Toxicokinetics animal models

Comparative Toxicokinetics. PBPK models have not been developed to compare the toxicokinetics of hydrogen sulfide in humans and animals. Studies providing quantitative data necessary to develop PBPK models would be useful. 

Comparative Toxicokinetics. The metabolism and excretion of orally administered phenol in 18 animal species have been compared to metabolism and excretion in humans (Capel et al. 1972). The rat was the most similar to the human with respect to the fraction of administered dose excreted in urine in 24 hours (95%) and the number and relative abundance of the 4 principal metabolites excreted in urine (sulfate and glucuronide conjugates of phenol and 1,4-dihydroxybenzene). The rat excreted a larger fraction of the orally administered dose than the guinea pig or the rabbit (Capel et al. 1972) and appears to be the least susceptible of the three species to respiratory, cardiovascular, hepatic, renal, and neurological effects of inhaled phenol (Deichmann et al. 1944). More rapid metabolism and excretion of absorbed phenol may account for the lower sensitivity of the rat to systemic effects of phenol. More information on the relative rates of metabolism of phenol in various species is needed to identify the most appropriate animal model for studying potential health effects in humans. 

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

Comparative Toxicokinetics. Metabolic pathways and mechanisms of hepatotoxicity of carbon tetrachloride have been the subject of many studies in intact animals and in vitro, and are therefore better understood than for many other chemicals. However, there are apparently no data on metabolism of carbon tetrachloride in humans. It would be valuable to conduct in vitro experiments with human liver samples and hepatocytes to determine whether metabolic pathways and toxic metabolites are similar to those found in animals. It would also be beneficial to identify an animal model in which MFO systems develop in uteroas they do in the human fetus. 

Polybrominated Diphenyl Ethers. Insufficient data are available to determine whether qualitative differences in the toxicokinetic disposition of PBDEs exist between humans and animals and among animal species. Differences are likely to be dependent on the specific congener or mixture studied, and pharmacokinetic modeling studies could help to detennine the validity of extrapolating data. Most of the available toxicokinetic studies of PBDEs have been performed in rats, and studies in other species could help to ascertain the most relevant animal model. 

Comparative Toxicokinetics. There are currently not enough data to evaluate any potential species-related differences in response to radium exposure by any route. It would be useful to have information on which animal models most closely approximate humans in this regard in order to help interpret the relevance to humans of any toxicity findings in animal studies. Studies on the toxicokinetics of radium following inhalation, oral, and dermal exposure are needed to compare the different routes of exposure. 

Poulin, P. and Krishnan, K., A quantitative structure-toxicokinetic relationship model for highly metabolised chemicals, Alt. Lab. Anim. (ATLA), 26, 45-59, 1998. 

For brevity, only the pivotal toxicology studies are given. Examples of studies not included are proof-of-concept, comparability, toxicokinetic, pharmacokinetic, pharmacodynamic, local tolerance, and miscellaneous in vitro and in vivo studies. Pharmacokinetic and pharmacodynamic experiments generally used the pivotal toxicology animal model(s) because of the species specificity of the biopharmaceutical. 

Comparative Toxicokinetics. One study in rabbits fed tetryl showed that the chemical is absorbed and metabolized (Zambrano and Mandovano 1956). Picramic acid was detected in the urine of these animals. Since there were no other studies available, the toxicokinetics cannot be compared. The best animal models for studying the health effects of the chemical are not known. Further studies would be useful to determine if the target organs are likely to be the same in humans and animals. 

From a practical viewpoint, human populations cannot be used to determine the rate of formation and clearance of markers and the influence of various factors on those rates. Therefore, most toxicokinetic studies are conducted in animal models. From detailed studies in animals, mathematical models are... 

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. 

Palmer et al. 1970 Willhite et al. 1990, 1992). Comparative toxicokinetic studies, per se, have not been performed. PBPK models for selenium administered orally as selenite or selenomethionine have been developed for humans, but no animal models were located. Animal models for the oral route would be useful in assessing toxicokinetic similarities and differences between species. 

From a methodological perspective, it is particularly challenging to investigate the effects of low-level exposure of long duration in animal models and compromises are inevitable. Nose-only exposures have been used by Benschop et al. (1998) to determine the toxicokinetics of soman stereoisomers in atropinized guinea-pigs and subsequently, related studies have been undertaken in marmosets (van Helden et al., 2005). Hulet et al. (2006) have investigated the effects of exposure concentration and duration on pupil... 

Katya-Katya et al. 1984 Klevay and Hyg 1973 Lam et al. 1982, 1985, 1988 Malta et al. 1981 Moore 1978 Murphy 1970 Smith and Larson 1946 Straube et al. 1980 Sturgis et al. 1927). Toxicokinetic studies have been performed in both humans and animals following oral exposure however, data are limited for inhalation and dermal exposures. The animal model used most often to evaluate the toxicokinetics of zinc are rats (Agren et al. 1991 Alexander et al. 1981 ... 

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