Types of Toxic Effects

This chapter builds on the basic concepts presented in chapter 3 and discusses the types of cancer and non-cancer effects that can occur from chemical exposure. It provides an overview of specific effects of some well-known chemicals, and relates these effects to the mechanisms of toxic action discussed in chapter 3. Effects on humans will be discnssed first, followed by effects on other species (i.e., ecological effects). 

Cancer toxicity is exhibited by the formation of tumors. Cancer is defined as uncontrolled cell division. The vast majority of cancers are as yet unrelated to chemical exposure. Currently in the United States, approximately four in ten people (45 percent in men, 38 percent in women) develop cancer over their lifetimes. Of those people developing cancer, the death rate is about 30 percent across all types of cancers. As of 2003, cancer was still the second leading cause of death in the United States (behind only heart disease). There are many types of cancers, and they are typically classified both by the organ primarily affected (e.g., lung, breast) and the type of tumor produced. Although many types of cancers are often fatal, several types are typically not fatal (e.g., skin melanomas from ultraviolet light exposure due to sunlight). 

However, if another agent, which could be a chemiccd, causes the initiated cell to be promoted (e.g., cell division occurs from the damc ed cell), then tumor formation might occur. 

This is one reason why cancer treatment is so difficult. There are many steles of carcinogenesis and many agents that act at different stages. In addition, there cu e multiple types of mechanisms at each stcige, complicating drug therapy that often requires knowledge of such mechanisms to be effective. 

Other chemicals do not directly act on DNA, but exert their carcinogenic effects by targeting other systems linked with protein production and use. These are known as epigenetic chemicals. Examples of these types of chemicals include asbestos, which causes a specific and rare form of lung cancer called mesothelioma estradiol, the natural female hormone referred to as estrogen saccharin, used as an artificial sweetener in the 1970s until it was reported In 1977 to lead to bladder tumors in mice and ethanol, contained in all alcoholic beverages. 

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Cumulative effects are those where there is progressive injury and worsening of the toxic effect as a result of repeated-exposure conditions. Each exposure produces a further increment of injury a dding to that already existing. Many materials known to induce a particular type of toxic effect by acute exposure can also eUcit the same effect by a cumulative procedure from repetitive exposure to a dose less than that causing threshold injury by acute exposure. 

Table 1. Examples of Differing Types of Toxic Effect Classified According to Time Scale for Development and Site Affected...

Depending on the circumstances of exposure, any given material may produce more than one type of toxic effect. Therefore, when describing toxicity for a particular material, it is necessary to define whether the effect is local, systemic, or mixed the nature of the injury the organs and tissues affected and the conditions of exposure, including route of exposure, number of exposures, and magnitude of exposure. 

This type of categorization, while convenient, might be misleading. It perhaps suggests that all chemicals having a common target produce the same type of toxic effect on that target. This is not the case, and we shall reveal several examples in the next chapter. 

Membranes separate cells from their external environment, and the internal components of cells from each other. Many biochemical processes taking place within cells occur on a framework of membranes. Toxicant interactions with membranes figure prominently in many types of toxic effect. 

Scientists skilled in epidemiology, toxicology, and related disciplines collect and evaluate all of the scientific literature containing information regarding the types of toxic effect the chemical under review has been shown to produce. Toxic effects include one or more of the many manifestations of toxicity described earlier in this book. The list of adverse health effects produced by the chemical are said to constitute its toxic hazards, and the critical review and evaluation leading to the list is the hazard identification step. A discussion of the extent to which causal associations with human disease or toxic harm have been established is an important aspect of this step. 

For most types of toxic effects (e.g., organ-specific, neurological, immunological, non-genotoxic carcinogenicity, reproductive, developmental), it is generally considered that there is a dose or... 

To show and evaluate some types of toxic effect, a particular species might be required. 

The number of receptor sites and the position of the equilibrium (Eq. 1) as reflected in KT, will clearly influence the nature of the dose response, although the curve will always be of the familiar sigmoid type (Fig. 2.4). If the equilibrium lies far to the right (Eq. 1), the initial part of the curve may be short and steep. Thus, the shape of the dose-response curve depends on the type of toxic effect measured and the mechanism underlying it. For example, as already mentioned, cyanide binds very strongly to cytochrome a3 and curtails the function of the electron transport chain in the mitochondria and hence stops cellular respiration. As this is a function vital to the life of the cell, the dose-response curve for lethality is very steep for cyanide. The intensity of the response may also depend on the number of receptors available. In some cases, a proportion of receptors may have to be occupied before a response occurs. Thus, there is a threshold for toxicity. With carbon monoxide, for example, there are no toxic effects below a carboxyhemoglobin concentration of about 20%, although there may be... 

The existence of "no-effect doses" for toxic compounds is a controversial point, but it is clear that to measure the exposure sufficiently accurately and to detect the response reliably are major problems (see below for further discussion). Suffice it to say that certain carcinogens are carcinogenic after exposure to concentrations measured in parts per million, and the dose-response curves for some nitrosamines and for ionizing radiation appear to pass through zero when the linear portion is extrapolated. At present, therefore, in some cases no-effect levels cannot be demonstrated for certain types of toxic effect. 

Furthermore, other types of toxic effect may also be stochastic events, if a reactive metabolite interacts with a critical protein or affects a gene involved with development of the embryo, for example. 

Figure 4.72 The various possible consequences of metabolism of a foreign compound. The compound may undergo detoxication (2) metabolic activation (3), which leads to interaction with critical targets (6) and may cause toxic effects (8 A). Alternatively, the parent compound might cause a direct toxic effect (1 B). Formation of a stable metabolite (7) could cause atoxic effect (9 C). The stable metabolite could be further metabolized to atoxic metabolite (10) responsible for a different toxic effect to C. The reactive metabolite may be detoxified (4/5). The types of toxic effect caused by the metabolites would be one or more of the various types shown.

This example of selective neurotoxicity particularly illustrates the potential importance of a similarity in chemical structure between an endogenous compound and a foreign compound in the distribution, localization, and type of toxic effect caused. 

Quantal types of toxic effects are known as "all or none" effects such as death, the presence of a tumor, or loss of consciousness. 

Immunotoxicity. Immunotoxicology comprises two distinct types of toxic effects the involvement of the immune system in mediating the toxic effect of a chemical and the toxic effects of chemicals on the immune system. The former is shown, for... 

For descriptive purposes, toxicology testing procedures can be conveniendy subdivided into general and specific forms. General toxicology studies are those in which animals are exposed to a test material under appropriate conditions and then examined for all types of toxic effects that the monitoring procedures employed allow. Specific toxicological studies are those in which exposed animals are monitored specifically for a defined toxic end point or effect. 

As we now know, teratogenesis does not occur only as a result of exposure to a chemical that is particularly toxic to cells or animals. This particular type of toxic effect simply depends on the chemical interfering with the processes of development (see Figure 7, pp. 41-3). Because the interference that underhes the teratogenic effect can be a very smaU or subtle change, it may have no significance or may not even occur in the... 

Hexane is a simple organic chemical, a volatile liquid used industrially as a solvent. Once absorbed into the body, it is changed by metabolism into other produas. One of these produas, in which the hexane has been oxidized, is able to reaa with proteins in the nerves, and this is what underlies its toxic elfeas. Similar solvents that do not form this product are not toxic to the nerves, while those that do, predictably cause the same type of toxic effects. 

This entry provides an overview of the anatomy and physiology of the GI system and later describes the type of toxic effects that can be observed with different classes of agents. 

The complexity of the in vivo system and the types of toxic effects (e.g., an effect could be the result of quite different toxic mechanisms) can make it a challenge to difficult to understand what has happened and its relevance to human risk assessment. For example, there could be potential confounding or masking of the findings in an in vivo test system. 

As already indicated for some types of toxic effect there will clearly be a dose threshold, below which there is no detectable response. This No Observed Effect Level (NOEL) may apply to either a quantal response such as death or a pathological lesion... 

These three types of toxic effect will be considered together as they are often all closely interrelated. Thus, toxic foreign compounds can affect the homeostasis of an organism by altering basic biochemical processes. These effects may often be reversible if inhibition of an enzyme or binding to a receptor is involved. A well defined dose-response relation is often observed with such effects, and the end-point... 

Pharmacodynamic-based toxic effects are those where there is altered responsiveness of the target site perhaps due to variations in the receptor. For example, individual variation in the response to digitoxin means that some patients suffer toxic effects after a therapeutic dose (see below Chapter 7). The inhibition of enzymes, blockade of receptors or changes in membrane permeability which underlie these types of effects often rely on reversible interactions. These are dependent on the concentration of the toxic compound at the site of action, and possibly the concentration of an endogenous substrate if competitive inhibition is involved. Therefore, with the loss of the toxic compound from the body, by the processes of metabolism and excretion, the concentration at the site of action falls and the normal function of the receptor or enzyme returns. This is in direct contrast to the type of toxic effect in which a cellular structure or macromolecule is permanently damaged, altered or destroyed by a toxic compound. In some cases, however, irreversible inhibition of an enzyme may occur, which if not fatal for the organism will require the synthesis of new enzyme, as is the case with organophosphorus compounds which inhibit cholinesterases. 

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