Archives of Toxicology, Supplement 8

Receptors and Other Targets for Toxic Substances Proceedings of the European Society of Toxicology Meeting Held in Budapest, June 11-14, 1984

Edited by P. L. Chambers, E. Cholnoky and C. M. Chambers

With 120 Figures

Springer-Verlag Berlin Heidelberg New York Tokyo

CLAIRE M. CHAMBERS and PHILIP L. CHAMBERS University of Dublin, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland

ESZTER CHOLNOKY

Chemical Works of Gedeon Richter Ltd., Pharmacological Research Centre, Toxicological Service, P.O. Box 27, 1475 Budapest, Hungary

ISBN -13:978-3-540-13670-5 e-ISBN-13 :978-3-642-69928-3 DOl: 10.1007/978-3-642-69928-3

Library of Congress Cataloging in Publication Data. European Society of Toxicology. Meeting (1984: Budapest, Hungary) Receptors and other targets for toxic substances. (Archives of toxicology. Supplement; 8) I. Poisons­Metabolism-<::ongresses. 2. Poisons-Physiological effect-<::ongresses. 3. Drug receptors-{;ongresses. I. Chambers, P. L. (Philip L.), 1931. II. Cholnoky, E. (Eszter), 1928. III. Chambers, C. M. (Claire M.). IV. Title. V. Series [DNLM: I. Poisons-metabolism-<:ongresses. 2. Receptors, Drug-metabolism-<:ongresses. WI AR496A v.8/QV 600 E896r 1984] RA1l90.E8 Suppl. vol. 8 [RA1216] 615.9 s 85-14880 ISBN-13:978-3-540-13670-5 (U.S.) [615.9]

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Contents

On the Occasion of the 25th Meeting of the European Society of Toxicology J. S. SCHOU ..................................................................... .

Young Scientists Award Lecture 1984: Species Differences in Carcinogenicity and Peroxisome Proliferation due to Trichloroethylene: A Biochemical Human Hazard Assessment C. R. ELCOMBE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

The Role of the Receptor in Toxicology

The Role of Immunoreceptors D. R. STANWORTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

The Role of the Estrogen Receptor in Diethylstilbestrol Toxicity K. S. KORACH and J. S. McLACHLAN ............................................... 33

The Role of Receptors in 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD Toxicity) L. DENCKER ..................................................................... 43

The Oncogene and its Potential Role in Carcinogenesis F. WONG-STAAL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Brain Glucocorticoid Receptors and Their Role in Behavioural Teratogenicity of Synthetic Glucocorticoids o. BENE§ovA and A. PAvLiK....................................................... 73

Effect of Dithiocarbamate-Fungicides and Thiurams on Haloperidol Binding in Rat Brain H. KOMULAlNEN and K. SAVOLAINEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Toxic Effects on the Gastrointestinal Tract

Mucosal Biotransformation of Toxins in the Gut o. HANNINEN .................................................................... 83

Intestinal Excretion of Toxic Substances K. ROZMAN ..................................................................... 87

VI Contents

Biochemical Changes of Intestinal Epithelial Cells Induced by Cytostatic Agents in Rats J. KRALOVANSZKY and N. PRAJDA .................................................. 94

Intestinal Pathology in the Dog Induced by Sublethal Doses of Amiodarone P. VIC, D. GoUY, F. LACHERETZ, B. VERSCHUERE, M. CROS, B. REMANDET, J. BERTHE, and G. MAZUE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Distribution of Glutathione and its Related Enzymes in Small Intestinal Mucosa of Rats T. OGASAWARA, H. HOENSCH, and E. E. OHNHAUS .................................... 110

Induction of Forestomach Lesions by Butylhydroxyanisole and Structurally Related Substances H.-J. ALTMANN, W. GRUNOW, P. W. WESTER, and U. MOHR ........................... 114

The Effect of Cyclophosphamide and Vincristine on Intestinal Protein Loss in Rats T. BERO and T. JAVOR ............................................................ 117

The Induction and Assessment of Rat Gastric Mucosal Lesions G. K. SALMON ................................................................... 122

The Technique of Gastric Endoscopy and Biopsy in the Dog S. M. WHITEHEAD, G. P. CREAN, G. B. LESLIE, and D. WILD ........................... 123

The Incidence of Neoplasms in Syrian Hamsters with Particular Emphasis on Intestinal Neoplasia A. FABRY ....................................................................... 124

Toxic Effects on Haemostasis and Blood

Thrombogenic Effects of Xenobiotics G. ZBINDEN and L. GRIMM ........................................................ 131

Toxicologically Relevant Disturbances of Haemostasis H. P. KU)CKING ................................................................. 142

Effects of Organic Solvents on Erythrocyte Membrane Acetylcholine Esterase Activity M. KORPELA and H. TAHTI ........................................................ 148

Changes of Haemostaseological Variables in Carbon Tetrachloride Poisoning in Rats H. P. KU)CKING, H. MULLER, and F. MARKWARDT ................................... 152

Influence of Antithrombin III on Carbon Tetrachloride Intoxication of Rabbits H. RONNEBERGER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

Increased Serum Alkaline Phosphatase Activity in Beagle Dogs: Mechanism, Diagnostic Considerations S. ELEK, I. LEMNT, I. POLGARI, and G. CSEH.. ........ .. .. ... .. ... .. .. ... ... .. ... ... . 160

Interaction of Rodenticides and Humic Acids - Effects on Prothrombin Activity S. GOLBS and V. FUCHS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Contents VII

Interpretation of Concentrations of Toxic Agents during Drug Safety Studies

Reasons for Monitoring Kinetics in Safety Evaluation Studies D. R. HAWKINS and L. F. CHASSEAUD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

A Decision Tree Approach for the Application of Drug Metabolism and Kinetic Studies to In Vivo and In Vitro Toxicological and Pharmacological Testing P. BACH and J. BRIDGES... ... ...... ...... .. .. . ..... ..... .. ..... .. ... ... ... ... ..... 173

Theoretical Aspects Pertinent to the Interpretation of Concentration Data W. RIESS ..•.•...........••..........•.••.•..•.•.•..•........••.•.............•.. 189

How to Identify Compounds Posing Problems in Absorption, Distribution and Elimination K. SCHMID ...................................................................... 196

A Questionnaire Assessing the Involvement of Toxicologists in Metabolism and Kinetics W. RIESS ........................................................................ 205

A Stochastic Approach in the Evaluation of Plasma Curves with Enterohepatic Recycling M. TARR and A. EORY ...........................•................................ 208

Endotoxin and Pharmacokinetics of Rifampicin J. LAVICKY, L. CELEDA, Z. URBANOVA., J. KvETINA, J. VANECEK, and H. RASKOVA. ......... 211

Local Toxicity and Pharmacokinetics After Intramuscular or Intralipomatous Injection of Different Drugs in Pigs O. SVENDSEN, L. BLOM, T. AAES-J0RGENSEN and J.-J. LARSEN.. .. ....... ... .. ...... .. ... 216

Distribution of Metabolites of the Potent fJ-Adrenoceptor Blocking Drug B 24/76 in Different Tissues of Rats under Toxic Conditions I. AMON, A. BAUMANN, B. HARTMANN, K. P. HENSCHEL and A. MULLER ................. 218

Functional and Morphological Changes in the Inner Ear

Principles in Cochlear Toxicity M. ANNIKO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

Link Between Functional and Morphological Changes in the Inner Ear - Functional Changes Produced by Ototoxic Agents and Their Interactions R. D. BROWN, C. M. HENLEY, J. E. PENNY, and S. KUPETZ ............................ 240

Toxic Effects of Pesticides

The Effect of Maneb, Zineb and Ethylenethiourea on the Humoral Activity of the Pituitary­Thyroid Axis in Rat A. LAISI, R. TUOMfNEN, P. MANNISTO, K. SAVOLAINEN, and J. MATTILA. . . . . . . . . . . . . . . . . . 253

Toxicokinetics of the Herbicide Dichlorprop and its Leucinate and Their Action on Liver Mixed Function Oxidases H. BEITZ, U. BANASIAK, S. GERICKE, and P. CLAUSING. ... .. .. ... ... .. .. .... .. ... ..... . 259

VIII Contents

Organochlorines and Mercury in Blood of a Fish-Eating Population at the River Elbe in Schleswig-Holstein, FRG A. LOMMEL, H. KRUSE, and O. WASSERMANN ......................................... 264

Pesticide-Drug Interaction in Rats G. FENYVESI, M. BOTOS, and J. IVAN................. ..... ....... ........ .. ...... ... 269

Dithiocarbamate Fungicides Decrease Histochemical Reactivity of Cholinesterases in the Gut Wall of Rat K. SAVOLAINEN and H. HERVONEN .................................................. 272

Biochemical Study of Muscle Samples from Chicken Embryos Affected by Wofatox 50 EC E. DELI, L. SOMLYAY, and L. VARNAGY ..... ..... ..... ........ .... .. ........ ...... ... 277

Investigation of Adrenal Steroid and 25-hydroxy-cholecalcipherol in Human Gramoxone Poisoning J. BARsoNY and F. KERTESZ ....................................................... 280

Group Intoxication with Gramoxone (Paraquat) Toxicological and Pathohistological Aspects L. HARSANYI, A. NEMETH, and A. LANG ............................................. 284

The Genetic Control of Paraquat Sensitivity of H-2 Congenic and Recombinant Mice A. NEMETH, P. NEMETH, L. HARSANYI and A. LANG ................................... 285

The Effect of Light on the Toxicity of Paraquat in the Mouse K. BARABAS, L. SZAB6, B. MATKOVICS, and G. BERENCSI .. .. ... ....... ........ ........ . 287

Changes of the Serum Superoxide Dismutase Content of Gramoxone Poisoned Patients, Measured by Anti-SOD Monoclonal Antibody P. NEMETH, L. RAcz, J. VARGA, A. LANG, A. NEMETH, and A. NEMETH.................. 288

Cardiodepression in Organophosphate Poisonings G. MAROSI, J. IVAN, and L. NAGYMAJTENYI .......................................... 289

The Effect ofOrganophosphoric Pesticides on T - and B-Lymphocytes and Antibody Production in Mice B. TIEFENBACH and P. LANGE ...................................................... 292

Toxicity Study of the Insecticide Ekalux 25 EC in Rats K. NAGY, M. BED6, M. Antal, J. SzEPVOLGYI, and A. J. N. ZSINKA 294

Effect of Different Antidotes in Ekalux 25 EC Poisoned Male Rats J. M. SZEBERENYI and K. LEHOTZKY ................................................ 295

Assessment of Acute Neurotoxic Effects of Different Kinds of Pesticides in Mice M. KARMos-VARSZEGI and I. DESI .................................................. 297

Subacute and Subchronic Toxicity of Dietary Bendiocarb in Rats N. K. NESKOVIC, M. VUlcSA, V.RADoNnc, D. STOJlC, D. JANKOVIC, and S. LJ. VITOROVI .. . 298

Effect of Lethal Dose of Trichlorphon on Different Biochemical and Physiological Parameters of Common Carp (Cyprinus Carpio L.) Z. JENEY, G. JENEY and J. OLAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Contents IX

Chlorate Poisoning: Mechanism of Toxicity C. S'I'JlFFEN and E. SINGELMANN .................................................... 300

Effect of Nabam and Ethylenethiourea on the Urinary Output of Rats K. SAVOLAINEN, S.-L. PELTONEN, and O. MUONA...................................... 301

Decis and Perocin Influence on the Activity of Serum Monoamine-Oxidase in Greenhouse Workers Z. ZAPRIENOV, V. PENEVA, D. CoNEVSKI, A. BAINOVA, C. KOZUHAROVA, B. DRAGNEv, and P. MOSHOEVA .................................................................... 303

Immunotoxicological Investigation of the Effects of a Pesticide; Cypermethrin I. DEsI, L. VARGA, I. DOBRONYI, and G. SZKLENARIK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305

Heavy Metal Toxicity

Effect of Some Heavy Metal Salts on Hepatic Mono-Oxygenases After Subchronic Exposure M. B. KADIISKA, T. S. STOYTCHEV and E. A. SERBINOVA ............................... 313

Intestinal Absorption of Aluminium in Rats G. B. VAN DER VOET and F. A. DE WOLFF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316

The Formation of Glutathione-Chromium Complexes and Their Possible Role in Chromium Disposition H. J. WmGAND, H. OTTENWALDER, and H. M. BOLT .................................. 319

Long-Term Exposure to Cadmium and Cardiovascular Alterations in the Rabbit M. CARMIGNANI and P. BoscoLO ................................................... 322

Lack of Substantial Neuroendocrine Changes in Short-Term High Dose Cadmium Treated Rats G. DE NATALE, A. LUCISANO, S. DAMIANO, D. CAPONE, and G. BASILE

Effect of Cadmium on Proteins M. STANKOVIC, B. STANffiIC, and A. P. GRUJIN

Interaction of Tin and Zinc in Some Processes of Heme Biosynthesis in Rabbits

327

329

G. ZAREBA and J. CHMlELNICKA .................................................... 330

The Effect of Chronic Thallium Administration on Testicular Enzyme Activities in the Rat C. GREGOTTI, L. FORMIGLI, A. DI NUCCI, P. POGGI, C. ROCCIO, R. SCELSI, L. MANZO, and F. BERTE .............................................. :..................... 332

MisceUaneous Toxicological Studies

The Effects of Methylg1yoxal on Central Synaptic Transmission in the Isolated Nerve Cord of the Cockroach (Periplaneta Americana L.) P. L. CHAMBERS, M. G. DAVIES, and M. J. ROWAN. .. . . . . .. .. . . . .. . . . . . . . . . .. . . . . .. . . . 337

The Role of Bile Acids in the Effect of Ethinylestradiol on the Biliary Excretion Rate of Exogenous Organic Anions A. PFEiFENR6rn, E. FISCHER, and F. VARGA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

x Contents

Substrate and Phenobarbital Induction of the Biliary Excretion of Exogenous Organic Anions in Rats E. FISCHER and F. VARGA ......................................................... 345

The Biliary EliInination of Sulfamerazin in Rat and Man - A Comparison T. GRAMAT'I1!, B. TEirnAAG, E. FISCHER, and F. VARGA ............... . . . . . . . . . . . . . . . . . 348

Preclinical Safety Studies with Temofel, a New Choleretic Compound E. CHOLNOKY, D. DANYI, K. ANvos, E. L. HEGYI, E. HERENDY, and S. KNEFFEL

Studies on Hyperoxaluria and Oxalate Stone Formation Induced by 2-Acetyl-3-Phenyl­Tetrahydro-1,2,4-0xadiazim-5-on

351

K. ANYos, L. NOOT, R. S. LUKAcs, L. CSALAY, and E. CHOLNOKY ..................... 357

The Biliary Elimination of Indomethacin in Man B. TERHAAG ..................................................................... 359

Increased Response of Cytochrome P-450 Dependent Biotransformation Reactions in Rat Liver to Repeated Administration of Inducers U. KLEEBERG, M. SOMMER, and W. KLINGER ......................................... 361

Influence of Pyrazolones on Hepatic Glutathione in Rats E. BIEN and M. WrIT ............................................................. 366

Comparative Study on the Sensitivity of Several Serum Enzymes in Detecting Hepatic Damage in Rats M. BAUMANN and M. BERAUER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 370

The Metabolism of Some Xenobiotics in Germ-free and Conventionalized Rats R. MACHOLZ, M. KUJAWA, J. SCHULZE, H. J. LEWERENz, and W. SCHNAAK .............. 373

The Effect of Prostacyclin on the Liver G. A. BALINT, G. KAUCSONY, A. PAP, and V. VARR6 ................................. 377

Role of Vitamins in Biotransformation of Xenobiotics P. I. LUKlENKo, M. I. BusHMA, and L. I. SUSHKO ..................................... 379

Possible Adrenal Involvement in Hydroxyurea Toxicity Defense Mechanisms P. PREZIOSI, A. NUNZIATA, S. MACRAE, E. RAGAZZONI, and M. VACCA.... ............... 380

Replacement Therapy Against Increased Hydroxyurea Toxicity in Pituitary or Adrenal Ablated Rats M. VACCA, N. DE GORI, R. DEL CARMINE, P. L. NAVARRA, and P. PREZIOSI

Testicular Toxicity of Antineoplastic Drugs During Postnatal Development of the Rat

385

R. BECHTER, R. H. MATTER, R. A. ETTLlN, and R. L. DIXON . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

Free and Bound Testosterone in Male Heroin Addicts S. LAFISCA, G. BOLELLI, F. FRANCESCHETTI, A. DANIELl, F. TAGLIARO, M. MARlGO, and C. FLAMIGNI ................................................................. 394

Effect of Single Treatment of Rats with Procarbazine on the Pituitary-Testicular Axis R. A. ETTLlN, F. HAnZISELlMOVlC, and U. HENNES .................................... 398

Contents XI

Toxic Effects of 3,7-Dimethylxanthine on Mature and Immature Male Rabbits M. G. SOFFlETTI, C. NEBBIA, and S. AMBDEO ......................................... 400

Pharmokinetics of Metoprolol in Relation to Polymorphic Sparteine Oxidation W. KIRCH, E. E. OHNHAUS, C. ZEKORN, M. EICHBLBAUM, H. SPAHN, and E. MUTSCHLER 401

Mutagenic Metabolites in Rat Urine After Dermal Exposure to 1,3-Diamino-Benzene S. CLBMMBNSBN, H. R. LAM, and A. BUCHERT ........................................ 403

Genotoxicity of Hexachlorobutadiene and Pentachlorobutenoic Acid: Correlation Between Induction of Unscheduled DNA Synthesis and Morphological Transformation in Syrian Hamster Embryo Fibroblasts D. SClnFFMANN, D. REICHERT, and D. RENSCHLER.................................... 407

Genotoxic Activity of Nitroimidazo(2,1-b)Thiazole Derivatives in Salmonella Typhimurium and Saccharomyces Cerevisiae Assays G. CANTBLLI FORTI, P. HRBLIA, M. C. GUERRA, M. PAOLINI, A. M. BARBARO, and G. L. BIAGI 408

Serum Enzymes in Toxicity of Trichloroethylene After Subchronic Ethanol Pretreatment E. SCHILLING, A. SmGBMUND, and V. GORISCH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409

Oral Intake of a Toluene-Containing Thinner. Effects and Headspace Gas Chromatographic Analytical Diagnosis K. ZAHLSBN, I. RYGNBSTAD, and O. G. NILSEN ....................................... 412

Circadian, Seasonal and Social Factors Influencing the Organic Solvent Toxicity D. L. WOLFF.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 416

Inhalation of Butanols: Changes in the Cytochrome P-450 Enzyme System K. AARSTAD, K. ZAHLSEN, and O. G. NILSEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 418

Circulating Steroids in Male Rats Following Inhalation of n-Alcohols A. M. CAMBRON, K. ZAHLSBN, E. HAUG, O. G. NILSEN, and K. B. ElK-NBS ............... ' 422

On the Embryotoxic Effects of Benzene and Its Alkyl Derivatives in Mice, Rats and Rabbits G. UNGvI.Ryand E. TATRAI ....................................................... 425

Biological Response to Nitrogen Oxide K. JACYSZYN and W. LBSmcKI................................................. ...... 431

The Use of Whole Embryo Culture in the Study of Teratogenic Mechanisms C. E. STEELE and R. MARLow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432

Behavioural Tests in the Postnatal Period After Prenatal Administration of Cyclophosphamide to Wistar Rats H. REx, C. SPRANG and D. WENDLER ............................................... 434

Grip Strength Test and Infrared Thermometry as Non-Invasive Methods to Complement Acute Toxicity Data in Mice H. NORDMANN ................................................................... 435

Behavioural Effects of Prenatal Exposure to Carbon Disulfide and to Aromatol in Rats K. LBHOTZKY, J. M. SzBIIBRilNYI, G. UNGVI.Ry, and A. KIss. . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

XII Contents

Styrene Metabolism and Striatal Dopamine Depletion in Rabbits A. MUTTI, A. ROMANELLI, M. FALZOI, S. LUCERTINI, and I. FRANCIDNI

The Influence of Ethanol Pretreatment and Social Isolation on Dopamine Release and Locomotor Activity in Mice

447

A. DIENEL, K. ANDREAS, H.-D. FISCHER, J. OEHLER, and J. SCHMIDT. . . . . . . . . . . . . . . . . . . . . 451

Metabolic Fate and Cardiovascular Effects of Arsenic in Rats and Rabbits Chronically Exposed to Trivalent and Pentavalent Arsenic M. CARMIGNANI, P. Boscow, and N. CASTELLINO..................................... 452

Relationships Between the Myocardial Concentrations of Antracyc1ine Antibiotics and Their Cardiotoxic Activity in the Rat H. HOFFMANN and A. HARTL ...................................................... 456

On the Safety Evaluation of Extracts from Synthetic Polymers Used in Medicine V. HABERMAN and D. WAITZOVA ................................................... 458

Intramuscular Injection and Muscle Damage: Comparison Between Morphological and Enzymatic Changes After Irritants, Drugs and Solvents Administration in Rabbits E. CAVALLETTI, I. CASCIARI, and O. TOFANETTI ....................................... 461

A Six Month Dermal Irritation Test with Anthralins in the GOttingen Miniature Swine H. HANlllJARVI, T. NEVALAINEN and P. MXNNIsTO .................................... 463

Separation of Immature and Adult Rat Hepatocytes into Distinct Subpopulations by Centrifugal Elutriation W. KLINGER, T. DEVEREUX, J. FOUTS, S. LoHR, D. CRAWFORD, J. DILmERTo, and R. SPARKS 469

Tests for Local Toxicity of Intramuscular Drug Preparations. Comparison of in Vitro and in Vivo Methods F. HI!lJELSE, O. SVENDSEN, and R. E. BAGDON ........................................ 474

Analysis of Cataract and Keratotic Damage Induced by 4-DiethylaminoethoxY-IX-Ethyl­Benzhydrol (RGH-6201) in Rats Z. BENcz, E. IVAN, and E. CHOLNOKY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476

Applicability of Evans Blue Diffusion for Predicting Eye and Skin Irritancy to Chemicals in the Rat J. MOLNAR, K. PAKSY, and Z. ZILAHY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480

Prediction of Toxicity Using Quantitative Structure-Activity Relationships G. DURA, G. N. KRASOVSKI, Z. I. ZHOLDAKOVA, and G. MAYER........................ 481

Structure-Activity-Adverse Effect Relationships of Condensated As-Triazine Derivatives L. PETOcZ, E. TONCSEV, E. BERENYI, and P. BENK6.................................... 488

A Mathematical Model Describing the Lethal Effects of High Temperature on Fish and Its Possible Application in the Planning of Toxicological Experiments M. KILGOUR and R. McCAULEY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489

In Vivo Formation of Carcinogenic Substance from Diethyl Pyrocarbonate in the Presence of Ammonia E. UZVOLGYI and F. BoJAN ........................................................ 490

Contents XIII

Subacute Oral Toxicity of Allyl Isothiocyanate in the Rat H. J. LEWERENz, R. PLASS, and R. MACHOLZ...... ..... ... .. ..... . .. .. ... . .. ... ... .. . 494

Preclinical Toxicity Studies with two Thymopoietin-Like Peptides E. IVAN, I. BODROGLIGETI, A. JUHASZ-NAGY, L. NEMET, and E. CHOLNOKY 495

Comparative Studies on the Effect of Some Macrolide Antibiotics on Their Own Demethylation M. MITCHEVA and Ts. STOYCHEV ................................................... 499

Ecto-A TPase in Rat and Mouse Thymocytes Cytotoxic Effects of Various Chemical Substances in Vitro G. HENNINGHAUSEN, E. M. HEHL, and J. RYCHLY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500

Toxicity of the Alkylating Agent Bendamustin U. HORN, A. HARTL, J. GUTTNER, and H. HOFFMAN................................... 504

The Leukemogenic Effect of Haloperidol in AKC3 Fl Hybrid Mice I. EMBER, V. THOMAZY, and L. MATYUS ............................................. 507

Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512