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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Induction of erythroleukemia cell adhesion by plant diterpene tumour promoters: a quantitative study and correlation with in vivo activities.

A potent tumour promoter on mouse skin, phorbol-9-myristate-9a-acetate, induces certain clones of Friend erythroleukemia cells to become adhesive to the surface of tissue culture dishes, whereas in the absence of this compound, these cells grow in suspension. We have quantitatively tested 20 other phorbol esters and related compounds for this effect. When the results are expressed as the concentrations of compounds which show half-maximum effect on cell adhesion, the decreasing order of potency is: phorbol-9-myristate-9a-acetate (3.

Microsome-mediated covalent binding of 1,2-dichloroethane to lung microsomal protein and salmon sperm DNA.

In order to determine whether the covalent binding of the carcinogen 1,2-dichloroethane to macromolecules is dependent on microsomes or cytosol, microsomes and cytosol from lungs of C57BL/6 X C3H/He F1 (hereafter called B6C3F1) mice and Osborne-Mendel rats were incubated with [1,2-14C]dichloroethane and salmon sperm DNA. 1,2-Dichlorothane binds covalently to microsomal protein and DNA only in the presence of microsomes, whereas cytosol has insignificant metabolic activation. The binding to macromolecules was significantly higher in the presence of native microsomes than denatured microsomes.

Carcinogenicity of hair dye components.

The available animal carcinogenicity data on hair dye components was reviewed. From this review it became clear that certain hair dye components, some of which are still in hair dye formulations now on the market, are animal carcinogens. The compounds of concern that are still in use are: 3-amino-4-methoxyaniline, 2-nitro-4-aminoaniline and 3-nitro-4-hydroxyaniline.

Prediction of carcinogenicity based on structure, chemical reactivity and possible metabolic pathways.

The carcinogenicity and chemical structure-reactivity relationships of alkylating and acylating agents have been examined for approximately one hundred compounds in these classes. The alkylating compound types of interest included epoxides, lactones, halo-ethers and 1,4-dichlorobutene-2. The acylating agents examined were dimethyl- and diethyl-carbamyl chloride.

Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice.

A series of 15 halogenated hydrocarbons of industrial and environmental importance were tested for carcinogenicity by chronic administration by one or more routes in Ha:ICR Swiss mice. Not all compounds were tested by the four routes of administration used. Allyl chloride, 1,2-dibromo-3-chloropropane, and vinylidene chloride were active as skin tumor initiators in the two-stage carcinogenesis assays; phorbol myristate acetate was used as a promoter.