Xenobiotics toxic effects

Starvation or disease can lead to rapid release of the stored xenobiotic and to delayed toxic effects. In one well-documented case in the Netherlands (see Chapter 5), wild female eider ducks (Somateria mollissima) experienced delayed neurotoxicity caused by dieldrin. The ducks had laid down large reserves of depot fat before breeding, and these reserves were run down during the course of egg laying. Dieldrin concentrations quickly rose to lethal levels in the brain. Male eider ducks did not lay down and mobilize body fat in this way and did not show delayed neurotoxicity due to dieldrin. 

Certain xenobiotics are very toxic even at low levels (eg, cyanide). On the other hand, there are few xenobiotics, including drugs, that do not exert some toxic effects if sufficient amounts are administered. The toxic effects of xenobiotics cover a wide spectrum, but the major effects can be considered under three general headings (Figure 53-1). 

Historically, organic environmental pollutants were hydrophobic, often persistent, neutral compounds. As a consequence, these substances were readily sorbed by particles and soluble in lipids. In modern times, efforts have been made to make xenobiotics more hydrophilic - often by including ionisable substituents. Presumably, these functional groups would render the compound less bioaccumulative. In particular, many pesticides and pharmaceuticals contain acidic or basic functions. However, studies on the fate and effect of organic environmental pollutants focus mainly on the neutral species [1], In the past, uptake into cells and sorption to biological membranes were often assumed to be only dependent on the neutral species. More recent studies that are reviewed in this chapter show that the ionic organic species play a role both for toxic effects and sorption of compounds to membranes. 

Considering additionally that the risk assessment of mixtures is presently an urgent issue, and that usually mixtures of exclusively organic chemicals or exclusively metals are investigated, in future more emphasis should be placed on the interactions of xenobiotic HIOCs with metals. Major research questions will include how these interactions influence bioavailability of both metals and HIOCs, interactions with biological membranes, uptake, and common toxic effects. 

The environmental behaviour of LAS, as one of the most widely-used xenobiotic organic compounds, has aroused considerable interest and study. As a result, it has been determined that, under certain conditions, LAS compounds are completely biodegradable however, in the marine environment their degradation is known to be slower. The presence of metabolites of the anionic LAS surfactants, the long and short chain SPC derivatives, in the aqueous environment is well known, and as such these degradation intermediates needed to be monitored (and tested for their toxic effects). 

What are some of the general modes by which terrestrial animals can diminish toxic effects of xenobiotics and how do these compare in fish ... 

Induction of enzymes involved in the metabolism of a test chemical is generally not a direct toxic effect exerted by the chemical, but a reaction toward a xenobiotic entering the body. 

The concept that infants and children may be a sensitive subgroup relates to their relative immaturity compared to adults. Children, as well as the unborn child, have in some cases appeared to be uniquely vulnerable to toxic effects of chemicals because periods of rapid growth and development render them more susceptible to some specific toxic effects when compared to adults. In addition to such toxicodynamic factors, differences in toxicokinetics may contribute to an increased susceptibility during these periods. It should be noted, however, that during the developmental and maturational periods the susceptibility to exposure to xenobiotics in children may be higher, equal, or even lower than in adults. Except for a few specific substances, not very much is known about whether and why the response to a substance may differ between age groups. It should also be borne in mind that, in terms of risk assessment, children are not simply small adults, but rather a unique population (Nielsen et al. 2001). 

Despite the scarcity of direct evidence, HA is generally believed to be present as a metabolic intermediate in mammalian tissues Recent studies on the reductive detoxification of HAs both by human NADH-cytochrome i>5 reductase and by human cytochrome b5 may be considered as additional supporting evidence for the in vivo formation of HA in mammalian cells that needs to be controlled in order to avoid the toxic effects of an excess of endogenously produced HA, as well as of HA produced by detoxification of xenobiotic HA derivatives " . 

The lowest dose effects of diuron are seen at 0.27 mg kg-1 per day. Almost all of the low-dose expression changes are related to genes involved with xenobiotic metabolism and transport, including cytochrome P450 enzymes and several transferases. These data indicate that the cells are responding appropriately to a potentially toxic xenobiotic. These effects are widespread across the set of chemicals tested in ToxCast, so it is of interest that 2,4-D does not trigger a similar xenobiotic metabolism response. 

In contrast, selective inhibition of enzyme activity involves highly specific interactions between the protein and chemical groups on the xenobiotic. An excellent example of this type of inhibition is seen in the toxic effect of fluoroacetate, which is used as a rodenticide. Although fluoroacetate is not directly toxic, it is metabolized to fluoroacetyl-CoA, which enters the citric acid cycle due to its structural similarity to acetyl-CoA (Scheme 3.5). Within the cycle, fluoroacetyl-CoA combines with oxalo-acetate to form fluorocitrate, which inhibits the next enzyme, aconitase, in the cycle [42]. The enzyme is unable to catalyze the dehydration to cis-aconitate, as a consequence of the stronger C-F bond compared with the C-H bond. Therefore, fluorocitrate acts as a pseudosubstrate, which blocks the citric acid cycle and, subsequently, impairs ATP synthesis. 

The study of receptors has not featured as prominently in toxicology as in pharmacology. However, with some toxic effects such as the production of liver necrosis caused by paracetamol, for instance, although a dose-response relation can be demonstrated (see chap. 7), it currently seems that there may be no simple toxicant-receptor interaction in the classical sense. It may be that a specific receptor-xenobiotic interaction is not always a prerequisite for a toxic effect. Thus, the pharmacological action of volatile general anesthetics does not seem to involve a receptor, but instead the activity is well correlated with the oil-water partition coefficient. However, future detailed studies of mechanisms of toxicity will, it is hoped, reveal the existence of receptors or other types of specific targets where these are involved in toxic effects. 

Environmental xenobiotic cycles. Much concern over toxic compounds springs from their occurrence in the environment. Different organisms in the complex ecological food webs metabolize compounds at different rates and to different products the metabolic end products are released back to the environment, either to be further metabolized by other organisms or to exert toxic effects of their own. Clearly, it is desirable to know the range of metabolic processes possible. 

The nasal epithelia are the first point of contact for respiratory toxicants. Because they contain xenobiotic metabolizing enzymes, they are susceptible to toxic effects caused by reactive intermediates. 

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