IRIS Public Science Meeting (May 2016)

UPDATE: EPA hosted a public science meeting on May 10, 2016 to discuss the availability of the public comment draft of the IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and related documents. The presentations from the meeting are now available.

At the May meeting, a public comment draft of the following assessment was discussed:

  • IRIS Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

Meeting Objective

IRIS hosted public science meetings to allow the public the opportunity to provide input and participate in discussions about draft IRIS assessment materials. In August 2013, EPA released the draft literature search and associated search strategy, evidence tables, and exposure response arrays for RDX to obtain input from stakeholders and the public prior to developing the draft IRIS assessment. In December 2013, EPA hosted an IRIS public science meeting to discuss those preliminary materials. The May 2016 meeting was held to discuss the public comment draft that was released for comments.

The objective of this public meeting was to obtain input from the scientific community, stakeholders, and the general public on the IRIS Toxicological Review of RDX (Public Comment Draft) prior to external peer review. This is in addition to the formal public comment period announced in a March 10, 2016 Federal Register Notice, where written comments can be submitted to the RDX docket [see Meeting Materials tab].

In October 2014, EPA’s IRIS Program announced an agreement with the National Academies’ National Research Council (NRC) to arrange for independent experts to participate in the IRIS public science meetings to provide input on the science underlying the development of IRIS assessments. The NRC will select a limited number of experts to join in the discussion of the key science topics at this meeting. Participation of these experts is meant to be supplementary and stakeholders and the public should continue to register as discussants.


The meeting was held on May 10, 2016.


The meeting was held at the EPA Conference Center at 2777 South Crystal Drive, Arlington, Virginia 22202. The meeting was also available by webinar/teleconference for remote participants.

Public participation. The IRIS Program used this meeting format intended to promote public discussion which emphasizes conversational exchanges over presentations. We wanted to hear the full range of scientific perspectives during these discussions. Accordingly, we requested that no more than two individuals from the same organization register as discussants on any particular topic. We also asked that discussants limit the number of slides used, and rely on them mainly to present concepts and data via figures and tables. After the discussants each had a turn, all meeting participants were invited to join the discussion.

Disclosures for discussants and commenters. To promote transparency, it was requested that persons submitting written or oral comments or participating as discussants on key science topics disclose: (1) The nature of any financial relationships (e.g., consulting agreements, expert witness support, or research funding) they may have with any organization(s) or entities having an interest in the assessment or issues under discussion; and (2) The extent to which their comments were reviewed by an interested party prior to submission.

Disclosures for submitting study results. If results or analyses of scientific research were submitted or presented, it was requested that the following information be provided where available: (1) Identification of the funding source(s) and sponsoring organization(s) of the research; (2) The extent to which the research findings were reviewed by an interested party prior to publication or submission, and identification of any such parties; and (3) The nature of any financial relationships between investigators who conducted the research and any organization(s) or entities having an interest in the assessment or issues under discussion.

Making submitted materials available to the public. To provide a reasonable opportunity for all stakeholders to participate in a thoughtful public dialogue on the science topics, meeting participants were requested to submit presented materials to the RDX docket [see Meeting Materials tab] and to in advance of the May 10th public meeting. 

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Meeting Agenda:

The final agenda(2 pp, 262K, About PDF) was posted on May 9, 2016.

Draft Toxicological Review Materials:

The assessment and associated discussion materials include:

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX): Lou D’Amico and Susan Rieth, Assessment Managers

Note: In 2013, EPA announced its plan to host public science meetings to solicit input from the public and to foster scientific discussion on draft IRIS assessment materials. For the public comment draft of RDX, IRIS is requesting public input on specific science topics—identified by the Program—that will aid with decision making within the current framework of the assessment prior to submitting it for peer review. In addition, the public will have an opportunity to provide comments on other scientific issues specific to the RDX assessment, during a separate session at the end of the meeting.

Key Science Topics:

Science Topic 1: Suppurative prostatitis as a marker for hazard to the urogenital system following RDX exposure.

The organ/system-specific reference dose for kidney/urogenital system effects is based on a dose-related increase in the incidence of suppurative prostatitis from a 2-year feeding study in male F344 rats (Levine et al., 1983b), which is the only 2-year study that examined the prostate. Some reports have hypothesized that the observed suppurative prostatitis is a secondary effect from a bacterial infection unrelated to RDX toxicity (ATSDR, 2012; Sweeney et al., 2012a; Crouse et al., 2006).

The public comment draft of the Toxicological Review for RDX proposes that while an opportunistic bacterial infection could have been the proximate cause of the suppurative prostatitis, the infection may also have been secondary to urogenital effects associated with RDX exposure. Although the pathogenesis of kidney and urogenital effects is unclear, suppurative prostatitis was considered to be a marker for the broader array of kidney and other urogenital effects observed by Levine et al. (1983b).

This is a complex and highly specialized topic, and the IRIS program would like to encourage further public discussion of the evaluation of suppurative prostatitis and whether the interpretation of the scientific evidence is consistent with a determination of hazard.

Presentation: An Overview (by EPA) of the IRIS Draft Toxicological Review of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) (20 pp, 441 K, About PDF)

Science Topic 2: Evaluation and use of RDX PBPK models.

The public comment draft of the Toxicological Review of RDX presents a summary, evaluation and further development of published PBPK models for RDX in rats, mice, and humans (Sweeney et al., 2012a; Sweeney et al., 2012b). Detailed discussion of these models and their elaboration by EPA is provided in the Supplemental Information to the Toxicological Review (Appendix C.1.5). As described in Section 2.1.2 of the Toxicological Review (Extrapolation using PBPK modeling), the IRIS Program concluded that uncertainties in the mouse model precluded its use for derivation of oral reference values, and instead relied on allometric BW3/4 scaling.

Two dose metrics were considered for interspecies extrapolation – the average concentration of RDX in arterial blood (expressed as area under the curve, AUC), and peak blood concentration (Cmax). The PODHEDs (points of departure expressed as a human equivalent dose) derived from application of AUC or Cmax as the dose metric are shown in Table 2-2 of the Toxicological Review for comparative purposes. EPA chose to use AUC as the appropriate dose metric for interspecies extrapolation of noncancer oral PODs derived from rat data based on some biological evidence for potential longer-term effects of binding to the GABAA receptor, and because of comparatively less uncertainty in model estimates based on this dose metric (summarized in Section 2.1.2).

The IRIS program would like to encourage further public discussion of the development and application of existing PBPK models, including the utility of the mouse model and the selection of AUC as the appropriate dose metric for modeling noncancer endpoints in rodents.

Presentation: Evaluation of the IRIS Draft PBPK Modeling of RDX (6 pp, 371 K, About PDF)

Science Topic 3: Neurotoxicity observed with RDX – including consideration of dose and duration of exposure and the potential relationship to mortality.

In the majority of studies, RDX exposure was associated with convulsions. Characterization of the relationship between mortality and convulsions was based on several studies that reported observing convulsions before unscheduled deaths (Crouse et al., 2006; Angerhofer et al., 1986; Levine et al.,1983b Cholakis et al., 1980). In addition, treatment-related mortality was observed in several studies at doses as low as those associated with nervous system effects (Crouse et al., 2006, Angerhofer et al., 1986; Levine et al., 1983b; Levine et al., 1981; Cholakis et al., 1980; Von Oettingen et al., 1949). The 90-day study by Crouse et al. (2006) provided the most detailed information on the relationship between convulsions and mortality.  However, additional individual animal data from this study (Johnson, 2015) did not show a clear correspondence between convulsions and mortality (e.g., not all animals that convulsed died during the study).

Because some studies identified mortality at the same dose of RDX that induced nervous system effects, additional analysis of the mortality data was undertaken. This analysis involved comparison of dose-response relationships for mortality in rodents exposed to RDX for durations up to 90 days with dose-response relationships for convulsions following similar exposure durations. Specifically, LD01 values (the dose expected to be lethal to 1% of the animals) derived using mortality data sets were compared to benchmark dose (BMD01) values for convulsions. In general, this comparison (in Chapter 2, Section 2.1) indicated that reference values derived from mortality data would be similar to the overall RfD for RDX based on convulsions, assuming the application of the same extrapolation procedures and uncertainty factors.

The critical effect upon which the overall RfD is based (convulsions) is considered to be of high severity. Accordingly, EPA used a benchmark response (BMR) of 1% extra risk, consistent with the EPA’s Benchmark Dose Technical Guidance. EPA presents uncertainties associated with the use of a 1% BMR in Section 2.1 of the Toxicological Review, along with the PODs one would derive using BMRs of 5 and 10% in the BMD modeling appendix of the Supplemental Information (Appendix D.1).

The IRIS program would like to encourage further public discussion of the relationship between convulsions and mortality, specifically, the impact of dose and duration of exposure on their occurrence, and other scientific input that could inform the selection of the BMR for convulsions.

Presentation: Realities of Human RDX Dose (1 pp, 37 K, About PDF)

Science Topic 4: Public comment on other science topics in the RDX assessment

A facilitated discussion with all attendees.

Presentation: Comments (by the ACC) at the EPA Public Science Meeting on RDX (7 pp, 254 K, About PDF)

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