aldrin and Liver-Neoplasms

Topics: Aldrin; Animals; Carcinogens; DDT; Dieldrin; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Induction; Food Contamination; Government Agencies; Liver Neoplasms; Lung Neoplasms; Neoplasms; Pesticide Residues; Pesticides; Photolysis; United States; United States Food and Drug Administration

Predicting the potential human health risk posed by chemical stressors has long been a major challenge for toxicologists, and the use of microarrays to measure responses to toxicologically relevant genes, and to identify selective, sensitive biomarkers of toxicity is a major application of predictive and discovery toxicology. To investigate this possibility, we investigated whether carcinogens (at doses known to induce liver tumors in chronic exposure bioassays) deregulate characteristic sets of genes in mice. Male C3H/He mice were dosed with two hepatocarcinogens (vinyl chloride (VC, 50-25 mg/kg), aldrin (AD, 0.8-0.4 mg/kg)), or two non-hepatocarcinogens (copper sulfate (CS, 150-60 mg/kg), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T, 150-60 mg/kg)). Large-scale molecular changes elicited by these four hepatotoxicants in liver tissues were analyzed using DNA microarray. Three days after administration, no significant phenotypic changes were induced by these four different hepatotoxicants in terms of histological examination or blood biochemical assay. However, unsupervised hierarchical analysis of gene expressional changes induced by hepatotoxicants resulted in two major gene subclusters on dendrogram, i.e., a carcinogen (VN, AD) and non-carcinogen group (CS, 2,4,5-T), and also revealed that distinct molecular signatures exist. These signatures were founded on well-defined functional gene categories and may differentiate genotoxic and non-genotoxic carcinogens. Furthermore, Venn diagram analysis allowed us to identify carcinogen and non-carcinogen-associated molecular signatures. Using statistical methods, we analyzed outlier genes for four different classes (genotoxic-, non-genotoxic-carcinogen, genotoxic-, non-genotoxic non-carcinogen) in terms of their potential to predict different modes-of-action. In conclusion, the identification of large-scale molecular changes in different hepatocarcinogen exposure models revealed that different types of hepatotoxicants are associated with different epigenetic changes and molecular pathways and that these large-scale characteristic molecular changes could be used as predictable toxicity markers.

Topics: 2,4,5-Trichlorophenoxyacetic Acid; Aldrin; Animals; Carcinogens; Chemical and Drug Induced Liver Injury; Copper Sulfate; Data Interpretation, Statistical; Gene Expression Profiling; In Situ Hybridization; Insecticides; Liver Neoplasms; Male; Mice; Mice, Inbred C3H; Microarray Analysis; Organ Size; RNA; Vinyl Chloride

In order to investigate whether the stimulation of liver DNA synthesis might be used to detect one class of hepatic tumor promoters, the incorporation of orally administered radiolabelled thymidine into liver DNA was determined in rats and mice 24 h after a single oral gavage of test compounds at various dose levels. Three DNA-binding hepatocarcinogens, aflatoxin B1, benzidine and carbon tetrachloride, did not stimulate but rather inhibited DNA synthesis (not for CCl4). Four hepatic tumor promoters, clofibrate, DDT, phenobarbital and thioacetamide, gave rise to a stimulation in a dose-dependent manner. Single oral doses between 0.02 and 0.3 mmol/kg were required to double the level of thymidine incorporation into liver DNA (= doubling dose, DD). Differences between species or sex as observed in long-term carcinogenicity studies were reflected by a different stimulation of liver DNA synthesis. In agreement with the bioassay data, aldrin was positive only in male mice (DD = 0.007 mmol/kg) but not in male rats of female mice. 2,3,7,8-TCDD was positive in male mice (DD = 10(-6) mmol/kg) and in female rats (DD = 2 X 10(-6) mmol/kg) but not in male rats. The assay was also able to distinguish between structural isomers with different carcinogenicities. [alpha]Hexachlorocyclohexane stimulated liver DNA synthesis with a doubling dose of about 0.2 mmol/kg in male rats whereas the [gamma]-isomer was ineffective even at 1 mmol/kg. So far, only one result was inconsistent with carcinogenicity bioassay data. The different carcinogenicity of di(2-ethylhexyl)adipate (negative in rats) and di(2-ethylhexyl)phthalate (positive) was not detectable. Both plasticizers were positive in this short-term system with DD's of 0.7 mmol/kg for DEHA and 0.5 mmol/kg for DEHP. The proposed assay is discussed as an attempt to devise short-term assays for carcinogens not detected by the routine genotoxicity test systems.

Topics: Adipates; Aflatoxin B1; Aflatoxins; Aldrin; Animals; Benzidines; Biological Availability; Carbon Tetrachloride; Carcinogens; Cell Division; Circadian Rhythm; DDT; Diethylhexyl Phthalate; DNA; DNA Replication; Female; Hexachlorocyclohexane; Isomerism; Liver; Liver Neoplasms; Male; Mice; Phenobarbital; Polychlorinated Dibenzodioxins; Rats; Thioacetamide

Five established hepatoma cell lines, 1 of rat origin and 4 derived from human liver carcinoma, were compared for their capacity to perform metabolic activation of one polycyclic hydrocarbon, benzo[a]pyrene (BP), and one cyclodiene chlorinated insecticide, aldrin. The results of these investigations indicated both species and individual differences among these cell lines. Aldrin was found to be converted into dieldrin much more efficiently by the rat hepatoma cell line than by any human cell lines, whereas 2 human lines displayed the highest BP-metabolizing activity whether measured as the amounts of water-soluble products or estimated by cytotoxic cell-mediated assays. Results also showed that one particular human cell line can replace, advantageously, V79 hamster cells as target in a cell-mediated assay owing to its incapability to metabolize BP and its high sensitivity to BP metabolites.

Topics: Aldrin; Animals; Benzo(a)pyrene; Benzopyrenes; Biotransformation; Carcinogens; Carcinoma, Hepatocellular; Cell Line; Cell Survival; Cricetinae; Cricetulus; Cytotoxicity, Immunologic; Humans; Kinetics; Liver Neoplasms; Liver Neoplasms, Experimental; Lung; Rats; Species Specificity

Topics: Aldrin; Animals; Benzopyrene Hydroxylase; Carcinoma, Hepatocellular; Cell Differentiation; Cell Line; Cholesterol 7-alpha-Hydroxylase; Cytochrome P-450 Enzyme System; Enzyme Induction; Epoxy Compounds; Liver Neoplasms; Mixed Function Oxygenases; Oxygenases; Rats; Steroid 12-alpha-Hydroxylase; Steroid Hydroxylases; Substrate Specificity

Topics: Aldrin; Chemical Industry; DDT; Dieldrin; Humans; Insecticides; Liver Neoplasms; Occupational Diseases; Time Factors; United States

Topics: Aldrin; Animals; Carcinogens, Environmental; Dieldrin; Dogs; Dose-Response Relationship, Drug; Environmental Health; Food Contamination; Government Agencies; Haplorhini; Humans; Liver Neoplasms; Mice; Neoplasms, Experimental; Rats; United States

The development of hyperplastic and neoplastic lesions of parenchymal cells of the liver adjacent to central veins was observed in C3H mice ingesting the chlorinated hydrocarbons, dieldrin or aldrin, in the diet. Lesions could be followed from pericentral hyperplasia to areas of hyperplasia, nodules of hyperplasia, small hepatocellular carcinomas, and large well-developed carcinomas, occasionally with metastases. Sometimes pericentral hyperplasia was diffuse throughout most or all of one lobe of the liver. These hyperplastic cells collided to become one large nodule and also one large carcinoma. The carcinomas were well-differentiated or moderately well-differentiated and grew on transplantation to isologous hosts. Histologically, the hyperplastic cells adjacent to central veins were increased in size, frequently with double nuclei. Carcinoma cells varied in size and shape and were huge with large nuclei, prominent nucleoli, and eosinophilic cytoplasm. Similar hepatocellular carcinomas were seen previously with carbon tetrachloride, another organochlorine chemical.

Topics: Aldrin; Animals; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Dieldrin; Female; Hepatic Veins; Hyperplasia; Liver Diseases; Liver Neoplasms; Male; Mice; Mice, Inbred C3H

The world food crisis is as critical today as when it was debated at the 1974 World Food Conference in Rome. Since the United States and Canada-and to a lesser extent, Australia and New Zealand-lead in the production of corn, wheat and soybeans, the North American "bread basket" has become the "market basket" of the world. For welfare, economic, and political reasons, our energies, resources, and deliberations must be expanded toward optimum production of wholesome food products. I do not recommend that we permit food additives in "questionably" safe or excessive concentrations in our agricultural products. I do recommend, however, that tolerance limits for food additives be established based on a comprehensive review of all contributing factors-the world food crisis and the rational interpretation of both positive and negative animal data as they relate to man. As Dr. Herbert Stokinger put it so aptly: "Avoid the establishment of unnecessarily severe standards." 2. Funds for research and teaching of food and nutrition should be greatly increased, so that all who can read and write may be made aware of the daily dietary requirements for the maintenance of good health. 3. Unsubstantiated scare tactics in publications of the scientific and lay press can only lead to well-intended but often emotionally-inspired restrictions, ordinances, and laws. Such decisions are likely to either under- or over-define the requirements and standards for food additives and other chemicals which are important to the well-being of the populace.

Topics: Aldrin; Animals; Carcinogens; DDT; Dieldrin; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Feeding Behavior; Food; Food Additives; Food Supply; History of Medicine; Humans; Liver Neoplasms; Mice; Nutritional Physiological Phenomena; Population; Research Design; Species Specificity; United States

Topics: Aldrin; Animals; Dieldrin; Humans; Legislation, Drug; Liver Neoplasms; Mice; United Kingdom; United States