Dose-effect analysis

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. 

A complete dose-response analysis was generated for PCP for doses from 0.625 to 20 mg/kg IP (data not shown). PCP exhibited dose-related anticonvulsant action when day one minus day three differ ence scores were compared for all doses tested. When retested with saline only on day five, no reduction in convulsant sever it or super-sensitive response was observed (day one minus day five), indicating no carryover drug effect 48 hours after dosing. At behavioral ly equivalent doses, all compounds assayed were clearly anticonvulsant (table 3). TCP was most potent at the doses tested. PCA was the most efficacious, and reduced convulsant severity by 2.58 points. As with PCP, none of the other phencycli-noids had any carryover effects 48 hours after dosing (day one minus day five). 

Waalkes, M.P., S. Rehm, C.W. Riggs, R.M. Bare, D.E. Devor, L.A. Poirier, M.L. Wenk, and J.R. Henneman. 1989. Cadmium carcinogenesis in male Wistar [Crl (Wl)BR] rats dose-response analysis of effects of zinc on tumor induction in the prostate, in the testes, and at the injection site. Cancer Res. 42 4282-4288. 

At the end of the toxicity test the toxicologists and pathologists list all the observations made for each individual animal in each dose group. Analysis of these results is needed to identify effects caused by the chemical under study. All observations - body weights, clinical measurements, histopathology, and so on - have to be included in the evaluation. 

The lack of information conveyed by total brain concentration is indicated by studies on KA-672 [6], a lipophilic benzopyranone acetylcholinestrase inhibitor. The compound achieved total brain concentrations of 0.39 iM at a dose of 1 mg kg" equivalent to the IC50 determined in vitro (0.36 juM). Doses up to 10 mg kg were without pharmacological effect. Analysis of CSF indicated concentrations of the compound were below 0.01 juM readily explaining the lack of activity. These low concentrations are presumably due to high (unbound) free drug clearance and resultant low concentrations of free drug in the plasma (and CSF). 

Combination of analysis and inference of possible consequences of the exposure to a particular agent based on knowledge of the dose-effect relationship associated with that agent in a specific target organism, system, or (sub)population. 

In case a NOAEL cannot be set for the critical effect, a LOAEL is then set and extrapolated to a NOAEL. The extrapolation from a LOAEL to a NOAEL can be regarded as part of the dose-response analysis. Consideration should therefore also be given to the uncertainties in the extrapolation of the LOAEL to the NAEL in cases where only a LOAEL is available as the starting point for the assessment. 

Walker MD, Strike TA, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979 5 1725-1731. 

Identification of volatile, soluble and covalently-bound metabolites of carbon tetrachloride detection of molecular alterations in cell changes in cell function time-course and dose-dependent analysis of cause and effect relati onshi ps. 

Van Lent-Evers, N.A., Mathot, R.A., Geus, W.P., van Hour, B.A., and Vinks, A.A. (1999) Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome a cost-effectiveness analysis. Ther Drug Monit 21 63-73. 

Pelham, W.E., Swanson, J., Furman, M., and Schwindt, H. (1995) Pemoline effects of children with ADHD a time-reponse by dose-response analysis on classroom measures./ Am Acad Child Adolesc Psychiatry 34 1504-1513. 

Cunningham, C., Siegel, L., and Offord D. (1991) A dose-response analysis of the effects of methylphenidate on the peer interactions and simulated classroom performance of ADD children with and without conduct problems. / Child Psychol Psychiatry Allied Disc 32 439 52. 

Ghoneim, M.M., Hinrichs, J.V., Mewaldt, S.P. Dose-response analysis of the behavioral effects of diazepam I. Learning and memory. Psychopharmacology 82, 291-295, 1984a. 

Furthermore, each cell division round has the potential danger of rearrangement of chromosome sections during mitosis and thus chromosome aberrations. A thorough theoretical and experimental analysis of the dose-effect relation of various canceroge-nic substances has shown that an increased cell division activity is an important risk factor for the creation of tumors (Cohen and Ellwein, 1990). All processes that lead to an increase in the rate of cell division will increase the probability of tumor formation, according to these investigations. 

Zacny, J.P. et al., A dose-response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers, J. Pharmacol. Exp. Ther., 268, 1, 1994. 

For calculation of the dose-effect curves, the probit method of statistical analysis is used. 

The majority of experimental mixture studies have analyzed the effects that arise from simultaneous exposure to chemicals. Very few studies exist where sequential exposure to several chemicals was analyzed. Only a concept founded on an understanding of the relationship between dose or concentration and exposure duration, time to effect, and recovery can hope to deal with the effect of sequential exposures. Conceptual frameworks for descriptions of time-dependent toxicity from a mechanistic perspective are available (e.g., Rozman and Doull 2000 Ashauer et al. 2006). However, the link between existing dose-time response models and a framework for mixture effect analysis from sequential exposure has yet to be made. A recent example of an interesting study that looked at sequential exposures is from Ashauer et al. (2007b), who base their analysis on a 1-compartment model for substance uptake, plus additional parameters for effect propagation and recovery. Generalizations are not yet in sight. 

Jonker MJ, Svendsen C, Bedaux JJM, Bongers M, Kammenga JE. 2005. Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysis. Environ Toxicol Chem 24 2701-2713. 

Hall, E.D. and Braughler, J.M. (1982) Effects of intravenous methylprednisolone on spinal cord lipid peroxidation and Na+ + K+-ATPase activity dose-response analysis during 1st hour after contusion injury in the cat. J. Neurosurg. 57, 247-253. 

Ikawa K, Eshima N, Morikawa N, Kawashima H, Izumi T, Takeyama M. Influence of concomitant anticonvulsants on serum concentrations of clonazepam in epileptic subjects an age- and dose-effect linear regression model analysis. Pharm Pharmacol Commun 1999 5 307-10. 

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