Linda A. Baldwin

Toxicology rethinks its central belief

Hormesis demands a reappraisal of the way risks are assessed.

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.

Chemical hormesis: its historical foundations as a biological hypothesis.

Despite the long history of hormesis-related experimental research no systematic effort to describe its early history has been undertaken. The present paper attempts to reconstruct and assess the early history of such research and to evaluate how advances in related scientific fields affected the course of hormesis-related research. The purpose of this paper is not only to satisfy this gap in current knowledge, but also to provide a foundation for the assessment of how the concept of hormetic dose-response relationships may have affected the nature of the bioassay especially with respect to hazard assessment practices within a modern risk assessment Eramework.

Hormesis: A Highly Generalizable and Reproducible Phenomenon With Important Implications for Risk Assessment

From a comprehensive search of the literature, the hormesis phenomenon was found to occur over a wide range of chemicals, taxonomic groups, and endpoints. By use of computer searches and extensive cross-referencing, nearly 3000 potentially relevant articles were identified. Evidence of chemical and radiation hormesis was judged to have occurred in approximately 1000 of these by use of a priori criteria. These criteria included study design features (e.g., number of doses, dose range), dose-response relationship, statistical analysis, and reproducibility of results. Numerous biological endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, reproductive responses, longevity, and cancer. Hormetic responses were generally observed to be of limited magnitude with an average maximum stimulation of 30 to 60 percent over that of the controls. This maximum usually occurred 4- to 5-fold below the NOAEL for a particular endpoint. The present analysis suggests that hormesis is a reproducible and generalizable biological phenomenon and is a fundamental component of many, if not most, dose-response relationships. The relatively infrequent observation of hormesis in the literature is believed to be due primarily to experimental design considerations, especially with respect to the number and range of doses and endpoint selection. Because of regulatory considerations, most toxicologic studies have been carried out at high doses above the low-dose region where the hormesis phenomenon occurs.

The Dose Determines the Stimulation (and Poison): Development of A Chemical Hormesis Database

A comprehensive effort was undertaken to identify articles demonstrating chemical hormesis. Nearly 4000 potentially relevant articles were retrieved from preliminary computer searches utilizing various keyword descriptors and extensive cross-referencing. A priori evaluation criteria were established including study design features (e.g., number of doses, dose range), statistical analysis, and reproducibility of results. Evidence of chemical hormesis was judged to have occurred in approximately 350 of the 4000 studies evaluated. Chemical hormesis was observed in a wide range of taxonomic groups and involved agents representing highly diverse chemical classes, many of potential environmental relevance. Numerous biologic endpoints were assessed, with growth responses the most prevalent, followed by metabolic effects, longevity, reproductive responses, and survival. Hormetic responses were generally observed to be of limited magnitude with the average low-dose maximum stimulation approximately 50% greater than controls. The hormetic dose-response range was generally limited to about one order of magnitude with the upper end of the hormetic curve approaching the estimated no-observed-effect level (NOEL) for the particular endpoint. Based on the evaluation criteria, high to moderate evidence of hormesis was observed in studies comprised of ≥ doses with <3 doses in the hormetic zone. The present analysis suggests that chem ical hormesis is a reproducible and generalizable biologic phenomenon. Over the last decade advances have been made providing mechanistic insight helpful in explaining the phenomenon of chemical hormesis in multiple biologic systems with various endpoints. The reason for the uncertainty surrounding the existence of hormesis as a “real phenomenon” is believed to be the result of its relatively infrequent observation in the literature due to experimental design considerations, especially with respect to the number of doses, range of doses, and endpoint selection.

Radiation hormesis: its historical foundations as a biological hypothesis

This paper represents the first systematic effort to describe the historical foundations of radiation hormesis. Spanning the years from 1898 to the early 1940‘s the paper constructs and assesses the early history of such research and evaluates how advances in related scientific fields affected the course of hormetic related research. The present effort was designed to not only address this gap in current knowledge, but to offer a toxicological basis for how the concept of hormetic dose-response relationships may affect the nature ofthe bioassay and its role in the risk assessment process.

Applications of hormesis in toxicology, risk assessment and chemotherapeutics

There is much debate over the fundamental shape of the dose-response curve in the low-dose zone, particularly in the fields of toxicology and risk assessment. The defaults, principally accepted dose-response models in the major texts in these areas and in government regulatory activities, are a threshold model for non-carcinogens and a linear model for most carcinogens. We have argued that in properly designed studies the U-shaped hormetic response predominates and is more fundamental. In this article, a broad range of basic issues associated with the acceptance of U-shaped dose responses as central to toxicology, pharmacology and their applications to risk assessment and medicine will be discussed.

Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis

This paper compares the historical developments of chemical and radiation hormesis from their respective inceptions in the late 1880‘s for chemical hormesis and early 1900‘s for radiation hormesis to the mid 1930‘s to 1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific community. This analysis documents that there were marked differences in their respective temporal developments, and the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able to attract prestigious researchers with international reputations from leading institutions, to be the subject of numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations ofboth chemical and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a coherent doseresponse theory using data of low dose stimulation from both the chemical and radiation domains; (2) difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of the practical and/or commercial applications of the concepts of low dose stimulation.

The marginalization of hormesis

Despite the substantial development and publication of highly reproducible toxicological data, the concept of hormetic dose-response relationships was never integrated into the mainstream of toxicological thought. Review of the historical foundations of the interpretation of the bioassay and assessment of competitive theories of dose-response relationships lead to the conclusion that multiple factors contributed to the marginalization of hormesis during the middle and subsequent decades ofthe 20th century. These factors include: (a) the close-association of hormesis with homeopathy lead to the hostility of modern medicine toward homeopathy thereby creating a guilt by association framework, and the carry-over influence of that hostility in the judgements of medically-based pharmacologists/ toxicologists toward hormesis; (b) the emphasis of high dose effects linked with a lack of appreciation of the significance of the implications of low dose stimulatory effects; (c) the lack of an evolutionary-based mechanism(s) to account for hormetic effects; and (d) the lack of appropriate scientific advocates to counter aggressive and intellectually powerful critics of the hormetic perspective.

Inorganics and Hormesis

The article is a comprehensive review of the occurrence of hormetic dose-response relationships induced by inorganic agents, including toxic agents, of significant environmental and public health interest (e.g., arsenic, cadmium, lead, mercury, selenium, and zinc). Hormetic responses occurred in a wide range of biological models (i.e., plants, invertebrate and vertebrate animals) for a large and diverse array of endpoints. Particular attention was given to providing an assessment of the quantitative features of the dose-response relationships and underlying mechanisms that could account for the biphasic nature of the hormetic response. These findings indicate that hormetic responses commonly occur in appropriately designed experiments and are highly generalizeable with respect to biological model responses. The hormetic dose response should be seen as a reliable feature of the dose response for inorganic agents and will have an important impact on the estimated effects of such agents on environmental and human receptors.