Toxicology of Industrial Compounds

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360 CARCINOGENESIS AT LOW DOSE years. This is equivalent to an increase from 40000 to 40001 as a cumulative incidence 0–64, but it has a completely different meaning. It can now be excluded that the additional individual would have lived tumour free for 80 years in the absence of the exogenous carcinogen. Final remarks With the ideas presented, fear of cancer from low dose or from rare exposures can possibly be reduced. This does not mean that small cancer risks should be tolerated. Carcinogens in the environment, for instance, affect all of us; the tumour-free life span is reduced in the entire population. The model should be valid for tissues with a high spontaneous tumour incidence and an exponentially steep age dependence indicative of a multistage requirement of 5–6 steps. For cells that can be transformed in 2 or 3 steps or that are specifically sensitive in certain phases of the development (in utero or during childhood), the model has to be reconsidered. This might be necessary for tumours with incidence peaks at a young age (leukaemia, tumours of the lymphatic tissues, brain, testis). Nevertheless, the latter tumour types are rare in comparison with cancer of the old age so that the concept should hold for the majority of the tumours in humans. References AMES, B.N., 1989, Endogenous DNA damage as related to cancer and aging, Mutat. Res., 214, 41–6. ANISIMOV, V.N., 1989, Dependence of susceptibility to carcinogenesis on species life span, Arch. Geschwulstforsch., 59, 205–13. DAY, N.E., 1983, Time as a determinant of risk in cancer epidemiology: the role of multi-stage models, Cancer Surv., 2, 577–93. GAYLOR, D.W., 1992, Relationship between the shape of dose-response curves and background tumour rates, Regul. Toxicol. Pharmacol., 16, 2–9. HARRIS, C.C., 1989, Interindividual variation among humans in carcinogen metabolism, DNA adduct formation and DNA repair, Carcinogenesis, 10, 1563–6. KODELL, R.L., FARMER, J.H., LITTLEFIELD, N.A., FRITH, C.H., 1980, Analysis of life-shortening effects in female Balb/c mice fed 2-acetylaminofluorene, J. Environ. Pathol. Toxicol, 3 69–88. LITTLEFIELD, N.A., FARMER, J.H. and GAYLOR, D.W., 1980, Effects of dose and time in a long-term, low-dose carcinogenic study, J. Environ. Pathol. Toxicol., 3, 17–34. LOEB, L.A., 1989, Endogenous carcinogenesis: molecular oncology into the twentyfirst century—Presidential address, Cancer Res., 49, 5489–96.
W.K.LUTZ 361 LUTZ, W.K., 1990a, Endogenous genotoxic agents and processes as a basis of spontaneous carcinogenesis, Mutat. Res., 238, 287–95. LUTZ, W.K., 1990b, Dose response relationship and low dose extrapolation in chemical carcinogenesis, Carcinogenesis, 11, 1243–7. RAABE, O.G., 1989, Scaling of fatal cancer risks from laboratory animals to man, Hlth Phys., 57 suppl. 1, 419–32. SCRABLE, H.J., SAPIENZA, C. and CAVENEE, W.K., 1990, Genetic and epigenetic losses of heterozygosity in cancer predisposition and progression, Adv. Cancer Res., 54, 25–62. TENNANT, R.W., 1993, Stratification of rodent carcinogenicity bioassay results to reflect relative human hazard, Mutat. Res., 286, 111–18.
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Toxicology of Industrial Compounds
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This edition published in the Taylo
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8. Pulmonary Toxicity Studies with
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Preface A large number of chemical
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Contributors May Akrawi Department
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Beverly M.Kulig TNO Toxicology, Dep
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Richard A.Versen Schuller MTC, Heal
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1 Biomonitoring and Absorption of I
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4 BIOMONITORING AND ABSORPTION OF I
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10 BIOMONITORING AND ABSORPTION OF
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2 Toxicokinetics and Biodisposition
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14 TOXICOKINETICS AND BIODISPOSITIO
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3 Metabolic Activation of Industria
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38 METABOLIC ACTIVATION OF INDUSTRI
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4 Sizing up the Problem of Exposure
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46 SIZING UP THE PROBLEM OF EXPOSUR
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5 Metabolism of Reactive Chemicals
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62 METABOLISM OF REACTIVE CHEMICALS
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6 Methods for the Determination of
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74 METHODS FOR THE DETERMINATION OF
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PART THREE Pulmonary toxicology of
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92 CARCINOGENIC POTENTIAL OF MAN-MA
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100 CARCINOGENIC POTENTIAL OF MAN-M
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118 PULMONARY TOXICITY STUDIES WITH
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130 PULMONARY HYPERREACTIVITY TO IN
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10 Mechanisms of Pulmonary Sensitiz
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140 MECHANISMS OF PULMONARY SENSITI
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150 OCCUPATIONAL ASTHMA INDUCED BY
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12 Biomarkers and Risk Assessment K
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160 BIOMARKERS AND RISK ASSESSMENT
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168 EXTRAPOLATION OF TOXICITY DATA
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14 Molecular Approaches to Assess C
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182 MOLECULAR APPROACHES TO ASSESS
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198 EVALUATION OF TOXICITY TO THE I
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208 USE OF LONG-TERM CULTURES OF HE
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PART FIVE Mechanisms of toxicity of
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224 PEROXISOME PROLIFERATION normal
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226 PEROXISOME PROLIFERATION demons
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228 PEROXISOME PROLIFERATION Specie
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230 PEROXISOME PROLIFERATION intend
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232 PEROXISOME PROLIFERATION BENTLE
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234 PEROXISOME PROLIFERATION KRAUPP
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236 PEROXISOME PROLIFERATION POPP,
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18 Neurotoxicity Testing of Industr
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240 NEUROTOXICITY TESTING OF INDUST
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256 ENDOCRINE TOXICOLOGY OF THE THY
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20 Testing and Evaluation for Repro
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282 TESTING AND EVALUATION FOR REPR
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PART SIX Toxicity of selected class
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302 SPECIAL POINTS IN THE TOXICITY
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Page 324 and 325: 310 TOXICOLOGY OF TEXTILE CHEMICALS
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Page 372 and 373: 358 CARCINOGENESIS AT LOW DOSE Tabl
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Page 378 and 379: 364 CONTROVERSIAL ISSUES IN SAFETY
Page 388 and 389: 374 INDEX 2-bromo-glutathionyl 64 B
Page 390 and 391: 376 INDEX Gas chromatography/mass s
Page 392 and 393: 378 INDEX mRNA analysis 211 Mutagen
Page 394 and 395: 380 INDEX Surfactants 338-55 acute
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