Nonlinearity in biology, toxicology, medicine最新文献

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.

Environmental exposures to ambient air particulate matter (PM), ozone (O(3)), 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, O(3), 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.

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 TD(50) (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.

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.

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.

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.

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.

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.

A protective apoptosis-mediated (PAM) process that is turned on in mammalian cells by low-dose photon (X and gamma) 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.