Human experimental systems

SC 1-4 Extrapolation of Risk from Non-Human Experimental Systems to Man... 

Of course, the term proven efficacy is central to any resource investment in this area. Basic information on time and dose responses in humans to complex foods rich in carotenoids (and other phytochemicals) is pitifully small. Much of our information is based upon inadequate databases derived from chemical analysis, in vitro models that have not been properly evaluated or validated, and short-term, high-dose human studies. Future research progress requires much more rigorous debate on the experimental systems employed... 

Because of the requirement by public health authorities that any chemical used in the production of food should pose no risk to the consumer, the safety of food chemicals has mostly been approached from the perspective of whether or not the chemical poses a toxicological hazard. If it does so then it is argued that it is likely to present some degree of risk to the consumer even if humans are exposed to very low levels of that chemical in their diets. However, if exposure is minimal, depending on the nature of the toxicity, it is likely that the risk is acceptable because it is so low. What is not considered, or even tested in the experimental systems designed to study the toxicological effects of chemicals, is whether there are levels of exposure where there might be potential health benefits. The assumption is made that any nonnatural, adventitious substance that can be shown to be toxic is unlikely to have health benefits. 

West, L.J. Defining critical windows in the development of the human immune system, Human Experimental Toxicology 21, 499,2002. 

In conclusion, phytic acid forms soluble complexes with Ca2+ at intestinal pH under a variety of conditions and fails to inhibit Ca2 bioavailability to mice in our experimental system. Despite the hazard in direct extrapolation of results obtained with animals kept on a well-defined dietary regimen to humans consuming a complex diet, many elements of which affect Ca2+ bioavailability, our data demonstrate the need for a reevaluation of the putative antinutritional properties of dietary phytate. Our further contention that adequate levels of dietary phytate may actually be beneficial due to its food preserving properties and its protection against colonic cancer will warrant a prospective epidemiological human study designed to assess the longterm effects of dietary phytate on mineral bioavailability and inflammatory bowel diseases. 

Several kinetic parameters can be measured on different experimental systems to account for the interaction of a compound with CYPs. For example when studying the metabolic stability of a compound, it could be measured in a recombinant CYP system, in human liver microsomes, in hepatocytes and so on. Each system increases in biological complexity. Although in the recombinant CYP system only the cytochrome under consideration is studied, in the case of the human liver microsomes, there is a pool of enzyme present that includes several CYPs, and finally in the hepatocyte cell system, metabolizing enzymes play an important role in the metabolic compound stability. In addition, transport systems are also present that could involve recirculation or other transport phenomena. The more complex the experimental system, the more difficult it is to extract information on the protein/ligand interaction, albeit it is closer to the in vivo real situation and therefore to the mechanism that is actually working in the body. 

For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions ... 

For complex exposures, including occupational and industrial exposures, the chemical composition and the potential contribution of carcinogens known to be present are considered by the Working Group in its overall evaluation of human carcinogenicity. The Working Group also determines the extent to which the materials tested in experimental systems are related to those to which humans are exposed. 

Inhibition of COX can be quantified in recombinant or natural enzyme preparations, cellular systems, isolated human cell populations such as platelets (COX-1) and white blood cells (COX-2), or in ex vivo stimulated whole blood samples The closer the experimental system is to the physiological state, the lower the selectivity for most COX-2-inhibitors. The standard test for comparison is considered to be a whole blood assay which mimics in vivo conditions like plasma binding (e.g. Patrignani et al., 1996). It is commonly accepted that reasonable variations occur between different laboratories (see data for Piroxicam). Therefore, whenever possible, data of several compounds generated with a given test system should be compared with each other. 

Cell kinetics is defined as the measurement of time parameters m biological systems. Traditionally, this has involved the use of radioactive precursors of DNA, such as tritiated thymidine (3HTdR), and autoradiography to detect their incorporation into DNA. This technique has provided detailed knowledge of cell kinetics in both in vitro and in vivo experimental systems. The technique, however, is time consuming and arduous and is not readily applicable to human tumor research because of ethical problems involved in incorporation of a radioisotope into DNA. 

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