Implementing Hormetic Effects in the Risk Assessment Process: Differentiating Beneficial and Adverse Hormetic Effects in the RfD Derivation Process

Hormetic effects have been purported to be both beneficial and adverse. The decision of whether an effect is adverse or beneficial can have important implications for public health and risk assessment. A functional approach is proposed for determining the types of responses available for the incorporation of hormesis in the RfD process. These response categories include: (1) beneficial; (2) adverse; and (3) either beneficial or adverse depending on specific circumstances. Examples of endpoints in each category are presented and discussed. Other issues affecting the RfD process include: (1) the integration of multiple hormetic responses; (2) the importance of endpoint selection in determining the type of hormetic response; and (3) the assumption of hormesis when responses are unobservable due to low background response in controls.     

Hormetic effects of curcumin: What is the evidence?

Curcumin (diferuloylmethane), a component of the yellow powder prepared from the roots of Curcuma longa or Zingiberaceae (known as turmeric) is not only widely used to color and flavor food but also used as a pharmaceutical agent. Curcumin demonstrates anti-inflammatory, anticarcinogenic, antiaging, and antioxidant activity, as well as efficacy in wound healing. Notably, curcumin is a hormetic agent (hormetin), as it is stimulatory at low doses and inhibitory at high doses. Hormesis by curcumin could be also a particular function at low doses (i.e., antioxidant behavior) and another function at high dose (i.e., induction of autophagy and cell death). Recent findings suggest that curcumin exhibits biphasic dose–responses on cells, with low doses having stronger effects than high doses; examples being activation of the mitogen-activated protein kinase signaling pathway or antioxidant activity. This indicates that many effects induced by curcumin are dependent on dose and some effects might be greater at lower doses, indicative of a hormetic response. Despite the consistent occurrence of hormetic responses of curcumin in a wide range of biomedical models, epidemiological and clinical trials are needed to assess the nature of curcumin’s dose–response in humans. Fortunately, more than one hundred clinical trials with curcumin and curcumin derivatives are ongoing. In this review, we provide the first comprehensive analysis supportive of the hormetic behavior of curcumin and curcumin derivatives.     

The effects of natural variation in background radioactivity on humans,animals and other organisms

Natural levels of radioactivity on the Earth vary by more than a thousand‐fold; this spatial heterogeneity may suffice to create heterogeneous effects on physiology, mutation and selection. We review the literature on the relationship between variation in natural levels of radioactivity and evolution. First, we consider the effects of natural levels of radiation on mutations, DNA repair and genetics. A total of 46 studies with 373 effect size estimates revealed a small, but highly significant mean effect that was independent of adjustment for publication bias. Second, we found different mean effect sizes when studies were based on broad categories like physiology, immunology and disease frequency; mean weighted effect sizes were larger for studies of plants than animals, and larger in studies conducted in areas with higher levels of radiation. Third, these negative effects of radiation on mutations, immunology and life history are inconsistent with a general role of hormetic positive effects of radiation on living organisms. Fourth, we reviewed studies of radiation resistance among taxa. These studies suggest that current levels of natural radioactivity may affect mutational input and thereby the genetic constitution and composition of natural populations. Susceptibility to radiation varied among taxa, and several studies provided evidence of differences in susceptibility among populations or strains. Crucially, however, these studies are few and scattered, suggesting that a concerted effort to address this lack of research should be made.     

Slow-down of age-dependent telomere shortening is executed in human skin keratinocytes by hormesis-like-effects of trace hydrogen peroxide or by anti-oxidative effects of pro-vitamin C in common concurrently with reduction of intracellular oxidative stress

The cellular life-span of cultivated human skin epidermis keratinocytes NHEK-F was shown to be extended up to 150% of population doubling levels (PDLs) by repetitive addition with two autooxidation-resistant derivatives of ascorbic acid (Asc), Asc-2-O-phosphate (Asc2P), and Asc-2-O-alpha-glucoside (Asc2G), respectively, but to be not extended with Asc itself. In contrast, hydrogen peroxide (H(2)O(2)) as dilute as 20 microM which was non-cytotoxic to the keratinocytes, or at 60 microM being marginally cytotoxic achieved the cellular longevity, unexpectedly, up to 160 and 120% of PDLs, respectively, being regarded as a hormesis-like stimulatory effect. The lifespan-extended cells that were administered with Asc2P, Asc2G, or 20 microM H(2)O(2) were prevented from senescence-induced symptoms such as PDL-dependent enlargement of a cell size of 14.7 microm finally up to 17.4 microm upon Hayflick's limit-called loss of proliferation ability as estimated with a channelizer, and retained young cell morphological aspects such as thick and compact shape and intense attachment to the culture substratum even upon advanced PDLs, whereas other non-extended cells looked like thin or fibrous shape and large size upon lower PDLs. The PDL-dependent shortening of telomeric DNA of 11.5 kb finally down to 9.12-8.10 kb upon Hayflick's limit was observed in common for each additive-given cells, but was decelerated in the following order: 20 microM H(2)O(2) > Asc2P = Asc2G > 60 microM H(2)O(2) > Asc = no additive, being in accord with the order of cell longevity. Intracellular reactive oxygen species (ROS) was diminished by Asc2P, Asc2G or 20 microM H(2)O(2), but not significantly by Asc or 60 microM H(2)O(2) as estimated by fluorometry using the redox indicator dye CDCFH. There was no appreciable difference among NHEK keratinocytes that were administered with or without diverse additives in terms of telomerase activity per cell, which was 1.40 x 10(4)-4.48 x 10(4) times lower for the keratinocytes than for HeLa cells which were examined as the typical tumor cells. Thus longevity of the keratinocytes was suggested to be achieved by slowdown of age-dependent shortening of telomeric DNA rather than by telomerase; telomeres may suffer from less DNA lesions due to the continuous and thorough repression of intracellular ROS, which was realized either by pro-vitamin C such as Asc2P or Asc2G that exerted an antioxidant ability more persistent than Asc itself or by 20 microM H(2)O(2) which diminished intracellular ROS assumedly through a hormesis-like effect.     

A Biomathematical Modeling Approach to Explain the Phenomenon of Radiation Hormesis

This study presents an improved version of a published biomathematical model, the Random Coincidence Model-Radiation Adapted (RCM-RA). That model describes how cancer mortality increases as dose rate increases in the high-dose rate range, as well as how mortality decreases as dose rate increases in the low-dose rate range. It was assumed that low-dose rates of ionizing radiation induce cellular defense mechanisms that also prevent or repair endogenous DNA damage caused by natural cell metabolism. The model presented describes the development of cancer by a phase of initiation that consists of a series of DNA lesions in the critical regions of tumor-associated genes such as proto-oncogenes or tumor-suppressor genes. Initiated cells can divide and form a clone of initiated cells. This clonal growth is called promotion and leads to premalignant cells. Premalignant clones can sustain further genomic damage that may lead to a malignant cell and ultimately a malignant tumor. The model thereby shares structural features with Moolgavkar's two-stage clonal expansion model. It was tested on published, U-shaped data of radon exposure in U.S. homes. The model correctly reflects the ratio of endogenous DNA damage to radiation-induced damage.     

Antioxidant Supplements versus Health Benefits of Brief/Intermittent Exposure to Potentially Toxic Physical or Chemical Agents

Although antioxidants can act locally to react with an oxidant, oral administration of “antioxidants” is quite useless in treating oxidative stress in tissues. Furthermore, it does not make sense to consider a vitamin as an antioxidant, but vitamin B3 leads to the in vivo formation of compounds that are essential for reducing this stress. A rigorous treatment of the subject indicates that to deal with oxidative stress, the most direct approach is to enhance the innate antioxidant mechanisms. The question is whether this is possible through daily activities. Diets can contain the necessary components for these mechanisms or may induce the expression of the genes involved in them. Another possibility is that pro-oxidant molecules in food increase the sensitivity and power of the detoxification pathways. This option is based on well-known DNA repair mechanisms after exposure to radiation (even from the Sun), or strong evidence of induction of antioxidant capacity after exposure to powerful pro-oxidants such as H₂O₂. More experimental work is required to test whether some molecules in food can increase the expression of antioxidant enzymes and/or improve antioxidant mechanisms. Identifying effective molecules to achieve such antioxidant power is critical to the food and nutraceutical industries. The potential of diet-based interventions to combat oxidative stress must be viewed from a new perspective.     

芦芽山林线白杄与华北落叶松径向生长特征比较

分别于2007年7月15日—8月7日和9月5日—10月9日,在山西芦芽山林线附近,应用树木径向变化记录仪测量了6株白杄和5株华北落叶松树干的径向生长过程,同步监测环境因子.结果表明：白杄与华北落叶松在7—8月对环境变化的敏感度无显著性差异,在相对低温干旱的9—10月,白杄对环境的敏感度更高;两树种的净生长曲线和累积变化曲线在7—8月呈上升趋势,9—10月则先下降而后基本保持不变,且白杄生长曲线的波动较大;两树种的茎干变化与水分条件显著相关,其中白杄受大气湿度和温度影响较强,而华北落叶松受土壤水分的影响较强.     

Peroxisome metabolism and cellular aging

The essential role of peroxisomes in fatty acid oxidation, anaplerotic metabolism, and hydrogen peroxide turnover is well established. Recent findings suggest that these and other related biochemical processes governed by the organelle may also play a critical role in regulating cellular aging. The goal of this review is to summarize and integrate into a model the evidence that peroxisome metabolism actually helps define the replicative and chronological age of a eukaryotic cell. In this model, peroxisomal reactive oxygen species (ROS) are seen as altering organelle biogenesis and function, and eliciting changes in the dynamic communication networks that exist between peroxisomes and other cellular compartments. At low levels, peroxisomal ROS activate an anti-aging program in the cell; at concentrations beyond a specific threshold, a pro-aging course is triggered.     

The effect of sexual harassment on lethal mutation rate in female Drosophila melanogaster

The rate by which new mutations are introduced into a population may have far-reaching implications for processes at the population level. Theory assumes that all individuals within a population have the same mutation rate, but this assumption may not be true. Compared with individuals in high condition, those in poor condition may have fewer resources available to invest in DNA repair, resulting in elevated mutation rates. Alternatively, environmentally induced stress can result in increased investment in DNA repair at the expense of reproduction. Here, we directly test whether sexual harassment by males, known to reduce female condition, affects female capacity to alleviate DNA damage in Drosophila melanogaster fruitflies. Female gametes can repair double-strand DNA breaks in sperm, which allows manipulating mutation rate independently from female condition. We show that male harassment strongly not only reduces female fecundity, but also reduces the yield of dominant lethal mutations, supporting the hypothesis that stressed organisms invest relatively more in repair mechanisms. We discuss our results in the light of previous research and suggest that social effects such as density and courtship can play an important and underappreciated role in mediating condition-dependent mutation rate.     

8-Oxo-7,8-dihydro-2’-deoxyguanosine,reactive oxygen species and ambulatory blood pressure in African and Caucasian men: The SABPA study

Abstract

Various studies indicate a relationship between increased oxidative stress and hypertension, resulting in increased DNA damage and consequent excretion of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxodG). The aim of this study was to compare urinary 8-oxodG levels in African and Caucasian men and to investigate the association between ambulatory blood pressure (BP) and pulse pressure (PP) with 8-oxodG in these groups.

We included 98 African and 92 Caucasian men in the study and determined their ambulatory BP and PP. Biochemical analyses included, urinary 8-oxodG, reactive oxygen species (ROS) (measured as serum peroxides), ferric reducing antioxidant power (FRAP), total glutathione (GSH), glutathione peroxidase (GPx) and glutathione reductase (GR) activity.

The African men had significantly higher systolic (SBP) and diastolic blood pressure (DBP) (both p < 0.001). Assessment of the oxidative stress markers indicated significantly lower 8-oxodG levels (p < 0.001) in the African group. The African men also had significantly higher ROS (p = 0.002) with concomitant lower FRAP (p < 0.001), while their GSH levels (p = 0.013) and GR activity (p < 0.001) were significantly higher. Single and partial regression analyses indicated a negative association between urinary 8-oxodG levels with SBP, DBP and PP only in African men. These associations were confirmed in multiple regression analyses (SBP: R² = 0.41; β = ?0.25; p = 0.002, DBP: R² = 0.30; β = ?0.21; p = 0.022, PP: R² = 0.30; β = ?0.19; p = 0.03).

Our results revealed significantly lower urinary 8-oxodG in African men, accompanied by a negative association with BP and PP. We propose that this may indicate a dose-response relationship in which increased oxidative stress may play a central role in the up-regulation of antioxidant defence and DNA repair mechanisms.