Examples of Risk Assessments of Human Metal Exposures and the Need for Mode of Action (MOA), Toxicokinetic-Toxicodynamic (TKTD) Modeling, and Adverse Outcome Pathways (AOPs)
Nordberg, GF; Fowler, BA; Nordberg, GF; Fowler, BA
Metals are elements and intrinsic components of the earth's crust. Humans have always been exposed to naturally occurring levels in the environment and some of the metals are essential for human health. Human activities such as mining and production of metals, materials for construction of buildings, ships, automobiles, consumer items, biocides, pesticides, and medicines all involve metals. Considerable exposures of humans have occurred in the past and continue today in working environments where these activities take place. By adding to the natural geochemical cycle of metals, for example, mercury, humans have increased the quantities in these cycles. This has caused increased levels in biota, such as fish, used for human consumption. Present human exposures to metals and their compounds therefore are increased compared to the natural exposure in the ancient past. It is important to make adequate risk assessments of these exposures in order to take adequate preventive measures so that adverse human health effects are avoided. Previous chapters in this book have described methods for risk assessment; Chapter 2 deals with measurements and descriptions of exposure, internal dose, and toxicokinetics; Chapter 3 describes how to perform biomonitoring defines mode of action (MoA), target dose, and adverse outcome pathways (AOPs). Chapter 4 discusses how to identify and assess hazard, and Chapters 5 and 6 reviews methods for dose-effect and dose-response relationships;and Chapter 7 on applied risk assessment deals with the translation of exposure and toxicological data into prevention and management of risks by regulatory action. The present chapter gives examples from available data on 14 metals and their compounds, what information is available, and their use in risk assessments performed by international and national organizations preparing preventive recommendations or regulations. The 14 metals included in this chapter represent well-investigated metals/metalloids like arsenic, cadmium, lead, and mercury where risk assessments are available from established organizations. The chapter deals with cadmium in more detail than it does with the other major metals because the cadmium section illustrates the use of toxicokinetic-toxicodynamic (TKTD) modeling in the risk assessment. The chapter also includes nickel, cobalt, and platinum, sensitizing metals in order to evaluate possible use of general knowledge on sensitization for risk assessment. A few metals are included where the database is limited such as gallium, indium, palladium, and the lanthanides (lanthanum, cerium, and gadolinium). For all the 14 metals, the chapter includes pertinent available data from the scientific literature and examples of risk assessments by recognized organizations, if available. Discussions consider the possible use of MoA, TKTD, and AOP models in the risk assessment of each metal.