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Carbon Monoxide Poisoning:

Toxicology:

  • This discipline is classically is known as the science of poisons. A modern definition is "the study of the adverse effects of chemicals on living organisms." Although it is an age-old science, toxicology has only recently become a discipline distinct from pharmacology, biochemistry, cell biology, and related fields. There are three central tenets of toxicology.

    1) "The dose makes the poison"; this implies that all chemical agents are intrinsically hazardous - whether they cause harm is only a question of dose. Even water, if consumed in large quantities, it can be toxic.

    2) Each chemical agent tends to produce a specific pattern of biological effects that can be used to establish disease causation.

    3) Toxic responses in laboratory animals are useful predictors of toxic responses in humans.

    The science of toxicology attempts to determine at what doses foreign agents produce their effects. The foreign agents of interest to toxicologists are all chemicals (including foods) and physical agents in the form of radiation, but not living organisms that cause infectious diseases.

    4) The discipline of toxicology provides scientific information relevant to the following questions:

    A. What hazards does a chemical or physical agent present to human populations or the environment?
    B. What degree of risk is associated with chemical exposure at any given dose?

    Toxicological studies, by themselves, rarely offer direct evidence that a disease in any one individual was caused by a chemical exposure. However, toxicology can provide scientific information regarding the increased risk of contracting a disease at any given dose and help rule out other risk factors for the disease. Toxicological evidence also explains how a chemical causes a disease by describing metabolic, cellular, and other physiological effects of exposure.


  • Toxicological Research Design
    Toxicological research usually involves exposing laboratory animals (in vivo research) or cells or tissues (in vitro research) to chemicals, monitoring the outcomes (such as cellular abnormalities, tissue damage, organ toxicity, or tumor formation), and comparing the outcomes with those for unexposed control groups. As explained below, the extent to which animal and cell experiments accurately predict human responses to chemical exposures is subject to debate.

    Because it is often unethical to experiment on humans by exposing them to known doses of chemical agents, animal toxicological evidence often provides the best scientific information about the risk of disease from a chemical exposure.

    In contrast to their exposure to drugs, only rarely are humans exposed to environmental chemicals in a manner that permits a quantitative determination of adverse outcomes.

    This area of toxicological research, known as clinical toxicology, may consist of individual or multiple case reports, or even experimental studies in which individuals or groups of individuals have been exposed to a chemical under circumstances that permit analysis of dose-response relationships, mechanisms of action, or other aspects of toxicology. For example, individuals occupationally or environmentally exposed to polychlorinated biphenyls (PCBs) prior to prohibitions on their use have been studied to determine the routes of absorption, distribution,metabolism, and excretion for this chemical. Human exposure occurs most frequently in occupational settings where workers are exposed to industrial chemicals like lead or asbestos; however, even under these circumstances, it is usually difficult, if not impossible, to quantify the amount of exposure. Moreover, human populations are exposed to many other chemicals and risk factors, making it difficult to isolate the increased risk of a disease that is due to any one chemical.


  • Toxicologists use a wide range of experimental techniques, depending in part on their area of specialization.Some of the more active areas of toxicological research are classes of chemical compounds, such as solvents and metals; body system effects,such as neurotoxicology, reproductive toxicology, and immunotoxicology; and effects on physiological processes, including inhalation toxicology, dermatotoxicology, and molecular toxicology (the study of how chemicals interact with cell molecules). Each of these areas of research includes both in vivo and in vitro research.

    1. In vivo research

    Animal research in toxicology generally falls under two headings:safety assessment and classic laboratory science,with a continuum in between. As explained elsewhere, safety assessment is a relatively formal approach in which a chemical's potential for toxicity is tested in vivo or in vitro using standardized techniques often prescribed by regulatory agencies, such as the Environmental Protection Agency (EPA)and the Food and Drug Administration (FDA).

    The roots of toxicology in the science of pharmacology are rooted in an emphasis on understanding the absorption, distribution, metabolism, and excretion of chemicals. Basic toxicological laboratory research also focuses on the mechanisms of action of external chemical and physical agents. It is based on the standard elements of scientific studies, including appropriate experimental design using control groups and statistical evaluation. In general, toxicological research attempts to hold all variables constant except for that of the chemical exposure. Any change in the experimental group not found in the control group is assumed to be perturbation caused by the chemical. An important component of toxicological research is dose-response relationships. Thus, most toxicological studies generally test a range of doses of the chemical.

    a. Dose-response relationships:

    Animal experiments are conducted to determine the dose-response relationships of a compound by measuring the extent of any observed effect at various doses and diligently searching for a dose that has no measurable physiological effect. This information is useful in understanding the mechanisms of toxicity and extrapolating data from animals to humans.

    b. Acute toxicity testing - lethal dose 50 (LD50):

    To determine the dose-response relationship for a compound, a short-term lethal dose 50 (LD50) is derived experimentally. The LD50 is the dose at which a compound kills 50% of laboratory animals within a period of days to weeks. The use of this easily measured end point for acute toxicity is being abandoned, in part because recent advances in toxicology have provided other pertinent end points, and in part because of pressure from animal rights activists to reduce or replace the use of animals in laboratory research.

    c. No observable effect level (NOEL):

    A dose-response study also permits determination of another important characteristic of the biological action of a chemical - the no observable effect level (NOEL). The NOEL sometimes is called a threshold, since it is the level above which observable effects in test animals are believed to occur and below which no toxicity is observed. Of course, since the NOEL is dependent on the ability to observe the effect, the level is sometimes lowered once more sophisticated methods of detection are developed. Do many of the effects of CO really have a NOEL, or do they behave as in "d." below?

    d. No threshold model and determination of cancer risk:

    Certain genetic mutations, such as those leading to cancer and some inherited disorders,are believed to occur without any threshold. In theory, the cancer-causing mutation to the genetic material of the cell can be produced by any one molecule of certain chemicals. The no threshold model led to the development of the one hit theory of cancer risk, in which each molecule of a cancer-causing chemical has some finite possibility of producing the mutation that leads to cancer. This risk is very small, since it is unlikely that any one molecule of a potentially cancer-causing agent will reach that one particular spot in a specific cell and result in the change that then eludes the body's defenses and leads to a clinical case of cancer. However, the risk is not zero. The same model also can be used to predict the risk of inheritable mutational events.

    e. Maximum tolerated dose (MTD) and chronic toxicity tests:

    Another type of study uses different doses of a chemical agent to establish over a 90-day period what is known as the maximum tolerated dose (MTD)(the highest dose that does not cause significant overt toxicity). The MTD is important because it enables researchers to calculate the dose of a chemical that an animal can be exposed to without reducing its life span, thus permitting evaluation of the chronic effects of exposure. These studies are designed to last the lifetime of the species. Chronic toxicity tests evaluate carcinogenicity or other types of toxic effects. Federal regulatory agencies frequently require carcinogenicity studies on both sexes of two species, usually rats and mice. A pathological evaluation is done on the tissues of animals that died during the study and those that are sacrificed at the conclusion of the study. CO exposure is not known to shorten life-span, unless immediate death results.


    ...... last changed 07/30/01



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