Answer Explanations 6
EPA's goal is to ensure that pesticides do not pose a risk to human health or the environment if used according to the label. Over many decades EPA and other competent regulatory bodies have developed and applied a testing, exposure and risk evaluation process to ensure that there is sufficient information to reliably support registration decisions that are protective of human health and the environment. The focus of a regulatory agency is on safety, and not on knowledge generation per se. Thus, regulatory agencies, like EPA strive to ensure that they require all the relevant information needed to inform decisions while avoiding the generation and evaluation of data that do not materially influence the scientific certainty of a regulatory decision. Thus, while certain interesting scientific questions arise, they do not alter the WOE conclusion about the genotoxic and carcinogenic risks posed by 1,3-D as, in my opinion, the information generated for the registration review of 1,3-D is sufficient for EPA to evaluate it's toxicokinetics, as well as for its genotoxic and carcinogenic risk potential to the general population. I do not identify any key data gaps that would affect this.
There is an abundance of data on 1,3-D beyond what is typically available for a pesticide active ingredient. The genetic toxicology panel, however, suggested that a new chromosomal aberration study would strengthen the conclusion concerning clastogenicity. Before such a study is conducted, a couple of questions should be considered - What is the purpose of the study, what is the best study design, and how would its findings impact the overall conclusion of cancer risk? It appears that most reviewers agree that there is not a need to consider data from structurally similar chemicals in the weight of evidence. And I agree that when adequate data are available on the chemical of interest, it should form the basis of the weight of evidence rather than inference from chemical-chemical extrapolation, which introduces uncertainty. But, given that data on structural analogs might be used to help clarify or strengthen a position, the sponsors might review how SAR data has been used in the past and consider whether the White paper needs to include a discussion on whether suitable analogs are found for the endpoint of carcinogenicity. Lastly, the peer review raised some good comments on how the White paper may be improved. Also, there were some uncertainties pointed out in the peer review, but I do not think they detract from the overall conclusion of risk. However, the White paper would benefit from a short hazard/risk characterization section toward the end of the White paper that provides the reasoning that underlies the choices in the available evidence as the foundation for conclusions, and a characterization of the uncertainties that puts these uncertainties in context of the overall weight of evidence.
This is a well studied chemical.
A more thorough and systematic discussion of a plausible mode of action (MOA) is needed to define conditions under which 1,3-D is likely to be (or not to be) carcinogenic for humans. Dismissing the relevance of various genotoxicity tests is not the same as establishing a MOA. Nor is saying that the various organs are not target tissues, when tumors were observed in those tissues.
Much of my responses below and above speak to the many data gaps making a WOE appraisal precarious here. Among the specific studies that might help close one or more of these gaps, I suggest: - an initiation/promotion assay - a more powerful traditional biossay (see response to question 5.6 above) - studies of human interindividual variation in GSH kinetics
Test in non-human primates. Test on offspring of pregnant animals.