Structured Development and Promotion of a Research Field: Hormesis in Biology, Toxicology, and Environmental Regulatory Science.

The ability of powerful and well-funded interest groups to steer scientific research in ways that advance their goals has become a significant social concern. This steering ability is increasingly being recognized in the peer-reviewed scientific literature and in findings of deliberative scientific bodies. This paper provides a case study that illustrates some of the major strategies that can be used to structure and advance a controversial research field. It focuses on hormesis, described as a type of dose-response relationship in toxicology and biology showing low-dose stimulation but high-dose inhibition, or the reverse. Hormesis proponents tout its significance, arguing that substances toxic at high doses and beneficial at lower doses should be regulated less stringently. We identify five strategies employed by hormesis proponents to foster its acceptance: (1) creating institutions focused on supporting hormesis; (2) developing terminology, study designs, and data interpretations that cast it in a favorable light; (3) using bibliometric techniques and surveys to attract attention; (4) aggressively advocating for the phenomenon and challenging critics; and (5) working with outside interest groups to apply the hormesis phenomenon in the economic and political spheres. We also suggest a number of oversight strategies that can be implemented to help promote credible and socially responsible research in cases like this one.

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.

Temporal stability of chemical hormesis (CH): Is CH just a temporary stop on the road to thresholds and toxic responses?

Chemical hormesis (CH) is currently described as a nonmonotonic, bidirectional dose-response relationship for chemicals, where a stimulatory, (beneficial?) response at low dose or exposure is followed by an inhibitory response at higher doses/exposures (or vice-versa). CH is depicted as U(J)-shaped or inverse U(J)-shaped curves, i.e., curve slopes change sign. Some describe CH as a homeostasis-preserving response; others view CH as adaptive or (pre)conditioning responses to chemical stress. One aspect of CH and stress hormesis in general that has not been researched is its temporal stability, i.e., persistence, particularly in experimental animals and humans having long-term chemical stressing. Once maximized, does the CH response remain operative over the entire time of chemical exposure? One possible reason for the question's neglect is that temporal stability, e.g., 'steady-state hormesis,' has been assumed. Another is that CH temporality is not well understood or has been under-appreciated as to its importance. Available data, mainly for simpler biological systems, describe cases of transitory CH. Other examples, in human and experimental animal studies, show transitory existence of CH and, in some specialized cases, persisting CH. Also, certain disease state-induced hormetic responses are transitory over time in humans. The question requires resolution if CH is to be considered (i) a stable and beneficial or adverse response, (ii) a stable dose-response model competitive with stable threshold and linear, nonthreshold (LNT) dose-response models, and (iii) a model having any impact on, or role in, regulatory and public health policies.

Lead remediation and changes in human lead exposure: some physiological and biokinetic dimensions.

This paper presents a qualitative and quantitative analysis of the various aspects of lead remediation effectiveness with particular reference to human health risk assessment. One of the key elements of lead remediation efforts at such sites as those under the Superfund program deals with populations at elevated exposure and toxicity risk in the proximity of, or at, the site of remediation, especially remediation workers, workers at other tasks on sites that were remediated down to some action level of lead concentration in soils, and groups at risk in nearby communities. A second element has to do with how one measures or models lead exposure changes with special reference to baseline and post-remediation conditions. Various biomarkers of lead exposure can be employed, but their use requires detailed knowledge of what results using each means. The most commonly used approach is measurement of blood lead (Pb-B). Recognized limitations in the use of Pb-B has led to the use of predictive Pb exposure models, which are less vulnerable to the many behavioral, physiological, and environmental parameters that can distort isolated or 'single shot' Pb-B testings. A third aspect covered in this paper presents various physiological factors that affect the methods by which one evaluates Pb remediation effectiveness. Finally, this article offers an integrated look at how lead remediation actions directed at one lead source or pathway affect the total lead exposure picture for human populations at elevated lead exposure and toxicity risk.

How prevalent is chemical hormesis in the natural and experimental worlds?

Hormesis is described as a biological phenomenon showing bidirectional (biphasic) responses to chemical or other stressors: stimulation at low doses and inhibition at high doses or vice-versa. The label applies to either radiation or chemical hormesis. This review addresses certain critical but persisting quantitative questions about chemical hormesis. For example, what is its actual generalizability in nature? Is hormesis generalizable enough to figure in risk analysis and regulatory efforts within human or ecological toxicant exposures? No evidence exists to show that chemical hormesis is a universally distributed biological phenomenon within some law, rule or principle (100% frequency) nor is there a reliable and consistent body of evidence that leads to identifying some significant and reproducible value for frequency of occurrence below the universality standard, i.e., <100% frequency. Lack of reliable and/or consistent evidence arises from diverse limits to study methods, i.e., methods were post-hoc evaluations of published data gathered for other purposes and using ad-hoc characterization approaches, rather than doing new studies. The literature selected for generalizability analyses has not been systematically pre-evaluated as a scientifically reliable representation of hormesis frequency in nature. Furthermore, database evaluations have used certain criteria not validated for this specific purpose, so that metric and what was measured are objects of scrutiny and ambiguity. Finally, simultaneous estimates of frequency of non-hormetic dose-response relationships, required for reliable determinations of hormesis frequency, were not done in these analyses. Chemical hormesis frequency estimates vary with conditions for characterization. For all these reasons, chemical hormesis still has limited use in health policy and regulatory thinking.

Limits to chemical hormesis as a dose-response model in health risk assessment.

This review presents and discusses the extent to which chemical hormesis meets five important requirements for performance of any dose-response model in the toxicological and regulatory sciences. These include (1) the requirement that there be a documented and accepted mechanistic basis for the dose-response model's plausible role and use in health risk assessment; (2) the requirement that any newly proposed dose-response methodology can be compared with current models as to reliability and scientific validity; (3) the requirement that the underlying reliability and stability of the model be established as to its temporal aspects, that is, minimal temporal lag between stressor contact and biological or toxicological response and temporal stability expressed throughout the prevailing relationship; (4) the requirement that the dose-response model be as broadly applicable as other dose-response methodologies being applied in human health risk assessment; and, (5) the requirement that any dose-response model proposed as default methodology can be characterized as to variability and uncertainty and will have a minimal likelihood of harm to the health of impacted populations. This review includes a brief treatment of definitions of hormesis and its place in nonmonotonic dose-response relationships. Overall, critical evaluation of chemical hormesis as a dose-response model in risk assessment shows it to have significant limits within the five requirements. These limits will impede any acceptance of chemical hormesis as a default approach in health risk assessment.

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.