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B L Van Duuren

Publications and source records attributed to B L Van Duuren.

At least 19 recordsLinked to original sources
PubMed1989

Comparison of potency of human carcinogens: vinyl chloride, chloromethylmethyl ether and bis(chloromethyl)ether.

The alpha-chloroether carcinogen chloromethylmethyl ether (CME) and its impurity bis(chloromethyl)ether (BCME) are direct-acting alkylating agents. Vinyl chloride (VC) is an indirect-acting carcinogen but its accepted carcinogenic intermediate, chloroethylene oxide, is also an alpha-chloroether. Both CME-BCME and VC have been in industrial use since about 1950. Hence, they were selected for comparison of potency as human carcinogens using numerous epidemiologic reports. There were 115 deaths due to angiosarcoma of the liver among several hundred thousand VC-exposed workers on the basis of reports from 10 countries during 1955 and 1984. Reports from five countries cited a total of 87 respiratory cancer deaths among only 3024 CME-BCME-exposed workers. If a recent court settlement in the United States is taken into account, the number of respiratory cancer deaths due to CME-BCME rises to 117. On the basis of these numbers of cancer deaths, and the levels and durations of exposure, it is concluded that VC is a weak human carcinogen compared to CME-BCME.

Animals↗
PubMed1989

Evidence for the covalent interaction of carbon tetrachloride with mouse liver chromatin DNA in vitro.

Whole chromatin was isolated from livers of 8-12 week-old male B6C3Fl hybrid mice and incubated with 14C-labelled carbon tetrachloride (14CCL4) in the presence of hepatic microsomes from the same animals and an NADPH-regenerating system. The experiments were carried out at various concentrations of 14CCl4 and incubation times. Under the conditions used, 14CCl4 metabolite(s) bind quantifiably to chromatin DNA (ch.DNA) in direct response to increases in 14CCl4 concentration and incubation time. Maximal binding (0.34 nmoles/mg DNA) occurs at 2 hrs when 10 umoles 14CCl4 was used for the incubation. Binding of 14CCl4 metabolite(s) to ch.DNA was/were significantly inhibited (84%) in the presence of the strong nucleophile, L-cysteine (5 mM). These results provide evidence for the covalent interaction of CCl4 metabolite(s) with DNA when organized as chromatin under aerobic incubation condition, which suggest the importance of the higher-order organization of DNA in chromatin and its reactivity with CCl4 metabolite(s).

Animals↗
PubMed1987

Distribution of carbon tetrachloride-metabolite(s) to DNase I-sensitive and -resistant chromatin.

The distribution of carbon tetrachloride (CCl4) metabolite(s) to DNase I-sensitive and -resistant regions of mouse hepatic chromatin was determined following incubation of whole chromatin with [14C]CCl4 in the presence of hepatic microsomes and an NADPH-regenerating system. At 2 h of incubation, [14C]CCl4 metabolite(s) bound essentially to the same extent to DNase I-sensitive and -resistant chromatin regions. Binding of [14C]CCl4 metabolite(s) to DNase I-resistant regions, however, increased significantly over the DNase I-sensitive regions when incubation was prolonged to 4 h. This result suggests that CCl4 does not bind preferentially to DNase I-sensitive regions of chromatin.

Biotransformation↗
PubMed1987

Time-related binding of the hepatocarcinogen carbon tetrachloride to hepatic chromatin proteins in vitro.

The in vitro covalent binding of 14C-labelled carbon tetrachloride [14C]CCl4 to histones and non-histone chromosomal proteins (NHCP) under microsome-mediated aerobic conditions was determined. Whole chromatin was prepared from purified nuclei isolated from livers of B6C3F1 hybrid mice and incubated with 2.5, 5.0 and 10.0 mumol [14C]CCl4 in the presence of microsomes isolated from the same tissue, at 4 mg protein, and an NADPH-regenerating system at 37 degrees C for varying incubation times. Binding of [14C]CCl4 to histones and NHCP was also determined in the presence of 5 mM L-cysteine. The results show that the activated intermediate of CCl4 bound more to histones than to NHCP in a dose- and time-dependent manner, and that 5 mM L-cysteine inhibited the binding of the activated intermediate of CCl4 to histones by 59%, without affecting the binding to NHCP. These data suggest different extents of alkylation or acylation between histones and NHCP by metabolically activated CCl4 under aerobic in vitro conditions, and differential inhibition of CCl4-alkylation-acylation by cysteine. This suggestion does not exclude other possible mechanisms of action.

Animals↗
PubMed1986

Spontaneous tumors in SENCAR mice.

A total of 305 female and 36 male SENCAR mice in six different groups were observed for 540 to 875 days for tumors as well as nonneoplastic lesions. Three of these groups were observed for their lifespans. The 123 females and 36 males, observed for their lifespans (800 to 875 days) showed median survival times ranging from 730 to 745 days. The average peak body weights were 42.4 g for females and 50.0 g for males. In the animals observed for their lifespans, the total tumor incidence was 65.6% for females and 69.4% for males. Both sexes showed a high incidence of papillary tumors of the lung, 16 to 39%, which was independent of aging. Females showed a 5.1 to 21.0% incidence of mammary tumors, which increased with age. Males showed a high incidence of hyperplastic nodules of the liver, i.e., 12 of 36 animals. Other frequently occurring tumors were leukemia and papillomas of the forestomach.

Animals↗
PubMed1986

Phorbol myristate acetate and catechol as skin cocarcinogens in SENCAR mice.

The enhancement of the carcinogenicity of benzo(a)pyrene (B[a]P) and beta-propiolactone (BPL) by the mouse skin cocarcinogens phorbol myristate acetate (PMA) and catechol were examined in female SENCAR mice, 30 per group. The carcinogen and cocarcinogen were applied simultaneously, three times weekly for 490-560 days. B(a)P and BPL were used at constant doses of 5 and 50 micrograms, respectively, in all experiments. PMA was used at three doses, 2.5, 1.0, and 0.5 micrograms per application, and catechol was used at one dose, 2 mg per application. Control groups included animals that received carcinogen only, cocarcinogen only, acetone only, and no treatment. The carcinogenicity of B(a)P and BPL were enhanced by the cocarcinogens, particularly in terms of tumor multiplicity. For both carcinogens, the most marked cocarcinogenic effects were observed at the lowest dose of PMA used (0.5 microgram per application). This observation applied for days to first tumor, animals with tumors, tumor multiplicity, and incidence of malignant skin tumors. Catechol applied alone did not induce any tumors; with PMA alone there were significant incidences of benign and malignant tumors, e.g., at a dose of only 0.5 microgram per application, 15 of 30 animals had 28 tumors, 5 of which were squamous carcinomas. In two-stage carcinogenesis experiments with 7,12-dimethylbenz(a)anthracene (DMBA) as initiator and PMA as promoter, SENCAR mice showed a greater susceptibility to tumor induction when compared to ICR/Ha mice used in earlier work. This susceptibility was most notable in terms of rate of tumor appearance and tumor multiplicity.

Animals↗
PubMed1986

Chronic bioassays of chlorinated humic acids in B6C3F1 mice.

Humic acids (Fluka), chlorinated to carbon:chlorine (C:Cl) ratios of 1:1 and 1:0.3, were administered to B6C3F1 mice, 50 males and 50 females per group, in the drinking water at a total organic carbon (TOC) level of 0.5 g/L. The mice were 6 to 8 weeks old at the beginning of the bioassays. The doses used were based on short-term (8 weeks) evaluations for toxicity, palatability, and weight gain. The chronic bioassays included the following control groups: unchlorinated humic acids (0.5 g/L), no-treatment (100 males and 100 females), dibromoethane (DBE, 2.0 mM in drinking water; positive control) and 0.44% sodium chloride in drinking water, i.e., at the same concentration as those receiving chlorinated humic acids. The chlorinated humic acids were prepared freshly and chemically assayed once per week. All chemicals were, with the exception of DBE, administered for 24 months; DBE was administered for 18 months. The volumes of solutions consumed were measured once weekly. All treatment groups showed normal weight gain except the DBE group. At the completion of exposure, the animals were sacrificed and necropsied, and tissue sections were taken for histopathology. No markedly significant increases in tumor incidences were evident in any of the organs and tissues examined in the chlorinated humic acid groups compared to unchlorinated humic acids and the no-treatment control groups. DBE caused the expected high incidence of squamous carcinomas of the forestomach. The chlorinated humic acids tested contained direct-acting alkylating agents, based on their reactivity with p-nitrobenzylpyridine (PNBP), and showed mutagenic activity in S. typhimurium.

Alkylation↗
PubMed1985

Carcinogenicity bioassays of bromoacetaldehyde and bromoethanol--potential metabolites of dibromoethane.

1,2-Dibromoethane (DBE) and two of its potential metabolites, bromoethanol (BE) and bromoacetaldehyde (BA), were tested for carcinogenicity in male and female B6C3F1 mice using 30 animals of each sex per group. The carcinogen DBE was included in this assay as a positive control. The compounds were administered in distilled drinking water using equimolar concentrations, 4 mmol, of the chemicals. The dose chosen was based on subchronic bioassays of three months' duration. The chronic tests were continued for approximately 450 days in the case of DBE and approximately 560 days for both BE and BA. DBE induced squamous carcinomas of the forestomach in 22 females and 26 males and squamous papillomas of the esophagus in 3 females. BE induced squamous papillomas of the forestomach only in 10 females and 9 males. BA did not induce a significant incidence of tumors of the forestomach. Significant tumor incidences at other sites were not observed in any groups including the distilled water control group. Based on these findings, it is unlikely that BE or BA are activated carcinogenic intermediates of DBE.

Acetaldehyde↗
PubMed1985

Cocarcinogenesis in vitro using Balb/3T3 cells and aromatic hydrocarbon cocarcinogens.

The mouse skin cocarcinogens fluoranthene, pyrene, and undecane were used with the indirect-acting carcinogen, benzo(a)pyrene (BP), and the direct-acting alkylating carcinogen, beta-propiolactone (BPL), in an in vitro transformation assay. Dose response, cytotoxicity, and transformation studies with these compounds were performed with a subclone (A31-1-1) of the Balb/3T3 cell line. Transformation frequencies were found to increase with increasing concentrations of BP used up to 1.0 micrograms/ml or when BPL was used up to 4.0 micrograms/ml. A significant increase (P less than 0.05) in the transformation frequency over that seen with carcinogen alone was observed when cells were exposed to a combination of fluoranthene (4.0 micrograms/ml) and BP (0.063 micrograms/ml) or pyrene (5.0 micrograms/ml) and BP (0.063 micrograms/ml). Thus, the transformation frequency obtained with BP + fluoranthene was 3.8 x 10(-4) compared to 1.2 x 10(-4) when BP was tested alone. Similarly, the transformation frequency using BP + pyrene was 2.8 x 10(-4) vs. 1.2 x 10(-4) when BP was tested alone. Undecane did not exert any cocarcinogenic effect with BP in the dose range tested. In this in vitro assay, no cocarcinogenic effect was observed when BPL was used with any of the above mouse skin cocarcinogens. All cells isolated from transformed foci showed characteristics of transformed cells including anchorage-independent growth.

Alkanes↗
PubMed1983

Evidence for binding of metabolically activated 1,2-dibromoethane to chromatin of forestomach and liver.

The covalent binding of metabolically activated 1,2-dibromoethane (DBE), a potent carcinogen, to chromatin constituents of forestomach and liver was examined in vitro. Chromatin was prepared from forestomach and liver of B6C3F1 mice and characterized. In order to activate DBE, microsomes and cytosol were isolated from mouse forestomach and liver and incubated with [14C]-DBE in the presence of a NADPH regenerating system. Results demonstrate that DBE bound covalently to the same extent to protein of microsomes and chromatin isolated from forestomach and liver. On the contrary, DBE bound significantly more to chromatin DNA of forestomach or liver than it did to salmon sperm DNA. It appears from these results that the metabolically activated DBE is more reactive to homologous DNA than exogenous DNA. Fractionation of DBE-bound chromatin protein into histone and nonhistone proteins resulted in higher binding of DBE to nonhistone than to histone proteins isolated from forestomach and liver.

Animals↗
PubMed1983

Chemical structure and carcinogenicity relationships of some chloroalkene oxides and their parent olefins.

Six epoxides of structurally related chloroalkenes were examined for their carcinogenicity by chronic testing in female ICR/Ha Swiss mice, 30/group. Repeated skin application three times weekly or s.c. injection once weekly were used for the life spans of the mice. The epoxides were: cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1,3-dichloropropene oxide, trans-1,3-dichloropropene oxide, trichloroethylene oxide (TCEO), and tetrachloroethylene oxide (PCEO). In mouse skin, cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1-,3-dichloropropene oxide, and trans-1,3-dichloropropene oxide induced statistically significant incidences of squamous carcinomas of the skin; TCEO did not cause any skin tumors; and PCEO resulted in three mice with benign skin tumors and one with a squamous carcinoma of the skin. Repeated s.c. injection of the four propene oxides induced statistically significant incidences of local tumors, mostly fibrosarcomas. This was not the case with TCEO and PCEO. The data are consistent with the carcinogenicity findings on the parent chloropropenes and suggest that the epoxides function as their activated carcinogenic intermediates. The essentially negative findings with TCEO and PCEO suggest further studies on the carcinogenicity of trichloroethylene and tetrachloroethylene.

Administration, Topical↗
PubMed1982

Formation of 6-dimethylcarbamyloxy-dGuo, 6-dimethylamino-dGuo and 4-dimethylamino-dThd following in vitro reaction of dimethylcarbamyl chloride with calf thymus DNA and 6-diethylcarbamyloxy-dGuo following in vitro reaction of diethylcarbamyl chloride with calf thymus DNA.

The rodent carcinogens dimethylcarbamyl chloride (DMCC) and diethylcarbamyl chloride (DECC) react with dGuo (pH 7.0-7.5, 37 degrees C, 4 h) to form the O6-acyl derivatives 6-dimethylcarbamyloxy-2'-deoxyguanosine (6-DMC-dGuo) and 6-diethylcarbamyloxy-2'-deoxyguanosine (6-DEC-dGuo), respectively. Reaction of DMCC with dThd under identical conditions yielded 4-dimethylamino-thymidine (4-DMA-dThd). Compounds 6-DMC-dGuo and 6-DEC-dGuo undergo a nucleophilic aromatic substitution reaction with dimethylamine (DMA) to form 6-dimethylamino-2'-deoxyguanosine (6-DMA-dGuo) via displacement of the C-6 dialkylcarbamyloxy moiety. The substitution reaction did not take place when diethylamine or NH3 were substituted for DMA. The structures of the new compounds 6-DMC-dGuo, 6-DEC-dGuo, 4-DMA-dThd and 6-DMA-dGuo were deduced from chemical analyses and syntheses, UV and nuclear magnetic resonance (NMR) spectra and electron impact, isobutane chemical ionization and source insertion isobutane chemical ionization mass spectra. It was postulated that 4-DMA-dThd was formed following reaction of the transient intermediate 4-DMC-dThd with DMA formed by hydrolysis of DMCC. Calf thymus DNA was reacted in vitro with DMCC (pH 7.0-7.5, 37 degrees C, 4 h) and the modified DNA hydrolyzed enzymatically to 2'-deoxynucleosides. Compounds 6-DMC-dGuo, 4-DMA-dThd and 6-DMA-dGuo were identified in the hydrolysate by high-pressure liquid chromatography (HPLC). In an identical manner 6-DEC-dGuo was identified following in vitro reaction of DECC with calf thymus DNA. Compounds 6-DEC-dGuo and 6-DMC-dGuo possess novel structures with respect to the types of adducts known to be formed between carcinogens and bases in DNA. The implications of these findings with respect to chemical mutagenesis and carcinogenesis is discussed. The structural relationship between N4-dimethyl-5-methylcytosine (4-dimethylamino-Thy) formed in DNA following in vitro reaction with DMCC and 5-methylcytosine, the only modified base found in vertebrate DNA is noted.

Animals↗
PubMed1982

Mutagenicity of chloroalkene epoxides in bacterial systems.

6 alpha-chloroepoxides have been tested for in vitro activity in a variety of systems. The epoxides were cis- and trans-1-chloropropene oxide, cis- and trans-1,3-dichloropropene oxide, trichloroethylene oxide and tetrachloroethylene oxide. The epoxides were assayed for mutagenicity in the absence of metabolic activation in S. typhimurium TA1535 and E. coli WP2 uvrA and for preferential inhibition of growth of DNA-repair-deficient E. coli. All 6 epoxides possessed DNA-modifying activity as evidenced by their ability to preferentially inhibit DNA polymerase-deficient E. coli. All of the test chemicals except trichloroethylene oxide were mutagenic for S. typhimurium and all except trichloroethylene oxide and tetrachloroethylene oxide were mutagenic for E. coli Wp2 uvrA. Cis- and trans-1,3-dichloropropene oxide were the most potent mutagens and DNA modifiers. For all cases, the cis isomers were more active than the corresponding trans isomers. alpha-Chloroepoxides are considered likely to be the active intermediates of the carcinogenic parent halo-olefins. These mutagenicity studies are considered relevant in assessing the carcinogenicity of the parent hydrocarbons.

DNA Polymerase I↗
PubMed1982

Chemical cocarcinogenesis with the use of a subclone derived from Balb/3T3 cells with catechol as cocarcinogen.

This study was performed for the detection of cocarcinogens by transformation in vitro with the use of a subclone of a Balb/3T3 cell line. Dose response, cytotoxicity, and transformation studies were done with the use of an indirect-acting carcinogen, benzo[a]pyrene (B[a]P), a direct-acting alkylating carcinogen, beta-propiolactone (BPL), and the mouse skin cocarcinogen catechol. The rate of transformation was notably higher in groups treated with B[a]P and catechol or BPL and catechol than in groups treated with either B[a]P or BPL. Catechol alone did not induce any transformation. All the cells isolated from the transformed foci showed characteristics of malignantly transformed cells, such as anchorage-independent growth. Thus chemical cocarcinogenesis was accomplished in vitro similar to that accomplished in in vivo studies reported earlier on mouse skin.

Animals↗