Toxicology studies of bromodichloromethane (CAS No. 75-27-4) in genetically modified (FVB Tg.AC Hemizygous) mice (dermal, drinking water, and gavage studies) and carcinogenicity studies of bromodichloromethane in genetically modified [B6.129-Trp53(tm1Brd) (N5) haploinsufficient] mice (drinking water and gavage studies).
Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine and naturally occurring organic matter (e.g., humic or fluvic acids) in water containing bromide. Bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicology and carcinogenicity studies. Male and female Tg.AC hemizygous mice received bromodichloromethane (at least 98%pure) by dermal application for 26 or 39 weeks, in drinking water for 26 or 42 weeks, or by gavage for 26 or 41 weeks. p53 Haploinsufficient mice received bromodichloromethane in drinking water for 26 or 42 weeks or by gavage for 26 or 41 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were dermally administered 0, 64, 128, or 256 mg bromodichloromethane/kg body weight in acetone, 5 days per week for 26 weeks, and groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses 5 days per week for 39 weeks. The survival and mean body and organ weights of all dosed groups of males and females were similar to those of the vehicle controls. There were no statistically or biologically significant increases in the incidences of neoplasms or nonneoplastic lesions. 26- AND 42-WEEK DRINKING WATER STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 20, 36, or 61 mg bromodichloromethane/kg body weight to males and 31, 61, or 130 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls during most of the study. Mean body weights of 175, 350, and 700 mg/L females were greater than those of the controls after weeks 10, 22, and 23, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was less at the beginning of the study, but was similar to that by controls at the end of the study. The decreased water consumption was related to poor palatability. Absolute heart and right kidney weights of exposed males were significantly less than those of the control group. The incidences of hepatocyte fatty change and hypertrophy in 350 and 700 mg/L females and cytoplasmic vacuolization in 700 mg/L females were significantly greater than those in the control group. Incidences of renal tubule dilatation in males exposed to 175 mg/L or greater, renal tubule hypertrophy in 350 and 700 mg/L males, and nephropathy and renal tubule degeneration in 700 mg/L males were also increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 42 weeks (equivalent to average daily doses of approximately 18, 33, or 64 mg/kg to males and 28, 49, or 111 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls at the end of the study. Due to poor palatability, water consumption decreased with increasing exposure concentration. Absolute right kidney weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of hepatocyte fatty change in all exposed groups of females, renal tubule dilatation in all exposed groups of males, and nephropathy in 700 mg/L males were significantly increased. 26- AND 41-WEEK GAVAGE STUDIES IN TG.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage, 5 days per week for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of dosed females were generally greater than those of the vehicle controls at the end of the study. The incidence of multiple squamous cell papilloma of the forestomach in 100 mg/kg females was significantly greater than that in the vehicle controls. The incidences of hepatocyte fatty change in all dosed groups of females, hepatocyte cytoplasmic vacuolization in 25 and 50 mg/kg females, renal tubule hypertrophy in 100 mg/kg females, and renal tubule degeneration in 100 mg/kg males were significantly increased. Groups of 10 male and 10 female Tg.AC hemizygous mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage, 5 days per week for 41 weeks. The survival of dosed males and females was similar to that of the control groups. Mean body weights of 25 mg/kg males and 100 mg/kg females were greater than those of the vehicle controls at the end of the study. The incidences of multiple squamous cell papilloma of the forestomach in 25 and 100 mg/kg females and of all squamous cell papillomas of the forestomach in 100 mg/kg females were significantly greater than those of the vehicle controls. The incidences of hepatocyte cytoplasmic vacuolization in 50 mg/kg females and hepatocyte fatty change in 50 and 100 mg/L females were significantly increased; the incidences of renal tubule degeneration in 100 mg/kg males was also significantly greater than that in the vehicle control group. 26- AND 42-WEEK DRINKING WATER STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L bromodichloromethane for 26 weeks (equivalent to average daily doses of approximately 16, 31, or 65 mg/kg to males and 26, 50, or 100 mg/kg to females). The survival of exposed males and females was similar to that of the control groups. Mean body weights of 350 and 700 mg/L males were less than those of the controls throughout most of the study. Mean body weights of 175, 350, and 700 mg/L females were less than control body weights after weeks 15, 23, and 18, respectively. In exposed males, water consumption declined with increasing exposure concentration. Water consumption by exposed females was similar to that by controls by the end of the study. The absolute heart weight of 700 mg/L males and absolute right kidney and liver weights of 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule dilatation in all exposed groups of males, renal tubule degeneration in 350 and 700 mg/L males, and the incidence of fatty change in hepatocytes of 700 mg/L females were significantly greater than those in the control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were exposed to drinking water containing 0, 175, 350, or 700 mg/L for 42 weeks (equivalent to approximately 14, 30, or 55 mg/kg to males and 22, 43, or 98 mg/kg to females). The survival of exposed males and females was similar to that in the control groups. Mean body weights of males exposed to 350 or 700 mg/L were less than those of the controls. Mean body weights in 700 mg/L females were less during the last three weeks of the study. Water consumption by exposed males was less than that by controls. The absolute right kidney weights in 350 and 700 mg/L males were significantly less than those of the control group. The incidences of renal tubule degeneration in 350 and 700 mg/L males were significantly greater than that in the control group. 26- AND 41-WEEK GAVAGE STUDIES IN P53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg bromodichloromethane/kg body weight in corn oil by gavage for 26 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. The mean body weights of males administered 50 or 100 mg/kg and females administered 50 mg/kg were less than those of the vehicle controls during most of the study. The absolute heart, right kidney, and right testis weights in 100 mg/kg males were significantly less than those of the vehicle controls. The absolute liver weight of 100 mg/kg females was significantly greater. The incidences of fatty change in hepatocytes of 100 mg/kg females and renal tubule degeneration in 100 mg/kg males were significantly greater than those in the vehicle control groups. Groups of 10 male and 10 female p53 haploinsufficient mice were administered 0, 25, 50, or 100 mg/kg in corn oil by gavage for 41 weeks. The survival of dosed males and females was similar to that of the vehicle control groups. Mean body weights of 50 and 100 mg/kg males were less than those of the vehicle controls throughout the study and those of 25, 50, and 100 mg/kg females were less after weeks 9, 14, and 24, respectively. The absolute liver weight of 100 mg/kg females was increased with respect to the vehicle controls, and the absolute heart and right kidney weights of 100 mg/kg males were decreased. The incidences of hepatocyte fatty change in 100 mg/kg males and females and renal tubule degeneration and nephropathy in 100 mg/kg males were significantly greater than those in the vehicle controls.


RESULTS
Peripheral blood micronucleus tests on male and female Tg.AC hemizygous and p53 haploinsufficient mice exposed to bromodichloromethane in drinking water, by dermal application, and by gavage for 26 weeks yielded mixed results but no clearly positive responses. Results in Tg.AC hemizygous mice were judged to be equivocal for both males and females in the drinking water study, equivocal in males and negative in females treated by dermal application, and negative in males and females treated by gavage. (ABSTRACT TRUNCATED)
D000279:Administration, Cutaneous; D000818:Animals; D015197:Carcinogenicity Tests; D005260:Female; D011905:Genes, ras / Q000235:genetics; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D022882:Trihalomethanes / Q000008:administration & dosage / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014874:Water Pollutants, Chemical / Q000008:administration & dosage / Q000633:toxicity*; D014881:Water Supply
D022882:Trihalomethanes; D016159:Tumor Suppressor Protein p53; D014874:Water Pollutants, Chemical; C025191:bromodichloromethane