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Edward J Calabrese

Publications and source records attributed to Edward J Calabrese.

At least 19 recordsLinked to original sources
PubMed2006

Hormesis outperforms threshold model in National Cancer Institute antitumor drug screening database.

Which dose-response model best explains low-dose responses is a critical issue in toxicology, pharmacology, and risk assessment. The present paper utilized the U.S. National Cancer Institute yeast screening database that contains 56,914 dose-response studies representing the replicated effects of 2189 chemically diverse possible antitumor drugs on cell proliferation in 13 different yeast strains. Multiple evaluation methods indicated that the observed data are inconsistent with the threshold model while supporting the hormetic model. Hormetic response patterns were observed approximately four times more often than would be expected by chance alone. The data call for the rejection of the threshold model for low-dose prediction, and they support the hormetic model as the default model for scientific interpretation of low-dose toxicological responses.

Animals↗
PubMed2006

The failure of dose-response models to predict low dose effects: a major challenge for biomedical, toxicological and aging research.

Recent detailed evaluations of the pharmacological, toxicological, and biogerontological literature indicate that the hormetic dose-response is quite common and highly generalizable by biological model, endpoint, and chemical class. Head-to-head comparisons of the hormetic model with the traditional threshold model have revealed the hormetic model to occur with considerably greater frequency in the biomedical literature. Despite these developments, the history of both pharmacology and toxicology reflects a strong acceptance and centralizing of the threshold model concept while profoundly marginalizing of the hormetic dose-response. This commentary will address why the biomedical community especially those in the areas of pharmacology and toxicology made an incorrect judgment that the most fundamental nature of the dose-response was threshold rather than hormetic and why this conclusion has continued to dominate these fields and their numerous applications despite convincing evidence to the contrary. These findings have particular relevance to the area of biogerontology since this discipline often resides at the pharmacological-toxicological interface.

Aging↗
PubMed2006

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.

Dose-Response Relationship, Drug↗
PubMed2006

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.

Animals↗
PubMed2005

Toxicological awakenings: the rebirth of hormesis as a central pillar of toxicology.

This paper assesses historical reasons that may account for the marginalization of hormesis as a dose-response model in the biomedical sciences in general and toxicology in particular. The most significant and enduring explanatory factors are the early and close association of the concept of hormesis with the highly controversial medical practice of homeopathy and the difficulty in assessing hormesis with high-dose testing protocols which have dominated the discipline of toxicology, especially regulatory toxicology. The long-standing and intensely acrimonious conflict between homeopathy and "traditional" medicine (allopathy) lead to the exclusion of the hormesis concept from a vast array of medical- and public health-related activities including research, teaching, grant funding, publishing, professional societal meetings, and regulatory initiatives of governmental agencies and their advisory bodies. Recent publications indicate that the hormetic dose-response is far more common and fundamental than the dose-response models [threshold/linear no threshold (LNT)] used in toxicology and risk assessment, and by governmental regulatory agencies in the establishment of exposure standards for workers and the general public. Acceptance of the possibility of hormesis has the potential to profoundly affect the practice of toxicology and risk assessment, especially with respect to carcinogen assessment.

Animals↗
PubMed2005

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.

Animals↗
PubMed2005

Paradigm lost, paradigm found: the re-emergence of hormesis as a fundamental dose response model in the toxicological sciences.

This paper provides an assessment of the toxicological basis of the hormetic dose-response relationship including issues relating to its reproducibility, frequency, and generalizability across biological models, endpoints measured and chemical class/physical stressors and implications for risk assessment. The quantitative features of the hormetic dose response are described and placed within toxicological context that considers study design, temporal assessment, mechanism, and experimental model/population heterogeneity. Particular emphasis is placed on an historical evaluation of why the field of toxicology rejected hormesis in favor of dose response models such as the threshold model for assessing non-carcinogens and linear no threshold (LNT) models for assessing carcinogens. The paper argues that such decisions were principally based on complex historical factors that emerged from the intense and protracted conflict between what is now called traditional medicine and homeopathy and the overly dominating influence of regulatory agencies on the toxicological intellectual agenda. Such regulatory agency influence emphasized hazard/risk assessment goals such as the derivation of no observed adverse effect levels (NOAELs) and the lowest observed adverse effect levels (LOAELs) which were derived principally from high dose studies using few doses, a feature which restricted perceptions and distorted judgments of several generations of toxicologists concerning the nature of the dose-response continuum. Such historical and technical blind spots lead the field of toxicology to not only reject an established dose-response model (hormesis), but also the model that was more common and fundamental than those that the field accepted.

Animals↗
PubMed2005

Cancer biology and hormesis: human tumor cell lines commonly display hormetic (biphasic) dose responses.

This article assesses the nature of the dose-response relationship of human tumor cell lines with a wide range of agents including antineoplastics, toxic substances (i.e., environmental pollutants), nonneoplastic drugs, endogenous agonists, and phyto-compounds. Hormetic-like biphasic dose responses were commonly reported and demonstrated in 136 tumor cell lines from over 30 tissue types for over 120 different agents. Quantitative features of these hormetic dose responses were similar, regardless of tumor cell line or agent tested. That is, the magnitude of the responses was generally modest, with maximum stimulatory responses typically not greater than twice the control, while the width of the stimulatory concentration range was usually less than 100-fold. Particular attention was directed to possible molecular mechanisms of the biphasic nature of the dose response, as well as clinical implications in which a low concentration of chemotherapeutic agent may stimulate tumor cell proliferation. Finally, these findings further support the conclusion that hormetic dose responses are broadly generalizable, being independent of biological model, endpoint measured, and stressor agent, and represent a basic feature of biological responsiveness to chemical and physical stressors.

Adaptation, Physiological↗
PubMed2005

Hormesis: how it could affect the risk assessment process.

If the hormetic dose-response were accepted as the default dose-response model for risk assessment, it could have important implications for environmental exposure standards for noncarcinogens and especially for carcinogens. Most notably it would lead to the recognition that carcinogens act via a threshold process rejecting the concept of linearity at low doses. The hormetic concept also provides agencies with a broader range of toxicologically based exposure options, which permit a consideration for avoiding harm, as well as possibly enhancing benefits for both normal and high-risk segments of the population. By dismissing hormesis, regulatory agencies such as EPA deny the public the opportunity for optimal health and avoidance of disease.

Animals↗
PubMed2004

Hormesis: from marginalization to mainstream: a case for hormesis as the default dose-response model in risk assessment.

The paper provides an account of how the hormetic dose response has emerged in recent years as a serious dose-response model in toxicology and risk assessment after decades of extreme marginalization. In addition to providing the toxicological basis of this dose-response revival, the paper reexamines the concept of a default dose model in toxicology and risk assessment and makes the argument that the hormetic model satisfies criteria (e.g., generalizability, frequency, application to risk assessment endpoints, false positive/negative potential, requirements for hazard assessment, reliability of estimating risks, capacity for validation of risk estimates, public health implications of risk estimates) for such a default model better than its chief competitors, the threshold and linear at low dose models. The selection of the hormetic model as the default model in risk assessment for noncarcinogens and specifically for carcinogens would have a profound impact on the practice of risk assessment and its societal implications.

Animals↗
PubMed2003

Hormesis and stage specific toxicity induced by cadmium in an insect model, the queen blowfly, Phormia regina Meig.

Hormesis is an adaptive response, commonly characterized by a biphasic dose-response that can be either directly induced, or the result of compensatory biological processes following an initial disruption in homeostasis [Calabrese and Baldwin, Hum. Exp.Toxicol., 21 (2002), 91]. Low and environmentally relevant levels of dietary cadmium significantly enhanced the pupation rate of blowfly larvae, while higher doses inhibited pupation success. However, dietary cadmium at all exposure levels adversely affected the emergence of the adult fly from the pupal case. Such findings represent the first report of a heavy metal displaying a hormetic-like biphasic response for pupation success, while at the same time displaying stage-specific toxicity at a later developmental period. These conclusions are based on substantial experimentation of over 1750 blowflies, in seven replicate experiments, involving 10 concentrations per experiment. These findings indicate the need to assess the impact of environmental stressors over a broad range of potential exposures as well as throughout the entire life cycle.

Animals↗
PubMed2003

The effects of diisopropylmethylphosphonate, a by-product of the production of sarin and a contaminant in drinking water at the Rocky Mountain Arsenal, on female mink.

This paper challenges the interpretation of the report on the effects of DIMP on mink with respect to mortality causation and organ-specific toxicity (i.e., liver, kidney, and thymus). During the second generation (F(1)) of a two generation toxicity study by on the effects of DIMP on female brown Ranch Wild mink, a cluster of six premature deaths occurred, being attributed to an unintentional anesthetic overdose that induced a stress-related syndrome rather than DIMP exposure. The present paper reveals that the six adult female mink (i.e., four DIMP treated and two controls) had medical conditions that pre-existed the administration of anesthetic. Three of the four DIMP-exposed mink that died displayed evidence of medically significant red blood cell damage and immune system involvement, while all six mink had elevated blood serum enzymes (ALT/AST) indicative of liver damage along with confirmatory histopathology indicating severe liver damage. These findings challenge the conclusion of Bucci et al. that the six mink deaths were solely caused by stress induced by anesthesia, and suggest DIMP related pre-existing conditions (e.g., red blood cell damage and elevated ALT/AST) may have contributed to the deaths in DIMP-treated mink. also inexplicably combined both the pregnant and non-pregnant animal data, thereby precluding an assessment of the effects of DIMP on pregnant and non-pregnant mink. A re-evaluation of the findings of the data revealed that pregnancy/lactation significantly influenced the incidence of physiologic alterations and histological lesions in the female mink for the kidney, liver, and thymus, findings that were masked by the combining of pregnant and non-pregnant results. Further evaluations indicated that DIMP treatment also significantly induced liver lesions in pregnant mink and kidney lesions in both pregnant and non-pregnant mink. These findings challenge the conclusions of Bucci et al. concerning the effects of DIMP on mink as well as identify for the first time that pregnancy/lactation in mink is a risk factor in the induction of thymic atrophy and the elevation of serum ALT/AST.

Animals↗
PubMed2003

The effects of diisopropylmethylphosphonate on female mink: how medical intervention biased mortality data.

This analysis retrospectively assessed the likelihood that medical intervention masked effects of diisopropylmethylphosphonate (DIMP) on female mink. Bucci et al. [Two-generation reproductive study in mink fed DIMP. Final report. Study no. TP-001. Prepared by Pathology Associates International, Jefferson, AR, USA, 1997] medically intervened in 24 out of 174 female mink to prevent mortality after an overdose of anesthetic was believed to have induced a life-threatening stress-syndrome. Bucci et al. [loc. cit.] dismissed the biological significance of the intervention since intervention occurred similarly in controls and treatment groups. The present investigation revealed that more (3-fold) DIMP-treated female mink surviving the intervention had abnormal physiological/clinical parameters at the time of intervention (9/10) than control female mink (3/9) (P<0.1). In addition, the severity of the physiological/clinical abnormalities increased with dose. These findings indicate that the DIMP treated female mink were more likely to have benefited from the intervention than the controls. The intervention, therefore, reduced the likelihood of observing treatment-related effects.

Animals↗
PubMed2003

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↗