An evaluation of the carcinogenic hazard of 1,4-dichlorobenzene based on internationally recognized criteria.

1,4-Dichlorobenzene (1,4-DCB) was shown to induce the formation of male rat renal tubule tumors and male and female mouse liver tumors when administered in a chronic bioassay. Since the original carcinogenicity findings, an extensive body of mechanistic information has been developed to elucidate the mode of action by which 1,4-DCB induces these effects and to evaluate the human relevance of the observed animal tumors. In addition, some regulatory and authoritative bodies (U.S. EPA and IARC) have developed rigorous scientific criteria for the amount and types of evidence needed to establish that a material causes kidney toxicity and tumors in male rats through a specific mechanism, alpha-2u-globulin nephropathy. This paper summarizes the mechanistic data developed for 1,4-DCB, which affords an understanding of the lack of human relevance of the male rat renal tubule tumors and mouse liver tumors; assesses that mechanistic data set utilizing the defined set of evaluation criteria formulated by U.S. EPA and IARC for alpha-2u-globulin nephropathy; and discusses the predictive power of mechanistic data developed to elucidate the mode of action of 1,4-DCB in inducing mouse liver tumors. Finally, there is a discussion of how some, but not all, regulatory and authoritative bodies have incorporated this substantial mechanistic data set for 1, 4-DCB into their cancer hazard evaluations and concluded that 1, 4-DCB presents little, if any, cancer hazard to humans.

Evaluation of unscheduled DNA synthesis (UDS) and replicative DNA synthesis (RDS) following treatment of rats and mice with p-dichlorobenzene.

p-Dichlorobenzene (PDCB) has been reported to produce tumors in the male and female mouse liver and in the male rat kidney in 2-year gavage studies (NPT, 1987). To elucidate the possible mechanisms of carcinogenicity more fully, UDS and RDS were evaluated in B6C3F1 mouse hepatocytes and F-344 rat kidney cells by autoradiography following in vivo administration of PDCB. All corn oil gavage doses of PDCB (300, 600, and 1,000 mg/kg) and the negative control resulted in < 0 net grains/nucleus (NG) in the mouse liver and rat kidney, indicating that PDCB does not induce UDS in either tissue. Compared to controls with < or = 0.29% hepatocytes in S-phase (%S), treatment of mice induced 0.46, 1.90, and 1.52 %S (males) and 2.61, 1.18, and 4.45 %S (females), which indicates that PDCB acts as an inducer of cell proliferation in the liver. In male rat kidney cells, the same doses produced 0.87, 0.67, and 1.01 %S (0.38% in controls) and in females 0.48, 0.43, and 0.32 %S (0.52% in controls), indicating that PDCB induces cell replication in the male but not the female rat kidney. Therefore, these data demonstrate that PDCB is not genotoxic in the mouse liver or rat kidney at single oral doses comparable to the daily doses given in the National Toxicology Program (NTP) bioassay (NTP, 1987). Furthermore, the increases in RDS support the hypotheses that mouse liver tumor formation occurs via stimulation of hepatocyte proliferation and male rat kidney carcinogenesis via increased renal cell proliferation.

A two-generation reproduction study with monochlorobenzene vapor in rats.

Groups of 30 male and 30 female Sprague-Dawley CD rats, designated as the F0 generation, were exposed to vapor of monochlorobenzene (MCB) at target concentrations of 0, 50, 150, or 450 ppm for 10 weeks prior to mating and during mating, gestation, and lactation. The progeny of the F0 generation was designated as the F1 generation and groups of 30 male and 30 female F1 animals were exposed to the same concentrations of MCB as the F0 parents. Exposure of F1 animals was initiated 1 week postweaning and lasted 11 weeks prior to mating and through mating, gestation, and lactation. All F2 pups were observed through weaning at which time they were killed. Observations made during the study included body weights, food consumption, mating and fertility indices, pup and litter survival indices, and histopathology of selected tissues. No mortality was observed during the course of this study. Body weights and food consumption for all treated groups were comparable to controls during the growth period. Maternal body weight data during gestation and lactation were also comparable between the control and treated groups. Mating and fertility indices for males and females for both generations appeared unaffected by treatment. Pup and litter survival indices for all treated groups were comparable to those of controls. Hepatocellular hypertrophy and renal changes (tubular dilation with eosinophilic material, interstitial nephritis, and foci of regenerative epithelium) were observed among F0 and F1 male rats exposed to 150 and 450 ppm MCB.(ABSTRACT TRUNCATED AT 250 WORDS)