The Experts below are selected from a list of 270 Experts worldwide ranked by ideXlab platform
Rex A. Pegram - One of the best experts on this subject based on the ideXlab platform.
-
The Impact of Scaling Factor Variability on Risk-Relevant Pharmacokinetic Outcomes in Children: A Case Study Using Bromodichloromethane (BDCM)
Toxicological sciences : an official journal of the Society of Toxicology, 2018Co-Authors: Elaina M. Kenyon, Rex A. Pegram, John C. Lipscomb, Barbara Jane George, Ronald N. HinesAbstract:Biotransformation rates extrapolated from in vitro data are used increasingly in human physiologically based pharmacokinetic (PBPK) models. This practice requires use of scaling factors, including microsomal content (mg of microsomal protein/g liver, MPPGL), enzyme specific content, and liver mass as a fraction of body weight (FVL). Previous analyses indicated that scaling factor variability impacts pharmacokinetic (PK) outcomes used in adult population dose-response studies. This analysis was extended to pediatric populations because large inter-individual differences in enzyme ontogeny likely would further contribute to scaling factor variability. An adult Bromodichloromethane (BDCM) model (Kenyon, E. M., Eklund, C., Leavens, T. L., and Pegram, R. A. (2016a). Development and application of a human PBPK model for Bromodichloromethane (BDCM) to investigate impacts of multi-route exposure. J. Appl. Toxicol. 36, 1095-1111) was re-parameterized for neonates, infants, and toddlers. Monte Carlo analysis was used to assess the impact of pediatric scaling factor variation on model-derived PK outcomes compared with adult findings. BDCM dose metrics were estimated following a single 0.05-liter drink of water or a 20-min bath, under typical (5 µg/l) and plausible higher (20 µg/l) BDCM concentrations. MPPGL, CYP2E1, and FVL values reflected the distribution of reported pediatric population values. The impact of scaling factor variability on PK outcome variation was different for each exposure scenario, but similar for each BDCM water concentration. The higher CYP2E1 expression variability during early childhood was reflected in greater variability in predicted PK outcomes in younger age groups, particularly for the oral exposure route. Sensitivity analysis confirmed the most influential parameter for this variability was CYP2E1, particularly in neonates. These findings demonstrate the importance of age-dependent scaling factor variation used for in vitro to in vivo extrapolation of biotransformation rates.
-
Disposition of Bromodichloromethane in Humans Following Oral and Dermal Exposure
Toxicological sciences : an official journal of the Society of Toxicology, 2007Co-Authors: Teresa L. Leavens, Benjamin C. Blount, David M. Demarini, Michael C. Madden, John L. Valentine, Martin Case, Lalith K. Silva, Sarah H. Warren, Nancy M. Hanley, Rex A. PegramAbstract:Exposure to Bromodichloromethane (BDCM), one of the most prevalent disinfection byproducts in drinking water, can occur via ingestion of water and by dermal absorption and inhalation during activities such as bathing and showering. The objectives of this research were to assess BDCM pharmacokinetics in human volunteers exposed percutaneously and orally to 13 C-BDCM and to evaluate factors that could affect disposition of BDCM. Among study subjects, CYP2E1 activity varied fourfold; 20% had the glutathione S-transferase theta 1-1 homozygous null genotype; and body fat ranged from 7 to 22%. Subjects were exposed to 13 C-BDCM in water (target concentration of 36 μg/l) via ingestion and by forearm submersion. Blood was collected for up to 24 h and analyzed for 13 C-BDCM by solid-phase microextraction and high-resolution GC-MS. Urine was collected before and after exposure for mutagenicity determinations in Salmonella. After ingestion (mean dose = 146 ng/kg), blood 13 C-BDCM concentrations peaked and declined rapidly, returning to levels near or below the limit of detection (LOD) within 4 h. The T max for the oral exposure ranged from 5 to 30 min, and the C max ranged from 0.4 to 4.1 ng/l. After the 1 h dermal exposure (estimated mean dose = 155 ng/kg), blood concentrations of 13 C-BDCM ranged from 39 to 170 ng/l and decreased to levels near or below the LOD by 24 h. Peak postdose urine mutagenicity levels that were at least twice that of the predose mean level occurred in 6 of 10 percutaneously exposed subjects and 3 of 8 orally exposed subjects. These results demonstrate a highly significant contribution of dermal absorption to circulating levels of BDCM and confirm the much lower oral contribution, indicating that water uses involving dermal contact can lead to much greater systemic BDCM doses than water ingestion. These data will facilitate development and validation of physiologically based pharmacokinetic models for BDCM in humans.
-
Effects of Bromodichloromethane on ex vivo and in vitro luteal function and Bromodichloromethane tissue dosimetry in the pregnant F344 rat.
Toxicology in vitro : an international journal published in association with BIBRA, 2007Co-Authors: Susan R. Bielmeier, Rex A. Pegram, Deborah S. Best, Randy A. Harrison, Ashley S. Murr, Jerome M. Goldman, Michael G. NarotskyAbstract:Abstract Bromodichloromethane (BDCM), a drinking water disinfection by-product, causes pregnancy loss, i.e. full-litter resorption, in F344 rats when treated during the luteinizing hormone (LH)-dependent period. This effect is associated with reduced maternal serum progesterone (P) and LH levels, suggesting that BDCM disrupts secretion of LH. To test the hypothesis that BDCM also affects luteal responsiveness to LH, we used ex vivo and in vitro approaches. For the ex vivo study (i.e., in vivo exposure followed by in vitro assessment), dams were dosed by gavage on gestation days (GD) 6–9 (plug day = GD 0) at 0 or 100 mg/kg/d. One hour after the GD-9 dose, rats were killed, blood was collected, and tissue concentrations of BDCM were assessed. Corpora lutea (CL) were incubated with or without hCG, an LH agonist, to stimulate P secretion. For the in vitro study, CL were pooled from untreated F344 rats on GD 9 and cultured with BDCM at 0, 0.01, 0.10 or 3.0 mM. BDCM was found at highest concentrations in adrenal, ovarian, adipose, and hypothalamic tissues. BDCM treatment decreased serum P and LH levels in vivo. Ex vivo, however, BDCM-exposed CL showed >2-fold increases in P secretion relative to controls. Both control and BDCM-exposed CL displayed a 2.4-fold increase in P secretion in response to hCG challenge. In contrast, in vitro exposures reduced CL responsiveness in a dose-related fashion while baseline levels were unaffected. It is unclear if the ex vivo ‘rebound’ reflects the removal of the CL from a possible direct inhibitory influence of BDCM, or a response to diminished LH stimulation in vivo. Thus, these data suggest that BDCM disrupts pregnancy in F344 rats via two modes: disruption of LH secretion, and disruption of the CL’s ability to respond to LH.
-
Bromodichloromethane inhibits human placental trophoblast differentiation.
Toxicological sciences : an official journal of the Society of Toxicology, 2003Co-Authors: Jiangang Chen, Rex A. Pegram, Twanda L. Thirkill, Peter N. Lohstroh, Susan R. Bielmeier, Michael G. Narotsky, Deborah S. Best, Randy A. Harrison, Kala Natarajan, James W. OverstreetAbstract:Epidemiological data suggest an association between exposures to Bromodichloromethane (BDCM), a trihalomethane found in drinking water as a result of drinking water disinfection, and an increased risk of spontaneous abortion. We previously hypothesized that BDCM targets the placenta and showed that the secretion of chorionic gonadotrophin (CG) was reduced in primary cultures of human term syncytiotrophoblasts exposed to BDCM. In the present study we extend this observation by evaluating the effects of BDCM on the morphological differentiation of mononucleated cytotrophoblast cells to multinucleated syncytiotrophoblast-like colonies. Addition of BDCM to cytotrophoblast cultures inhibited the subsequent formation of multinucleated colonies in a dose-dependent manner, as determined by immunocytochemical staining for desmosomes and nuclei. The effect was seen at BDCM concentrations between 0.02 and 2 mM and was confirmed by quantitative image analysis. Secretion of bioactive and immunoreactive chorionic gonadotropin was also significantly inhibited in a dose-dependent manner under these culture conditions, and cellular levels of CG were also reduced. Trophoblast viability was not compromised by exposure to BDCM. We conclude that BDCM disrupts syncytiotrophoblast formation and inhibits CG secretion in vitro. Although other tissue targets are not ruled out, these data substantiate the idea that BDCM targets the placenta and could have implications for understanding the adverse pregnancy outcomes associated with BDCM exposure in humans.
-
Effect of Bromodichloromethane on Chorionic Gonadotrophin Secretion by Human Placental Trophoblast Cultures
Toxicological sciences : an official journal of the Society of Toxicology, 2003Co-Authors: Jiangang Chen, Twanda L. Thirkill, Peter N. Lohstroh, Susan R. Bielmeier, Michael G. Narotsky, Deborah S. Best, Randy A. Harrison, Kala Natarajan, Gordon C. Douglas, Rex A. PegramAbstract:Bromodichloromethane (BDCM) is a trihalomethane found in drinking water as a by-product of disinfection processes. BDCM is hepatotoxic and nephrotoxic in rodents and has been reported to cause strain-specific full-litter resorption in F344 rats during the luteinizing hormone-dependent phase of pregnancy. In humans, epidemiological studies suggest an association between exposure to BDCM in drinking water and increased risk of spontaneous abortion. To begin to address the mechanism(s) of BDCM-induced spontaneous abortion, we hypothesized that BDCM targets the placenta. Primary cultures of human term trophoblast cells were used as an in vitro model to test this hypothesis. Trophoblasts were allowed to differentiate into multinucleated syncytiotrophoblast-like colonies, after which they were incubated for 24 h with different concentrations of BDCM (20 nM to 2 mM). Culture media were collected and assayed for immunoreactive and bioactive chorionic gonadotropin (CG). Cultures exposed to BDCM showed a dose-dependent decrease in the secretion of immunoreactive CG as well as bioactive CG. The lowest effective BDCM concentration was 20 nM, approximately 35-times higher than the maximum concentration reported in human blood (0.57 nM). Trophoblast morphology and viability were similar in controls and cultures exposed to BDCM. We conclude that BDCM perturbs CG secretion by differentiated trophoblasts in vitro. This suggests that the placenta is a likely target of BDCM toxicity in the human and that this could be related to the adverse pregnancy outcomes associated with BDCM.
Matthew K Ross - One of the best experts on this subject based on the ideXlab platform.
-
Glutathione transferase theta 1-1-dependent metabolism of the water disinfection byproduct Bromodichloromethane.
Chemical Research in Toxicology, 2003Co-Authors: Matthew K Ross, Rex A. PegramAbstract:Bromodichloromethane (CHBrCl 2 ), a prevalent drinking water disinfection byproduct, was previously shown to be mutagenic in Salmonella that express rat GSH transferase (GST) theta 1-1 (GST T1-1). In the present study, in vitro experiments were performed to study the kinetics of CHBrCl 2 reactions mediated by GST in different species as well as the isoform specificity and reaction products of the GST pathway. Conjugation activity of CHBrCl 2 with GSH in mouse liver cytosol was time- and protein-dependent, was not inhibited by the GST a, μ, and π inhibitor S-hexyl-GSH, and correlated with GST T1-1 activity toward the substrate 1,2-epoxy-3-(4'-nitrophenoxy)propane. Conjugation activities in hepatic cytosols of different species toward CHBrCl 2 followed the order mouse > rat > human. As compared with CH 2 Cl 2 , the catalytic efficiency (k c a t /K m ) of conjugation of CHBrCl 2 with GSH by pure recombinant rat GST T1-1 was ∼3-6-fold less. Taken together, this suggests that GST T1-1 is the primary catalyst for conjugation of CHBrCl 2 with GSH and that flux through this pathway is less than for CH 2 Cl 2 . The initial GSCHCl 2 conjugate formed was unstable and degraded to several metabolites, including GSCH 2 OH, S-formyl-GSH, and HCOOH. Addition of NAD + to cytosol did not alter the rate of conjugation of CHBrCl 2 with GSH; however, it did increase the amount of [ 1 4 C]-HCOOH produced (∼10-fold). A similar result was seen in a reaction containing pure rat GST T1-1 and GSH-dependent formaldehyde dehydrogenase, indicating that GSCH 2 OH was formed as a precursor to S-formyl-GSH. The half-life of synthetic S-formyl-GSH in pH 7,4 buffer was ∼1 h at ambient temperature and decreased to ∼7 min in pH 9.0 buffer, and it does not react with deoxyguanosine. In conclusion, GST T1-1 conjugation of CHBrCl 2 has been definitively demonstrated and the kinetics of conjugation of CHBrCl 2 with GSH characterized in mouse, rat, and human hepatic cytosols. The significance of this GST pathway is that reactive GSH conjugates are produced resulting in possible formation of DNA adducts. Comparisons with CH 2 Cl 2 suggest that the reactive intermediates specific to GSH conjugation of CHBrCl 2 are more mutagenic/genotoxic than those derived from CH 2 Cl 2 .
-
glutathione transferase theta 1 1 dependent metabolism of the water disinfection byproduct Bromodichloromethane
Chemical Research in Toxicology, 2003Co-Authors: Matthew K Ross, Rex A. PegramAbstract:Bromodichloromethane (CHBrCl(2)), a prevalent drinking water disinfection byproduct, was previously shown to be mutagenic in Salmonella that express rat GSH transferase (GST) theta 1-1 (GST T1-1). In the present study, in vitro experiments were performed to study the kinetics of CHBrCl(2) reactions mediated by GST in different species as well as the isoform specificity and reaction products of the GST pathway. Conjugation activity of CHBrCl(2) with GSH in mouse liver cytosol was time- and protein-dependent, was not inhibited by the GST alpha, mu and pi inhibitor S-hexyl-GSH, and correlated with GST T1-1 activity toward the substrate 1,2-epoxy-3-(4'-nitrophenoxy)propane. Conjugation activities in hepatic cytosols of different species toward CHBrCl(2) followed the order mouse > rat > human. As compared with CH(2)Cl(2), the catalytic efficiency (k(cat)/K(m)) of conjugation of CHBrCl(2) with GSH by pure recombinant rat GST T1-1 was approximately 3-6-fold less. Taken together, this suggests that GST T1-1 is the primary catalyst for conjugation of CHBrCl(2) with GSH and that flux through this pathway is less than for CH(2)Cl(2). The initial GSCHCl(2) conjugate formed was unstable and degraded to several metabolites, including GSCH(2)OH, S-formyl-GSH, and HCOOH. Addition of NAD(+) to cytosol did not alter the rate of conjugation of CHBrCl(2) with GSH; however, it did increase the amount of [(14)C]HCOOH produced ( approximately 10-fold). A similar result was seen in a reaction containing pure rat GST T1-1 and GSH-dependent formaldehyde dehydrogenase, indicating that GSCH(2)OH was formed as a precursor to S-formyl-GSH. The half-life of synthetic S-formyl-GSH in pH 7.4 buffer was approximately 1 h at ambient temperature and decreased to approximately 7 min in pH 9.0 buffer, and it does not react with deoxyguanosine. In conclusion, GST T1-1 conjugation of CHBrCl(2) has been definitively demonstrated and the kinetics of conjugation of CHBrCl(2) with GSH characterized in mouse, rat, and human hepatic cytosols. The significance of this GST pathway is that reactive GSH conjugates are produced resulting in possible formation of DNA adducts. Comparisons with CH(2)Cl(2) suggest that the reactive intermediates specific to GSH conjugation of CHBrCl(2) are more mutagenic/genotoxic than those derived from CH(2)Cl(2).
Byron E Butterworth - One of the best experts on this subject based on the ideXlab platform.
-
Induction of micronuclei in wild-type and p53(+/-) transgenic mice by inhaled Bromodichloromethane.
Mutation research, 2002Co-Authors: Vincent R Torti, Alison J Cobb, Victoria A Wong, Byron E ButterworthAbstract:Bromodichloromethane (BDCM) is commonly present in trace amounts in drinking water as a disinfection by-product. BDCM has been shown to be carcinogenic in mice and rats when given by gavage at relatively high doses. Genotoxic activity as well as induced regenerative cell proliferation may contribute to the carcinogenic potential of BDCM. The purpose of the current studies was to evaluate the ability of BDCM to induce micronuclei (MN) in bone marrow and blood of wild-type and p53(+/-) mice on the C57BL/6 and FVB/N genetic backgrounds using the inhalation route of exposure. Toxicity studies were being conducted in this laboratory with inhaled BDCM to select doses for longer-term cancer bioassays using wild-type and p53(+/-) transgenic mice on different genetic backgrounds. Bone marrow samples from these experiments were evaluated for the induction of MN after 1 and 3 weeks of exposure. Accumulation of MN in the peripheral blood was also evaluated at the 13-week time point of a cancer study with the p53(+/-) mice. For the 1-week time point, male C57BL/6 wild-type and p53(+/-) mice and FVB/N wild-type and p53(+/-) mice were exposed daily for 6h per day for 7 consecutive days to atmospheric BDCM concentrations of 0, 1, 10, 30, 100, or 150 ppm. In a second experiment, mice were exposed daily for 6h per day for 3 weeks to atmospheric BDCM concentrations of 0, 0.5, 1, 3, 10, or 30 ppm. Resulting levels of polychromatic erythrocytes (PCE) containing MN were assessed in the bone marrow. For all of the 1- and 3-week exposure groups, the only statistically significant increase in the percentage of bone marrow PCE cells containing MN was in the 1-week 100 ppm BDCM exposure group in the FVB/N wild-type mice (control 0.26% versus exposed 1.16%). C57BL/6 p53(+/-) mice and FVB/N p53(+/-) mice were exposed daily for 6 h per day for 13 weeks to atmospheric BDCM concentrations of 0, 0.5, 3, 10, or 15 ppm. MN were quantified in samples of peripheral blood. Statistically significant increases in the percentage of peripheral blood NCE cells containing MN were seen at the highest BDCM exposure group of 15 ppm in both the C57BL/6 p53(+/-) strain (control 0.36% versus exposed 0.67%) and the FVB/N p53(+/-) strain (control 0.36% versus exposed 0.86%). These data indicate weak induction of MN by BDCM, but only at high atmospheric concentrations relative to normal environmental exposures and with extended periods of exposure. Although comparisons are difficult because responses were negative or marginal, the p53 genotype or the genetic background did not appear to substantially alter susceptibility to the genotoxic effects of BDCM.
-
induction of micronuclei in wild type and p53 transgenic mice by inhaled Bromodichloromethane
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2002Co-Authors: Vincent R Torti, Alison J Cobb, Victoria A Wong, Byron E ButterworthAbstract:Bromodichloromethane (BDCM) is commonly present in trace amounts in drinking water as a disinfection by-product. BDCM has been shown to be carcinogenic in mice and rats when given by gavage at relatively high doses. Genotoxic activity as well as induced regenerative cell proliferation may contribute to the carcinogenic potential of BDCM. The purpose of the current studies was to evaluate the ability of BDCM to induce micronuclei (MN) in bone marrow and blood of wild-type and p53(+/-) mice on the C57BL/6 and FVB/N genetic backgrounds using the inhalation route of exposure. Toxicity studies were being conducted in this laboratory with inhaled BDCM to select doses for longer-term cancer bioassays using wild-type and p53(+/-) transgenic mice on different genetic backgrounds. Bone marrow samples from these experiments were evaluated for the induction of MN after 1 and 3 weeks of exposure. Accumulation of MN in the peripheral blood was also evaluated at the 13-week time point of a cancer study with the p53(+/-) mice. For the 1-week time point, male C57BL/6 wild-type and p53(+/-) mice and FVB/N wild-type and p53(+/-) mice were exposed daily for 6h per day for 7 consecutive days to atmospheric BDCM concentrations of 0, 1, 10, 30, 100, or 150 ppm. In a second experiment, mice were exposed daily for 6h per day for 3 weeks to atmospheric BDCM concentrations of 0, 0.5, 1, 3, 10, or 30 ppm. Resulting levels of polychromatic erythrocytes (PCE) containing MN were assessed in the bone marrow. For all of the 1- and 3-week exposure groups, the only statistically significant increase in the percentage of bone marrow PCE cells containing MN was in the 1-week 100 ppm BDCM exposure group in the FVB/N wild-type mice (control 0.26% versus exposed 1.16%). C57BL/6 p53(+/-) mice and FVB/N p53(+/-) mice were exposed daily for 6 h per day for 13 weeks to atmospheric BDCM concentrations of 0, 0.5, 3, 10, or 15 ppm. MN were quantified in samples of peripheral blood. Statistically significant increases in the percentage of peripheral blood NCE cells containing MN were seen at the highest BDCM exposure group of 15 ppm in both the C57BL/6 p53(+/-) strain (control 0.36% versus exposed 0.67%) and the FVB/N p53(+/-) strain (control 0.36% versus exposed 0.86%). These data indicate weak induction of MN by BDCM, but only at high atmospheric concentrations relative to normal environmental exposures and with extended periods of exposure. Although comparisons are difficult because responses were negative or marginal, the p53 genotype or the genetic background did not appear to substantially alter susceptibility to the genotoxic effects of BDCM.
Heinz Klöser - One of the best experts on this subject based on the ideXlab platform.
-
Antarctic macroalgae — Sources of volatile halogenated organic compounds
Marine Environmental Research, 1999Co-Authors: Frank Laturnus, Christian Wiencke, Heinz KlöserAbstract:Abstract Twenty-eight different species of Antarctic macroalgae were collected from December 1991 to February 1992 at King George Island, South Shetlands, and investigated for their release of volatile halogenated organic compounds (VHOCs). Dibromomethane, bromoform, dibromochloromethane, Bromodichloromethane, diiodomethane and chloroiodomethane were identified and their rates of release determined. For the first time the release of 1,2-dibromoethane from macroalgae is reported. Of all compounds investigated, bromoform is released in very high rates from all species studied, with the highest release rates from the brown algae Desmarestia anceps (3.9 μg g−1 wet algal weight d−1), Desmarestia menziesii (1.3 μg g−1 wet algal weight d−1), Cystosphaera jacquinotii (0.84 μg g−1 wet algal weight d−1) and Himantothallus grandifolius (0.3 μg g−1 wet algal weight d−1). Dibromomethane, diiodomethane, dibromochloromethane and 1,2-dibromoethane were also major compounds, but released at lower rates. Release rates of Bromodichloromethane and chloroiodomethane were very low for most species. Release of VHOCs occurred from all parts of the thallus of the macroalga. The highest rates were measured in species with a high surface-to-volume ratio. This indicates the formation of VHOC in photosynthetically and metabolically active cortex (surface located) cells. The biological role of these substances and their input into the Antarctic environment is discussed.
Vincent R Torti - One of the best experts on this subject based on the ideXlab platform.
-
Induction of micronuclei in wild-type and p53(+/-) transgenic mice by inhaled Bromodichloromethane.
Mutation research, 2002Co-Authors: Vincent R Torti, Alison J Cobb, Victoria A Wong, Byron E ButterworthAbstract:Bromodichloromethane (BDCM) is commonly present in trace amounts in drinking water as a disinfection by-product. BDCM has been shown to be carcinogenic in mice and rats when given by gavage at relatively high doses. Genotoxic activity as well as induced regenerative cell proliferation may contribute to the carcinogenic potential of BDCM. The purpose of the current studies was to evaluate the ability of BDCM to induce micronuclei (MN) in bone marrow and blood of wild-type and p53(+/-) mice on the C57BL/6 and FVB/N genetic backgrounds using the inhalation route of exposure. Toxicity studies were being conducted in this laboratory with inhaled BDCM to select doses for longer-term cancer bioassays using wild-type and p53(+/-) transgenic mice on different genetic backgrounds. Bone marrow samples from these experiments were evaluated for the induction of MN after 1 and 3 weeks of exposure. Accumulation of MN in the peripheral blood was also evaluated at the 13-week time point of a cancer study with the p53(+/-) mice. For the 1-week time point, male C57BL/6 wild-type and p53(+/-) mice and FVB/N wild-type and p53(+/-) mice were exposed daily for 6h per day for 7 consecutive days to atmospheric BDCM concentrations of 0, 1, 10, 30, 100, or 150 ppm. In a second experiment, mice were exposed daily for 6h per day for 3 weeks to atmospheric BDCM concentrations of 0, 0.5, 1, 3, 10, or 30 ppm. Resulting levels of polychromatic erythrocytes (PCE) containing MN were assessed in the bone marrow. For all of the 1- and 3-week exposure groups, the only statistically significant increase in the percentage of bone marrow PCE cells containing MN was in the 1-week 100 ppm BDCM exposure group in the FVB/N wild-type mice (control 0.26% versus exposed 1.16%). C57BL/6 p53(+/-) mice and FVB/N p53(+/-) mice were exposed daily for 6 h per day for 13 weeks to atmospheric BDCM concentrations of 0, 0.5, 3, 10, or 15 ppm. MN were quantified in samples of peripheral blood. Statistically significant increases in the percentage of peripheral blood NCE cells containing MN were seen at the highest BDCM exposure group of 15 ppm in both the C57BL/6 p53(+/-) strain (control 0.36% versus exposed 0.67%) and the FVB/N p53(+/-) strain (control 0.36% versus exposed 0.86%). These data indicate weak induction of MN by BDCM, but only at high atmospheric concentrations relative to normal environmental exposures and with extended periods of exposure. Although comparisons are difficult because responses were negative or marginal, the p53 genotype or the genetic background did not appear to substantially alter susceptibility to the genotoxic effects of BDCM.
-
induction of micronuclei in wild type and p53 transgenic mice by inhaled Bromodichloromethane
Mutation Research-genetic Toxicology and Environmental Mutagenesis, 2002Co-Authors: Vincent R Torti, Alison J Cobb, Victoria A Wong, Byron E ButterworthAbstract:Bromodichloromethane (BDCM) is commonly present in trace amounts in drinking water as a disinfection by-product. BDCM has been shown to be carcinogenic in mice and rats when given by gavage at relatively high doses. Genotoxic activity as well as induced regenerative cell proliferation may contribute to the carcinogenic potential of BDCM. The purpose of the current studies was to evaluate the ability of BDCM to induce micronuclei (MN) in bone marrow and blood of wild-type and p53(+/-) mice on the C57BL/6 and FVB/N genetic backgrounds using the inhalation route of exposure. Toxicity studies were being conducted in this laboratory with inhaled BDCM to select doses for longer-term cancer bioassays using wild-type and p53(+/-) transgenic mice on different genetic backgrounds. Bone marrow samples from these experiments were evaluated for the induction of MN after 1 and 3 weeks of exposure. Accumulation of MN in the peripheral blood was also evaluated at the 13-week time point of a cancer study with the p53(+/-) mice. For the 1-week time point, male C57BL/6 wild-type and p53(+/-) mice and FVB/N wild-type and p53(+/-) mice were exposed daily for 6h per day for 7 consecutive days to atmospheric BDCM concentrations of 0, 1, 10, 30, 100, or 150 ppm. In a second experiment, mice were exposed daily for 6h per day for 3 weeks to atmospheric BDCM concentrations of 0, 0.5, 1, 3, 10, or 30 ppm. Resulting levels of polychromatic erythrocytes (PCE) containing MN were assessed in the bone marrow. For all of the 1- and 3-week exposure groups, the only statistically significant increase in the percentage of bone marrow PCE cells containing MN was in the 1-week 100 ppm BDCM exposure group in the FVB/N wild-type mice (control 0.26% versus exposed 1.16%). C57BL/6 p53(+/-) mice and FVB/N p53(+/-) mice were exposed daily for 6 h per day for 13 weeks to atmospheric BDCM concentrations of 0, 0.5, 3, 10, or 15 ppm. MN were quantified in samples of peripheral blood. Statistically significant increases in the percentage of peripheral blood NCE cells containing MN were seen at the highest BDCM exposure group of 15 ppm in both the C57BL/6 p53(+/-) strain (control 0.36% versus exposed 0.67%) and the FVB/N p53(+/-) strain (control 0.36% versus exposed 0.86%). These data indicate weak induction of MN by BDCM, but only at high atmospheric concentrations relative to normal environmental exposures and with extended periods of exposure. Although comparisons are difficult because responses were negative or marginal, the p53 genotype or the genetic background did not appear to substantially alter susceptibility to the genotoxic effects of BDCM.
