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PRINCIPLES OF TOXICOLOGY

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Toxicology is the study of the harmful effects of chemicals, including drugs, on living organisms. Many books (see General References), and particularly Toxicologic Profiles published by the Agency for Toxic Substances and Disease Research, cover in detail the toxicology of individual substances. Freely available search engines allow access to innumerable Web pages with toxicological data, courses, and comments, the reliability of which requires careful assessment. This chapter focuses on generic and conceptual issues relating to properties of toxic substances in general, how they enter and move through the body, and the kinds of pathophysiologic effects that they exert on various targets within the body that ultimately lead to the health effects. The rapid advances being made in molecular toxicology are beyond the scope of this chapter.

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Historians1 trace the modern history of toxicology back to Paracelsus (1493–1541), who recognized that a substance that was physiologically ineffective at very low dose might be toxic at high dose and therapeutic at intermediate dose. However, Gallo2 identified human use of natural venoms in antiquity with a number described in the famed Ebers Papyrus (ca 1500 BC). In the Middle Ages, poisoning became a political tool and toxicological understanding therefore a necessity for both perpetrator and victim. In the past century, toxicology developed under the combined impetus of a burgeoning chemical industry, the quest for therapeutic agents, and concern over adulterated foods. In 1906, the United States enacted the Food and Drug Act, perhaps stimulated more by muckraking writings such as Upton Sinclair's The Jungle3 than by toxicologists.2

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Although the general principles haven't changed since the previous edition (1998), toxicology is passing through a genetic revolution, with a heavy emphasis on understanding toxic mechanism at the presumably most basic level, the gene and its expression. Still in its infancy, and driven at first more by commercial ventures than scientific questions,4,5 toxicogenomics and proteomics offer great promise, but can be dealt with only slightly in this chapter. Likewise, the widespread importance of oncogenes, growth factors, cell cycling, cytokines, apoptosis as well as gene regulation, transcription factors, messenger cascades, have stimulated extensive research,6 but can be mentioned only briefly.

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Toxic chemicals (a) enter and move through the environmental media (air, water, soil, food) at various concentrations until they come into contact with a target individual; (b) are taken up by inhalation, ingestion, through the skin, or by injection (exposure); (c) are absorbed into the bloodstream (uptake) reaching a certain concentration (blood level); (d) undergo complex toxicokinetics involving metabolism, conjugation, storage, and excretion as well as delivery to target organs (dose to target); and (e) affect some molecular, biochemical, cellular, or physiological structure or function to produce their adverse effect.

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Internal distribution and the dose reaching a target organ, tissue, or cell are constantly modified by binding to carrier molecules, metabolic activation (or inactivation), storage in ...

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