Reevaluation of a Twenty-Four-Month Chronic Toxicity/Carcinogenicity Study of Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in the B6C3F1 Hybrid Mouse

Abstract

Hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) has been widely used as an explosive in U.S. army munitions formulations since World War II. Two-year carcinogenicity studies revealed RDX to be noncarcinogenic in two strains of rats, but a 2-year carcinogenicity study in B6C3F1 mice revealed an increased incidence of hepatocellular neoplasms in females. Based on results of the study in B6C3F1 mice, RDX has been classified as a possible carcinogen. The authors reevaluated the archived histological sections from the B6C3F1 mouse study, using current histopathologic diagnostic criteria and interpretations. The earlier evaluation showed a statistically significant increase in the incidence of hepatocellular adenoma/carcinoma in female mice from the three highest dose groups (7, 35, and 175/100 mg/kg/day). The revaluation yielded a slightly lower incidence at each of the dose levels in female mice. The reduced number of hepatocellular neoplasms was largely due to reclassification of hepatocellular adenomas as foci of cytoplasmic alteration, in compliance with current diagnostic criteria. The reevaluation was reviewed by a pathology working group (PWG), which arrived at a consensus classification of each lesion. Based on the consensus diagnoses of the PWG, only one female group (35 mg/kg/day) showed a significant increase when compared to controls. The incidence of hepatocellular neoplasms for all groups, including the 35 mg/kg/day group, was within the reported incidence range for spontaneous hepatocellular neoplasms in female B6C3F1 mice. The increased incidence of hepatocellular neoplasms in female mice given RDX at 35 mg/kg/day was interpreted as equivocal evidence of a carcinogenic effect.

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

“…Benchmark dose analysis of hepatocellular neoplasms (adenomas and carcinomas) in female B6C3F1 mice ingesting RDX in feed for two years (Lish et al, 1984;Parker et al, 2006). (Lish et al, 1984) (a) with concurrent control response (b) with historical control response (Maronpot et al, 1987).…”

“…Both in vivo studies where RDX was administered, the mouse bone marrow micronucleus assay and rat dominant lethal mutation test (Cholakis et al, 1980), were negative. In vitro tests of RDX alone (that is, not as part of a mixture) Table 1 Statistical analysis of hepatocellular neoplasms (adenomas and carcinomas) in female B6C3F1 mice ingesting RDX in feed for two years (Lish et al, 1984;Parker et al, 2006 Maronpot et al (1987). b Differs significantly from concurrent control (chi-squared test).…”

“…Mice (Lish et al, 1984;Parker et al, 2006) Groups of B6C3F1 mice (85/sex/group) were given RDX in feed at initial dosage levels of 0, 1.5, 7, 35 and 175 mg/kg/day by Lish et al (1984). At study week 11, the dosage in the high group was reduced to 100 mg/kg/day due to mortality in that group.…”

“…The 24-month pathology results for the female mice were reevaluated by a pathology working group using current diagnostic criteria (Parker et al, 2006) and are summarized in Table 1. The pathology working group further noted the lack of treatment related precursor lesions (i.e., foci of cellular alteration) in the study.…”

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

“…General physicochemical properties, toxicological data and carcinogenicity bioassays for RDX in rats and mice have been reviewed by various authors (McLellan et al, 1992;ATSDR, 1995;Parker et al, 2006). The neurotoxic eff ects of RDX have been reported in animals and humans (ATSDR, 1995).…”