Toxicity is weary dangerous for our body. Toxicology studies unwanted effects of chemical or physical agents, including drugs and pollutants on living organisms. There are many branches of toxicology including those that focus on the toxicity to a specific organ system or on issues associated with food safety, metal toxicity, reproductive and developmental toxicology, regulatory toxicology, occupational health, forensic toxicology, epidemiology (the study of populations to determine the frequency and distribution of disease and measure risks), and cancer development. Some of these specialties are described below.
All drugs have the potential to produce unwanted and toxic effects. The scope of undesired effects is broad. Some are only bothersome, like dry mouth, while others are life-threatening. The potential for toxicity is accessed during the development of all new drugs. If narrow margin exists between an effective dose and a toxic dose, the drug generally requires close monitoring. A blood test may be used to determine if the drug is present at a therapeutic concentration or may be used to assess the effect of the drug on certain targets of toxicity.
Due to factors such as age, genetic variations and the presence of disease, toxic doses among individuals may vary. Active research is currently underway in the area of pharmacogenetics that aims to identify genetic variations that exist among the population and how these variations affect drug response and toxicity. This research will translate into tests that will assist drug and dose selection, thus tailoring drug therapy for a given individual.
Some manifestations of toxicity:
At toxic levels, drugs and other substances can cause cells of a target organ to die. If the insult is severe or prolonged, the organ may not regain normal function. The outcome reflects the ability of the particular organ to regenerate and respond to damage.
The lungs are exposed to many biologically active substances such as asbestos and ozone through inhalation. The bloodstream can also deliver toxic substances to the lung. Certain cancer chemotherapeutic substances can cause lung damage, and the potential for this toxic manifestation has to be weighed against the potential life-saving effects of these drugs. During the repair process total recovery may be achieved, however, sometimes the damaged cells are replaced by fibrous tissue that does not allow the normal gas exchange processes, intensifying the damage caused by the initial insult.
The liver is a target of many toxic substances. The blood draining the stomach and small intestine is transported directly to the liver, exposing it to relatively high amounts of ingested drugs or toxins. The liver provides a protective effect by altering many drugs or ingested toxins thereby “neutralizing” and/or increasing the removal of these “foreign” substances from the body. In some cases, this process goes awry and a more toxic substance is produced. For example, with acetaminophen (Tylenol®) overdose, one of the products the liver produces attacks the liver itself and can result in liver failure. The neutralizing substance that normally detoxifies this product and increases its excretion is exhausted in the presence of excessive amounts of the drug. Other drugs can affect the liver through an immune response or by impairing bile flow.
The sunlight can convert certain drugs present in the skin to forms that increase the potential for sun burning. This is the reason avoidance of sun exposure is recommended while taking certain drugs such as the tetracyclines, sulfonamide antibiotics (“sulfa” drugs) and St. John’s Wort.
The kidneys are susceptible to the toxic effects of certain drugs in part due to their high blood flow and role as an excretory organ. A large percentage of kidney function must be lost before the impairment causes symptoms or is detected by routine examination. Blood tests that measure blood urea nitrogen (BUN) and creatinine (a normal product of muscle breakdown) are frequently used to evaluate kidney function or to check for toxicity when drugs that may affect the kidneys are given. The kidney is a site of toxicity for substances such as carbon monoxide, lead, and mercury.
Genotoxicity results when the toxin interacts with DNA, resulting in gene mutations or cancer formation. Although the toxic effect of most substances occurs shortly after their ingestion, genotoxic effects often manifest years later. Certain drugs including some cancer chemotherapeutic agents or environmental toxins may also impair sperm formation.
Examples of non-drug toxins:
Increased incidence of toxicity to chemicals in the environment has increased as the number of chemicals used in everyday life has increased. These chemicals affect not only those that work with them directly but also those who use the products and those exposed to contamination in the air and in the water supply. The Environmental Protection Agency (EPA) oversees the chemical industry while workers safety is the focus of the Occupational Safety and Health Administration (OSHA).
Toxic substances present in outside air include carbon monoxide, sulfur dioxide, and nitrogen dioxide. Carbon monoxide impairs the ability of red blood cells to transport oxygen to tissues for respiration. The action of UV light on nitrogen dioxide leads to ozone production that can cause impaired lung function. Sulfur dioxide can also be converted into substances that cause lung damage. Inhalation of particulates such as asbestos and coal dust can likewise cause lung damage. Indoor toxins can result from the use of cleaning products, paints, and solvents in the presence of poor air circulation.
Food additives, metals, and pesticides are other forms of environmental toxins. By normal hand to mouth activity, many children experience lead poisoning through chronic, low-level exposure. Lead toxicity can cause reduced IQ and attention span, hyperactivity, impaired growth, reading and learning disabilities, hearing loss, insomnia, and a range of another intellectual, and behavioral effects. Bacterial and fungal by-products can contaminate foods and cause toxicity when ingested. An unknown percentage of the population experiences toxic effects associated with the food additive monosodium glutamate (MSG). The symptoms include a headache, chest pain, rapid heartbeat, nausea, drowsiness, and weakness. It may also precipitate an asthmatic attack in some asthmatics.
Toxicity involving the immune system:
Toxicity to certain drugs may involve the immune system. The immune system can be impaired (immunosuppression) leading to an increased chance of developing an infection or infrequently, an increased risk of developing cancer. (Sometimes drugs with an immunosuppressant action are intentionally used. An example is in the prevention of rejection in the case of organ transplants.)
The activity of the immune system in response to a drug can also cause tissue damage. Hypersensitivity reactions or drug allergies may be immediate or delayed. The immediate reactions occur quickly after exposure to the offending substance to which the person has been previously sensitized. It may manifest as difficulty breathing, rashes, whelps, increased nasal secretions and decreases in blood pressure that may proceed to shock. It is thought that some forms of asthma result from an immune response to certain chemicals in the workplace. Other forms of drug hypersensitivity involve the destruction of cells of the circulatory system or cause the precipitation of immune complexes in the blood vessels causing an inflammatory response known as serum sickness. Serum sickness generally manifests as skin eruptions, painful joints, swollen lymph glands, and fever.
Most side effects of drugs do not represent true allergies and it is important to distinguish the difference. It is possible to adjust the dose of a drug in a non-allergic situation to avoid side effects, but a true allergic response can occur at any dose and therefore the drug should never be taken again.
A teratogen is a substance that is capable of causing birth defects in a fetus. The Food and Drug Administration has developed a classification of drugs based on the information available about their safety during pregnancy. Drugs are rated A, B, C, D, or X. Drugs in the A category are considered safe in human pregnancy and those in the X category have been proven to cause fetal abnormalities. Unfortunately, most drugs have not been adequately tested and there are few in the A category. Some examples of drugs in the X category are isotretinoin (Accutane®) and warfarin.
Most known teratogens cause birth defects if the fetus is exposed during a critical period, but are not harmful at other times. The first 10 weeks of pregnancy is generally regarded as the most critical when it comes to birth defects because it is during this stage that the organs form and the fetus is most susceptible to injury. However, toxicity can occur at other stages of the pregnancy.
Depressant drugs, such as tranquilizers and pain medications are given to the mother close to delivery may impair a baby’s ability to breath shortly after delivery. In addition, the brain continues to grow throughout the pregnancy, and substances that affect brain development can have serious consequences at any stage of development. It is best if a woman discusses the medications (both prescription and over-the-counter) she is taking with her physician when she first plans to become pregnant.
The branch of toxicology that deals with toxicity associated with criminal activity is forensic toxicology. A post-mortem analysis may include determination of the presence of drugs, volatile substances such as carbon monoxide, and other toxic chemicals in body fluids and tissues, and evaluates their potential role as a factor in the cause of death.
The presence of drugs or toxins that can modify behavior or performance may also be evaluated by the forensic toxicologist by analyzing blood, the breath or other specimens. The urine is commonly tested for the presence of drugs and their metabolites as an indicator of prior use or abuse.
In vitro toxicology testing:
There is much interest in developing nontraditional methods to determine drug toxicity. An example of a standard “in vitro” test is the Ames bioassay in which a chemical shown to be a bacterial mutagen may be further evaluated as a mammalian carcinogen.
Mathematical and computer models can complement animal experimentation by enabling scientists to predict the way in which an organism may respond to exposure at varying levels of a chemical and to design better experiments. Other alternative methods include tissue cultures, transgenic cells and animals, and increased use of invertebrates and non-mammalian species such as fish. The Frog Embryo Teratogenesis Assay-Xenopus (FETAX), for example, can be used to screen chemicals for their potential to cause birth defects. This system can potentially detect growth retardation, structural malformation, and behavioral and functional deficits.
Various companies are designing constructs to resemble human tissues for drug and toxin testing. An example includes a construct resembling the outer corneal cell layers of the human eye that can be used to test for potential eye irritancy. Constructs resembling the epidermis are being used to test for cutaneous irritancy, the effect of UV exposure, and skin permeability testing. DNA array analysis of RNA from cell culture experiments can identify fingerprints of substances that signal a given toxic effect. These tests are among many that will advance the goals of toxicologists in developing knowledge for the improvement of the health and safety of living beings and the protection of their environment.
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