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Biomedical subjects

E K Weisburger

Publications and source records attributed to E K Weisburger.

At least 19 recordsLinked to original sources
PubMed1993

Predictive strategies for selecting 379 NCI/NTP chemicals evaluated for carcinogenic potential: scientific and public health impact.

The a priori criteria used by the National Cancer Institute/National Toxicology Program (NCI/NTP) are described for 379 chemicals selected and evaluated for carcinogenic potential. We classified the chemicals according to exposure and structural categories and evaluated the predictive ability of the scientific selection criteria of chemicals suspected of being carcinogenic in advance of any study. Of the 379 chemicals, 253 (67%) were selected with a suspicion of carcinogenicity; 171 (68%) of these 253 chemicals induced cancer in at least one of the sex-species experiments. The other 126 (33%) chemicals were selected mainly, but not exclusively, on the basis of exposure considerations and production volumes; only 27 (21%) of these were judged to be positive. Overall, 198 (52%) of the 379 chemicals studied induced tumors in at least one organ of one sex of one species, but only 87 (23%) of these 379 chemicals were positive in both species and are considered most likely to present carcinogenic hazards to humans. Importantly, 78 (90%) of these 87 chemicals were selected with a prospective suspicion of carcinogenicity. Although the program has studied only a part of the "Universe of Chemicals" (defined as chemicals to which humans are exposed), the scientific data generated are essential for developing structure activity data bases of potentially hazardous chemical classes and for predicting the carcinogenicity of chemicals not yet studied. Thus, the bioassay program has had beneficial and crucial impacts on public health, as demonstrated by the use of these data by international, Federal, and State regulatory agencies to reduce or eliminate exposures to chemicals shown to be unequivocally carcinogenic in laboratory animals.

Animals↗
PubMed1990

Ethylene dichloride: the influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats.

Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiolabeled EDC was affected. The urinary excretion of 14C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered 14C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.

Animals↗
PubMed1989

Current carcinogen perspectives: De minimis, Delaney and decisions.

Advances in analytical chemistry, as applied to foods, as well as further investigations of the role of essential trace elements, constituents of natural products, and metabolic processes, have all shown that the Delaney clause of the 1958 Food Additives Amendment is an anachronism. Although the limitations of this clause are now known, prospects for its deletion are not very promising.

Carcinogens↗
PubMed1986

Final report of the Color Additive Scientific Review Panel.

The Color Additives Scientific Review Panel considered whether there was information sufficient to perform a carcinogenic risk assessment on the colors D&C Red No. 19 (R-19), D&C Red No. 37 (R-37), D&C Orange No. 17 (O-17), D&C Red No. 9 (R-9), D&C Red No. 8 (R-8) and FD&C Red No. 3 (R-3) and to evaluate the assessments sent to FDA as part of the petitions for use of the colors for drug and external uses by the Cosmetic, Toiletry and Fragrance Association (CTFA). There is a lack of human data concerning the colors for making a human health assessment, so the assessments are based upon the extrapolation of animal data. The risk assessments are determined for exposure to single chemicals. Excluded from consideration are possible effects from exposure to multiple chemicals, such as co-carcinogenesis, promotion, synergism, antagonism, etc. In the light of recent efforts in establishing a consensus in risk assessment, the Panel has determined that the CTFA assessments for R-10, O-17, and R-9 are consistent with present acceptable usages, although it questions some of the assumptions used in the assessments. The Panel identified a number of general assumptions made, and discusses their validity, their impact on total uncertainty, and the potential options to address the gaps in understanding that necessitate the assumption. The Panel also derived revised risk estimates using more "reasonable" assumptions than "worst-case" situations, for 90th percentile and average exposure. For those assumptions that are easily quantifiable, the Panel's estimates are less than an order of magnitude lower than the CTFA risk estimates, indicating that the underestimates and overestimates of the CTFA risk estimates tend to balance each other. The impact of most of the assumptions is not quantifiable. The assessment for R-3 is complicated by the fact that there is no good skin penetrance study for this color. It was assumed that the penetrance is similar to that of another water-soluble xanthene color, R-19. It is expected that the absorption of the color is not likely to exceed that of the smaller molecule, R-19. Therefore, the risk estimates are similar to the CTFA estimates, but with different reasoning. The estimates for R-8 and R-37 are different from the others in that there is a lack of any exposure or toxicological information on these colors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Identification and classification of carcinogens: procedures of the Chemical Substances Threshold Limit Value Committee, ACGIH. American Conference of Governmental Industrial Hygienists.

The Chemical Substances Threshold Limit Value Committee of the American Conference of Governmental Industrial Hygienists has refined its procedures for evaluating carcinogens. Types of epidemiologic and toxicologic evidence used are reviewed and a discussion is presented on how the Committee evaluates data on carcinogenicity. Although it has not been conclusively determined whether biological thresholds exist for all types of carcinogens, the Committee will continue to develop guidelines for permissible exposures to carcinogens. The Committee will continue to use the safety factor approach to setting Threshold Limit Values for carcinogens, despite its shortcomings. A compilation has been developed for lists of substances considered to be carcinogenic by several scientific groups. The Committee will use this information to help to identify and classify carcinogens for its evaluation.

Carcinogens↗
PubMed1986

Effect of microsomal enzyme inducers on the urinary excretion pattern of mutagenic metabolites of the carcinogen 2,4-toluenediamine.

2,4-Toluenediamine [(TDA) CAS: 95-80-7] was administered to rats pretreated with the microsomal enzyme inducers phenobarbital (PB), beta-naphthoflavone (beta NF), or 3-methylcholanthrene (MCA). The 24-hour urines of male F344 rats were examined for their mutagenic potency by means of the Salmonella assay, with the Aroclor 1254-pretreated rat liver S-9 fraction as an activating system. No revertants were found with TDA or its urinary metabolites in the absence of the S-9 fraction. In the presence of S-9, the number of revertants increased as the concentration of TDA or its urinary metabolites increased. The urinary metabolites, generated after the microsomal enzyme inducers (PB, beta NF, MCA), had increased mutagenic activity as compared with the controls (saline, corn oil). In the presence of beta-glucuronidase (beta G), increased numbers of TA98 revertants were noted in the urine of rats pretreated with PB, saline, or corn oil. Addition of sulfatase did not alter the number of TA98 revertants. Conversely, beta G treatment of urine from rats pretreated with MCA or beta NF led to a decrease in the number of TA98 revertants as compared to levels in urine without beta G. Addition of known urinary metabolites of TDA, such as 4-acetylamino-2-aminobenzoic acid or 2,4-diacetylaminobenzoic acid, to beta NF-pretreated rat urine had no inhibitory effect on the mutagenicity in the absence of beta G. However, in the presence of beta G, the inhibitory effect was similar to that noted with beta NF-pretreated rat urine. Upon separation of urinary metabolites (beta NF-pretreated rat urine) into free, conjugated, and water-soluble forms, the maximum number of TA98 revertants was associated with the free ethyl acetate-extractable fraction, which accounted for the total mutagenic activity associated with the original volume of urine. Conjugated metabolites showed much less mutagenic activity, and an inhibitory principle was associated with the water-soluble fraction.

Animals↗
PubMed1984

Neoplastic response of F344 rats and B6C3F1 mice to the polymer and dyestuff intermediates 4,4'-methylenebis(N,N-dimethyl)-benzenamine, 4,4'-oxydianiline, and 4,4'-methylenedianiline.

Feeding 4,4'-methylenebis(N,N-dimethyl)benzenamine [CAS: 101-61-1; 4,4'-methylenebis(N,N-dimethylaniline)] to inbred F344 rats increased the incidence of thyroid lesions (hyperplasia, adenomas, and carcinomas) in both sexes, especially in the female rats. 4,4'- Oxydianiline (CAS: 101-80-4) in the diet increased adenomas and carcinomas in the thyroid gland and neoplastic nodules and carcinomas in the liver of male and female F344 rats. In addition to increasing thyroid adenomas in females and hepatocellular adenomas or carcinomas in male and female B6C3F1 mice, 4,4'- oxydianiline increased adenomas of the harderian gland in male and female mice. 4,4'- Methylenedianiline (CAS: 101-77-9) in the drinking water increased neoplasms of the thyroid gland and liver in F344 rats and B6C3F1 mice.

Aniline Compounds↗
PubMed1983

Influence of disulfiram on mutagenicity of the urinary metabolites of 2-acetylaminofluorene and N-hydroxy-2-acetylaminofluorene in the Salmonella test system.

Male Sprague-Dawley rats were fed control diet or 0.65% disulfiram (DS) in the diet for up to 20 days. Groups of these animals were injected with 2-acetylaminofluorene (AAF) or N-hydroxy-2-acetylaminofluorene (N-OH-AAF) after 3, 10 and 20 days, in order to study the effects of DS administration on the mutagenic activity of urinary metabolites of the carcinogens. Administration of DS alone for 20 days did not increase significantly the mutagenicity of urine. Urine from rats administered either of the carcinogens showed mutagenic activity which was increased appreciably in the presence of S9 and beta-glucuronidase. Urine from rats which also were fed DS showed an even greater increase in revertants under these conditions. The results indicate that DS increased the excretion of glucuronide metabolites of the carcinogens.

2-Acetylaminofluorene↗
PubMed1983

Inhibitory effects of carbon tetrachloride on dimethylnitrosamine metabolism and DNA alkylation.

The effect of CCl4 pretreatment (dose range from 0.5 to 2.0 ml/kg body weight) on the pathways of dimethylnitrosamine (DMN) metabolism was investigated. The oxidative-N-demethylation by the enzymes, DMN-demethylase I and II operating at low (4 mM) and high (200 mM) substrate concentration, respectively, was greatly reduced in a dose-dependent manner. In addition, the generation of an electrophilic intermediate capable of methylating DNA, specifically at the N-7 and O-6 positions of guanine, was completely inhibited by CCl4 (0.5 ml/kg body weight) pretreatment. When indole feeding (1% in the diet for 8 days prior to CCl4 administration) was employed as a means to enhance DMN-demethylase activities, it was found that the reduction of DMN-demethylase activities was more pronounced in these rats than in the controls. In agreement with earlier findings, 7-methylguanine and O6-methylguanine were not detectable in the CCl4 pretreated group. These results suggest that CCl4 exerts a strong inhibitory action on hepatic DMN metabolism, in particular on the pathway leading to alkylation of DNA guanine. This phenomenon may explain the protective role of CCl4 against DMN-induced hepatotoxicity and perhaps, carcinogenicity, believed to be closely associated with the abnormal modifications of DNA.

Alkylation↗