Biphasic toxicodynamic features of some antimicrobial agents on microbial growth: a dynamic mathematical model and its implications on hormesis

<p>Abstract</p> <p>Background</p> <p>In the present work, we describe a group of anomalous dose-response (DR) profiles and develop a dynamic model that is able to explain them. Responses were obtained from conventional assays of three antimicrobial agents (nisin, pediocin and phenol) against two microorganisms (<it>Carnobacterium piscicola </it>and <it>Leuconostoc mesenteroides</it>).</p> <p>Results</p> <p>Some of these anomalous profiles show biphasic trends which are usually attributed to hormetic responses. But they can also be explained as the result of the time-course of the response from a microbial population with a bimodal distribution of sensitivity to an effector, and there is evidence suggesting this last origin. In light of interest in the hormetic phenomenology and the possibility of confusing it with other phenomena, especially in the bioassay of complex materials we try to define some criteria which allow us to distinguish between <it>sensu stricto </it>hormesis and biphasic responses due to other causes. Finally, we discuss some problems concerning the metric of the dose in connection with the exposure time, and we make a cautionary suggestion about the use of bacteriocins as antimicrobial agents.</p> <p>Conclusions</p> <p>The mathematical model proposed, which combines the basis of DR theory with microbial growth kinetics, can generate and explain all types of anomalous experimental profiles. These profiles could also be described in a simpler way by means of bisigmoidal equations. Such equations could be successfully used in a microbiology and toxicology context to discriminate between hormesis and other biphasic phenomena.</p

Resolving intertracer inconsistencies in soil ingestion estimation.

In this article we explore sources and magnitude of positive and negative error in soil ingestion estimates for children on a subject-week and trace element basis. Errors varied among trace elements. Yttrium and zirconium displayed predominantly negative error; titanium and vanadium usually displayed positive error. These factors lead to underestimation of soil ingestion estimates by yttrium and zirconium and a large overestimation by vanadium. The most reliable tracers for soil ingestion estimates were aluminum, silicon, and yttrium. However, the most reliable trace element for a specific subject-day (or week) would be the element with the least error during that time period. The present analysis replaces our previous recommendations that zirconium and titanium are the most reliable trace elements in estimating soil ingestion by children. This report identifies limitations in applying the biostatistical model based on data for adults to data for children. The adult-based model used data less susceptible to negative bias and more susceptible to source error (positive bias) for titanium and vanadium than the data for children. These factors contributed significantly to inconsistencies in model predictions of soil ingestion rates for children. Correction for error at the subject-day level provides a foundation for generation of subject-specific daily soil ingestion distributions and for linking behavior to soil ingestion

A Toxicological Basis to Derive a Generic Interspecies Uncertainty Factor.

A new method is proposed to derive the size of the interspecies uncertainty factor (UF) that is toxicologically and statistically based. The method involves quantifying interspecies variation in susceptibility to numerous toxic substances via the use of binary interspecies comparisons that are converted to a 95% UF. This interspecies UF represents an estimate of the upper 95% of the population of 95% prediction intervals (PI) for binary interspecies comparisons within four categories of phylogenetic relatedness (species within genus, genera within family, families within order, orders within class). The 95% interspecies UFs range from a low of 10 for species within genus up to 65 for orders within class. Most mammalian toxicology studies involving mice, rats, cats, dogs, gerbils, and rabbits are orders-within- class categories for human risk assessment and would be provided a 65-fold UF. Larger or smaller interspecies UF values could be selected on the level of protection desired

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

Modeling Effective Dosages in Hormetic Dose-Response Studies

BACKGROUND: Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. METHODOLOGY/PRINCIPAL FINDINGS: The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0-1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0-26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. CONCLUSIONS/SIGNIFICANCE: The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint