Mechanisms and toxicity of chemical carcinogens and mutagens mutagens

158 on the individual enantiomers. Separation of individual enantiomers in biological fluids after administration of racemic drugs is no longer an i n s u r m o u n t a b l e problem. Extensive research in analytical chemistry, in particular over the last several years, has provided a variety of approaches. With this technology in h a n d our understanding of the behavior of the individual enantiomers of racemic drugs in the body should greatly improve a s should the value of pharmacokinetics in the elucidation of mechanisms of drug actions and as a tool for more accurate prediction of pharmacologic-toxicologic effects. This technology should also be applied to routine therapeutic drug level monitoring.

Acknowledgements We thank Dr Thomas E. Gaffney

80% of human tumours are caused by environmental factors Mechanisms and Toxicity of Chemical Carcinogens and Mutagens edited by W . G . Flamm and R . J . Lorentzen, Princeton Scientific Publishing Co., 1985. £53.35 (pp xii + 264) I S B N 0 911131 12 4

Cancer is not a single disease, b u t a complex of diseases which share common features but have a variety of causes; carcinogenesis is a progressive process, and is subject to modulation b y different agents at the various steps involved. Faced with this complexity and with the knowledge that more than 20% of deaths in countries such as the USA and the UK result from cancer, one school of thought advises that research emphasis should be placed on early detection and more effective therapy including prevention of metastasis, more specific cytotoxic drugs and better drug delivery systems. A n alternative approach which is the justification for this

TIPS - April 1986

for valuable discussions and Marie Meadowcroft for typing the m a n u script. Supported by NHLBI grant 29566.

References 1 Williams,K. and Lee, E. (1985)Drugs 30, 333-354 2 Wilkinson,G. R. and Shand,D. G. (1975) Clin. Pharmacol. Ther. 18, 377-389 3 Breimer, D. D. and van Rossum, I. M. (1973) J. Pharm. Pharmacol. 25, 762-764 4 Wingard,L. B., O'Reilly,R. A. and Levy, G. (1978)Clin. Pharmacol. Ther. 23, 212217 5 J/ihnchen,E., Meinertz,T.,Gilfrich,H.-J., Groth, U. and Martini, A. (1976) Clin. Pharmacol. Ther. 20, 342--349 6 Godbillon,J., Richard, J., Gerardin, A., Meinertz, T., Kasper, W. and J/ihnchen, E. (1981) Br. J. Clin. Pharmacol. 12, 621629 7 Eichelbaum, M., Mikus, G. and Vogelgesang, B. (1984) Br. J. Clin. Pharmacol. 17, 453-458 8 Vogelgesang,B.,Echizen,H., Schmidt,E. and Eichelbaum,M. (1984) Br. J. Clin.

volume in a series on A d v a n c e s in Modern Environmental Toxicology,

is that, in the light of epidemiological evidence that more than 80% of h u m a n tumours are caused by environmental factors, the agents causing cancer should be identified and avoided. The emphasis in this book is on genetic mechanisms of carcinogenesis, and the ten chapters deal with: a historical perspective of chemical carcinogenesis; the somatic mutation model; the detection of mutagens; metabolic activation; chemical interactions with DNA; m a m m a l i a n DNA repair assays; carcinogenesis and mutagenesis in m a m m a l i a n cells in culture; a comparison of the animal and h u m a n carcinogenicity of environmental, occupational and therapeutic chemicals; and the question of the existence of thresholds and extrapolation from high to low dose. Many of these chapters are useful a n d informative, including Brian C h a p m a n ' s review of somatic mutation and the chapter by Charlene McQueen and Gary Williams on mammalian cell DNA repairs assays. For me, the most important contribution is Carl Barrett and Eugene Elmore's com-

Pharmacol. 18, 733-740 9 Coltart,D. J. and Shand, D. G. (1970)Br. Med. J. 3, 731-734 9 von Bahr, C., Hermansson, J. and Tawara, K. (1982)Br. J. Clin. Pharmacol. 14, 79-82 11 Silber, B., Holford, N.H.G. and Riegelman, S. (1982) J. Pharm. Sci. 71, 699--704 12 Walle,T. (1985)Drug Metab. Dispos. 13, 279-282 13 Adams,S. S., Breloff,P. and Mason,C. G. (1976) J. Pharm. Pharmacol. 28, 256-257 14 Lee, E. J. D., Williams, K., Day, R., Graham,G. and Champion,D. (1985)Br. J. Clin. Pharmacol. 19, 669-674 15 Kfipfer,A., Desmond,P. V., Schenker,S. and Branch, R.A. (1982) J. Pharmacol. Exp. Ther. 221, 590-597 16 Kiipfer,A., Desmond, P., Patwardhan, R., Schenker,S. and Branch,R. A. (1984) Clin. Pharmacol. Ther. 35, 33-39 17 Lennard,M. S., Tucker,G. T., Silas,J. H., Freestone,S., Ramsay,L. E. and Woods, H.F. (1983) Clin. Pharmacol. Ther. 34, 732-737 18 Banfield,C., O'Reilly,R., Chan, E. and Rowland,M. (1983)Br. J. Clin. Pharmacol. 16, 669-675 19 O'Reilly,R. A. (1982)Circulation 65, 202207

parison of carcinogenesis and mutagenesis in cultured mammalian cells, for, since 80% of h u m a n cancers are of epithelial origin, I feel that more emphasis should be placed on research on diploid h u m a n epithelial cell neoplastic transformation at the expense of studies on aneuploid rodent fibroblasts. The book suffers from repetition and an u n e v e n n e s s of quality. These faults cannot be totally avoided in multi-author works, but are particularly noticeable here. Finally, I was left with a feeling that a n u m b e r of other important questions had not been adequately addressed, including the following: (1) Is the distinction between genetic and epigenetic carcinogens real and based on a meaningful use of 'epigenetic' and an acceptable degree of understanding of the mechanisms involved, or is it merely a convenient way of avoiding chemicals which complicate current thinking on 'genetic' mechanisms b y failing to conform? (2) Why have so m a n y short-term methods for detecting mutagens been developed, why has there been such reluctance to select from among them, and w h y have those involved been so ready to allow them to be viewed as tests for carcinogens? (3) Is the mouse lymphoma

159

TIPS - April 1986 L 5 1 7 8 T K + / - assay of any use whatsoever? (4) W h a t confidence can be placed in the ability of methods incorporating a rat liver $9 mix to identify chemicals likely to be metabolized to carcinogenic derivatives in man? (5) H o w can research on genetic mechanisms of carcinogenesis be integrated with work on other

factors which influence tumourigenesis, so that carcinogenic potency in man, as o p p o s e d to carcinogenic potential in cells or in animals, can be meaningfully assessed?

Neurotoxins with some omissions

both the diverse nature of the subject, as well as the challenge it presents in our u n d e r s t a n d i n g of the mechanism of toxicity of various agents on the nervous system. It is gratifying to see a wide international authorship in the book: with contributions from Europe and Japan equal to those from North America. There are a total of 30 chapters roughly d i v i d e d into four sections with a reasonable n u m b e r of tables and illustrations. There are more than 2300 references contained in the whole work. Part one has nine chapters and deals with basic pathophysiology as well as giving a broad morphological approach to u n d e r s t a n d i n g putative neurotoxins. There are outstanding contributions on the peripheral nervous system, the action of drugs of abuse on the reward system of the brain, and neuropeptides and addiction. However, it was disappointing to see no mention of endogenous excitotoxins that might cause neurological disease or MPTP-induced parkinsonism. A rather short second section (four chapters) presents interesting

Drug and Chemical Toxicology 3/ Neurotoxicology edited by Kenneth Blum and Luigi Manzo, Marcel Dekker, 1985. US$99.75 (USA and Canada) US$119.50 (outside USA) (pp. xviii + 676) ISBN 0 8247 7283 0 The nervous system presents a most important and uniquely vulnerable target for drug and chemical toxicity. It is, therefore, not surprising that study and interest in the nervous system has become a rapidly growing sub-speciality within toxicology over the last 20 years. Neurotoxicology is the most recent of three volumes in a series on Drug and Chemical Toxicology which, according to the series' editors, was established in order to provide a means b y which leading scientists may present new and important information around a diverse and flexible theme. This is indeed an interesting and stimulating volume, which succeeds in enlarging one's appreciation of

MICHAEL BALLS

FRAME, Eastgate House, 34 Stoney Street, Nottingham NG1 1NB, UK, and Department of Human Morphology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK.

overviews of those groups of drugs well established as having neurotoxic potential such as the major tranquillisers, anticonvulsants and anticancer agents. A much longer third section (eleven chapters) deals with the various well k n o w n neurotoxins within the h u m a n environment. There are thus basic reviews on heavy metals such as lead and mercury, chlorinated and organophosphorus pesticides, halogenated hydrocarbons, cyanide, finally animal and marine neurotoxins. This was a section with perhaps too much emphasis on heavy metals that would have benefited from additional contributions on solvent abuse and occupational solvent exposure, also newer areas such as dietary intolerance and food additives. The final section of the book (six chapters) deals with the assessment of neurotoxins and covers a n u m b e r of experimental and behavioural animal models of neurotoxicity also the application of various electrophysiological techniques. The book, despite its omissions, will certainly appeal to both basic scientists working in the neurosciences also the clinician with interests in neurology or toxicology. It also presents an excellent review of neurotoxicology that is ideal for postgraduate courses in either the neurosciences or toxicology. R O B I N A. B R A I T H W A I T E

Regional Laboratory for Toxicology, Dudley Road Hospital, Birmingham, B18 7QH, UK.