Dose response definition

Study length and the frequency of treatment are design aspects that must also be considered. These are aspects in which the objective of detection and dose-response definition conflict. 

Elazard evaluation or the definition of the effects that may occur, including dose-response characteristics and other intrusive processes. 

Before proceeding to some of the more technical aspects of toxicology and the general subject of dose-response, several important definitions used by the profession and appearing in the literature are provided below (in alphabetical order). 

Human embryonic kidney cells, 21 Human genome, 2 Hydrogen bonding, 10 Hypothesis testing definition of, 239 description of, 227, 233 dose-response curves for, 239-243 F-test, 242t... 

The PBPK model development for a chemical is preceded by the definition of the problem, which in toxicology may often be related to the apparent complex nature of toxicity. Examples of such apparent complex toxic responses include nonlinearity in dose-response, sex and species differences in tissue response, differential response of tissues to chemical exposure, qualitatively and/or quantitatively difference responses for the same cumulative dose administered by different routes and scenarios, and so on. In these instances, PBPK modeling studies can be utilized to evaluate the pharmacokinetic basis of the apparent complex nature of toxicity induced by the chemical. One of the values of PBPK modeling, in fact, is that accurate description of target tissue dose often resolves behavior that appears complex at the administered dose level. 

A few definitive experiments are needed to complete our knowledge of acute dose-response relationships for ozone. Research is necessary in the case of PAN and other oxidants. More important is the need for studies of crop and native species over growing seasons with chronic oxidant exposures. At the same time, additional work with field chambers, filtered or nonfiltered, is needed. 

A few definitive experimental designs are needed to further our knowledge of acute dose-response information on ozone. Much of this... 

Other terms often used indiscriminately for the dose-response relationship include concentration-effect relationship and dose-effect relationship. According to the joint OECD/IPCS project (OECD 2003 a), which has developed internationally harmonized generic and technical terms used in chemical hazard and risk assessment, the following definitions have been provided although consensus was not achieved ... 

As no international consensus has been achieved in the OECD/IPCS project (OECD 2003a) in order to differentiate between dose (concentration)-response (effect) relationship and because it in reality is difficult to understand the subtle differences in the different terms as defined in the OECD/IPCS project, the broader and more general definition provided in the TGD (EC 2003) will be used in this book, and will generally be referred to as dose-response. Consequently, the term dose will, in this book, generally mean both dose and exposure concentration unless otherwise stated. 

For continuous data, there are still a number of outstanding issues regarding the benchmark including (Crump 2002) (1) definition of an adverse effect (2) whether to calculate the BMD from a continuous health outcome, or first convert the continuous response to a binary (yes/no) response (3) quantitative definition of the BMD, in particular in such a manner that BMD from continuous and binary data are commensurate (4) selection of a mathematical dose-response model for calculating a BMD (5) selection of the level of risk to which the BMD corresponds and (6) selection of a statistical methodology for implementing the calculation. 

The TGD (EC 2003), Chapter 3.8, on sensitization gives definitions of skin and respiratory sensitization, and provides advice on the data to be used in the effects assessment, evaluation on the available data, and assessment of the dose-response relationship to be used in the EU-specific risk assessments. 

One of the most evident limitations in the NOAEL approach in the derivation of tolerable intakes is that it does not take into account the slope of the dose-response curve for the particular response of interest (Section 4.2.4). The NOAEL is by definition one of the doses tested, and apart from ensuring that the number and spacing of data points are adequate to provide a reasonable estimate of the NOAEL, all other data points are ignored. Although the NOAEL could be considered an estimate of the tme NAEL, the quality of the estimate cannot be assessed. For the dose-response relationship and precision in the NOAEL, consideration should therefore be given to the uncertainties in the NOAEL as the surrogate for the NAEL. 

The NOAEL is not very accurate with respect to the degree to which it corresponds with the (unknown) tme NAEL. One of the most evident limitations in the NOAEL setting is that it does not take into account the shape of the dose-response curve, including its slope, for the effect as the NOAEL by definition is one of the doses tested in the specific experimental study, and all other data points are ignored. In case a NOAEL cannot be set for the critical effect, a LOAEL is then set and extrapolated to a NOAEL this extrapolation can also be regarded as part of the dose-response analysis. 

The Margin of Exposure (MOE) in the context of the assessment of compounds that are both genotoxic and carcinogenic, as defined in EFSA (2005), is different from the OECD/IPCS definition given above The Margin of Exposure (MOE) is the ratio between a defined point on the dose-response curve (reference point) for the adverse effect of the compound in the animal carcinogenicity study and the estimated human intake of the compound. ... 

Phase III studies represent the confirmatory phase of drug development, which takes several years and usually involves several thousand patients at multiple trial centers. Large patient numbers are required in these trials to provide convincing documentation of clinical efficacy and safety, a more complete adverse event profile and covariates and estimates of variability in dose response relationship due to individual differences in pharmacokinetics and pharmacodynamics. They are aimed at definitively determining a drug s effectiveness and side-effect profile. Most of these studies are double-blind and placebo-controlled, sometimes with the option of open-label long-term extensions. 

---