1 **Draft Charge to the Science Advisory Board for the IRIS Toxicological Review of Hexahydro** 

**- 1,3,5** 

**- trinitro** 

**- 1,3,5** 

**- triazine (RDX)** 

**M arch**  **2016**

**Introduction**

The U.S. Environmental Protection Agency (EPA) is seeking a scientific peer review of a draft Toxicological Review of Hexahydro

- 1,3,5

- trinitro

- 1,3,5

- triazine (RDX) developed in support of the Agency’s online database, the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by EPA’s National Center for Environmental Assessment (NCEA) within the Office of Research and Development (ORD).

IRIS is a human health assessment program that evaluates scientific information on effects that m ay result from exposure to specific chemicals in the environment. Through IRIS, EPA provides high quality science

- based human health assessments to support the Agency’s regulatory activities and decisions to protect public health. IRIS assessments contain information for chemicals that can be used to support hazard identification and dose

- response assessment, two of the four steps in the human health risk assessment process. When supported by available data, IRIS provides health

effects information and t oxicity values for health effects (including cancer and effects other than cancer) resulting from chronic exposure. IRIS toxicity values may be combined with exposure information to characterize public health risks of chemicals; this risk characterization information can then be used to support risk management decisions.

An existing assessment for RDX includes a reference dose (RfD) posted on the IRIS database in 1988 and oral slope factor (OSF) and a cancer descriptor posted in 1990. The IRIS Program i s conducting a reassessment of RDX. The draft Toxicological Review of RDX is based on a comprehensive review of the available scientific literature on the noncancer and cancer health effects in humans and experimental animals exposed to RDX. Additionally, appendices for chemical and physical properties, toxicokinetic information, summaries of toxicity studies, and other supporting materials are provided as Supplemental Information (see Appendices A to D) to the draft Toxicological Review.

The draft ass essment was developed according to guidelines and technical reports published by EPA (see Preamble ), and contains both qualitative and quantitative characterizations of the human health hazards for RDX, including a cancer descriptor of the chemical’s human carcinogenic potential, a noncancer toxicity value for chronic oral exposure (RfD), and a cancer risk estimate for oral exposure.2 **C harge questions on the draft Toxicological Review**  **of RDX**

1. **Literature search/study selection and evaluation** 

**.** The sec tion on Literature Search Strategy | Study Selection and Evaluation describes the process for identifying and selecting pertinent

studies. Please comment on whether the literature search strategy, study selection considerations, and study evaluation considerations are appropriate and clearly described. Please identify addition al peer

- reviewed studies that the assessment should consider

.

2. **Toxicokinetic modeling.** In A ppendix C, S ection C.1.5, the draft assessment presents a summary, evaluation, and further development of published PBPK models for RDX in rats, mice, and humans (Sweeney et al., 2012a, b).

2a. Are the conclusions reached based on EPA’s evaluation of the models scientifically supported? Do the revised PBPK models adequately represent RDX toxicokinetics? Are the model assumptions and parameters clearly presented and scientifically supported? Are the uncertainties in the model appropriately considered and discussed?

2b . The average concentration of RDX in arterial blood (expressed as area under the curve) was

selected over peak concentration as the dose metric for interspecies extrapolation for oral points of departure (PODs) derived from rat data. Is the choice of dose metric for each hazard sufficiently explained and appropriate? The mouse PBPK model was not used to derive PODs for noncancer or cancer endpoints because of uncertainties in the model and because of uncertainties associated with selection of a dose metric for cancer endpoints. Is this decision scientifically supported?

2c. In S ection 2.1.3 of the draft assessment, an uncertainty factor of 10 for human variation is applied in the derivation of the RfD. D oes the toxicokinetic modeling support the use of a

diffe rent factor instead?

3. **Hazard identification and dose** 

**– response assessment** 

**.** In Chapter 1, the draft assessment evaluates the available human, animal, and mechanistic studies to identify health outcomes that

may result from exposure to RDX

. In Chapter 2, the draft assessment develops organ/system

specific reference values for the health outcomes identified in Chapter 1 , then selects overall reference values for each route of exposure

. The draft assessment uses EPA’s guid ance documents (see http://www.epa.gov/iris/basic

- information

- about

- integrated

- risk

information

- system#guidance ) to reach the following conclusions.

[Note: As suggested by the Chemical Assessment Advisory Committee panel that reviewed the draft IRIS assessment of benzo[a]pyrene, the charge questions in this section are organized by health outcome, with a question on each hazard identification followed by questions on the

corre sponding organ/system

- specific toxicity values. This suggestion, however, entails some redundancy, as some questions apply equally to multiple health outcomes. ]

3 a. **Nervous system effects.** 

(i) **Nervous system hazard**  (S ections 1. 2 .1, 1. 3 .1)

**.** The draft assessment concludes that nervous system toxicity is a human hazard of RDX exposure

. Please comment on

whether the available human

, animal , and mechanistic studies support this

conclusion. Please comment on whether the selection of convulsions as the endpoint to represent this hazard is scientifically supported and clearly described.3 (ii) **Nervous system**

**- specific toxicity values**  (Section 2.1.1). P lease comment on

whether the selection of studies reporting nervous system effects is scientifically supported and clearly described

. Considering the difference in toxicokinetics between gavage and dietary administration (described in Appendix C , Section C .1 , and in the context of specific hazards in the toxicological review) , is it appropriate to consi der the Crouse et al. (2006) study, which used gavage administration? Please comment on

whether the characterization of convulsions as a severe endpoint, and the potential relationship to mortality, is appropriately described.

( i i i) **Points of departure f**  **or nervous system endpoints**  ( S ection 2.1.2). Please comment

on whether the calculation of PODs for these studies is scientifically supported and clearly described. Does the severity of convulsions warrant the use of a benchmark response level of 1% extra risk ? Is calculation of the lower bound on the benchmark dose ( BMDL ) for convulsions appropriate and consistent with the EPA’s Benchmark

Dose Guidance ?

(i v ) **Uncertainty factors for nervous system endpoints**  ( S ection 2.1.3). Please comment

on whether the application of uncertainty factors to these PODs is scientifically supported and clearly described

. The subchronic and database uncertainty factors

inco rporate multiple considerations; p lease comment specifically on the scientific

rationale for the applic ation of a subchronic uncertainty factor of 1 and a database uncertainty factor of 3

. 1

(v) **Nervous system**

**- specific reference**  **dose** ( S ection 2.1.4). Please comment on whether the organ/system

- specific reference dose derived for nervous system effects

is scientifically supported and clearly characterized.

3b. **Kidney and other urogenital system effects.**

(i) **Kidney and other urogenital system hazard** ( S ections 1.2.2, 1.3.1). The draft assessment concludes that kidney and other urogenital system toxicity is a potential human hazard of RDX exposure. Please comment on whether the available human, animal, and mechanistic studies support this conclusion. Pl ease comment on whether the selection of suppurative prostatitis as the endp oint to represent this hazard is scientifically supported and clearly described.

(ii) **Kidney and other urogenital system** 

**- specific**  **toxicity values** (Section 2.1.1). Please

comment o n whether the selection of the Levine et al. (1983) study that describes kidney and other urogenital system effects is scientifically supported and clearly

described.

(ii i ) **Points of departure for kidney and other urogenital system**  **endpoints** ( S ection 2.1.2). Please comment on whether the calculation of a POD for th is stud y is scientifically supported and clearly described.

1 Note that the database uncertainty factor applies to each of the hazards identified in the toxicological

review.4 ( i v) **Uncertainty factors for kidney and other urogenital system endpoints**  (S ection 2.1.3). Please comment on whether the a pplication of uncertainty factors to the POD is scientifically supported and clearly described.

(v) **Kidney and other urogenital system**

**- specific reference**  **dose** (S ection 2.1.4). Please comment on whether the organ/system

- specific reference dose derived fo r kidney and other urogenital system effects is scientifically supported and clearly

characterized.

3c. **Developmental and reproductive system effects.**

(i) **Developmental and reproductive system hazard** (S ections 1.2.3, 1.3.1). The draft

assessment concludes that there is suggestive evidence of male reproductive effects

associated with RDX exposure, based on evidence of testicular degeneration in male

mice

. The draft assessment did not draw any conclusions as to whether developmental effects are a human hazard of RDX exposure. Please comment on whether the available human, animal, and mechanistic studies support th ese conclusion s.

(ii) **Reproductive system**

**- specific toxicity values**  (S ection 2.1.1). Please comment on
whether the selection of the Lish et al. (1984) study that describes male reproductive

system effects is scientifically supported and clearly described.

(i ii ) **Points of departure for reproductive system**  **endpoints** (S ection 2.1.2). Please

commen t on whether the calculation of a POD for th is stud y is scientifically supported and clearly described.

(i v) **Uncertainty factors for reproductive system endpoints**  (S ection 2.1.3). Please comment on whether the application of uncertainty factors to th e POD is scientifically supported and clearly described.

(v) **Reproductive system**

**- specific reference**  **dose** (S ection 2.1.4). Please comment on whether the organ/system

- specific reference dose derived for reproductive system

effects is scientifically supporte d and clearly characterized.

3d. **Other noncancer hazards** (S ections 1.2.4, 1.2.6, 1.3.1). The draft assessment did not draw any conclusions as to whether liver, ocular, musculoskeletal, cardiovascular, immune, or gastrointestinal effects are human hazards of RDX exposure

. Please comment on whether the available human, animal, and mechanistic studies support this conclusion

.

3e. **Cancer.**

(i) **Cancer hazard** (S ections 1.2.5, 1.3.2). There are plausible scientific arguments for

more than one hazard descriptor as discussed in S ection 1.3.2. The draft assessment

concludes that there is suggestive evidence of carcinogenic potential for RDX, and that this descriptor applies to all routes of human exposure. Please comment on whether the available human, animal, and mechanistic studies support this conclusion.

(i i) **Cancer**

**- specific toxicity values**  (Section 2.3.1). As noted in EPA’s 2005 Guidelin e s for Carcinogen Risk Assessment , “ W hen there is suggestive evidence, the Agency generally5 w ould not attempt a dose

- response assessment, as the nature of the data generally would not support one; however, when the evidence includes a well

- conducted study, quantitative analyses may be useful for some purposes, for example, providing a sense of the magnitude and uncertainty of potential risks, ranking potential hazards, or setting research priorities. ” Does the draft assessment adequately explain the rationale for quantitative analysis, considering the uncertainty in the data and the suggestive n ature of the weight of evidence, and is the selection of the Lish et al. (1984) study for this purpose scientifically supported and clearly described ?

(iii) **Points of departure for cancer**  **endpoints** (S ection 2. 3 .2 , 2.3.3). Please comment on

whether the calculation of PODs and oral slope factors is scientifically supported and clearly described.

4. **Dose**

**- response analysis.**  In Chapter 2, the draft assessment uses the available human, animal, and mechanistic studies to derive candidate toxicity values for each hazard that is credibly

associated with RDX exposure in Chapter 1

, identify an organ/system

- specific RfD, then select s an overall toxicity value for each route of exposure. The draft assessment uses EPA’s guidance documents (see http://www.epa.gov/iris/basic

- information

- about

- integrated

- risk

information

- system#guidance ) in the following analyses.

4a

. **Oral reference dose for effects other than cancer**  (S ection s 2 .1 .5

– 2.1. 8 ). The draft

assessment presents an overall oral reference dose of 3 × 10 -3 mg/kg -d ay
, based on nervous system effects as described in the Crouse et al. (2006) study

. Please comment on whether

this selection is scientifically supported and clearly described , including consideration of mortality as described in S ection 2.1.6 , and consideration of the organ/system

- specific

reference dose derived from the toxicity study by Cholakis et al. (1980) that is lower (by approximately five fold ) as described in Section 2.1.4.

4b

. **Inhalation reference**  **concentration for effects other than cancer**  (S ection 2.2 ). The

draft assessment does not derive an inhalation reference concentration as the available

studies were insufficient to characterize inhalation hazard and conduct dose

- response analysis, and no toxicokinetic studies of RDX were available to support development of a

PBPK inhalation model

. If you believe that the available data might support an inhalation reference concentration, please describe how one might be derived.

4c

. **Oral slope factor for cancer** (S ection 2.3 .3

– 2.3.4 ). The draft assessment pr esents an overall oral slope factor of 0.038 per mg/kg -d ay based the combination of liver and lung

tumors in female mice. Please comment on whether this derivation is scientifically supported and clearly described.

4d

. **Inhalation unit risk for cancer** (S ection 2.4). The draft assessment does not derive an

inhalation unit risk because inhalation carcinogenicity data were not available, nor were toxicokinetic studies of inhalation of RDX available to support development of an inhalation

PBPK model

. If you believe that the available data might support an inhalation unit risk, pl ease describe how one might be derived.

5. **Executive summary** . Does the executive summary clearly and appropriately present the major

conclusions of the assessment?