Hormesis Outperforms Threshold Model in National Cancer Institute Antitumor Drug Screening Database

Calabrese, Edward J.; Staudenmayer, John; Stanek, Edward J.; Hoffmann, George

doi:10.1093/toxsci/kfl098

Cited by 135 publications

(133 citation statements)

References 9 publications

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“…Cd, As, Hg) (Calabrese and Blain, 2004;Helmcke et al, 2010), dioxins (Rozman et al, 2005), pesticides (Cedergreen, 2008) and therapeutic agents (Calabrese and Baldwin, 2003a). The repeated occurrence of low-dose stimulation has led to suggestions that the hormesis model could even replace the logistic as the default in toxicology (Calabrese, 2008;Calabrese et al, 2006). This could have profound implications for chemical management, as regulation using hormesis (over traditional logistic models) could both alter permissible levels (Calabrese and Cook, 2005) and also providing a public perception of risk that "a little stress might be good for you" or more eloquently "what doesn't kill you makes you stronger"…”

Section: Life-cycle Toxicity Tests For Dcmu and Ag Npsmentioning

confidence: 99%

Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial

Tyne

Little

Spurgeon

et al. 2015

Ecotoxicology and Environmental Safety

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Tests to assess toxic effects on the reproduction of adult C. elegans after 72 h exposure for two chemicals, (3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)), also known as diuron, and silver nanoparticles (Ag NPs) indicated potential, although not significant hormesis. Follow up toxicity tests comparing the potential hormesis concentrations with controls at high replication confirmed that the stimulatory effect was repeatable and also statistically significant within the test. To understand the relevance of the hormesis effects for overall population fitness, full lifecycle toxicity tests were conducted for each chemical. When nematodes were exposed to DCMU over the full life-span, the hormesis effect for reproduction seen in short-term tests was no longer evident. Further at the putative hormesis concentrations, a negative effect of DCMU on time to maturation was also seen. For the Ag NPs, the EC50 for effects on reproduction in the life-cycle exposure was substantially lower than in the short-term test, the EC50s estimated by a three parameter log logistic model being 2.9 mg/L and 0.75 mg/L, respectively. This suggests that the level of toxicity for Ag NPs for C. elegans reproduction is dependent on the life stage exposed and possibly the duration of the exposure. Further, in the longer duration exposures, hormesis effects on reproduction seen in the short-term exposures were no longer apparent. Instead, all concentrations reduced both overall brood size and life-span. These results for both chemicals suggest that the hormesis observed for a single endpoint in shortterm exposure may be the result of a temporary reallocation of resources between traits that are not sustained over the full life-time. Such reallocation is consistent with energy budget theories for organisms subject to toxic stress.3

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Section: Life-cycle Toxicity Tests For Dcmu and Ag Npsmentioning

confidence: 99%

Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial

Tyne

Little

Spurgeon

et al. 2015

Ecotoxicology and Environmental Safety

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“…A detailed description of the NCI database, experimental design, and methods is given in Calabrese et al (2006). Briefly, data from stage 2 of the NCI testing procedure were evaluated on 2189 compounds considered to be E. J.…”

Section: A High Through-put Study Of 2189 Chemicals On 13 Strains Of mentioning

confidence: 99%

“…A value of 5% was selected for the BMD, in part because this percentage was approximately one standard deviation of control response. The BMD 5 was estimated by a linear interpolation between the concentration immediately above and below the 95% response, similar to Figure 1 in Calabrese et al (2006). Doses used to derive the BMD 5 were not included in the low-dose range.…”

Section: Determining a Benchmark Dosementioning

confidence: 99%

Predicting Low Dose Effects for Chemicals in High Through-Put Studies

Stanek¹,

Calabrese

2010

Dose-Response

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ᮀ High through-put studies commonly use automated systems with 96-well plates in which multiple chemicals are tested at multiple doses using log-2 dose increments after a suitable incubation period. There are typically multiple (ranging from five to eleven) doses on each chemical, and occasionally plate replications of the dose-response studies. The target endpoint for such studies is typically the LC50, but for some chemicals, there may be multiple doses below a benchmark dose where there is no apparent adverse response relative to control response. We show how an estimation approach can lead to clearly interpretable results about response in the low dose region using data from a high throughput study of 2189 chemicals on yeast. Accurate estimates can be obtained of response for study chemicals by using best linear unbiased predictors (BLUPs) in a mixed model, and summarized via plots with expected response (assuming no low-dose effect) with confidence intervals for response below the benchmark dose for each chemical, providing an informative summary of response at low doses. We conclude that this approach can provide valuable insights that would be missed if the observational data were only considered through the lens of statistical methods appropriate for experimental studies.

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“…These compounds were tested on a panel of 13 yeast strains, each having one or two mutations affecting damage-response functions (DNA damage repair or cell cycle control) homol-ogous to those mutated in human cancers. Previous analyses of these NCI data have shown that responses below the toxic threshold were poorly predicted by the threshold model, yet highly consistent with a hormetic, inverted U-shaped concentration-response model (Calabrese et al 2006a(Calabrese et al , 2008. The initial studies evaluated the individual responses of concentrations and their replication below estimated Benchmark Doses (BMDs) but they did not explore the individual concentration-response relationships or the magnitude of stimulation with respect to hormesis.…”

Section: Introductionmentioning

confidence: 99%

Quantification of Hormesis in Anticancer-Agent Dose-Responses

et al. 2009

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ᮀ Quantitative features of dose responses were analyzed for 2,189 candidate anticancer agents in 13 strains of yeast (Saccharomyces cerevisiae). The agents represent a diverse class of chemical compounds including mustards, other alkylating agents, and antimetabolites, inter alia. Previous analyses have shown that the responses below the toxic threshold were stimulatory and poorly predicted by a threshold dose-response model, while better explained by a hormetic dose-response model. We determined the quantitative features of the hormetic concentration-responses (n = 4,548) using previously published entry and evaluative criteria. The quantitative features that are described are: (1) the width of the concentration range showing stimulation above 10% of the control (mean of 5-fold), (2) the maximum stimulation of the concentration-responses (mean of 27% above the control), and (3) the width from the maximum stimulation to the toxicological threshold (mean of 3.7-fold). These results show that 52.5% of the 2,189 chemicals evaluated display hormetic concentration-responses in at least one of the 13 yeast strains. Many chemicals showed hormesis in multiple strains, and 24 agents showed hormesis in all 13 strains. The data are compared to previously reported quantitative features of hormesis based on published literature.

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Hormesis Outperforms Threshold Model in National Cancer Institute Antitumor Drug Screening Database

Cited by 135 publications

References 9 publications

Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial

Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial

Predicting Low Dose Effects for Chemicals in High Through-Put Studies

Quantification of Hormesis in Anticancer-Agent Dose-Responses

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