Physicochemical Modifiers

Many anthropogenic pollutants find their way into watercourses, either through leaching, spillage, run-off or through licensed effluent discharge. A number of volatile or gaseous chemicals, such as dioxins, may contaminate terrestrial as well as aquatic environments at a local or global level. PCBs of low molecular weight are more prone to volatilisation and are thus more likely to spread through the atmosphere, causing terrestrial pollution via deposition onto soil or biota. For example, high concentrations of PCBs have been detected in the Arctic polar regions, as a result of dispersal by aerial transport.7®-80

A chemical must have certain physicochemical properties to elicit an endocrine disrupting effect. For example, the ability to enter the body and to cross the cell membrane into the cellular medium requires a degree of lipophilicity. Lipophilic potentials may be compared by reference to the chemical's octanol-water coefficient (usually expressed as log Kow). This property, together with molecular size and chemical structure, has an important influence on the bioaccumulation

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80 D.J. Thomas, B. Tracey, H. Marshall and R.J. Nostrom, Sci. Total Environ., 1992, 122, 135.

potential of a chemical and determines the maximum effective exposure concentration. Reduced planarity of a compound lowers uptake and bioaccumulation potential. Prey-predator interactions can result in biomagnification within the food chain, resulting in a constant internal dose; effects may then manifest themselves accordingly.

However, not all EDs with a high log Kow possess or require the ability to bioaccumulate in order to be biologically active. For example, phthalate plasticisers, chlorophenols from Kraft mill effluents and natural or synthetic hormones can influence an organism's hormone profile and affect reproductive function and immune response without exhibiting bioaccumulation.81,82

It might be assumed that a prerequisite for an endocrine disrupting chemical to operate through a receptor-mediated process is a molecular structure similar to that of the natural hormone for which it shows agonistic or antagonistic activity. However, it has been demonstrated that, at least in the case of the oestrogen receptor, a chemical may show activity without having obvious structural similarity. This has resulted in the oestrogen receptor being labelled 'promiscuous' by some researchers. Nonetheless, it appears that an active, charged chemical group at the para position (usually phenolic and, in the case of oestrogen mimics, mirrored at the opposite position) may be a key structural requirement for attachment to the cellular receptor.

In addition to their endocrine disrupting properties, it must be appreciated that many of the chemicals in question possess more general toxic properties, which may be potentiated by metabolism by the organism. Several PAHs, PCBs and PCDDs are carcinogenic, while certain phthalate esters can enhance the excretion of zinc, potentially leading to zinc deficiency. Zinc, an essential element, plays a vital role in spermatogenesis and mature T-cell production. Deficiency may result in abnormalities of the male reproductive system, depletion of spermatogenesis and suppression of the immune system.

Bioconcentration, Bioaccumulation and Biomagnification. These aspects are determined by the physicochemical properties of a chemical, an organism's ability to excrete the chemical, the organism's lipid content and its trophic level. Bioconcentration relates to the difference between the environmental concentration and that of the body tissues. A high bioconcentration factor (BCF) predisposes to bioaccumulation. The upper limit of bioaccumulation is determined by lipid levels in the organism's tissues. Whether the resultant body burden causes biomagnification in the food chain depends upon the metabolic capabilities of the exposed organism.

Different species within a given environment will be exposed to varying concentrations and mixtures of compounds, and will exhibit different accumulation patterns. Congener patterns (in the case of PCBs, for example) may also vary in the same species at different locations, reflecting the varying concentrations in their major food source.83

81 J. E. Harries, D. A. Sheaham, S. Jobling, P. Matthiessen, M. Neall, J. P. Sumpter, T. Taylor and N.

82 A. E. Karels, M. Soimasuo, J. Lappivarara, H. Leppanen, T. Aaltonen, P. Mellanen and A. O. J.

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Biotransformation and Excretion. Selective biotransformation is known to influence the biological effects of chemicals at both the species and individual level. Specific cytochrome P450 subfamilies (CY P450) of the mixed function oxidase system have evolved throughout the vertebrate classes as a means of chemically modifying steroid hormones and exogenous lipophilic compounds into forms suitable for conjugation reactions to form more hydrophilic and hence more excretable compounds. An explosion of genetic diversity in these enzymes has occurred over the last 400 million years, especially in the case of the CYP2B superfamily. The CYP1A superfamily, responsible for metabolising planar compounds, is present in all marine vertebrates and is highly inducible in fish and birds. In contrast, CYP2B, responsible for metabolising non-planar compounds, appears undeveloped in most groups but is well developed in terrestrial mammals and some birds. The development of plant chemical defence mechanisms seems to have played a major role in the evolution of the mixed function oxidase systems of animals via selective evolutionary pressure. Emergence of the CYP2B superfamily coincides with the development of terrestrial animals and exposure to a more varied diet, and has been found to be absent in animals with a monophagus diet. Interestingly, pinnipeds (having readopted a marine environment and become largely monophagus) are restricted in their ability to metabolise organochlorine compounds compared to terrestrial mammals, although some species, specific differences are apparent. 7 5

Aquatic organisms, such as fish and invertebrates, can excrete compounds via passive diffusion across membranes into the surrounding medium and so have a much reduced need for specialised pathways for steroid excretion. It may be that this lack of selective pressure, together with prey-predator co-evolution, has resulted in restricted biotransformation ability within these animals and their associated predators. The resultant limitations in metabolic and excretory competence makes it more likely that they will bioaccumulate EDs, and hence they may be at greater risk of adverse effects following exposure to such chemicals.

In general, terrestrial vertebrates must biotransform endogenous steroids and many xenobiotic compounds to more soluble forms before being able to excrete them via the urine and/or bile. In addition, terrestrial animals are more likely than their aquatic counterparts to be exposed to a varied diet containing exogenous lipophilic compounds. This appears to have resulted in evolutionary pressure to develop more elaborate metabolic and excretory systems. Research on the mixed function oxidase systems of birds has shown differences associated with both species and diet.84 For example, cormorants, sparrowhawks and peregrine falcons possess only low aldrin epoxidase activity (the enzyme responsible for biotransforming co-planar chlorinated compounds in birds), compared to omnivorous species such as herring gulls. A larger proportion of the higher-chlorinated PCBs (relative to total body burden) have been reported for the European otter (Lutra l. lutra)8 Arctic fox,86 and polar bear.87 Similar PCB

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Livingstone, Pergamon Press, Oxford, 1992, p. 83.

84 M. C. Fossi, A. Massi, L. Lari, C. Leonzio, S. Focardi, I. Marsili and A. Renzoni, Sci. Total

patterns have been found in polecats feeding on either terrestrial (small rodents) or aquatic (amphibian) prey despite different exposures, leading to the suggestion that the similarities were attributable to metabolic rather than dietary factors.88 A recent study on selective dietary accumulation in the European otter showed that although the lower chlorinated PCBs are more prevalent at the lower trophic levels of the foodweb, biomagnification through the foodchain resulted in the higher chlorinated PCBs making up approximately 80% of the total PCB body burden compared to a level of 30-50% in their diet. This has been attributed to metabolic differences between species, with otters being able to excrete the lower chlorinated PCBs and thus gaining a higher body burden of co-planar compounds.8®

In many of the organisms so far studied, EDs are also active inducers of the lower P450 subfamilies (i.e. CYP1A1, CYP2B, CYP3B), which are involved with steroid metabolism. Each subfamily appears to have a particular affinity for specific isomers of the steroid hormones. Compounds induce different subfamilies and this can lead to preferential metabolism of a particular isomeric form altering the hormonal profile of the organism. Alternatively, this may occur through EDs acting as antagonists of particular CYP 450s, which could potentially result in the build-up of particular hormones within the organism.90

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