Toxicokinetics, toxicodynamics, and toxicology

Tilman Hahn, Konrad Botzenhart, Fritz Schweinsberg Institut fiir Allgemeine Hygiene und Umwelthygiene Universitat Tubingen, Tubingen, Germany 

Highest exposures ean be found in workplaee (e.g., evaporation of solvents) or during spe-eial proeesses (e.g., leaks of normally elosed systems). Aeute and severe solvent aeeidents often happen in workplaees (high solvent eoneentrations, intermittent high-level exposures, high duration of exposure). Apart from working sites, various other emission sourees of solvents should be eonsidered, e.g., eonsumer produets. 

The deseription of exposure parameters (type of solvents, eoneentrations, duration, routes of exposure) are important for the evaluation of toxieokineties. Solvents and other ehemieals are usually emitted as a mixture of various substanees. Therefore, the risk assessment of emitted solvents is diffieult to aseertain. Solvent eoneentrations and duration of exposure vary in most eases (intermittent high-value peaks, periods of low exposure). The exposure is influeneed essentially by surrounding oeeupational and environmental eondi-tions, sueh as working elimate, proteetive equipment and by individual parameters sueh as eating habits. 

The exposure to solvents is regulated by relevant threshold limit values. Exposure and exposure values ean be eontrolled by defined methods (e.g., ambient and biologieal monitoring). 

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This chapter is subdivided into 4 main parts. The first part introduces the fundamental principles of toxicokinetics and toxicodynamics, and their importance for risk assessment, with particular emphasis on mixtures. The second part describes the state of the art in toxicokinetics, and the third part in toxicodynamics. Both later sections focus on how each aspect is dealt with in human toxicology and ecotoxicology. The differences and limitations in each field are addressed. Finally, a general discussion, conclusions, and recommendations for future research explore the application potentials of these approaches, with particular attention to cross-fertilization between human toxicology and ecotoxicology, and where they may hold some promises. 

Hack CE. 2006. Bayesian analysis of physiologically based toxicokinetic and toxicodynamic models. Toxicology 221 241-248. 

Toxicology is the subdiscipline of pharmacology concerned with adverse effects of chemicals on living systems. Toxic effects and mechanisms of action may be different from therapeutic effects and mechanisms for the same drug. Similarly, at the high dose of drugs at which toxic effects may be produced, rate processes are frequently altered compared with those at therapeutic doses. For these reasons, the terms toxicodynamics and toxicokinetics are now applied to these special situations. 

An understanding of the role of toxicokinetics and toxicodynamics in the manifestation of hazard is fundamental to designing safer chemicals and can guide early design choices. Toxicokinetics and toxicodynamics use the same principles to study toxicological phenomena as those that are used to study the therapeutic use of chemicals as medicines. Toxicokinetics is concerned with the time course of action of chemicals that involves the disposition of a chemical affected by absorption, distribution, metabohsm and excretion commonly referred to by the acronym ADME. 

As mentioned previously, the assessment of hazard and risk to humans from exposure to chemical substances is generally based on the extrapolation from data obtained in smdies with experimental animals. In the absence of comparative data in humans, a basic assumption for toxicological risk assessment is that effects observed in laboratory animals are relevant for humans, i.e., would also be expressed in humans. In assessing the risk to humans, an assessment factor is applied to take account of uncertainties in the differences in sensitivity to the test substance between the species, i.e., to account for interspecies variability (Section 5.3). If data are available from more than one species or strain, the hazard and risk assessment is generally based on the most susceptible of these except where data strongly indicate that a particular species is more similar to man than the others with respect to toxicokinetics and/or toxicodynamics. Two main aspects of toxicity, toxicokinetics and toxicodynamics, account for the namre and extent of differences between species in their sensitivity to xenobiotics this is addressed in detail in Chapter 5. 

A WHO/IPCS (2005) Harmonization Project Document has proposed using chemical-specific toxicological data instead of default assessment factors, when possible. The concept of Chemical-Specific Adjustment Factors (CS AFs) has been introduced to provide a method for the incorporation of quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics into the risk assessment procedure, by modifying the relevant default UF of 10. Incorporation of toxicokinetic or toxicodynamic data becomes possible if each factor of 10 is divided into appropriately weighted sub-factors as suggested by Renwick (1991, 1993) and adopted by WHO/IPCS (1994), see Section 5.2.1.3. 

The authors noted that, in comparison with the scaling factor, the traditional 10-fold factor contains an additional extrapolation factor for possible additional toxicokinetic or toxicodynamic variability apart from the basal metabolic rate scaling. This additional factor, which can be interpreted as the traditional 10-fold factor divided by the scaling factor, ranges from approximately 1.5 for the mouse (10/7= 1.4) to approximately 6 for the rhesus monkey (10/1.6 = 6.3). The authors considered that the additional factor thus comprises levels of safety, which are currently nonuniform, and this inhomogeneity is not supported toxicologically. 

What is toxicogenomics and how does this science related to toxicological chemistry How does this science relate to toxicokinetics and toxicodynamics. 

Risk assessment of potential adverse human health effects from chemical mixture exposures may be conducted using health effects information from 1) toxicological bioassays, 2) epidemiological studies, and 3) computer models of toxicokinetic and toxicodynamic processes (i.e., in silico toxicology). 

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