Cancer mode of action, weight of evidence, and proposed cancer reference value for hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX)

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX, CAS No. 121-82-4) is a component of munitions formulations, and has been detected in groundwater samples collected at various US military sites. Clean up target levels for RDX may be derived based on consideration of acceptable cumulative human exposure as expressed in toxicity reference values. Evaluations of the cancer weight of evidence and possible modes of action (MOA) for RDX-induced cancer were conducted. It was concluded that the available data provide suggestive evidence of human carcinogenic potential for RDX. While a mutagenic/genotoxic MOA for RDX is unlikely, no alterative MOA is strongly supported by the available data. A nonlinear (threshold) approach to the assessment of human cancer risk was recommended, and a recommended chronic cancer reference dose of 0.08 mg/kg/day was derived. For comparison only, computations using a linear approach were also conducted, yielding a cancer risk specific dose of 0.000235 mg/kg/day for 1 in 105 risk; this value is 2.6-fold higher the current US EPA risk specific dose for 1 in 105 risk. Thus, cleanup standards based on human health risk from RDX exposure could potentially depend on the willingness of risk managers to accept a nonlinear MOA and nonlinear toxicity risk value derivation.

► Available data provide suggestive evidence of human carcinogenic potential for RDX.
► A mutagenic/genotoxic mode of action (MOA) for RDX is unlikely.
► No alternative (nonmutagenic) MOA is strongly supported by available data.
► A chronic cancer reference dose (RfD) of 0.08 mg/kg/day is proposed.