Reproductive stimulation by low doses of xenoestrogens contrasts with the view of hormesis as an adaptive response

We discuss the similarities and differences of two types of effects that occur at low but not high doses of chemicals: hormesis and stimulation by oestrogenic endocrine-disrupting chemicals or xenoestrogens. While hormesis is a general phenomenon evoked by many compounds, oestrogenic stimulation occurs for specific chemicals that disrupt actions of endogenous oestrogen. Both types of phenomena can induce an inverted-U dose-response curve, resulting from low-dose stimulation of response, and thus challenge current methods of risk assessment. Hormesis is generally thought to be caused by an over-reaction of detoxification mechanisms, which is considered an adaptive response that should protect an organism from subsequent stress. One view of the hormetic low-dose stimulatory response, i.e., increased performance, is that it is beneficial. In contrast, we propose that for manmade xenoestrogens this is never the case. This is demonstrated with examples for low doses of the oestrogenic environmental chemicals bisphenol A and octylphenol, and the oestrogenic drug diethylstilbestrol. Adverse low-dose effects include oviduct rupture, an enlarged prostate, feminization of males and reduced sperm quality. These adverse stimulatory effects divert energy needed for other processes, resulting in reduced fitness. In conclusion, while there are similarities (inverted-U dose-response), there are also differences, adaptive response for hormesis versus adverse stimulatory response for low doses of manmade xenoestrogens, that have been almost totally ignored in discussions of hormesis. We propose that the risk posed by low doses of manmade xenoestrogens that show inverted-U dose-response curves is underestimated by the current threshold model used in risk assessment, and this is likely to apply to other endocrine-disrupting chemicals.     

Stress Biology and Hormesis: The Yerkes–Dodson Law in Psychology—A Special Case of the Hormesis Dose Response

This article traces the historical foundations of the Yerkes–Dodson Law from its experimental foundations in the first decade of the 20th century, to its recognition as a generalizable phenomenon in multiple species including humans and to more current attempts to understand its molecular basis within the framework of stress-related biological processes. Within this context, the biological and dose-response characteristics of the Yerkes–Dodson Law are evaluated and compared to the hormesis dose-response model. Based on this evaluation, which includes study design analysis, statistical models of multiple factor/chemical interaction, and a comparative assessment of the quantitative features of these respective dose-response relationships and their molecular foundations, the Yerkes–Dodson Law is shown to represent a special case of the general concept of hormesis illustrating the interaction of two independent study variables, which has typically been observed to be an additive response, although not theoretically restricted to one. The conceptual integration of the Yerkes–Dodson Law within the hormetic dose response framework adds further support for the generalization of the hormesis concept.     

Stress biology and hormesis: the Yerkes-Dodson law in psychology--a special case of the hormesis dose response

This article traces the historical foundations of the Yerkes-Dodson Law from its experimental foundations in the first decade of the 20th century, to its recognition as a generalizable phenomenon in multiple species including humans and to more current attempts to understand its molecular basis within the framework of stress-related biological processes. Within this context, the biological and dose-response characteristics of the Yerkes-Dodson Law are evaluated and compared to the hormesis dose-response model. Based on this evaluation, which includes study design analysis, statistical models of multiple factor/chemical interaction, and a comparative assessment of the quantitative features of these respective dose-response relationships and their molecular foundations, the Yerkes-Dodson Law is shown to represent a special case of the general concept of hormesis illustrating the interaction of two independent study variables, which has typically been observed to be an additive response, although not theoretically restricted to one. The conceptual integration of the Yerkes-Dodson Law within the hormetic dose response framework adds further support for the generalization of the hormesis concept.     

Scientific Foundations of Hormesis. Part 2. Maturation,Strengths, Limitations,and Possible Applications in Toxicology,Pharmacology, and Epidemiology

The notion of hormesis has undergone numerous modifications in the course of the 20th century. Because of its unfortunate association with homeopathy, hormesis did not gain acceptance among biomedical professionals. The lack of a plausible mechanism for its occurrence may have contributed much to the rejection of this concept. This treatise outlines the conceptual struggle for an understanding of the widespread occurrence of low dose effects that appear to be opposite to those caused by high doses as also seen in hormesis. An incomplete conceptualization of time as a fundamental variable of effects (in addition to dose) is identified as one of the major reasons why hormetic responses were not observed more frequently than was reported by Calabrese and Baldwin.⁷ The definition of hormesis as an (over)compensation response to an inhibitory signal lacks a designation for (over)compensation responses to stimulatory signals in the other direction. Hormoligosis, which was coined by Luckey for all low-dose stimulatory responses of toxins, is suggested as a suitable term for generalizing the latter types of effects. Both types of effects are recognized as originating in a homeostatic overcompensation response that optimizes the ability of an organism to meet challenges beyond the limits of normal (unexercised) adaptation. Thus, repeated biochemical/physiologic/immunological, etc. exercises like physical exercise make an organism more fit and hence both hormetic and hormoligotic effects will have life-prolonging consequences. A more complete generalization was developed by linking hormesis/hormoligosis with the vast literature on Selye's general adaptation syndrome to stress. According to this broader view, stress is just one type of homeostatic exercise making organisms more fit for future biochemical/physiological/immunological, etc. challenges. Therefore, both hormesis and hormoligosis are manifestations of two nonmutational evolutionary principles — homeostasis and optimization.     

The hormesis database: the occurrence of hormetic dose responses in the toxicological literature

In 2005 we published an assessment of dose responses that satisfied a priori evaluative criteria for inclusion within the relational retrieval hormesis database (Calabrese and Blain, 2005). The database included information on study characteristics (e.g., biological model, gender, age and other relevant aspects, number of doses, dose distribution/range, quantitative features of the dose response, temporal features/repeat measures, and physical/chemical properties of the agents). The 2005 article covered information for about 5000 dose responses; the present article has been expanded to cover approximately 9000 dose responses. This assessment extends and strengthens the conclusion of the 2005 paper that the hormesis concept is broadly generalizable, being independent of biological model, endpoint measured and chemical class/physical agent. It also confirmed the definable quantitative features of hormetic dose responses in which the strong majority of dose responses display maximum stimulation less than twice that of the control group and a stimulatory width that is within approximately 10-20-fold of the estimated toxicological or pharmacological threshold. The remarkable consistency of the quantitative features of the hormetic dose response suggests that hormesis may provide an estimate of biological plasticity that is broadly generalized across plant, microbial and animal (invertebrate and vertebrate) models.     

Hormesis and high-risk groups

The concept of hormesis (i.e., biological phenomena characterized by dose-response relationships displaying low-dose stimulation and high-dose inhibition) has important implications for current risk assessment practices because of its generalizability with respect to experimental model, agent, and endpoint measured. This paper addresses the question of whether hormesis is present in high-risk subpopulations and highly susceptible species. Evaluation of published data revealed that hormetic dose-response relationships occur with similar quantitative characteristics among species and individuals that display widely differing susceptibility to various toxicants. This observation suggests that the cause of the differential susceptibility in the more susceptible organisms is not due to the absence of the hormetic response but to some other factor(s). However, despite the recognition that hormetic responses are common and similar in susceptible and resistant organisms there are sufficient examples indicating that some strains/individuals may lack the capacity to produce the low-dose stimulatory response. Thus, the capacity to display hormetic effects is one of a variety of factors affecting differential susceptibility to xenobiotics and needs to be addressed within the hazard assessment process.     

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.     

Hormesis: a generalizable and unifying hypothesis

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of > 20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.     

Hormesis: A Generalizable and Unifying Hypothesis

The present article represents a comprehensive effort to assess the hypothesis that hormesis is a highly generalizable biological phenomenon independent of environmental stressor, biological endpoint, and experimental model system. The evaluative methodology and complementary approaches employed to assess this question are (1) evolutionary biology-based theoretical paradigm; (2) evaluation of >20,000 toxicology articles using a priori entry and evaluative criteria; (3) evaluation of 17 large-scale studies each providing data on numerous agents tested in the same experimental model by the same research team; (4) the assimilation of experimental pharmacological data on 24 receptor systems in which biphasic dose responses have been established reproducibly along with hormetic mechanism elucidation; and (5) assessment of the original hormesis database with 1600 dose-response relationships demonstrating evidence consistent with the hormesis hypothesis. The complementary approaches for assessing hormesis provided strong support for its credibility as a central biological theory based on its high frequency of occurrence and quantitative features of expression within microbe, plant, and invertebrate and vertebrate animal systems. The findings suggest that hormetic effects represent evolutionary-based adaptive responses to environmentally induced disruptions in homeostasis. Such adaptive responses, which are incorporated into organismal integrative physiological systems and now clarified at the mechanistic level for more than two dozen receptor systems, provide a cogent basis for the application of hormetic mechanisms in the elucidation of fundamental evolutionary-based biological processes and in the development of novel clinical modalities.     

Scientific foundations of hormesis. Part 2. Maturation,strengths, limitations,and possible applications in toxicology,pharmacology, and epidemiology

The notion of hormesis has undergone numerous modifications in the course of the 20th century. Because of its unfortunate association with homeopathy, hormesis did not gain acceptance among biomedical professionals. The lack of a plausible mechanism for its occurrence may have contributed much to the rejection of this concept. This treatise outlines the conceptual struggle for an understanding of the widespread occurrence of low dose effects that appear to be opposite to those caused by high doses as also seen in hormesis. An incomplete conceptualization of time as a fundamental variable of effects (in addition to dose) is identified as one of the major reasons why hermetic responses were not observed more frequently than was reported by Calabrese and Baldwin. The definition of hormesis as an (over)compensation response to an inhibitory signal lacks a designation for (over)compensation responses to stimulatory signals in the other direction. Hormoligosis, which was coined by Luckey for all low-dose stimulatory responses of toxins, is suggested as a suitable term for generalizing the latter types of effects. Both types of effects are recognized as originating in a homeostatic overcompensation response that optimizes the ability of an organism to meet challenges beyond the limits of normal (unexercised) adaptation. Thus, repeated biochemical/physiologic/immunological, etc. exercises like physical exercise make an organism more fit and hence both hormetic and hormoligotic effects will have life-prolonging consequences. A more complete generalization was developed by linking hormesis/hormoligosis with the vast literature on Selye's general adaptation syndrome to stress. According to this broader view, stress is just one type of homeostatic exercise making organisms more fit for future biochemical/physiological/immunological, etc.challenges. Therefore, both hormesis and hormoligosis are manifestations of two nonmutational evolutionary principles--homeostasis and optimization.     

The Definition of Hormesis and its Implications for In Vitro to In Vivo Extrapolation and Risk Assessment

This article comments on some of the basic questions put forward in state-of-the-art discussions on hormesis. There seems to be a need for a better definition of the concept itself and reconsideration of whether all biphasic dose-response curves should be considered representative for hormesis. Hormesis may be restricted to phenomena that proceed by mechanisms that are broadly generalizable and represent possibly beneficial overcompensation in response to an adverse stimulus. Using the concept that hormesis is defined as such, the biphasic effect of quercetin on cell proliferation, but also several other receptor-mediated biphasic dose-response phenomena, should not be related to hormesis. Taking into account hormesis in the procedures for risk assessment on compounds characterised by a threshold for the adverse effect is another matter for considerable debate. In our opinion, this would require the reduction of safety factors, providing the possibility for beneficial hormesis-type effects for some people, at the cost of increased chances on adverse effects for other parts of the population. Whether this is a proper way forward remains to be discussed. Improvement of risk assessment strategies may include taking into account biphasic dose-response curves, but should rather start with the consideration of proper physiologically based pharmacokinetic (PBPK) models for better extrapolation of differences in toxicokinetics going from high- to low-dose exposure, as well as taking into account kinetics for gene repair systems. Without considering in vivo toxicokinetics in the in vitro models, extrapolation from in vitro biphasic dose-response curves on cell proliferation to in vivo cell proliferation is difficult to do. Altogether, it is concluded that hormesis is an important phenomenon, especially from the scientific point of view, but that its consequences for risk assessment and the possibilities for in vitro to in vivo extrapolation may remain limited without additional mechanistic insight.     

The definition of hormesis and its implications for in vitro to in vivo extrapolation and risk assessment

This article comments on some of the basic questions put forward in state-of-the-art discussions on hormesis. There seems to be a need for a better definition of the concept itself and reconsideration of whether all biphasic dose-response curves should be considered representative for hormesis. Hormesis may be restricted to phenomena that proceed by mechanisms that are broadly generalizable and represent possibly beneficial overcompensation in response to an adverse stimulus. Using the concept that hormesis is defined as such, the biphasic effect of quercetin on cell proliferation, but also several other receptor-mediated biphasic dose-response phenomena, should not be related to hormesis. Taking into account hormesis in the procedures for risk assessment on compounds characterised by a threshold for the adverse effect is another matter for considerable debate. In our opinion, this would require the reduction of safety factors, providing the possibility for beneficial hormesis-type effects for some people, at the cost of increased chances on adverse effects for other parts of the population. Whether this is a proper way forward remains to be discussed. Improvement of risk assessment strategies may include taking into account biphasic dose-response curves, but should rather start with the consideration of proper physiologically based pharmacokinetic (PBPK) models for better extrapolation of differences in toxicokinetics going from high- to low-dose exposure, as well as taking into account kinetics for gene repair systems. Without considering in vivo toxicokinetics in the in vitro models, extrapolation from in vitro biphasic dose-response curves on cell proliferation to in vivo cell proliferation is difficult to do. Altogether, it is concluded that hormesis is an important phenomenon, especially from the scientific point of view, but that its consequences for risk assessment and the possibilities for in vitro to in vivo extrapolation may remain limited without additional mechanistic insight.     

Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.     

Hormesis [biological effects of low-level exposure (B.E.L.L.E.)] and dermatology

Hormesis is characterized by nonmonotonic dose response that is biphasic, displaying opposite effects at low and high doses. Its occurrence has been documented across a broad range of biological models and diverse types of exposure. The effects of hormesis at various points can be beneficial or detrimental, depending on the context in which they occur. Because 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 dermatology. Better understanding of this phenomenon will likely lead to different strategies for risk assessment process employed in the fields of dermatologic toxicology and pharmacology. More focus should be redirect from looking only at adverse effects at high levels of exposure to characterizing the complex biological effects, both adverse and beneficial, at low levels of exposure. Low-dose toxicology and pharmacology will not only provide a significant research challenge but also should contribute to better methods for low-dose risk assessment for complex mixtures of chemical compounds. This refocusing from high- to low-dose effects will shift the focus in the field of toxicology from emphasizing on adverse effects into studying the biological effects of chemical compounds on living organisms, taking into account the realization that the ultimate biological effect of a chemical may vary with its dose, the endpoint, the target organ considered, the interaction with other cell types/systems, and/or the combined exposure with other chemicals. The skin, with its ready accessibility, and its own areas of non-invasive technology, should provide fertile options to not only understand skin, but further explore practical implications in human and animal. 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.     

Quantification of Hormesis in Anticancer-Agent Dose-Responses

Quantitative features of dose responses were analyzed for 2,189 candidate anticancer agents in 13 strains of yeast (Saccharomyces cerevisiae). The agents represent a diverse class of chemical compounds including mustards, other alkylating agents, and antimetabolites, inter alia. Previous analyses have shown that the responses below the toxic threshold were stimulatory and poorly predicted by a threshold dose-response model, while better explained by a hormetic dose-response model. We determined the quantitative features of the hormetic concentration-responses (n = 4,548) using previously published entry and evaluative criteria. The quantitative features that are described are: (1) the width of the concentration range showing stimulation above 10% of the control (mean of 5-fold), (2) the maximum stimulation of the concentration-responses (mean of 27% above the control), and (3) the width from the maximum stimulation to the toxicological threshold (mean of 3.7-fold). These results show that 52.5% of the 2,189 chemicals evaluated display hormetic concentration-responses in at least one of the 13 yeast strains. Many chemicals showed hormesis in multiple strains, and 24 agents showed hormesis in all 13 strains. The data are compared to previously reported quantitative features of hormesis based on published literature.     

Hormesis [biological effects of low level exposures (BELLE)] and dermatology

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.     

Stimulation versus inhibition--bioactivity of parthenin, a phytochemical from Parthenium hysterophorus L

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 ED(50) values (2 DAT). This clearly demonstrated an over-compensatory response. Inhibition of leaf area at 13 DAT reached ED(50) 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 (ED(90)). 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.     

Defining hormesis: the necessary tool to clarify experimentally the low dose-response relationship

The authors comment on Calabrese and Baldwin's paper 'Defining Hormesis', which, to date, is the first attempt to provide a definition of hormesis that goes beyond the different interpretations of this phenomenon reported in the literature. While appreciating the effort made in this study to place hormesis in a general and at the same time specific context, the authors believe some clarifications are needed as regards the quantitative features of this phenomenon. In this connection, they speculate on whether Calabrese and Baldwin think it appropriate to include hormesis assessment criteria in the document, referring in particular to those reported in a previous paper. The authors share Calabrese and Baldwin's conclusion that future experimental models designed to study hormetic phenomena must necessarily include the time factor, which not only guarantees this phenomenon will be detected, but is also able to detect the specific type of hormesis.     

Drug development and hormesis: changing conceptual understanding of the dose response creates new challenges and opportunities for more effective drugs

This review proposes that the emerging acceptance of the hormetic dose-response model in toxicology and pharmacology has the potential to significantly change important aspects of drug development. Two situations where the hormesis concept may affect drug development are considered: one in which low-dose stimulation may represent an adverse/unwanted effect (eg, stimulation of tumor cell proliferation by antitumor drugs), the other in which low-dose stimulation defines the therapeutic zone (ie, a beneficial or intended effect; eg, cognition enhancement in Alzheimer's disease treatment). Examples are used to demonstrate that the hormetic dose-response model has implications for the definition of an ideal candidate for a therapeutic agent, as well as implications for study designs needed to assess the quantitative features of the dose-response relationship.