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Appendix A Dose-Effect, Dose-Response Concepts of Toxicology The dose-effect, dose-response concepts of toxicology provide a framework for examining the biologic effects of toxic metals. These concepts and their application to human exposures to heavy metals are discussed fully in "Effects and Dose-Response Relationships of Toxic Metals." Here we will initially summarize these concepts through a series of definitions and then discuss their specific application to lead. Critical Effect - The critical effect is not the most serious, but rather the most sensitive and specific biologic change, beyond acceptable physiologic variation, which is caused by the presence of a toxic substance. Although many different effects may occur, the critical effect is defined as the first measurable adverse effect. "Sub-critical effects" are measurable biologic changes which do not impair cellular function, but which are directly related to the concentration of a toxic substance. Critical Site - The critical site is the location in the body where the critical effect occurs. It may be a system, organ, cell type or cell component. Dose - In experimental animals, an administered dose is readily quantified but this Is not true of humans. For humans we can estimate the amount taken in and for this we use the term "external dose." Since this is an indefinite amount for humans we must relate response to a tissue level such as blood concentration and we use the term "internal dose" for this tissue level. The "external dose" is the quantity of a toxic agent which enters the organism through the lungs, gastrointestinal tract, skin, etc., a portion of which may be excreted before reaching the "critical site." The "internal dose" is the quantity of a toxic agent which is absorbed and reaches the critical site. Since the concentration of a toxic agent at the critical site can rarely, if ever, be measured in human studies, the concentration is measured in a body fluid such as blood or urine. The concentration of a toxic agent in blood or urine is then used as an indicator of the internal dose. Dose-Effect Relationship - The dose-effect relationship is a relationship in which a quantitative change in a metabo- lite Affect) is directly related to the concentration (dose) of a toxic substance. A typical dose-effect relationship is graphically illustrated by an "s" shaped curve when dose is plotted on the abscissa and degree of effect on the ordinate. 13