Hormetic Dose-response Relationships Research Articles

Time Is Ripe for Targeting Per- and Polyfluoroalkyl Substances-Induced Hormesis: Global Aquatic Hotspots and Implications for Ecological Risk Assessment.

Globally implemented ecological risk assessment (ERA) guidelines marginalize hormesis, a biphasic dose-response relationship characterized by low-dose stimulation and high-dose inhibition. The present study illuminated the promise of hormesis as a scientific dose-response model for ERA of per- and polyfluoroalkyl substances (PFAS) represented by perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). A total of 266 hormetic dose-response relationships were recompiled from 1237 observations, covering 30 species from nine representative taxonomic groups. The standardized hormetic amplitudes followed the log-normal probability distribution, being subject to the limits of biological plasticity but independent of stress inducers. The SHapley Additive exPlanations algorithm revealed that the target endpoint was the most important variable explaining the hormetic amplitudes. Subsequently, quantitative frameworks were established to incorporate hormesis into the predicted no-effect concentration levels, with a lower induction dose and a zero-equivalent point but a broader hormetic zone for PFOS. Realistically, 10,117 observed concentrations of PFOA and PFOS were gathered worldwide, 4% of which fell within hormetic zones, highlighting the environmental relevance of hormesis. Additionally, the hormesis induction potential was identified in other legacy and emerging PFAS as well as their alternatives and mixtures. Collectively, it is time to incorporate the hormesis concept into PFAS studies to facilitate more realistic risk characterizations.

Behavioral Posology: A Novel Paradigm for Modeling the Healthy Limits of Behaviors

AbstractOne of the challenges faced by behavioral scientists is the lack of modeling methodologies for accurately determining when a behavior becomes problematic. The authors propose “behavioral posology” as a novel modeling paradigm for quantifying the healthy limits of behaviors through the concept of behavioral dose. As an example of this paradigm, a pharmacokinetic/pharmacodynamic model of a hypothetical digital behavior is presented, based on opponent process theory. The generic model can be adapted to simulate Solomon and Corbit's model of affective dynamics from 1974, and the model predicts features of addiction such as hedonic allostasis, withdrawal, and apparent tolerance. A behavioral frequency response analysis (BFRA) of the model demonstrates how behavior repetition may result in a hormetic dose–response relationship that depends on the frequency of the behavior. The model can be experimentally validated using Ecological Momentary Assessment, allowing researchers to hypothesize, model, and test causal mechanisms for behavioral addictions. The potential for behavioral posology to be applied as a clinical support tool in psychological medicine is discussed, as this modeling framework may help to detect and limit behaviors being performed too frequently based on factors such as the person's moral beliefs.

Statistical modeling of hormesis quantities in inverted U-shaped dose-response relationships by reparameterization of a bilogistic model

Statistical procedures that allow quantitative determination of hormesis features are required for quantitative characterization of hormesis to provide information on the biphasic dose-response phenomenon and its variability. Only a direct estimate of individual effective doses in hormetic dose-response relationships is possible using prior extensions of the bilogistic model of Beckon and coworkers. This study presented further extensions of the model to determine the toxic potency and hormetic dose zone by estimating two effective doses simultaneously. In addition, the extended models allow for partitioning the hormetic dose zone through the dose of maximum stimulation. This study demonstrated a 4-step statistical modeling approach to quantify 20 hormesis quantities. The applicability and challenges of the mathematical procedures are discussed based on a few examples of hormetic dose-response relationships. The syntaxes for the analyses were provided as Appendix to demonstrate its implementation in SAS® statistical software. Given the variability of hormetic dose-responses generated from toxicological studies in many disciplines, the proposed approach cannot apply to all dose-response patterns. However, we hope the proposed extensions could provide versatile statistical tools for quantitatively exploring a variety of biphasic dose-response curves.

A Conserved Mechanism for Hormesis in Molecular Systems.

Hormesis refers to dose-response phenomena where low dose treatments elicit a response that is opposite the response observed at higher doses. Hormetic dose-response relationships have been observed throughout all of biology, but the underlying determinants of many reported hormetic dose-responses have not been identified. In this report, we describe a conserved mechanism for hormesis on the molecular level where low dose treatments enhance a response that becomes reduced at higher doses. The hormetic mechanism relies on the ability of protein homo-multimers to simultaneously interact with a substrate and a competitor on different subunits at low doses of competitor. In this case, hormesis can be observed if simultaneous binding of substrate and competitor enhances a response of the homo-multimer. We characterized this mechanism of hormesis in binding experiments that analyzed the interaction of homotrimeric proliferating cell nuclear antigen (PCNA) with uracil DNA glycosylase (UNG2) and a fluorescein-labeled peptide. Additionally, the basic features of this molecular mechanism appear to be conserved with at least two enzymes that are stimulated by low doses of inhibitor: dimeric BRAF and octameric glutamine synthetase 2 (GS2). Identifying such molecular mechanisms of hormesis may help explain specific hormetic responses of cells and organisms treated with exogenous compounds.

Hormetic dose responses induced by organic flame retardants in aquatic animals: Occurrence and quantification

The organic flame retardants (OFRs) have attracted global concerns due to their potential toxicity and ubiquitous presence in the aquatic environment. Hormesis refers to a biphasic dose response, characterized by low-dose stimulation and high-dose inhibition. The present study provided substantial evidence for the widespread occurrence of OFRs-induced hormesis in aquatic animals, including 202 hormetic dose response relationships. The maximum stimulatory response (MAX) was commonly lower than 160% of the control response, with a combined value of 134%. Furthermore, the magnitude of MAX varied significantly among multiple factors and their interactions, such as chemical types and taxonomic groups. Moreover, the distance from the dose of MAX to the no-observed-adverse-effect-level (NOAEL) (NOAEL: MAX) was typically below 10-fold (median = 6-fold), while the width of the hormetic zone (from the lowest dose inducing hormesis to the NOAEL) was approximately 20-fold. Collectively, the quantitative features of OFRs-induced hormesis in aquatic animals were in accordance with the broader hormetic literature. In addition, the implications of hormetic dose response model for the risk assessment of OFRs were discussed. This study offered a novel insight for understanding the biological effects of low-to-high doses of OFRs on aquatic animals and assessing the potential risks of OFRs in the aquatic environment.

English

Hormesis is a biphasic dose (concentration)-response phenomenon characterized by low dose stimulatory and high dose inhibitory effects exerted by stressors on living organisms. Recently, there has been increased interest in the phenomenon and statistical models for its exploration in toxicological studies. The bilogistic model of Beckon et al. is one of such models for modeling biphasic dose-response relationships in toxicological studies. However, there is no explicit formula for the estimation of effective doses (EDK) with the model. In this study, a simple general approach was suggested to reparameterize the model, leading to a range of mathematical models for determination of effective doses at both stimulatory and inhibitory ranges in inverted U-shaped hormetic dose-response relationships. The reparameterized models were tested on experimental data from three different in vitro experimental systems obtained from literature and our experiment. They were successfully applied to test for significance of hormesis and estimate effective doses and their statistical properties. In addition, reparameterization of the model for a particular effective dose (EDK) did not affect estimation of other parameters (such as x1, x2, β1, β2 and M). The reparameterized models provided useful tools for adequate exploration of the tested hormetic dose-response relationships. The extended models could hopefully be versatile in characterization of variable hormetic dose response relationships in many toxicological disciplines.   Key words: Toxicity, hormesis, hormesis quantities, model extension, concentration-responses.

Effect of microplastics on aquatic biota: A hormetic perspective

As emerging pollutants, microplastics (MPs) have been found globally in various freshwater and marine matrices. This study recompiled 270 endpoints of 3765 individuals from 43 publications, reporting the onset of enhanced biological performance and reduced oxidative stress biomarkers induced by MPs in aquatic organisms at environmentally relevant concentrations (≤1 mg/L, median = 0.1 mg/L). The stimulatory responses of consumption, growth, reproduction and survival ranged from 131% to 144% of the control, with a combined response of 136%. The overall inhibitory response of 9 oxidative stress biomarkers was 71% of the control, and commonly below 75%. The random-effects meta-regression indicated that the extents of MPs-induced responses were independent of habitat, MP composition, morphology, particle size and exposure duration. The results implied that the exposure to MPs at low and high concentrations might induce opposite/non-monotonic responses in aquatic biota. Correspondingly, the hormetic dose response relationships were found at various endpoints, such as reproduction, genotoxicity, immunotoxicity, neurotoxicity and behavioral alteration. Hormesis offers a novel perspective for understanding the dose response mode of aquatic organisms exposed to low and high concentrations of MPs, highlighting the necessity to incorporate the hormetic dose response model into the ecological/environmental risk assessment of MPs.

Estimating the no-observed-adverse-effect-level (NOAEL) of hormetic dose-response relationships in meta-data evaluations

The number of studies reporting hormetic responses is rapidly increasing, and quantitative evaluations are needed to improve the understanding of hormetic dose responses. However, there is no standardized methodology to estimate the no-observed-adverse-effect-level (NOAEL) of hormetic dose-response relationships developed using data mined from the published literature. Here, we propose a protocol that can be followed to estimate NOAEL, a process that is illustrated using a specific example. This protocol can be used for maintaining a mutual language (since NOAEL can be defined in different ways), permitting comparisons among different studies, and facilitating cumulative science.

Quantitative Evaluation of Hormesis in Breast Cancer Using Histoculture Drug Response Assay.

Purpose:Hormesis is a phenomenon of growth stimulation at low doses and inhibition at higher doses. In cancer treatment, little is known about how hormesis affects cancer cell proliferation. We evaluated the hormetic dose–response relationship of paclitaxel using surgically resected breast cancer specimens on the basis of histoculture drug response assay (HDRA).Methods:We used surgically resected fresh tumor specimens from 22 patients with breast cancer: 17 invasive ductal, 3 mucinous, and 2 other “special-type” cancers. All patients were female, ranging in age between 40 and 86 (median 60) years. Small pieces of viable cancer tissue were placed on collagen gel and cultured for 7 days with paclitaxel. Inhibition rates of paclitaxel at several concentrations were measured and fitted to a sigmoid dose–response curve.Results:Hormesis was observed in 9 of the 22 cases; ED50 of cytotoxic effect was significantly higher (P = .0036) in hormesis (H) group (44.6 ± 4.2 µg/mL) than in nonhormesis (N) group (26.7 ± 3.5 μg/mL).Conclusion:We evaluated hormesis in breast cancer tissue using HDRA for the first time although previously confirmed in cultured cells. Hormesis seems to occur in patients undergoing treatment with anticancer agents, especially in a metastatic setting. Meanwhile, tumor growth may be stimulated in patients who are resistant to paclitaxel.

Biphasic effect of abscisic acid on plants: an hormetic viewpoint

Abscisic acid (ABA) is a major phytohormone that regulates development and growth. Increasingly, the literature indicates that ABA enhances and inhibits a spectrum of plant responses within an hormetic-like biphasic dose–response manner. A recent extensive study on the response of a variety of Arabidopsis lines to ABA suggested the widespread occurrence of hormetic dose responses. Our independent reassessment of these data reveals the occurrence of more than 30 hormetic dose–response relationships with quantitative features fully consistent with the substantial and extensively assessed literature on plant hormesis. This analysis significantly extends earlier findings indicating that ABA mediates a broad spectrum of hormetic dose responses in plants. ABA-induced hormesis provides a novel framework for research with the potential to advance the current scientific bases of plant ecology, physiology, and toxicology and to enhance agricultural yields and productivity.

Effects of urban land-use on largescale stonerollers in the Mobile River Basin, Birmingham, AL.

During the spring and fall of 2001 and the spring of 2002 a study was conducted to evaluate the health of the largescale stoneroller (Campostoma oligolepis) populations in streams along an urban land-use gradient. Sites were selected from a pool of naturally similar sub-basins (eco-region, basin size, and geology) of the Mobile River basin (MRB), using an index of urban intensity derived from infrastructure, socioeconomic, and land-use data. This urban land-use gradient (ULUG) is a multimetric indicator of urban intensity, ranging from 0 (background) to 100 (intense urbanization). Campostoma sp. have been used previously as indicators of stream health and are common species found in all sites within the MRB. Endpoints used to determine the effects of urban land-use on the largescale stoneroller included total glutathione, histology, hepatic apoptosis, condition factor and external lesions. Liver glutathione levels were positively associated with increasing urban land-use (r(2) = 0.94). Histopathological examination determined that some abnormalities and lesions were correlated with the ULUG and generally increased in prevalence or severity with increasing urbanization. Liver macrophage aggregates were positively correlated to the ULUG. The occurrence of nucleosomal ladders (indicating apoptotic cell death) did not correspond with urban intensity in a linear fashion. Apoptosis, as well as prevalence and severity of a myxozoan parasite, appeared to have a hormetic dose-response relationship. The majority of the biomarkers suggested fish health was compromised in areas where the ULUG ≥ 36.

Inference for the existence of hormetic dose-response relationships in toxicology studies.

In toxicology studies hormesis refers to a dose-response relationship with a stimulatory response at low doses and an inhibitory response at high doses. In this manuscript, we particularly focus on a J-shaped dose-response relationship for binary cancer responses. We propose and examine two new flexible models for testing the hypothesis of hormesis in a Bayesian framework. The first model is parametric and enhances the flexibility of modeling a hormetic zone by using a non-linear predictor in a multistage model. The second model is non-parametric and allows multiple model specifications, weighting the contribution of each model via Bayesian model averaging (BMA). Simulation studies show that the non-parametric modeling approach with BMA provides robust sensitivity and specificity for detecting hormesis relative to the parametric approach, regardless of the shape of a hormetic zone.

Pretreatment but not subsequent coincubation with midazolam reduces the cytotoxicity of temozolomide in neuroblastoma cells.

BackgroundTemozolomide (TMZ) induces a G2/M cell cycle arrest and is used for treatment of paediatric tumours, especially neuroblastomas. Patients treated with TMZ frequently receive midazolam for sedation prior to surgery and other interventions. Previous studies suggested both cytoprotective and apoptosis-inducing properties of midazolam. Therefore, the impact of midazolam on TMZ-induced cytotoxicity was investigated in vitro.MethodsHuman neuroblastoma cells were incubated with midazolam alone, as a pretreatment prior to incubation with TMZ or a coincubation of both. Cell viability and proliferation was analysed (XTT and BrdU assay) after 24 h and flowcytometric cell cycle analysis was performed after 24 and 48 h.ResultsMidazolam alone increased cell viability at lower concentrations (2, 4, 8, 16 μM), whereas higher concentrations (128, 256, 512 μM) reduced cell viability. Pretreatment with midazolam 6 h prior to TMZ incubation reduced cytotoxic effects (IC25 1005 ± 197 μM; IC50 1676 ± 557 μM; P < 0.05) compared to incubation with TMZ alone (IC25 449 ± 304 μM; IC50 925 ± 196 μM) and reduced the antiproliferative effect of TMZ (1000 μM) by 43.9 % (P < 0.05). In contrast, cytotoxic effects of TMZ were increased (IC75 1175 ± 221 μM vs. 2764 ± 307 μM; P < 0.05) when midazolam pretreatment was followed by coincubation of midazolam and TMZ. Cell cycle analysis revealed increased fractions of cells in G2/M phase after TMZ treatment (100 μM; 48 h), irrespective of midazolam pretreatment.ConclusionMidazolam causes a hormetic dose–response relationship in human neuroblastoma cells. Pretreatment with midazolam reduces the cytotoxic and antiproliferative effects of TMZ without interfering with G2/M cell cycle arrest. In contrast, subsequent midazolam coincubation increases overall cytotoxicity.

In Vitro Safety/Protection Assessment of Resveratrol and Pterostilbene in a Human Hepatoma Cell Line (HepG2)

The aim of this work was to evaluate in vitro the genotoxic and/or antigenotoxic effects of resveratrol (RESV) and pterostilbene (PTER) on HepG2 cells. Moreover, additional tests were performed to evaluate early and late apoptosis events induced by the tested stilbenes. RESV and PTER did not show any genotoxic activity. As regards antigenotoxicity testing, RESV and PTER showed a typical, U-shaped hormetic dose-response relationship characterized by a biphasic trend with small quantities having opposite effects to large ones. HepG2 cells treated with PTER exhibited a marked increase in early apoptosis (40.1%) at 250 microM; whereas, the highest concentration tested for both RESV and PTER significantly increased the proportion of HepG2 cells undergoing late apoptosis (32.5 and 51.2%, respectively). The observed pro-apoptotic activity could, at least in part, explain the hormetic response observed when the compounds were tested for antigenotoxicity (i.e., in the presence of induced DNA damage).

Estimation of a benchmark dose in the presence or absence of hormesis using posterior averaging.

U.S. Environment Protection Agency benchmark doses for dichotomous cancer responses are often estimated using a multistage model based on a monotonic dose-response assumption. To account for model uncertainty in the estimation process, several model averaging methods have been proposed for risk assessment. In this article, we extend the usual parameter space in the multistage model for monotonicity to allow for the possibility of a hormetic dose-response relationship. Bayesian model averaging is used to estimate the benchmark dose and to provide posterior probabilities for monotonicity versus hormesis. Simulation studies show that the newly proposed method provides robust point and interval estimation of a benchmark dose in the presence or absence of hormesis. We also apply the method to two data sets on carcinogenic response of rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Sublethal effects of the beta-blocker sotalol at environmentally relevant concentrations on the New Zealand mudsnail Potamopyrgus antipodarum.

Monitoring sublethal effects of pharmaceuticals on nontarget species in aquatic environments has become an important topic in ecotoxicology, yet few studies have been conducted concerning the effects of beta-blockers on aquatic organisms. The present study investigated the effects of the beta-blocker sotalol (SOT) at 3 environmentally relevant concentrations on life-history traits of the New Zealand mudsnail Potamopyrgus antipodarum. Based on the pharmacodynamic properties of SOT, the authors hypothesized reduced numbers of embryos in the brood pouches, decelerated growth of adult snails, and smaller size of neonates, but no effect on mortality rates of adults. Contrary to the hypothesis, the total number of embryos was significantly higher after 56 d of exposure at nominal concentrations of 0.05 µg/L and 1.0 µg/L by 107% and 73%, respectively. No differences in embryo numbers were observed at earlier time-points. Therefore, the mode of action seems to be an extension of the reproductive period rather than an increase of the embryo production. Furthermore, our results indicate a hormetic dose-response relationship, because no effects were observed at the highest test-concentration (6.5 µg/L). Mortality, growth of adult snails, and neonate sizes were not affected by the beta-blocker. Given the strong influence on reproduction, the effects of sublethal concentrations of SOT and other beta-blockers deserve better consideration in ecotoxicological risk assessment.

Ozone acting on human blood yields a hormetic dose-response relationship

The aim of this paper is to analyze why ozone can be medically useful when it dissolves in blood or in other biological fluids. In reviewing a number of clinical studies performed in Peripheral Arterial Diseases (PAD) during the last decades, it has been possible to confirm the long-held view that the inverted U-shaped curve, typical of the hormesis concept, is suitable to represent the therapeutic activity exerted by the so-called ozonated autohemotherapy. The quantitative and qualitative aspects of human blood ozonation have been also critically reviewed in regard to the biological, therapeutic and safety of ozone. It is hoped that this gas, although toxic for the pulmonary system during prolonged inhalation, will be soon recognized as a useful agent in oxidative-stress related diseases, joining other medical gases recently thought to be of therapeutic importance. Finally, the elucidation of the mechanisms of action of ozone as well as the obtained results in PAD may encourage clinical scientists to evaluate ozone therapy in vascular diseases in comparison to the current therapies.

Hormetic dose-response relationship of lithium on motor cortical excitability

Hormetic dose-response relationship of lithium on motor cortical excitability

The hormetic effect of cadmium on the activity of antioxidant enzymes in the earthworm Eisenia fetida

The hormetic dose–response relationships induced by environmental toxic agents are often characterized by low-dose stimulation and high-dose inhibition. Confirmation of the general phenomenon of hormesis may have significant implications for ecological risk assessment, although the mechanisms that underlie hormesis remain an enigma. In this study, a model-based approach for describing a dose–response relationship incorporating the hormetic effect was applied to the detection and estimation of the hormetic effect of cadmium (Cd) on the activity of antioxidant enzymes in the earthworm Eisenia fetida. The results showed that Cd at low concentrations induced an increase in the activity of catalase and superoxide dismutase (SOD), but high concentrations inhibited the enzymes, and this was reflected in an inverted U-shaped curve. The maximum hormetic magnitude of SOD activity was higher than that of catalase. The presence of hormesis induced by cadmium in the earthworm may be related to activation of adaptive pathways.

Behavioral, Physiological and Biochemical Hormetic Responses to the Autoxidizable Dye Methylene Blue

The goals of this review were to identify methylene blue (MB) as a compound that follows hormetic behavior for a wide range of effects and to address the question of what is unique about MB that could account for its wide applicability and hormetic behavior as a drug. The MB hormetic dose-response relationship is exemplified by an increase in various behavioral, physiological and biochemical responses with increasing dose, followed by a decrease in the same responses with an even higher dose, until the responses are equal to control responses. With MB doses increasing beyond the hormetic zone, the responses decrease even further, until they are below the control responses. At doses spanning its hormetic zone, MB can increase select responses until they are 130-160% of control. For example, low doses of MB produce maximum behavioral and biochemical responses with averages of approximately 140% of control. As MB dose is raised outside the hormetic zone the response decreases below the control response, as exemplified by MB's ability to increase cytochrome oxidase activity at intermediate doses, while decreasing cytochrome oxidase activity at higher doses. It is proposed that MB's autoxidizable chemical property may be responsible for its unique biological action as both a metabolic energy enhancer and antioxidant that is frequently characterized by hormetic dose-response relationships.