Dose-response assessment confidence level

The BMD approach has been put forward as an alternative to the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) approach for health effects because it provides a more quantitative alternative point of departure for the first step in the dose-response assessment (International Programme on Chemical Safety, in press). The BMD approach is based on a mathematical model being fitted to the experimental data within the observable range and estimates the dose that causes a low but measurable response (the benchmark response) typically chosen at a 5% or 10% incidence above the control. The BMD lower limit (BMDL) refers to the corresponding lower limit of a one-sided 95% confidence interval on the BMD. Using the lower bound takes into account the uncertainty inherent in a given study and assures (with 95% confidence) that the chosen benchmark response is not exceeded. 

In animal experiments exposures can be carefully controlled, and dose-response curves can be formally estimated. Extrapolating such information to the human situation is often done for regulatory purposes. There are several models for estimating a lifetime cancer risk in humans based on extrapolation from animal data. These models, however, are premised on empirically unverified assumptions that limit their usefulness for quantitative purposes. While quantitative cancer risk assessment is widely used, it is by no means universally accepted. Using different models, one can arrive at estimates of potential cancer incidence in humans that vary by several orders of magnitude for a given level of exposure. Such variations make it rather difficult to place confidence intervals around benefits estimations for regulatory purposes. Furthermore, low dose risk estimation methods have not been developed for chronic health effects other than cancer. The... 

It is important that both the qualitative and quantitative characterization be clearly communicated to the risk manager. The qualitative characterization includes the quality of the database, along with strengths and weaknesses, for both health and exposure evaluations the relevance of the database to humans the assumptions and judgements that were made in the evaluation and the level of confidence in the overall characterization. The quantitative characterization also includes information on the range of effective exposure levels, dose-response estimates (including the uncertainty factors applied), and the population exposure estimates. Kimmel et al. (2006) reviewed many of the components of the risk characterization for reproductive and developmental effects and provided a comprehensive list of issues to be considered for each of the components of the risk assessment. 

Historically, risk assessment for noncancer endpoints has been based on the identification of a no observed adverse effect level (NOAEL) from a toxicity study with an animal model. The NOAEL is then divided by appropriate uncertainty factors to take potential inter- and intraspecies differences in response into account. However, this approach does not take into account the size of the toxicity study or the shape of the dose-response curve. The benchmark dose (BMD) approach has been suggested as an alternative to a NOAEL (Crump 1984). A BMD is a dose or concentration that produces a predetermined change (e.g., 10% or 1 standard deviation) in response rate of an adverse effect (called the benchmark response or BMR). A BMDL is the statistical lower confidence limit on the dose or concentration at the BMD. The BMD and BMDL are calculated using mathematical dose-response models, which make appropriate use of sample size and the shape of the dose-response curve (EPA 2009b, 2000a). The BMDL is like a NOAEL (i.e., as a point of departure) and is divided by an appropriate composite uncertainty factor to derive a reference value. 

Exposure-response (ER) analysis has become an important tool to interpret QT data from TQT studies and has been used to predict QT effects in patients for the targeted indication, including patients with impaired clearance of the dmg (Garnett et al. 2008 Piotrovsky 2005). ER analysis has also been applied to QT data derived from early SAD/MAD studies. Since the doses in SAD studies are often escalated to MTD, high plasma levels often are obtained, which allows for the evaluation of potential ECG effects over a wide range of plasma concentrations. With increasing confidence in data derived from these types of studies, the relevant question as to whether early QT assessment can replace the TQT study has been raised (Darpo... 

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