Dose-Response Relationships variation

The dose-response relationship for each biopharmaceutical can be analyzed, and the variation between subjects in the study population can be derived. A representative curve, presented as drug concentration versus effect intensity, is shown in Figure 5.8. It indicates that variation exists in intensity at a given drug concentration and in drug concentration at a given level of intensity. The steepness or slope of the... 

Although the hepatotoxicity of NDMA has been established unequivocally in numerous acute, intermediate and chronic duration oral studies with animals, relatively few of the studies delineate dose-response relationships and appropriate information regarding thresholds for this effect is not available. As noted for lethality, reported hepatotoxic doses for all species occur in the same general range with variations attributable more to intraspecies differences than treatment schedule or method. Human fatalities due to oral and inhalation exposure to NDMA have been reported in which hemorrhagic, necrotic and cirrhotic alterations in the liver were observed, indicating that NDMA produces similar hepatic effects in humans and animals. Therefore it is reasonable to expect that NDMA also will be hepatotoxic in humans at sublethal doses. 

While the dose-response relationship observed in cancer bioassays is commonly nsed as the basis for risk characterization for substances that are considered as carcinogens, the extent to which it meaningfully informs risk is limited by the small number of dose groups and the magnitude of the variation between exposure of humans and administered doses. The limited munbers of doses examined is necessarily a function of the costs associated with close-to-lifetime observation of gronps of (commonly) 50 animals each. 

Lutz, W. K., Gaylor, D. W, Conolly, R. B., and Lutz, R. W. (2005). Nonlinearity and thresholds in dose-response relationships for carcinogenicity due to sampling variation, Ic arithmic dose scaling, or small differences in individual susceptibility. Toxicol Appl Pharmacol 207, S565-S569. 

Two types of dose-response relationships are observed. The first is the incremental change in response of a single system or individual as the dose is increased. The second is the distribution of reponses in a population of individuals given different doses of the agent. The former are frequently used for the determination of the mechanism of interaction between the chemical and the biological system. The latter describe the response of a population of individuals and can also be used to determine multimodal responses indicative of genetic variations. 

As described in a highly referenced document (NRC, 1983), important components of this process include hazard identification, assessment of exposure and dose-response relationships, and characterization of the risk. Uncertainty factors are built into the risk assessment process to account for variations in individual susceptibility, extrapolation of data from studies in laboratory animals to humans (i.e. interspecies variation in toxicokinetics), and extrapolation from high-dose to low-dose exposures. In the case of the association between exposure to chemicals and drugs and autoimmunity or autoimmune diseases, much of the information needed to evaluate risk in the context of the traditional United States National Research Council paradigm is not available. The following represents a discussion of issues in chemical-induced autoimmunity relevant to the use of existing data and data needs in risk assessment. 

By determination of factors including the dose-response relationship, potency, species variation in susceptibility mechanism of toxicity. 

The general covariance of natural leaf water and leaf nitrogen concentration (Scriber and Feeny, 1979) and a variety of other leaf chemicals (such as tannins, fiber, lignins, oils) confounds interpretations of insect-plant interactions. Diurnal variations in plant chemistry sometimes may be comparable to seasonal changes (Scriber, 1977 Pate, 1980). Although artificial diets permit investigation of chemical mechanisms and dose-response relationships between herbivores and specific chemicals, such information cannot be readily used for prediction of larval growth on plant tissues. 

Virtually all other models used to assure the safety of ingested or inhaled substances are variations of the food and drug safety models (described below) the nutrients model based on dose-response relationships the in-market monitoring and surveillance model the novel foods and food additives models, based on a reasonable certainty of no harm and the drug model, based on risk-benefits assessments. 

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