Toxicology rethinks its central belief.
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Animals↗
Biomedical subjects
Linda A Baldwin
Publications and source records attributed to Linda A Baldwin.
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.
Adaptation, Physiological↗
Chemotherapeutics and hormesis.
This article represents the first comprehensive assessment of hormetic effects of chemotherapeutic agents. Hormetic dose-response relationships were reported for a wide range of chemotherapeutics, including antibiotics, antiviral, and antitumor agents as well as substances that affect hair growth, prostate function, cognitive performance, and numerous other endpoints. Particular attention was given to assessing the quantitative features of the dose response, the underlying mechanistic features of the biphasic nature of the dose response, and the clinical implications of hormetic responses. Recognition of the hormetic-like biphasic nature of the dose response is expected to have an important impact on the design of experiments to assess chemotherapeutics and how such agents may be employed more successfully in clinical applications.
Animals↗
Peptides and hormesis.
The article provides a broad assessment of the occurrence of hormetic-like biphasic dose-response relationships by over 30 peptides representing many major peptide classes. These peptide-induced biphasic dose responses were observed to occur in a extensive range of tissues, affecting an diverse range of biological endpoints. Despite diversity of peptides, models and endpoints, the quantitative features of the biphasic dose responses are remarkably similar with respect to the amplitude and width of the stimulatory response. These findings strongly suggest that hormetic-like biphasic dose responses represent a broadly generalizable biological phenomenon.
Animals↗
Ethanol and hormesis.
This article provides a detailed assessment of the toxicological and pharmacological literature concerning alcohol-induced biphasic dose-response relationships. The assessment reveals that alcohol-induced hormetic-like dose-response relationships are commonly observed, highly generalizeable according to model and endpoint and quantitative feature of the dose response. These findings have important implications affecting study design, animal model, and endpoint selection as well as clinical applications.
Animals↗
The hormetic dose-response model is more common than the threshold model in toxicology.
The threshold dose-response model is widely viewed as the most dominant model in toxicology. The present study was designed to test the validity of the threshold model by assessing the responses of doses below the toxicological NOAEL (no observed adverse effect level) in relationship to the control response (i.e., unexposed group). Nearly 1,800 doses below the NOAEL, from 664 dose-response relationships derived from a previously published database that satisfied a priori entry criteria, were evaluated. While the threshold model predicts a 1:1 ratio of responses "greater than" to "less than" the control response (i.e., a random distribution), a 2.5:1 ratio (i.e., 1171:464) was observed, reflecting 31% more responses above the control value than expected (p < 0.0001). The mean response (calculated as % control response) of doses below the NOAEL was 115.0% +/- 1.5 standard error of the mean (SEM). These findings challenge the long-standing belief in the primacy of the threshold model in toxicology (and other areas of biology involving dose-response relationships) and provide strong support for the hormetic-like biphasic dose-response model characterized by a low-dose stimulation and a high-dose inhibition. These findings may affect numerous aspects of toxicological and biological/biomedical research related to dose-response relationships, including study design, risk assessment, as well as chemotherapeutic strategies.
Animals↗
Hormesis: the dose-response revolution.
Hormesis, a dose-response relationship phenomenon characterized by low-dose stimulation and high-dose inhibition, has been frequently observed in properly designed studies and is broadly generalizable as being independent of chemical/physical agent, biological model, and endpoint measured. This under-recognized and -appreciated concept has the potential to profoundly change toxicology and its related disciplines with respect to study design, animal model selection, endpoint selection, risk assessment methods, and numerous other aspects, including chemotherapeutics. This article indicates that as a result of hormesis, fundamental changes in the concept and conduct of toxicology and risk assessment should be made, including (a) the definition of toxicology, (b) the process of hazard (e.g., including study design, selection of biological model, dose number and distribution, endpoint measured, and temporal sequence) and risk assessment [e.g., concept of NOAEL (no observed adverse effect level), low dose modeling, recognition of beneficial as well as harmful responses] for all agents, and (c) the harmonization of cancer and noncancer risk assessment.
Animals↗
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.
Age Factors↗
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.
Animals↗