Threshold, response

Patel, A. K., Hallett, M. B., Campbell, A. K. (1987). Threshold responses in production of reactive oxygen metabolites in individual neutrophils detected by flow cytometry and microfluorimetry. Biochem. J. 248, 173-80. 

This process, therefore, provides positive feedback and results in a threshold response to the initial depolarisation. 

Bingbam E, Falk HL Environmental carcinogens. The modifying effect of cocarcinogens on the threshold response. Arch Environ Health 19 779, 1969... 

Fig. 1.1 Interaction between allergen and adenosine receptor agonists with respect to histamine release from guinea-pig chopped lung (left) or bronchoconstriction in the guinea pig in vivo (right). Tissues and animals were passively sensitized to ovalbumin. In the histamine release assay, a threshold response to allergen is augmented concentration-dependently by NECA. In the whole animal, a single intravenous injection of APNEA markedly enhances the bronchoconstrictor response to allergen (J.R. Fozard and H.J. Pfannkuche, unpublished observations 1994)...

Shown in Figure 5 are the calculated response surfaces for both the threshold separation (CRF-4) and time-corrected normalized resolution product (CRF-5). As expected, the threshold response surface is discontinuous, with 3 local optima in contrast, the response surface for CRF-5 is smooth, with no apparent local optima. 

Additional information on the main health effects of DEHP is discussed below. Because its effects are exerted in animals in a dose-related manner, exhibit threshold responses, and are not necessarily relevant to humans due to rodent-specific mechanisms, and concentrations of DEHP in the environment are almost certain to be well below effect thresholds, ambient levels exposure are not expected to be toxicologically significant, even in the vicinity of hazardous waste sites. DEHP therefore is not expected to pose a serious public health concern for the vast majority of the population. 

Johansen, J.D., Andersen, K.E., Rastogi, S.C., and Menne, T., Threshold responses in cinnamic-aldehyde-sensitive subjects results and methodological aspects, Contact Dermatitis, 34, 165, 1996. 

In an effort to simulate the theoretical behavior of neuron cells, researchers in the 1940 s and the 1950 s such as McCullogh, Pitts, and Rosenblatt developed functions that mimicked the threshold response of a synapse. Their theory of synapses held that the output of a neuron cell was at or near zero until the sum of all of the input potentials connected to it passed a certain threshold, at which point the cell s output would be at or near one. Mathematically, their neuron functions yielded a binary or a sigmoidal response to a linear combination of its inputs, and could be connected... 

We have indicated that intensity dependent phenomena may be useful in at least two distinct ways. One is to obtain something approaching a "threshold detector" resist response. To obtain a threshold development response in typical positive resists is difficult, since the development rate is in general a smoothly varying function of the photochemical reaction progress. The application of a layer of polymer with the bleaching characteristics shown in Figure 5 provides a way to obtain such threshold response with conventional resists, provided an excimer laser is used in the illumination system. 

Two examples of alternative approaches to cancer risk assessment would be estimations based on threshold-response (EPA, 2005a) and benchmark dose modeling (EPA, 1995, 2000). As a practical matter, if the proposed basis of safety relies on a threshold or mode-of-action characterization to dismiss or mitigate animal tumor data, PDA would reconunend that the safety narrative clearly discuss the scientific rationale and present all relevant data for consideration. In the absence of adequate evidence to the contrary, PDA presumes that certain assumptions are appropriately protective of safety, namely that (i) the induction of tumors in animals is relevant to human... 

Animal studies show the olfactory and limbic pathways are particularly susceptible to kindling, the ability of a stimulus previously unable to induce a seizure to later induce one. Animal studies also show that acute administration of a high dose or intermittent repeated low-dose exposures to chemicals cause limbic kindling , and that this response is amplified depending on the time between stimuli. Kindling without a seizure has been shown to cause affective behavior changes in animals. Kindling could amplify reactivity and lower the threshold response to low levels of chemicals. 

Rusch, J. and Levine, M. (1996). Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo. Curr. Opin. Genet. Dev. 6 416-423. 

The data supporting the hormetic dose-response therefore not only far exceeds normal proof of concept criteria but have been employed in the development of drugs for numerous human conditions, thereby satisfying a stronger proof of application requirements. In head-to-head direct comparisons the hormesis model far outcompeted the threshold and linear at low dose models (Calabrese and Baldwin 2001, 2003c Calabrese et al. 2006). In fact, while the threshold model was shown to poorly predict below threshold responses the linear at low-dose models, the LNT models cannot be practically validated in either moderate or large-scale studies. 

Specific examples of such bistable behavior arise in models of combustion. In the simplest case, a two-component system, that includes the distribution of the fuel and of the temperature field, is appropriate. The reaction takes place only when the temperature is above a certain ignition temperature, with a burning rate that is an increasing function of the local temperature following the Arrhenius law (Eq. (3.43)). The burning of fuel is an exothermic reaction that increases the local temperature and results in even higher reaction rates. This leads to the autocatalytic character of the system, while the ignition temperature acts as a threshold, responsible for the bistability. 

It is essential that a broad dose response relationship be established. The initial goal should be to estimate the threshold response. This typically is achieved by high-end dosing to establish frank effect and lowest observed effect levels. Subsequent experimentation should be designed to explore possible subthreshold responses with the threshold as part of the frame of reference. In order to study subthreshold responses it is advisable to explore a 1000-fold dose range below the threshold, with semi-log dose spacing. This would involve the use of at least six doses below the established threshold. 

The threshold may be estimated following a traditional EPA-based NOEL approach, which identifies the highest dose that does not differ from the control group in a statistically significant manner. This dose would be called the NOEL, and would serve as a quasi-estimate of the threshold. An alternative approach would employ the benchmark dose (BMD) methodology in which data are modeled to estimate a response that approaches the threshold response level. 

Should hormetic dose responses have to be demonstrated in each case or can it be assumed to occur if it is in fact far more common than the threshold response Should there be a default dose response model Why Why not ... 

Veng-Pedersen, P. et al., A system approach to pharmacodynamics. Plasma iron mobilization by endogenous erythropoietin in the sheep fetus evidence of threshold response in spontaneous hypoxemia, J. Pharm. Sci., 82 804—807, 1993. 

IMSs perform successfully in several applications where only threshold response is necessary or important, and examples include the detection of explosives and... 

The partial dissociation of avoidance and activity in P. cinereus was unexpected. It appeared to be the result of avoidance being a threshold response to predation risk, whereas activity was a graded response to such a risk. But it was unclear why activity should continue to increase during the day after avoidance had reached maximum values. More extreme avoidance scores should logically have occurred during the day, especially in the highest-threat (salamander-diet) trials. 

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