Inference for the existence of hormetic dose–response relationships in toxicology studies

Kim, Steven; Bartell, Scott M.; Gillen, Daniel L.

doi:10.1093/biostatistics/kxw004

Cited by 10 publications

(8 citation statements)

References 27 publications

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“…Polyphenol antioxidants have emerged with neuroprotective properties able to treat neurodegenerative diseases. The majority of these natural compounds are not only active scavengers of free radical species but also are capable of modulating prosurvival and antiapoptotic signaling pathways (Texel and Mattson, 2011;Mattson, 2014;Murugaiyah and Mattson, 2015;Kim et al, 2016). With respect to synthetic drugs showing generally only one mechanism of action, these compounds have a greater potential based on multiple lines of neuroprotection, such as (i) direct scavenging of free radicals; (ii) enhancement of endogenous cellular antioxidant potential by Nrf2 transcription factor pathway activation; (iii) modulation of signal transduction cascades; or (iv) regulation of gene expression.…”

Section: Discussionmentioning

confidence: 99%

Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Pennisi

Crupi

Paola

et al. 2016

J of Neuroscience Research

132

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Alzheimer disease (AD) is a progressive neurodegenerative disorder leading to cognitive decline, neuropsychiatric symptoms, disability, caregiver burden, and premature death. It represents the most prevalent cause of dementia, and its incidence rates exponentially increase with increasing age. The number of Americans living with AD is rapidly increasing. An estimated 5.4 million Americans of all ages have AD in 2016. One in nine people aged 65 and older has AD, and by midcentury, someone in the United States will develop the disease every 33 sec. It is now accepted that neuroinflammation is a common feature of neurological disease. Inflammasomes, which are a multiprotein complex part of the innate immune system, induce inflammation in response to various stimuli, such as pathogens and stress. Inflammasomes activate proinflammatory caspases, such as caspase-1, leading to the activation of the proinflammatory cytokines interleukin (IL)-1b, IL-18, and IL-33, which promote neuroinflammation and brain pathologies. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing-3 (NLRP3) inflammasome is the best characterized in neurodegenerative diseases, in particular AD. Recent research suggests that NLRP3 could possibly be used in targeted therapies to alleviate neuroinflammation. Modulation of endogenous cellular defense mechanisms may be an innovative approach to therapeutic intervention in AD and other disorders associated with neuroinflammation and neurodegeneration. Herein, we introduce the hormetic dose-response concept and present possible mechanisms and applications to neuroprotection. We summarize the mechanisms involved in activation of the NLRP3 inflammasome and its role in neuroinflammation. We also address and propose the potential therapeutic utility of the nutritional antioxidants sulforaphane and hydroxytyrosol against particular signs and symptoms of AD. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Pennisi

Crupi

Paola

et al. 2016

J of Neuroscience Research

132

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“…This parameterization is referred to as the L4 model, where L4 stands for the logistic regression with 4 parameters β 0 , β 1 , β 2 , and β 3 . A similar parameterization was discussed by Kim et al 17 Compared to the L3 model, the L4 model is more flexible while it maintains the same form of hypothesis testing H 0 : β 1 ≥ 0 versus H 1 : β 1 < 0. As shown in Figure 2, the L3 model is limited to a symmetric hormetic zone only (figure on the left), and the L4 model is able to generate an asymmetric hormetic zone by adding the power parameter β 3 (figures in the middle and on the right).…”

Section: Methodsmentioning

confidence: 99%

Model Averaging with AIC Weights for Hypothesis Testing of Hormesis at Low Doses

Kim

Sanders

2017

Dose-Response

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For many dose–response studies, large samples are not available. Particularly, when the outcome of interest is binary rather than continuous, a large sample size is required to provide evidence for hormesis at low doses. In a small or moderate sample, we can gain statistical power by the use of a parametric model. It is an efficient approach when it is correctly specified, but it can be misleading otherwise. This research is motivated by the fact that data points at high experimental doses have too much contribution in the hypothesis testing when a parametric model is misspecified. In dose–response analyses, to account for model uncertainty and to reduce the impact of model misspecification, averaging multiple models have been widely discussed in the literature. In this article, we propose to average semiparametric models when we test for hormesis at low doses. We show the different characteristics of averaging parametric models and averaging semiparametric models by simulation. We apply the proposed method to real data, and we show that P values from averaged semiparametric models are more credible than P values from averaged parametric methods. When the true dose–response relationship does not follow a parametric assumption, the proposed method can be an alternative robust approach.

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“…To test for hormesis, the Mack-Wolfe test, a nonparametric rank test for detecting "umbrella" alternatives to monotonic functions, could be performed on the BFRA curves. [79,80] In this way, researchers can use behavioral posology to hypothesize, model, and test causal mechanisms for behavioral addictions.…”

Section: Experimental Validation Of Behavioral Pk/pd Modelsmentioning

confidence: 99%

Behavioral Posology: A Novel Paradigm for Modeling the Healthy Limits of Behaviors

Henry

Pedersen

Williams

et al. 2023

Advcd Theory and Sims

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One of the challenges faced by behavioral scientists is the lack of modeling methodologies for accurately determining when a behavior becomes problematic. The authors propose “behavioral posology” as a novel modeling paradigm for quantifying the healthy limits of behaviors through the concept of behavioral dose. As an example of this paradigm, a pharmacokinetic/pharmacodynamic model of a hypothetical digital behavior is presented, based on opponent process theory. The generic model can be adapted to simulate Solomon and Corbit's model of affective dynamics from 1974, and the model predicts features of addiction such as hedonic allostasis, withdrawal, and apparent tolerance. A behavioral frequency response analysis (BFRA) of the model demonstrates how behavior repetition may result in a hormetic dose–response relationship that depends on the frequency of the behavior. The model can be experimentally validated using Ecological Momentary Assessment, allowing researchers to hypothesize, model, and test causal mechanisms for behavioral addictions. The potential for behavioral posology to be applied as a clinical support tool in psychological medicine is discussed, as this modeling framework may help to detect and limit behaviors being performed too frequently based on factors such as the person's moral beliefs.

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Inference for the existence of hormetic dose–response relationships in toxicology studies

Cited by 10 publications

References 27 publications

Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

Model Averaging with AIC Weights for Hypothesis Testing of Hormesis at Low Doses

Behavioral Posology: A Novel Paradigm for Modeling the Healthy Limits of Behaviors

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