Toxicity of Metal Compounds: Knowledge and Myths

Tutorial Cite This: Organometallics 2017, 36, 4071-4090

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Toxicity of Metal Compounds: Knowledge and Myths Ksenia S. Egorova and Valentine P. Ananikov* N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky prospect, 47, Moscow 119991, Russia ABSTRACT: Organometallic reagents and metal catalysts are used ubiquitously in academia and industry. Not surprisingly, the biological activity and environmental danger of metal compounds have become topics of outstanding importance. In spite of the rapid development of toxicology during the last decades, several common historically established “beliefs” are still frequently circulating in the organometallic community. In this Tutorial, we discuss existing opinions concerning (1) possibilities of toxicity measurements, (2) high toxicities of heavy-metal compounds, (3) correlation between the structure of a metal compound and its toxicity, (4) biological effect of direct/indirect contacts with metal compounds, and (5) dangers of metal nanoparticles. Basic concepts of toxicity studies and known data are described in the Tutorial step by step upon discussion of these issues. The main goal of this Tutorial is to demonstrate that the toxicity of a metal cannot be regarded as a constant property, since it depends on the oxidation state, ligands, solubility, morphology of particles, properties of the environment, and several other factors. As far as such chemically labile species as metal compounds are concerned, the nature of biological effects should not be assumed or taken for granted; indeed, reliable conclusions cannot be made without dedicated measurements. effects,24,26,40−43 studies on mechanisms of toxic effects,27,28,39,44−49 analysis and mathematical models,24,27,31,41,42,45,50−55 and interdisciplinary connection of toxicology with biology and medicine.27−29,31,56−63 In the present review, we will not repeat the topics discussed in detail in the literature. We will focus on the toxicity of metal compounds from the point of view of chemists working in the areas of organometallic compounds and catalyst development. In particular, longstanding beliefs circulating in the scientific community will be considered.64 In fact, many of these beliefs do not reflect the reality and can be called “myths”. Necessary basic concepts related to toxicity studies are introduced in the text upon consideration of the corresponding topics.

1. INTRODUCTION The rapid development of organometallic chemistry and catalysis in the recent decades has changed the face of modern chemical science and has made numerous breakthrough contributions to organic synthesis, pharmaceutical applications, chemical industry, materials science, energy research, and several other areas.1−9 Fundamental insights into the structures, properties, and reactivities of stable organometallic complexes and highly reactive intermediate species have driven paramount progress in the field. Nowadays, the ubiquitous use of metal complexes and nanoparticles as catalysts, as well as of metal-containing compounds as reagents, is an inherent component of chemical transformations and synthesis.1−18 Even more cutting-edge opportunities are expected in such areas as the development of selective catalysts to build molecular complexity, the tuning of nanoparticle reactivity with atomic precision, and the rational design of biocatalytic reactions with metal-containing active centers in enzymes.19−23 Such widespread use of metal compounds has highlighted the significance of environmental and toxicity issues. Minimization of inevitable harmful effects on living organisms and maintenance of cost-efficient solutions are required for sustainable development. The analysis of a complete life cycle of chemical processes (including recycling, waste management, and penetration of metal traces into the environment) emphasizes the importance of understanding the toxicity of metal compounds. Indeed, this area of toxicology is developing very rapidly and is being promoted by recent tremendous progress in molecular biology and health science. There are several excellent books and reviews dealing with general aspects of toxicity,24−31 measurements of biological activity,27,28,32−39 data on toxic © 2017 American Chemical Society

2. WHAT IS TOXICITY? There are several definitions of toxicity, and it is typically defined as “the ability of a chemical to cause a deleterious effect when the organism is exposed to the chemical”30 or the ability of a substance to cause “a harmful effect when administered, either by accident or by design, to a living organism”.28 A slightly different definition suggests to consider toxicity as “an adverse change from normality, which may be irreversible”,27 and this definition highlights an important role of reliable experimental measurements of the “adverse change” and “normality”. Adverse changes “affect the well-being of the organism, either temporarily or permanently”, whereas normality is considered “in statistical terms of the normal distribution”.27 This calls for a task to Received: August 5, 2017 Published: November 13, 2017 4071

DOI: 10.1021/acs.organomet.7b00605 Organometallics 2017, 36, 4071−4090

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relationship is employed if an observed effect belongs to the all or none category, that is, cannot be quantified, whereas the dose− effect relationship is exploited if the level of a chemical dose correlates with the quantifiable level of an observed effect.31 The following values are commonly used for characterizing acute toxicity. LD50: the median lethal dose, or the dose which kills 50% of members of a tested population LC50: the median lethal concentration, or the concentration at which 50% of members of a tested population are killed ED50: the median effective dose, or the dose which produces some “all or nothing” effect in 50% of members of a tested population EC50: the median effective concentration, or the concentration at which 50% of members of a tested population demonstrate some “all or nothing” effect LD50 and ED50 are usually expressed in milligrams of substance per kilogram of body weight, whereas LC50 and EC50 are normalized to the environment (e.g., milligrams of substance per liter of media). In the case of various inhibitory processes, IC50 is often used, which is the half-maximum inhibitory concentration, or the concentration at which a substance inhibits a particular process, e.g. an enzymatic reaction, by half. Note that these doses and concentrations can depend strongly on the administration route. Various indices of irritation and sensitization of skin, eyes, and mucosa are also employed, together with NOAEL (no observed adverse effect level, or the highest statistically nonsignificant dose tested) and LOAEL (lowest observed adverse effect level, or the lowest tested dose which imposes a statistically significant effect).28,31,42,65 According to these values, toxicity ratings of chemicals can be compiled. As an example, Table 1 shows the toxicity rating on the basis of the LD50 values for a single oral dose studied in rats.

separate adverse changes from normal variations or from beneficial effects, especially in the case of metals present in essential compounds or drugs (as intended components or as contaminants). The next point concerns the amount of a chemical compound considered; as the famous statement attributed to Paracelsus goes, “the right dose differentiates a poison from a remedy”.28 Modern toxicology addresses these issues by combining the achievements of biology, chemistry, and medicine for studying the possible toxic effects of numerous substances, both natural and artificial, from simple elements to large, complex molecules. The studies are often associated with various difficulties due to the complexity of processes in the living organism. Toxicity is usually manifested as a cascade of reactions, and understanding the mechanisms which cause the final toxic effect is often crucial for correct determination and prediction of the toxic potential of a given substance. In the present review, we start the discussion with denoting toxicity parameters and giving a brief description of measurement methods (section 3). The toxicity of metal compounds is considered next (section 4), followed by its possible correlation with the structure (section 5) and discussion of practical questions (section 6). Finally, a rather controversial topic of metal nanoparticle toxicity is considered (section 7).

3. MYTH 1: TOXICITY IS EASY TO MEASURE It is often believed that the toxicity of a given compound can be described by a direct parameter, which is relatively easy to measure. However, it should be pointed out that the results of toxicity measurements depend on many factors, including the exposure time, the dose administered, the measurement technique, and the nature of the biological object being affected. In terms of the exposure time, toxicity can be roughly divided into acute and chronic. Acute toxicity manifests “within a relatively short time interval after toxicant exposure (i.e., as short as a few minutes to as long as several days)”; it is usually caused by a single exposure to the chemical30 and is used as an indicator of a poisoning event or as a characteristic of the toxic potential of a substance. In contrast, chronic toxicity is manifested as sublethal effects after prolonged exposure, usually to small quantities of a toxicant (the exposure times are often a significant part of the estimated lifetime of the organism).30 In some cases, subchronic toxicity is considered, which is defined as “toxicity due to exposure to quantities of a toxicant that do not cause any evident acute toxicity for a time period that is extended, but is not so long as to constitute a significant part of the lifespan of the species in question” (30−90 days for mammals).30 Mechanisms underlying acute and chronic toxicity usually differ; however, these two types of toxicities cannot always be easily distinguished from each other, and in some cases acute toxicity can lead to chronic toxicity. It should be noted that the possibility of acute toxicity manifestation depends on the substance dose: even beneficial and safe compounds can cause acute toxicity when a sufficiently large dose is used. Still, the dose increase does not necessarily mean the development of chronic toxicity.26,28 Acute toxicity is measured by determining a dose−response relationship or by building a dose−response curve. According to the established definition, the dose−response relationship is “an association between the dose and the incidence of a defined biological effect in an exposed population, usually expressed as a percentage”.31 It should not be confused with the dose−effect relationship, which is “an association between the dose and the resulting magnitude of a continuously graded change, either in an individual or in a population”.31 Thus, the dose−response

Table 1. Example of Toxicity Ratinga,42

a

LD50, single oral dose tested in rats. Reproduced with permission from ref 42. Copyright 2002 Elsevier.

3.1. System Selection for Toxicity Measurements. The selection of a system for toxicity measurements is a very important part of the work, and usually the choice is governed by the problem being analyzed. More specific problems, such as the level of a concrete inhibitory effect imposed on a concrete protein, demand less complicated systems, whereas more general questions requires very sophisticated experimental schemes. In vitro systems, such as cell cultures or isolated proteins, are practical for large-scale preliminary screenings, when several substances are tested. However, studies on the safety of a chemical in humans requires the appropriate systems, as close to the human organism as possible. Among other things, the similarities in absorption, metabolism, and excretion of a tested 4072


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Figure 1. Evaluated parameters and key levels of toxicological studies: from organisms to individual molecules.66

Table 2. Comparison of Toxicity Studies Carried out in Vivo and in Vitroa param

in vivo

in vitro

level of response types of questions being asked by the study end points metabolism administration route life span species selection interpretation of results in general terms extrapolation to human

tissue, cell, cellular organelle simple one metabolic studies should be carried out separately limited limited more limited difficult very difficult

predictive capacity technical demands

whole organism complex many usually does not require separate metabolic studies flexible relatively long relatively wide (different species can be used if necessary) relatively easy relatively easy due to similarity of biochemical and physiological processes, as well as of mechanisms of toxicity relatively high (up to 70% of toxicities in human) generally low (in standardized cases)

costs (money and time)

high

a

fragmentary (potentially high for single end points) can be very high (many nonstandard, poorly reproducible cases) usually lower

Adapted and reproduced with permission from ref 27. Copyright 2008 CRC Press.

chemical should be addressed. There are a limited number of laboratory animals which are commonly used as in vivo test systems. Rodents, such as rat and mouse, are the most popular objects. In addition, ex vivo systems can be employed, when animals are sacrificed after receiving one or several doses of a chemical under study and their tissues are investigated.27 The key biological levels of organization at which toxicity can be studied include whole organisms (mouse, rat, rabbit, dog, monkey, and, in cases of incidental exposure, human), separate organs and tissues of these organisms, cells and organelles (usually in cell cultures), and individual molecules (nucleic acids, proteins, lipids) (Figure 1). Investigation of organs and tissues provides information on the accumulation and distribution of a toxicant, whereas at the levels of whole organisms, cell cultures, and individual molecules, quantitative data such as LD50, LC50, IC50, NOAEL, and LOAEL, can be obtained. Comparison of in vitro and in vivo investigations (Table 2) suggests the insufficiency of in vitro studies alone to be used as the basis of the toxicological profile of a substance. The main advantages of in vitro methods are their relative simplicity and low cost. However, these methods usually cannot provide any reliable data on the metabolism of a toxicant or its long-term effects, and their results cannot be extrapolated to higher organisms. Moreover, the standardization of in vitro studies can be rather difficult due to significant effects of even minor changes in conditions or composition. Nevertheless, in vitro experiments can be essential at the initial stages of toxicity investigation. A preparatory investigation is usually required for determining a correct dose level or range. Gradually increasing doses or concentrations of a chemical are applied to a system of choice until an expected reaction occurs, which means that a maximum tolerated dose level (MTD, the dose producing an “acceptable”

level of toxicity, or the dose that, if exceeded, will result in an “unacceptable” risk of toxicity67) or concentration has been achieved. In in vitro studies, a wide range of doses or concentrations is usually used.27 The Organization for Economic Co-operation and Development (OECD) issues special guidelines for various tests on acute, subchronic, and chronic toxicities, as well as reproductive and developmental toxicities, carcinogenicities, and immunotoxicities.68 3.2. In Vitro Studies. As can be seen from Table 2, the major advantage of in vitro systems is their simplicity, whereas their major disadvantage is their inability to mimic the inner structure of a complex organism and, in particular, chronic responses to a chemical. For in vitro studies, the mechanism of action of a substance should be known, and the compound should be watersoluble, because lipophilic substances can demonstrate poor penetration into an in vitro system.27 Nevertheless, these systems find extensive application in toxicological studies. Currently, the following in vitro systems are employed: isolated enzymes, subcellular organelles, cell cultures (including primary (freshly derived) and secondary (immortal) cultures and stem cells), tissue slices, intact organs, embryos, and fertilized eggs.27 In vitro studies usually produce EC50, LC50, and IC50 values, together with descriptions of corresponding deleterious effects observed in organs and tissues. Some common examples of using in vitro systems in toxicity studies (Table 3) show that they can assess a rather large number of various parameters and processes. Thus, dedicated cell cultures are employed for investigating organ toxicity, metabolism, kinetics, growth effects, mutagenicity, carcinogenicity, and ecotoxicity. Metabolic studies also often include enzymatic systems, whereas bacteria are useful for studying mutagenicity and ecotoxicity. 4073


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Organometallics Table 3. Application of in Vitro Systems in Toxicity Studiesa param/process studied target organ toxicity metabolism kinetics toxicity (viability/ growth inhibition) genotoxicity/ mutagenicity carcinogenicity reproductive toxicity irritation and corrosion ecotoxicology (viability/growth inhibition)

system type cell cultures (liver, kidney, nervous system, immune system, lung), tissue slices (nervous system, lung) enzymes, microsomes, cell cultures cell cultures (absorption, clearance studies) cell cultures, tissue slices cell cultures, bacteria cell cultures, bacteria, in silico cell cultures, embryo cultures, whole embryos, limb buds (organogenesis) organs, fertilized eggs cell cultures, bacteria, algae, Daphnia magna, ex vivo systems

a

Based on data from A Guide to Practical Toxicology and A Textbook of Modern Toxicology.27,28

The MTT/MTS colorimetric assay is among the most popular techniques used in preliminary in vitro studies on toxicity.35,69,70 A schematic representation of the MTS assay is provided in Figure 2. A stock solution of a compound under study (in this case, metal compounds are shown as examples) is used for preparation of the concentration gradient, which is applied to cells growing on a microplate (wells marked “metal + cells”). Since solutions of many metal compounds are colored and can influence light absorption, the same compound gradient is applied to empty wells, which contain the compound solutions only (wells marked “metal w/o cells”); afterward, this optical density is used for adjustment of the final values. Each test point is studied in triplicate for statistical averaging. Boundary wells are filled with phosphate-buffered saline (PBS) to avoid evaporation effects. After the plate is incubated for a particular time period (e.g., 24 h), MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) solution is added to all the test and control wells, and after additional 4 h, the optical density is measured. The assay is based on the ability of cellular NAD(P)H-dependent oxidoreductases to reduce tetrazolium dyes to purple formazan products (Scheme 1). Under certain conditions, the activity of such enzymes can be correlated with the number of viable cells in the culture. Figure 3 shows a typical picture of a resulting microplate after the experimental measurements (the difference between the living and dead cells can be easily seen). The three upper rows of wells (“salt + cells”) contain cells incubated with solutions of a metal salt; the three lower rows of wells (“salt w/o cells”) contain solutions of the metal salt without cells for adjustment of the salt influence on the final optical density values. The purple color corresponds to the living cells, which reduce MTS to a purple product. An exemplary dose−response curve for a plate-based assay, such as the MTT/MTS assay, is shown in Figure 4. In this plot, both negative (0%) and positive (100%) controls are present. 0% control does not contain a chemical under investigation, whereas 100% control contains a compound that provides the maximum possible response. Note that in Figure 4 the maximum activity of the test chemical is lower than that of the 100% control and, therefore, there are two different values for EC50/IC50: absolute and relative. The first is related to the activity of the 100% control; at this concentration the test compound produces half the activity provided by the 100% control. The second corresponds to the intrinsic maximum response of the test compound.36

Figure 2. General procedure of standard MTS assay (MTS = 3-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)2H-tetrazolium; PBS = phosphate-buffered saline).

3.3. In Vivo Studies. The number of species used for in vivo studies is rather limited, particularly due to ethical issues. 4074


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Scheme 1. Reduction of MTS (3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) by Cellular Oxidoreductase Enzymes in the Presence of PES (Phenazine Ethosulfate) to a Purple Formazan Product with an Absorbance Maximum at 490 nm in PBS

on the flora and fauna. Stable, water-soluble compounds can penetrate almost everywhere and can end up thousands of kilometers from the point of initial spilling. Thus, careful assessment of their dangers is a crucial task. Figure 5 shows an example of ecosystems that can be vulnerable to contamination by various pollutants. Similarly to studies on living organisms, apart from intrinsic toxicity, ADME (adsorption, distribution, metabolism, and elimination) of a chemical should be investigated. Among the issues under consideration are (1) physicochemical characteristics of a compound (solubility, volatility, adsorption, and desorption), (2) chemical behavior (stability, potential ways of degradation and elimination), (3) effects on bacteria and other microorganisms, and (4) effects on higher organisms (Daphnia magna, fish, earthworms, etc.). Both in vitro and in vivo models are employed in ecotoxicological studies. The usual parameters used for describing ecotoxicity are NOEC (no observed effect concentration) and LC50 (median lethal concentration).27,28 In summary, numerous factors should be accounted for when the toxicity of a substance is studied. Though simple laboratory tests can provide us with some information on the toxic potential of a given compound, these data are related only to special experimental conditions employed and are difficult to extrapolate to other organisms or to broader environmental effects. In spite of the aforementioned belief, toxicity is difficult to measure in one type of experiment and to describe by a single informative parameter.

Figure 3. Photo of 96-well microplate after MTS assay. A metal salt is used as an example, its concentration ranging from 25 mM to 1 μM, from left to right.

Currently, such investigations employ rodents (mice, rats, hamsters), rabbits, dogs, minipigs, and nonhuman primates. In vivo studies usually produce NOAEL, LOAEL, ED50, and LD50 values, together with descriptions of corresponding deleterious effects observed in organs and tissues. Table 4 shows examples of application of in vivo systems in studies on acute, subchronic, and chronic toxicities. The most common tests on toxicity include oral and inhalation (for volatile or particulate substances) tests, as well as eye and skin irritation and sensitization (in case of acute or subchronic toxicity). In the case of chronic toxicity, carcinogenic potential and reproductive toxicity are also assessed. 3.4. Environmental Toxicology. Environmental toxicology studies toxic effects imposed by chemicals on ecosystems, especially

4. MYTH 2: HEAVY METAL COMPOUNDS ARE VERY TOXIC From a physiological viewpoint, metals can be roughly divided into essential ones, which are required in the body for some

Figure 4. Exemplary dose−response curve for defining EC50/IC50 of a substance. Reproduced with permission from ref 36. Copyright 2011 Wiley-VCH Verlag GmbH & Co. KGaA. 4075


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Organometallics Table 4. Application of in Vivo Systems in Toxicity Studiesa type of toxicity

measd param

oral eye irritation dermal irritation and sensitization inhalation

LD50 subjective ranking subjective ranking

90 day tests

NOAEL

repeated dose dermal tests 28−90 day inhalation tests

subjective ranking

chronic toxicity and carcinogenicity

NOAEL, LDLo/LCLo, subjective ranking NOAEL, LDLo/ LCLo, subjective ranking

reproductive toxicity and teratogenicity

LC50

LCLoc

notes Acute Toxicity Other acute effects, such as cause of death, also can be derived. Cornea, iris, conjunctiva and eyelids are examined, and the observed effects are ranked on a numerical scale. Primary irritation, cutaneous sensitization, phototoxicity, and photosensitization are investigated, and the observed effects are ranked on a numerical scale. These tests are used when a supposed toxic agent is volatile or particulate. Adverse effects on the respiratory system and other organs can be studied Subchronic Toxicity Usually oral exposure is used. Appearance, food consumption, body weight, behavior, respiration rate, ECG, EEG,b blood, urine, and feces are surveyed. Such tests also can provide information on affected organs and the place of accumulation of a chemical. Tests are run for 21−28 days, and the observed effects are ranked on a numerical scale. Such tests are complicated because of difficulties in preparing stable aerosols; they provide information on the possibility for a given chemical to penetrate into an organism via lungs. Morphological alterations are also investigated. Chronic Toxicity Test substances are administered orally or by inhalation. The duration depends on the test animal (2 years for rats or mice). Appearance, food consumption, body weight, behavior, respiration rate, ECG, EEG, blood, urine, and feces are surveyed. Single- and multiple-generation tests are available. The fertility index, the number of live births vs total births, gestation duration, litter condition and survival, and other parameters are assessed.

a

Based on data from refs 28, 30, and 43. bAbbreviations: ECG, electrocardiogram; ECG, electroencephalogram. cLCLo/LDLo is the lethal concentration/dose low, the lowest concentration/dose of a chemical which leads to death of an individual animal.

Figure 5. Ecosystems possibly vulnerable to contamination by chemical pollutants. Reproduced with permission from ref 71. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.

cannot say: “this metal is very toxic” or even “this metal is more toxic than that one”. Such propositions can be applied only to particular compounds of particular metals, for which extensive toxicological information has been obtained. For example, the LD50 (oral rat) value of PtCl4 is about 300 mg kg−1, but for PtCl2 it is above 3400 mg kg−1.61 Therefore, according to Table 1, PtCl4 can be classified as “moderately toxic”, whereas PtCl2 is “slightly toxic”. This fact is illustrated by Figure 6, which shows “periodic tables of toxicity” of transition and post-transition metals. These tables are based on rat oral LD50 values provided in material safety data sheets (MSDSs) for all available compounds of particular transition and post-transition metals (Figure 6A), their chlorides (Figure 6B), and their oxides (Figure 6C). Thus, the toxicity of a given metal is highly dependent on its

functions, and nonessential ones, which are missing from the organism. The latter are sometimes opposed to the former as metals that impose toxic effects. Nevertheless, it has been clearly established that essential metals can be as dangerous as nonessential metals, if taken in excess.25,26,41,61 According to popular opinion, heavy metals present the highest danger to the environment.72−77 However, this notion has been receiving much criticism lately, and the assumed definition of “toxic heavy metals” should be avoided without dedicated assessment.31,61 When the toxicity of metals is discussed, it is often forgotten that biological properties of pure elements and of their compounds can differ greatly because of differences in solubility, oxidation state, bioavailability, etc. Thus, in many cases we 4076


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Figure 6. Toxicity of transition and selected post-transition metals. Relative toxicity estimation is based on (A) all compounds of transition and selected post-transition metals for which the data are available, (B) their chlorides, and (C) their oxides. The toxicity rating (D) is based on the corresponding table from Hazardous Chemicals Handbook.42 Rat oral LD50 values, in mg kg−1, from Sigma-Aldrich MSDSs are used as data sources, except for some cases, where mouse oral LD50 values from Sigma-Aldrich or data from Santa Cruz and Science Lab MSDSs are used. Metals for which no data can be found are shown in gray. Note that organometallic compounds are excluded from consideration.

(see also section 2), which should be replaced with multidimensional toxic profiles describing toxic effects of the metal with respect to its intrinsic characteristics, such as oxidation state, ligands, counterions, etc., as well as external features (biological object, environmental properties, etc.). Table 5 partially illustrates the notion by the example of simple compounds of chromium: depending on the oxidation state and composition, the toxicity of these chemicals varies from 52 to >15000 mg kg−1 (rat oral LD50). Notably, some chromium compounds are significantly more toxic than the corresponding compounds of “heavier” metals (rat oral LD50 values of 440 and 1302 mg kg−1 for CrCl3 and RhCl3, respectively).83 Similar pictures can be obtained for other metals (Figure 6). There is also a recent trend in chemical science and industry of arguing for the total dismissal of catalytic metal complexes and their replacement with organic catalysts. For comparative purposes, an overview of oral toxicity (LD50, oral rat) of selected inorganic metal compounds and organometallic compounds, in comparison with common solvents and poisons, is given in Figure 7. It can be seen that metal compounds do not invariably manifest higher toxicity, in comparison to common organic compounds. It should also be remembered that the picture can be rather different for toxic effects investigated in different test systems. However, at the moment, LD50 (oral rat) is the most studied toxicity parameter and, therefore, is utilized for the comparison. Such an alerted attitude against metal compounds has also influenced the field of metallodrugs. Sometimes a prejudice against metal-based drug candidates can be seen. Nevertheless, the discovery of high anticancer activity of cisplatin (cis-diamminedichloroplatinum(II), cis-Pt(NH3)2Cl2) has led to the appearance of numerous candidates for metal-based drugs.86,87 The metals used in these compounds include Pt(II) and Pt(IV), Pd(II), Ru(II), Au(I) and Au(III), Cu(II), Rh(I) and Rh(III), Ir(III), and others.88−90 These drugs bind to DNA or proteins, thus inhibiting crucial cellular processes.89 In order to kill tumor

state: e.g. nickel(II) and Zn(II) chlorides demonstrate moderate toxicity, whereas their oxides are practically nontoxic. 4.1. Recent Trends in “Green” and Sustainable Catalyst Development. Catalysis has become an integral part of modern science and technology. Both inorganic metal compounds and organometallic compounds are widely engaged as catalysts in the laboratory and industrial practice.61,78−80 From the viewpoint of waste management, the employment of catalysts in organic synthesis is seen as “the key to green and sustainable chemistry”.81 However, metal-based catalysts also can be dangerous, and in the case of widespread catalytic metals, such as nickel, copper, iron, palladium, platinum, etc., significant amounts of them penetrate the environment annually.61 Thus, the assessment of their toxicity should be an obligatory phase of the developmental procedure for every metal-containing catalyst. Currently, the acceptable content of metal impurities in various products, e.g. drug formulations, is regulated strictly by the ICH guidelines. The risk assessment includes the following principles: (1) identification of known and potential sources of metal impurities in the drug, (2) evaluation of a particular impurity in the drug, and (3) comparison with the established permitted daily exposure.82 It is generally assumed that so-called heavy metals (e.g., palladium, platinum, rhodium, etc.) are significantly more harmful than lighter metals (nickel, copper, cobalt, etc.). In fact, this statement is often employed to advocate the use of nickel- and copperbased catalysts.72−77 Lower costs of these abundant metals also promote their spread in modern catalysis. However, according to a recent analysis, the available data on the toxicity of simple salts of these metals, which are used in the preparation of more complex catalytic systems, do not support such a view.61 Moreover, it seems that, at the moment, there are no catalytically demanded metals for which comprehensive toxic “portraits” could be built. The reason for this flaw is in the lack of reliable data: as we state in the current Tutorial, the “general” toxicity of a metal (or any other element) can be a faulty concept 4077


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Data from Sigma-Aldrich MSDSs are used as the data sources. The coloring is based on the toxicity rating provided in Figure 6.

To summarize this section, two points should be mentioned. First, heavier metals are not necessarily more toxic than the lighter metals. Moreover, an opposite picture is often observed, depending on the compound (Figure 7). Heavier metals such as palladium, platinum, and rhodium can be as green as lighter metals (nickel, copper, etc.), if handled properly within the catalytic process. From a toxicity viewpoint, there is no clear evidence for marking heavy metals as non-green in catalyst development or organometallic chemistry. Second, in general, the toxicity of regular metal complexes corresponds to the low or moderate level and can be below the values typical for popular organic compounds (Figure 7), which does not support the “toxic metal” belief.

cells, metallodrugs must possess high cytotoxicity per se; however, this also often means high systemic toxicity. As with other drugs, this disadvantage should not be seen as a stumbling block in the application of metallodrugs. It can be controlled by optimizing the structure of metal compounds and also can be conceptually improved by the development of metal prodrugs or systems for target delivery.91−93

5. MYTH 3: TOXICITY CAN BE ROUTINELY CORRELATED WITH STRUCTURE AND COMPOSITION OF METAL COMPOUNDS There is a common misconception that the composition and structure of a compound can be directly correlated with its toxic effects. To get an insight into this topic, two powerful external factors influencing the toxicity of a chemical should be

Table 5. Comparison of Acute Toxicities of Various Compounds of Chromiuma

a

Figure 7. Overview of toxicity of inorganic metal compounds (by examples of chlorides and oxides), organometallic compounds (by examples of organotins), common solvents, and poisons. LD50 (oral rat, mg kg−1) values are shown on a logarithmic scale84 (TCDD = 2,3,7,8-tetrachlorodibenzo-pdioxin). Based on the data from refs 24, 83, and 85. The coloring corresponds to the toxicity rating provided in Figure 6. 4078


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next subsection, we will discuss the special case of metal compounds: that is, organometallic compounds. 5.1. Organometallic Compounds in the Environment. Organometallic compounds represent a special case for toxicity studies. Due to the presence of metal−carbon bonds, several transformations can occur under physiological conditions (upon contact with biological fluids). Thus, the toxic effect may be caused not only by the organometallic compound itself but also by the corresponding degradation products. Some organometallic compounds are also volatile, which facilitates their distribution in the environment.24 In the aqueous environment, organometallic compounds are prone to various transformations of both abiotic and biotic nature, such as degradation (hydrolysis) and alkylation. Many (though not all) metal alkyl and aryl derivatives undergo hydrolysis, resulting in metal hydroxide and hydrocarbon. The stabilities of several organometallic compounds in water are summarized in Table 6. Some metals (e.g., palladium and platinum) can form

considered: its transformations in the environment and the nature of the biological object being affected. Here, we will briefly discuss the former, whereas the latter will be dealt with in section 6. Metal ions can precipitate, adsorb, or form complexes, which, in turn, can undergo various transformations (Figure 8). In nature,

Table 6. Examples of Stability of Organometallic and Organoelement Compounds in Watera

Figure 8. Transformations of metal ions in the aquatic environment. There is an equilibrium among free ions, organic/inorganic complexes, and metal bound to organic/inorganic particles. Adapted and reproduced with permission from ref 31. Copyright 2015 Elsevier.

compound R2Hg, R4Sn, R4Pb (CH3)nSn(4−n)+

many metals are found as oxides and sulfides in minerals and ores. Industrial waste airborne particles also often contain metal oxides. Indeed, there are several studies addressing the toxicological properties of metal oxides and also sulfides. However, due to high water solubility, chlorides and acetates are the most popular subjects of toxicological studies. Solubility is one of the major drivers of toxicity, because it affects bioavailability of a chemical. Still, it should be remembered that, whereas the water solubility of a chemical is a good indicator of its solubility in biological fluids, the latter can differ from the former because of differences in pH and the presence of possible organic ligands in living organisms.25,31 As a representative example, a study on cadmium chloride, cadmium sulfide, and cadmium oxide administered into rat lungs can be considered. The lung tissues were collected after a 30 day period, and the three compounds demonstrated similar retention half-times, in spite of significant differences in their water solubilities. However, their distribution in the lung, kidney, and liver differed considerably, evidencing differences in dissolution/penetration of these chemicals in the organism.31 In the aqueous environment, metal compounds are prone to hydrolysis, which may lead to the formation of an insoluble product25,31 or release of potentially dangerous compounds (e.g., hydrogen chloride is released upon the hydrolysis of FeCl3).61 Since oxidation−reduction (redox) processes are widespread in biological systems, the redox potential of a metal also can influence its biological activity. Even essential metals with important biological functions can cause severe damage. Thus, copper and iron are known inducers of oxidative stress. If a metal possesses the corresponding redox potential, it can interfere with the reactions occurring in the living cells and can produce harmful highly reactive oxygen species (ROS), as in Fenton’s reaction:25,29,31,61

(CH3)3Pb+ (CH3)2Pb2+ (CH3)2As+ CH3As2+ (CH3)2AsH, CH3AsH2

stability and water solubility stable, slightly soluble, diffuse to atmosphere; higher alkyls less stable and less volatile soluble, methyltin units stable but made hexa- and pentacoordinate by H2O, OH−; species are solvated, partly hydrolyzed to various hydroxo species soluble, hydrolyzes as methyltins above; dismutates to (CH3)4Pb and (CH3)2Pb2+ at 20 °C soluble as (CH3)3Pb+; slowly disproportionates to (CH3)3Pb+ and CH3+; these reactions cause eventual complete loss of (CH3)3Pb+ and (CH3)2Pb2+ from water hydrolyzes to (CH3)2AsOH, then to slightly soluble [(CH3)2As]2O hydrolyzes to CH3As(OH)2, then to soluble (CH3AsO)n insoluble, diffuse to atmosphere, air-unstable

a

Adapted and reproduced with permission from ref 24. Copyright 2003 Wiley-VCH Verlag GmbH & Co. KGaA.

hydrolytically stable metal−carbon bonds. In the aqueous environment and sediments, organometallic compounds are often coordinated with sediments and particulate matter. For volatile compounds, their photochemical stability also should be considered; the lifetime of organometallic species in the atmosphere is relatively short (from hours to days), and as a result of their decomposition, metals and hydrocarbons are formed.24,94,95 The difference in behavior between coordination compounds and organometallic compounds can be pronounced. In many coordination compounds, rather labile metal−ligand bonds can be a reason for metal release and can provide a direct access to the metal center. In contrasts, in many organometallic compounds (if stable metal−carbon bonds are present) transformation of the ligand framework on the periphery of the metal center can occur first. As reported for transition metals, the strength of the metal− carbon bond depends on the type of the carbon atom and follows the trend M−Csp > M−Csp2 > M−Csp3.96 Thus, understanding the reactivity and stability of metal−carbon bonds is of primary importance to reveal the biological effect of organometallic compounds. Organometallic compounds of biogenic origin are present in nature. Methyltransferases from bacteria, fungi, and algae, as well as from higher organisms, can transfer methyl groups on a metal.97 Metal−C bonds can be found in some bioorganometallic

Fe 2 + + H 2O2 → Fe3 + + •OH + OH−

Apart from the intrinsic physicochemical properties of a compound, the manifestation of its toxicity is directly related to its bioavailability, which depends strongly on mechanisms of its absorption and elimination from the organism, as well as on routes of exposure. These topics are covered in section 6. In the 4079


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complicated;52 their possible biogeochemical cycle is shown in Figure 9. A brief comparison suggests that organometallic compounds possess higher toxicity in comparison to inorganic metal salts (Table 7). Tributyltin(IV) has a dramatic harmful effect on aquatic life and therefore is considered one of the most toxic human-made compounds.52,99,100 Organotin(IV) cations are highly prone to the formation of complexes with ligands of both inorganic (hydroxide) and organic (acetate, malonate, succinate, lactate) origins available in the environment. Inside the organism, organotin(IV) compounds are supposed to interact with thiol groups of proteins, thus leading to their irreversible inhibition.24,52 Nevertheless, the absolute values of toxicity of organometallic compounds can be similar to those of some organic compounds, solvents, etc. (see Figure 7). Overall, it is hardly possible to draw a direct rule for correlating the structure with toxicity, neither for inorganic/organometallic compounds nor for pure organic molecules. In summary, the toxicity cannot be easily correlated with the structure and composition of metal compounds. Such correlations can be drawn only within a particular test system and are difficult to generalize. Moreover, in the case of organometallic compounds, it is a challenge to identify the structure that causes the most pronounced toxic effect. Due to liability and facile reactivity of metal-containing compounds, they can undergo profound structural transformation before affecting living organisms.

complexes, such as cobalamin, and in active centers of various enzymes (carbon monoxide dehydrogenase, hydrogenases, reductases). In contrast to biomethylation, bioalkylation is a significantly rarer event, though it can occur for arsenic, tin, lead, mercury, etc. Still, the most problematic biologically active organometallic components are human-made. These chemicals include tri-n-butyltin compounds and tetraethyllead, which have proved to be rather stable and harmful for ecology. Moreover, inorganic metal compounds can be transformed into organometallic ones via alkylation or carbonylation (biotic or abiotic) in the environment.24,52 Numerous studies on environmental transformations, bioaccumulations, and toxic effects of organotin, organolead, organoarsenic, and organomercury compounds have been accumulated so far. Organotins are among the most studied organometallic compounds in terms of toxicology, because of their considerable industrial value. Therefore, here we will briefly discuss the ecological dangers of these chemicals. The tin−carbon bond is resistant to water, atmosphere, and heat and is sensitive to UV radiation, strong acids, and electrophilic agents.24 As with other compounds, the solubility of organotins strongly depends both on their composition and on environmental factors, such as pH, presence of possible ligands in solution, etc. Triorganotin(IV) compounds are generally poorly soluble, whereas di- and monomethyltin(IV) chlorides possess high water solubility. In the absence of coordinating ligands, there are cations or various hydrolysis products of organotins in solution. Though adsorption of organotins is supposed to be reversible, these compounds can stay in sediments for a considerable time, therefore imposing long-term environmental effects. They are rather stable substances; still, their degradation and subsequent transformation into inorganic tin species can occur via biological or abiotic decomposition. The ways of transformation and bioaccumulation of organotin compounds can be rather

6. MYTH 4: AVOIDING CONTACTS WITH METALS In daily laboratory practice, a researcher usually deals with small quantities of metal compounds, which do not cause poisoning if handled properly. However, a different view should be taken upon consideration of large-scale industrial processes. Significant

Figure 9. Possible biogeochemical cycle of organotin compounds. The routes listed are (a) bioaccumulation, (b) deposition or release from biota, (c) biotic or abiotic degradation, (d) photolytic degradation resulting in production of free radicals, (e) biomethylation, (f) demethylation, (g) disproportionation reactions, (h) sulfide-mediated disproportionation reactions, (i) SnS formation, (j) formation of methyl iodide by reaction of dimethyl β-propiothein (DMPT) with aqueous iodide, (k) CH3I methylation of SnX2, (l) oxidative methylation of SnS by CH3I with formation of methyltin triiodide, and (m) transmethylation reaction between organotins and mercury. Abbreviations: R, organic moiety; X, anion. Reproduced with permission from ref 98. Copyright 2000 Elsevier. 4080


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Organometallics Table 7. Comparison of Acute Toxicities of Metal Salts and Organometallic Compoundsa

a

Oral LD50, in mg kg−1. The coloring is based on the toxicity rating provided in Figure 6.

amounts of metal (in overall) may penetrate into the environment as contaminants in various products, as components of wastes, or in the case of emergency. Therefore, considering different pathways of interactions of metal compounds with the environment and routes of exposure is of primary importance. 6.1. Routes of Exposure. There are numerous ways for a chemical to enter the human body upon occupational or environmental exposure; it can be inhaled, ingested, and injected or it can make contact with the skin. The point of entry is also important; thus, subcutaneous, intravenous, intramuscular, and intraperitoneal injections can produce different toxic effects in the organism.28 If we leave aside the intentional administration of chemicals for experimental or medical purposes, metals and their compounds usually penetrate the human body with food, water, and air, as well as through the skin. In the air, metals are mainly present as aerosols (airborne particulate matter), which form from the Earth’s crust and are released as industrial wastes. The metal content and size of particles in these aerosols depend on their source; they are known to include iron, aluminum, magnesium, zinc, nickel, copper, cobalt, chromium, vanadium, manganese, lead, and other metals. However, for humans, food and drink are the major sources of metal exposure. Similarly to air, food and water contain metals due to their natural occurrence on Earth and, in some cases, due to industrial activities. Considerable penetration through the skin has been observed for compounds of some metals, such as chromium, copper, lead, and mercury, especially in cases of occupational exposure.26,29,31,41 Figure 10 shows the main routes by which a metal compound can affect the human organism. In the following subsections, we will discuss some of these routes in more detail. 6.2. Absorption and Deposition. The human body reacts to the appearance of a toxic chemical, as well as to imbalances in concentrations of essential compounds, by activating several protective mechanisms, which operate at the levels of (1) the

Figure 10. Routes of exposure, distribution, and clearance of metal compounds in the human organism.101

respiratory tract (pulmonary alveolar macrophages consume inhaled particles), (2) the gastrointestinal tract (efficiency of ion adsorption can be modulated), (3) the intestine (intestinal microbiota detoxifies potentially harmful ions), (4) the epidermis (strong binding of metal ions modulates absorption through the skin), and (5) extra- and intracellular metal-binding proteins, which modulate the transport and metabolism of metals.58 Nevertheless, these mechanisms often cannot fully alleviate the harmful effects of a chemical. After penetrating into the lung (with air) or gastrointestinal tract (with food or water), a metal is deposited on the airway 4081


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Thus, an intricate network of transporters, carriers, and chaperons is required for safe handling of copper in the organism.61,94,103−105 Similarly, Fe3+ should be reduced to Fe2+ to be absorbed by the duodenum. Since iron ions are prone to participation in redox reactions, they are “detoxified” by binding to various protein ligands, such as hemoglobin and ferritin. The digestive environment also has a significant effect on the ligands of metal species.61,94 Compounds of nonessential metals also undergo various transformations inside the organism. Among the most studied examples is the cellular mechanism of action of the anticancer agent cisplatin. Inside the cell, cisplatin undergoes ligand substitution due to a significantly lower concentration of chloride ions in the cytosol, in comparison to the extracellular matrix, with the formation of cationic solvated products. These products can efficiently bind DNA, which in turn hinders cell division and ultimately leads to cell death.86,87,106 Thus, metabolic transformations may toxify or detoxify a given metal compound. Such transformations can present an attractive opportunity of developing metal drugs, which would be lethal to single-cell organisms (bacteria) and nontoxic to humans. The issue of metabolism also raises the point of the time dependence of biological activity (toxicity) manifestation. 6.3. Clearance. The biological half-time of metals in the organism significantly varies both between metals and between organs. Clearance of particles from the respiratory tract is defined by the place of deposition. Thus, particles in the extrathoracic or tracheobronchial regions can be removed by sneezing or nose blowing, dissolution and absorption into the lymph or blood, and endocytosis by epithelial cells or phagocytes, whereas particles in the alveolar region can be cleared by dissolution and absorption into the lymph or blood, endocytosis, and transfer into the systemic circuit. When airborne particles first penetrate into the respiratory tract, their short-term clearance is preferentially realized by the ciliated epithelium, which drives mucus toward the pharynx, where it can be swallowed and can subsequently enter the gastrointestinal tract. Deficiencies in the mucosal transport are often associated with clearance disturbances. If particles are deposited in the regions lacking the ciliated epithelium, their clearance occurs significantly more slowly. Phagocytes realize long-term clearance in the distal airways and alveoli. Such particles also can dissolve in body fluids and penetrate into the lymph or blood system.31 The main routes of metal excretion from the gastrointestinal tract are via the intestinal mucosa into the GI lumen and from the liver with the bile or from the pancreas with the pancreatic juice. After excretion in the bile, a metal can be reabsorbed in the GI tract, thus entering the enterohepatic recirculation (Figure 10). Many metals are also eliminated from the body via renal excretion. Metals bound to low-molecular-weight proteins can be cleared from the plasma into the tubular fluid of the kidney.31 Apart from these major routes of elimination, metals also can be removed from the body with saliva, perspiration, expiration, lactation, skin, hair, and nails (Figure 10).31 For more details about clearance topic, see refs 28, 29, 44, and 57. 6.4. Skin Sensitization. A special case of adverse effects imposed by metals on the human organism is allergic contact dermatitis (ACD), which is an inflammation reaction of the skin caused by a contact with a chemical. Ten to fifteen percent of humans are supposedly subject to contact hypersensitivity to metals. The most common case is allergy to nickel; thus, about 15% of the human population suffer from hypersensitivity to nickel(II) sulfate. This is followed by cobalt chloride and

walls or is absorbed by the mucosa; from there, a part of the metal is transferred into the circulation systems of the organisms. The fate of airborne particles directly depends on their size. The place of their deposition is dictated by their mass median aerodynamic diameter (MMAD).102 Thus, particles with MMADs larger than 10 μm and smaller than 10 nm are usually caught in the nasal passages, whereas those in between penetrate into the lung alveoli more efficiently. Since the nose filters off particles significantly more successfully than the mouth, the fraction of deposited particles depends on the mode of breathing. Apart from the size, the shape, hygroscopicity, and surface charge also affect the deposition of a particle. In the respiratory tract, particles can deposit by impaction (mostly for larger particles in the nose, throat, and larger bronchi), sedimentation (mostly for larger particles in the alveoli and smaller airways), or diffusion (for submicrometer particles).31 Metal compounds can enter the gastrointestinal (GI) tract with food and drink or with mucus, after being cleared from the respiratory tract. Other sources of metals in the GI tract are bile and pancreatic fluids, together with exfoliated intestinal mucosal cells. Intestinal microflora can oxidize or reduce metal compounds, therefore affecting their absorption and excretion from the GI tract. The chemical form of a metal determines its absorption, and the difference is especially pronounced when inorganic and organic metal compounds are compared (e.g., methylmercury, 90% absorption; inorganic mercury(II) salts, 100 days) very low less readily endocytosed medium low medium sufficient for tumor induction medium

high high very rapid (1−2 days) high not endocytosed none already dissolved very low insufficient for tumor induction not detected

insoluble intermediate slow (30−50 days) low not readily endocytosed low low low insufficient for tumor induction not detected

a

Based on Figure 1 from ref 112. bData from refs 44 and 113. 4083


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Organometallics Table 9. Acute Toxicity of Organotin Compoundsa

charge, and reactivity.48 Thus, the toxicity of CuO nanoparticles toward sea urchin (Lytechinus pictus) was suggested to be significantly alleviated by the presence of impurities.118 Some examples of the factors governing the environmental fate and toxicity of nanoparticles are provided in Table 10. Accordingly, the assessment of the environmental effect of nanoparticles is supposed to be a complex and time-consuming procedure (Figure 13). Metal nanoparticles have been shown to induce various toxic effects, including cytotoxicity, oxidative stress, and DNA damage.47,49,61,117 There are standardized in vitro and in vivo approaches for estimating the toxicity of nanoparticles. However, such studies often produce contradictory results, and multiple cell type based assays and multiple doses are strongly recommended due to frequent discrepancies among the data obtained in different biological systems. Moreover, surface defects also hinder the characterization of nanoparticle toxicity, and different samples of the same material can manifest different toxic effects. Therefore, more repetitions of experiments are often required to obtain statistically relevant data, in comparison to the case for soluble metal salts. In the case of metal nanoparticles, thorough characterization is especially important, because the behavior of a certain particle depends strongly on the environment (see examples in Table 11).47,48,115,117 Metal nanoparticles seem to be able to penetrate the human body via almost every route available.61,115 They are suggested to violate the blood−brain barrier, therefore entering the brain.120 Metal nanoparticles are also supposed to be able to enter small capillaries, which facilitates their efficient distribution throughout the body.115 Exact mechanisms of nanoparticle-induced toxicity have not yet been revealed. Among the most frequently discussed mechanisms are the ROS generation and effects imposed by released metal ions. Nevertheless, in some cases the observed toxicity could not be linked to either of these phenomena.47,48,61 Other suggested explanations include electrostatic interactions between the cell surface and nanoparticles: thus, negatively charged bacterial membranes can attract positively charged metal nanoparticles, which can result in disruption of the lipid bilayer. These observations are further confirmed by the influence of the charge or presence of surface adsorbates on the toxicity of nanoparticles.47 The cell is the ultimate target, at which metal nanoparticles exhibit their cytotoxic activities. An overview of metal nanoparticle properties affecting the cellular processing is given in Figure 14. Metal nanoparticles can enter the cell by utilizing various pathways, which depend on the nanoparticle size, surface morphology, and possibility of interactions with certain proteins or lipids, but the first contact between the nanoparticle and the cell is usually electrostatic. Then nanoparticles are enclosed by the cellular membrane and are uptaken by the cell via endocytosis; hydrophobicity and small size are thought to correlate directly with higher uptake. The fate and toxicity of nanoparticles inside the cell is closely related to their stability. The acidic environment of lysosomes can cause oxidation, reduction, or dissolution of the nanoparticle surface, and the resulting chemical modifications and metal ions can be subsequently released into the cytoplasm, where they can inhibit thiol groups of cellular proteins, facilitate the production of free radicals, and impose other toxic effects. Nondegradable metal nanoparticles can accumulate inside the cell or can be eliminated, possibly via exocytosis.49,117 All in all, metal nanoparticles represent an extremely complex subject to explore in terms of biological activity and effect

Oral LD50, in mg kg−1. Adapted and reproduced with permission from ref 24. Copyright 2003 Wiley-VCH Verlag GmbH & Co. KGaA. The coloring is based on the toxicity rating provided in Figure 6.

a

uptake. Similarly, organolead and organomercury compounds also manifest neurotoxicity.24,52 In summary, it is hardly possible to avoid contacts with metalcontaining species in the modern urban society. Under real-life conditions metal-containing contaminants can penetrate into the living organisms via different pathways, and the overall observed effect can result from various contributions.

7. MYTH 5: ALL NANOPARTICLES ARE TOXIC Metal nanoparticles are applied in various industrial and engineering fields, and the amount of their production keeps increasing annually, which is accompanied by the corresponding increase in their content in the environment. Eventually, metal nanoparticles are released into water and soil, ending up in the aquatic surroundings and ecosystems.48,61,114,115 There are broadly discussed controversial opinions on the toxicity of nanoparticles, presenting them from extremely toxic to almost harmless. Thus, metal nanoparticles deserve a special consideration within the scope of this Tutorial. In contrast to molecular compounds, the toxic effects of metal nanoparticles are considered to be governed by both composition and morphology, the latter being most important for the selection of the uptake route, via which the particle penetrates the organism and, eventually, the cell.61 Moreover, metal nanoparticles are prone to undergo various transformations in the environment (Figure 11),116 and their chemical stability can be one of the major factors controlling the biological activity of the species, which finally affect an organism.114,117 Figure 12 shows common routes of interactions of metal nanoparticles with aquatic ecosystems. The manifestation of metal nanoparticle toxicity is supposed to be related to (1) nanoparticle morphology, including size and surface properties, such as defects, (2) chemical composition, (3) stability, including solubility and reactivity, and (4) redox transformation of the particle surface which can lead to oxidative stress.47−49,114 It should be noted that the presence of contaminants and natural organic matter also can affect the nanoparticle toxicity, in particular, by influencing the surface morphology, 4084


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Figure 11. Possible reactions of nanoparticulate materials in natural aquatic media (nanoiron oxide particles (NIOPs) are used as examples). Abbreviations: Df, fractal dimension; NOM, natural organic matter; RNIP, reactive nanoiron particles. Reproduced with permission from ref 116. Copyright 2014 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 12. Release, transformations, transport, and uptake of metal nanoparticles (MNPs) in an aquatic environment. Abbreviations: NOM, natural organic matter; ROS, reactive oxygen species. Reproduced with permission from ref 48. Copyright 2017 Elsevier. 4085


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Organometallics Table 10. Factors Influencing Fate of Metal Nanoparticles (MNPs)a MNP TiO2 CeO2 CuO ZnO ZnO Fe/Al oxides a

factorsb

mechanism

contaminant (Cd) pH, NOM, agglomeration, dissolution pH, NOM, agglomeration, dissolution temperature, organic acid coating, carbonate salts, shape contaminant (E. coli), pH, ionic strength

comment

adsorption release of Ce2+

contaminant affinity impacts MNP fate primary factors: solution pH and amount of suspended NOM; dissolution of CeO2 is negligible over 7 days

release of Cu2+

extent of agglomeration affects toxicity of CuO NPs

dissolution of ZnO and release increasing temperature leads to increased aggregation and subsequently to decreased dissolution of Zn2+ dissolution, aggregation uncoated ZnO dissolves faster; presence of Ca2+ facilitates aggregation; rod-shaped NPs are more toxic than spheres due to faster dissolution and larger contact area adsorption, nonelectrostatic electrostatic charge is a primary factor of adsorption of E. coli on model MNPs; adsorption of and electrostatic forces E. coli decreases isoelectric point of Fe/Al oxides

Reproduced with permission from ref 48. Copyright 2017 Elsevier. bAbbreviation: NOM, natural organic matter.

Figure 13. Assessment of environmental impact associated with exposure to nanomaterials. Abbreviations: HT Exp., high-throughput experiments; LT Exp., low-throughput experiments; nano-SAR, nanostructure−activity relationship. Reproduced with permission from ref 119. Copyright 2013 American Chemical Society.

Table 11. Factors Influencing Toxicity of Metal Nanoparticles (MNPs)a MNP

factors

TiO2

Cd; size of TiO2 polymer coating salinity

CuO ZnO ZnO Al2O3 a

pH As(V) (pollutant)

target organism Pseudokirchneriella subcapitata (green alga) Chlamydomonas reinhardtii (green alga) Thalassiosira pseudonana (marine diatom) Folsomia candida (springtail) Ceriodaphnia dubia (water flea)

toxic effects decreased bioavailability of Cd2+ due to sorption/complexation of Cd2+ ions to the TiO2 surface; combined toxic effect of TiO2 and Cd increased toxicity of polymer-coated CuO due to increased accessibility to cells increasing salinity decreases toxicity; release of bioavailable Zn2+ affects cell activities increasing pH decreases toxicity; bioavailability of Zn depends on NP dissolution adsorption of As(V) onto Al2O3 renders the latter more toxic

Reproduced with permission from ref 48. Copyright 2017 Elsevier.

on living organisms. Without dedicated measurements, regular assumptions (even those proven for corresponding metal salts) should not be used to describe the biological properties of metal nanoparticles. Equally important, higher toxicity should not be automatically attributed to nanoparticles without an experimental proof. The data accumulated so far are insufficient to obtain a general picture of nanoparticle dangers. Currently, the only thing we can state with certainty is that every case can be unique, and

comprehensive studies are required for revealing universal patterns of nanoparticle toxicity.

8. CONCLUSIONS As a summation of the discussion and experimental data, the following points should be mentioned. 8.1. Belief #1: Toxicity is an Easily Measurable Property of a Metal Compound. To our regret, the facts are 4086


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possible transformations of the compound inside the biological system. 8.4. Belief #4: Avoiding Direct Contact with Metal Species Can Solve the Problem. In the modern urban society, we interact with metals daily, including metal contaminants in water, food, and air, as well as metal traces in industrial products (drugs, plastics, etc.). Complete avoidance of such indirect (nonintended) contact with metal-containing components is nearly impossible. In routine laboratory practice, a researcher usually deals with small quantities of metal compounds, which are safe if handled properly. However, in large-scale industrial processes significant amounts of metals can enter the environment. It should be remembered that the data collected in the laboratory are often hard to extrapolate to the industrial practice due to differences in quantities of chemicals and routes of their operation. Thus, we should be aware that, in real life, metalcontaining compounds can affect the living organisms in different ways, and the overall adverse effect develops due to various contributions. 8.5. Belief #5: All Nanoparticles Are Toxic. Nanoparticles in generaland metal nanoparticles in particularare tricky objects. Their transformations in the environment are often intricate and difficult to predict. Thus, it is hard to establish which exact substance finally interacts with an organism and causes deleterious effects. Now we can state only that each nanoparticle is a unique case, and each unique case demands dedicated measurements. The accumulated data are insufficient for attributing harmful properties to all metal nanoparticles. The main message of this review is that the toxicity of a metal should not be seen as a persistent characteristic: it can vary depending on the oxidation state, ligands, solubility, and morphology of the compounds and also can be affected greatly by the environment. Currently, the employment of toxicity data often involves only rather specific issues or particular cases, which are by far insufficient to make ultimate deductions and assumptions and are the cause of various misbeliefs persistent in the scientific community. Only comprehensive, multispecies, and multiassay studies can solve the problem. Such studies should provide both toxicological and environmental assessments of a particular compound, as established by OECD and other guidelines. Possible metabolic transformations of this compound in a given organism should also be considered. Most importantly, thorough documentation of all experimental protocols should be provided. The available research data often lack crucial descriptions and conditions and thus do not allow direct comparison of toxicity values measured by different research groups.121 At the moment, there are not enough data for comprehensive evaluation even of the most widespread metal compounds. Another level of complexity is anticipated, because catalytic systems are known to generate a variety of metal species, to form “cocktails” of catalysts and dynamic catalytic systems.21 In this case, different metal species (such as metal salts, metal clusters, and metal nanoparticles) are generated in situ during the catalytic reaction and can be simultaneously present in the reaction mixture. Revealing the toxic effect of a “cocktail” of catalysts would require building a comprehensive toxicity profile and deciphering the mechanisms of toxicity. Undoubtedly, our limited knowledge on toxic effects of metals currently provides more questions than answers. The increasing importance of the area will stimulate tremendous research activity, and many seminal discoveries should be anticipated in the near future.

Figure 14. Physicochemical properties governing cellular processing of metal nanoparticles. Reproduced with permission from ref 49. Copyright 2013 American Chemical Society.

unfavorable: the outcome of toxicity determination is governed by numerous factors, which are often difficult to forecast. In each particular case, the outcome depends on selecting appropriate test systems and techniques. At the moment, it is virtually impossible to obtain the “full picture” of all possible toxic manifestations of a substance once in the environment; however, the scientific community has developed sophisticated methods and frameworks that allow building rather realistic toxic profiles. 8.2. Belief #2: Heavy Metals Correspond to More Toxic Compounds in Comparison to Lighter Metals. Surprisingly, this belief seems ungrounded. The existing experimental data do not support the notion of toxic heavy metals and benign lighter metals. In the first place, it should be remembered that there is no such property as “general toxicity” of an element. Toxic features of a metal depend on its oxidation state, ligands, etc., and we can operate only with the values of toxicity of particular compounds measured under particular conditions. In the case of nanoparticles, their morphology and size are also of major importance. Thus, some compounds of palladium and platinum can be significantly less toxic than the corresponding compounds of “essential” nickel and copper. In overall, metal complexes demonstrate moderate toxicity in comparison to solvents and many other organic compounds. 8.3. Belief #3: Toxicity Can Be Directly Correlated with the Structures of Metal Compounds. No, as a general rule it cannot. Rather, such correlations are possible only for a limited number of compounds in a particular test system. Usually, no reliable extrapolation from one system to others can be made. The reason for this difficulty is in external factors governing the manifestation of toxicity of a given compound under given conditions, namely the nature of the test object, which also determines 4087


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(14) Fairlamb, I. J. S.; Lee, A. F., Fundamental Pd0/PdII Redox Steps in Cross-coupling Reactions: Homogeneous, Hybrid Homogeneous− Heterogeneous to Heterogeneous Mechanistic Pathways for C−C Couplings. In C-H and C-X Bond Functionalization: Transition Metal Mediation; Ribas, X., Ed.; Royal Society of Chemistry: Cambridge, U.K., 2013; pp 72−107. (15) Boronat, M.; Leyva-Perez, A.; Corma, A. Acc. Chem. Res. 2014, 47 (3), 834−844. (16) Schlögl, R. Angew. Chem., Int. Ed. 2015, 54 (11), 3465−3520. (17) Tyo, E. C.; Vajda, S. Nat. Nanotechnol. 2015, 10 (7), 577−588. (18) Trzeciak, A. M., Pd Nanoparticles for Coupling Reactions and Domino/Tandem Reactions. In Nanocatalysis in Ionic Liquids; Prechtl, M. H. G., Ed.; Wiley-VCH: Weinheim, Germany, 2016; p 63−81. (19) Ananikov, V. P.; Khemchyan, L. L.; Ivanova, Y. V.; Bukhtiyarov, V. I.; Sorokin, A. M.; Prosvirin, I. P.; Vatsadze, S. Z.; Medved’ko, A. V.; Nuriev, V. N.; Dilman, A. D.; Levin, V. V.; Koptyug, I. V.; Kovtunov, K. V.; Zhivonitko, V. V.; Likholobov, V. A.; Romanenko, A. V.; Simonov, P. A.; Nenajdenko, V. G.; Shmatova, O. I.; Muzalevskiy, V. M.; Nechaev, M. S.; Asachenko, A. F.; Morozov, O. S.; Dzhevakov, P. B.; Osipov, S. N.; Vorobyeva, D. V.; Topchiy, M. A.; Zotova, M. A.; Ponomarenko, S. A.; Borshchev, O. V.; Luponosov, Y. N.; Rempel, A. A.; Valeeva, A. A.; Stakheev, A. Y.; Turova, O. V.; Mashkovsky, I. S.; Sysolyatin, S. V.; Malykhin, V. V.; Bukhtiyarova, G. A.; Terent’ev, A. O.; Krylov, I. B. Russ. Chem. Rev. 2014, 83 (10), 885−985. (20) Ananikov, V.; Liu, X.; Schneider, U. Chem. - Asian J. 2016, 11 (3), 328−329. (21) Eremin, D. B.; Ananikov, V. P. Coord. Chem. Rev. 2017, 346, 2−19. (22) Sigel, R. K.; Pyle, A. M. Chem. Rev. 2007, 107 (1), 97−113. (23) Key, H. M.; Dydio, P.; Clark, D. S.; Hartwig, J. F. Nature 2016, 534 (7608), 534−537. (24) Organometallic Compounds in the Environment, 2nd ed.; Craig, P., Ed.; Wiley: Chichester, U.K., 2003. (25) Elements and Their Compounds in the Environment: Occurrence, Analysis and Biological Relevance, 2nd ed.; Merian, E., Anke, M., Ihnat, M., Stoeppler, M., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (26) Gilbert, S. G. A Small Dose of Toxicology: The Health Effects of Common Chemicals; CRC Press: Boca Raton, FL, 2005. (27) Woolley, A. A Guide to Practical Toxicology: Evaluation, Prediction, and Risk, 2nd ed.; Informa Healthcare USA: New York, 2008. (28) A Textbook of Modern Toxicology; Hodgson, E., Ed.; Wiley: Hoboken, NJ, 2010. (29) Metal Ions in Toxicology: Effects, Interactions, Interdependencies; Sigel, A.; Sigel, H.; Sigel, R. K. O.; Eds.; RSC Publishing: Cambridge, U.K., 2011. (30) Dictionary of Toxicology; Hodgson, E.; Roe, R. M.; Mailman, R. B.; Chambers, J. E., Eds.; Elsevier: London, San Diego, Waltham, Oxford, 2015. (31) Handbook on the Toxicology of Metals, 4th ed.; Nordberg, G. F., Fowler, B. A., Nordberg, M., Eds.; Elsevier: London, Waltham, San Diego, 2015. (32) Stem Cell-Derived Models in Toxicology; Clements, M., Roquemore, L., Eds.; Humana Press: New York, 2017. (33) Weyermann, J.; Lochmann, D.; Zimmer, A. Int. J. Pharm. 2005, 288 (2), 369−376. (34) Kroemer, G.; Galluzzi, L.; Vandenabeele, P.; Abrams, J.; Alnemri, E. S.; Baehrecke, E. H.; Blagosklonny, M. V.; El-Deiry, W. S.; Golstein, P.; Green, D. R.; Hengartner, M.; Knight, R. A.; Kumar, S.; Lipton, S. A.; Malorni, W.; Nunez, G.; Peter, M. E.; Tschopp, J.; Yuan, J.; Piacentini, M.; Zhivotovsky, B.; Melino, G. Cell Death Differ. 2009, 16 (1), 3−11. (35) Scherliess, R. Int. J. Pharm. 2011, 411 (1−2), 98−105. (36) Sebaugh, J. L. Pharmaceut. Statist. 2011, 10 (2), 128−134. (37) Holden, P. A.; Gardea-Torresdey, J. L.; Klaessig, F.; Turco, R. F.; Mortimer, M.; Hund-Rinke, K.; Cohen Hubal, E. A.; Avery, D.; Barceló, D.; Behra, R.; Cohen, Y.; Deydier-Stephan, L.; Ferguson, P. L.; Fernandes, T. F.; Herr Harthorn, B.; Henderson, W. M.; Hoke, R. A.; Hristozov, D.; Johnston, J. M.; Kane, A. B.; Kapustka, L.; Keller, A. A.; Lenihan, H. S.; Lovell, W.; Murphy, C. J.; Nisbet, R. M.; Petersen, E. J.; Salinas, E. R.; Scheringer, M.; Sharma, M.; Speed, D. E.; Sultan, Y.; Westerhoff, P.; White, J. C.; Wiesner, M. R.; Wong, E. M.; Xing, B.;

AUTHOR INFORMATION

Corresponding Author

*E-mail for V.P.A.: [email protected]. ORCID

Valentine P. Ananikov: 0000-0002-6447-557X Notes

The authors declare no competing financial interest. Biographies Ksenia Egorova graduated from Lomonosov Moscow State University with a M.Sc. in Biochemistry in 2006. Between 2006 and 2011, she worked at the Institute of Molecular Genetics of Russian Academy of Sciences and got a Ph.D. in Molecular Biology in 2010. Currently, she is a senior researcher at the Zelinsky Institute of Organic Chemistry. Her research interests include biological activity, toxicity of metals, cancer proteomics, ionic liquids, and carbohydrate research. Valentine Ananikov received his M.Sc degree in 1996 (biochemistry), Ph.D. degree in 1999 (organic chemistry and catalysis), and Habilitation in 2003, and in 2005 he was appointed Professor and Laboratory Head of the Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences. In 2008 he was elected as a Member of the Russian Academy of Sciences. In 2012 he became Professor of the Chemistry Department of Moscow State University. He was a recipient of the Russian State Prize for Outstanding Achievements in Science and Technology (2004), an Award of the Science Support Foundation (2005), a Medal of the Russian Academy of Sciences (2000), Liebig Lecturer by the German Chemical Society (2010), Balandin Prize for outstanding achievements in the field of catalysis (2010), Organometallics Distinguished Author Award Lectureship by the American Chemical Society (2016), and Hitachi High-Technologies Award In Appreciation for Novel Approach and Outstanding Contribution to Setting New Standards for Electron Microscopy Applications in Chemistry (2016). His research interests are focused on mechanistic studies, catalysis, biological activity, and green chemistry.

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ACKNOWLEDGMENTS The authors acknowledge Russian Science Foundation for support (Grant 14-13-01030). REFERENCES

(1) Muci, A. R.; Buchwald, S. L., Cross-Coupling Reactions. In Practical Palladium Catalysts for C-N and C-O Bond Formation; Miyaura, N., Ed.; Springer: Berlin, Heidelberg, New York, 2002. (2) Metal Catalyzed Cross-Coupling Reactions and More; de Meijere, A., Brase, S., Oestreich, M., Eds.; Wiley-VCH: Weinheim, Germany, 2014. (3) Organotransition Metal Chemistry: From Bonding to Catalysis; Hartwig, J. F., Ed.; University Science Books: Sausalito, CA, 2010. (4) Correa, A.; Garcia Mancheno, O.; Bolm, C. Chem. Soc. Rev. 2008, 37 (6), 1108−1117. (5) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108 (8), 3351−3378. (6) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110 (3), 1746−1787. (7) Molnar, A. Chem. Rev. 2011, 111 (3), 2251−2320. (8) Johansson Seechurn, C. C.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51 (21), 5062−5085. (9) Fürstner, A. ACS Cent. Sci. 2016, 2 (11), 778−789. (10) Copéret, C.; Chabanas, M.; Petroff Saint-Arroman, R.; Basset, J.M. Angew. Chem., Int. Ed. 2003, 42 (2), 156−181. (11) Astruc, D.; Lu, F.; Aranzaes, J. R. Angew. Chem., Int. Ed. 2005, 44 (48), 7852−7872. (12) Trzeciak, A. M.; Ziółkowski, J. J. Coord. Chem. Rev. 2007, 251 (9− 10), 1281−1293. (13) Crabtree, R. H. Chem. Rev. 2012, 112 (3), 1536−1554. 4088


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Organometallics Steele Horan, M.; Godwin, H. A.; Nel, A. E. Environ. Sci. Technol. 2016, 50 (12), 6124−6145. (38) O’Brien, P. J.; Edvardsson, A. Chem. Res. Toxicol. 2017, 30 (3), 804−829. (39) In vitro Environmental Toxicology - Concepts, Application and Assessment; Reifferscheid, G., Buchinger, S., Eds.; Springer: Cham, Switzerland, 2017. (40) Patnaik, P. Handbook of inorganic chemicals; McGraw-Hill: New York, 2003. (41) Handbook on Metals in Chemical and Analytical Chemistry; Seiler, H. G., Sigel, A., Sigel, H., Eds.; Marcel Dekker: New York, 1994. (42) Carson, P. Hazardous Chemicals Handbook, 2nd ed.; ButterworthHeinemann: Oxford, Woburn, 2002. (43) Lewis, R. J. S. Sax’s Dangerous Properties of Industrial Materials, 11th ed.; Wiley: Hoboken, NJ, 2004. (44) Nickel and Its Surprising Impact in Nature; Sigel, A., Sigel, H., Sigel, R. K. O., Eds.; Wiley: Chichester, U.K., 2007. (45) Organic Metal and Metalloid Species in the Environment: Analysis, Distribution, Processes and Toxicological Evaluation; Hirner, A. V., Emons, H., Eds.; Springer: Berlin, Heidelberg, 2004. (46) Advances in Molecular Toxicology; Fishbein, J. C., Heilman, J., Eds.; Academic Press: Waltham, San Diego, Oxford, London, 2015; Vol. 9. (47) Djurišić, A. B.; Leung, Y. H.; Ng, A. M.; Xu, X. Y.; Lee, P. K.; Degger, N.; Wu, R. S. Small 2015, 11 (1), 26−44. (48) Joo, S. H.; Zhao, D. J. Hazard. Mater. 2017, 322, 29−47. (49) Zhu, M.; Nie, G.; Meng, H.; Xia, T.; Nel, A.; Zhao, Y. Acc. Chem. Res. 2013, 46 (3), 622−631. (50) Computational Systems. Pharmacology and Toxicology; Johnson, D. E., Richardson, R. J., Eds.; Royal Society of Chemistry: Croydon, U.K., 2017. (51) Schweitzer, G. K.; Pesterfield, L. L. The Aqueous Chemistry of the Elements; Oxford University Press: New York, 2010. (52) Organometallics in Environment and Toxicology; Sigel, A., Sigel, H., Sigel, R. K. O., Eds.; RSC Publishing: Cambridge, U.K., 2010. (53) Atmospheric and Biological Environmental Monitoring; Kim, Y. J., Platt, U., Gu, M. B., Iwahashi, H., Eds.; Springer: Dordrecht, Heidelberg, London, New York, 2009. (54) Persson, M.; Hornberg, J. J. Chem. Res. Toxicol. 2016, 29 (12), 1998−2007. (55) Uppal, K.; Walker, D. I.; Liu, K.; Li, S.; Go, Y. M.; Jones, D. P. Chem. Res. Toxicol. 2016, 29 (12), 1956−1975. (56) Metallomics and the Cell; Banci, L., Ed.; Springer: Dordrecht, Heidelberg, New York, London, 2013. (57) Interrelations between Essential Metal Ions and Human Diseases; Sigel, A., Sigel, H., Sigel, R. K. O., Eds.; Springer: Dordrecht, Heidelberg, New York, London, 2013. (58) Lansdown, A. B. G. The Carcinogenicity of Metals: Human Risk through Occupational and Environmental Exposure; RSC Publishing: Cambridge, U.K., 2014. (59) Niu, L.; Li, Y.; Li, Q. Inorg. Chim. Acta 2014, 423, 2−13. (60) Jaouen, G.; Vessières, A.; Top, S. Chem. Soc. Rev. 2015, 44 (24), 8802−8817. (61) Egorova, K. S.; Ananikov, V. P. Angew. Chem., Int. Ed. 2016, 55, 12150−12162. (62) Wani, W. A.; Prashar, S.; Shreaz, S.; Gómez-Ruiz, S. Coord. Chem. Rev. 2016, 312, 67−98. (63) Egorova, K. S.; Gordeev, E. G.; Ananikov, V. P. Chem. Rev. 2017, 117 (10), 7132−7189. (64) Several topics in the considered area dealing with toxicity and biological activity of metal compounds are a subject of continuous debate. Not unexpectedly, provoking discussions appear due to polar opinions and lack of experimental data. In this Tutorial, we tried to provide a balanced description and to touch upon the most interesting questions. The discussions cited in this Tutorial should not be considered as a final proof, since in many cases the amount of available experimental data is insufficient. Rather, we try to eliminate biases and to stimulate further studies in this fascinating area.

(65) Compendium of Chemical Terminology. Gold Book; International Union of Pure and Applied Chemistry: Research Triangle Park, NC, 2014. (66) Images from www.all-free-download.com and PDBE (Protein Data Bank in Europe, www.ebi.ac.uk, entry 3lii) are used in the figure. (67) Chevret, S. Maximum Tolerable Dose (MTD). In StatsRef: Statistics Reference Online; Wiley: Hoboken, NJ, 2014. (68) OECD: www.oecd.org (accessed Oct 2017). (69) Hansen, M. B.; Nielsen, S. E.; Berg, K. J. Immunol. Methods 1989, 119 (2), 203−210. (70) Niles, A. L.; Moravec, R. A.; Riss, T. L. Expert Opin. Drug Discovery 2008, 3 (6), 655−669. (71) Egorova, K. S.; Ananikov, V. P. ChemSusChem 2014, 7 (2), 336− 360. (72) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 2013 (1), 19−30. (73) Hyster, T. K. Catal. Lett. 2015, 145 (1), 458−467. (74) Guo, S.; Yang, P.; Zhou, J. S. Chem. Commun. 2015, 51 (60), 12115−12117. (75) Khan, M. S.; Haque, A.; Al-Suti, M. K.; Raithby, P. R. J. Organomet. Chem. 2015, 793, 114−133. (76) Li, Y. Y.; Yu, S. L.; Shen, W. Y.; Gao, J. X. Acc. Chem. Res. 2015, 48 (9), 2587−2598. (77) Castellanos-Blanco, N.; Arévalo, A.; García, J. J. Dalton Trans. 2016, 45 (34), 13604−13614. (78) Murakami, M.; Ishida, N. J. Am. Chem. Soc. 2016, 13759−13769. (79) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116 (14), 8003−8104. (80) Pelletier, J. D.; Basset, J. M. Acc. Chem. Res. 2016, 49 (4), 664− 677. (81) Sheldon, R. A. Green Chem. 2017, 19 (1), 18−43. (82) ICH Guideline for Elemental Impurities. http://www.ich.org (accessed Oct 2017). (83) Sigma-Aldrich: http://www.sigmaaldrich.com/ (accessed Oct 2017). (84) Several compounds, such as PdCl2, toluene, acetone, n-butanol, ethanol, and 1,2-dichlorobenzene, are presented twice in the figure due to the wide published ranges of their LD50 values. (85) TOXNET. Toxicology Data Network: https://toxnet.nlm.nih. gov (accessed Oct 2017). (86) Jamieson, E. R.; Lippard, S. J. Chem. Rev. 1999, 99 (9), 2467− 2498. (87) Wang, D.; Lippard, S. J. Nat. Rev. Drug Discovery 2005, 4 (4), 307−320. (88) Spreckelmeyer, S.; Orvig, C.; Casini, A. Molecules 2014, 19 (10), 15584−15610. (89) Medici, S.; Peana, M.; Nurchi, V. M.; Lachowicz, J. I.; Crisponi, G.; Zoroddu, M. A. Coord. Chem. Rev. 2015, 284, 329−350. (90) Timerbaev, A. R. TrAC, Trends Anal. Chem. 2016, 80, 547−554. (91) Graf, N.; Lippard, S. J. Adv. Drug Delivery Rev. 2012, 64 (11), 993−1004. (92) Hang, Z.; Cooper, M. A.; Ziora, Z. M. Biochemical Compounds 2016, 4, 2. (93) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. Chem. Rev. 2016, 116 (5), 3436−3486. (94) Bernhard, M.; Brinckman, F. E.; Sadler, P. J. The Importance of Chemical ″Speciation″ in Environmental Processes; Springer-Verlag: Berlin, Heidelberg, New York, London, Paris, Tokyo, 1986. (95) Gasser, G.; Ott, I.; Metzler-Nolte, N. J. Med. Chem. 2011, 54 (1), 3−25. (96) Ananikov, V. P.; Musaev, D. G.; Morokuma, K. Organometallics 2005, 24 (4), 715−723. (97) Thayer, J. S. Appl. Organomet. Chem. 2002, 16 (12), 677−691. (98) Gadd, G. M. Sci. Total Environ. 2000, 258 (1−2), 119−127. (99) Appel, K. E. Drug Metab. Rev. 2004, 36 (3−4), 763−786. (100) Graceli, J. B.; Sena, G. C.; Lopes, P. F.; Zamprogno, G. C.; da Costa, M. B.; Godoi, A. F.; Dos Santos, D. M.; de Marchi, M. R.; Dos Santos Fernandez, M. A. Reprod. Toxicol. 2013, 36, 40−52. (101) Images from www.all-free-download.com are used in the figure. 4089


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Organometallics (102) Mass median aerodynamic diameter (MMAD) is the median of the distribution of airborne particle mass relative to the aerodynamic diameter. The aerodynamic diameter of an irregular particle is the diameter of a spherical particle with a density of 1000 kg m−3 and the same settling velocity in the air as that of the irregular particle. (103) Lönnerdal, B. Am. J. Clin. Nutr. 2008, 88 (3), 846S−850S. (104) Roberts, E. A.; Sarkar, B. Am. J. Clin. Nutr. 2008, 88 (3), 851s− 854s. (105) Inesi, G. IUBMB Life 2017, 69 (4), 211−217. (106) Johnstone, T. C.; Suntharalingam, K.; Lippard, S. J. Philos. Trans. R. Soc., A 2015, 373 (2037), 20140185. (107) Saito, M.; Arakaki, R.; Yamada, A.; Tsunematsu, T.; Kudo, Y.; Ishimaru, N. Int. J. Mol. Sci. 2016, 17 (2), 202. (108) Darlenski, R.; Kazandjieva, J.; Pramatarov, K. Int. J. Dermatol. 2012, 51 (5), 523−530. (109) Goldenberg, A.; Vassantachart, J.; Lin, E. J.; Lampel, H. P.; Jacob, S. E. Dermatitis 2015, 26 (5), 216−223. (110) List of MAK and BAT Values 2017: Maximum Concentrations and Biological Tolerance Values at the Workplace; Deutsche Forschungsgemeinschaft: Weinheim, Germany, 2017. (111) Martin, S. F. Curr. Opin. Allergy Clin. Immunol. 2015, 15 (2), 124−130. (112) Goodman, J. E.; Prueitt, R. L.; Thakali, S.; Oller, A. R. Crit. Rev. Toxicol. 2011, 41 (2), 142−174. (113) Perry, D. L. Handbook of Inorganic Compounds, 2nd ed.; CRC Press: Boca Raton, FL, 2011. (114) Auffan, M.; Rose, J.; Wiesner, M. R.; Bottero, J. Y. Environ. Pollut. 2009, 157 (4), 1127−1133. (115) Schrand, A. M.; Rahman, M. F.; Hussain, S. M.; Schlager, J. J.; Smith, D. A.; Syed, A. F. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2010, 2 (5), 544−568. (116) Wagner, S.; Gondikas, A.; Neubauer, E.; Hofmann, T.; von der Kammer, F. Angew. Chem., Int. Ed. 2014, 53 (46), 12398−12419. (117) Friehs, E.; AlSalka, Y.; Jonczyk, R.; Lavrentieva, A.; Jochums, A.; Walter, J.-G.; Stahl, F.; Scheper, T.; Bahnemann, D. J. Photochem. Photobiol., C 2016, 29, 1−28. (118) Torres-Duarte, C.; Adeleye, A. S.; Pokhrel, S.; Mädler, L.; Keller, A. A.; Cherr, G. N. Nanotoxicology 2016, 10 (6), 671−679. (119) Cohen, Y.; Rallo, R.; Liu, R.; Liu, H. H. Acc. Chem. Res. 2013, 46 (3), 802−812. (120) Sharma, H. S.; Sharma, A., Nanoparticles aggravate heat stress induced cognitive deficits, blood−brain barrier disruption, edema formation and brain pathology. In Neurobiology of Hyperthermia; Sharma, H. S., Ed.; Elsevier: Oxford, U.K., 2007; Vol. 162, pp 245−273. (121) Upon preparation of this Tutorial, we were surprised by insufficient experimental description in many studies on biological activity. Even important parameters such as temperature, exact formulas and concentrations, exposure time, experimental protocols, etc. were sometimes missing. Such incomplete descriptions make reliable comparisons of reported biological activity data for different metal compounds impossible. The inability to follow common measurement standards is one of the major stumbling blocks in this area.

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Toxicity of Metal Compounds: Knowledge and Myths

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