A Practical Approach, Second Edition=Ronald D. Ho.pdf

350 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTable 9.11Comparison of attributes of species used in developmental and reproductivetoxicity studies (continued)Model Perceived Advantages Perceived DisadvantagesDogStudies of kinetics possibleNonrodent modelOffspring number sufficientRoutinely used in repeated-dose toxicitystudiesSemen can be obtained for longitudinalassessmentRadiographs possible to study fetalmorphologyPlacentation more like humans(no inverted visceral yolk sac)Significant fetal periodSeasonal breedersPoor depth of historical databaseHigh inbreeding coefficientExpense may lead to small group sizesLimited history of use with some validation studiesNonhumanprimateSize and multiple sampling sitesStudies of kinetics possibleNonrodent modelTrue fetal phaseRoutinely used in repeated-dose toxicitystudiesPhylogenetically close to humansReproductive physiology more similar to thatof humansExcellent model to assess biologicsSemen can be obtained for longitudinalassessmentRadiographs possible to study fetalmorphologyPlacentation similar to humans(no inverted visceral yolk sac)Kinetics often different than in humansGenerally single offspring per pregnancyLong gestation periodProne to abortionPoor depth of historical databaseStudies of fertility and functional reproductiveoutcome problematicInterpretation dependent on adequate historicalcontrol data due to cost factors usually leadingto small group sizesExpense and limited availability may lead to smallgroup sizesSome species are seasonal breeders(e.g., Rhesus)aListed as a negative attribute because it is anatomically different than in higher orders of mammals; however,probably should only be considered a negative, that is, producing nonconcordant effects, for large, proteinaceousmolecules or other agents that affect proteolysis and/or pinocytosis.Source: Holson, J.F., Pearce, L.B., and Stump, D.G., Birth Defects Res. (Part B), 68, 249, 2003.C. Characterization of Dose-Response CurveBroadly defined, the dose response of a particular chemical is the dynamic relationship betweenexposure and biological response(s) in the test system. In toxicity studies, plotting the effect(abscissae) versus a series of doses (ordinates) describes the dose-response relationship of anadverse finding for a population of animals. This model assumes that all members of the populationare either positive responders or nonresponders, and the relationship is defined as a quantal doseresponserelationship. 41 Dose-response curves are typically classified into one of three generalmodels: (1) threshold model, (2) linear model, or (3) U-shaped model. The threshold model foradverse responses assumes that there is a dose at which no effect is produced. The linear modelassumes that some effect occurs at any dose. With increasing dose, the shape of the dose-responsecurve will change until either a maximal response or maternal mortality occurs. For cancer endpoints,the linear model is typically assumed and applied. For noncancer endpoints, includingdevelopmental and reproductive toxicity, the threshold model is typically used. U-shaped modelshave been described for important nutritional substances required for homeostasis and for certainhormones. 42 For example, at low doses associated with dietary deficiency, adverse effects maymanifest. However, as the dose increases through the essential range, the adverse response isdiminished or ablated. As the dose is increased further, an adverse response manifests and increaseswith increasing dose similar to that described for the threshold and linear models.© 2006 by Taylor & Francis Group, LLC