Dose-effect relationship, definition

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. 

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. 

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. 

Campbell, J. B., Woolley, D. E., Vijayan, V. K. and Overmann, S. R. (1982). Morphometric effects of postnatal lead exposure on hippocampal development of the 15-day-old rat. Dev. Brain Res., 3, 595 Carmichael, N. G., Winder, C. and Lewis, P. D. (1981). Dose response relationships during perinatal lead administration in the rat a model for the study of lead effects on brain development. Toxicology, 21, 117 Carmichael, N. G., Winder, C. and Lewis, P. D. (1982). Effects of chronic low level intake on the developing rat brain definition of an experimental system with preliminary findings. Neuropathol. Appl. NeurobioL, 8, 240 Carpenter, S. J. (1974). Placental transfer of lead. Env. Health Perspectives, 7,129 Carroll, P. T., Silbergeld, E. K. and Goldberg, A. M. (1977). Alteration of central cholinergic function by chronic lead acetate exposure. Biochem. Pharmacol, 26, 397... 

Early blood lead measurements were used to assemble dose—response relationships for clinical toxic effects, and this was the case during the 1950s to the 1970s. With the availability of an accepted measure of body dose, one could be alerted to the likely degree of poisoning. With time and in more recent years, the clinical and scientific definitions of significant adverse effects of lead have been associated with lower and lower blood lead thresholds. 

The usual definitions of maximal effect (E ) and potency EC or IC50) require another look at this stage before proceeding to developing mathemahcal relationship between drug concentration, dose, and body fxmchons using a PK/PD approach. ... 

The most serious theoretical side effect of inositol treatment could be reversal of therapeutic effects of Li or induction of mania in patients with bipolar disorder. So far, this has not been definitely seen in four patients with bipolar depression who were treated with full 12 g of inositol daily for depression [Levine et al. 1995a] or in 18 Li -treated patients with bipolar disorder who were treated with low-dose inositol for polyuria [Bersudsky et al. 1992] or EEG abnormalities [Barak et al. 1994]. The pathophysiological relationship of inositol reversal of Li side effects and inositol therapeutic efficacy in depression and panic is not clear. 

Further research is required in this relatively new field to establish definitive data regarding differentiation between internal incorporation (ingestion) and external contamination (environmental), effect of hair type on analyte incorporation, time course of analyte appearance, dose vs. analyte concentration relationships, and the mechanism of drug entry into hair. Already this novel technique has proved useful in a wide variety of applications, and will unquestionably become more popular in future years. 

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