Toxicodynamics and toxicokinetics

There are several points along the pathway to hazard that can be influenced through molecular design that are described in more detail later in this chapter. The magnitude and duration of a toxic event can be minimized through influencing the toxicodynamic and toxicokinetic phases associated with the manifestation of toxicity. 

In the 2002 review of the RfD and RfC processes (US-EPA 2002), the growing support for the use of CSAFs in place of DAFs was noted, and this will provide an incentive to fill existing data gaps. The US-EPA has not yet established a guidance for the use of chemical-specific data for deriving UFs, but the division of UFs into toxicodynamic and toxicokinetic components is in the RfC methodology (US-EPA 1994). It was pointed out that, for many substances, there are relatively few data available to serve as an adequate basis to replace defaults for interspecies differences and human variability with more informative CSAFs. Currently, relevant data for consideration are often restricted to the component of uncertainty related to interspecies differences in toxicokinetics. 

Most extrapolations from animal experimental data in the risk assessments require the utilization of uncertainty factors. This is because we are not certain how to extrapolate across species, with species for the most sensitive population, and across duration. To account for variations in the general population and to protect sensitive subpopulations, an uncertainty factor of 10 is used by EPA and ATSDR. The value of 10 is derived from a threefold factor for differences in toxicokinetics and for threefold factor for toxicodynamics. To extrapolate from animals to humans and account for interspecies variability between humans and other mammals, an uncertainty factor of 10 is used by EPA and ATSDR, and as with intraspecies extrapolations, this 10-fold factor is assumed to be associated with in toxicodynamics and toxicokinetics. An uncertainty... 

Both the toxicodynamics and toxicokinetics of OP nerve agents can be explained by their biochemical characteristics of interacting with cholinesterases and other hydrolases. Inhibition of cholinesterases in the blood is the first target for OPs according to the principle of first come, first served (Benschop and de Jong, 2001). 

Scientists then determine the appropriate uncertainty (or safety) factors to apply to the no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for the critical effect, based on considerations of the available toxicity, toxicodynamic, and toxicokinetic data. Uncertainty factors (UFs) used in the estimation of safe doses are necessary reductions to account for the lack of data and inherent uncertainty in these extrapolations. Other areas of uncertainty include extrapolations of subchronic-to-chronic exposure, LOAEL to NOAEL, and use of an incomplete database. The major assumptions underlying each of these UFs are described in Table 1. 

Chemical Specific Adjustment Factors (CSAFs) provide a consistent approach for incorporating mechanistic data to replace the default uncertainty factors for interspe-cies extrapolation and intraspecies variability (IPCS, 2001). This framework is based on early work by Renwick (1993) and applied by IPCS (1994), in which the default uncertainty factor of 10 for interspecies differences is divided into two factors of 2.5 and 4.0 for toxicodynamics and toxicokinetics, respectively. The default factor of 10 for infraspecies variability is similarly divided into two equal factors for toxicodynamics and toxicokinetics. Any one or all of these four subfactors can be replaced by chemical-specific data. The CSAFs have been used by the U.S. EPA in deriving an RfD for boron (U.S. EPA, 2004a) and by Health Canada in deriving a TC for 2-butoxyethanol (Health Canada, 2000). 

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. 

In their analyses, statistics on the relevant extrapolation factor from animals to humans, as reported in the literature, were considered synoptically, and distinctions were made between (1) publications which focused on allometrically justifiable differences (2) publications which examined the toxicodynamic or toxicokinetic variability and (3) pubhcations which considered the total (gross) interspecies factor. In addition, consideration of PBPK models was discussed as a possible alternative. 

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

The term toxicokinetics denotes the absorption, distribution, excretion, and metabolism of toxins, toxic doses of therapeutic agents, and their metabolites. The term toxicodynamics is used to denote the injurious effects of these substances on vital functions. Although many similarities exist between the pharmacokinetics and toxicokinetics of most substances, there are also important differences. The same caution applies to pharmacodynamics and toxicodynamics. 

Information of importance in test animal selection is the similarity in toxicodynamics and metabolism to that of humans. Although all of the necessary information may not be available for humans, it can often be inferred with reference to metabolism and excretion of related compounds, but it is clearly ill advised to use an animal that differs from most others in the toxicokinetics or metabolism of the compound in question or that differs from humans in the nature of the end products. Dose selection... 

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. 

Renwick examined the nature of the UFs generally applied for intraspecies and interspecies extrapolations. He proposed the division of each of these UFs into subfactors to allow for separate evaluations of differences in toxicokinetics and toxicodynamics. The toxicokinetic considerations include absorption, distribution, metabolism, and excretion of a toxic compound, and therefore address differences in the amount of the parent compound or active metabolite available to the target organ(s). The toxicodynamic considerations are based on variations in the inherent sensitivity of a species or individual to chemical-induced toxicity, and may result from differences in host factors that influence the toxic response of a target organ to a specified dose. The advantage to such a subdivision is that components of these UFs... 

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