EPA should more clearly describe how and why ED01 values were determined in animals and transferred to human equivalents for the various noncancer end points and address risk estimate calculations using alternative assumptions (e.g., ED05). Whereas ED01 is conceptually a viable POD, the committee has concerns about how the ED01 is computed and whether there are adequate data at the ED01 level to ensure an acceptable level of confidence in the conclusions derived from using the ED01. The dynamic range approach EPA used to compute ED01 for continuous response is flawed in that the change of 1% total range may not identify any meaningful toxic effects, that 1% change may be well within random variation in the absence of exposure, and that the use of total range is less sensitive than use of a control range because total range can be much wider.
EPA should provide a discussion of the dose-response effects of TCDD, other dioxins, and DLCs on the adult female reproductive system that result in endocrine disruption in animals. The impact of the dose-response data provided in these studies on human risk assessment should be presented.
With respect to human noncancer end points, the Reassessment text should be revised to include the relevant, more recent data and, when appropriate as discussed above, to reflect study quality and data uncertainty of the studies referenced.
For available human, clinical, noncancer end point data, EPA should establish formal principles of and a formal mechanism for evidence-based classification and systematic statistical review, including meta-analysis when possible. The application of systematic review, followed by evidence-based classification, leads to a more explicit statement of, and concrete appreciation of, the level of certainty (and, correspondingly, of uncertainty) that can be accorded the answers to specific questions in a particular field.
When the mechanism is established, currently available and newly available human clinical studies should be subject to such systematic review and formal evidence-based assessment. The quality of the available evidence should be reported, and the strength or weakness of a presumptive association should be classified according to currently accepted criteria for levels of evidence. Animal studies have shown that TCDD can cause a variety of noncancer effects. These studies support both the EPA position of the plausibility of corresponding human effects and the need to devise adequately designed investigations that will answer the questions in man.
In making its final recommendations, EPA should incorporate and integrate the relevant data from both human and animal studies, as appropriate, according to the levels-of-evidence hierarchy devised.
EPA is encouraged to review newly available studies on the effects of TCDD on cardiovascular development in its risk assessment for noncancer end points.