Toxicokinetics experimental models

Estimation of this radiation dose is sometimes accomplished by modeling the sequence of events involved in the acquisition, deposition, clearance, and decay of radium within the body. While based on the current understanding of experimental data on radium toxicokinetics, different models make different assumptions about these processes, thereby resulting in different estimates of dose and risk. These models are described in numerous reports including BEIR IV (1988), ICRP (1979), and Raabe et al. (1983). In this section, the toxicokinetics of radium are described based on the available experimental data rather than on descriptions derived from models. 

Comparative Toxicokinetics. In humans, the targets for trichloroethylene toxicity are the liver, kidney, cardiovascular system, and nervous system. Experimental animal studies support this conclusion, although the susceptibilities of some targets, such as the liver, appear to differ between rats and mice. The fact that these two species could exhibit such different effects allows us to question which species is an appropriate model for humans. A similar situation occurred in the cancer studies, where results in rats and mice had different outcomes. The critical issue appears to be differences in metabolism of trichloroethylene across species (Andersen et al. 1980 Buben and O Flaherty 1985 Filser and Bolt 1979 Prout et al. 1985 Stott et al. 1982). Further studies relating the metabolism of humans to those of rats and mice are needed to confirm the basis for differences in species and sex susceptibility to trichloroethylene s toxic effects and in estimating human heath effects from animal data. Development and validation of PBPK models is one approach to interspecies comparisons of data. 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

A review of the literature (Krishnan and Brodeur 1991) demonstrated that the majority of toxicokinetic interaction results from metabohc induction or inhibition caused by some components of the mixture. These interactions may alter tissue dosimetry and thereby the toxicity of components in the mixture. The tissue doses of chemicals in mixture can be predicted with PBTK models when the binary interactions between aU of the components in the mixture are known (Haddad et al. 1999a,b, 2000a,b). However, the quantitative characteristics of each of these binary interactions have to be determined by experimentation. Given the complexity of the mixtures, to which humans are exposed, this would obviously require an unreahstic large number of experiments in order to characterize the quahtative and quantitative nature of the possible interactions. 

The major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Physiological toxicokinetic (or pharmacokinetic) models represent descriptions of biological systems and can be used to describe the behaviour of chemicals in the intact animal. Such models have been used to predict the disposition of butadiene and metabolites in rats, mice, and humans. For the case of rats and mice, these predictions can be compared with experimental data. In some cases (see below), the models successfully describe (and accurately predict) the disposition of butadiene and metabolites. Human physiological toxicokinetic model predictions normally cannot be verified due to lack of experimental data. 

Filser, 1993 Kohn Melnick, 1993 Bond et al., 1994 Medinsky et al., 1994 Csanady et al., 1996 Sweeney et al., 1997) predicted, species specifically, similar toxicokinetic behaviour of butadiene. The only exception was the first model of Kohn and Melnick (1993), which contained much higher theoretically derived partition coefficients than the experimentally determined ones, leading to prediction of butadiene storage in fat tissue. In a second, extended version, the authors used average values of the partition coefficients determined experimentally by Johanson and Filser (1993) and Medinsky etal. (1994). 

Another physiological toxicokinetic model (Tardif et al., 1993b, 1997) has been used to predict potential interactions between, e.g., toluene, ethylbenzene and we/tr-xylene the model and experimental data from exposed volunteers indicate that no biologically significant changes in their toxicokinetics will occur if these three solvents are present in the air as a mixture within the permissible concentrations for mixtures (Tardif et al., 1997). A model approach also predicted that interactions between dichloromethane and toluene at their current threshold limit values are not relevant for humans (Pclekis Krishnan, 1997). 

Comparative Toxicokinetics. A limited number of studies exist regarding the comparative toxicokinetics of orally administered silver compounds in rats, dogs, monkeys, and humans. A more complete comparison of the absorption and elimination of silver in humans and rats may be warranted given that much of the toxicokinetic data comes from rats. It would also be useful to acquire data on the comparative toxicokinetics of various silver compounds in several species of experimental animals and in humans following inhalation and dermal exposure in order to model the kinetics of silver deposition across different exposure scenarios and within sensitive populations. 

In summary, in studies of chemical toxicity, pathways and rates of metabolism as well as effects resulting from toxicokinetic factors and receptor affinities are critical in the choice of the animal species and experimental design. Therefore it is important that the animal species chosen as a model for humans in safety evaluations metabolize the test chemical by the same routes as humans and, furthermore, that quantitative differences are considered in the interpretation of animal toxicity data. Risk assessment methods involving the extrapolation of toxic or carcinogenic potential of a chemical from one species to another must consider the metabolic and toxicokinetic characteristics of both species. 

In the mechanistic models used to predict effects of time-variable exposure to organisms, a distinction can be made between 1) l-step models that consider the toxicokinetic terms uptake, elimination, and critical body residues and 2) 2-step models that besides toxicokinetics also address the toxicodynamic terms injury and repair. A disadvantage of these models is that their parameterization is compound-and species-specific and hence requires many experimental data (Section 6.2.3). 

The toxicokinetics of MTBE have been studied in animal models, primarily rodents. The information available to date on the biological fate of ETBE and TAME indicates that their kinetics are expected to be similar to those of MTBE. This has been confirmed experimentally in rodents, in in vitro systems using liver microsome homogenates, and also in studies with human volunteers inhaling these fuel oxygenates while at rest or during light exercise. 

Validation of the model. Since the model (Shyr et al. 1993) was developed concurrently with toxicokinetic experiments being conducted in the same laboratory, the model was used to predict the outcome of experiments that were yet to be run (Medinsky et al. 1990 Sabourin et al. 1992a, 1992b, 1993). Variables that were not predictive were modified according to the experimental data. Thus, the model was developed and refined in conjunction with the data it used for validation. The model was successful in predicting urinary metabolites from the three routes of exposure. 

Carrier G, Brunet RC, Caza M and Bouchard M (2001) A toxicokinetic model for predicting the tissue distribution and elimination of organic and inorganic mercury following exposure to methyl mercury in animals and humans. 1. Development and validation of the modd using experimental data in rats. Toxicol Appl Pharmacol 171 38-49. 

In this section the toxicokinetics of radon is described based on the available experimental data rather than descriptions derived from models. The toxicokinetics of radon, as it relates to the development of adverse health effects in exposed populations, is further complicated by the transformation of radon to radon daughters. These progeny may be present with radon in the environment and inhaled or ingested along with radon and/or they may be formed in situ from the transformation of the radon absorbed in the body. 

In addition to the role of genetically modified animals in target safety assessment and investigating mechanisms of toxicity, a key use of these animal models is the assessment of drug metabolism and toxicokinetics of experimental therapeutics, with drug exposure playing an important role in overall safety. The properties of absorption, disuibntion, metabolism, and elimination (ADME) for small-molecnle... 

---