摘要:

Hormesis is a dose–response phenomenon characterized by a low-dose stimulation and a high-dose inhibition. The hormesis concept claims that as the dose of the agent being studied is reduced the response of the endpoint being measured does not simply get smaller and smaller, drifting into background noise but actually reverses course and changes to an opposite response. That is, a chemical that causes cancer at high doses is predicted to display a risk of the cancer at low doses that is actually less than the unexposed controls. In toxicological terms, the hormesis dose response may be seen as either a J-shaped dose response or an inverted U-shaped dose response depending on the endpoint being measured (Fig. 1). In the case of disease incidence, such as heart disease or cancer, the dose response would be J-shaped. In the case of endpoints such as growth, longevity or cognitive function, the dose response would be inverted U-shaped. The concept of hormesis has been demonstrated to be widely generalizable across models, endpoints, and chemical classes, including metal and organometal compounds.1–7Hormetic effects occur in response to the induction of low level stress or toxicity and reflects a modest overcompensation adaptive response. Consequently, in the case of essential metals exposures inducing hormesis are considered to be slightly higher than the upper bound limit of optimality for those metals.(A) The most common form of the hormetic dose–response curve depicting low-dose stimulatory and high-dose inhibitory responses, the β- or inverted U-shaped curve. Endpoints displaying this curve include growth, fecundity and longevity. (B) The hormetic dose–response curve depicting low-dose reduction and high-dose enhancement of adverse effects (J-shaped curve). Endpoints displaying this curve include carcinogenesis, mutagenesis and disease incidence.The hormetic effect of metals was observed as early as the 1880's when Professor Hugo Schulz, working in a makeshift laboratory at the University of Griswald in northern Germany, observed that numerous disinfectants including several heavy metals, such as inorganic mercury, reproducibly enhanced the metabolism of yeasts at low doses while being inhibitory at higher doses.8The findings of Schulz were confirmed and extended by a number of other researchers using other biological models including plants and bacteria (see Calabrese and Baldwin9–13for a comprehensive review of the history of chemical and radiation hormesis). In fact, the historical literature on hormesis is overwhelmingly dominated by investigators using heavy metals at leading research institutions such as Columbia University, Stanford University and Yale University where basic understandings concerning the qualitative and quantitative features of the hormetic dose response were established. The work of Branham at Columbia in 1929 replicated the yeast findings of Schultz and firmly established that the low-dose stimulation typically occurred after an initial disruption in homeostasis. Therefore, implying that the stimulatory response, which is the so-called hormetic bump on the dose–response curve, represents an overcompensation response.Fig. 2displays the dose–time–response of Branham's work concerning the effects of mercury on the metabolism of yeasts. In the initial time point measured there is a decrease in metabolic endpoint. Subsequent time points demonstrate an increase in metabolic endpoint especially at low doses. The dose response eventually takes the form of the hormetic dose–response relationship, although this would have been missed if only the initial time point had been considered. Branham14was able to show this type of dose–time–response for numerous disinfectant agents (see Calabrese15for a review of the overcompensation hypothesis of hormesis with numerous supportive examples).The effects of mercuric chloride on yeast metabolism (data from Branham14).In general, there has been a large number of dose–response relationships published in the toxicological literature which provide evidence of hormesis. A database developed by Calabrese has nearly 6000 examples of possible hormetic dose responses with approximately 1000 using a metal compound. Inclusion into the database was restricted only to the following conditions: (1) that a concurrent control was employed and (2) that a 10% or statistically significant stimulation in effect occurred when a depression was expected or a 3% or statistically significant depression in effect occurred when a stimulation was expected.Tables 1–4summarize some general features of the dose–responses from metal compounds currently in our hormesis database, including the specific number of examples, how they distribute across the given metals, the biological models and endpoints displaying hormesis, the frequency of publication over time, and quantitative features of the dose response. Although it must be emphasized that the current database is added to on a weekly basis and that the data provided here are a current snapshot, the general consistency in the dose response features with other classes of agents suggests that these findings are likely to be reasonably stable. Other findings such as the patterns of endpoints measured and relative proportions of metals in the database are likely to be more variable.Metals and the number of dose–responses by animal model in the hormesis databaseMetal saltsTotalAnimalPlantOtherIn vivoIn vitroIn vivoIn vitroList of what is included in each metal category in the tables are as follows: Cadmium: cadmium ion, cadmium acetate, cadmium chloride, cadmium nitrate, cadmium oxide, cadmium sulfate; Copper: copper, copper(ii) sulfate, copper acetate, copper carbamate, copper chloride, copper oxalate, copper oxide, copper sulfate pentahydrate, cupric acetate, cupric sulfate, cupric isoleucenate; Lead: lead, lead acetate, lead arsenate, lead chloride, lead nitrate, lead sulfate; Mercury: mercury, mercury chloride, mercury nitrate, mercury acetate, mercury sulfate; Zinc: zinc ion, zinc arsenite, zinc chloride, zinc nitrate, zinc sulfate; Aluminium: aluminium, aluminium chloride, aluminium sulfate; Arsenic: arsenic trioxide, arsenic trisulfide, sodium arsenate, sodium arsenic trioxide, sodium arsenite, lead arsenate, zinc arsenite; Nickel: nickel, nickel chloride, nickel dichloride, nickel sulfate; Chromium: chromium, potassium chromate, potassium dichromate, chromium acetate, chromium chloride, chromium oxide, sodium chromate; Vanadium: sodium metavanadate, sodium orthovanadate, sodium vanadate, vanadium pentoxide; Selenium: disodium selenate, selenium sulfide, selenate, sodium selenate, sodium selenite; Cobalt: cobalt, cobalt chloride, cobalt nitrite, cobalt sulfate; Organometals: methyl mercury, lead acetate, triphenyltin, trimethyltin, phenylmercury acetate, methyl mercury chloride, copper acetate, sodium aurothiomalate, gold bisthiomalate complex, auranofin, aurocyanide, triethylphosphine gold chloride, mercury acetate,N-butyltin trichloride,N-butyltin hydroxide oxide,p-hydroxymercuribenzoate, ethyl mercury chloride, sodium acetate, sigma-hydroxy-n-butyl dibutyltin chloride, chromium acetate, methyl mercury hydroxide, cadmium acetate, mercury acetate, methoxyethylmercury acetate, Potassium acetate, ethyl mercuric phosphate, copper carbonate, copper oxalate, sodium lactate, calcium carbonate, manganese carbonate, cupric acetateCadmium1805453332021Copper135677131830Lead10642331687Mercury9621461856Zinc1022438101713Aluminium8311751140Arsenic6542914315Nickel391142418Chromium26124154Vanadium18711000Selenium1836621Cobalt1343042Total salts881240 (27%)261 (30%)164 (19%)100 (11%)117 (13%)Organometals13244 (33%)38 (29%)30 (23%)11 (8%)9 (7%)Total dose responses in the database56211546 (28%)1049 (19%)1942 (35%)646 (11%)438 (8%)Metals and the number of dose–responses by endpoint typein the hormesis databaseMetal saltsTotalGrowthMetabolicLongevity/survivalImmune responseReproduction/developmentMutagenic/cancerDamage/diseaseBehavioral endpoint is not included in the table; therefore, if the numbers do not add up to the total, the remainder was a behavioral endpoint.For a list of what is included in each metal category in the table seeTable 1.Cadmium180606813122421Copper13545302323401Lead10638282241200Mercury96355105401Zinc1022741250900Aluminium83414200000Arsenic65391750220Nickel39261020100Chromium2661530110Vanadium1851000201Selenium1851100110Cobalt137310002Total salts881334 (38%)326 (37%)74 (8%)43 (5%)90 (10%)6 (0.7%)6 (0.7%)Organometals13249 (37%)58 (44%)3 (2%)15 (11%)4 (3%)0 (0%)0 (0%)Total dose responses in the database56212627 (47%)1382 (25%)409 (7%)425 (8%)434 (8%)207 (4%)93 (2%)Metals and the number of dose–responses by percent maximum stimulatory response in an inverted-U shaped curvein the hormesis databaseMetal SaltsTotal≥110 < 150≥150 < 200≥200 < 500≥500 < 1000≥1000 (% Control)J-shaped curves only made up 4% of the total dose responses for metals; therefore, the a separate table was not prepared for the J-shaped responses.For a list of what is included in each metal category in the table seeTable 1.The total in this table may be different from the total number in other tables, the remaining dose responses are from J-shaped curves.Cadmium168103322265Copper13381252160Lead10364191910Mercury9047171463Zinc9943213041Aluminium8246211500Arsenic63458532Nickel392215101Chromium23183200Vanadium1771432Selenium1761622Cobalt11100100Total salts845492 (58%)163 (19%)140 (17%)31 (4%)16 (2%)Organometals12878 (61%)24 (19%)19 (15%)1 (1%)2 (2%)Total dose responses in the database51853024 (54%)1030 (18%)840 (15%)147 (3%)119 (2%)Metals and the number of dose–responses by stimulatory range in the hormesis databaseMetal salts≥1 < 10≥10 < 100≥100 < 1000≥1000TotalFor a list of what is included in each metal category in the table seeTable 1.The total in this table may be different from the total number in other tables because calculation of the range was not possible for all dose responses for various reasons (e.g.data presentation precludes exact determination of range).Cadmium404112497Copper62008Lead27167252Mercury19234046Zinc24115343Aluminium35142051Arsenic27162348Nickel9132024Chromium53109Vanadium32106Selenium51006Cobalt62008Total salts206 (52%)144 (36%)36 (9%)12 (3%)398 (100%)Organometals38 (54%)23 (33%)7 (10%)2 (3%)70 (100%)Total dose responses in the database1292 (51%)876 (35%)232 (9%)114 (5%)2514 (100%)The present analysis reveals that hormetic dose responses have been widely reported in the toxicological literature for a wide range of metals including aluminium (Al), arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), gold (Au), lead (Pb), mercury (Hg), nickel (Ni), selenium (Se), tin (Sb) compounds, vanadium (V), and zinc (Zn). However, the database indicates that the majority of the research on metals displaying a hormetic effect has been published in more recent years (i.e.after 1970) (data not shown) with cadmium being the metal most researched, followed by copper, lead, zinc and mercury.It commonly happens in research that the hormetic response is unexpected and not considered in the initial design of the study. This would explain the diverse study designs found in the hormesis database. Studies dealing with animal models comprise nearly 60% of the entries in the database, while plants make up about 30% (Table 1). The distribution ofin vivoandin vitrostudy designs differs markedly across metal. The types of endpoints demonstrating evidence of hormesis were principally reported for various growth and metabolic parameters (Table 2). However, hormetic effects have also been seen with longevity, immune response, reproduction, and development, as well as cancer and disease especially for Cd, Cu, Pb, and Zn.The quantitative features of the dose responses of the metals generally revealed that the amplitude of the stimulatory response was typically less than two-fold greater than the control value (Table 3), the width of the stimulatory response (Table 4) was almost always less than l00-fold, and the maximum stimulatory response was typically less than a factor of 10 below the zero equivalent point (ZEP) (data not shown). These features of the hormetic dose response for metals were quite similar for agents of other chemical classes.4These consistent features of the hormetic dose response are important in several respects including those relating to study design such as the number of doses and the spacing of the doses.Of particular note is that the range of biological endpoints measured for which the hormetic response was established was broad, including a wide range of tissues, cell types and functions. While the spectrum of hormetic dose–response relationships needs to be clarified, several responses were believed to be beneficial within the context studied. For example, the effects of Al on brain protein synthesis are thought to be adaptive;16,7the consumption of low doses of fluoride has been associated with optimal bone development;7low doses of Cd decrease testicular (Fig. 3),17as well as, increases fecundity in both daphnia18and fish (Fig. 4);19low doses of Pb increase the branching of neural cells (Fig. 5),20brain enzyme activity (Fig. 6),21springtail survival (Fig. 7);22low doses of Cu increase the survival of both springtails (Fig. 8)22and nematodes (Fig. 9)23and low doses of multiple agents (Cd, Hg, and Zn) increase phagocytosis in clams (Fig. 10).24These findings suggest that at least for some organisms the effects of low doses of normally considered toxic metals may have the potential to serve the health and survival of the affected species.Cadmium and rat testicular cancer (data from Waalkeset al.17)Effect of cadmium on egg production in the fathead minnow (Pimephales promales) (data from Pickering and Gast19).Effect of lead on neural cell branching (data from Crumptonet al.20)Effect of lead acetate on brain activity (in vitro) (data from Sandhir and Gill21)Effect of lead on springtail survival (data from Sandifer and Hopkin22)Effect of copper on springtail survival (data from Sandifer and Hopkin22)Effect of copper on nematode survival (data from Korthalset al.23)Effects of metals on phagocytosis in the clam,Mya arenaria, hemocytes (data from Brousseauet al.24)

ISSN:1464-0325    

DOI:10.1039/b400468j

出版商:RSC    

年代:2004

数据来源: RSC