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

DEVELOPMENTAL AND REPRODUCTIVE TOXICITY STUDY FINDINGS 413Alternatively, additional breeding phases can be introduced to the extant study designs, using naivemales and/or females in an effort to minimize the number of animals required. When identified,gender-specific effects can give valuable guidance toward identification of possible modes of action.C. Relevancy and Risk AnalysisDespite adequate integrity of the database and resolution of particular biologic dynamics anddimensions, consideration of the relevancy of the data and subsequent risk analysis must beaddressed. These issues include interspecies and temporal comparisons of measures of dosimetryand knowledge of mode and mechanism of action.8. Were appropriate toxicokinetic comparisons made between experimental studies and estimatedhuman pharmacokinetics or exposure scenarios?The appropriate toxicokinetic assessments are key to standardizing internal dose, establishingbioavailability, and determining possible dose-dependent kinetics and/or potential changes inmetabolism over the course of exposure. Adverse developmental and reproductive effects may bethe result of sufficiently high C max or AUC exposures or a combination thereof. Because examplesof both cases exist (e.g., valproic acid for C max and cyclophosphamide for AUC), the observedeffects must be considered in terms of the proper internal exposure measure. In the case of at leastone chemical (2-methoxyethanol), dysmorphogenesis can be attributed to both the AUC and C max ,depending on the critical period of development. In mice, 2-methoxyethanol exposure on GD 8caused exencephaly, with a high correlation to the maternal plasma C max , independent of thematernal AUC. 141 However, 2-methoxyethanol exposure of mice on GD 11 elicited paw malformationswith a better correlation to the AUC than to the C max . 142 Therefore, prenatal response tointernal dose (as measured by C max or AUC) at one specific point in development does notnecessarily apply to all points in development.Further use of toxicokinetic data may help determine whether effects observed in neonatesoccur because of exposure during gestation or lactation. Elaborate schemes involving milk production,collection, consumption, and bioavailability may be constructed to address neonatalexposure questions. However, the use of simple fostering studies (mutual exchange of littersbetween treated and untreated dams) with direct toxicokinetic measurements from offspring bloodmay provide a more reliable and straightforward means of answering those questions.9. Are there significant differences in the pattern, timing, or magnitude of the exposure betweenguideline studies and human scenarios?Standard experimental animal models employed in hazard identification have greatly compressedperiods of organogenesis relative to the timing of human development. Single daily administrationsof drugs with short half-lives may result in very low systemic exposures during critical developmentalwindows and may not be adequate for assessing developmental toxicity over the entiresusceptible period. These cases may require multiple administrations each day or alternate exposuremethods (e.g., continuous infusion or dietary administration) to maximize exposure duration.Multiple administrations per day have become more commonplace in the last 5 years, with theadvent of more extensive use of toxicokinetics.10. Is concordance of effects among species evident?Effects manifesting in multiple species signal enhanced concern for human risk, and the concernincreases further when the number of species increases. However, the absence of such multiplicitydoes not necessarily diminish concern. 5 Response variability between species most often appearsto indicate a mode of action difference that can be critical to appropriate animal model selectionfor human hazard identification. “Apparent” lack of concordance among species can arise viaseveral different scenarios. A difference in sensitivity, implying a biological basis (i.e., not amaternally controlled or metabolic basis), is often cited as a primary reason for discordance betweenspecies. However, this claim has historically been made without comparing appropriate measuresof internal dose (exposure) among the species in question. Examples where an apparent lack of© 2006 by Taylor & Francis Group, LLC