Toxicokinetic Considerations

TCDD and related chemicals, as well as the pharmacokinetics of dioxins in experimental animals. For CDDs, toxicity and toxicokinetics cannot be dealt with separately. Based on results from research in these fields, it has become apparent that the comparison of responses from animals to humans (or even between animal species) should be done on the basis of body-burden or target-tissue dose, rather than on the basis of administered dose. By doing so, species-specific toxicokinetic considerations such as dose-dependent distribution, the existence of tissue-specific sequestering chemical entities (i.e., CYP1A2), and body composition (i.e., percent fat) can be taken into account. A discussion of relationships between administered dose, body burden, and biological responses is presented below. 

Describe what is known about the mechanism of action/toxicity of the exposure and any toxicokinetic considerations that may influence the toxicity of the exposure at specific life stages. 

This present chapter focuses on some critical aspects influencing dermal absorption. This is followed by an overview of existing dermal absorption methodologies, including a discussion regarding the validation of these model systems. Some toxicokinetic considerations regarding the use of percentage of absorption in present risk assessment are presented. Finally, some considerations for improvement of dermal risk assessment, with special attention to dermal kinetic aspects, are provided. 

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... 

Physiologically based toxicokinetic models are nowadays used increasingly for toxicological risk assessment. These models are based on human physiology, and thus take into consideration the actual toxicokinetic processes more accurately than the one- or two-compartment models. In these models, all of the relevant information regarding absorption, distribution, biotransformarion, and elimination of a compound is utilized. The principles of physiologically based pharmaco/ toxicokinetic models are depicted in Fig. 5.41a and h. The... 

Exposure Assessment. Single and multiple dose pharmacokinetics, toxicokinetics and tissue distribution studies in relevant species are useful. Proteins are not given orally demonstrating absorption and mass balance is not typically a primary consideration. Rather, this segment of the test should be designed to determine... 

Operational and metabolic considerations generally make urine sampling and assay of limited value for toxicokinetic purposes. 

The threshold for a specific effect may vary considerably for different exposure routes and for different species because of differences in the toxicokinetics for different species and exposure routes, and possibly also because of differences in the toxicodynamics. The NOAEL and LOAEL derived for a given smdy will therefore in general depend on the experimental smdy design, i.e., species, sex, age, strain, and developmental status of animals number of animals per exposure level selection of exposure levels the spacing between the exposure levels duration of exposure and sensitivity of methods used to measure the responses. Thus, the sensitivity of a particular smdy may... 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

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. 

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. 

In a more recent publication, ECETOC (2003) noted that route-to-route extrapolation is only feasible for substances with a systemic mode of action, and should take dose rate and toxicokinetic data into account. It was noted that the following points need to be taken into consideration when conduction a route-to-route extrapolation with systemic toxicity data ... 

The WHO emphasized that guideline values for carcinogenic substances computed using mathematical models must be considered at best as a rough estimate of the cancer risk, as these models do not usually take into account a number of biologically important considerations, such as toxicokinetics, DNA repair, or immunological protection mechanisms. However, the models used are conservative and probably err on the side of caution. 

The rat will usually be the species of choice for the standard oncogenicity study because there is greater confidence in its predictivity for human carcinogenicity than the mouse or hamster. The species chosen, however, should be the most appropriate based on considerations such as pharmacology, repeated-dose toxicity, metabolism and toxicokinetics. 

Environmental toxicity considerations for choice of solvents include the degree of absorption reported in the literature, exploration of toxic mechanisms, and the use of Stmcture-Activity Relationships (SAR). The relative seriousness of the toxic effect depends upon the extent of exposure to the substance, its bioavailability, and the importance of the physiologic process that the substance has disrupted (DeVito, 1996a). Over this information must be laid the physical parameters of the solvent s use (i.e., amount, state, reaction environment, etc). This requires a basic understanding of the processes involved in chemical toxicokinetics and toxicodynamics. 

The assumption that PBBs and PBDEs share many toxicological characteristics with PCBs also does not consider geometrical differences due to the higher atomic weight and considerably larger molecular volume of bromine compare to chlorine (Hardy 2000, 2002). These differences contribute to dissimilar physical/chemical properties that can influence the relative toxicokinetics and toxicities of the chemicals. 

Physiological toxicokinetic models have been presented describing the behaviour of inhaled butadiene in the human body. Partition coefficients for tissue air and tissue blood, respectively, had been measured directly using human tissue samples or were calculated based on theoretical considerations. Parameters of butadiene metabolism were obtained from in-vitro studies in human liver and lung cell constituents and by extrapolation of parameters from experiments with rats and mice in vivo (see above). In these models, metabolism of butadiene is assumed to follow Michaelis-Menten kinetics. 

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