Response to the society of toxicology task force re-examination of the ED01 study.
This communication has re-examined and justified certain of the NCTR's analyses and recommendations from the ED01 Study, which were either misunderstood or misinterpreted by the SOT Task Force. In addition, we have shown that some of the Task Force's own analyses and interpretations are subject to review on scientific grounds. The Task Force's rejection of the linear extrapolation method recommended by the NCTR was stated because of a suspected force-fitting of a linear model to data, an approach that is not part of the NCTR procedure. In suspecting a protective effect of 2-AAF against bladder tumors, the Task Force used an inappropriate model that overpredicted the background bladder tumor rate in control mice. Contrary to the Task Force's belief, a failure to account adequately for time to tumor response was more characteristic of analyses performed by the Task Force rather than those performed by the NCTR. The Task Force's questioning of the multistage model for risk assessment was based on its use of inappropriate, crude tumor data rather than upon NCTR's use of the multistage model with time-adjusted tumor data. The Hartley-Sielken model did not fit the ED01 tumor data as well as the Task Force had presumed. In a risk extrapolation comparison by the Task Force, a coarse time partition of the ED01 data that had been questioned by the Task Force actually produced more stable results than a finer partition proposed by the Task Force. Another problem in the Task Force report concerns the change of protocol. Instead of resulting in a loss of strength as anticipated by the Task Force, the change of protocol during the ED01 Study resulted in an increase in information as alluded to by the Task Force. If the Task Force's proposal for restricting the length of feeding studies had been followed in the ED01 Study, most of the dose related tumor information would not have been obtained. Also, the Task Force's belief that low doses of 2-AAF had some effect on the prevention of early death was not supported by a statistical analysis. In summary, the review conducted by the SOT Task Force contained some misleading representations of the data from the ED01 Study and statements that showed a misunderstanding of NCTR's analyses of the study.
D000375:Aging; D002273:Carcinogens; D004305:Dose-Response Relationship, Drug; D008954:Models, Biological; D012306:Risk; D012984:Software; D013997:Time Factors; D014116:Toxicology / Q000379:methods*; D014481:United States; D014486:United States Food and Drug Administration
D002273:Carcinogens