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

20 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONTable 2.3Intracellular eventsIntercellular eventsOrgan level eventsOrganism level eventsLitter responsesLevels of mechanistic inquiry for developmental toxicityBiochemical and molecular mechanisms of action define key intracellular events forboth normal and abnormal developmental responses.Specific cell-cell interactions and activities define activities for specialized cellpopulations.Specialized functions of organs define organ development and function.Embryonic and fetal responses are defined by the collective responses of organ andintra- and intercellular events.The combined embryo and fetal responses of a litter are defined within the singlematernal unit.(valproic acid derivatives), 17 and phenols. 18 Note that many of these SARs are determined using invitro as well as in vivo investigations to establish relationships.The fourth guideline concerns the strength and consistency of occurrence of the adverse outcomewith the postulated critical mechanistic event. For example, if the proposed mechanisms of actionfor compound X is that it inhibits neuronal cell division by 50% in the brain during early brainformation, causing microcephaly, then to determine the strength of this mechanistic association,two types of model experiments could be planned. First, the investigator could determine if otheragents that cause a comparable decrease in cell division at this time in development also causemicrocephaly. Secondly, the investigator could see if blocking the effects of compound X on celldivision would reverse the incidence of microcephaly. Cross-species extrapolation of results couldalso increase the consistency of these observations as key mechanistic processes. Although theseexample observations provide clues, failure to see these changes does not mean that the mechanistichypothesis must be abandoned.The last guideline relates to the importance of coherence in the overall mechanistic hypothesis. Ifa possible molecular or cellular basis can be described for the proposed mechanism of action, then thiscoherence provides a stronger degree of confidence in the postulated pathway. If no molecular basisis found, then the proposed mechanism may have a difficult battle for acceptance because it may be amechanism whose conception may have outpaced related molecular experimentation.D. Levels of Mechanistic InquiryOur current lack of understanding of the events underlying teratogenicity reflects the complexityof the developmental process. It may never be possible to describe every molecular or cellular eventthat ultimately leads to dysmorphogenesis. However, of the myriad of potential effects elicited bychemical and physical agents on embryonic development, it is probable that only a relative fewrepresent critical events responsible for developmental toxicity. Therefore, it is essential to identifythe key events, based on an understanding of the toxicological properties of the agent and thebiological processes involved. To gain an understanding of developmental toxicity, investigationsmust focus on multiple biological levels. The initial molecular and subcellular events must bedefined along with key processes occurring at the cellular, tissue, and organ level. Investigationsat the organ system and organism level are then required. Table 2.3 lists these levels of mechanisticinquiry for developmental toxicity. Recognition of these levels is critical for several reasons. First,mechanisms are frequently defined at only a single level. Thus, a cellular mechanism of action willbe defined in isolation from events occurring at higher levels of organization. Later investigatorsworking only at the fetal level may dismiss these mechanistic observations because strict temporalor dose-response relationships may be unclear at the higher level of investigation. However, if bothlevels are examined, both observations can be confirmed and a broader appreciation for the mechanisticcomplexities involved can be realized. The possibility of multiple mechanisms should berecognized; an adverse developmental outcome will probably not be attributable to a single eventbut rather to a cascade of events.© 2006 by Taylor & Francis Group, LLC