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Dichloroacetic acid (DCA) is carcinogenic to the B6C3[F.sub.1] mouse and the F344 rat. Given the carcinogenic potential of DCA in rodent liver and the known concentrations of this compound in [...]

BACKGROUND: Trihalomethanes (THMs) and haloacetic acids (HAAs) are regulated disinfection by-products (DBPs); their joint reproductive toxicity in drinking water is unknown. OBJECTIVE: We aimed to evaluate a drinking water mixture of the four regulated THMs and five regulated HAAs in a multigenerational reproductive toxicity bioassay. METHODS: Sprague-Dawley rats were exposed (parental, [F.sub.1], and [F.sub.2] generations) from gestation day 0 of the parental generation to postnatal day (PND) 6 of the [F.sub.2] generation to a realistically proportioned mixture of THMs and HAAs at 0, 500x, 1,000x, or 2,000x of the U.S. Environmental Protection Agency's maximum contaminant levels (MCLs). RESULTS: Maternal water consumption was reduced at [greater than or equal to] 1,000x; body weights were reduced at 2,000x. Prenatal and postnatal survival were unaffected. [F.sub.1] pup weights were unaffected at birth but reduced at 2,000x on PND6 and at ≥ 1,000x on PND21. Postweaning [F.sub.1] body weights were reduced at 2,000x, and water consumption was reduced at [greater than or equal to] 500x. Males at 2,000x had a small but significantly increased incidence of retained nipples and compromised sperm motility. Onset of puberty was delayed at 1,000x and 2,000x. [F.sub.1] estrous cycles and fertility were unaffected, and [F.sub.2] litters showed no effects on pup weight or survival. Histologically, [P.sub.0] (parental) dams had nephropathy and adrenal cortical pathology at 2,000x. CONCLUSIONS: A mixture of regulated DBPs at up to 2,000x the MCLs had no adverse effects on fertility, pregnancy maintenance, prenatal survival, postnatal survival, or birth weights. Delayed puberty at [greater than or equal to] 1,000x may have been secondary to reduced water consumption. Male nipple retention and compromised sperm motility at 2,000x may have been secondary to reduced body weights. http://dx.doi.org/10.1289/ehp.1408579, Introduction Disinfection of drinking water is important in controlling microbial contamination in tap water and has proven to be a major advancement in public health. However, oxidizing disinfectants react with [...]

Abstract Background Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC). Results To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expression-related changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-γ metabolic responses were functional in both cell lines, but IFN-γ anti-proliferative responses functioned only in tumor cells. Conclusions Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon.

Background: Simian Virus 40 (SV40) immortalization followed by treatment of cells with 3-methylcholanthrene (3-MC) has been used to elicit tumors in athymic mice. 3-MC carcinogenesis has been thoroughly studied, however gene-level interactions between 3-MC and SV40 that could have produced the observed tumors have not been explored. The commercially-available human uroepithelial cell lines were either SV40-immortalized (HUC) or SV40-immortalized and then 3-MC-transformed (HUC-TC). Results: To characterize the SV40 - 3MC interaction, we compared human gene expression in these cell lines using a human cancer array and confirmed selected changes by RT-PCR. Many viral Large T Antigen (Tag) expressionrelated changes occurred in HUC-TC, and it is concluded that SV40 and 3-MC may act synergistically to transform cells. Changes noted in IFP 9-27, 2'-5' OAS, IF 56, MxA and MxAB were typical of those that occur in response to viral exposure and are part of the innate immune response. Because interferon is crucial to innate immune host defenses and many gene changes were interferon-related, we explored cellular growth responses to exogenous IFN-γ and found that treatment impeded growth in tumor, but not immortalized HUC on days 4 - 7. Cellular metabolism however, was inhibited in both cell types. We conclude that IFN-γ metabolic responses were functional in both cell lines, but IFN-γ anti-proliferative responses functioned only in tumor cells. Conclusions: Synergism of SV40 with 3-MC or other environmental carcinogens may be of concern as SV40 is now endemic in 2-5.9% of the U.S. population. In addition, SV40-immortalization is a generally-accepted method used in many research materials, but the possibility of off-target effects in studies carried out using these cells has not been considered. We hope that our work will stimulate further study of this important phenomenon. [ABSTRACT FROM AUTHOR]

Mutagenicity assays with Salmonella have shown that 3-chloro-4-(dichloromethyl)-5-hydroxy-2[5 H ]-furanone (MX), a drinking-water disinfection by-product, is a potent mutagen, accounting for about one-third of the mutagenic potency/potential of chlorinated drinking water. The ability of MX to induce mutations was investigated in the liver of medaka ( Oryzias latipes ), a small fish model, utilizing the cII transgenic medaka strain that allows detection of in vivo mutations. Methylazoxymethanol acetate (MAMAc), a carcinogen in medaka, served as a positive control. Fish were exposed to MX at 0, 1, 10, or 30 mg/L for 96 h, whereas the MAMAc exposures were for 2 h at 0, 0.1, 1, or 10 mg/L. Both exposures were conducted under static water conditions and with fasted medaka. Following exposure, fish were returned to regular culture conditions to allow mutation expression for 15 or 40 d for MX or for 15 or 32 d for MAMAc. Mutations were not induced in medaka exposed to MX for 96 h. However, a concentration- and time-dependent increase in mutations was observed from the livers of fish exposed to 1 and 10 mg/L MAMAc. In conclusion, mutation induction was not observed in the livers of cII medaka exposed to MX for 96 h; however, studies are planned to examine mutation induction in the gills and skin to explore the possibility that MX-induced DNA damage occurs primarily in the tissues of initial contact. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have linked the consumption of chlorinated surface waters to an increased risk of two major causes of human mortality, colorectal and bladder cancer. Trihalomethanes (THMs) are by-products formed when chlorine is used to disinfect drinking water. The purpose of this study was to examine the ability of the THMs, trichloromethane (TCM), bromodichloromethane (BDCM), dibromochloromethane (DBCM), and tribromomethane (TBM), to induce DNA strand breaks (SB) in (1) CCRF-CEM human lymphoblastic leukemia cells, (2) primary rat hepatocytes (PRH) exposed in vitro, and (3) rats exposed by gavage or drinking water. Methods: DNA SB were measured by the DNA alkaline unwinding assay (DAUA). CCRF-CEM cells were exposed to individual THMs for 2 hr. Half of the cells were immediately analyzed for DNA SB and half were transferred into fresh culture medium and incubated for an additional 22 hr before testing for DNA SB. PRH were exposed to individual THMs for 4 hr then assayed for DNA SB. F344/N rats were exposed to individual THMs for 4 hr, 2 weeks, and to BDCM for 5 wk then tested for DNA SB. Results: CCRF-CEM cells exposed to 5- or 10-mM brominated THMs for 2 hr produced DNA SB. The order of activity was TBM>DBCM>BDCM; TCM was inactive. Following a 22-hr recovery period, all groups had fewer SB except 10-mM DBCM and 1-mM TBM. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB, unassociated with cytotoxicity, were observed in PRH or F344/N rats exposed to individual THMs. Conclusion: CCRF-CEM cells exposed to the brominated THMs at 5 or 10 mM for 2 hr showed a significant increase in DNA SB when compared to control cells. Additionally, CCRF-CEM cells exposed to DBCM and TBM appeared to have compromised DNA repair capacity as demonstrated by an increased amount of DNA SB at 22 hr following exposure. CCRF-CEM cells were found to be positive for the GSTT1-1 gene, however no activity was detected. No DNA SB were observed in PRH or F344/N rats exposed to individual THMs. [ABSTRACT FROM AUTHOR]

A life-time exposure study was conducted to assess the carcinogenicity of bromodichloromethane (BDCM) administered in the drinking water to male F344/N rats and B6C3F[sub 1] mice. In mouse, the calculated mean daily BDCM concentrations (measured concentrations corrected for on-cage loss of chemical) were 0.06, 0.28 and 0.49 g/l. Time-weighted water consumption of 135, 97, and 89 ml/kg/day resulted in mean daily doses of 8.1, 27.2, and 43.4 mg BDCM/kg/day. No changes in feed consumption, final body weight, or survival were observed. Kidney weights were significantly depressed at 27.2 and 43.4 mg BDCM/kg/day. There was no increase in neoplasia in the liver, kidney, spleen, testis, bladder, sections along the alimentary tract, excised lesions, or at any other organ site. In rat, the corrected mean daily BDCM concentrations were 0.06, 0.33, and 0.62 g/l. Time-weighted water consumption of 65, 63, and 59 ml/kg/day yielded 3.9, 20.6 and 36.3 mg BDCM/kg/day. No alterations in feed consumption, body weight gain, and survival were seen. Kidney weight was significantly depressed in the 36.3-mg/kg/day treatment group. There was a significantly enhanced prevalence and multiplicity of hepatocellular adenomas at 3.9 mg BDCM/kg/day (15.5% and 0.16/animal vs. 2.2% and 0.02/animal for the control). Hepatocellular carcinomas increased from 2.2% and 0.02/animal for the control and 3.9 mg BDCM/kg/day to 8.3% and 0.10/animal at 20.6 mg BDCM/kg/day. The combined neoplasms were enhanced at 3.9 and 20.6 mg BDCM/kg/day. Liver neoplasia was depressed to the control value at 36.3 mg BDCM/kg. The prevalence of basophilic and clear cell, but not eosinophilic cells, altered foci of cells declined with increasing dose. BDCM did not increase cancer in the large bowel, renal tubules, or in any of the other tissues examined. Renal tubular hyperplasia was observed at 36.3 mg BDCM/kg (15.8% vs. 8.7% for the control group). Under the conditions of the study, BDCM in the drinking water was not carcinogenic in the male B6C3F[sub 1] mouse, but was carcinogenic in the male F344/N rat based on an increased hepatocellular neoplasia. [ABSTRACT FROM AUTHOR]