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^U: l/?^J This work wasfunded by a grantfrom the Health and Safety Executive, ILK. Any conclitfionj drown are those of the authors. ^Reproductive Hazards of Industrial CJiemicals An evaluation of anini4f and human data SUSAN M ^IIARLOW ano FRANK M. SULLIVAN Department of Pharmacology (7y'j Hospital Medical School Vnivnsity of London l-'XiV. C? COM.!. J9B2 t::vZsi uttiwitY ACADEMIC PRESS A Suht 'ximry of /tarcourt Bract Jaraaarich, tabhrhor* London New York Puns - San Diego San Francisco S3o Paulo Sydney * Tokyo Toronto OLI 3148 O IiI 3149 m ACADEMIC PRESS INC. (LONDON) LTD. 24/2S Oval Road London NWI United Stales Edition /mKiiW by ACADEMIC PRESS INC. 111 Firth Avenue New YoiL, New York 10003 Copyright 1982 by ACADEMIC PRESS INC. (LONDON) LTD. All Rights Reserved No part of ihii book may be reproduced in any form by photostat, microfilm, or any other means, without written permission from the publishers British Library Cataloguing in Publication Data Barlow, S. M. Reproductive hazards of industrial chemicals. I. Human reproduction 2. Chemicals--Toxicology I. Title II. Sullivan. F.M. 6)66 QP25) Library of Congress Catalog Card Number. 82-71008 ISBN: 0-12-078960-4 Phototypeset by Latimer Trend & Company Ltd, Plymouth Printed in Great Dritam by St Edmundsbury Press Preface Reproductive hazards Irom industrial elicitncal exposure is one of (lie fastest growing areas of concern in toxicology today. This is not yet matched however, by any substantial body or reliable evidence that would permit some assessment of the extent of the potential problem. This information gap extends from inadequate or non-existent animal toxicology studies right through to the absence of epidemiological studies on humans exposed to the majority of industrial chemicals. Most human evidence has come as a result of industrial or envitonmental accidents with gross over-exposure. Thus, even with chemicals such as lead, organic mercury, chlordccone, dibromochloropropane (DBCP), and organo-chlorine compounds known to affect human reproduction, the evidence is inadequate to assess the effects of low levels of exposure. We were invited by the fJ.K. Health and Safety Executive to collect and review the available evidence on the reproductive toxicity of approximately 50 industrial chemicals chosen from the Threshold Limit Values (TLV) list because of their general interest or widespread use. It was hoped that such a review would show the range and types of informal ion available on industrial chemicals and possibly indicate the size of the potential reproductive hazard. We took it upon ourselves to exclude a few substances such as inorganic lead about which a great deal or easily obtained information is already available We also added some others such as DBCP which we knew had already presented a reproductive hazard to exposed workers. This was to illusi rate the value and limitations of animal studies for prediction of human hazards and to demonstrate the value of epidemiological studies in workers exposed not only in the production or such substances but also in their subsequent use. This book therefore obviously cannot be regarded as a catalogue of all of the potentially hazardous chemicals, but is a detailed review of all the available evidence on some out of many thousands of such chemicals. However, it includes many substances with widespread use as solvents and intermediates and wilh environmental impact as pollutants, and we hope will be of interest and value to those concerned wilh industrial health and hygiene and environmental pollution in its widest sense. Each chemical has been reviewed using the same general format. First animal studies on relevant pharmacology and toxicology, endocrine and gonadal effects have been described. This is followed by animal data on ferti lity and pregnancy including teratogenicity, mulligeneration, postnatal and OLI 3150 Vl 1 ' 'V1*1 1 behavioural teratology studies where available. In the mutagenicity sections only studies on mammalian cells in vitro and in vivo have been reviewed. Carcinogenicity studies have only been very briefly covered by reference to the excellent International Agency for Research on Cancer (I.A.R.C.) World Health Organization (W.H.O.) monographs unless specific data on transplac ental carcinogenicity studies were found. The animal studies are followed by reports of human studies following the same general format where possible. Each review ends with a brief summary and our evaluation of the potential hazard to reproduction. A section on reproductive outcome by occupational groups has also been included. In this, the individual chemical or chemicals responsible for the effects may not have been identified, but they indicate the need for further work to attempt to do so. We are grateful to our numerous colleagues, library assistants and secretarial friends for their help in producing this book and to the Health and Safety Executive for funding the project which turned out to be a much bigger job than any of us had imagined. June 1982 S. M. BARLOW F. M. SULLIVAN Contents Preface ........... v PART I Scientific background to testing and recognition of reproduc tive hazards ... I Reproductive hazards . . . . . 3 Historical perspectives ...... 3 The range of possible reproductive hazards of industrial chemicals .............................................................................. 4 - Reproductive toxicity testing in animate . ... 9 Single generation studies ...... 9 Fertility studies in males.........................................................12 Mulligeneration studies Interpretation of animal experiments and extrapolation to humans ........ 14 Assessment or reproductive effects in humans ... 23 Mutagenicity testing ....... 28 Reproductive hazards associated with different occupa tional groups............................................................................ 32 Spontaneous abortions .........................................................32 Malformations and perinatal deaths .... 34 Cancer in the offspring........................................................ 35 Gene mutations in offspring.............................................. 38 Conclusion......... 40 Effects reported in male workers.............................................. 40 Effects reported in female workers . s .41 Effects reported in animal studies but with no human evidence .. . .41 vii 13 PART 2 Review of compounds Background io the review of compounds. ... Literature search ...... Criteria for acceptable methodology in animal studies Mutagenicity ........ Carcinogenicity ....... 45 45 47 49 49 format comprising animal studies, hurium studies and a summary and evaluation. Animal and fiuiiian studies are sub divided into sections on pharmacology and toxicology, en docrine and gonadal effects,fertility, pregnancy, mutagenicity and carcinogenicity. 1. Acrylonitrile ....... ^0 2. Aniline. ........ ^5 3. Arsenic and its Compounds........................................ 4. Benzene ... . .83 5. Ben/o(a)pyTen'' ........ *4 6. Beryllium . .119 7. Boric Acid (Boron) ... *26 8. Cadmium and its Compounds . .136 9. Carbon Monoxide............................................................ 10. Carbon Tetrachloride.......................................................200 11. Chiordecone (Kepone).......................................................212 12. Chloroform.......................................................................... 230 13. Chloroprene.......................................................................... 239 14. Dibromochloropropane (DBCP) .... 253 !5. Dichlorobenzene.................................................................269 16. 1,1-Dichloroethane.......................................................273 17. Dichloromethane.................................................................276 18. Dioxane..................................................- 283 19. Epichlorohydrin.................................................................287 20. Ethylene Dibromide (Dibromoethane) 296 21. Ethylene Dichloride....................................................... 3' 22. Ethylene Oxide ....... 316 23. Fluorocarbons.................................................................326 24. Formaldehyde.................................................................334 25. Formamides.......................................................................... 346 26. Lead (Organic)................................................................ 360 27. Manganese and its Compounds .... 370 OLI 3151 28. Mercury and its Compounds (Inorganic) . 386 29. Methyl n-Bulyl Ketone ...... 407 30. Methyl Chlorofotm ...... 410 31. Methyl Ethyl Ketone (MEK) . . 413 32. Nitrogen Dioxide . .417 31. ,)/one....................................................................................422 34. Platinum and its Compounds . . 4H 35. Polybrominaled Biphenyls (PUB) .... 437 36. Polychlorinated Biphenyls (PCB) .... 455 37. Selenium and its Compounds ..... 483 38. Styrene................................................... 501 39. Tellurium and its Compounds . .... 515 40. Tetrachloroelhylene ...... 523 41. Thallium and its Compounds ..... 530 42. Toluene ........ 538 43. Toluene-2,4-Diisocyanate ..... 550 44. o-Toluidine ........ 553 45. Trichloroethylene ... .' 556 46. Vinyl Chloride................................................................ 566 47. Vinylidenc Chloride ...... 583 48. Xylene............................................................................... 592 Index 600 P\u^r oS r'fc a