Animal models extrapolation

Another interesting finding was that two structurally close analogues of (15a), namely compounds (15b) and (15c), showed marked species-related differences in activity they behaved as weak antagonists towards hTRPVl, and weak agonists towards rTRPVl [78]. This observation indicates that great caution should be taken when extrapolating TRPVl actions from animal models to humans ... 

When applying any of these models it is crucial to understand the main transport mechanisms as well as the metabolic route and characterization of the activity of the transporter/enzyme involved. It is well recognized that the activities of carrier-mediated processes in Caco-2 cells are considerably lower than in vivo [20, 42, 48] therefore, it is crucial to extrapolate in vitro cell culture data to the in vivo situation with great care [18, 20, 42, 48], This is especially important when carrier-mediated processes are involved, as evidenced by a recent report which showed significant differences in gene expression levels for transporters, channels and metabolizing enzymes in Caco-2 cells than in human duodenum [48], If an animal model is used, then potential species differences must also be considered [18, 20, 45],... 

Immunotoxicology data most often available for use in risk assessment is derived from experimental animal studies. Although animal models provide an opportunity to establish more reliable exposure estimates and conduct more informative tests than human studies, the level of accuracy that can be achieved using such data in extrapolating to humans is often a matter of debate. In immunotoxicology testing, a set of tests usually referred to... 

Selgrade, M.K., Air pollution and respiratory disease extrapolating from animal models to human health effects, Immunopharmacology, 48, 319, 2000. 

The degree of exposure of the fetus to a particular substance can be best assessed in human subjects, but concerns of fetal safety have restricted the use of this approach. Moreover, clinical studies cannot elucidate the various mechanisms that contribute to transplacental transport of a particular compound. There are many structural differences between the human placenta and the placenta of other mammalian species, which complicates extrapolation of data obtained from in vivo animal models to humans [7], Thus, several ex vivo and in vitro techniques have been developed to study the placental role in drug transfer and metabolism during pregnancy and there are some excellent articles that discuss these systems in detail [7], Both isolated tissues and various cell culture techniques are currently in use and these have been summarized below. 

The last two decades have seen the introduction of several distinct functional imaging techniques that can be used to investigate centrally active compounds working in the brain in vivo. These techniques provide windows through which to observe phenomena in the intact and fully functional central nervous system. When applied to studies with human volunteers or patients one can obtain information that cannot be extrapolated from animal models, and from areas such as the brain and neurotransmitter systems that would otherwise be inaccessible in vivo. When combined with peripheral measurements and objective and subjective assessments of behavior, these methods can be used to explore how psychopharmaceuticals influence central nervous svtem activity and behavior. Moreover, compounds with a known mechanism of action can be employed as tools to understand how different elements of the central nervous system work. 

Many experimental obs vations, some of which have predicted human cancer data, have been possible because of organ-specific animal models for chemical carcinogenesis. These models, being similar to thdr human counterparts, strengthen the association of environmental exposures with cancer development, and aid in the extrapolation of carcinogenesis data from animal species to humans. They also provide a valuable resource for studies of pathogenesis, risk-modifying factors, and cancer prevention. 

Search for and validate animal models to analyse toxicological aspects of reproductive biology to develop appropriate systems that are reproducible, low cost and easier to extrapolate to human disease. 

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. 

REACH aims to protect both the environment and human health from the industrial chemicals used in Europe, which refer to tens of thousands of substances. In this case, the ideal systems to be evaluated are human health and environment. However, the legislation defines a series of models, which can be used to assess the effects on these two major systems. Animal models are quite often mentioned, in case of toxicity studies and bioaccumulation. Examples of such models are models using rat and fish. Rat and mouse, typically, are used as models for human health, and fish is useful for environmental endpoints. However, it is well recognized that humans are different from rodents for a series of biochemical processes. To study carcinogenicity, for instance, a battery of tests is common, using rat and mouse, both male and female animals. Differences are often found in the different rodent experiments, and this highlights the problems in extrapolating results to humans. Still, in vivo experiments are a fundamental way to study toxicity. 

For food allergens, validated animal models for dose-response assessment are not available and human studies (double-blind placebo-controlled food challenges [DBPCFCs]) are the standard way to establish thresholds. It is practically impossible to establish the real population thresholds this way. Such population threshold can be estimated, but this is associated with major statistical and other uncertainties of low dose-extrapolation and patient recruitment and selection. As a matter of fact, uncertainties are of such order of magnitude that a reliable estimate of population thresholds is currently not possible. The result of the dose-response assessment can also be described as a threshold distribution rather than a single population threshold. Such distribution can effectively be used in probabilistic modeling as a tool in quantitative risk assessment (see Section 15.2.5)... 

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