Dose-related effect, definition

The effects of thiazide-type diuretics on carbohydrate tolerance cannot be ignored (50). There is a definite relation between diuretic treatment, impaired glucose tolerance, and biochemical diabetes, and a possible relation with insulin resistance (64). It is well estabhshed that the effect of thiazides on blood glucose is dose-related, probably linearly, while the antihjrpertensive effect has httle relation to dose (65-67). There is relatively httle information on the time-course numerous short-term studies have shown that the blood glucose concentration increases in 4-8 weeks (68). The evidence that current low dosages impair glucose tolerance in the long term is not entirely consistent, perhaps because of differences between studies... 

The beneficial effects were related to these plasma concentrations, as were the time to the first bout of atrial fibrillation, the frequency of bouts of atrial fibrillation, and the time between episodes. However, when atrial fibrillation occurred there was no difference in the ventricular rate in the different groups. Adverse effects necessitated drug withdrawal in four patients one had heart failure and two had gastrointestinal symptoms. These effects were not dose-related, although there were too few occurrences for a definitive conclusion. The authors suggested that this stepwise approach, with increasing doses of propafenone and increasing doses of quinidine could be beneficial in the treatment of paroxysmal atrial fibrillation. 

Some aspects of degree of concern currently can be considered in a quantitative evaluation. For example, EPA considers human and animal data in the process of calculating the RfD, and these data are used as the critical effect when they indicate that developmental effects are the most sensitive endpoints. When a complete database is not available, a database UF is recommended to account for inadequate or missing data. The dose-response nature of the data is considered to an extent in the RfD process, especially when the BMD approach is used to model data and to estimate a low level of response however, there is no approach for including concerns about the slope of the dose-response curve. Because concerns about the slope of the dose-response curve are related to some extent to human exposure estimates, this issue must be considered in risk characterization. (If the MOE is small and the slope of the dose-response curve is very steep, there could be residual uncertainties that must be dealt with to account for the concern that even a small increase in exposure could result in a marked increase in response.) On the other hand, a very shallow slope could be a concern even with a large MOE, because definition of the true biological threshold will be more difficult and an additional factor might be needed to ensure that the RfD is below that threshold. 

Cardiotoxicity, which can lead to congestive heart failure and death, is a toxic effect of the anticancer drug, doxorubicin. A cumulative dose-effect analysis demonstrated that doxorubicin cardiotoxicity is related to the lifetime dose of the drug (Figure 18.12) and provided the basis for the definition of safe lifetime dose levels (7). The lifetime dose of doxorubicin is now limited to less than 400-450 mg/m, which is associated with a <5% risk of developing congestive heart failure. 

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