WSU ESRP 531 - Fundamentals of Environmental Toxicology

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1Lecture 15Soft Tissue Toxicity (Carcinogenicity)ES/RP 531Fundamentals of Environmental ToxicologyInstructor: Allan [email protected] 2005Definitions Mutagen / Mutagenicity a substance directly interacting with DNA,causing a change in its structure Oncogen / Oncogenicity a substance causing benign or malignanttumors chronic disease characterized by benignor malignant tumors Carcinogen / Carcinogenicity substance capable of causing malignanttumors a chronic disease marked by malignanttumorsA Few Comments onCarcinogenicity Testing Battery of tests Mutagenicity Clastogenicity Tumorigenicity Carcinogenicity Must use MTD (maximum tolerated dose) Usually use three doses total and a no-dosecontrol Modern carcinogenesis theoryMaximum Tolerated Dose Highest dose of toxicant during the choronicstudy that can be predicted not to alter theanimal’s longevity through effects other thancarcinogenicity Causes no more than a 10% weight decrementas compared to the non-dosed control group Does not produce clinical signs of toxicity Doest not cause pathological lesions other thanthose that may be related to a neoplasticresponse (i.e., abnormal cell growth) Does not shorten animal’s life spanNeoplasm (“new growth’) = tumor (swelling or mass)2Sequences of OncogenesisNeoplastic Transformation(Initiation)Neoplastic Development(Promotion & Progression)Normal Cell Neoplastic CellPreneoplastic CellBenign neoplasmNeoplastic Cell Malignant NeoplasmInitiationGenetic alterationDNA adductsEpigenetic effects Cell replicationPromotionClonal ExpanstionCell replicationReduced apoptosisProgressionGenetic alterationHeterogeneityCell replicationReduced apoptosisTransformationGenetic alterationOncogene activationSuppressor gene inactivationCell replicationReduced apoptosisNeoangiogenesis“Stem Cells”Williams 2001Neoplastic Transformation(Initiation)Normal CellPreneoplastic CellNeoplastic CellInitiationGenetic alterationDNA adductsEpigenetic effects Cell replicationOncogene activationSuppressor gene inactivationCell replicationReduced apoptosis“Stem Cells”Williams 2001Neoplastic Development(Promotion & Progression)Neoplastic CellBenign neoplasmMalignant NeoplasmPromotionClonal ExpanstionCell replicationReduced apoptosisProgressionGenetic alterationHeterogeneityCell replicationReduced apoptosisNeoangiogenesisWilliams 2001Normal cellFirst mutation(cell seems normal but is predisposedto proliferate excessivelySecond mutation(cell normal butproliferates too much)3rd MutationStructuralchanges4th or latermutationMalignant cell(Uncontrolled growth;Abnormal differentiation)Thus, one mutation doesnot cause cancer.Mutations Are Normal & Frequent ~100,000 oxidative DNA hits per day inrat ~10,000 oxidative DNA hits per day inhuman Most of these mutations are repaired,but mutations still can accumulate incell lines during agingEstimates by Ames et al. 1993Contraverting Repair Mechanisms Mutations normally repaired High doses lead to cell death andchronic cell division in an attempt toreplace dead cells More probability of mutations because ofrepair mistakes, especially if cells sufferingtoxicity3Steady State Oxidative Damage to DNA Increases with AgeOxo-guanidine Found in Rat Liver TissueAmes et al. (1993) Proc. Natl. Acad. Sci. 90: 7915Why Mechanism of InteractionIs Important in UnderstandingCarcinogenicity and theRelationship to DoseEllwein & Cohen 1990Experiments with Liver andBladder Cells Exposed to 2-AAF(acetyl aminofluorene)Liver cells are more sensitive than bladder cells to tumorprevalence; but tumor incidence drops with shorter exposure(Cohen & Ellwein 1990)Liver tumorsBladder tumorsAt all doses of 2 AAF (acetyl aminofluorene), liver and bladder cellsproliferate in the presence of toxicant; rate of proliferation isrelated to exposure period (from Cohen & Ellwein 1990)Age (months)Organ Cell Population(as % of initial)Bladder urothelial cellsLiver hepatocytes150 ppm100 ppmAll doses75 ppm60 ppm45 ppmMutation vs. Mitogenisis 2-AAF is hydroxylated in liver stem cells to an activemutagenic form, but not in older differentiated cells Mutated cells proliferate at same rate as liver’s normalgrowth rate Thus, formation of tumors is related to the probability ofmutations in the stem cells In bladder, N-hydroxyaminofluorene is formed(highly mutagenic); can mutate any age of cell in thebladder Tumors formed only at doses above 60 ppm as a result ofmitogenic (hyperplasia) response Tumors formed only when cell proliferation occursLima and Van der Laan 2000Tumor PromotionMitogenic StimulationSignal Transduction Changes Tumor supressor gene function Cell to cell communicationActivation of Nuclear Receptors Programmed Cell DeathCell proliferation in target organsmore relevant in organis with minimal proliferation profile(for ex., liver, urinary bladder)Mechanisms of Carcinogenesis by Nongenotoxic Compounds4Main Mechanisms ofNongenotoxic Carcinogenicity Chronic cell injury Immunosuppression Increased secretion of trophic hormones Receptor activation Other (e.g., cytochrome P450 induction)Lima and Van der Laan 2000Biologically Based ClassificationScheme for Rat Carcinogens Genotoxic Cause DNA mutations Theoretically no threshold However, dose level can still cause cell toxicity Depends on metabolism in specific tissues Effect likely to persist after dosing stops Non-genotoxic (epigenetic) Reaction or interference of contaminant with specific cellreceptor or growth factor Usually a threshold for an effect Effect related to cell toxicity and regeneration Cells “heal” after dosingThresholdAssumptionof NonlinearResponseNo ThresholdAssumptionof LinearResponseDoseNo. ofTumorsCancer Testing Dilemma:Response at high testing doses are extrapolated to low doseexposures. Estimation of hazard depends on knowingthe “true” shape of the dose-response curveObserved ResponsesMisconceptions AboutCarcinogenicity Cancer rates are soaring Actually, incidence rate of some types of cancer isstable, some is decreasing, and some is rising For example, NHL (Non-Hodgkin’s) lymphoma andprostate cancer rates have increased Stomach and lung cancer incidence have declined Weir et al. 2003 Cancer incidence rates for all cancer sites combinedincreased from the mid-1970’s through 1992; Decreased from 1992 through 1995; Observed


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WSU ESRP 531 - Fundamentals of Environmental Toxicology

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