dieldrin and Cell-Transformation--Neoplastic

In 1987, the US Environmental Protection Agency (EPA) classified aldrin and dieldrin as category B2 carcinogens, i.e. probable human carcinogens, based largely on the increase in liver tumors in mice fed either organochlorine insecticide. At that date, the relevant epidemiology was deemed inadequate to influence the cancer risk assessment. More time has now elapsed since early exposures of manufacturing workers to aldrin/dieldrin; therefore, updated epidemiological data possess more power to detect exposure-related differences in cancer risk and mortality. Also, recent experimental studies provide a plausible mode of action to explain the mouse specificity of dieldrin-induced hepatocarcinogenesis and call into question the relevance of this activity to human cancer risk. This monograph places this new information within the historic and current perspectives of human cancer risk assessment, including EPA's 1996 Proposed Guidelines for Carcinogen Risk Assessment. Updated epidemiological studies of manufacturing workers in which lifetime exposures to aldrin/dieldrin have been quantified do not indicate increased mortality or cancer risk. In fact, at the middle range of exposures, there is evidence of a decrease in both mortality from all causes and cancer. Recent experimental studies indicate that dieldrin-induced hepatocarcinogenesis in mice occurs through a nongenotoxic mode of action, in which the slow oxidative metabolism of dieldrin is accompanied by an increased production of reactive oxygen species, depletion of hepatic antioxidant defenses (particularly alpha-tocopherol), and peroxidation of liver lipids. Dieldrin-induced oxidative stress or its sequelae apparently result in modulation of gene expression that favors expansion of initiated mouse, but not rat, liver cells; thus, dieldrin acts as a nongenotoxic promoter/accelerator of background liver tumorigenesis in the mouse. Within the framework of EPA's Proposed Guidelines for Carcinogen Risk Assessment, it is proposed that the most appropriate cancer risk descriptor for aldrin/dieldrin, relating to the mouse liver tumor response, is 'not likely a human carcinogen', a descriptor consistent with the example of phenobarbital cited by EPA.

Topics: Aldrin; Animals; Carcinogens; Cell Transformation, Neoplastic; Dieldrin; DNA, Neoplasm; Humans; Insecticides; Neoplasms; Risk Factors

Dieldrin has been shown to induce liver tumors selectively in mice. Although the exact mechanism is not fully understood, previous studies from our laboratory and others have shown that dieldrin induced liver tumors in mice through a non-genotoxic mechanism acting on tumor promotion stage. Two studies were performed to examine the role of nuclear receptor activation as a possible mode of action (MOA) for dieldrin-induced mouse liver tumors. In the initial study, male C57BL/6 mice (6- to 8-week old) were treated with dieldrin in diet (10 ppm) for 7, 14, and 28 days. Phenobarbital (PB), beta-naphthoflavone (BNF) and Di (2-ethylhexyl) phthalate (DEHP) were included as positive controls in this study for evaluating the involvement of CAR (constitutive androstane receptor), AhR (aryl hydrocarbon receptor) or PPARα (peroxisome proliferator activated receptor alpha) in the MOA of dieldrin hepatocarcinogenesis. A significant increase in hepatocyte DNA synthesis (BrdU incorporation) was seen in treated mice compared with the untreated controls. Analysis of the expression of the nuclear receptor responsive genes revealed that dieldrin induced a significant increase in the expression of genes specific to CAR activation (Cyp2b10, up to 400- to 2700-fold) and PXR activation (Cyp3a11, up to 5- to 11-fold) over untreated controls. The AhR target genes Cyp1a1 and Cyp1a2 were also slightly induced (2.0- to 3.7-fold and 1.7- to 2.8-fold, respectively). PPARα activation was not seen in the liver following dieldrin treatment. In addition, consistent with previous studies in our lab, treatment with dieldrin produced significant elevation in the hepatic oxidative stress. In a subsequent study using CAR, PXR, and CAR/PXR knockout mice, we confirmed that the dieldrin-induced liver effects in mouse were only mediated by the activation of CAR receptor. Based on these findings, we propose that dieldrin induced liver tumors in mice through a nuclear receptor CAR-mediated mode of action. The previously observed oxidative stress/damage may be an associated or modifying factor in the process of dieldrin-induced liver tumor formation subsequent to the CAR activation.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Cell Transformation, Neoplastic; Constitutive Androstane Receptor; Cytochrome P450 Family 2; Dieldrin; DNA Replication; Enzyme Induction; Insecticides; Liver; Liver Neoplasms; Male; Mice, Inbred C57BL; Mice, Knockout; Oxidative Stress; PPAR alpha; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Steroid Hydroxylases

The levels of gap junctional intercellular communication (GJIC) were studied in normal, morphologically altered and morphologically transformed colonies formed in the Syrian hamster embryo (SHE) cell transformation assay. The colonies were selected from non-exposed dishes or dishes exposed to 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.16 microM), di(2-ethylhexyl)phthalate (DEHP, 77 microM), Na-orthovanadate (vanadate, 3.4 microM) or dieldrin (25 microM) for 7 days during colony formation. TPA, DEHP and vanadate induced increased frequencies of morphological transformation of colonies. At the same time, TPA and DEHP decreased GJIC in the colonies by approximately 30% under the conditions used. All categories of colonies were equally affected. Vanadate did not change the level of GJIC in any of the categories of colonies compared to unexposed control. Dieldrin strongly suppressed GJIC in all colonies without increasing the frequency of transformation. The compounds affected GJIC after short-term exposures (4 and 24 h) to cell monolayers rather similarly to that found after long-term exposure to the colonies. Transformation assays with coexposure of dieldrin together with the transforming agents vanadate, DEHP or benzo[a]pyrene did not increase transformation frequencies compared to the transforming agents alone. The GJIC level in all coexposure groups was similar to that of dieldrin alone. Furthermore, regardless of whether dieldrin was present or not, removal of vanadate 24 h before fixation of the colonies caused a slight decrease in the transformation frequency. The results suggest that: (i) morphologically transformed colonies have the same ability of intercellular communication as normal colonies; (ii) decreased GJIC is probably not either sufficient or necessary to induce transformation of SHE cell colonies; (iii) a decreased level of GJIC does not necessarily increase the susceptibility of SHE cells for transformation; and (iv) inhibition of GJIC may not have an impact on the maintenance of the transformed phenotype of SHE cell colonies.

Topics: Animals; Cell Communication; Cell Division; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Dieldrin; Diethylhexyl Phthalate; Down-Regulation; Embryo, Mammalian; Intercellular Junctions; Mesocricetus; Tetradecanoylphorbol Acetate; Vanadates