Toxicokinetics dose-toxicity relationships

The explanation of the pharmacokinetics or toxicokinetics involved in absorption, distribution, and elimination processes is a highly specialized branch of toxicology, and is beyond the scope of this chapter. However, here we introduce a few basic concepts that are related to the several transport rate processes that we described earlier in this chapter. Toxicokinetics is an extension of pharmacokinetics in that these studies are conducted at higher doses than pharmacokinetic studies and the principles of pharmacokinetics are applied to xenobiotics. In addition these studies are essential to provide information on the fate of the xenobiotic following exposure by a define route. This information is essential if one is to adequately interpret the dose-response relationship in the risk assessment process. In recent years these toxicokinetic data from laboratory animals have started to be utilized in physiologically based pharmacokinetic (PBPK) models to help extrapolations to low-dose exposures in humans. The ultimate aim in all of these analyses is to provide an estimate of tissue concentrations at the target site associated with the toxicity. 

Hazard characterization consists of qualitative or quantitative evaluation of the adverse health effects associated with different agents, whether they are chemicals or microorganisms. This step comprises several elements, like toxicokinetics (absorption, distribution, metabolism, and excretion of the toxic agent), mechanism of toxic action, dose-response relationships, target organs and different end points, like acute or chronic toxicity, teratogenicity, neoplastic manifestations, and so forth. 

Second, lead s kinetic behavior in vivo provides the means by which one can identify and exploit biomarkers of toxic lead exposures as well as determine the dose portion of critical dose—toxic response relationships for lead poisoning. Measurement of lead in whole blood and its relatively reliable use in determining both systemic lead exposure and the extent of toxic injury (dose—response relationships) is mainly feasible because we understand how Pb s toxicokinetic behavior in blood relates to the temporal and toxicological... 

A critical question in fetal Pb toxicokinetics is how one best measures dose—response relationships among various exposure biomarkers as well as relationships governing dose—toxic response relationships. It is now accepted that bone Pb is a better biomarker in constmcting dose—toxic response relationships for a variety of toxic effects than are indicators such as PbB. This was demonstrated in Chapter 13 describing cardiovascular effects of Pb. 

It is difficult to establish uniform guidelines for pharmacokinetic studies for biotechnology-derived pharmaceuticals. Single and multiple dose pharmacokinetics, toxicokinetics, and tissue distribution studies in relevant species are useful however, routine studies that attempt to assess mass balance are not useful. Differences in pharmacokinetics among animal species may have a significant impact on the predictiveness of animal studies or on the assessment of dose response relationships in toxicity studies. Alterations in the pharmacokinetic profile due to immune-mediated clearance mechanisms may affect the kinetic profiles and the interpretation of the toxicity data. For some products there may also be inherent, significant delays in the expression of pharmacodynamic effects relative to the pharmacokinetic profile (e.g., cytokines) or there may be prolonged expression of pharmacodynamic effects relative to plasma levels. 

Data on the toxicokinetics of a substance can be very useful in the interpretation of toxicological findings, and may replace the use of some default extrapolation factors used in route-to-route (Section 5.5) or interspecies extrapolations (Section 5.3). In addition, interindividual differences in sensitivity to toxicants may be identified on the basis of toxicokinetic data, thereby making it possible to make the risk assessment more comprehensive by including sensitive subpopulations (Section 5.4). In conjunction with information on the relationship between concentration-dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

In conjunction with information on the relationship between concentration/dose at the target site and the toxic effect, toxicokinetic information may be an important tool for extrapolation from high to low dose effects. 

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. 

Determination of exposure and toxic effects of chemicals also requires knowledge of toxicokinetics. Toxicokinetics is the study of changes in the levels of toxic chemicals and their metabolites over time in various fluids, tissues, and excreta of the body, and determines mathematical relationships to explain these processes. These processes depend upon uptake rates and doses, metabolism, excretion, internal transport, and tissue distribution. Methods for determining these processes include studies with laboratory animals, volunteer human subjects, persons accidentally exposed to high doses of chemicals, and experiments with tissue or organs cultured in the laboratory. Computer simulations of such processes are often formulated using complex mathematical equations. 

Preclinical pharmacokinetic (PK) studies provide information useful for supporting efficacy and safety evaluation studies in animals, preclinical and clinical study designs, dosing regimen development, and interpretation of toxicity data. These studies provide PK data that may be useful in dose escalation in healthy volunteers and patients. Toxicokinetics is a major component of toxicology studies. It enables the investigation of the relationship between drug dose and measured concentration, primarily the establishment of the dose proportionahty and hnearity or nonlinearity in pharmacokinetics. 

GB, GD, and VX to determine the in vitro mass balance of these OPs. They developed a mathematically based toxicokinetic model for the estimation of the upper limit of Hu BChE dose required for protection against OP toxicity. The model addressed the relationship between the Hu BChE dose needed to maintain 30% of residual red blood cell (RBC) AChE activity and other parameters (level and duration of OP exposure, bimolecular rate constants of inhibition of Hu AChE and Hu BChE by OPs, and time elapsed from enzyme administration). They validated the Hu BChE dose by in vitro experiments and data from published human studies (Ashani et al., 1998 Ashani and Pistinner, 2004). The proposed model suggested that the upper limit doses of 134, 115, and 249 mg/kg of Hu BChE were sufficient to protect RBC AChE above 30% following a challenge with 1 X LD50 of VX, GD, and GB, respectively. 

An adequate characterization of the dose/exposure portion of reported dose—responses for lead requires discussion of the merits and limits of those exposure biomarkers which have traditionally been used and others which are relatively new and gaining favor. These two broad groups of exposure assessment instruments are further stratified in terms of temporal and toxicokinetic relationships for lead s associated toxic responses and in terms of accessibility and acceptability for routine use in the research and medical communities. 

---