Fields Of Expertise Within Toxicology

Toxicology can be classified according to the effects on the organ systems damaged. Alternatively, it can be classified according to the mechanisms of toxicity. Almost anything that can go wrong with almost any tissue in the body will occur. Each of these areas comprises its own realm of toxicological expertise. We will first examine several examples of organ-based toxicity. In some cases there will be extensive overlap between categories. One of the important questions is why there frequently is specific target organ toxicity. We will examine some aspects of this question. Most frequently the answer relates to the specific biological characteristics of the tissues.

1.6.1 Chemical Carcinogenesis

Because of the intense public interest that exists in cancer prevention and the resulting political interest, chemical carcinogenesis is a gigantic and relatively well-funded field. Amazon.com (as of June 2006) lists nearly 80 books in print on the topic. Google.com lists over 200,000 hits on the topic. The National Library of Medicine's Medline lists nearly the same number of articles on the topic within the scientific or medical literature. Not only is the extent of effort indicated by these numbers, but also the diffuse, difficult, intractable, and fractal nature of the field.

Carcinogenesis is a multiple-step, progressive process. Causes of such damage can include alkylating agents, active oxygen species, and radiation. These causes of injury can also lead to genetic toxicology. Much of the current mechanistic interest is centered on dysregulation of cellular growth control mechanisms [3].

1.6.2 Genetic Toxicology

There is a great degree of overlap between the topics of genetic toxicity and chemical carcinogenesis. This is because many of the stepwise changes that occur during the development of neoplasia consist of somatic mutations that result in changes in growth regulation of the affected tissues.

The field more commonly thought of as genetic toxicology deals with changes in what might be termed legacy genes, those genes that are passed from one generation to the next. These changes occur as a result of unrepaired injury to the cellular DNA and the effects are almost always bad. The safety screening required for carcinogenesis in drug and chemical discovery is extensive [4].

1.6.3 Developmental Toxicology/Reproductive Toxicology

The topic of teratogenesis as a disruption of the control of embryological development is covered later in this chapter. Safety screening requires evaluation of developmental and reproductive toxicity of the compounds of interest [5].

1.6.4 Blood and Bone Marrow

Hematotoxicity is another area of active investigation. Benzene is an excellent example of the extremes that can be caused by substances that are toxic to the bone marrow. Chronic exposure to benzene can cause either leukemia, or bone marrow injury that can lead to aplastic anemia [6,7]. Agranulocytosis and aplastic anemia are infrequent but deadly toxic effects of several drugs. Anemias related to deficiencies of each of the formed elements of the blood also are known, and some of these are toxicological in origin. For example, thrombocytopenia is an established and potentially deadly adverse effect of heparin, though the etiology may be immunological [8].

1.6.5 The Immune System

The function of the immune system is to protect the internal environment of the body against external attack [9]. Because the nature of the attack can be so varied, bacterial, fungal, viral, and the presence of foreign proteins, the immune system has become one of great complexity. Antibody-mediated immunity and cellularly mediated immunity both exist, and the stimulus-response characteristics of this system and the necessary control mechanisms are also very complex.

Decreased immunological competency can lead to susceptibility to infections, and it can also lead to cells that lack the capacity to control their growth. In contrast, excess activity can cause the immune system to attack the host organism, itself. Both of these adverse effects can result from xenobiotic exposure.

Among the drugs that can decrease immunological competence are anti-inflammatory steroids, cyclosporine, and tacrolimus. Certain of these compounds are used to prevent transplant rejection, but they simultaneously carry the risk of allowing infection to occur. The aplastic anemia caused by the bone marrow toxicity of benzene was described above. Lead and chlorinated aryl hydrocarbons such as hexachlorobenzene also can cause bone marrow suppression.

Inappropriate immunological activation has been known for a long time. Anaphylaxis following sensitization is an example. Another example is that untreated beta-hemolytic streptococcus infections can lead to rheumatic fever and damage to the heart valves. This appears to occur because the streptococcus organism and our heart valves share a common antigen, and development of immunity against the former leads to damage to the latter.

Immunotoxicology is a discipline still in its infancy. Perhaps, this is most clearly bourn out by the recent experience in Great Britain in which a monoclonal antibody that was designed as an agonist to a receptor on T-lympho-cytes was first given to six human volunteers. The dose given was much lower (500 times) than that which had been safe in animals. Nevertheless, the result was a massive release of cytokines leading to global organ failure. At this time all have survived the event, though it was not certain for some time that this would happen. This is an excellent example of species differences, and it is clear that much more work must be done to characterize human immunologi-cal responses when potential immunological stimulants are in the process of drug discovery [10,11].

1.6.6 The Liver

The liver has two main functions in the body [12]. The first is maintenance of internal nutritional homeostasis through facilitation of lipid absorption and intermediary metabolism. As described later, the large metabolic capacity of the liver renders it vulnerable to heavy metals through binding of the metals to and inactivation of electrophilic ligands.

The second function of the liver is to deal with various endogenous substrates and dietary xenobiotics through their metabolism and biliary excretion. Several toxicities are associated with disturbances of this function. One example is the oxidative dechlorination of carbon tetrachloride and other chlorinated hydrocarbons to free radical metabolites that bind to and destroy hepatic tissues. Another example of toxicity by metabolic activation occurs with acetaminophen. A trace metabolite of acetaminophen is a very reactive quinoneimine. Under normal usage of this analgesic, this metabolite is not a problem because it is inactivated by binding to reduced glutathione. However, when an overdose of acetaminophen is taken, the protective glutathione becomes depleted and the reactive metabolite covalently binds to and destroys hepatic parenchymal tissue.

Cirrhosis of the liver is one of the most well-known adverse effects of chronic alcohol abuse. The cholesterol-lowering, life-prolonging statin drugs must be monitored routinely for hepatotoxicity and rhabdomyolosis. A Google search on the terms "statins," "hepatotoxicity," and "review" produced over 22,000 hits indicating this is a very active field of interest.

1.6.7 The Kidney

For the same reasons as described for the liver, heavy metals and compounds converted to active metabolites can also be toxic to the kidney, which is very active metabolically [13,14]. With certain quinones, reduced glutathione can enhance toxicity, rather than being protective [15].

Gentamycin and other aminoglycoside antibiotics are toxic to the kidney. Use of these compounds necessitates repeated dosage adjustments according to drug blood levels.

1.6.8 The Respiratory System

As is the case with the skin, the lungs are in constant contact with the external environment [16]. Exposure to the toxins in cigarette smoke is one of the most common causes of congestive, obstructive damage in the respiratory system. Occupational exposure to asbestos and medically necessary exposure to drugs such as cyclophosphamide and carmustine can also cause lung injury. Inhalations of coal dust and cotton fibers are other occupational hazards to the lungs.

1.6.9 The Nervous System

The central nervous system is one of the most complex organs in living systems [17]. Neurotoxicity can be manifested rather globally, or very specifically, depending on the poison. One example of a very specific toxicity occurs with MPTP, a notorious meperidine analogue that can destroy the substantia nigra and leads to a very severe Parkinson-like syndrome. Another example of rather global neurotoxicity occurs with lead encephalopathy. Other metals can also be highly neurotoxic.

Developmental retardation occurs following exposure to metals, and this has been instrumental in decreasing the amount of lead used in gasoline and indoor paints. Maternal alcohol drinking during pregnancy can also cause developmental retardation manifested as fetal alcohol syndrome. Organo-phosphates can cause acute injury related to acetylcholine accumulation and certain ones such as triothocresylphosphate can cause delayed axonal degeneration. Picrotoxin, camphor, and strychnine are examples of powerful con-vulsants. Anesthetics and analgesics can lead to respiratory depression and hypoxia. Carbon monoxide and cyanide also cause general hypoxic damage to the brain and to other high oxygen demand organs of the body. The literature abounds with other examples of substances that are toxic to the nervous system.

1.6.10 Behavioral Toxicity

Many poisons can disturb mental and rational function leading to behavioral abnormalities. Psychototoxins include phencyclidine, LSD, and fungal toxins. Less commonly, stimulants such as cocaine and amphetamine can cause psychiatric problems. Psychiatric effects of high doses of corticosteroids have also been described. In addition to the developmental retardation, some investigators believe that cognitive impairment, hyperactivity, and perhaps even antisocial behavior may be caused by childhood lead exposure. Public discussion of these subtle toxic effects is highly politicized because childhood exposure to lead still occurs as a risk factor in slums and tenements.

1.6.11 Cardiotoxicity

Compared to many of the other organs, the heart must continuously maintain beating activity [18]. There is little energy storage capacity in the heart, which therefore must be producing the energy it uses in real time. Drugs that decrease the capacity of the heart to use substrate and generate ATP can be very harmful to the heart. Examples of toxicants believed to act by this mechanism include cyanide, glycolysis inhibitors such as emetine [19], and Krebs-cycle metabolism inhibitors such as the cardiotoxic anthracycline doxorubicin [18].

In addition to the necessity of continuous energy generation, the heart must maintain rhythmic function throughout its lifetime. Substances such as cocaine and cyclopropane that decrease the reuptake of norepinephrine after its release from noradrenergic neurons are prone to cause fatal arrhythmias. Additionally drugs that modify plasma membrane ion channel function can also cause arrhythmias. More recently cardiotoxicity from drugs that prolong the QT-interval has been reported. Such drugs include several antimicrobial agents, antidepressants, and anti-migraine agents. This broadly based toxicological effect has clear implications for the drug discovery process [20].

1.6.12 Dermal Toxicity

The skin is the primary organ of contact between the organism and its environment. There is extensive commercial interest in dermal toxicology and safety screening because of the many different products used topically for therapeutic and cosmetic purposes. Similar comments can be made about ocular products.

Some of the toxic effects to the skin are allergic in nature. The response to poison oak or poison ivy is an example. Corrosive injury to the skin can occur following contact with many household products. Cutaneous responses to certain drugs can include dangerous exfoliative dermatitis and the StevensJohnson syndrome [21,22].

1.6.13 The Reproductive Systems

In addition to chemical carcinogenesis, teratogenesis is a toxic effect that catches the public's attention. The public response to thalidomide was so great that it is still very difficult to get the drug approved for newer indications. Once we know what a toxic effect can be, toxicologists are quite effective in developing animal tests that screen for that effect. For example, the fetotoxic effects of compounds such as Accutane® and the angiotensin converting enzyme inhibitors are known from screening studies, and a large teratogenic disaster such as thalidomide should not happen, again. It is a commentary on human nature that the fetal alcohol syndrome still continues to occur.

1.6.14 Endocrine Systems

Toxic changes can be caused by endocrine agonists, antagonists, and disrup-tors. There are estrogen active compounds such as diethylstilbesterol and dioxin. Natural and synthetic thyroid antagonists such as propylthiouracil are known. Agonists and antagonists for adrenocortical hormones have been described. Oral contraceptives are risk factors for increased blood clotting and stroke. Estrogens are risk factors for breast and uterine cancers, and there is much interest in the associated risks from environmental estrogen pollutants (e.g., the REACH initiative).

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