Chemical Properties, Environmental Fate, and ... - ACS Publications

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Chemical Properties, Environmental Fate, and Degradation of Seven Classes of Pollutants Sergio Manzetti,†,‡ E. Roos van der Spoel,† and David van der Spoel*,† †

Uppsala Center for Computational Chemistry, Science for Life Laboratory, Department of Cell and Molecular Biology, University of Uppsala, Box 596, SE-75124 Uppsala, Sweden ‡ Fjordforsk A.S., Midtun, 6894 Vangsnes, Norway ABSTRACT: Industrialism has brought a long series of benefits for modern civilization. Concomitantly, reversible and irreversible changes have been inflicted upon the environment, affecting humans, animals, and whole ecosystems and leading to effects such as declining reproduction in modern human beings, developmental challenges on various species, and destroyed habitats and ecosystems across the globe. In this context, a vast repertoire of modern and older literature is reviewed for a series of pollutants and their status as of 2014. The compound classes covered in this review are polychlorinated biphenyls, halogenated hydrocarbons, estrogen analogues, phthalates, dioxins, perfluorinated compounds, and brominated flame retardants. These groups represent ubiquitous pollutants, of which some have circulated in the environment for more than 60 years. In this context, this review describes the chemical properties, the environmental fate, and the toxicological effects of these classes of pollutants on humans and animals, including an introductory section on the detoxification systems that are triggered in most species upon intoxication. This combined review of in vivo transformation, chemistry, toxicological properties, and structure−activity relationships of pollutants aids in the understanding of the fate, biomagnification, bioaccumulation, and transformation of these compounds, which is essential for toxicologists, environmental scientists, and environmental legislators. The review is concluded with an outlook.

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CONTENTS

1. Introduction 2. Detoxification Enzymes and Pathways 3. Pollutants 3.1. Polychlorinated Biphenyls 3.2. Halogenated Hydrocarbons 3.3. Estrogen Analogues 3.4. Phthalates 3.5. Dioxins 3.6. Perfluorinated Compounds and Brominated Flame Retardants 4. Conclusions Author Information Corresponding Author Notes References

degenerative effects afflicting various species of animals and other living organisms have been reported. Large-scale catastrophes may result from oil spills, the uncontrolled release of chemicals in the environment,6−10 or a combination of the two.11 Generic health problems may be caused by pollution like exhaust emissions or poor wastewater decontamination, which can particularly affect populations in urban and industrial regions.12−18 Parallel to the direct toxic effects caused by pollution and the release of chemicals in the environment, the accumulation of persistent compounds in the food chain represents an additional serious threat, where organic compounds, organometallic compounds, and heavy metals accumulate and transfer from prey to predator, starting from plants and plankton-sized organisms and ending up in higher animals.19−22 These two mechanisms of pollution-induced effects on living organisms follow specific patterns of intoxication, including dermatological exposure,23 airborne (pulmonary) intoxication on terrestrial and avian species,18,24,25 intoxication in aquatic species through respiration, and dietary exposure for all species.26,27 Examples of toxin-containing food sources that

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1. INTRODUCTION Man-made chemicals released in the environment can cause damage to ecosystems and, ultimately, humans. Examples abound, but, to name a few, cyto-toxicological stress and necrosis to vegetation and fauna,1,2 increased risks of cancer and reproductive disorders in animals and humans,3−5 and © 2014 American Chemical Society

Received: January 13, 2014 Published: March 19, 2014 713

dx.doi.org/10.1021/tx500014w | Chem. Res. Toxicol. 2014, 27, 713−737

Chemical Research in Toxicology

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have been reported include contaminated farm fish,28 heavymetal-exposed foods,29 and cultivated vegetables,30 but other sources of exposure of toxins to humans, animals, and the environment are important as well.31−34 Environmental toxins can be categorized into several classes: polychlorinated biphenyls (PCBs), halogenated hydrocarbons (HAHs), estrogen analogues, phthalates, dioxins, perfluorinated compounds, brominated flame retardants, polycyclic aromatic hydrocarbons (PAHs), and heavy metals. We have reviewed the environmental fate of PAHs recently,35 and other groups have focused on heavy metals;36−38 therefore, these classes of toxins are not considered here. In the context of intoxication with these toxins, all organisms have biochemical mechanisms of degradation and transformation to convert toxins to excreted solubilized products; however, these detoxification pathways have not been evolutionary tuned to break down man-made chemicals, which implies that many of these chemicals remain in the terrestrial and atmospheric cycles of conversion without proper degradation.35 The accumulation of pollutants in living organisms may increase their toxic potential, as in the case of the catalytic oxidation of PAHs, which yields carcinogenic and reactive metabolites.39,40 The conversion of pollutants thus includes a series of metabolites that can have different effects in different parts of the food chain depending on metabolic activation, conjugation, and biomagnification. In the following sections, we first describe detoxification processes in general; subsequently, the major sets of pollutants are introduced, with a concentration on their chemical and toxic properties and their interaction with organisms. The main focus of this review is on “new” pollutants such as polyfluorinated compounds, brominated flame retardants, and on long-preserved compounds such as PCBs and dioxins.

substrates are transformed into thiol conjugates for increased solubility and excretion via the bile duct49 and the urinary tract.50 Detoxification is performed by metalloenzymes as well, two of which are particularly related to catalytic conversion of xenobiotic compounds: metallothionein51 and the dizinc alkaline phosphatase system.52,53 The former comprises a group of sulfur-dependent enzymes that are expressed in the presence of toxins and extraneous molecules introduced in the cell,54 including heavy metals.55,56 Metallothioneins are found in the entire animal and plant kingdoms57 (where they are known as plant MTs). In the animal kingdom, their expression pattern is concentrated in the kidneys and the urinary tract, where they bind mercury, cadmium, arsenic, and even bismuth atoms and ions and also scavenge free radicals generated during oxidative stress.58−60 The detoxification mechanism of metallothioneins is dependent on zinc chaperones, and it relies on a cysteine tail that the enzymes use to trap the metal ion.61 The second group mentioned above, the dizinc alkaline phosphatase proteins (ALPs), are expressed in most tissues and organs, encompassing the kidneys, intestines, and the liver.62−64 The ALPs degrade molecules such as lipopolysaccharides during nutrient transformation and also detoxify biomolecular toxins65−68 and inorganic toxins, including cadmium.69 Another group of detoxification enzymes are the superoxide dismutases and arylesterases, which are involved in the detoxification of xenobiotcs and extragenous compounds introduced into cells through either diet or other means of intoxication.70 The superoxide dismutases (SOD) are a family of proteins that protect cells from free radicals and reactive oxygen species (ROS) and are also involved in the incorporation of metal species as functional groups in proteins in prokaryotes and eukaryotes.71,72 In both of these domains of biology, the SOD family comprises the metal-specific detoxification enzymes manganese superoxide dismutase (MnSOD), copper−zinc superoxide dismutase (CuZnSOD), iron superoxide dismutase (FeSOD), and nickel superoxide dismutase (NiSOD),72 which all carry out the conversion of metal species into bioactive forms for metabolic functions.72 In the animal and plant kingdoms, SOD is primarily expressed during oxidative stress occurring during respiratory and muscular function and during assimilation of nutrients, respectively.73−75 In animals, SOD is also central in inducing tissue repair upon injury and physiological stress,76 depicting its role in the removal and detoxification of molecular species resulting from intoxication or injury, with O2− and O2−• as its prime substrates.77 Arylesterases were originally discovered in rabbit plasma in 1961 and are found in all vertebrates.78,79 They are also expressed in bacteria and plants,80,81 where they function as hydrolyzing enzymes in the catabolism of xenobiotics and extrageneous toxins as well as nutrients such as lipids and esters.82 Expression of arylesterases in humans and mammals is predominantly in the lung, liver, skin, and blood. 83 Arylesterases have been shown to degrade pesticides and herbicides in vitro83 through a mechanism of hydrolysis of the N-methyl groups of its substrates to carboxyl groups and subsequent conjugation to sulfate and glucuronate groups.84 Arylesterases have been studied in the context of the degradation of herbicides, pesticides, and insecticides,85−87 particularly in studies of human exposure to these compounds in industrial and agricultural workers.88 Arylesterases, as well as the related choline-esterases, yield metabolites of the pesticides

2. DETOXIFICATION ENZYMES AND PATHWAYS The mechanisms of biological degradation of pollutants are represented by conserved pathways and systems that are similar among most species, particularly vertebrates.41 The most wellunderstood detoxification system is through the cytochrome P450 gene family, whose genes encode 60 members of membrane-bound oxidase enzymes.41 Several of these 60 members perform a catalytic conversion of chemical compounds into solubilized forms, the products of which are subsequently released via the urine, sweat, and other body fluids from organs and tissues.42−44 The xenobiotic-selective group of the P-450 system is expressed in humans on the seventh chromosome at the q22 cluster, which encompasses four known members and potentially encompasses several other members with effective specificity to pollutants.41 Interestingly, this genetic cluster has a very high rate of natural mutation,41 indicating an active and continuous adaption of organisms to a changing chemical environment. The ability of species to adapt to environmental stress and pollution is, in other words, continuously challenged, and the effects of this challenge will be more critical for the most advanced species, which have slower adaptation rates than microorganisms and fungi. Other systems are involved in the detoxification of xenobiotics as well.45 The glutathione S-transferase enzymes are part of a superfamily that encodes for a group of dimeric enzymes expressed predominantly in the liver of animals.46,47 Like the P-450 enzymes, glutathione S-transferase members are expressed both for endogenous substrates and for exogenous and xenobiotic substrates including heavy metals.48 These 714



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(predominantly Cu and Pb), persistent organic compounds, and PCBs in the environment.113,114 The major threat from released pollutants is the contamination of aquatic ecosystems such as oceans, rivers, ponds, and lakes as well as groundwater and drinking water, which is due to the volatilization of and exposure to pollutants that are transported across thousands of kilometers in the atmosphere.111 Particularly in urbanized and industrial regions, the dispersion of pollutants from the soil, water, and air phases extends to all living organisms, vegetation, and aquatic environments, affecting viability and health.35 Aqua-terrestrial ecosystems such as coastlines and river deltas are particularly affected, where sea birds and land animals interact with aquatic species.115−118 Example studies report detrimental effects on the reproduction of ring-billed gulls and show the highest concentrations of flame retardants ever registered in bird species across the Great Lakes.118 Similar findings are registered in Belgium on raptors with high levels of PCBs found in liver and tissue samples119 and in DDT-related contamination of bird eggs in South Africa.117 The level of ecotoxicity is influenced by abiotic (chemical) and biotic (organism-dependent) degradation.111 PCBs, dioxins, and perfluorinated compounds represent the most persistent compound classes.110,120−122 In the following sections, we examine these and other classes of pollutants. 3.1. Polychlorinated Biphenyls. Polychlorinated biphenyls (PCBs) are a group of chemical compounds used in microelectronic circuits, plastics, resins, chlorinated rubbers, and flame retardants.114,123,124 PCBs were first noted as a pollutant in sea birds in 1969 in the Stockholm archipelago, with particularly high concentrations observed in white-tailed eagles.125 Their toxic effects are initiated by detoxification in the liver, causing hormonal interference, sexual and reproductive disorders,126−128 diabetes,129 neurological disorders,130 developmental problems,131 cognitive problems,132 metabolic problems,133 and cancer.134−136 The structure and chemical components of PCBs are chlorinated benzene rings in bicyclic arrangements,124 yielding either coplanar congeners with their ortho-position free (Figure 1) or transversal types with occupied ortho-positions, which are less toxic. Structure−activity studies indicate that the degree of chlorination enhances the persistence of the PCB, thus delaying their degradation in vivo and ex vivo.137 Furthermore, the lateral Cl atoms are known to induce the highest toxicity (Figure 1), implying that occupied para- and meta-positions, as in 3,3′,4,4′tetra-, 3,3′,4,4′,5-penta-, and 3,3′,4,4′,5,5′-hexachlorobiphenyl, yield fully planar congeners with the highest toxicity.137−139 The mechanism of toxicity of PCBs is related to their ability to bind to the cytochrome detoxification system (P-450 and P448),140 inducing overexpression of the aryl hydrocarbon receptor141 that, in turn, induces the expression of heat-shock proteins (vide supra) and triggers a series of events related to cytotoxic responses, including suppression of lymphocyte activity and hormonal interference.142,143 When PCBs interfere with hormone metabolism, the mechanism displays crossbinding to the estrogen receptor,144 inducing erroneous growth differentiation signals to the DNA through disturbance of the polymerase proteins.128 A particular example of the toxic effects of PCBs is demonstrated in the alteration of hormonal expression patterns in thyroid glands, which affects hormonemediated transcription of genes.145,146 This hormone-interfering mechanism is facilitated by the structural similarity that PCBs have to the thyroid hormone, inducing activation/

in the form of phospho- and sulfur-coupled anions that are excreted to the urine.88 The described detoxification machinery is dependent on receptors and proteins that are bound to the cell surface and is activated upon exposure to non-natural chemicals and extrageneous toxic compounds. These receptors are responsible for the delivery of the toxic agents to the oxidation processing system, situated in the cytosol,89 and the most active receptor of xenobiotics known is the aryl hydrocarbon receptor (AhR).89,90 The AhR has a multispecific affinity for substrates, encompassing synthetic, environmental, and dietary compounds, and it cooperates with the heat-shock protein systems (HSP90 and p23) during exposure to xenobiotics for the transport of the toxin across the membrane to the degrading CYP-enzymes of the P-450 system.89,91,92 Structure−activity relationships have shown that the binding site of AhR has an approximate size of 14 × 12 × 5 Å3, delineating a rather large pocket for accommodation of substrates during uptake for detoxification.93,94 Although AhR is a crucial component in the detoxification system, its action can also lead to increased intoxification because of its nonselective action, leading to uncontrolled uptake of toxic compounds, which may increase toxicity and mutagenicity upon oxidation by the detoxification enzymes.95−97 An example of this increased genotoxicity is that mercury can be transformed to the extremely hazardous methylmercury during detoxification in bacteria.98 The incomplete degradation or conjugation and complexation of pollutants to bioassimilable compounds, such as glucurate,84 may, in other words, create poisonous bioassimilable compounds including nutrient mimickers.99 Systems such as ponds, lakes, and larger water systems with confined geomorphologies are particularly vulnerable to the bioaccumulative effect,100−103 and large aquatic systems such as the Baltic and Mediterranean are known to contain a wide range of pollutants accumulating in their food chains.104−107

3. POLLUTANTS The majority of the pollutants found in the environment are due to direct emissions and waste products from industrial activity, wastewater, agriculture, the transport sector, incineration, and, more recently, electronic waste deposition. Largescale generation and accumulation of pollutants has taken place since the middle of the 18th century in the industrialized world but is now rapidly increasing globally.108 Because all pollutants have different half-lives, the biological and ecological degradation periods differ from months to decades, and some pollutants have been documented to persist in humans for more than 10 years109 and in the environment for more than 250 years.110 Therefore, the various classes of pollutants, including their metabolites and breakdown products from degradation, yield a complete profile of toxicity that describes their complete toxicological properties from their source to the exposed species and eventually to the affected food chain.35,111 The total amount of pollutants released daily in the environment is not known. However, an estimated 1−2.5 million tons of pesticides are applied in agriculture,111 of which half a million tons are applied in the U.S. alone.112 In addition, over 4 million tons of pesticides, including metals, are applied for wood preservation in the U.S.,112 and a significantly larger amount is probably applied worldwide. Electronic waste deposition ranges upward of 20−50 million tons yearly throughout the world, with most of it occurring in East Asia and Africa, resulting in significant dispersion of heavy metals 715



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excretion of PCBs then follows their binding to xenobiotic transporters (e.g., glucuronic acid, sulfonic acid) for transport to the urine or gall,152,153 yielding up to 90% secretion rate in rats, depending on the level of chlorination of the PCB.148 The remaining parts that are not excreted are retained in the body and in tissues with high fat content.154 Elimination of accumulated PCBs occurs with time and through milk, egg yolk, and fetus, defining PCBs as teratogenic toxins (inducing harm on the fetus).154 The passing from the maternal individual to the offspring yields higher concentrations that have been found particularly in the eggs of birds,155 turtles,156 and fish157 and that has been shown to affect children as well after exposure through the placenta and breast feeding.132,158,159 The chemical properties of PCBs are principally differentiated by (a) their number of chlorine atoms and (b) the relative orientation of the two phenyl rings to one another (Figure 2). The chemical features of the PCBs are visible primarily by the electronegative effect exerted by the chlorine atoms on the benzene rings, which yield a semipolarized molecule with high electron stability on the peripheral atoms and a delocalized electron density across the aromatic rings (Figure 2). The toxicity of PCBs is dependent on the angle of inclination between the rings and the number of chlorinated groups.138,139,160 A study on packing patterns of similar pollutants (PAHs) reports that PAH molecules arrange with respect to one another in a fashion similar to supramolecular complexes.162 For the case of PCBs, a similar principle can be expected to apply such that coplanar PCBs pack more orderly than nonplanar congeners, resulting in different cluster hydrophobic effects and in their different potential to accumulate in adipocytes and fat tissue.154 Other hydrophobic

Figure 1. Coplanar polychlorinated biphenyls. The most toxic congeners of the PCB family include (A) 4,4′-dichloro-biphenyl, (B) 3,4,4′-trichloro-biphenyl, (C) 3,4,4′,5-tetrachloro-biphenyl, (D) 3,3′,4,4′-tetrachloro-biphenyl, (E) 3,3′,4,4′,5-pentachloro-biphenyl, and (F) 3,3′,4,4′,5,5′-hexachloro-biphenyl.

suppression of thyroid function by binding to the thyroid receptors.147 PCBs accumulate in tissues, particularly fat, liver, skin, and, in some part, nerve tissues.119,148,149 During detoxification, the PCB molecule is dehalogenated by the P-450 system in active microsomes in the liver, where NADPH acts as a reducing agent.150 The reductive dehalogenation catalysis encompasses a binding to the heme group of the CYP2 enzymes with stereoisomeric selectivity,151 which usually releases the PCB with one less chlorine group after catalytic reduction. The

Figure 2. Electron localization map (inner grid) and electrostatic potential (outer grid) of 4,4′-dichloro-biphenyl (A), 3,4,4′,5-tetrachloro-biphenyl (B), and 2,2′,4,4′,5,5′-hexachloro-biphenyl (C). (A, B) Two coplanar congeners with a higher localization on the chloride atoms (blue color on the inner-surface grid) and on the electrons on the peripheral ring atoms (hydrogens). The electrostatic potential map (outer grid) shows the effects of the slight transversal torsion of the bicyclic groups in congener A. This molecule is not fully coplanar and has a torsion of ∼25° across the biphenyl axis. Fully coplanar molecule B, however, which has no rotation between the two rings, has a negative electrostatic energy occurring between the biphenyl rings (red clouds). (C) The nonplanar congener C (with ∼90° torsion between the phenyl rings) has two occupied ortho-positions and a completely different electrostatic profile compared to the two coplanar congeners, A and B; it also displays a higher negative electrostatic energy across the Coulombic surface (indicator on the right bar). These features are crucial for structure−activity relationship studies of PCBs, and they illustrate the electronic properties and the higher toxicity of coplanar-type PCBs over nonplanar-type PCBs.160 ELF: electron localization function (red, high electron localization probability; blue, low electron localization probability). Images were generated with the Amsterdam Density Functional package.161 716



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kidneys, liver, testes, and other organs, where they additionally induce lipid peroxidation and anti-inflammatory reactions,175 leading to organ damage and hepatotoxicity.176 In a worst case scenario, when large quantities are inhaled directly, ataxia, cardiac arrhythmia, and eventually death may follow from exposure to HAHs.169 The mechanism of toxicity of HAHs requires bioactivation by the cytochrome P-450 system,174 which yields a series of reactive metabolites, including peroxide metabolites.177 The process of intoxication leads to genotoxicity by direct DNA binding, particularly of 1,2-dibromoethane, bromotrichloromethane, chloroform, carbontetrachloride, and trichloroethylene,178 which induce the formation of DNA adducts at guanine sites.179 1,2-Dibromoethane, the most carcinogenic substance of those listed, is also involved in the induction of DNA strand breaks during intoxication,180 a property that is otherwise observed only for extremely strong toxins and γ-radiation. During detoxification, HAHs are solubilized by conjugation to glucuronic acid in the liver for excretion to the urine and gall and via microsomal activity;181 however, some HAHs (such as CCl4) are expunged via the lungs without any chemical modification.173,182 Halothane (C2HBrClF3) is a historical example of a HAH used as an anesthetic (by inhalation). It turned out to cause hepatitis in rare cases following conversion to trifluoroacetic acid183 by cytochrome P-450 2E1184,185 and his since been abolished to a large extent. HAHs are broken down in the environment by microbes, fungi, and plants,186 which degrade HAHs made up of chains up to four carbons and bromoalkanes with chains up to 10 carbons, by the enzyme haloalkane dehalogenase187 (Figure 4). The biotic degradation of HAHs in the environment is one major path of environmental transformation188 in addition to bioaccumulation in fish and animals.189,190 Degradation of

contaminants with planar structures are also reported to follow the toxicity-to-planarity pattern of PCBs.138,139,160 3.2. Halogenated Hydrocarbons. Halogenated hydrocarbons (HAHs) are compounds made up of alkane and arene groups and with their end positions usually substituted by a halogen group (most often chlorine, Figure 3). HAHs derive

Figure 3. Conventional types of HAHs. Applied in industrial products such as rubbers, dyes, solvents, aerosols, fire extinguishers, adhesives, pesticides, and herbicides.169 (A) Chloroform, (B) dichloroethylene, (C) dichlorodiphenyltrichloroethane (DDT), (D) ethylene bromide, (E) ethidium bromide, (F) carbontetrachloride, and (G) 1,2dichloroethane.

from modern industrial activity for the production of chemicals for dyes, solvents, cleaning agents, pesticides, and intermediates for chemical synthesis.163,164 HAHs have been produced in megaton volumes during the 1970s and have been released in the environment in large quantities, resulting in high concentrations in the atmosphere, particularly of CCl2F2 and CCl3F.163 HAHs were distributed from industrial plants to air and further from air to water, reaching humans and animals through diet and drinking supplies.164 The chemical stability and inertness of halogenated hydrocarbons163 makes them particularly persistent, and they are eventually sedimented in sea beds and in the soil of exposed (industrial) areas and wastedeposition sites.165 HAHs are volatile and have been found in the stratosphere, where they affect the ozone layer.166,167 In urbanized locations, HAHs were found at higher concentrations prior to the introduction of lead-free gasoline, for instance, with 1,2-dibromoethane and 1,2-dichloroethane reported in air samples in the UK.168 During the periods of largest emissions, HAHs were released at an estimated 20 megatons per year from industrial production in the U.S. alone,163 excluding emissions from traffic, waste deposition, accidental spills, and the agricultural sector. HAHs accumulate in various tissues in animals and man164 and are related to increased cancer incidence in humans170 by acting as either cocarcinogens or carcinogens.171 Specific studies show that HAHs cause damage to the central nervous system (CNS) and affect cardiac function as well as causing toxic effects on the lungs and liver in humans and animals. HAHs also induce cytotoxic effects in algae and plants.169,172−175 HAHs are further known to accumulate in

Figure 4. Haloalkane dehalogenase. The active site is shown encircled in green, and the surface is colored on the basis of electrostatic potential (blue, positive electrostatic fields; red, negative electrostatic fields). The catalysis of the haloalkane dehalogenase follows a hydrolysis of the halogen atom via the active site encompassed by His289 and Asp124. Asp124 is responsible for the first step of the hydrolysis of the halogen followed by a replacement of the halo site with a hydroxyl group from a His289-polarized water molecule.193 Image generated with PyMol.194 717



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HAHs is catalyzed by the enzyme, which provides a favorable electrostatic environment;191 however, the efficiency of these enzymes is highly substrate-specific, as has been shown by mutation analyses.192 The toxic properties of HAHs increase with the number of halogenated groups (as in for PCBs and dioxins), which, during detoxification, cause lipid peroxidation when in contact with lipids in the cell by forming reactive radicals of lipids, which then interact with biomolecules and DNA.195 Additionally, the formation of the radicals of HAHs, for instance, CCl3• from CCl4 (formed by the P-450 system) induces the formation of the peroxy radical CCl3O2−• that interacts with biomolecules in the cytosol, causing cytotoxic oxidative stress.196 Radical formation and propagation yields reactive products that bind to and react with DNA, and this is the main source of the carcinogenic and mutagenic properties of HAHs. Excessively high concentrations of HAHs eventually yield complete cell lysis by forming peroxidized lipid membrane components, dissolving the membrane structure.197 Other toxic properties of HAHs depend on their hydrophobic properties198 through their ability to merge with the membrane and pass to the cytosol; this is particularly applicable to the largest HAHs (such as DDT, Figure 3). The smallest HAHs, such as ethylene bromide and ethylene chloride, display their toxic effects based on the large molar dose of chlorinated groups for their peroxidative and DNA-adduct-forming effects.172 Interestingly, recent structure−activity relationship studies indicate that the electronic properties of HAHs are suitable indicators for assessing the toxicity of the HAH species,199 with emphasis on their LUMO and HOMO energy levels (lowest unoccupied molecuar orbitals and highest occupied molecular orbitals, respectively). Although some HAHs are ultimately biodegradable, the degradation process requires a long time and implies a considerable hazard to organisms. Some of the more persistent HAHs, such as DDT, have had their use prohibited in many places; however, this well-known toxin is still applied in some cases, for example, against the malaria mosquito.200 3.3. Estrogen Analogues. Estrogen analogues encompass a variety of compounds with chemical and structural similarities to natural estrogens, including bisphenol A (BPA) and its derivatives,201−203 steroidal estrogens,204−206 alkylphenol ethoxylates,207 and certain PCBs208 as well as other compounds originating from the pharmaceutical and chemical industries.209 Estrogen analogues derive from materials applied for the synthesis of plastic products, bottles, containers, and food packaging as well as from medicinal compounds applied in the health sector, including drugs and hormones.210 Plastics are the largest source of estrogen analogues in the environment, however. BPA has been used extensively in plastic containers during recent decades because of its resistance against the thermal stress and strain caused by the materials exposure to sunlight. In the U.S., BPA was also used in thermal paper until 2006, after which it was replaced by BPS, another derivative of bisphenol.211 The environmental persistence and toxicity of such products has been reported in the media and has caused significant complaints from consumers.212 The environmental persistence of BPAs and estrogen analogues leads to the accumulation in the environment, particularly the contamination of groundwater213 and aquatic ecosystems214 because its initial release is triggered by solubilization of molecules from plastic waste,202 discarded BPA-coated consumer materials,201 leakage from waste landfills to the environment,215 and poor wastewater decontamination.206

Estrogen analogues stimulate the estrogen receptors in animals and humans and bind to DNA, inducing feminizing and nonfeminizing effects on development and affecting menstruation216 and reproduction of animals and humans.217,218 In humans, estrogen analogues have been linked to contributing to earlier sexual maturation in girls201 and abnormal genital development in boys.219,220 Depending on the type, estrogen analogues may bind to DNA and cause strand breaks through oxidative reactions.221 BPA, for instance, binds selectively to the estrogen receptor and induces mutagenic effects and DNA damage.144,210,222 The structures of estrogen analogues are similar to one another and are characterized by cyclic components interconnected by carbon bonds with one or more alcohol group (Figure 5).

Figure 5. Estrogen analogues: (A) 4,4′-(propane-2,2-diyl)diphenol (BPA), (B) 4,4′-sulfonyldiphenol, (C) 1,1-bis(4-hydroxyphenyl)cyclohexane, (D) 1,4-bis(2-(4-hydroxyphenyl)-2-propyl)benzen, (E) estrone, (F) 17β-estradiol, (G) estriol, and (H) diethylstilboestrol. Molecules A−D belong to the bisphenol type of estrogen analogues, whereas E−G are steroidal estrogen analogue types. H, diethylstilbestrol (DES), is a variant of bisphenols with extremely strong toxicity.223

Recent studies show that BPA, which has been produced on an industrial scale since the early 1940s, is the estrogen analogue with the highest presence in nature, reaching a minimum of 100 tons released into the atmosphere per year through industrial production and incineration processes.224,225 The main route of exposure to humans is through ingestion, as BPA derives from polycarbonate plastics in food and drink 718



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Figure 6. Most common phthalates found in consumer products: (A) diethyl phthalate, (B) dibutyl phthalate, (C) benzyl butyl phthalate, (D) di-(2ethylhexyl) phthalate, (E) monoethyl phthalate, (F) monobutyl phthalate, (G) monobenzyl phthalate, and (H) monoethylhexyl phthalate. The toprow molecules are precursors of the in vivo activated metabolites, which are presented in the bottom row. All forms have been recommended in recent studies for regulatory restrictions; however, only di-(2-ethylhexyl) phthalate has received attention from legislative authorities.244

containers.226 A recent study showed that BPA is found in a large fraction of the population of the U.S., as BPA was detected in the urine of more than 90% of individuals tested (sample size of 2500 people).227 BPA and plastic derivatives have also been suggested as being related to diabetes, neurological effects affecting brain development, obesity, altered psychological behaviors, and cardiovascular diseases.225 Finally, bisphenol and its derivatives have been implicated in toxic effects in animals, egg development, and hatching frequencies.228 Recent studies suggest that bisphenol is accumulated in the body and has a longer half-life than previously expected, although it was thought to be secreted directly through the urine.224 The possible routes of uptake of bisphenol may include dermal and aerial absorption as well.229 The presence of estrogen analogues in the environment has sparked studies on the composition of contaminants in European groundwater systems.213 The results showed that bisphenol was sixth in terms of the highest concentrations of contaminants in ground waters, with a maximum measured concentration of 2.3 μg/L of groundwater. Low doses of estrogen analogues administered over prolonged periods affect development in humans and animals,219 and microgram per kilogram of body weight doses have been recently shown to affect fetus development.230 Estrogen analogues can be excreted by the liver and kidneys after conjugation to glucuronic acid in the microsomes by the specific enzyme UGT2B1.231 A similar mechanism of excretion is found in zebra fish and rainbow trout,232 and, interestingly, another study showed that excretion may also involve oxidation to a carboxyl form of the bisphenol structure.233 Estrogen analogues are degraded biotically in the environment via a variety of microorganisms that assimilate them as carbon sources, aerobically or anaerobically.234 Most cases of biological degradation of estrogen analogues have been reported from microbial cultures in sludge from wastewater and in soil samples from agricultural sites.235,236 The eventual complete lifecycle is conclusively encompassed by (1) production and fabrication of estrogen analogue sources (plastic, rubber, etc.), (2) absorption in humans and animals through ingestion, dermal exposure, or inhalation, (3) excretion via glucuronic acid to wastewater, (4) accumulation in ground waters and soils, (5) partial degradation by microbial activity, and (6) re-entrance into the food chain.

The toxicity of estrogen analogues is determined by their chemical properties, particularly the geometrical similarity to estrogen. This similarity facilitates the binding of estrogen analogues to estrogen receptor α, as was recently demonstrated by examining quantitative structure−activity relationship (QSAR) properties of a series of estrogen analogues.237,238 The results by Meyers et al.237 showed that DES (Figure 5) and bisphenol types were the estrogen analogues with the highest binding affinity to the estrogen receptor. Steroidal estrogens and phytoestrogens also appear to have high binding affinity to the estrogen receptor; however, the QSAR analysis showed a higher binding affinity of bisphenol types to the estrogen receptor.237 The chemical properties of the estrogen analogue determine its potential mutagenicity. BPA was, for instance, shown to be mutagenic.233,239 In these studies, estrogenicity was attributed to all of the bisphenols, but mutagenicity was attributed only to some, such as BPA. The molecular basis for this differentiation is not known, as no reactivity studies were performed in the context of DNA binding in this study.239 Earlier studies240,241 as well as more recent studies show, however, that BPA induces the formation of adducts but does not induce mutagenesis242 (i.e., it does not affect the DNA code during and after replication). Recent quantum-chemical studies suggest that the unsubstituted carbons on the ring moieties of BPA lead to adduct formation with guanosine residues.243 However, earlier studies indicated that the activated metabolites of BPA were responsible for adduct formation, where bisphenol-o-quinone was a suggested candidate;240 this, however, was not confirmed by other work. 3.4. Phthalates. Phthalates are a group of environmental toxins that derive from plastic products such as toys and blood bags as well as from fixatives and detergents.244 Phthalates are also found in consumer products and cosmetics, including soaps, shampoos, paints, nail polishes, glues, hair sprays, insect repellants, and medical products.245 Phthalates have been associated with reproductive disorders in humans and animals, with particular focus on reduced sperm viability246 and declining sperm counts in industrialized countries,247−249 but also with cancer.250 Phthalates like di(2-ethylhexyl) phthalate (DEHP, Figure 6) have been reported to induce testicular injuries in animal models upon long- and short-term exposure.251,252 The reported toxicological damage was caused by activated metabolites of DEHP and other tested phthalates, 719



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which were converted to monoester forms by nonspecific esterases in the mucosa membranes.252 Other studies of phthalates showed fertility-reducing effects on mice, toxic effects on animal models, and tissue-degrading effects of DEHP in the perineal region of rats.253−255 The latter of these studies showed that di-n-butyl phthalate (DBP) was even more toxic than DEHP because it produced more severe testicular atrophy in animal models.255 Major atrophy effects because of DBP were reported to occur within 4−6 days in rat models, and the major metabolite was shown to be the corresponding monoester (MDP) in urine samples.256 Phthalates are toxic to aquatic organisms such as fish and algae in fresh and salt waters.257 The analysis of aquatic organisms showed that phthalates induce acute toxicity at concentrations ranging from 0.21 to 377 mg/L, and the most hydrophobic types were found to be the most toxic.257 From the accumulated evidence, it can be concluded that the toxic effects of DEHP, butyl benzyl phthalate, and di-n-butyl phthalate (Figure 6) are related to the exposure to the activated metabolites via the intrauterine area in animals and humans.246 N-Butyl-benzyl phthalate has been recently reported to exert estrogenic activity by disrupting the endocrine system because of its similarity to estrogens (Figure 6),258,259 delineating an additional ecotoxicological and toxicological quality to this group of pollutants. Phthalates do not accumulate in vivo after metabolysis and, as with the other pollutants mentioned earlier, are conjugated to glucuronic acid after conversion to their monoesther forms244,260 (Figure 6). Conversion includes the generation of hippuric acid and benzoic acid, of which the former has been shown to be weakly toxic.258 The process of detoxification of phthalates is catalyzed by the liver, which has been found, however, to suffer lesions after incubation with phthalates over extended exposure periods in animal models. 250 The conversion of these pollutants in vivo induces the release of metastable products that retain the functional groups that are associated with toxicity (Figure 6). Therefore, aquatic environments, which are contaminated via leaking from plastic compounds deriving from sources like landfills or direct disposal of plastic in the environment, may be particularly susceptible to these compounds.261,262 The functional and structural characteristics that define the structure−activity properties of phthalates are reported in a recent analysis.263 There, similar scores of toxicity were attributed to phthalates as to PCBs based on reactivity profiles delineated in the QSAR expressions.263 These expressions include the similarity of the analyzed molecules to hormones, yielding relatively high scores for di-n-butylphthalate in particular, which was found to be structurally related to BPA in the analysis.263 An earlier QSAR/SAR analysis of phthalates showed that the length of the alkyl chains has a central role in their structure−activity relationship, as these tails contribute to the aggregation of molecules by forming microdroplets in aqueous environments exposed to phthalate contamination.264 Because such microdroplets have been found in wastewater,265 it has been concluded that the aquatic availability of phthalates is significant.266 Sholtz et al. reported that the shorter-carbonchain phthalates displayed a higher toxicity266 than longchained members, in contrast to the results in ref 264. The same study also suggested that monoesther metabolites should be regarded as more important environmental toxins than their parent phthalate structures.265

Phthalates are biodegradable and minerazable to CO2 by specific bacteria; however, the rate of these processes and the occurrence of these bacteria in the environment are not known.267 3.5. Dioxins. Dioxins are a class of pollutants that are composed of halogenated cyclic compounds containing either the dioxane or furan functional groups in their structures (Figure 7). Dioxins encompass congeners of polychlorinated

Figure 7. Examples of dioxin structures: (A) 2,3,7,8-tetrachlorodibenzodioxin, (B) 1,2,3,7,8-pentachlorodibenzodioxin, (C) 1,2,3,4,7,8hexachlorodibenzodioxin, (D) 1,2,3,7,8,9-hexachlorodibenzodioxin, (E) 1,2,3,7,8-pentachlorodibenzofuran, (F) 2,3,7,8-tetrachlorodibenzofuran, (G) 1,2,3,7,8,9-hexachlorordibenzofuran, and (H) octachlorodibenzofuran. A−D are structures of selected dibenzodioxins with a conserved dioxane group at their centers, and E−H are structures of specific dibenzofurans with a monooxidized furane group at the core of their structures.

dibenzodioxins (PCDDs), polychlorinated dibenzofurans, and also planar PCBs (which are discussed in section 3.1). The main source of dioxins is from incineration plants and industrial combustion activities,268 from the transport sector through exhaust emissions,269,270 from general combustion processes.271 Dioxins are produced as byproducts from industrial activities, such as paper bleaching, pesticide manufacturing, and the chemical industry, and they are found in wastewater sludge at significant concentrations.272 Dioxins appeared in the environment particularly after World War I, peaked in concentration during the 1960s and 1970s, and have declined slowly since.273 The persistence and bioaccumulative potential of dioxins makes them a grave environmental problem; for instance, the dioxins generated during the Vietnam War continue to cause significant problems.274 The Seveso accident in Italy, which caused an environmental disaster that spread dioxins over several square 720



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After uptake, dioxins bind to the dioxin receptor (Ah receptor) and are transported to the cell’s nucleus, where they undergo catalytic detoxification by the cytochrome P-450 system and by mono-oxygenase enzymes.298−300 The detoxification leads to the formation of arachidonate metabolites of the dioxin (dioxins conjugated to arachidonic acid) as well as glucuronic metabolites,301 where the former trigger the expression of jun and fos genes, resulting in an elevation of a pro-oxidant state in the cell.302,303 The activated state of cytotoxic stress then causes a series of events promoted by calcium release and cyclooxygenase expression,304 which eventually leads to genotoxic effects on the DNA and carcinogenesis from formed radicals.282,305,306 The pathological results are hepatotoxicity, gastric lesions, wasting, lymphoid involution, and death (at high doses).282 The reproductive effects of dioxins represent a separate spectrum from the toxicity of dioxins; however, the molecular basis for these effects is not clear. Recent studies show that dioxins trigger estrogen-like effects in mice307 and that dioxinlike agonists activate the estrogen receptor signaling pathway,308 inducing alternations in the sexual and functional development in humans and animals.309 Furthermore, dioxins are stored and transferred via breast milk, placenta, and maternal cord blood, leading to developmental disorders, cognitive impairment, and behavioral abnormalities in the offspring.310−313 QSAR studies indicate that nanogram per kilogram doses are sufficient to cause intoxication. The mechanism of intoxication depends on the following chemical and biochemical properties: (a) The binding kinetics of the main target of pollutants, the aryl hydrocarbon-receptor (AhR), increase with the level of halogenations of the dioxin,314,315 (b) the lipophilicity of the dioxin affects the level of accumulation in fat-tissues,316 and (c) the level of halogenation affects the ability of dioxins to trigger the formation of superoxide radicals in the cell.317 By considering various structures of dioxins (Figure 7), the first criterion (a) can be attributed to all dioxins; nevertheless, the positions of the chloride atoms on the benzene rings differentiates their binding properties to the AhR and thus affects their potency.318 It is noteworthy that chlorinated positions on the lateral sites of the structures increase binding affinity, particularly in relation to the furan species of dioxins, and the planar area of the dioxin congeners favors binding to the AhR-receptor compared to other less planar congeners.318 Dioxins are lipophilic because of their aromatic moieties, but because of this, they are simultaneously more fat soluble than pure aliphatic groups, which facilitates traversing the cellular membrane. Binding to AhR almost always triggers superoxide dismutase (c), leading to the production of reactive oxygen and nitrogen species as a general and nonspecific defense against the dioxin. However, the unusually low concentrations required to define intoxication by dioxins in QSAR studies highlight the endocrine-disruptive properties of dioxins, which follows from their similarity to hormones and thus affects DNA and gene transcription. Recent studies sustain that dioxins bind to the estrogen receptor (Figure 8) and that dioxin affinity to the estrogen receptor is increased in combination with estradiol.319 Endocrine disruption is facilitated by the structural features of dioxins, which have been linked to estrogen-dependent tumors.320 Biomolecular mechanisms underlying the estrogenic effects of dioxins have been reported in a recent study by Ohtake et al.321 They found that the ARNT/Ahr dimer

kilometers, sparked the establishment of the Seveso directives, which implemented regulations to avoid large-scale dioxin releases into the environment.275 Dioxins are unusually persistent molecules, as their structures (Figure 7) yield high chemical stability and lipophilicity; therefore, they have half-lives which are estimated to be 50− 100 years110 with particularly long preservation periods in soils, rivers, and sea sediments.276 Given the presence of several chlorinated groups, the cyclic units of dioxins (benzene, furan, and dioxin) are inaccessible to oxidizing agents, requiring dehalogenation before oxidation, a catalytic process that has been reported only in bacteria.277 The slowest processes of degradation of dioxins are estimated to be more than 240 years for the hexa-chlorinated dioxin congeners, whereas the minimum required time for complete degradation is estimated to be 17 years for some furan congeners.110 Studies from the late 1980s showed high concentrations of dioxins in samples taken from individuals who participated in spraying the herbicide Agent Orange in the Vietnam War.278 Children exposed in the Seveso accident showed measurable concentrations of dioxins from the accident taken in samples 30 years later.279 The most toxic chlorinated dioxins, furans, and some dioxinlike PCBs cause similar effects but differ significantly in their potency. 2,3,7,8-TCDD (Figure 7A) is the most potent one. The potency of the various dioxins/furans is compared with that of TCDD, which gives a toxic equivalency factor (TEF) for each compound. The factor for TCDD is defined as 1, whereas as the other dioxins are given equal or lower factors. This is used mainly when estimating the potency of mixtures. The factor of each compound is multiplied by its concentration/ amount, and all of the results are added to give the TCDD equivalent (TEQ). The TEF values are updated regularly as new information becomes available.280 Dioxins have properties that lead to disruption of reproduction in animals, neurological damage, induction of cancer, teratogenesis, and interference with the endocrine system, inducing feminizing and nonfeminizing hormonal interference that affects reproductive development.281−289 Dioxins accumulate in small organisms and are transferred through the food chain to higher-order animals in higher doses.290 Dioxins cause liver toxicity and induce the expression of high levels of cytochrome P-450 1A1.281 Dioxins have been shown to cause inactivity of spermatozoa in a recent study from Japan.281 In this study, the sources of dioxin contamination in wildlife were reported to be herbicides applied in rice fields, industrial and municipal waste incinerators, and illegal dumping of waste in sensitive habitats.281 Furthermore, dioxins form a specific threat to aquatic environments, as has been noted for sea birds and polar bears.291−293 Recent studies from South Korea have shown the presence of tetrachlorinated dibenzodioxins and dibenzofurans in flounder, mullet, and gizzard fish, with particularly high concentrations of 2,3,7,8-tetrachlorodibenzodioxin (Figure 7).294 The dioxins were found to accumulate in bottom-residing species, such as mussels and clams, which contained a large number of dioxin congeners. Aquatic environments are more sensitive to biomagnification than terrestrial ones, as more species feed off the bottoms sediments and become carriers of higher dioxin doses that are subsequently ingested by larger species.294−297 In such environments, many species have a higher fat content to cope with lower ambient temperatures and carry more pollutants in their fat reserves. 721



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combustion, impurities, or exhaust emissions.340 PFCs encompass several members of linear polyfluorinated carbon chains with hydrophilic ends. Members of the PFC family include perfluorobutanesulfonate, perfluorobutanoate, and perfluorodecanoate, and there are at least 20 perfluorinated chemicals in use today (Figure 9).

Figure 8. Molecular surface of the estrogen hormone receptor. The estrogen analogue is visible in green and is engulfed in the molecular surface of the receptor. Structure illustrated with PyMol.194 The molecule is colored by the electrostatic potential, where red is negative and blue is positive. Because the binding site is on a white (neutral) location, substrates compatible with the receptor are not typically very polar.

associates to estrogen receptors (ER) α and β, triggering estrogenic activation and transcription after dioxin intoxication. Specific microbes degrade dioxins in both aerobic and anaerobic environments, applying dehalogenating enzymes where the congeners are deprived of one chloride atom per catalytic cycle.322−324 Recent studies show that some anaerobic bacteria carry out the unusual process of dehalorespiration, where the reductive dechlorination is coupled to energy metabolism via the dependence of specific cofactors, making certain dioxins suitable as carbon sources.325 Other groups of bacteria oxidize dioxins through the action of a group of enzymes known as the angular oxygenases, which oxidize the angular positions of dioxins, inducing a solubilizing effect on the congeners. Some genera that degrade dioxins are Sphingomonas, Pseudomonas, Burkholderia, and Geobacter,326,327 and these strains have also been used in demonstration experiments for sludge decontamination.328 3.6. Perfluorinated Compounds and Brominated Flame Retardants. Perfluorinated compounds (PFCs) and brominated flame retardants (BFRs) are groups of industrial compounds that are extensively used as flame retardants and are therefore presented in the same section even though there are some chemical differences. PFCs and BFRs have been found in the environment virtually everywhere; they have been traced in polar bears and other wildlife as well as in humans.329−336 BFRs and PFCs are used in consumer products, textiles, carpets, paints, electronic equipment, lubricants, chemicals, and fire extinguishers;329,337,338 they are applied to delay incineration and combustion of the material, and in this manner, they reduce the risk of house and building fires. PFCs and BFRs are strongly biopersistent and reside in the body of humans and animals over long periods and were recently found at considerable concentrations (nanograms per kilogram) in a series of assessments of the general population in industrialized western countries.329,339 Various PFCs are traceable in outdoor samples taken in rural areas and urban areas because they are semivolatile and occur in high-traffic areas as byproducts of

Figure 9. Typical perfluorinated compound (PFCs): (A) perfluorobutanesulfonate, (B) perfluorobutanoate, (C) perfluorodecanoate, (D) perfluoropentanesulfonate, and (E) perfluorooctanoate. The general structure is a linear chain of carbon atoms saturated with fluorine atoms and has one or two hydrophilic ends.

BFRs represent a series of compounds including biphenyls, alkanes, and cyclic and aromatic compounds (Figure 10) that are brominated to modulate the material’s properties, including color, structure, and physical stability. Several of these substances have been recently traced in placenta, umbilical cord blood, breast milk, serum, plasma, and blood of humans and animals.341,342 PFCs have not been subjected to proper regulations and are under heavy scrutiny, particularly because of their persistence, and their bioaccumulative and toxic properties were established in consensus at the 2006 Stockholm convention.343 PFCs have been traced in Canada, the U.S., and in the E.U. in the aquatic, terrestrial, and air phases stretching over 6000 km across the atmosphere344−347 in addition to in Japan348 and in the Arctic.349 The pattern of distribution of PFCs indicates that their transport is facilitated by trade winds and they can migrate across large distances. The distribution of PFCs also reaches indoor environments, with nanogram per cubic meter levels in indoor air, household dust (microgram levels), and tap water,350 leading to contamination of the aquamarine food web.339,351,352 PFCs have also been detected in fish, where two types of PFCs in particular have been found to accumulate in trout and sea food from China at nanogram per gram of tissue concentrations.353,354 Freshwater fish in the Bavarian region have been reported to contain nanogram levels of PFCs in muscle tissue.339 More critically, entire Inuit populations in Northern Canada have been found to be subjected to PFC 722



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circulation, enhancing their bioaccumulative potential.375,376 Their structures, particularly of the PFCs, present carbon sites that are fully occupied with fluorine atoms, which makes them difficult to excrete because they are not lipophilic or hydrophilic; however, recent studies show that excretion mechanisms involve conjugation to glucuronic acid as well as glutathione conjugation to their oxidized hydrophilic ends.377 Studies on humans show that some PFCs are not excreted at all, whereas others are readily secreted through the urine.378,379 Genuis et al.378 reported that the PFC perfluorohexansulfonate remains in the body for a minimum of 1.5 years with minor fluctuations in concentration. Another group reported that the half-life of PFCs in humans and animals may be even longer, up to 4 years.380 There is evidence from rats exposed to perfluorinated octane sulfonic acid that PFCs trigger the cytochrome P-450 system and peroxisomes during detoxification.381 In parallel to this, detoxification attempts on PFCs can also be inhibited by other PFCs, according to early studies on the P-450 system, through a potential mechanism of saturation of the P-450 system.382 Other studies show that some PFCs (perfluorinated fatty acids) are secreted only through the biliary tract, other PFCs may be excreted through the urinary system,379 and even hair is an attributable route of excretion for PFCs.383 Recent studies show that there are differences between male and female rats in the excretion pattern of PFCs, where females excreted some 20% more of a specific PFCs than male rats.384 Detoxification of BFRs has been studied in more detail, and it was found that the hepatic detoxification system is triggered, encompassing the cytochrome system, mono-oxygenases, superoxide dismutase enzymes, and glucoronidases for oxidation and conjugation.385,386 Liver microsomes are particularly active in the process of detoxification, with some limitations on metabolizing highly brominated compounds.387 Monohydroxylation or dihydroxylation (adding one or two OH groups) to BFRs have been reported to be central catalytic processes exerted by the cytochrome CYP enzymes.388 These enzymes are found in most animals but with different efficiencies, as rats were found to detoxify BFRs more readily than pigeons.389 Rats were shown to accumulate BFRs at high rates in the adipose tissue, and hydroxylated BFR metabolites were secreted through urine and feces.389 Three other forms of excreted metabolites were registered in rats, although their chemical structure remains undetermined.390 Bioaccumulation of BFRs has also been found in marine species such as tropical sponges and algae, where several brominated metabolites were isolated from samples recently.391−394 The environmental fate of BFRs and PFCs has been studied to some extent. Microbial degradation of BFRs has been documented since the early 1980s, encompassing aerobic, anaerobic, and marine microbial degradation of brominated compounds,395−398 with the exotic properties of the haloalkane dehalogenases found only in bacteria and plants (Figure 4, section 3.2). Brominated biphenyls can also be degraded by methane- and propane-fixing bacteria in sediment samples.399,400 The products, metabolites, and released compounds from these microbial reactions are, however, not known, and the environmental life cycle of BFRs therefore remains elusive, calling for further research to develop methods for complete remediation of such compounds in the environment. PFCs are degraded slowly in the environment by enzymecatalyzed dehalogenation reactions.401 Because PFCs repel both fatty compounds and aqueous compounds, their end station in

Figure 10. Brominated flame retardants: (A) bromofluoromethane, (B) dibromodifluoromethane, (C) bromotrifluoromethane, (D) 2,2′,4tribromodiphenylether, (E) 2,4,4′-tribromodiphenylether, (F) 2,2′,4,4′,6-penta-bromodiphenylether, and (G) decabromodiphenyl ethane. The level of saturation with bromine increases the physical stability of the materials toward oxidation and combustion.

contamination because of their traditional fish and meat diet.355 Although the dispersal of PFC compounds is global already, not all of the environmental effects have been elucidated. BFRs are of equal toxicological concern, as they have been identified in children’s serum and in adults, where they accumulate in lipid tissue.356−358 BFRs affect nerve development in fetuses and newborn children and cause delays and problems in cognitive and motor development in infants, as they associate with thyroid function through hormonal interference.357,359−361 The toxicity of PFCs has been under scrutiny, and several studies have failed to conclude the existence of toxic effects of PFCs;362−364 however, other studies have demonstrated reduced intercellular communication and inhibited cell proliferation,365 cellular homeostasis and toxic responses in dolphin cells and rat liver cells,366 alternation of cell membrane properties,367 carcinogenesis,368,369 tumor promotion in rainbow trout,370 and narcotic effects on Daphnia magna.371 Larger cohort studies have shown long-term effects leading to a higher number of bladder cancer deaths in a perfluorooctanesulfonylfluoride-exposed environment at a production facility.372 A further study showed liver hypertrophy and reduced serum cholesterol and glucose levels as well as an increases in hepatic palmitoyl CoA oxidase.372 Neuroendocrine effects have been triggered in rats exposed to PFCs, including altered serum corticosterone levels and norepinephrine concentrations in the hypothalamus.373 PFCs have also been demonstrated to have a high biomagnification potential, as piglets were shown to have higher concentrations of PFCs in the blood than the sow.374 The detoxification mechanisms of BFRs and PFCs are poorly understood. A recent review suggests that PFCs are excreted via the liver and kidney and are potentially reabsorbed via the intestines to the blood, a process known as enterohepatic 723



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Table 1. Principal Properties of the Seven Classes of Pollutants Described half-life in the environment

pollutant

chemical properties

PCB

decades−centuries

aromatic/lipophilic

HAHs estrogen analogues phthalates dioxins

years−decades months−years

aromatic/lipophilic aromatic/hydrophilic

? decades−centuries

lipophilic aromatic/lipophilic

PFC

?

BFR

?

semihydrophilic, halophilic aromatic/lipophilic

DNA binding

target systems

implicated in cancer

hormone receptors, lymphocytes, thyroid gland testes, kidneys, liver, breast, nerve system hormone system

yes

yes428,429

yes yes

hormone system, testes, glands endocrine system, nerve system, testes, breast nerve system and brain, testes, maternal milk placenta, breasts, serum, plasma, nerve system and brain

? yes

yes (see relevant chapter) DNA damage, mutagenicity (see relevant chapter) ? yes (see relevant chapter)

?

yes (see relevant chapter)

?

?

the environment is in the terrestrial and groundwater phases.401 Metabolism of such compounds in groundwater reserves is expected to occur slowly, as groundwater is low on light, reducing the possibility of photocatalytic breakdown that is frequently associated with degradation of pollutants. Smaller PFCs like tetrachloroethane (and potentially tetrafluoroethane) can be degraded by Dehalococcoides; however, larger congeners of the PFCs are not known to be degraded by bacteria.401 Larger PFCs may be degraded by atmospheric and aquatic reactions involving OH radicals,402 causing the transformation of PFCs to perfluoroinated carboxylic acids in the environment. Nitrate forms can be produced through interaction with nitroradicals, leading to stable products of PFCs.403 Photolytic degradation has been registered in the Great Lakes in the U.S. based on degradation products of PFCs;404 however, the life cycle of PFCs has not been mapped completely, and existing studies suggest that no complete degradation of PFCs takes place.405 A QSAR study on the binding of PFCs to the thyroid hormone transport protein transthyretin suggested a decreasing order of binding affinity, with perfluorohexane sulfonate > perfluorooctane sulfonate/perfluorooctanoic acid > perfluoroheptanoic acid > (sodium) perfluoro-1-octanesulfinate > perfluorononanoic acid.406 The length of the chain and the functional group at the end of the chain thus determine the binding strength of PFCs to the thyroid protein, and this may be related to PFC toxicity.366,375 PFCs with sulfonic groups tend to be more toxic, and an increasing length of the chain is known to increase toxicity.407 PFCs with a length shorter than seven carbon atoms do not accumulate in rainbow trout, and bioconcentration factors increase by a factor of eight for each fluorinated site for PFCs with a length of 8−12 carbons.353 There are, however, no existing QSAR results on binding to the cytochrome system, AhR, or estrogen receptor, all of which are possible candidates for interaction with PFCs. QSAR studies have been performed on the ability of BFRs to inhibit estradiol activity and to bind to the thyroid hormone receptor and to the plasma transport protein transthyretin.408 BFRs have been found to exert androgen antagonism and progesterone antagonism and to inhibit estradiol metabolism, which makes them endocrine disruptors because they display higher potencies than natural ligands and clinical drugs tested for positive controls.408 Further QSAR studies show that the highest potencies and metabolic degradation rates are attributed to less brominated BFRs with bromine substitutions in ortho-positions and with bromine-free meta- and parapositions 409 (see the examples of relevant ring structures in Figure 10). The same study reports that the similarity to

androgens and the nucleophilicity of BFRs serve as criteria to assess their toxicity computationally.

4. CONCLUSIONS The persistent organic compounds presented in this review share chemical structures that exert high chemical stability, high reactivity after metabolic conversion to active metabolites, high lipophilicity and fat solubility, and extraordinary long chain lengths, particularly for PFCs (Table 1). Many of these compounds require years to centuries to be degraded and fully removed from the environment. The toxicological effects exerted by these compounds encompass endocrine disruption, carcinogensis, and feminizing and antireproductive effects, particularly on males among examined species, as well as neurotoxicity and induction of cognitive and developmental disorders. Genotoxicity, potentially leading to cancer, has been implicated for multiple categories of pollutants in this review.178,242 A series of events at the level of DNA transcription and translation plays a role in addition to the chemical properties of the compounds, resulting in three different categories of toxicological effects: genotoxicity, implying a chemical reaction of a compound with DNA, mutagenicity, implying a genotoxicity without an effect on the cell cycle, and carcinogenicity, a genotoxic effect that directly affects cell cycle mechanisms. The reactivity of a molecular species is an important predictor of genotoxicity; however, other factors like transport properties are important as well.410 Several paths of natural degradation exist; however, these often require specialized microbial environments, photocatalysis, or chemical atmospheric degradation in the environment, for instance, through radical reaction, which may take years to complete. Even then, some compounds do not completely reach a fully mineralized state or conversion to inactive forms. For each of the categories that we have examined in this review, we list suggestions for further research here. (1) Polychlorinated biphenyls. PCBs are a principal group of pollutants that are abundant in electronic waste in particular and are increasing in quantities released to the environment, including transport from industrialized countries to developing countries.411 Research should focus on alternative materials in order to phase out the use of PCB completely. New methods for destruction and/or incineration of these compounds, with specific filtering and removal of toxic incineration products, should be developed for handling PCB-containing waste. (2) Halogenated hydrocarbons. Because halogenated hydrocarbons are emitted mainly through industrial processes and application 724



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in no way be used to argue that the risks of exposure to a cocktail of pollutants is negligible if all pollutants remain under their respective tolerance levels.419,420 The failure to apply the precautionary principle (agreed upon in the United Nations’ Rio declaration on environment and development) to the introduction of new compounds in the environment has led to a situation where PFCs and BFRs are now applied ubiquitously without a full investigation into their toxicity. (“Principle 15: In order to protect the environment, the precautionary approach shall be widely applied by states according to their capabilities. Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation.”) The use of nanomaterials, for example, in electronic devices and personal-care products, may lead to similar problems in the near future,421,422 but systematically testing compounds for toxicity may be extremely tedious, for example, see ref 423. If all new products were either completely recyclable or biodegradable within a short period, then many problems would be prevented. For instance, recent overview papers have clearly shown that it is possible to move to predominantly organic farming without jeopardizing the world’s food supply.424,425 Similarly, an acetylation process for preserving wood that does not require or produce toxic chemicals has been known for almost a century426 but has only recently been commercialized. Hence, there is enormous technical potential to reduce the burden on ecosystems resulting from pollutants, but this potential may be difficult to realize in a world with increasing trade liberalization.427

of some chemical products, the research on this class of pollutants should be focus on recycling and proper wastehandling technologies. Incineration and nonselective release of these chemicals in the environment, like in landfills, should be prevented. (3) Estrogen analogues. The chemical properties responsible for adduct formation to DNA must be identified because not much is known about this process. New studies of the effect of these compounds on aquatic species are needed too, as the environmental fate of estrogen analogues is closely coupled to sea waters, rivers, lakes, and sediments.35 (4) Phthalates. Future research should encompass assessment of the environmental concentration of monoesthers in soils, sediments, wastewaters, and groundwaters (in a similar fashion as the study in ref 213). Future studies should also evaluate the half-life of phthalate monoesthers and further scrutinize the effects that phthalates induce on mammals and other animals, as monoesther metabolites have been reported to be more potent environmental toxins than phthalates.265 The increased toxicity of phthalates with increased hydrophobicity also warrants further research because the mechanism of toxicity is not completely clear. DNA-binding and interference studies with hormone receptors are also relevant for further research. (5) Dioxins. These compounds are retained at high levels in the environment,412 affecting humans and animals and disturbing human development at the evolutionary level.413−415 New studies are needed to address how their spread, based on industrial activities, incineration, and other processes can be prevented. (6) Perfluorinated compounds and (7) brominated flame retardants. These compounds, particularly PFCs, are emerging pollutants with no studies performed on their longterm effects. A set of cohort studies or large-group studies organized by national institutes of health and environmental and health ministries should be considered. These compounds have a particularly high dissemination level, as they are present in nearly all consumer products, yet they represent a source of pollution and contamination of natural environments and an environmental stress impact that we are only beginning to understand. No knowledge on their interaction with DNA with or without modifications from detoxification processes is available. Studies on the potential carcinogenic properties of their metabolites and also on the nonmetabolized PFCs are required. Studies on environmental fate after incineration and waste disposal are also required. Several of the compounds treated here resemble natural substrates; it is therefore logical that some of these can interfere with metabolism of nutrients, affecting the proper growth of various species and thus entire ecosystems of their natural substrates. Habitat loss and climate change form the largest threats to the viability of ecosystems worldwide,416 and because humans represent the apex in the global food chain, humanity is under threat as well. The presence of pollutants in the environment is a direct threat to ecosystems, but the importance relative to other hazards has not been quantified in the same manner.416 There are, however, many examples of pollutants directly involved in the decline of ecosystems, such as the muchdiscussed recent case of the decline of honeybees that has been attributed to pesticide exposure.417,418 Most studies reported in this review are on the effect of single compounds; however, the combined effect of multiple pollutants may, under many circumstances, be stronger than the sum of its parts.418,419 The fact that such issues are much harder to investigate than single cause-and-effect studies should

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AUTHOR INFORMATION

Corresponding Author

*Tel: +46184714205; E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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