The importance of hormesis to public health

BACKGROUND: Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models, diverse types of exposure, and a variety of outcomes. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. OBJECTIVE: Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. DISCUSSION: Hormesis appears to be more common than dose-response curves that are currently used in the risk assessment process [e.g., linear no-threshold (LNT)]. Although a number of mechanisms have been identified that explain many hormetic dose-response relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. CONCLUSIONS: We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.     

Hormesis: why it is important to toxicology and toxicologists

This article provides a comprehensive review of hormesis, a dose-response concept that is characterized by a low-dose stimulation and a high-dose inhibition. The article traces the historical foundations of hormesis, its quantitative features and mechanistic foundations, and its risk assessment implications. The article indicates that the hormetic dose response is the most fundamental dose response, significantly outcompeting other leading dose-response models in large-scale, head-to-head evaluations. The hormetic dose response is highly generalizable, being independent of biological model, endpoint measured, chemical class, and interindividual variability. Hormesis also provides a framework for the study and assessment of chemical mixtures, incorporating the concept of additivity and synergism. Because the hormetic biphasic dose response represents a general pattern of biological responsiveness, it is expected that it will become progressively more significant within toxicological evaluation and risk assessment practices as well as have numerous biomedical applications.     

Radiation hormesis: challenging LNT theory via ecological and evolutionary considerations

Ecological and evolutionary considerations suggest that radiation hormesis is made up of two underlying components. The first (a) is background radiation hormesis based upon the background exposure to which all organisms are subjected throughout evolutionary time. The second and much larger component (b) is stress-derived radiation hormesis arising as a protective mechanism derived from metabolic adaptation to environmental stresses throughout evolutionary time especially from climate-based extremes. Since (b) > > (a), hormesis for ionizing radiation becomes an evolutionary expectation at exposures substantially exceeding background. This biological model renders linear no-threshold theory invalid. Accumulating evidence from experimental organisms ranging from protozoa to rodents, and from demographic studies on humans, is consistent with this interpretation. Although hormesis is not universally accepted, the model presented can be subjected to hypothesis-based empirical investigations in a range of organisms. At this stage, however, two consequences follow from this evolutionary model: (1) hormesis does not connote a value judgement usually expressed as a benefit; and (2) there is an emerging and increasingly convincing case for reviewing and relaxing some recommended radiation protection exposure levels in the low range.     

The importance of hormesis to public health

Hormesis is a specific type of nonmonotonic dose response whose occurrence has been documented across a broad range of biological models and diverse types of exposure. The effects that occur at various points along this curve can be interpreted as beneficial or detrimental, depending on the biological or ecologic context in which they occur. Because hormesis appears to be a relatively common phenomenon that has not yet been incorporated into regulatory practice, the objective of this commentary is to explore some of its more obvious public health and risk assessment implications, with particular reference to issues raised recently within this journal by other authors. Hormesis appears to be more common than doseresponse curves that are currently used in the risk assessment process. Although a number of mechanisms have been identified that explain many hormetic doseresponse relationships, better understanding of this phenomenon will likely lead to different strategies not only for the prevention and treatment of disease but also for the promotion of improved public health as it relates to both specific and more holistic health outcomes. We believe that ignoring hormesis is poor policy because it ignores knowledge that could be used to improve public health.     

Hormesis and its place in nonmonotonic dose-response relationships: some scientific reality checks

OBJECTIVE: This analysis is a critical assessment of current hormesis literature. I discuss definitions, characterization, generalizability, mechanisms, absence of empirical data specific for hormesis hypothesis testing, and arguments that hormesis be the "default assumption" in risk assessment. DATA SOURCES: Hormesis, a biological phenomenon typically described as low-dose stimulation from substances producing higher-dose inhibition, has recently garnered interest in several quarters. The principal sources of published materials for this analysis are the writings of certain proponents of hormesis. Surprisingly few systematic critiques of current hormesis literature exist. Limits to the phenomenon's appropriate role in risk assessment and health policy have been published. DATA SYNTHESIS: Serious gaps in scientific understanding remain: a stable definition; generalizability, especially for humans; a clear mechanistic basis; limitations in the presence of multiple toxic end points, target organs, and mechanisms. Absence of both arms-length, consensus-driven, scientific evaluations and empirical data from studies specifically designed for hormesis testing have limited its acceptance. CONCLUSIONS: Definition, characterization, occurrence, and mechanistic rationale for hormesis will remain speculative, absent rigorous studies done specifically for hormesis testing. Any role for hormesis in current risk assessment and regulatory policies for toxics remains to be determined.     

Nutritional hormesis

OBJECTIVE: Hormesis, the biological and toxicological concept that small quantities have opposite effects from large quantities, is reviewed with emphasis on its relevance to nutrition. RESULTS: Hormetic and other dose-response relationships are categorized, depicted, and discussed. Evidence for nutritional hormesis is presented for essential vitamin and mineral nutrients, dietary restriction, alcohol (ethanol), natural dietary and some synthetic pesticides, some herbicides, and acrylamide. Some of the different hormetic mechanisms that have been proposed are reviewed. CONCLUSIONS: The credence and relevance of hormesis to nutrition are considered to be established. The roles of hormesis in nutritional research and in formulating nutritional guidelines are discussed. SPONSORSHIP: The New York City Department of Health and Mental Hygiene.     

Hormetic effects in pharmacology: pharmacological inversions as prototypes for hormesis

A biological, physiological or biochemical response to a drug at a low dose may be completely opposite to that response when a larger dose is administered. Also, a response to a single dose of an agent may shortly afterwards be completely reversed. These observations are as old as the use of medicinal preparations or alcoholic beverages. The term "pharmacological inversions" can be used to describe these phenomena. A subset of the dose-response relationship is that of "hormesis." This term, "hormesis," is often used to denote the beneficial response of an organism to a low dose of a physical or chemical agent and a detrimental response to a much larger dose. Many, but not all, of the pharmacological inversions can serve as prototypes of hormesis. Examples of the dose-time effect or the dose-response relationship (which may include the phenomenon of hormesis) can be found among these agents: alcoholic beverages, anesthetic gases, barbiturates, some tranquilizers, many vitamins, caffeine, nicotine, salicylates, enzyme inducers and some toxic metals.     

The bioavailability of chemicals in soil for earthworms

The bioavailability of chemicals to earthworms can be modified dramatically by soil physical/chemical characteristics, yet expressing exposure as total chemical concentrations does not address this problem. In order to understand the effects of modifying factors on bioavailability, one must measure and express chemical bioavailability to earthworms in a consistent, logical manner. This can be accomplished by direct biological measures of bioavailability (e.g., bioaccumulation, critical body residues), indirect biological measures of bioavailability (e.g., biomarkers, reproduction), or indirect chemical measures of bioavailability (e.g., chemical or solid-phase extracts of soil). If indirect chemical measures of bioavailability are to be used, they must be correlated with some biological response. Bioavailability can be incorporated into ecological risk assessment during risk analysis, primarily in the estimation of exposure. However, in order to be used in the site-specific ecological risk assessment of chemicals, effects concentrations must be developed from laboratory toxicity tests based on exposure estimates utilizing techniques that measure the bioavailable fraction of chemicals in soil, not total chemical concentrations.     

Ad hoc and Fast Forward: The Science of Hormesis Growth and Development

Background

Hormesis is a binary response phenomenon with low-dose stimulation (or inhibition) of effects by substances producing opposite high-dose responses. Hormesis, after decades of obscurity, has undergone a renaissance in recent years, with rapid growth benefiting greatly from the systematized efforts of such proponents as the hormesis group at the University of Massachusetts-Amherst led by Edward J. Calabrese.

Objective

In this commentary I analyze chemical hormesis methodology with reference to ad hoc scientific approaches for defining and characterizing hormesis.

Discussions

Proponents of hormesis have attempted a scientific characterization of hormesis through a battery of ad hoc methodologies using unvalidated criteria and other mechanisms for persistent database searches rather than through de novo hypothesis testing specific for hormesis. Here I discuss various scientific problems with this search-over-experiment approach, as well as other aspects of attempts at defining and characterizing the field.

Conclusions

Wide acceptance of hormesis by the broad scientific community and adoption of hormesis by public agencies for inclusion in health and regulatory policies have not occurred. Reasons may include the singular nature of hormesis research and directions followed in hormesis methodologies.     

低剂量三氯乙烯诱导下谷胱甘肽转移酶Ω-1的表达变化

目的分析低剂量三氯乙烯(TCE)诱导的细胞兴奋效应时,谷胱甘肽转移酶Ω-1(GSTO-1)的表达变化。方法利用前期的双向电泳和质谱结果,参照前期兴奋效应的剂量设计,提取染毒细胞的mRNA和总蛋白,进一步使用实时定量RT-PCR和Western blotting分别从mRNA和蛋白水平上验证GSTO-1的表达变化。结果 Western blotting分析发现,0.1mmol/LTCE剂量组能诱导GSTO-1蛋白表达是对照组的2倍,但随着剂量的增加,蛋白表达改变不明显(与对照组相比,P<0.05)。RT-PCR结果提示:低剂量TCE能诱导GSTO-1基因表达增加,随着剂量的增加,表达反而有所减少。结论低剂量TCE能诱导GSTO-1基因及蛋白表达增加。     

Improved empirical models describing hormesis

During the past two decades, the phenomenon of hormesis has gained increased recognition. To promote research in hormesis, a sound statistical quantification of important parameters, such as the level and significance of the increase in response and the range of concentration where it occurs, is strongly needed. Here, we present an improved statistical model to describe hormetic dose-response curves and test for the presence of hormesis. Using the delta method and freely available software, any percentage effect dose or concentration can be derived with its associated standard errors. Likewise, the maximal response can be extracted and the growth stimulation calculated. The new model was tested on macrophyte data from multiple-species experiments and on laboratory data of Lemna minor. For the 51 curves tested, significant hormesis was detected in 18 curves, and for another 17 curves, the hormesis model described that data better than the logistic model did. The increase in response ranged from 5 to 109%. The growth stimulation occurred at an average dose somewhere between zero and concentrations corresponding to approximately 20 to 25% of the median effective concentration (EC50). Testing the same data with the hormesis model proposed by Brain and Cousens in 1989, we found no significant hormesis. Consequently, the new model is shown to be far more robust than previous models, both in terms of variation in data and in terms of describing hormetic effects ranging from small effects of a 10% increase in response up to effects of an almost 100% increase in response.     

Adverse effects of nutritional inadequacy and excess: a hormetic model

I address and explain the increased risk of adverse effects from nutrients by using the paradigm of hormesis, the biological and toxicological concept that small quantities have opposite effects from large quantities. To provide necessary background, I categorize, depict, discuss, and contrast hormetic and other dose-response relations. I review some of the different hormetic mechanisms that others have proposed. I then use the hormetic paradigm to explain adverse effects from essential nutrients, including vitamin D. The hormesis paradigm could be useful to nutritional scientists in their consideration of nutritional adverse effects.     

Structure-activity models of chemical carcinogens: state of the art, and new directions

Chemical carcinogenicity has been the target of numerous attempts to create predictive models alternative to the animal ones, ranging from short-term biological assays (e.g. mutagenicity tests) to theoretical models. Among the theoretical models, the application of the science of structure-activity relationships (SAR) has earned special prominence. The qualitative approach to SAR has lead to the identification of a large number of reactive chemical substructures that are both mutagenic and carcinogenic. More sophisticated developments are the quantitative structure-activity relationship (QSAR) models, that link the physical chemical or structural properties of the molecules to the toxicological endpoints. Both approaches provide strong support to the process of risk assessment of the chemicals, especially in the phase of priority setting. Among the areas potentially able to contribute to further developments of (Q)SAR, the novel chemical relational databases are presented and discussed. The freely downloadable ISSCAN database on chemical carcinogens is presented.     

辐射生物效应多样性的统一辐射剂量生物效应理论模型和应用研究

目的 试图从理论上提出辐射生物效应多样性的辐射剂量生物效应理论,建立统一的全剂量辐射生物效应理论模型,定量描述和解释辐射生物效应的多样性。方法 总结提出辐射剂量生物效应理论的6个原理的基础上,建立统一剂量辐射生物效应理论模型。结果 提出辐射生物效应多样性的辐射剂量生物效应理论,建立了8个辐射剂量生物效应方程,可以定量描述和解释辐射生物效应的多样性。结论 建立的辐射剂量生物效应理论和理论模型,定量描述和解释辐射剂量生物效应:一般损伤效应、低剂量兴奋性效应、旁效应和超敏效应。该理论和理论模型适用于其它广义刺激:物理因子、化学因子、生物因子、心理、药物、毒物、信息等剂量生物效应关系,可称为广义刺激剂量生物效应理论模型,具有重要的学术意义和应用价值。     

Use of physical,chemical, and biological indices to assess impacts of contaminants and physical habitat alteration in urban streams

Human activities in urban areas can lead to both chemical pollution and physical alteration of stream habitats. The evaluation of ecological impacts on urban streams can be problematic where both types of degradation occur. Effects of contaminants, for example, may be masked if stream channelization, loss of riparian vegetation, or other physical stressors exert comparable or larger influences. In the Aberjona watershed (near Boston, MA, USA), we used physical, chemical, and biological indices to discern the relative impacts of physical and chemical stressors. We used standard protocols for assessing the biological condition of low-gradient streams, sampling macroinvertebrate communities from several different habitat types (e.g., overhanging bank vegetation, undercut bank roots, and vegetation on rocks). We strengthened the linkage between chemical exposure and macroinvertebrate response by measuring metal concentrations not only in sediments from the stream bottom but also in the vegetative habitats where the macroinvertebrates were sampled. Linear regression analysis indicated that biological condition was significantly dependent (95% confidence level) on contaminants in vegetative habitats, but not on contaminants in sediments from the stream bottom. Biological condition was also significantly dependent on physical habitat quality; regression analysis on both contaminants and physical quality yielded the best regression model (r2 = 0.49). Similar biological impairment was observed at sites with severe contamination or physical impairment or with moderate chemical and physical impairment. These results have implications for the management of urban streams.     

Hormesis Associated with a Low Dose of Methylmercury Injected into Mallard Eggs

We injected mallard (Anas platyrhynchos) eggs with methylmercury chloride at doses of 0, 0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 μg mercury/g egg contents on a wet-weight basis. A case of hormesis seemed to occur because hatching success of eggs injected with 0.05 μg/g mercury (the lowest dose) was significantly greater (93.3%) than that of controls (72.6%), whereas hatching success decreased at progressively greater doses of mercury. Our finding of hormesis when a low dose of methylmercury was injected into eggs agrees with a similar observation in a study in which a group of female mallards was fed a low dietary concentration of methylmercury and hatching of their eggs was significantly better than that of controls. If methylmercury has a hormetic effect at low concentrations in avian eggs, these low concentrations may be important in a regulatory sense in that they may represent a no-observed adverse effect level (NOAEL).     

Surface Chemistry and Quartz Hazard

The variability of quartz hazard is related to the characteristics of particulate toxicants. Although these have the same chemical composition, they exist in various forms and surface states, each one eliciting different biological responses. On the basis of data from the literature, surface chemical properties are associated to the subsequent stages reported by Donaldson and Borm, 1998 in the mechanistic model proposed for quartz carcinogenicity. Surface radicals and iron-derived reactive oxygen species (ROS) are implicated in oxidative stress, considered to be the key event in the development of fibrosis and lung cancer. Other chemical functionalities related to cytotoxicity, however, modulate the overall pathogenicity by regulating transport and clearance. The chemical features deriving from the intrinsic characteristics of a silica dust—e.g. its origin—as well as those generated by external factors—e.g. contaminants, associated minerals—are discussed in relation to their possible role in the pathogenic mechanism.     

Assessing cumulative health risks from exposure to environmental mixtures - three fundamental questions

Differential exposure to mixtures of environmental agents, including biological, chemical, physical, and psychosocial stressors, can contribute to increased vulnerability of human populations and ecologic systems. Cumulative risk assessment is a tool for organizing and analyzing information to evaluate the probability and seriousness of harmful effects caused by either simultaneous and/or sequential exposure to multiple environmental stressors. In this article we focus on elucidating key challenges that must be addressed to determine whether and to what degree differential exposure to environmental mixtures contributes to increased vulnerability of exposed populations. In particular, the emphasis is on examining three fundamental and interrelated questions that must be addressed as part of the process to assess cumulative risk: a) Which mixtures are most important from a public health perspective? and b) What is the nature (i.e., duration, frequency, timing) and magnitude (i.e., exposure concentration and dose) of relevant cumulative exposures for the population of interest? c) What is the mechanism (e.g., toxicokinetic or toxicodynamic) and consequence (e.g., additive, less than additive, more than additive) of the mixture's interactive effects on exposed populations? The focus is primarily on human health effects from chemical mixtures, and the goal is to reinforce the need for improved assessment of cumulative exposure and better understanding of the biological mechanisms that determine toxicologic interactions among mixture constituents.     

低剂量辐射生物效应的研究进展

低剂量辐射(low-dose radiation,LDR)生物效应仍然是放射生物学领域的研究热点.随着研究的深入,对LDR产生的各种生物效应及其机制不断完善.越来越多的证据表明,LDR诱导的生物效应和高剂量辐射不同,这些研究对"线性无阈"模型提出质疑.本文从LDR诱导的旁效应、兴奋效应、适应性反应以及低剂量辐射超敏感性...