Chapter Three - Biomonitoring, Mode of Action (MOA), Target Dose, and Adverse Outcome Pathways (AOPs)

Abstract

Risk and hazard assessments are crucial in order to estimate the likelihood of human disease or other adverse health effects resulting from existing human exposures to metals and their compounds on an individual or mixture basis. External exposures produce internal doses that produce the toxic dose at the site of action, named the target dose. The target organ that suffers toxicity at the lowest external exposure level is the critical organ and the adverse effect that occurs at the lowest external exposure is the critical effect. This effect is critical because it is crucial for preventive action (for definitions of concepts, see Appendix). It is thus important to try to estimate the target dose as accurately as possible. Unfortunately, it is seldom possible to measure this dose in living humans or animals. The concentration of the toxic metal species in the critical organ may be measured or estimated and is often a useful surrogate for the target dose. Biological monitoring (synonym: biomonitoring), for example, measurements of concentrations of metal compounds in tissues, blood, or urine, is often used as a basis for estimating target dose/concentration in critical organ. Toxicodynamics describes the mechanism or mode of action of toxicants, how they can cause tissue damage, and under what conditions in terms of tissue concentrations and time of tissue exposure/dose do adverse effects on tissue structure and function occur. When these conditions can be described in quantitative terms and when, in addition, a toxicokinetic model can be described, a quantitative toxicokinetic-toxicodynamic (TKTD) dose–response model can be set up and be used to predict relationships between exposure dose and the expected frequency of adverse health effects. A TKTD model may constitute a major part of an adverse outcome (AO) pathway describing the linking between a molecular initiating event and AO at the biological level of organization.