Reaction Example
Reaction Product(s)
Oxidative reactions Hydroxylation →
Epoxidation →
Deamination →
N-Dealkylation →
N-Hydroxylation →
Dehalogenation (oxidative)* →
O-Dealkylation →
Desulfuration
Sulfoxidation —S— → —S—O—
S-Dealkylation →
Reaction Example
Reaction Product(s)
Reductive reactions Dehalogenation (reductive) →
Azo-reduction →
Nitro-reduction —NO2 → —NH2
*The chlorine can be replaced by any halogen.
While the process of biotransformation is generally one of advantage to the organism from the toxicity point of view there are also many examples of toxicity where it is the metabolite that is the offending moiety rather than the parent molecule. One example of this is with the formation of epoxides (an oxygen bridge across two carbons) which are very reactive and have been implicated as important in the process of carcinogenicity.
The genotoxicity of 1,3-butadiene, for example, involves the formation of epoxide metabolites. Other phase I biotransformations are carried out by enzymes other than those of the P450 system, such as the flavin-containing monooxygenase, epoxide hydrolase, esterases, amidases, and alcohol and aldehyde dehydrogenases. Some substrates are also metabolised by a peroxidase-dependent co-oxidation. To extend the above example with epoxides, the epoxide hydrolase enzyme may biotransform the epoxide to a dihyrodiol that may be further biotransformed to the diol epoxide, which may play a critical role in carcinogenesis. As can be appreciated from this one example, biotransformation can be a complex process with many steps to either detoxification or, in some cases, to toxic moieties.
Phase II biotransformation generally results in the addition of a relatively large moiety to the substrate, which is often the product of a phase I reaction. Examples of the different sorts of phase II biotransformation reactions include:
■ Glucuronyl transferase
■ Glutathione S-transferase
■ Sulfotransferase
■ Amino acid conjugase
■ Methyl transferase
■ N-Acetyl transferase.
An example of the most common of these reactions, glucuronidation, is shown in Figure 2.7. The products of phase II reactions are often far more water soluble than the substrates, thereby promoting the overall excretion of the chemical. The glucuronidation process uses uridine-5′-diphospho-α-D-glucuronic acid (UDPGA) as a cofactor and is carried out mainly in the endoplasmic reticulum of the liver.
Another common phase II reaction is via the enzyme glutathione S-transferase, which is actually a family of enzymes responsible for the eventual formation of mercapturic acid or thioether metabolites. These have been determined in urine in biological monitoring for exposure to some chemicals. As the name implies the cofactor for the enzyme is the tripeptide, reduced glutathione. This is a widely studied reactant in the detoxification of a variety of chemicals. If its supply is limited increased toxicity may be observed.
While it has been stated that the biotransformation of chemicals overall is a detoxification process, it must be remembered that many chemicals are toxic because they are biotransformed; that is the metabolites of some chemicals actually cause the toxicity. This has been extensively studied and the reader is referred to other texts for further information. As it is important to understand how biotransformation can result in a toxic product, and as it is also important that the reader appreciates the value of such knowledge, a salient example is to be found with n-hexane in Chapter 14 on solvents.
Toxicokinetics
The quantitative study and mathematical description of the disposition of chemicals related to their toxic effects is termed toxicokinetics. Thus the amount absorbed, the relative distribution to different tissues, the rate of removal by biotransformation and/or excretion are all included in a toxicokinetic appraisal of the movement of a chemical through the body. While there will be no attempt to detail the field of toxicokinetics in this text it should be appreciated by the reader that important information is attainable from understanding the kinetics of chemicals in the body. For example, the amount absorbed will be a factor in the toxicity of a chemical—if none is absorbed then there will be no systemic toxicity at a site removed from the portal of entry. The reader should be warned not to oversimplify this, however, as lack of absorption of particles like nickel subsulfide from the lung may in fact be a major factor in the toxicity expressed at that site. That is, no absorption does not simply equate to no toxicity.
Knowledge of the toxicokinetics of a chemical also allows prediction of body burdens of a chemical, both temporally and quantitatively, even after exposure has stopped. It is also crucial to know about the kinetics (and biotransformation) of a chemical when planning or implementing urinary monitoring programs. This can be clearly appreciated by considering this aspect in the chlordimeform exercise in Chapter 19.
The application of toxicokinetics is also important in the risk assessment process both in extrapolating from high dose to low dose and across species. Knowledge of saturation of kinetic processes at high dose as compared to low dose must be integrated into the risk assessment process if it is known to occur. Similarly, differences in the quantitative
handling of chemicals across species can be crucial to a meaningful risk assessment for a chemical. It should be appreciated, however, that often critical pieces of data, such as the kinetics in humans, may not be readily available or obtainable for ethical reasons.
How chemicals affect the body
There are different types of toxic effects that chemicals have on the body as listed in Table 2.6. Local effects, as opposed to systemic effects, are discussed elsewhere in this text (Chapter 3). The differences between acute and chronic effects have been addressed earlier in this chapter. This generally relates to effects as well where there may be a reaction due to a single one-off exposure, perhaps to a high amount of a chemical. On the other hand a toxic response to another chemical may be seen after repeated long-term, low-level exposures as is usually the case with carcinogenic effects. Most chemicals will result in immediate effects but for some there will be a delay before the toxicity is manifest. An example of both can be found with paraquat where at a high enough dose death will be immediate, but at a moderate dose death is delayed until about 2 weeks after intoxication. The delayed death is due to pulmonary insufficiency related to fibrosis in the lungs.
Many toxic effects, like death, are irreversible while others may be reversed—for example, by regeneration of liver tissue after toxic insult to that organ. While ultimately all toxicity is related to interactions at the molecular level, the result may be visible only at the cellular level. For example, liver toxicity may be seen as death of the parenchymal cells but may be related to destruction of cellular lipids or covalent binding of chemical molecules to cellular macromolecules.
There are also specific types of effects that require some attention. Allergic reactions are not uncommon and are of concern with workplace chemicals such as toluene diisocyanate (TDI). Here one individual may become sensitive to TDI, reacting to very low levels, while a workmate remains unaffected. Hypersensitivity or idiosyncratic responses are those seen in particular individuals and are related to some underlying metabolic abnormality. They occur at exposure levels well below those at which the
‘normal’ population would respond. The term is often used to account for otherwise inexplicable observations in particular people. Carcinogenic, genotoxic and developmental effects are specific types of effects that are dealt with in separate chapters.