Dose-Response

Hormesis, or biological effects of low level exposures (BELLE), is characterized by nonmonotonic dose response which is biphasic, displaying opposite effects at low and high dose. Its occurrence has been documented across a broad range of biological models and diverse type of exposure. Since hormesis appears to be a relatively common phenomenon in many areas, the objective of this review is to explore its occurrence related to dermatology and its public health and risk assessment implication. Hormesis appears to be a common phenomenon in in-vitro skin biology. However, in vivo data are lacking and the clinical relevance of hormesis has yet to be determined. Better understanding of this phenomenon will likely lead to different strategies for risk assessment process employed in the fields of dermatologic toxicology and pharmacology. We believe that hormesis is a common phenomenon and should be given detailed consideration to its concept and its risk assessment implications, and how these may be incorporated into the experimental and regulatory processes in dermatology. The skin, with its unique characteristics, its accessibility, and the availability of non-invasive bioengineering and DNA microarray technology, will be a good candidate to extend the biology of hormesis.

The objective of this study was to determine if exposure to divalent cations, Cd²⁺, Ni²⁺, and Co²⁺ would lead to malformations in Xenopus laevis embryos, and whether addition of Mg²⁺ and Zn²⁺; separately and in combination, would reduce their toxicity and teratogenicity on the embryos of Xenopus laevis as assessed by 96-h FETAX tests. Results indicate that exposure to Cd²⁺, Ni²⁺ or Co²⁺ lead to an increase in toxicity and teratogenicity in embryos, whereas Mg²⁺, Zn²⁺, or a combination of them reduced the toxic and teratogenic effects of these divalent cations. Modulation of Cd²⁺, Ni²⁺ or Co²⁺ toxicity and teratogenicity by Mg²⁺ and Zn²⁺, varied with the metal. Zn²⁺ was observed to be a better suppressor of Co²⁺ toxicity and teratogenicity than Mg²⁺. In contrast, Ni²⁺, and Cd²⁺ teratogenicity was reduced more prominently by Mg²⁺. On the other hand, combination of Mg²⁺ and Zn²⁺ showed potentialization effect on all divalent cation toxicity and teratogenicity. We concluded that Mg²⁺ and Zn²⁺ reduced the toxicity and teratogenicity of Cd²⁺, Ni²⁺, Co²⁺.

Radiation-induced DNA damage clusters have been proposed and are usually considered to pose the threat of serious biological damage. This has been attributed to DNA repair debilitation or cessation arising from the complexity of cluster damage. It will be shown here, contrary to both previous suggestions and perceived wisdom, that radiation induced damage clusters contribute to non-problematic risks in the low-dose, low-LET regime. The very complexity of cluster damage which inhibits and/or compromises DNA repair will ultimately be responsible for the elimination and/or diminution of precancerous and cancerous cells.

Confounding factors in radiation pulmonary carcinogenesis are passive and active cigarette smoke exposures and radiation hormesis. Significantly increased lung cancer risk from ionizing radiation at lung doses < 1 Gy is not observed in never smokers exposed to ionizing radiations. Residential radon is not a cause of lung cancer in never smokers and may protect against lung cancer in smokers. The risk of lung cancer found in many epidemiological studies was less than the expected risk (hormetic effect) for nuclear weapons and power plant workers, shipyard workers, fluoroscopy patients, and inhabitants of high-dose background radiation. The protective effect was noted for low- and mixed high- and low-linear energy transfer (LET) radiations in both genders. Many studies showed a protection factor (PROFAC) > 0.40 (40% avoided) against the occurrence of lung cancer. The ubiquitous nature of the radiation hormesis response in cellular, animal, and epidemiological studies negates the healthy worker effect as an explanation for radiation hormesis. Low-dose radiation may stimulate DNA repair/apoptosis and immunity to suppress and eliminate cigarette-smoke-induced transformed cells in the lung, reducing lung cancer occurrence in smokers.

Parthenium hysterophorus L. is an invasive weed that biosynthesizes several phytochemicals. The sesquiterpene lactone parthenin receives most attention regarding allelopathy of the plant or potential herbicidal properties. Since parthenin exhibits dose-dependent phytotoxicity with low dose stimulation, this study investigated the occurrence and temporal features of parthenin hormesis in Sinapis arvensis L. sprayed with parthenin under semi-natural conditions. Dose/response studies showed that the occurrence and the magnitude of hormesis depended on climatic conditions and the parameter measured. Within the tested dose range, stimulatory responses were only observed under less-stressful conditions and were most pronounced for leaf area growth [138 % of control; 13 days after treatment (DAT)]. Temporal assessment of leaf area development showed that doses causing a stimulatory response at the end of the experiment (< 0.42 ± 0.04 kg/ha; 13 DAT) were initially inhibitory up to ED₅₀ values (2 DAT). This clearly demonstrated an overcompensatory response. Inhibition of leaf area at 13 DAT reached ED₅₀ values on average at 0.62 ± 0.12 kg/ha, and S. arvensis was completely inhibited at doses exceeding 1.81 ± 0.56 kg/ha (ED₉₀). Based on these findings, implications of parthenin hormesis are discussed with respect to allelopathy of P. hysterophorus and exploitation of growth stimulatory responses in agriculture.

The public fear of radiation is in part driven by the Linear No Threshold Hypothesis (LNTH), or the concept that each and every ionization increases the risk for cancer. Even if this were true, it is important to recognize that the increased risk is very small at low doses and cannot be detected. This paper demonstrates the large number of assumptions and extrapolations needed when using the LNTH to estimate low-dose cancer risk. The manuscript provides information at every level of biological organization suggesting that many of these linear assumptions do not hold. While the initial damage may be produced linearly with dose, the processing of that damage is very non-linear. Finally, the paper provides the unique prospective on radiation-induced cancer, demonstrating that it takes large amounts (total energy) of radiation delivered to large populations to detect an increase in cancer frequency. These observations are supported by both theoretical calculations and examples based on past human radiation exposure.

The 1986 April 26^th Chernobyl event was the worst nuclear power accident—it killed 31 people. Its significance was exaggerated immensely because of the pervasive fear of ionizing radiation that has been indoctrinated in all of humanity. In reality, our environment includes radiation from natural sources, varying widely in intensity, to which all living things have adapted. The effect of radiation on organisms is primarily on their damage control biosystem, which prevents, repairs and removes cell damage. Low doses stimulate this system, while high doses inhibit it. So low doses decrease the incidences of cancer and congenital malformations; high doses have the opposite effect. Efforts by radiation protection organizations to lower exposures to (human-made) radiation to as low as reasonably achievable (ALARA) provide no benefit. They only create inappropriate fear—barriers to very important applications of nuclear technology in energy production and medicine.

This study explored the effects of long-term bathing in radon hot springs on oxidative damage and antioxidation function in humans. In this study, blood was collected from residents in the Pingshan radon hot spring area (RHSA), Jiangzha RHSA, and control area (CA). 8-Hydroxydeoxyguanosine (8-OHdG) and thioredoxin reductase (TrxR), representing oxidation and antioxidant levels, respectively, were analyzed as indices. Compared to the CA group, the RHSA group in the Pingshan and Jiangzha areas showed significantly decreased 8-OHdG levels (Z = −3.350, −3.316, respectively, P < .05) and increased TrxR levels (Z = 2.394, 3.773, respectively, P < .05). The RHSA and CA groups in Jiangzha had lower levels of TrxR and 8-OHdG compared to those in Pingshan. This finding may be related to the different radon concentration levels, bathing time and other factors. Results suggested that long-term bathing in radon hot spring may activate antioxidant function and reduce oxidative damage in the body.

S-Allyl cysteine (SAC), an organic compound and a natural constituent of Allium sativum, commonly known as garlic have been consumed in routine foods are known to possess various biological activities. Nevertheless, scientific evidence on the protective effect of SAC against neonatal asthmatic rats is not available. Hence, the present study aimed at investigating the anti-asthmatic activity of SAC in neonatal asthmatic rats using Wistar rats. The study conducted in 4 groups consists of normal control rats, asthma-induced, asthma animals administered with SAC (25 mg/kg), and SAC control. At the end of the experimental period, inflammatory cells in bronchoalveolar lavage fluid (BALF), inflammatory markers, fibrinogen level, activated partial thromboplastin time, coagulation factor activity, and histopathology were elucidated. The current investigation exhibits that SAC significantly reduced the total leukocytes, with restored fibrinogen level, and activated partial thromboplastin time. In addition, the levels of inflammatory cytokines such as TNF-α (tumor necrosis factor- α), IL-6 (Interleukin 6), and IL-1β have also attenuated in SAC treated animals. Furthermore, the mRNA expression levels of COX2 (cyclooxygenase-2), MCP-1 (monocyte chemoattractant protein-1), RANTES (regulated upon activation, normal T cell expressed and secreted), and eotaxin were reduced in SAC treated animals. Treatment of rats with SAC significantly reduced inflammation and eosinophil infiltration in the lungs. These results suggest that SAC exert protection in neonatal asthmatic rats suffering from acute or chronic inflammation by inducing anti-inflammatory and cell-protective responses.

Omeprazole, a proton pump inhibitor blocks the H⁺/K⁺-ATPase channels of gastric parietal cells. It is used for the treatment of peptic ulcer. Prolonged use of omeprazole may involve in inducing anemia. The key marker of eryptosis includes membrane blebbing, cell shrinkage and phosphatidylserine (PS) exposure at the cell surface. In current study, the eryptotic, oxidative as well as hemolytic effects of therapeutical doses (0.5, 1 and 1.5 µM) of omeprazole were investigated after exposing erythrocytes for 48 hours. Investigation of eryptosis was done by cell size measurement, PS exposure determination and calcium channel inhibition. As a possible mechanism of omeprazole induced eryptosis, oxidative stress was investigated by determining the catalase, glutathione peroxidase and superoxide dismutase activities. Similarly, necrotic effect of omeprazole on erythrocytes was also evaluated through hemolysis measurement. Results of our study illustrated that 1.5 µM of omeprazole may induce significant decrease in superoxide dismutase, glutathione peroxidase and catalase activities as well as triggered the erythrocytes shrinkage, PS exposure and hemolysis. Role of calcium was also confirmed in inducing erythrocyte shrinkage. It is concluded that the exposure of erythrocytes with 1.5 µM omeprazole may enhance the rate of eryptosis and hemolysis by inducing oxidative stress.

Tendinopathy is a common painful musculoskeletal disorder treated by injection of analgesics and nonsteroidal anti-inflammatory drugs (NSAIDs), which are believed to have cytotoxicity toward tenocytes. Ascorbic acid is an antioxidant that promotes collagen biosynthesis and prevents free radical formation. It is believed to protect tenocytes from oxidative stress. The optimal concentration of ascorbic acid, especially when used in conjunction with anesthetics and NSAIDs injection, to treat different stages of tendinopathies is unknown. Human tenocytes were isolated from a torn edge of the supraspinatus tendon of a 51-year-old male patient during arthroscopic repair. We monitored real-time changes in human tenocyte proliferation upon exposure to different concentrations of ascorbic acid, bupivacaine, and ketorolac tromethamine using the xCELLigence system. No significant changes in cell index were observed between the control group and tenocytes treated with the 3 concentrations of ascorbic acid. Tenocytes exposed to 0.5% bupivacaine and 30 or 15 mg/mL ketorolac tromethamine revealed significant reduction in tenocytes proliferation. Bupivacaine 0.5% with 250 μg/mL ascorbic acid and 15 mg/mL ketorolac tromethamine with 250 μg/mL ascorbic acid showed the least cytotoxicity against tenocytes. The optimal ascorbic acid concentration required to reduce the cytotoxic effects of bupivacaine and ketorolac tromethamine was demonstrated using this platform.

Studies of pulmonary toxicity induced by oral exposure to n-hexane are very few, in contrast to those studying the exposure by inhalation. This research tackles the oral toxic effect of n-hexane solvent on the lungs after subchronic exposure of Wistar male rats at 300, 600, and 1200 mg/kg, respectively, each day for 8 weeks. The pneumotoxicity observed in this study was marked by an immune toxicity in the form of a significant increase in the levels of white blood cells, lymphocytes, granulocytes, and eosinophils, as well as a significant increase in relative and absolute lung weight in both groups treated at the doses of 600 and 1200 mg/kg. n-Hexane also resulted in a significant increase in serum total proteins and acid phosphatase in the 3 doses tested daily for 8 weeks. In addition, we found a significant increase in total protein and a decrease in glutathione at 600 and 1200 mg/kg, in the pulmonary homogenate. Furthermore, the rate of lipid peroxidation increased in the 3 doses tested. Histological findings revealed a pneumonia characterized by bronchopneumonia, fibronecrotic lesions, congestion, hemorrhage, type II pneumocyte hyperplasia, alveolar lesions, bronchial epithelium degradation, and inflammation.

The aim of this paper is to assess the historical role of radiotherapy in the treatment of sinus infections. This assessment involved a literature-based review of how radiotherapy was used to treat sinus infections in the first half of the 20^th century. Low doses of x-rays were used with considerable success to treat nearly 3,000 patients of sinus infection in a span of 12 years with these cases being reported in leading medical journals as case studies. The mechanism of x-ray induced reduction of inflammation and increased tissue repair is uncertain but appears to be related to the development of a multifactorial and integrative anti-inflammatory phenotype.

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.

Although statistical analyses of epidemiological data usually treat the exposure variable as being known without error, estimated exposures in epidemiological studies often involve considerable uncertainty. This paper investigates the theoretical effect of random errors in exposure measurement upon the observed shape of the exposure response. The model utilized assumes that true exposures are log-normally distributed, and multiplicative measurement errors are also log-normally distributed and independent of the true exposures. Under these conditions it is shown that whenever the true exposure response is proportional to exposure to a power r, the observed exposure response is proportional to exposure to a power K, where K < r. This implies that the observed exposure response exaggerates risk, and by arbitrarily large amounts, at sufficiently small exposures. It also follows that a truly linear exposure response will appear to be supra-linear—i.e., a linear function of exposure raised to the K-th power, where K is less than 1.0. These conclusions hold generally under the stated log-normal assumptions whenever there is any amount of measurement error, including, in particular, when the measurement error is unbiased either in the natural or log scales. Equations are provided that express the observed exposure response in terms of the parameters of the underlying log-normal distribution. A limited investigation suggests that these conclusions do not depend upon the log-normal assumptions, but hold more widely. Because of this problem, in addition to other problems in exposure measurement, shapes of exposure responses derived empirically from epidemiological data should be treated very cautiously. In particular, one should be cautious in concluding that the true exposure response is supra-linear on the basis of an observed supra-linear form.

Radiation-induced gastric injury is a serious concern that may limit the duration and the delivered dose of radiation. However, the genome-wide molecular changes in stomach upon ionizing radiation have not been reported. In this study, mouse stomach was irradiated with 6 or 12 Gy X-ray irradiation and we found that radiation resulted in the atrophy of gastric mucosa and abnormal morphology of chief and parietal cells. Radiation-induced gastric injury was accompanied by an increase in the serum levels of pepsinogen A and pepsinogen C but not gastrin-17. The expression profiles of messenger RNA (mRNA) and long noncoding RNA (lncRNA) in normal and irradiated gastric tissues were measured by microarray analysis. Results revealed 17 upregulated and 10 downregulated mRNAs were consistent in 6 and 12 Gy irradiated gastric tissues, including D site-binding protein (Dbp) and fibrinogen-like protein 1 (Fgl1). Thirteen upregulated and 96 downregulated lncRNAs were commonly changed in 6 and 12 Gy irradiated gastric tissues. The dysregulated mRNAs were implicated in multiple pathways and showed coexpression with lncRNAs. To identify motifs for transcription factors and coactivators in the proximal promoter regions of the dysregulated RNAs, the bioinformatic tool Biopython was used. A variety of common motifs that are associated with transcription factors were identified, including ZNF263, LMX1B, and Dlx1. Our findings illustrate the molecular changes during radiation-induced gastric injury and the potential transcription factors driving this alteration.