Animals and Alternatives in Toxicity Testing

Transcription

1 o Animals and Alternatives in Toxicity Testing Editors Michael Balls RosemaryJ. Riddell Alastair N. Worden \ 1983 E;»CI.'. fs- ACADEMIC PRESS A Subsidiary of Harcourt Brace Jovanovich, Publishers London New York Paris San Diego San Francisco Sao Paulo Sydney Tokyo Toronto

2 CONTENTS Contributors Preface i v ACUTE TOXICITY Acute Toxicity Testing V.K.H. Brown 1 Short-term Testing in Drug Development J.S.L. Fowler 16 Alternatives in Acute Toxicity Testing M.C. Tattersall 23 Roy Goulding (Rapporteur) 26 PHARMACOKINETICS Application of Pharmacokinetics J.W. Bridges, L.F. Chasseaud, G.M. Cohen & C.H. Walker 31 Immunology in Safety Evaluation Klara Miller 67 Pharmacokinetics and Pesticides G.T. Brooks 71 C.H. Walker (Rapporteur) 75 LONG-TERM TOXICITY Long-term Toxicity Ralph Heywood 79 Is There an Alternative? S.R. Walker 93 Repeat-dose Long-term Toxicity Studies J.P. Griffin 98 A.N. Worden (Rapporteur) 104 CARCINOGENICITY Carcinogenicity ' I.F.H. Purchase 109 Carcinogenicity Testing F.J.C. Roe 127 New Approaches J.W. Weisburger 131

3 Peter Knox (Rapporteur) 135 MATHEMATICAL MODELLING Mathematical Modelling M.S. Tute 137 Structure-toxicity Studies David Bawden 151 Mathematical Models in Pharmacotoxicity E.R. Carson 154 Quantitative Use of Structural Designs J.C. Dearden 160 David Machin (Rapporteur) 165 DESIGN OF EXPERIMENTS Statistical Contributions to Experimental Design G.F. Healey 167 Statistics and the Objectives of FRAME D.O. Chanter 188 Design and Analysis of Carcinogenicity Studies P.N. Lee 191 David Machin (Rapporteur) 194 REPRODUCTIVE TOXICITY Reproductive Toxicity C.L. Berry 197 In Vitro Reproductive Toxicity Studies Keith Snell 207 Problems in Current Reproductive Toxicity Testing N.A. Brown 214 Alternative Methods A.K. Palmer 218 Hazards to Development Ruth Clayton 221 A.N. Worden (Rapporteur) 226 NEUROTOXICITY Neurotoxicity A.J. Dewar 229

4 Neurotoxicity Testing: Some Observations H.W. Reading 284 The Integrative Approach Robert Hess, G. Krinke & J. Schaeppi 288 Human Accidents Nigel Legg 294 A.N. Worden (Rapporteur) 296 INHALATION TOXICITY Inhalation Toxicity D.G. Clark 299 Inhalation Toxicology R.C. Brown & Alan Poole 300 Recommendations D.G. Clark & R.C. Brown 309 A.N. Worden (Rapporteur) 311 DERMAL TOXICITY Testing for Cutaneous Toxicity Ronald Marks 313 Skin Phototoxicity in Man A.R. Young 327 Dermal Toxicity J.M. Faceini & J.P. Guillot 329 N.J. Van Abbe (Rapporteur) 335 OCULAR TOXICITY Eye Irritancy Testing D.W. Swanston 337 In Vitro Studies on Ocular Irritancy M.C. Scaife 367 An Isolated Rabbit Eye Technique Michael York 369 Dosage-volume, Sample Size and Predictability S.J. Williams 371 N.J. Van Abbe (Rapporteur) 378 Addendum on Dermal and Ocular Toxicity N.J. Van Abbe 379

5 GENOTOXICITY Short-term Tests for Genotoxicity B.J. Dean & Peter Hodges 381 Cytogenetic Monitoring of Human Populations D.J. Kirkland 409 Some Comments on Genotoxicity Testing Eric Longstaff 414 In Vitro Assays J.M. Parry 419 Peter Hodges (Rapporteur) 426 HUMAN STUDIES Evaluation of Toxicity in Man N.W. Shephard 429 Drug and Chemical Toxicity in Humans P.N. Bennett 435 Lessons Learned W.H.W. Inman 439 Paul Turner (Rapporteur) 442 REGULATIONS Regulatory Aspects Dennis V.W. Parke 445 The Need for Flexibility Andrew Cockburn 457 Consultation with the Regulatory Authorities A.N. Worden 459 Improving Legislation R.S. Vine 462 D.M. Conning (Rapporteur) 467 DEVELOPMENT OF ALTERNATIVES The FRAME Research Programme Michael Balls 471 The Johns Hopkins Center A.M. Goldberg 476

6 DISCUSSIONS Round Table Discussion K.J. Obrink (Chairman) 481 Summing-up Leon Golberg 493 APPENDIX Report of the FRAME Toxicity Committee 501 Subject Index 541