- Related Topics:
- neurotoxin
- toxin
- endotoxin
- systemic poison
- toxicity
Although the immune system generally protects the body, it can respond in certain ways that are detrimental to some individuals. Allergy, or hypersensitivity, is a condition of increased reactivity of the immune system toward an antigen that leads to adverse effects. Substances that cause allergies are known as allergens.
Confusion is sometimes caused by the terms hypersensitivity, hypersusceptibility, and idiosyncrasy. Hypersensitivity is a reaction to a chemical or substance in certain individuals and has a basis in the immune system. Hypersusceptibility is an increased predisposition of certain individuals to react to a chemical. Because of biological variability among humans, some individuals respond to a chemical at a dose too low to produce a similar effect in others. Idiosyncrasy is a genetically determined hypersusceptibility.
Allergic responses differ from the usual toxic responses in three ways. First, the allergic response does not occur during the first exposure to an allergen, but is evident only after at least one previous exposure. In rare occasions, an allergic response can occur on the first exposure to a chemical if the individual has already developed a hypersensitivity toward a closely related chemical. For example, people allergic to one kind of penicillin are usually allergic to other penicillins as well. Second, allergy is specific to both the allergen and the individual. Unlike in a toxic response, in which everyone exposed develops the response if a sufficient dose is administered, only a small fraction of the exposed population is sensitized by an allergen, regardless of the dose. Third, the amount of a chemical required to elicit an allergic response is usually much less than that required to produce a toxic response.
There are four types of hypersensitivities (allergies): immediate, cytotoxic, immune-complex, and delayed. Each differs from the others in the mechanism of induction and the responses produced. Immediate hypersensitivity is the most common form of allergy. Delayed hypersensitivity is the second most common, whereas cytotoxic and immune-complex hypersensitivities are relatively rare.
Immediate hypersensitivity, also called anaphylaxis, produces IgE in response to an allergen that binds to the surface of mast cells or basophils. When reexposed to the allergen, the antigen-binding end of IgE on mast cells and basophils binds the allergen, triggering a release of anaphylactic mediators from these cells. These mediators, such as histamine and serotonin, cause the contraction of certain smooth muscles (e.g., those of the respiratory tract, leading to bronchoconstriction in asthmatic attacks), relaxation of blood vessels (e.g., in the skin, resulting in redness, or in the whole body, causing a fall in blood pressure as in anaphylactic shock), and increased permeability of capillary walls (e.g., in the skin, leading to local edema as seen in urticaria). The unique characteristic of immediate hypersensitivity is its rapid onset, with the response initiated within a few minutes of allergen exposure.
The anaphylactic mediators affect tissues differently. Thus, the allergic response depends on where the immune reaction takes place. In the skin, immediate hypersensitivity can result in skin eruptions or urticaria, characterized by wheals with redness. In the respiratory system, it can produce hay fever or asthma. In the gastrointestinal tract, allergic gastroenteritis, an inflammatory condition of the stomach and intestine, may result. Systemic anaphylaxis may involve the entire body, with shock as a key feature.
A second type of hypersensitivity is cytotoxic hypersensitivity, which has a gradual onset. After reexposure to an allergen, the allergen molecules attach to the surfaces of blood cells, forming an antigen new to the body. IgG or IgM binds to the new antigen on the blood cells, lysing blood cells via either complement fixation or antibody-dependent cell cytotoxicity. If the lysed cells are red blood cells, hemolytic anemia results. If platelets (the blood components intrinsic to blood clotting) are lysed, however, the blood clotting mechanism is impaired.
In a third type of allergy, immune-complex hypersensitivity, the allergen-IgG complex precipitates in tissues, resulting in inflammation via complement fixation. Immune-complex hypersensitivity in the kidney results in an inflammatory injury of the glomeruli (glomerulonephritis), and in the lung it leads to a pneumonia-like condition known as hypersensitivity pneumonitis.
Delayed hypersensitivity differs from other types in not involving humoral immunity. Upon reexposure to the allergen, sensitized T-lymphocytes release lymphokines, which trigger a series of inflammatory reactions. The inflammation leads to the development of allergic contact dermatitis in the skin and a chronic form of hypersensitivity pneumonitis in the lung. Symptoms of allergic contact dermatitis develop gradually, taking a day or two to reach maximum levels, which is the best way to distinguish allergic contact dermatitis from atopic dermatitis with similar symptoms. In contrast, the chronic form of hypersensitivity pneumonitis develops insidiously and not in a fixed time.
Teratogenesis
Teratogenesis is a prenatal toxicity characterized by structural or functional defects in the developing embryo or fetus. It also includes intrauterine growth retardation, death of the embryo or fetus, and transplacental carcinogenesis (in which chemical exposure of the mother initiates cancer development in the embryo or fetus, resulting in cancer in the progeny after birth).
Intrauterine human development has three stages: implantation, postimplantation, and fetal development. The first two stages are the embryonic stages and last through the first eight weeks after conception. The fetal stage begins in the ninth week and continues to birth.
Depending on the developmental stage, chemical exposure in the mother can result in different degrees of toxicity in the embryo or fetus. In the preimplantation period, a toxic chemical can kill some of the cells in the blastocyst, resulting in the death of the embryo. During the postimplantation period, chemical-induced cell death leads to one of two outcomes. If death is confined to those cells undergoing active cell division at the moment, the corresponding organs are affected, resulting in malformation. If the cell death is generalized without significant replication by the remaining cells to sustain life, the embryo dies. During the third, fetal, period, chemical injury can retard growth or, if severe enough, kill the fetus.
The genesis of a particular organ (organogenesis) occurs at a specific time during gestation and is not repeated. Because organogenesis is a tightly programmed sequence of events, each organ system has a critical period during which it is sensitive to chemical injury. Chemical exposure in a critical period is likely to produce malformations of that organ and not others; however, because there is some overlapping of critical periods of organ development and because chemicals frequently remain in the embryo for a period of time, malformations of more than one organ usually occur. Since organogenesis occurs mostly in the embryonic stages, chemical exposure in the first trimester should be minimized, if possible.
Little is known about mechanisms of teratogenesis. It is thought that some teratogens produce malformations directly by killing the cells in the embryo. Teratogens can also produce malformations indirectly by causing maternal toxicity, resulting in oxygen or nutrient deficiency for the embryo. A few well-known examples are discussed below.
Thalidomide is a drug originally marketed to combat nausea and vomiting in pregnancy. It was discovered in the 1960s in West Germany to cause rare limb defects, among other congenital anomalies. The discoveries about thalidomide triggered legislation requiring teratogenicity testing for drugs.
Chronic alcohol ingestion during pregnancy is the most common cause of congenital problems in mental development. Ingestion of more than 30 millilitres (1 ounce) of ethyl alcohol per day during pregnancy can lead to the development of fetal alcohol syndrome, characterized by intrauterine growth retardation and subsequent learning disabilities, such as distractibility, language disorders, and low IQ. Heavier consumption of alcohol, more than 60 millilitres per day, by a pregnant woman can result in malformations of the fetal brain and in spontaneous abortions.
Diethylstilbestrol (DES) is a drug used primarily from the 1940s to the ’50s to prevent miscarriage. The drug is an example of a chemical that can produce transplacental carcinogenesis. It was discovered in the early 1970s that exposures to diethylstilbestrol before the ninth week of gestation could lead to the formation of rare vaginal and cervical cancers in female progenies.
Carcinogenesis
Carcinogens are chemicals that can produce tumours, abnormal tissue growths caused by a loss of control in cell replication. Most tumours are solid masses (e.g., lung cancer), but some do not occur as tissue swellings (e.g., leukemia).
Tumours may be benign or malignant. Benign tumours are to a certain degree controlled in their growth. As a result, benign tumours maintain some form of cellular organization and grow rather slowly over a period of years. In contrast, cell growth in malignant tumours is almost totally uncontrolled. Cells in malignant tumours grow very rapidly in a disoriented fashion.
Benign tumours are encapsulated by a fibrous layer and so do not invade surrounding tissue. Malignant tumours invade surrounding tissue. Thus, while a benign tumour grows at one site, a malignant tumour sends out cancerous cells via the blood and lymphatic system to distant sites of the body, spreading by a process known as metastasis. The invasion of surrounding tissues by a malignant tumour produces various symptoms.
Carcinogenesis is a complicated process in which many factors are known to play significant roles. Certain external environmental factors are important. For instance, cigarette smoking is known to cause predisposition to the development of lung cancer. A diet low in fibre content and high in fat is correlated with a high incidence of colorectal cancer. In addition, internal factors, such as hormonal imbalances and immunosuppression, can also increase the chance of developing tumours. Sensitivity to chemical carcinogens is known to be species-dependent. A chemical carcinogen may induce tumours in one animal species but not another, and a species that is sensitive to one carcinogen may be resistant to another. Known human carcinogens include some anticancer drugs, aromatic (containing a benzene ring in its chemical structure) amino and nitro compounds, metals, radionuclides, and miscellaneous chemicals. In humans the respiratory tract is the most common target for chemical carcinogens, followed by the liver and the blood.
Although there have been many theories on the mechanism of chemically induced tumour formation, it is now thought that DNA is the target of most chemical carcinogens. The carcinogens interact with the DNA and interfere with its normal function. Because DNA controls cellular functions, when DNA is damaged, the cell presumably loses control and divides in a chaotic fashion. A clone of the parent cell is generated, and these cells maintain the chaotic replication, which ultimately leads to the formation of a tumour. In general it takes 10 to 20 years for the initial DNA damage in one cell to develop into a recognizable tumour.
Carcinogens that are thought to produce cancer in laboratory animals by altering the DNA are referred to as genotoxic carcinogens. They are either direct-acting or indirect-acting chemicals.
Direct-acting (reactive) genotoxic chemicals can themselves interact with DNA. Indirect-acting genotoxic carcinogens do not bind to DNA until they have been biotransformed in the body to reactive chemicals. Among the indirect-acting carcinogens, polycyclic aromatic hydrocarbons, nitrosamines, and nitrosonornicotine are found in cigarette smoke. Polycyclic aromatic hydrocarbons are also formed in charcoal-broiled meat. Nitrosamines can be formed by the nitrosation of nitrite-cured, protein-rich food, such as nitrite-cured meat and fish, in the intestine.
Chemicals that produce cancer by a mechanism other than by binding to DNA are known as epigenetic carcinogens. The mechanisms by which epigenetic carcinogens produce tumours are not known with certainty, but various theories have been proposed. Cytotoxins are thought to kill cells in the target organ. The cell death increases cell replication by the remaining cells, which somehow results in tumour development, possibly by stimulating the division of cells that have previously had their DNA damaged by a genotoxic carcinogen.
It has been proposed that hormones and chemicals which modify the activities of the endocrine system create a physiological imbalance in organs dependent for their functioning on a particular hormone. With the imbalance, the organ may lose its normal physiological control and tumour growth may occur. This may be the mechanism by which estrogens in postmenopausal women lead to development of uterine cancer and the reason antithyroid agents, such as 3-amniotriazole, produce thyroid tumours.
Chemicals that depress the immune system are thought to produce tumours by impairing cell-mediated immunity, which is important in the normal elimination of tumour cells. The development of tumours involves two main steps: initiation and promotion. Initiation is the creation by genotoxic carcinogens of a cell with abnormal DNA. After initiation, promoters stimulate the replication of these neoplastic cells and facilitate the development of the tumour. Initiators include genotoxic chemicals. Although promoters do not produce tumours directly, they are still considered carcinogens because they can lead to the development of tumours in concert with an initiator. Promoters include large chlorinated hydrocarbon molecules (e.g., DDT, PCBs, TCDD, butylated hydroxy antioxidants, and saccharin) and tetradecanoyl phorbol acetate in croton oil.
Mutagenesis
Mutagenesis is the alteration of genes. Substances able to produce mutations are naturally genotoxic substances. Once a gene is mutated in a cell, the altered gene can be passed on to daughter cells. The body has ways to repair some of these gene alterations so that the genetic damage does not always propagate.
The effect that a mutation has depends on the cell in which the mutation occurs. In the somatic cells of most organs, mutation either has no effect, causes one cell to die, or causes a cell to divide at an uncontrolled rate so that a tumour develops. If the mutation occurs in germ cells (egg and sperms), there may be detectable changes or birth defects, or stillbirth may result.
