid relaxation. Doses of 20 and 61 cGy were equal in inducing DNA breaks in mouse spleen lymphocytes as assayed by the comet assay. Of note, the level of DNA damage by 20–61 cGy doses of chronic irradiation (0.07 mGy/h) was similar to that an induced by an acute (28.2 Gy/h) dose of 14 cGy. The bone marrow micronucleus test revealed that an increase in polychromatic erythrocytes with micronuclei over a background level was induced by very low-level γ-irradiation with a dose of 61 cGy only, with the extent of the cytogenetic effect being similar to that of 10 cGy high-dose-rate exposure. In summary, presented results support the hypothesis of the nonlinear threshold nature of mutagenic action of chronic low dose-rate irradiation.
doi:10.1080/15401420490507521
PMCID: PMC2657484  PMID: 19330145
ionizing radiation; low doses; very low dose-rate irradiation; single-strand DNA breaks; comet assay; cytogenetic effects
25.  Secondary Ultraweak Luminescence from Humic Acids Induced by γ-Radiation 
Humic substances (HSs) are products of biochemical transformations of plant and animal residues that make up a major fraction of the organic carbon of soil and aquatic systems in the environment. Because radioisotopes occur in the Earth’s crust and because the entire biosphere is continuously exposed to cosmic radiation, ionizing radiation continually interacts with HSs. This chronic irradiation could have a significant ecological impact. However, very few publications are available that address possible consequences of chronic exposure of HSs to ionizing radiation from terrestrial and cosmic sources. This study was conducted to investigate possible impacts of exposure of HSs to ionizing radiation.
Dried humic acid (HA) or its associated aqueous solution (in 0.1 M Na2CO3) were exposed to absorbed γ-radiation in high doses of 1–90 kGy using a 60Co source. Following the γ-ray exposures, a secondary, ultraweak radiation emanation with wavelengths in the spectral range λ= 340–650 nm was recorded as a long-lived chemiluminescence (CL) from the aqueous solutions; however, the CL was not observed after irradiating dry HA.
Absorption spectra (for λ=240–800 nm) of irradiated solutions indicated that polymerization/degradation processes were operating on the HA macromolecules. The effect of specific CL enhancers (luminol and lucigenin) on the intensity and kinetics of the CL implicated the participation of reactive oxygen species and free radicals in the CL and polymerization/degradation processes. For the range of absorbed doses used (1–10 kGy), the intensity of the induced CL was nonlinearly related to dose, suggesting that complex radical formation mechanisms were involved.
doi:10.1080/15401420490507468
PMCID: PMC2657483  PMID: 19330147
humic acid; luminescence; γ-irradiation

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