Resistance functional endpoints

The majority of early publications that can be reasonably identified as comprising immunotoxicology reported altered resistance to infection in animals exposed to various environmental or industrial chemicals. Authors logically concluded that xenobiotic exposure suppressed immune function since the immune system is ultimately responsible for this resistance to infection. Subsequent studies demonstrated that suppression of various cellular and functional endpoints accompanied or preceded increased sensitivity to infection, and that administration of known immunosuppressants likewise decreased host resistance. The human health implications of these studies, that chemical exposure reduced resistance to infection, drove the initial focus of many immunotoxicologists on functional suppression, and provided the theoretical and practical underpinnings of immunotoxicity testing. 

Concentrations of compound to be used in omic investigations would ideally cause no measurable change in cell viability, i.e., LC0 or NOAEL, and induce cellular stress, as indicated by an appropriate stress marker such as supernatant lactate [55] or a functional endpoint such as trans-epithelial electrical resistance (TEER) for epithelial cells [56]. This concentration can be defined as the point of departure of decreased viability in the dose range finding experiments, i.e., the highest possible LC0. 

Fig. 4 Functional endpoints for airway resistance and lung dynamic compliance calculations. Shown on the right side is the calculation for airway resistance (Raw) where Raw = AP/AF calculated at points of isovolume. Shown on the feyi side is the calculation for dynamic compliance (Cdyn) where Cdyn = AV/AP calculated at points of isofiow (typically zero flow). (AP— pressure difference, AF— flow difference, AV— volume difference)...

The results of in vitro exposures to different classes of chemicals can be useful when assessing the direct effects of chemicals on certain immunological endpoints, differences in susceptibility among species (at the cellular level), and differences in susceptibility within a species but between different immune functions. However, such an approach on its own cannot take into account such factors at the whole-organism level including exposure, absorption, metabolism and excretion, the built-in redundancy of the immune system, as well as host resistance. 

Is the effect a measure of function or a single endpoint measurement Functional measures such as host resistance of phagocytosis involve multiple cells and immunocomponents and, therefore, are considered to be more biologically relevant than a significant change in a single endpoint measurement (e.g., T-cell number). 

PURPOSE AND RATIONALE Measurement of cardiac function and morphology is a key part of the preclinical evaluation of experimental medicinal compounds. Blood pressure, heart rate, and electrocardiogram evaluation are part of the core portfolio of safety pharmacology studies carried out in conscious telemetry dogs. If results from the core battery of tests raise concern then supplemental studies are conducted to measure endpoints such as left ventricular pressure, pulmonary arterial pressure, heart rate variability, baroreflex, cardiac output, ventricular contractility and vascular resistance. However, many... 

The HCE-T Tissue Construct (Gillette model) uses a transfected human corneal epithelial cell line (Kahn et al., 1993) cultured on collagen-membrane cell culture inserts, which, at the air-liquid interface, stratify to form a four- to six-layer epithelium, known as the HCE-T model. Transepithelial permeabiUty (TEP) to sodium fluorescein and transepitheUal electrical resistance (TER) have been identified as physiologically relevant parameters to evaluate the barrier function of the corneal epithelium. Cell viability can be determined by the MTT assay, and histomorphology can also be used as an endpoint (Kruszewski et al., 1997). 

Although bacterial clearance studies and models of infection are useful for showing how particle inhalation can alter host resistance to infection, analysis of cell type and function after in vivo or in vitro particle exposure can produce more detailed information about the molecular and cellular processes affected by the toxicant. Overall interpretation of these experiments is difficult because some studies show suppression of phagocytosis and downregulation of immune cytokines, whereas others indieate an increase in these functions, suggesting a state of activation. These eontradictory results can often be explained by differences in experimental protoeols and culture techniques, the endpoints under study, species from which the eells are derived, and the type of particle used. It is well to keep the old toxicology adage in mind, however, that the dose makes the poison, and that subtoxic concentrations of substances can often be beneficial or at least stimulatory. 

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