Dose-Response Relationships diversity

At the start of this section, we derived Equation 5.8 to model dose-response relationships. This equation is elegantly simple and essentially identical to the Michaelis-Menten equation from our studies on enzymes. Receptors, however, are more diverse and more complicated than enzymes. Clark s straightforward equation models few receptors accurately, and Stephenson s equation (5.18) has emerged as the best available description of occupancy theory. While Stephenson s additions may result in a more accurate model, the simplicity of Clark s original theory remains attractive. Many receptor studies still rely on Clark s model and work around its deficiencies as best as possible. 

It is well known that there is a major problem in the health care system in the United States related to providing new drugs that are effective and relatively safe in a wide diversity of patients with undifferentiated diseases whose individual dose-response relationship varies based on genetic, disease, environmental, and life-style factors. While many may argue over... 

Are biphasic dose-response relationships with similar quantitative features using different animal models, measuring widely differing endpoints and with highly diverse chemical agents, likely to be manifestations of the same biological concept Discuss the pros and cons of this interpretation. Or should they aU be treated as a specific phenomenon ... 

The task for ecotoxicity assessment is to provide qualitative and quantitative indicators of the potential environmental impacts of chemicals, such as changes in the abundance of individual species or the diversity of the species community, taking into account the concentration and the time of exposure (dose-response relationships). Toxic action at the level of the organism may be classified according to Ariens (1984) ... 

The available evidence for PbBO as a dose metric in Pb toxicology and epidemiology documents that it (1) is a cumulative but not inert dose/exposure metric which both serves to quantify stored Pb and, in metabolicaUy diverse settings, released Pb as an endogenous source of systemic Pb exposure (2) may be a better Pb exposure correlate with various toxic effects than PbB in settings where resorptive releases are significant or long term, e.g., in retired Pb workers or in children, older children, or adults whose Pb-exposure histories foretell sizeable stores of bone Pb and (3) is likely a measure of the source of much of the Pb that is released on provocative chelation and that better reflects potential toxicity risk than PbB. However, the relative robustness of PbBO in dose—response relationships versus other measures of toxic dose, e.g., PbB or chelatable Pb, wiU vary case to case. 

A wide diversity of dose-response (incidence) relationships has been observed among the neoplasms induced experimentally by chemicals (Zeise et al., 1987), radiation (UNSCEAR, 1977) or both. Although neoplasms of virtually every type have been induced in one experiment ra- another, not all types of neoplasms are observed in animals of any one species or strain. Under some conditions, moreover, the incidence of certain neoplasms has actually been observed to decrease with increasing dose of whole-body irradiation (see Figure 3.1). 

Part 4 continues with lead-specific discussions of the four components of a human health risk assessment as structurally articulated in 1983 by the NAS/NRC (1983) Chapter 21, human health hazard characterization for lead and diverse human populations Chapter 22, dose—toxic response relationships for lead in humans Chapter 23, illustrative uses of case- or setting-specific lead exposure characterizations and. Chapter 24, the last part of health risk assessment, the overall final and most quantitative step in actualizing (in a relative sense) the estimates of risk outcomes. 

Regardless of the techniques used, the goals should be to characterize the pharmacokinetics in the patient population, and to quantify the dose-concentration-effect relationship. Phase Ila studies allow the first characterization of pharmacokinetics in patients, but opportunities for pharmacodynamic evalnation or phar-macokinetic/pharmacodynamic modeling may be more limited than in Phase 11b. With Phase Ilb data over several doses, it may be possible to define this relationship, or at least obtain estimates of the lowest useful concentration and the concentration beyond which additional response is not anticipated. Since Phase 11 patient popnla-tions tend to be larger and more diverse than the healthy volunteers nsed in Phase I studies, there are further opportunities to help identify sources of interindividual variability in pharmacokinetics and pharmacodynamics. 

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