Photodynamic

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Figure 1. Examples of phototoxic compounds.

Solar radiation can also be harmful to biota via less direct mechanisms; specifically by dramatically increasing the toxicity of many natural and anthropogenic organic compounds [16-18] (see Figure 1). In fact, many species of plants and animals have evolved mechanisms that take advantage of photoac-tivated toxicity to defend against predators, foragers, and infectious agents [19].

These defense mechanisms involve production of compounds that, once ingested, adsorbed, or absorbed by predators, act as sensitizers of cellular and tissue damage in the threatening species. The numerous defensive compounds produced include acetylenes, benzopyrans and furans, furanocoumarins, and other classes of compounds [18,19]. The evolutionary processes underlying the history of plant photo-defense and pest adaptation is well understood and generally regarded as achieving some level of constantly-shifting balance. The same cannot be said for the phototoxic effects of anthropogenic compounds, including the fairly short-lived pesticide a-terthienyl, organic dyes, and PAHs.

The PAHs are of particular concern in aquatic environments. They have accumulated in many locations to concentrations in sediment and water that are well above those required to cause significant phototoxicity when tested in the laboratory. The PAHs also, in nearly every contaminated site, consist of hundreds of unsubstituted and variously substituted compounds that differ in their capacity for photoactivation, uptake, degradation, and environmental modification, including potential photo-modification to more toxic products [16,20-24], The complexity of these mixtures makes predictions of phototoxicity risk a uniquely site-specific task, relative to other contaminants. PAHs are of ongoing concern because they still are introduced into surface waters by urban and industrial runoff, petroleum releases, and aerial deposition [22,25]. Most PAHs present in aquatic systems are also relatively recalcitrant to environmental degradation, and are bioaccumulative, having logKow values ranging from 2 to 7. The breadth of the PAH contamination problem is clear from the fact that PAHs are significant contributors to the contamination at over 60% of the United States Environmental Protection Agency's National Priorities List of SuperFund cleanup sites [http://www.atsdr.cdc.gov/tfacts69.html].

7.2 Terminology

The increase in toxicity of compounds in the presence of U V or visible radiation has been variously termed photoactivation, photoinduction, photosensitization, photodynamic action, phototoxicity, or combinations of these terms [16,17,26]. Largely due to the history of the science, the most consistent terminology is that photodynamic photosensitization, or photosensitized photodynamic action, refers very specifically to conditions where a sensitizing chemical is present, and toxic action requires the presence of oxygen [27]. A sensitizer is any chemical that responds to photons, and acts as a receptor for the transfer of that energy into a chemical or biological system. Not all photosensitized toxicity necessarily involves photodynamic action. While empirical evidence abounds for oxygen-associated photosensitization, there is also a strong theoretical basis for direct interaction of excited state sensitizers with biomacromolecules (e.g., intercalation of PAH with DNA [28]). There is also a strong theoretical basis, as well as some empirical evidence, for photon-mediated enhanced toxicity resulting from modification of parent compounds to more toxic products via photodegradation processes (which may involve oxygen) [21,23,29,30]. It has been theorized also that metals in aquatic systems that are maintained in relatively non-toxic, ligand-bound states, may be released from those complexes upon irradiation by solar radiation. In fact, this is a photosensitized reaction; as it is the ligand itself (e.g., dissolved organic carbons) that is the receptor of the photon energy which releases metal from the ligand-metal complex. Some photosensitized toxicity mechanisms do not directly photochemically involve the compounds that trigger the effects. For example, the disease porphyria, the accumulation of elevated levels of heme precursors, can be triggered by pesticides and pharmaceutical compounds that are not sensitizers themselves [8]. In this case, it is the heme precursors that act as photosensitizers once they achieve sufficient concentrations in irradiated tissues, primarily the epidermis.

Rather than attempt to incorporate complex terminology that would be precisely descriptive of each mechanism, I will use the very general terms photoactivated toxicity or phototoxicity throughout this chapter. Only where particular mechanisms have been identified, or are of importance to the discussion, will the more specific terms just discussed be applied, generally where photodynamic photosensitization or photomodified toxicity has been demonstrated.

7.3 Historical perspective

The fact that the chemical activity of many compounds is greatly increased in the presence of solar radiation has been recognized for millennia. Arguably, the first recorded documentation of photoactivation can be found in Egyptian and Indian writings dating as far back in history as 2000 BC, where application of the sap of plants such as false Bishop's Weed (Ammi majus, Umbelliferae), Psorlea coryligolia, and others, followed by immediate exposure to solar radiation, was recommended as a treatment for vitiligo [31,32]. The active ingredient present in the sap of these plants used to treat vitiligo was identified by Fahmy and Abu-Shady [33] as 8-methoxypsoralen. Since that time, numerous additional psoralens and other allelochemicals have been identified in a broad range of plant species, including figs, lemons, limes [34], and certain oranges (Citrus bergamia) [35], celery [36], and other species too numerous to list [37], In many cases, the discovery and isolation of these compounds has led to their use in a variety of phototherapies for the treatment of psoriasis, eczema, some forms of cancer, and other afflictions [32].

As well as these beneficial (either for the plant or for humankind) uses of photoactivation of plant compounds, there are equally numerous and varied examples of harmful phototoxic responses to plant compounds. Many plants potentially ingested by livestock can initiate photosensitizing responses [38]. In particular, plants that produce sufficient concentrations of furanocoumarins, hypericin, and cercosporin have been documented to affect livestock in this manner [39]. A specific example of non-target species photosensitization by plant compounds is the dramatic erythemic response of agricultural workers exposed to the sap of celery (Apium graveolens) plants during harvest [40].

Extreme cases were first reported in celery strains bred specifically for their resistance to fungus (pink-rot disease). The compounds produced trigger fatal phototoxicity in pest species, as well as severe photodermatitis in field workers [41]. It has also been well documented that celery plants stressed by fungal invasion produce elevated levels of these compounds (3 to 30 times higher than normal) [42]. Cases of photodermatitis triggered in humans by ingestion of celery (e.g., [36]) and other plants [43] are also occasionally reported.

The number of photoactive compounds present in the environment has expanded considerably due to the activities of man; Santamaría and Prino [18] listed 380 compounds, including many that were anthropogenic, over three decades ago (examples of phototoxic compounds are illustrated in Figure 1). Several insecticides, either synthesized or refined from naturally-occurring compounds, have been produced and used in commercial agriculture e.g., organic dyes including erythrosin-B, registered for control of houseflies in chicken farming [44], and alpha-terthienyl, used extensively in mosquito control [45]. Additional photoactive compounds produced for purposes other than their phototoxic potential include many pharmaceuticals (e.g., tetracycline antibiotics and phenothiazine tranquilizers), organic dyes, and PAHs, which are present at some level in all petroleum products, coal gas, creosote, soot, and numerous other anthropogenic chemicals [27].

These early historical examples of phototoxicity were of terrestrial origin and occurrence. The potential for photoactivated toxicity in aquatic systems was not considered until the 1900s, probably because exposure to natural compounds described and prescribed by ancient herbalists and naturalists occurred terrestrially, and did not have an aquatic counterpart. Most natural compounds do not accumulate in aquatic systems because they are either rapidly degraded once free of plant tissues, do not enter aquatic systems, or are rapidly diluted if they do. The potential for photoactivated toxicity increased dramatically as PAHs, photoactivated pesticides, and other potential sensitizers were released into the environment and, in some cases, accumulated in high concentrations in aquatic systems.

That phototoxicity might be a concern in aquatic systems was first suggested by the work of Jodlbauer and Tappeiner [46] who demonstrated that anthracene was phototoxic to Paramecia (reference by Santamaría and Prino [18], see Table 1). Later, Mottram and Doniach [47,48] and Doniach [49] studied the photoactivation of several additional PAHs in Paramecia, with the specific goal of comparing the compound's potential for both carcinogenicity and phototoxicity. It is interesting to note that these researchers were the first to incorporate various controls to demonstrate that the compounds were not toxic in the absence of UVR, that irradiation of the exposure media prior to exposure did not increase toxicity, and that increasing the duration of the uptake period prior to UV exposure increased toxicity. These latter two points illustrated that, at these exposure levels, photoactivated toxicity occurred within the organism, rather than in the exposure matrix. Prior to the 1970s, most research on phototoxicity in aquatic organisms focused on the relationship between carcinogenicity and phototoxicity and was driven by the assumption that testing for the latter effect was much simpler than testing for the former, and could be used for rapid screening. Paramecia remained the model organisms in studies that both elucidated this relationship, and expanded the list of compounds known to be phototoxic [50-56]. In work discussed at length later, Morgan and Warshawsky [57] demonstrated that several PAHs were phototoxic to brine shrimp (Artemia salina).

The specific organisms used in these studies were selected for practical experimental expediency in addressing critical medical questions, rather than because they were aquatic, or because their response to exposure might represent potential effects in aquatic systems. The realization that phototoxicity could be of significant concern specifically in aquatic systems was made serendipitously by Bowling et al. [58] during anthracene fate and effect studies with fathead minnows (Pimephales promelas) conducted in natural radiation in 1980 and 1981. This work clearly demonstrated that solar radiation exposure dramatically increased the toxicity of anthracene, most notably at concentrations well below those that had caused mortality in laboratory exposures (in the absence of UVR). These exposures were conducted in outdoor troughs maintained at the Savannah River site (Aiken, SC). This system provided an elegant way for the authors to largely disprove the hypothesis that photomodification of anthracene dissolved in exposure water could cause toxicity. Fish held in shade downstream of unshaded sections were not affected, whereas fish held in full solar radiation downstream of shaded sections were. Also, when fish were allowed to depurate anthracene prior to solar radiation exposure, they were not affected. Although not definitive, these results strongly suggested that the primary mechanism of toxicity was excitation of chemical present in tissues, rather than photo-modification of external compound. Also, this was the first report of phototoxicity in fish or other aquatic vertebrates.

Subsequent to Bowling et al.'s [58] work, researchers have quantified or characterized the toxicity of numerous PAH and other mostly anthropogenic compounds, elucidated the chemical mechanisms underlying photactivated toxicity, and addressed several of the components necessary to begin ecological risk assessment for these effects in nature. In addition to the PAHs, the pure compounds a-terthienyl (e.g., [59,60]) and phenylheptatriene [61], 2,4,6-trinitro-toluene, dinitrotoluenes, diaminotoluene (and several of their metabolites) [62-64], and carbaryl [65] (although Wernersson [66] found no activation) have been demonstrated to be phototoxic in aquatic environments. In addition, complex mixtures (containing primarily PAHs) present in petroleum products [67-69] and various sediments [70-73] have been shown to be phototoxic. The dependence of oxygen on the phototoxicity process has been demonstrated numerous times (e.g., [61,74-77]) and factors (in addition to oxygen) that might ameliorate phototoxicity, including dissolved organic carbon [78,79], ^-carotene [80], and turbidity [73], have been studied, and the sensitivity of early lifestages has been investigated [81-83].

In general, the research to date has defined the potential for phototoxicity of specific compounds to individual species. Several authors have discussed the importance of considering the environmental and ecological factors that miti gate these conditions, including photoperiod, UV dose, and the spectral characteristics of solar radiation in specific habitats [75,84-91] and potential adaptation in exposed populations [92,93].

7.4 Mechanisms of action

The chemical/physical process common to all photoactivated toxicity events is the absorption of photon energy (Figure 2A), generally in the 280 to 400 nm wavelength range, by a sensitizer molecule (e.g., PAH) [94,95]. The energy absorbed results in promotion of electrons from their ground-state orbitals to

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