Document DDBJZXjpK6Yr1wgL04xLO4beo

FJ Ttit'W Vol N pp ttO^IOdlO. J4|l Primed m Gfc^i Bfiuin All nyM> reserved 001 S-:m l OM607.04tola) o Copyright O idMl Perg^muft Sw.. ^td INTERSPECIES RESPONSE TO CARCINOGENS AND OESTROGENS V. A. Drill Department of Pharmacology. College of Medicine. Unucrtitty of Illinois at the Medical Center. Chicago. IL httMt). USA I Received Id January IVRI | Summary--Carcinogenic chemicals produce specific malignancies in a wide variety of animal species and in a high proportion of the treated animals. Oestrogens do no) demonstrate a carcinogenic profile, producing malignancies in a limited number of animal species and in a low proportion of the treated animals. The effect of oestrogens depends on both species and strain. I Introduction absorption and metabolism, is a general biological Dr Leon Golberg has contributed to toxicology not only as the founder and longtime Editor of Food and Cosmetics Toxicology, but also by his research and publications <cf. Golberg, 1974, 1978). It may be remembered that Dr Golberg was one of the discoverers of diethylstilboestrol, the first syn thetic oestrogen to be developed (Dodds, Golberg, Lawson & Robinson, 1938). The oestrogens are often cited as being carcinogenic in animal studies, and in this brief review I should like to summarize responses response obtained in a variety of species. Indeed, based on the concept of covalent binding to DNA, we would expea a carcinogen to produce essentially the same effea in different species of animals. When a given compound induces the same carcinogenic re sponse in several different species it may be predicted, depending on dosage and duration of exposure, that a carcinogenic response will also be obtained in man. Two other characteristics of carcinogens should also be noted; of a range of species to oestrogens and to contrast the (i) Carcinogens induce their specific neoplastic I results with the effects of carcinogens. The discussion of the effects of oestrogens will be limited to their effects in a high proportion of the treated animals (Table 2). action on the breast and the uterine cervix and endo (ii) The increased incidence of specific neoplasms i metrium. is obtained in a relatively short period of time. The neoplastic response is discerned before the i * Interspecies response to carcinogens Compounds such as 2-naphthylamine. aflatoxin B,. end of an 18-month toxicity study in the mouse or a 2-yr chronic toxicity study in the rat. * asbestos, and the other examples listed in Table I, '-i produce their characteristic tumorigenic effect in a number of different species (1ARC. 1972. 1974, 1976 & lnterspecies response to oestrogens 1977; Irving. Wiseman 8l Young, 1967; Miller & Eno- The effea of oestrogens on the occurrence of malig moto. 1964; Miller, Miller St Hartman, 1961). Cleariy nancies of the mammary gland, uterine cervix and the response to a specific carcinogen is not limited to endometrium in different species of animals is sum one or two species but. allowing for differences in marized in Table 3. It is apparent from this summary Table I. Examples of specter responses to carcinogens Carcinogenic response of Compound* Target site Mouse Rat Hamster Guinea-pig Rabbit Dog Monkey Man 2-Naphthylamnte LAmmobi phenyl MNNG V-OH-AAF Anatoxin B( Asbestos? Bladder Bladder GI tract GI tract Liver Pleural mesorhelium. lung + 4* 4* 4* +t 4* 0 + 444- 4* 4* 44* 4- 4- 4- 4* 4* + 4* 1 4* + 0 4* 4- 4* + m Positive effect 0 No effea MNNG - \-Melhyl-.V-nitro-iV-niirosoguanidine (V-OH-AAF /V-Hydroxy-2-acctylaminoRuorene * Xdministered orally unless otherwise stated, tlntrapcruoneal. ineffective orally in the mouse. 1 Inhalation. r r | J.-, 921001 RovvVer a 607 k 608 V A. Dull Table 2. Time and intensm of carcinogenic response. Effect of N-hydroxy-2-acetylamtnofluorene in miff and rats Target site Percentage of animals with cancer Mammary gland. Forestomach! Livert Urinary bladder! Mammary gland! Forestomach! Liver! In female mice* after... treated control la rats* after... M F M F M F 10 months 9 75 2 5 0 3 months . 27 0 12 months 19 125 t2 5 2 5 months 45 0 14 months 30t I5t 23 12 9 8 months 0 67 9 60 64 13 'Mouse data from Miller et al. 1964; rat data from Miller er al. 1961. tSurvival rates of the treated and control groups differed; life-table analysis is necessary. {Data is for treated animals only since there were no malignant tumours in control mice at 14 months, or in control rats at 8 months. that oestrogens do not produce comparable effects in several different species or a response of the magni tude that is characteristic of a carcinogen. A positive effect of oestrogen is restricted to certain special situations. Breast cancer Articles on hormones and cancer may state that exogenous oestrogen causes breast cancer in mice, but such a statement is only partly true. It is usually not recognized or appreciated that oestrogen will increase the incidence of breast cancer only in male mice from inbred strains that possess a transmissible milk factor (a mammary tumour virus); oestrogen is ineffective in male mice from a low-tumour strain, i.e. without the milk (actor. Neither mestrano! nor ethinyloestradiol increases the occurrence of mammary cancer in CF-LP females, a low-tumour strain (Committee on Safety of Medicines. 1972; Drill 1974; Lee, 1979). The effect of oestrogen in the female rat is very variable. As indicated in Table 3 oestrogen may be without effect or may produce mammary cancer in as many as 27% of the treated animals. The reason for this marked variation is unknown although it may possibly represent in part the variation that is encountered in untreated female rats. For example, Durbin et al. (1966) found the normal incidence of mammary adenocarcinoma m untreated rats to vary between 0 and 18%. and in our studies the probability of tumour development based on life-table analysis varied from 0 to 15-7% (Drill, 1974). References to studies of breast cancer in other spe cies are cited in several reviews (Drill. 197S & 1981). Of particular interest is the absence of an effect of oestrogen in dogs and monkeys treated with different doses of oestrogen for 6 or more years. A variety of clinical studies also demonstrates the lack of a relationship between exogenous oestrogen and breast cancer. In five retrospective case-controls there was no association between use of an oestrogen and the relative risk for breast cancer, and a series of 12 clinical studies did not demonstrate an increased occurrence of cases of breast cancer in women treated with oestrogens (cf. Drill 1975 & 19811 Cervical cancer The oral administration of oestrogen may occasion ally induce cervical carcinomas in mice, but oestro gens do not produce cervical cancer in other species (Drill 19761 Even in the mouse the overall incidence of cervical carcinomas is low and is not diaractcristic of the effects of a carcinogen (Table 31 Gimcal studies do not provide any evidence that the long-term use of oestrogen induces cervical cancer (Drill 19761 indi cating good agreement between the experimental and clinical data. Endometrial cancer The relationship of exogenous oestrogen to endo metrial cancer is currently the subject of intensive clinical study. However, oestrogens do not act as typical carcinogens in animals, producing a slight Table 3. Comparison of carcinogenic effects of oestrogens ut female animals Carcinogenic response to oestrogens of" Target site Mouse Rat Guinea-pig Rabbit Dog Monkey Man Breast Uterine cervix Endometrium 0* tlWJ (2-1%) +t 0 0 0 0 0 0 000 000 0 + 7 0 0 0* 0 m No effect m Borderline effect 'Positive in male mice with mammary tumour virus. tRange from 0% to 27% with adenocarcinoma. + - Positive effect 3^ iuOl ft Q'vV Ver f O'M-r- ' 1 1 spe1981). ^ of nt s the n en n >ls ics of e ed t ed i: ne opecies dence :: lie u es use of indiil nd 1 4 1 j i * 1 i> a i { i e oei ve ici as slight Comparison of carcinogens and oestrogens 604 effect in the mouse and possibly a positive effect in the rabbit, but no effect in other species (Table 3). A strain difference in response may be present in mice, as the carcinoma was present in eight of 71 BDH-SPF mice and only in 3 of 461 other mice (Drill. 1979 & 1980). Carcinomas may possibly occur in the rabbit, but information in this species is very limited; the rabbit may be an atypical species as cancer may occur in as many as 56% of untreated rabbits in the Tans breed (Greene, 1959). A complete review of clinical data on oestrogen administration and endometrial cancer is beyond the scope of this paper and only general comments will be made on the subject. Much of the clinical data is derived from retrospective case-control studies (which measure association), and in a tabulation of nine studies a risk was absent in four studies and present in five of the studies (Drill, 1980). In the study of Horwitz & Feinstein (1978) the relative risk varied from 12-0 to 1-7 depending on the sampling procedure (see also Horwitz & Feinstein, 1980). More recently, an increase in risk has also been reported by Hulka, Kaufman, Fowler, Grimson & Greenberg (1980) and Shapiro, Kaufman, Slone, Rosenberg, Miettinen et at. (1980) and some authors have found a higher risk with increasing duration of use of oestrogens. In contrast, a series of retrospective case-control studies conducted in Europe has failed to demonstrate a risk for endometrial cancer in oestro gen-users (Lauritzen, 1978; Salmi. 1979 St 1980; Volker. Kannengiesser, Majewski & Vasterling, 1978). Antunes, Stolley. Rosenhein, Davies, Tonascia at. (1979) found a relative risk of either 6-0 or 2-1 depend ing on the control group selected, indicating again the variation in results that can be obtained. Ultimately, prospective clinical data will be required if we are to reach a definite conclusion on oestrogens and endo metrial cancer, and in view of the present status of this area the clinical studies are indicated by a ques tion mark in Table 3. Discussion It has been established that chemicals that are car cinogenic in man will produce a similar cancer m a variety of animal species. In view of this correlation, chemicals and drugs can be evaluated in animals to predict potential human carcinogenicity. The sus pected carcinogen should produce an effect that is not limited to one (or two) species of animals (Table l); indeed, based on a DNA mechanism we would expect to obtain a similar organ response in most of the species tested. Secondly, in appraising carcino genicity the magnitude of the response should also be considered: it is usually not appreciated that the known carcinogens produce a positive organ-specific response in a high proportion of the test animals (Table 21 Research papers on hormones often state that oes trogens have been shown to be carcinogenic in ani mals. that oestrogens induce tumours in five species of animals, or that oestrogens are hormonal carcinogens. Although such statements have some validity when applied to specific animal studies, they are in general based on a lack of understanding of the effects of oestro-t'ns m animals. For example, it is often stated that oestrogens induce cancer in mice, but it is not stated or appreciated that the effect is confined to male mice from specific inbred strains that possess a mammary tumour virus (Drill. 1981). The effect of oestrogens on the mammary gland, uterine cervix or the uterine endometrium of different animal species does not demonstrate a carcinogenic profile. Although oestrogens may produce an organ-specific response in the mouse or rat (Table 3), they do not produce the interspecies effect characteristic of a car cinogen. The effect of oestrogen is strain- and speciesdependent. Also, when a positive response is obtained only a small proportion of the treated animals are affected, a response that is not typical of a carcinogen. Clinical data do not demonstrate a relationship between oestrogen administration and the occurrence of breast or cervical cancer, agreeing well with the absence of a carcinogenic profile in animal studies. The clinical appraisal of oestrogens and endometrial cancer is still in progress and in view of the conflicting data that have been obtained, a definite conclusion cannot presently be drawn. It is generally accepted that the induction of cancer by chemicals involves the covalent binding of the chemical or its metabolites to DNA. Thus, an esti mate of carcinogenic potential can be made by pro cedures that are not dependent on tumour induction. In a highly significant study Lutz St Schlatter (1979) measured the covalent binding of various chemicals to DNA in rat liver. They demonstrated that very potent hepatocarcinogens such as aflatoxin B, or M, have a high covalent binding index (CBI). Benzene, which does not induce liver tumours gave a very low CBI. and oestrone and ethinyioestradiol gave a CBI slightly less than that of benzene, essentially a nega tive result Oestrogens are necessary for the growth and func tion of the female reproductive organs and to the extent that they produce functional organs in women they lay the groundwork for the development of cancer. As such they are not carcinogens, but they develop the organs to a functional state that is re sponsive to carcinogenic influences. The oestrogens have at tunes been called cocarcinogens or facultative carcinogens, but such terms are not entirely satisfac tory; perhaps the oestrogens are best described as having a non-specific permissive action. REFERENCES Antunes. C. F. M,, Stolley. P. D. Rosenhein. N. B.. Davies J L.. Tonascia. J. A, Brown. C, Burnett L Rutledge. A.. Pokemper, M. St Garcia. R. (19791 Endometrial cancer and estrogen use. New Engl. J. Med. 300. 9. Committee on Safety of Mediones (1972). Carcinogenicity Tests of Oral Contraceptives. HMSO. London. Dodds. E. C. Golberg. L, Lawson, W. St Robinson. R. (1938). Oestrogenic activity of alkylated stilboestrols Nature. Land. 142, 34. Drill. V. A. (1974). Experimental and clinical studies on relationship of oestrogens and oral contraceptives to breast cancer. Excerpta Medics Int. Congress Scries. No. 311. p. 200. Drill V. A. (1975). Oral contraceptives: Relation to mam mary cancer, benign breast lesions, and cervical cancer. A. Rev. Pharmac. IS. 367. 32^001 RcwVer ^ 610 V A Drill Drill. V A (1976) Effect of estrogens and progestms on the cervix uteri. J Toxicol, envtr Hlth. Suppl. I. 193 Drill. V A (19791 Evaluation of the carcinogenic effects of estrogens, progestins and oral contraceptives on cervix, uterus and ovary of animals and man. Archs Toxicol. Suppl. 2. 59. Drill. V. A. (1980). Relationship of estrogens and oral conTracepnves to endometrial cancer in animals and women. J reprod Med. 24, 5. Drill. V. A (1981). An overview of studies on estrogens, oral contraceptives and breast cancer. Prog. Drug Res. In press. Durbin. P. W,, Williams. M. H.. Jeung. N. & Arnold. J. S (1966). Development of spontaneous mammary tumors over the life-span of the female Charles River (SpragueDawley) rat: The influence of ovariectomy, thyroidec tomy. and adrenalectomy-ovariectomy Cancer Res. 26, 400. Golberg. L. (Editor) (1974). Carcinogenesis Testing of Chemicals. CRC Press. Cleveland. OH. Golberg. L. (19781 Toxicology: Has a new era dawned? Pharmac. Rev. 30, 351. Greene, H. S. N. (1959). Adenocarcinoma of the uterine fundus in the rabbit. Ann. N Y. Acad. Set. 75, 535. Horwuz. R. I. 4 Fetnstein. A.-R. (1978). Alternative analy tic methods for case-controls studies of estrogens and endometrial cancer. New Engl J. Med. 299, 1089. Horwuz. R. I. 4 Feinstein. A. R. (1980). The problem of "Protopathic Bias' in case-control studies. Am. J. Med. 68. 255 Hulka. B. S.. Kaufman. D G.. Fowler. W. C_ Jr, Grimson. R. C. 4 Greenberg. B. G. (1980). Predominance of early endometrial cancer after long-term estrogen use. J. Am. med. Ass 244. 2419. IARC Working Group (1972). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. I. p. 74. International Agency for Research on Cancer. Lyon. IARC Working Group (1974). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Some Aromatic Amines. Hydrazine and Related Sub stances. S-Nitroso Compounds and Miscellaneous Alkyl ating Agents. Vol. 4 p 97 International Agency for Research on Cancer. Lyon. IARC Working Group (19761. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man Some Naturally Occurring Substances. Vol. 10. p. 51. In ternational Agency for Research on Cancer. Lyon. IARC Working Group (1977). IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man Asbestos. Vol. 14. p 1. International Agency for Research on Cancer. Lyon. Irving. C. C, Wiseman, R . Jr Sc Young. J. M. (1967). Carci nogenicity of 2-acetylaminoftuorene and V-hydroxv-2acetylaminofluorene in the rabbit. Cancer Res. 27. 838 Launtzen. Ch. (1978). Ostrogene und Endometriumkarzinom. Stellungnahme zur Verbflentlichung der Arznetmittel-Kommission. Fortschr. Med. 96, 2293 Lee, A. E. (1979). Tumour incidence in mice after oestrogen and progesterone treatment. Br. J Cancer 40. 319 Lutz. W K St Schlatter. Ch. (1979). In vivo covalent bind ing of chemicals to DNA as a short-term test for carcinogenicity. Archs Toxicol. Suppl. 2. 411. Miller. E. C.. Miller. J. A 4 Enomoto. M (19641 The comparative carcinogenicities of 2-acetylaminofluorene and us .V-hydroxy metabolite in mice, hamsters, and guinea pigs. Cancer Res. 24, 2018. Miller. E. C. Miller, J. A. 4 Hartmann. H. S. (1961). /V-Hydroxy-2-acetylaminoAuorene: A metabolite of 2acetylammofluorene with increased carcinogenic activity in the rat. Cancer Res. 21, 815. Salmi. T. (1979). Risk factors in endometrial carcinoma with special reference to the use of estrogens. Acta obstet. gynec. scand. Suppl. 86. I. Salmi. T. (1980). Endometrial carcinoma risk factors with special reference to the use of oestrogens. Acta endocr Suppl. 233. 37. Shapiro, S_ Kaufman. D. W.. Slone. D. Rosenberg. L.. Miettinen. O. S, Stolley. P. D, Rosenheim. N. B.. Wat ting. W. G.. Leavitt. T_ Jr 4 Knapp. R. C. (1980). Recent and past use of conjugated estrogens in relation to adenocarcinoma of the endometrium. New Engl J. Med. MS, 485. Volker. W.. Kannengiesser. U. Majewsku A. 4 Vasterlmg. H. W. (1978). Ostrogentherapie und Endometriumkarzinom. Geburtsh. Frauenhetlk. 38. 735. 921001 RowVerJC k7 6 U M Metzler (Metzler & McLachlan. 1981). Both the epoxide itself and two rearrangement products could be seen in the gas chromatogram, in a pattern which was also obtained when synthetic DIES-2.3-oxide was gaschromatographed. Therefore. DIES must be con sidered to be oxidized at the aromatic ring and at the ofefinic double bond. There was no indication of ali phatic hydroxylation. The oestrogenicity of EE-DIES is about the same as that of E-DES (Dodds ei al. 1939). Again, no infor mation is available so far about the foetotoxicity and eenotoxicity of this compound. Conclusion Current evidence shows that the synthetic oestro gen. DES. is metabolized to a variety of oxidative metabolites along several pathways involving reactive intermediates. This fact, and-a positive response in several assays, indicating genetic damage, raise the possibility that metabolic activation may be involved m the carcinogenic effect of DES. The exact mechanistms) accounting for the organ-directed carcinogeni city of DES is not known, but several possibilities are conceivable (Metzler & McLachlan. 1979). Examples are the formation of reactive metabolites that retain their oestrogenicity and are thus accumulated in oes trogen target organs, and the preferential formation of reactive metabolites in those organs by specific enzymes. The first possibility can be exemplified by E-DES-3.4-oxidc (Fig. 2). which has been found to be highly oestrogenic in nio and in vitro (Korach. Metzler St McLachlan. 1978). An attractive hypoth esis for the organ-specific activation of DES would be peroxidase-mediated oxidation, since oestrogeninducible peroxidase activity exists in all organs that depend on oestrogens for growth (Anderson. Kang & DeSombre. 1975). It appears that certain DES analogues such as HES and E.E-DIES may be useful for clarifying further the role of metabolic activation in the genetic toxicity and carcinogenicity of DES. These compounds are power ful oestrogens but they have different routes of metab olism. It will be of interest to determine whether their effects in the different in vitro and in ni o systems can reasonably be correlated with certain metabolic path ways. Acknowledgement--The studies carried oui in our labora tory and cited in this paper have been supported by the Deutsche Forschungsgemetnschaft. REFERENCES \ndcnon. W. A. Kang. Y.-H. St DeSombre. E. R. (19751. Endogenous peroxidase: Specific marker enzyme for tissues displaying growth dependency on estrogen. J. Cell Biol. 64. 668. Blackburn. G. M,, Thompson. M. H Sl King. H. W. S. (19761. Binding of diethylsiilboesiroi to deoxyribonucleic acid by rat liver microsomal fractions in uiro and in mouse ioeial cells in culture. Btochem J. 158. 643. Give. D. Johnson. K. O.. Spector. J F S.. Batson. A. G. St Brown. M. M. M. (1979L Validation and characteriz ation of the L5I78Y.TK* * mouse lymphoma mutagen assay system. Mutation Res. 59. 61. Dodds E. C. (19621. Stilbcstrol's questions. In On Cancer and Hormones: E'savi in Experimental Bioloaw p. 321. The University of Chicago Press. Chicago. IL. Dodds E. C.. Golberg. L,, Lawson. W. & Robinson. R. (19381 Oestrogenic activity of certain synthetic com pounds. Nature. Land. 141, 247. Dodds. E. C.. Golberg. L, Lawson. W. St Robinson. R. (1939). Synthetic oestrogenic compounds related to sltlbene and diphenylethane. Part I. Proe. R. Soc. Ser B 127. 140. Engel. L. L, Weidenfeld. J. St Merriam. G R. (19761. Metabolism of diethylstilbestrol by rat liver: A prelimi nary report. J. Toxicol, enrir. Nltk Suppl. I. 37. Fink. D. J. (1978). DES Task Force Summary Report. DHEW Publication No. INIH) 80-1688. Forsberg. J.-G. (1979). Physiological mechanisms of di ethylstilbestrol organotropic carcinogenesis. Archs Toxi col. Suppl. 2. 263. Gottschlich. R. St Metzler. ' * (1981). Oxidative metab olites of the teratogen a: - transplacental. carcinogen diethylstilbestrol in the fetal Syrian golden hamster. J encir. Path. Toxicol. In press. Herbst, A. L. I1976). Summary of the changes in the human female genital tract as a consequence of maternal di ethylstilbestrol therapy. J. Toxicol, enrir. Hlth Suppl. I. 13. Herbst A. L. Ulfelder. H. St Poskanzer. D. C. (197)). Ade nocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearance in young women. New Engl. J. Med. 284. 878. IARC Working Group (1979). IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Sex Hormones UIV Vol. 21. p. 173. Inter national Agency for Research on Cancer, Lyon. Korach. K. S. Metzler. M. St McLachlan. J. A. (1978). Estrogenic activity in riro and in vitro of some diethylstilbestrol metabolites and analogs. Proc. natn. Acad. Set. US.A. 75. 468. Lutz. W. K. (1979). In vivo covalent binding of organic chemicals to DNA as a quantitative indicator in the pro cess of chemical carcinogenesis. Mutation Res. 65. 289. McLachlan. J. A. St Dixon. R. L. (1976k Transplacental toxicity of diethylstilbestrol: A special problem in safety evaluation. In Advances in Modern Toxicology. Vol. I. Part I. Edited by M. A. Mehlman. R. E. Shapiro St H. Blumenthal. p. 423. Hemisphere Publishing Corporation. Washington. DC. McMartin. K. E. Kennedy. K. A_ Greenspan. P_ Alam. S. N.. Greiner. P. & Yam. J. (1978k Diethylstilbestrol: A review of its toxidty and use as a growth promotant in food-producing animals. J. enrir. Path. Toxicol, t. 279 Martin. C. N,, McDermid. A. C. St Garner. R. C. (1978) Testing of known carcinogens and noncarctnogens for their ability to induce unscheduled DNA synthesis in HeLa cells. Cancer Res. 38. 2621. MeydL R_ New-bold. R. R_ Metzler. M. St McLachlan. J. A. 11981k Organ cultures of the fetal mouse genual tract metabolize diethylstilbestrol (DES) Proc. Am A. Cancer Res. 22. l(M. Mazur. A. St Shorr. E. (1942k The isolation of sulbesirol monoglvcuromde from the urine of rabbits. J biol Chem. 144. 283. Metzier. M. 119731. Metabolic activation of dieihylstilbestrot: Indirect evidence for the formation of a snlbene oxuie intermediate in hamster and rat. Biochrm Pharmac. 24. 1449. Metzler. M. (1978k Synthesis of diethvlstilbestrol metab olites. o-Hydroxy-dienestrol and derivatives. Tetrahed ron 34. 3)13. Metzler. M. 11981k The metabolism of diethylstilbestrol. CRC Cru. Rev. Biochem. 18. 171, Metzler. M_ Gottschlich. R. St McLachlan. J. A (1980) Oxidative metabolism of snlbene estrogens In Estrooens in the Environment. Edited by J. A McLachlan. p 293 Elsevier.North-Holland Biomedical Press New York Metzler, M. St McLachlan. J. A. it97gal Proposed nomen- ()'!? 921001 RowVerK I lion. R. ic com- uon. R. J to sill ier. B. (1976). prelimi- Seport. of diToxi- netab.inogen nster. J. ie human imal diSuppl. t. 1V Adea I stil- on the teals to ). Inter- 11978), lethylujd. St i rganic ie pro. 289. lacental in safety Vol. I. ro A H joraiion. lam. S. trol: A jtant in I. 279. (19781. ms for ests in chlan. genual n .gre ..Ibcstrol J. biol. Istilbes>tilbene Phar- metabtrahed- ubestroL (19801 urogens p. 293. York, nomen- -> ! * f f i 1 * i i Ji V i i i i i Metabolic activation of carcinogenic diethylstilboestrol 615 dature for diethylstilbestrol metabolites. J. rrnir. Path. Toxicol. 2. 579. Merrier. M. A McLachlaa ). A. (1978b). Peroxidase- mediated oxidation, a possible pathway for metabolic activation of diethylstilbestrol. Btochem. btophys. Res. Common. 85, 874. Metzier. M. A McLachlan. J. A. (1978c). Oxidative metab olites of diethylstilbestrol in the fetal, neonatal and adult mouse. Biochem. Pharmac. 77, 1087. Metzier. M. & McLachlan. J. A. (1979). Diethylstilbestrol metabolic transformation in relation to organ specific tumor manifestation. Archs Toxicol. Suppl. 2. 275. Metzier. M. A McLachlan. J. A. (19811 Oxidative metab olism of the synthetic estrogens hexestrol and dienestrol indicates reactive intermediates. Proceedings of the Second International Symposium on Biological Reactive Intermediates. Guildford. England. In press. Metzier. M. A Neumann. H.-G. (1977). Epoxidation of (he stilbenc doubic bond, a major pathway in ammostilbcnc metabolism. Xtnobionca 7, 117. Okey. A. B. A Nebert. D W. (1979). Covalent binding of diethylstilbestrol to DNA catalyzed by hepatic and uterine microtomes Proc. Am. Ass. Cancer Res 20 205. Pienta. R. J. (1980). Transformation of Syrian hamster embryo cells by diverse chemicals and correlation with their reported carcinogenic and mutagenic activities. In Chemical Mutagens. Edited by F. J. de Series A A. Hollaender. p. 175. Plenum Publishing Corp.. New York. Purdy, R. H,, Meltz, M. L, Goodwin. T. J. A Williams. M. J. (1979). Chemical transformation by diethylstilbestrol. and its metabolism in a mammalian cell culture system. Poster presented at the National Institute of Health Sciences Symposium on Estrogens m the Environment. Raleigh. North Carolina. USA. September 10-12. Rudiger. H. W_ Haenisch. F, Metzier. M. Oesch. F. <fc Glatt. H. R. (1979V Metabolites of diethylstilboestrol induce sister chromatid exchange in human cultured fibroblasts. Nature. Land. 281, 392. P2IC01 RowVerK 094 I