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September 7, 1983 W einberg Consulting Group Inc. '.... - . , ------------- -------------- -- ----------------------------------------------------------------------- -- 2 8 2 8 Pennsylvania Avenue NW, Suite 301 W ashington, D.C. 2 0 0 0 7 (202) 342-6513 Dr. Allan Ford Mail Code EISA Monsanto Company 8Q0 N. Lindbergh Boulevard St. Louis, MO 63167 Dear Al: I have just completed the review o f the first part of the literature search which we are conducting and think that this is a good point at which to write to both convey first impressions and discuss a major issue. This first search was o f three public data bases. "CHEMICAL ABSTRACTS," "MEDLINE," and "BIOLOGICAL ABSTRACTS" for the years 1979 through the present. The strategy of the search was to find all citations for dioxins, 2,4,5-T, 2,4-D, benzofurans, and, in addition, to find all references to ehlorophenols in the two biological data bases. We found about 1000 separate citations. I have completed my first review of all of the citations. This involved reading the abstracts (where available) and the titles and key words where the abstracts were not available. My first impression is that about 40% of all of the articles recovered deal with chorinated phenols with no mention of dioxin. I have marked a number of these for your attention and will forward copies of these to you by the end o f this week. Under my current assignment with Townely <5c Updyke, I am not reviewing these further. I would be interested in knowing, however, if we turn up anything which is of interest to you but is not in your file. My second impression, and the one about which this letter is w ritten, is, about 25 percent of the articles about dioxins deal with enzyme induction and subcellular receptor activities. It would appear that there is a significant amount o f work going on in this area -- much more work than one would consider if one reads just Poland's work. Clearly there are two sites for which dioxin affinity is high, where dioxin is a significant tool in mapping the enzyme site and whee dioxin is used to evaluate the charactersitics of the receptor. Comparisons are being made with other similar enzyme inducers and other m aterials which a ffec t the receptor site. I find these % comparisons of great interest because a number of materials, hexobarbital for example, seem to cause some o f the same subcellular e ffe c ts but, and this is a big but, these materials do not have the usual sequeale alleged to "follow dioxin and/or chlorinated phenols exposure. That is to say, there are many materials which have affinities for the same receptors which do not cause cancer or do not a ffec t immunosensitivities, etc. a 1 .,<! e M SUBJECT TO PROTECTIVE ORDER. Q 23789 -2 - I am trying to compile all of the papers on receptor site activation and on enzyme induction that deal with dioxins, benzofurans, PCBs, DDT-like molecules, and chlorinated phenols. We should consider writing a summary of these. You must have a better view of the overall field of enzyme induction, of receptor activities, and o f the e ffe cts such the changes in P-450 and related m oieties, e tc ., before following Poland only. This has been a long letter which may be summarized in 3 points: (a) there is a great deal of work underway in the areas of enzyme induction and receptor mapping which must be understood before adopting Poland as the guide; (b) the work indicates that these e ffe cts, (i.e., enzyme induction and receptor activation) may not signal any key sequelae or health effects and hence must be Understood to be able to deal with Carnow; and (c) a review of these two areas is in order. I hope this has been useful. I hope to speak with you after you have reviewed this so that we can determine what is the next step. Very truly yours, WEINBERG CONSULTING GROUP Inc. Myron S. Weinberg, Ph.D. cc: Dr. William McCarville SUBJECT TO PROTECTIVE ORDER. C23790 September 7,1983 Weinberg Consulting Group Inc. 2 8 2 8 Pennsylvania Avenue NW, Suite 301 W ashington, D.C. 2 0 0 0 7 (202) 342-6513 Dr. Allan Ford Mail Code EISA Monsanto Company 800 N. Lindbergh Boulevard St. Louis, MO 63167 Dear Al: I am trying to learn more about three subjects which are relevant to the various dioxin-related cases with which we are dealing. I would so licit your help in gettin g more information on these. The first deals with the use of chlorinated phenols contam inated by dioxin. It would appear that chlorinated phenols are widely used. Can you get me a list or a description of all of the uses to which chlorinated phenols are put? Are these used directly by the consumer? How widespread is dioxin contam ination o f th ese chlorinated phenols? Could the average consumer com e in contact with either the chlorinated phenols and/or the dioxins contained therein? Finally, are chlorinated phenols formed during the chlorination of drinking water? To what extent does this happen? Does the EPA have standards for chlorinated phenols and similar compounds in drinking water? The second area of interest is YUSHO, a disease described by either Japanese or Formosans as related to exposure to PCBs and/or dioxins. What do you have in your file on this? Have you built any literature on this? Do we know where the exposure comes from? Does it, perhaps, come from pesticide use? I would like your help in better understanding YUSHO. The third area (and final for this letter but no means final for the program) is in understanding the role played by iron metabolism in disease associated with dioxin and/or chlorinated phenols. It would appear that there is a delicate balance of nutritional iron in reducing and/or enhancing any disease process associated with these materials. Are you aware of any references and/or literature disucssing this? Have you hear of any considerations of this interaction by the various medical groups involved in this? I do not know how this will work as y e t but I would fe e l it is something we should understand in these cases. Al, I would appreciate any input you have on these subjects. Talk to you soon. Very truly yours, Myron S. Weinberg, Ph.D SUBJECT TO.PROTECTIVE ORDER. C23791 W einberg Consulting Group Inc. 2 8 2 8 Pennsylvania Avenue NW , Suite 301 W ashington, D.C. 2 0 0 0 7 (202) 342-6513 LAWYERS' WORK PRODUCT PRIVILEDGED AND CONFIDENTIAL October 31, 1983 Dr. William Gaffey Building "G" Monsanto Company 800 N. Lindbergh Boulevard St. Louis, MO 63167 Dear Bill: I am sure that you have seen the enclosed. Do you consider this as unique or are there other such reports which im plicate working in a chlorophenol-producing and/or -using plant with lymphomata? I would like you thoughts on this if you have the tim e. Thanks for your help on this. Very tpuly yours, WEINBERG CONSULTING GROUP Inc. Myron S. Weinberg, Ph.D. MSW/vh Enclosure SUBJECT TO PROTECTIVE ORDER. C23S13 6 2 6 THE LANCET, SEPTEMBER 16,' 1 9 7 8 extremities (10%), unspecified debility'(3%), and speech trou bles (2%), Combinations of disabilities were common. There, was-considerable variation, between the assessment made by - the g .p ., the district nursing services, and the- geriatric depart- . rhent regarding the incidence of these types of disabilities. The numbers cited "correspond to the assessment made hy-the geri- atric'depanment. - Two-thirds of the referred pensionen wished for, or at least contemplated, change of accommodation. Requests for allo cation of accommodation in nursing-homes were met in about 50% of the cases, whereas only 23% of the requests for shel tered housing were met. After assessment, treatment and pro vision of necessary services and improvements m living condi tions it was decided, in 51% of cases,'that the referred pensioner could and should remain at home. . Almost all of the pensioners had been referred because of imminent or established breakdown in their ability to cope in dependently in their own homes. The figures demonstrare that geriatric assessment and consequent action help many elderly people to. continue independent living outside institutions '-- and such' assessments reduce ;by half), the need for insti o bacteria without 5-9 mix; bacteria with 5-9 mix; A bacteria with 5-9 mix and YahagiV 4procedure. tutional care for frail elderly people; and body-weight). The test animals were fed daily with _Middelfart Sygehus, 5500 Middelfan, Denmark R. K.RAJCAUER steamed cooked salted fish and fresh water, whereas the con trol rats were given fresh water and animal chow salted to the concentration found in the salted fish. Pooled urine from each SALTED FISH AND NASOPHARYNGEAL CARCINOMA IN SOUTHERN CHINESE pair of rats was concentrated about a 100-fold,13 dissolved in - 4 ml dimethylsulphoxide, and subjected to the Ames test. Mutagenic activity for both TA100 and TA98 was found in Sir,-- The unusually high incidence of nasopharyngeal car all the salted-fish preparations tested and all showed a dose- cinoma ( n .p .c .) in southern Chinese both in and outside China responsive curve (see figure). Since TA 100 and TA98 detect has been known for over fifty years and is thus likely to be the different mutagens, there was probably more than one product of a traditional environment peculiar to southern mutagen in the preparations tested- In most cases mutagenic Chinese. The age-specific incidence curves for southern activity was enhanced by liver microsomal activation, and in Chinese of both sexes rises steeply after the age of 19-24 years. some cases also by preincubating the bacteria with S-9 mix at Ho,1*3"*-has suggested that the aetiology involves ah interaction 25C for 20 min before the test.14This procedure causes selec between a genetically determined susceptibility, early infection tive enhancement of the activity of N-nitroso compounds, sug by the ubiquitous Epstein-Barr virus (e.b.v.), and consump gesting that some of the mutagens in the samples tested are tion of a traditional preserved food by southern Chinese from N-nitroso compounds. .- early childhood. Salted fish, a traditional food frequently con Mutagenic activity was also found in urine from the experi sumed during weaning and post-weaning periods, contains a mental rats with a dose-response relationship. variety of volatile* nitrosarames,45"6 compounds which induce Our findings may explain the inductipn of carcinoma in rats tumours in the nasal cavities and/or nasopharyngeal tube in fed with salted fish16 and the high incidence of n .p .c . in south animals.789"101Carcinomas appeared in the nasal cavity and ern Chinese, although one must be cautious in extrapolating maxillary sinus of 4 of 22 albino rats fed salted fish for 12-24 events in animals, especially under experimental condition?, to months (ref. 11 and unpublished). the human situation. We have applied the Ames mutagenicity test12 using the TA100 and TA98 strains o{ Salmonella cyphimurium and mammalian microsomal (S-9 mix) activation to extracts of We thank the,, World Health Foundation :Hong Kong} and the Hong Kong Anti-Cancer Society for financial assistance. salted fish and to the urine of albino rats which had consumed such fish. Salted-fish extracts were prepared by mincing and suspension in dimcthylsulphoxide (2 ml/g of fish) with Medical and Health Department, Instituteof Radiology and Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong J.H.C.H o D. P. Huang vigorous- shaking for 24 h and centrifugation at 10 000 rev/ min for 10 min at room temperature. The Ames test was done Department of Biochemistry, University of Hong Kong Y. Y. Fong with the supernatants. Urine samples were collected for 72 h from 4 pairs of fish-con suming rats and 4 pairs of controls (matched for sex, age FAMILIAL AND SPORADIC HODGKIN'S DISEASE ASSOCIATED WITH OCCUPATIONAL WOOD EXPOSURE 1. Ho, H. C..J. R. CollrSurg. Edin. 1975, 20, 223. _2. Ho,-H. C. in Cancer in Asia, Opportunity for Prevention, Detection and Treatment. Gann Monograph on Cancer Research ho. 18. p. 49. 1974. ^ SiR,-- The aggregation of Hodgkin's disease in communities and families has suggested the influence of environmental risk 3. Ho, J. H. C. Int.J. Radiat. Oncol. Biol.Phxs. 1978,4, 181. * 4. Fong, Y.Y., Chan, W C iVur^re. 1973,243,421. 5. Fong, Y. Y., Chan, W. C. Fd Cosmet. Toxicol. 1976,14,95. 6. Huang, D. P., Ho, J. H. C., Gough, T. A., \X'ebb, K. S.J. Food Safety, 1977, factors, particularly of an infectious nature.1 Evidence impli cating industrial o r chemical agents has been scarce, although an excess risk has been reported among woodworkers2 J and 7. Cardesa, A:, Pour. P., Haas, H., Althoff, J., Mohr, U. Cancer, 1976, 37, 346. 8. Althoff, J., Mohr, ., Page, N., Reznik, G. J natn Cancer Inst. 1974, 53. 795. 9. Pour, P.t Kruger, F. W,, Cardesa, A.. Althoff, j.; Mohr, U. 7. natn Cancer Inst. 1973.1, 1019. ' 10. Haas, H., Mohr, U., Kruger. F. W. J. natn Cancer Inst. 1973,51, 1295. organic chemists.4 An occupational exposure may have contributed to a fami- 13. Yamasaki, E.r Amies, B. N. Proc. natn Acad. Sci. U S A ., 1977, 74, 355514. Yahagi, T., Nagao, M., Seino, U., Matsushima, T., Sugimura', T.. Okada. SK.Mutat.Res. 1977,48.121. 11. Huang, D. P., Saw, D , Teoh, T. B., Ho, J, H. C. Paper presented at the 1. Gutcnsohn, N., Cole, P. In t.J . Cancer, 1*77, If, 595. _ International Symposium on Etiology <md Control of Nasopharyngeal 2. Milham, S., Hesscr, J. E. Lancet, 1967, ii, 136. - ^Carcinoma in Kyoto, April 1977 to be published;. 12. Ames, B. N,, McCann, J.t Yamasaki, E.,Afutur. Res. 1975.31, 347. 3. Grufferman, S., Duong, T.r Cole, P. J. natn Cancer Inst. 1976, 5.7, 1-193. 4. Olin, R. Lancet, 1976, ii, 916. - V,iS' -y. ` ...j As T SUBJECT TO- PROTECTIVE ORDER. C23814 THE LANCET, SEPTEMBER 16,1978 627 . 1 LEGEND f B . MALE.HODGKIN'S DISEASE NS - NODULAR SCLEROSIS MC - MIXED CELLULAR IT Y c FEMALE. OTHER CANCER 11 SIBS. SEX NOT SPECIFIED lumbering, with a relative risk of 4-2 (95% confidence interval _ 1-4--12-5). Repons of Hodgkin's disease among workers in the wood in dustry have stimulated interest in various physical properties of wood.6 7_In the family under study, -there was-conspicuous * exposure to chemical preservatives, notably p.c.p., which is ex pensively used in the lumber and wood industry (1969 world production 2-1 x 1056*kg). However, only two of the four family members with Hodgkin's disease were occupationally exposed, suggesting the interplay between genetic and environmental determinants, as illustrated by the susceptibility to radiogenic cancers among person's with xeroderma pigmentosum, bilateraL retinoblastoma,'or the basal-cell naevus syndrome.1 However, P.C.P. easily escapes from the workplace into the general en vironment,9 10-especially water supplies* and is present in the urine of occupationally exposed and "normal" individuals.-11 P.G.P. is not known to be carcinogenic, but data are limited and commercial preparations.usually contain structurally related compounds, like dioxin, which is carcinogenic in rodents.!2 Since p.c.p. is applied to lumber at many stages in its pro cessing, beginning at the sawmill, unrecognised exposure may occur among many wood-utilising occupational groups. Thus, it may be that the association between occupational wood exposure and Hodgkin's disease (and perhaps nasal cancer) is related to the use of particular chemical preservatives. We thank Dr Lyle Wong of the Hawaii Epidemiologic Studies Pro gram for p.c .p. determinations on patient III-3. *- 168) AGE AT DIAGNOSIS / ` DECEASED Environmental Epidemiology Branch, National Cancer Institute, ~ Bethesda, Maryland 20014, L'.S.A. Providence, Rhode Island - - Mark H. Greene . Louise A. Brinton Jo.seph F. Fraumeni Richard D'Amico Pedigree of a familial Hodgkin's disease kindred (N.C.I. 'Epi demiology Branch no. 323). CHROMOSOMAL DAMAGE AND HAIR DYES lial occurrence of Hodgkin's disease affecting three sibs and a first cousin (see figure). All cancers reported were histologically verified. Except for one child with isolated IgA deficiency (IV-1), detailed laboratory investigation of family members ishowed no abnormalities of immune function, chromosome structure, or Epstein-Barr virus litre. Two brothers with Hodgkin's disease (III-3, 4) had been employed by a fenceinstallation company for 15 and 12 years, respectively, and worked primarily with cedar wood products immersed in a fungicide/insccticide solution, pcntachlorophenol (p.c p .). The brothers prepared and applied the preservative solution by hand, without protective clothing, and the one sib still employed at the time of study had high levels of p.c.p. in the serum (1299 p.p.b.) and urine (90 p.p.b.). There were no simi lar exposures in the remaining two familial cases. Hodgkin's disease (nodular-sclerosis type) also developed in an unrefated 31-year-old employee of the same company (average number of workers 15). Since a positive association between woodworking and Hodgkin's disease has not been -consistently observed, we examined the occupational statements on death certificates in North Carolina counties with a significant proportion of the population employed in furniture-manufacturing and lumber ing. In an earlier study,910this approach was used to confirm the relationship between nasal cancer and woodworking pre viously reported in the U.K. Between 1956 and. 1974, there were 167 deaths from Hodgkin's disease lunong white males. To each case, two control certificates chosen from other causes of death were matched by sex, race, county of death, age, and year of death. An excess risk was found only among occupa tional groups with wood and paper exposure. Matched triplet analysis'revealed a relative risk of 1*4 (95% confidence interval 0-8-2*3). The major difference occurred for carpentry and Sir,-- Having been .asked by a U.JS. Congressional com mittee to evaluate the quality of certain epidemiological studies of the possible carcinogenicity of hair dyes I read the July 15 paper by Dr Kirkland and colleagues (p. 1-24). For teaching physicians about research methodology and biostatistics this report could be used as a "museum o f pathology", .displaying a plethora of violations of fundamental scientific principles. (1) The study cannot be reproduced because the procedure used to obtain the two groups under investigation is not described, except for a statement that they were " volunteers" . . - (2) in most auch studies the number of controls equals (and often exceeds) the number of cases. Kirkland et al. do not explain why they compared 36 controls and 60 hair timers. (3) Having designed a study to test a hypothesis about the effects .of hair dyes on timers and non-iimers Kirkland et al. analysed the data and found -no difference in the two groups. They then defined a new hypothesis, and, using the same data, constructed new sets of cases and controls. The results of-this post hoc act of hypothesis gener ation are presented and inteipreted as though they emerged from a valid act of hypothesis testing. " - . (4) The authors examined 100 cells m all of 9& people. 1 would expect the results to be expressed in terms of.damaged people, but all the data are shown only for the 9600 cells counted. J 32 chromatid breaks in 2800 cells of a group o f 28 subjects (mean 0-047 breaks'per cell) does not tell us whether 2 subjects each had 66 breaks and 26 had no breaks or whether the 28 subjects all had 4 or. 5 breaks.-Further- more, the subsequent statistical analyses are improperly conducted as 6. Robinson, T. Lancet, 1972, ii, 771. 7. Sabine, J. R., Horion, B. J., Wicks,-M. B. J. nata Cancer Inst. 1973,"50, - 1237. - - 8. Strong, 'L . C. in Genetics of Human Cancer -(edited-by J. J. Mulvihill, - R. W. Miller, and J. F. Frauroeni); p. 401. - 9 Norup, B. Water Res. 1972,6, 1585. = 10. Fountaine, J. E., Joshipura, P. B., Keiiher, P. NJbid. 1976,10,18S-. 11. Cranmer,-M.,Freal, J. Life Sci.3970,9,121: . - _* 12-Van Miller, J. P., Lawlich,-}., Allen, J. R .C hemosphere, 1977,6,625. 5. Brinton, L. A., Blot, W. J., Stone, B. J., Fraumem, J. F. Cancer~Res. 1977. 37,3473. 1. Venitt, S., Kirkland, D. J., Searle, C. E., Hamden, D.-G.~Lancct, 1976, i, C TT A SUBJECT TO PROTECTIVE ORDER.