Dose-response assessment definition

An important similarity between human and ecological assessment of mixtures is the structure of the assessment procedure. Both procedures are often organized along a series of consecutive steps, that is, problem definition, hazard identification, exposure assessment, effect- or dose-response assessment, and risk characterization... 

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 ... 

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 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. ... 

Based in this information difference between the NOEL and human exposure or the risk at a given exposure is determined. Humans may be exposed to chemicals in the air, water, food, or on the skin. From the concentrations of a chemical in these different compartments the external daily exposure is estimated. The response to the chemical depends upon duration and route of exposure, the toxicokinetics of the chemical, the dose-response relationship and the susceptibility of the individual. Thus, the precise definition of the terms hazard, exposure, and risk is essential to understand toxicological evaluations (details on data requirements and procedures for risk assessment are given subsequently). 

Both models assume that the mixture under study is fully described in its chemical composition and that the dose-response curves of all compounds in the mixture are known. Both models are extensively covered in the literature both theoretically (Teuschler et al., 2002 Backhaus el al., 2003 Vighi et al., 2003) and when applied in case studies (Nirmalakhandan et al., 1997 Altenburger et al., 2000 Richardson et al., 2001 Backhaus et al., 2003). Using and interpreting either of the models, the reader has to be aware that both are mere simplifications of a very complex reality. A lot of cases can be found in the literature illustrating mixture effects not accounted for by the aforementioned models (Preston et al., 2000 Chu and Chow, 2002) and validity should be assessed case by case. A critical paper on how to deal with different mixture risk definitions has been written by Hertzberg and MacDonell (2002). 

For all these reasons, PBPK models are and will continue to be increasingly used in toxicology. This is especially true in risk assessment studies since better definition of the internal tissue dose, may contribute to reduce the uncertainty associated with extrapolation to human beings of responses observed in animal toxicity studies in which animals usually receive high doses of xenobiotics by routes often different from the one(s) anticipated in human exposures. 

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