Researchers and advanced students in Toxicology. Also, biologists, pharmacologists, and teratologists from academia, industry, and governmental agencies; domestic, wildlife, and aquatic specialists; environmentalists; regulatory agencies.
An Introduction to Reproductive & Developmental Toxicology
Chapter 4. Chapter 8. Chapter Section XI. Ramesh C. He is recipient of Murray State University's distinguished researcher award of the year, and Outstanding research award of the year We are always looking for ways to improve customer experience on Elsevier.
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Institutional Subscription. Free Shipping Free global shipping No minimum order. To address U. Numerous scientific workshops, roundtable discussions, and symposia have been held to discuss a variety of aspects of both DNT and DIT including appropriate endpoints, methodologies, and the evolving state of the science for DNT Buelke-Sam et al. In fact, the general design of the current DNT testing paradigm is somewhat redundant to the standard DART protocol, because body weight, clinical observations, measures of sexual maturation, and brain weight are conducted for both studies.
Even more importantly, there is a significant overlap in the developmental life stages assessed across the various study designs; in particular, each study includes exposures during gestation, to parturition, and through early postnatal life Fig. While additional animals are available from DNT designs, the incorporation of DIT endpoints into a DNT study has been deemed not generally feasible due to the size and technical complications associated with DNT protocols Holsapple et al.
However, it has been proposed that DIT endpoints be added onto existing reproductive toxicity studies where feasible Holsapple et al. While the general concept of evaluating all three organ systems after developmental exposures within the same test population has been demonstrated Chapin et al.
Prior workshops, symposia, and roundtable discussions have focused primarily on the state of the science of both DIT and DNT, including appropriate endpoints and methodologies to evaluate them and how they are, should, or should not yet be applied in human health risk assessment. Though the conclusion from many of these scientific gatherings has been to add endpoints onto existing studies to minimize overall animal use and maximize the data gathered from individual studies, no session has yet evaluated the actual technical feasibility and potential challenges of this approach.
Therefore, the objective of this Sunset Session at the Annual Meeting of the Society of Toxicology was to provide a forum to discuss whether and how the assessment of DART, DNT, and DIT could be integrated into a single study for hazard identification purposes to conserve multiple resources, including making more efficient use of animal resources.
Specific questions were posed during the session Table 1 to guide the discussion. While the time available during the SOT session was limited, the panelists did address most of the questions. The discussion began with the acknowledgment that a combination endpoint study has already been demonstrated as feasible Chapin et al. The study was technically quite challenging and required the coordinated effort of multiple laboratories, but participants felt that it provided a reasonably comprehensive screen. While the panelists recognized the technical complexity, all agreed that a combination endpoint study was important and highly desirable from an animal use and resource standpoint.
A study that included all endpoints to comply with all three studies will likely be too cumbersome; however, the objectives could be satisfied in a manageable study by limiting which endpoints to retain, number of days on which tests were performed, etc.
As such, the panelists agreed that the first question in Table 1 should be answered in the affirmative. Examples of such integration already exist. As recently described by Carmichael et al. As described by Cooper et al. Some of the benefits of the proposed approach were identified as the assessment of multiple types of outcomes from the same population of animals and far fewer animals used than when separate DNT and standard DART studies are conducted. Additionally, the FDA guidance on immunotoxicity evaluation suggests that DIT can be performed using rats available in standard reproductive studies, rather than needing a stand-alone study.
Along these lines, the panel agreed that immunotoxicity parameters assessed in a DART study would likely be sufficient to determine the immunotoxic potential of the test article in adults Holsapple et al. There was some discussion around whether such a combination endpoint study should be conducted routinely or only as needed [i. Triggers have been utilized in determining the need for DNT testing based upon recommendations of Levine and Butcher, and have been proposed for the conduct of a DIT study Holsapple et al.
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Nevertheless, some panelists questioned whether the proposed triggers are adequate or whether sufficient data would be available early enough in product development to indicate when such a combination endpoint study is needed. However, the general consensus of the panel was that combined-endpoint studies should be encouraged for preliminary screening of new i.
Reproductive and Developmental Toxicology by Ramesh C. Gupta - cransebnartcoldie.gq
In that case, the rationale for conducting combined-endpoint studies should be based on a case-by-case basis depending upon specific trigger s. It was also recently noted that these limitations could be addressed in further specialized tests within the existing testing scheme; however, such assessments may not be required in all cases, and the triggers for them in the standard two-generation DART test may be absent Cooper et al.
In addition, the panelists agreed that, as neurotoxicity and immunotoxicity studies with either adults or juvenile animals become required testing in some regulatory arenas, these triggers would likely become less important, as the studies would be conducted nonetheless. This lack of consensus was primarily driven by disagreement among panelists regarding which DNT endpoints were most predictive of a potential adverse effect. It was noted that the DNT study design was conceived as a battery of tests to screen across a number of semi-independent structural and functional neurological domains Francis et al.
Thus, because effects are often observed in some but not all tests, it was questioned how the choice could be made to eliminate specific tests and whether all currently employed tests are necessary. In order to accommodate the need to retain all currently evaluated endpoints, one suggestion was to consider conducting a second breeding of the parental generation in a two-generation reproduction study, or alternatively, using an F2 generation to assess either DNT or DART endpoints.
It was reported that studies have been submitted to EPA in which serial breeding of the parental generation was conducted and DNT endpoints were successfully evaluated in the resulting offspring F1a or F1b. Nevertheless, other panelists disagreed with the contention that certain tests cannot be eliminated, suggesting that some of the evaluations e.
Still others questioned whether the functional observational battery FOB data from the DART or DNT studies conducted to date should be compared with the neurotoxicological findings or histopathology from general toxicology studies to help determine the most appropriate and predictive endpoints. It was indicated that some of these kinds of analyses have been conducted Makris et al.
Regarding DIT endpoints, the panelists agreed with previous workshop recommendations Holsapple et al.