Home Random Page


CATEGORIES:

BiologyChemistryConstructionCultureEcologyEconomyElectronicsFinanceGeographyHistoryInformaticsLawMathematicsMechanicsMedicineOtherPedagogyPhilosophyPhysicsPolicyPsychologySociologySportTourism






MECHANISMS OF TOXICITY

Toxicology is the scientific discipline that studies the detection, effects, and mechanisms of action of poisons and toxic chemicals. Toxicity is a relative phenomenon that depends on the

inherent structure and properties of a chemical and on its dose. Dose-response curves are typically generated in laboratory animals exposed to various amounts of a chemical. A typical

dose-response curve for acute toxicity is illustrated in Figure 9-1 . In this example, a measurable response occurs at a dose of 0.1 mg/kg; this is defined as the threshold dose. To the left of

this dose, at subthreshold levels, there is no measurable response. For this chemical, this is the no observed effect level and can be considered a safe dose. This information is used to

establish a daily or annual threshhold limit value or permissible exposure level for occupational exposures. Frequently, a plateau is reached at higher doses; this is defined as the ceiling

effect. It is uncertain whether carcinogens show a threshold effect or whether the dose-response curve should be extrapolated linearly to zero.[4]

Despite the inherent limitations of toxicity testing in animals, several important toxicologic principles have been established by this experimental approach. Exogenous chemicals are

absorbed after ingestion, inhalation, or skin contact, and then distributed to various organs ( Fig. 9-2 ). Chemicals are frequently metabolized, often by multiple enzymatic pathways, to

products that may be more toxic or less toxic than the parent chemical. One or more of these products then interacts with the target macromolecule, resulting in a toxic effect.[5] The site of

toxicity is frequently the site where metabolism or excretion of toxic metabolites occurs. The dose administered (external dose) may not be the same as the biologic effective dose delivered

to the target organ and target macromolecule.

Figure 9-1The dose-response curve for acute chemical toxicity. Th, threshold dose; STh, subthreshold levels. (Data from Hughes WW: Essentials of Environmental Toxicology: The

Effects of Environmentally Hazardous Substances on Human Health. Washington, DC, Taylor & Francis, 1996, p. 33.)

Figure 9-2Absorption and distribution of toxicants. (From Hodgson E, Levi PE: Absorption and distribution of toxicants. In Hodgson E, Levi PE [eds]: A Textbook of Modern Toxicology.

Stamford, CT, Appleton & Lange, 1997, p. 52.)

Figure 9-3Biotransformation of lipophilic toxicants to hydrophilic metabolites. (Adapted from Hodgson E: Metabolism of toxicants. In Hodgson E, Levi PE [eds]: A Textbook of Modern

Toxicology. Stamford, CT, Appleton & Lange, 1997, p. 57.)

TABLE 9-3-- Organ-Specific Carcinogens in Tobacco Smoke

Organ Carcinogen

Lung, larynx Polycyclic aromatic hydrocarbons

4-(Methylnitrosoamino)-1-(3-pyridyl)-1-buta-none (NNK)

Polonium 210

Esophagus N'-Nitrosonornicotine (NNN)

Pancreas NNK (?)

Bladder 4-Aminobiphenyl, 2-naphthylamine

Oral cavity (smoking) Polycyclic aromatic hydrocarbons, NNK, NNN



Oral cavity (snuff) NNK, NNN, polonium 210

Data from Szczesny LB, Holbrook JH: Cigarette smoking. In Rom WH (ed): Environmental and Occupational Medicine, 2nd ed. Boston, Little, Brown, 1992, p. 1211.

such synergism is the increase in risk of lung cancer in cigarette smokers exposed to asbestos.[13]

Mainstream cigarette smoke inhaled by the smoker is composed of a particulate phase and a gas phase; tar is the total particulate phase without water or nicotine. There are 0.3 to 3.3

billion particles per milliliter of mainstream smoke and more than 4000 constituents, including 43 known carcinogens. Examples of the organ-specific carcinogens found in tobacco smoke

and snuff are listed in Table 9-3 . In addition to these chemical carcinogens, cigarette smoke contains carcinogenic metals such as arsenic, nickel, cadmium, and chromium; potential

promoters such as acetaldehyde and phenol; irritants such as nitrogen dioxide and formaldehyde; cilia toxins such as hydrogen cyanide; and carbon monoxide. Carbon monoxide is a

colorless, odorless gas produced during incomplete combustion of fossil fuels or tobacco. It has 200 times higher affinity for hemoglobin than oxygen does and it impairs release of oxygen

from hemoglobin. Thus, carbon monoxide exposure decreases the delivery of oxygen to peripheral tissues. Carbon monoxide also binds to other heme-containing proteins such as

myoglobin and cytochrome oxidase. Nicotine is an important constituent of cigarette smoke. It is an alkaloid that readily crosses the blood-brain barrier and stimulates nicotine receptors in

the brain. It is also responsible for the acute pharmacologic effects associated with tobacco use that are most likely mediated by catecholamines: increased heart rate and blood pressure,

increased coronary artery blood flow, increased contractility and cardiac output, and mobilization of free fatty acids. Nicotine is responsible for tobacco addiction.

The inhaled agents in cigarette smoke may act directly on the mucous membranes, may be swallowed in saliva, or may be absorbed into the bloodstream from the abundant alveolar

capillary bed. By various routes of delivery, the constituents of cigarette smoke act on distant target organs and cause a variety of systemic diseases, listed in Table 9-4 . The greatest

numbers of deaths attributable to cigarette smoking are due to lung cancer, ischemic heart disease, and chronic obstructive lung disease. Lung cancer is caused by multiple carcinogens and

promoters in cigarette smoke. As described in Chapter 15 , specific preneoplastic changes are found in the tracheobronchial lining of cigarette smokers. These cellular changes

Figure 9-4aA, Xenobiotic metabolism: phase I reactions. FMO, flavin-containing monooxygenase; PHS, prostaglandin-H synthases.

Figure 9-4bB, Xenobiotic metabolism: phase II reactions (see text for details). (Adapted from Parkinson A: Biotransformation of xenobiotics. In Klaasen CD [ed]: Casarett and Doull's

Toxicology: The Basic Science of Poisons, 5th ed. New York, McGraw-Hill, 1996, pp. 113–186; and Hodgson E, Levi PE [(eds]: A Textbook of Modern Toxicology. Stamford, CT,

Appleton & Lange, 1997, pp. 57, 95.)

TABLE 9-4-- Deaths per Year Attributable to Cigarette Smoking in the United States

Number of Deaths


Date: 2016-04-22; view: 705


<== previous page | next page ==>
Disease Number of Workers Percentage | Cause of Death Men Women
doclecture.net - lectures - 2014-2024 year. Copyright infringement or personal data (0.01 sec.)