Document om5X9ja3okjrzNMzXkddgBGpr

o PORTIONS OF DR. JOSEPH K. PRINCE'S CHAPTER DM "IMMUNOTOXICOLOGY & CHEMICAL CARCINOGENESIS" FROM THE BOOK ENVIRONMENTAL TOXICOLOGY. Th i s c h a p t e r e s t a b l i s h e s t h e - r e l a t i o n s h i p b e t w e e n a b r e a k d o w n o f THE b o d y 's IMMUNE SYSTEMS AND VARIOUS DISEASES.. ESPECIALLY SOFT TISSUE CANCERS. . M. T. Hazcc-Hagclstcin. W. M. G. Tunbridge. J. Reprad. Fend, Suppl. 6, 123 (19791. 12. K. Ramasbarma and M. R. Sairam. Ann. N .. Acad. Sci. 383.307 (19821. 13. _____ _ M. R. Ranganalhan. Acta Endocrinol. {Copenhagen} 98. 496 0981). 14. N. G. Seidah. J. Rochemont. J. Hamclin. M. Lis. M. ChrOien. J. Biol. Chem. 156. 7977 (1981). 15. M. R. Sairam. in Hormonal Proteins and Pep tides: Gonadotropins. C. H, Li, Ed. (Academic Press, New York. 1983). vol. 11. pp. 1-79. 16. A. V. Schally. Science 202. 18 (1978). 17. M. 0 . Dayhoff. Protein Sequence Data Base. Update (National Biomedical Research Founda tion. Washington. D.C.. 1983). 18..C. C. Q. Chin. J. M. Brenner. F. Wold. J. Biol. Chem. 256. 1377 (1981). 19. M. J. Holland. J. P. Holland. G. P. Thill, K. A. Jackson, ibid., p. 1385, 20. The existence of homology in structure as well as function among distinctly related eucaryotes has been reported; see L. "T. Hunt and M. O. Dayhoff, in Peptides: Structure and Biological Function. E. Gross and J. Meinhofcr, Eds. (Pierce Chemicals. Rockford. III.. 1979). p. 757; 0^ M. O. Dayhoff. in Atlas of:\ft/ein- Sequence 3. P. Honcharand W. Halperin. Lancet 1981-1.618 and Structure (National Bibtricaical^Research^ (1981); P. Honchar. M. Fingerhut. W. Halperin. Foundation. Washington. D.C.. 1978). vol. 5. in preparation. suppl. 3: K, Lederis et al.. Can. J. Biochem. 4. W. Wagner, paper presented at the SOEH Con Cell. Biol. 61. 602 (1983); K. C. Robbins. H. N. ference. The Scientific and Social Response Antoniades. S. G. Bevarc, N. W. Hunkapillcr. from Exposure to Dioxin and Related Materials S. A. Aaronson. Nature (London) 305. 605 (Society for Occupational and Environmental (1983). Health. Arlington. Va., December 1983). The 21. The peptide corresponding to the 31-amino-actd Environmental Protection Agency, report was sequence was synthesized by the solid-phase originally intended to be released'in November method. The purity of the synthetic peptide was 1983. but has not yet been released. established by HPLC and paper electrophoresis, and its amino acid composition was identical to 5. T. Sterling and A. Arundel, NCAP News, in press. the proposed sequence [R. B, Merrifield.T. Am. 6. O. Axelson and L. Sundcll, Work Environ. Chem. Soc. 85. 2149 (1963); D. Yamashiro and Health 11. 21 (1974), C. H. Li. ibid. 100. 5174 (1978); C. H. Li. D. 7. L. Hardell, M. Eriksson, P. Lenner. E. Lund- Yamashiro, K. Ramasharma, M. R. Sairam. gren. Br. J. Cancer 43. 169 (1981). unpublished data). 8. Ton That Tung. Chirurgie 99. 427 0 973). 22. Supported by the Ford Foundation and the 9. A. Westing. Ed., Proceedings, International Medical Research Council of Canada. We thank C. A. Paulsen. G. Bleau, R. Vauclair. and M. O. Dayhoff for their contributions, and C. Chagnon Symposium on the Long-Term Consequences o f Chemical Warfare in Vietnam (Stockholm Inter national Peace Research Institute. Stockholm. Labelle and R. Camere for technical assistance. Sweden. 1983). * To whom correspondence should be directed. 10. E. Silbergeld. paper presented at the SOEH Conference, The Scientific and Social Response 28 November 1983: revised 17 January 1984 from Exposure to Dioxin and Related Materials (Society for Occupational and Environmental Health. Arlington, Va., December 1983). 6 January 1984 Health Effects of Dioxin The evidence of deleterious health consequences from the environmental use of substances containing 2,3,7,8-telrachlorodibenzo-p-dioxin (TCDD) has appeared in a multitude of studies. Philip H. Abelson's editorial (7) on the dioxin issue is based on a number of misleading inaccuracies about this evidence. First, the results of the accident at Seveso, Italy, are not limited to mild cases of chloracne, despite Abelson's statement that " No significant change was observed in the incidence of sponta neous abortions, congenital malforma tions, or postnatal development." The Seveso data (2) show a sharp increase in spontaneous abortions during the first trimester of 1977, followed by a slow decrease to 1976 levels and significant increases in risk of malformations. For example, there was a 100 percent in crease in the rate of spina bifida, a 71 percent increase in the rate of neural tube defects, an elevenfold increase in hypospadias, and a 110 percent increase in polydactyly. A number of these mal formations are frequently observed in animals exposed to TCDD. The Seveso data are still being analyzed for postnatal effects. Second, the National Institute of Oc cupational Safety and Health (J) and recently the Environmental Protection Agency (4) followed workers exposed to TCDD in industrial accidents and found, in sharp disagreement with scientists who analyzed that data for industry, a multiple increase in soft tissue carcino mas and lymphomas. Third, the question is not whether TCDD has to be ingested before it is toxic (obviously it has to make effective contact) but whether there is an effect from the presence of elevated environ mental levels of TCDD, especially as a result of herbicide spraying (5). There is ample evidence that the latter is the case. Multiple studies by Swedish investiga tors, notably, Axelson and Sundell (6) and Hardell and Erikson and their col leagues (7) show an increase in soft tis sue carcinomas in railway and forestry workers exposed to environmental TCDD. Observations from Vietnam (3) have reaffirmed increased liver cancer among populations exposed to Agent Or ange during the Vietnam War (3). Spon taneous abortions, stillbirths, and mal formations are still reported in these areas (9). Fourth, it is misleading to stress the great variability of the median lethal dose (LD50) when commenting on the value of animal experiments. It would be more accurate to point to the uniformly low effective doses for producing carcin ogenic and teratogenic effects (70). T h e o d o r D. S t e r l in g Faculty o f Interdisciplinary Studies, Department o f Computer Science, Simon Fraser University, Burnaby, British Columbia, Canada V5A JS6 References and Notes 1. P. H. Abelson. Science 220. 1337 (1983). 2. P. Bnizzi ei a/., " Binh defects in TCDD pollut ed areas" (Provisional Report, Seveso Binh Defects Registry, Seveso, Italy, 1981); Reporto Conclusino Sui Deferit Congeniti Ed Altri Esiti Sfavorevoii Di Gravidanza Relaveti Nella Popolazione Del L'Area Di Seveso Interasata Dali' Inquinamento Da TCDD 1L 0.7.1976 (Registro Delle Malformazioni, Seveso, 28 June 1983). Pro and con evidence and differing points of view on questions concerning the toxicity of dioxin are cited in a large number of articles and books. Three publications that contain a total of hun dreds of references are 1) Further Review o f the Safety-for Use in the U.K. o f the Herbicide 2,4,5-T from the Advisory Committee on Pesti cides, London, December 1980; 2) Agent Orange Dioxin--The Health Effects o f "Agent Orange" and Poly chlorinated Dioxin Contaminants, a technical report prepared by the Council on Scientific Affairs of the Advisory Pan el on Toxic Substances of the American Medical Association, Chicago, Illinois, October 1981; and 3) Human and Environmental Risks o f Chlorinated Dioxins and Related Compounds, edited by Richard E. Tuck er, Alvin L. Young, and Allan P. Gray (Plenum Press, New York. 1983). As Sterling points out, a number of investigators have taken the position that TCDD has been a causative agent of soft tissue sarcomas. However, to other ex perts, the evidence is not compelling. The Agent Orange report includes the following statement (p. 28): " While 2,4,5,-T and 2,4-D pesticides (phenoxy herbicides in Agent Orange) have been used in agriculture, forest management, and residential landscaping for over 30 years, there is still no conclusive evi dence that they and/or TCDD (a contam inant of Agent Orange) are mutagenic, carcinogenic, or teratogenic in man, nor that they have caused reproductive diffi culties in the human." -- P h il ip H. A b e l so n 26 January 1984 C03739 1202 S riF .N rF .. V O I. 723 rI .* f y "y lU - li^ liitU M onsanto Company 1101 17th S t r e e t . N .W . W ashington. 0 C 2 0 0 3 6 Phone. (202) 4 5 2 - 8 8 8 0 \J fiu. 3 C0374D . NEWS/INFORMATION FROM SOUTH DAKOTA CONGRESSMAN TOM DASCHLE 603 5eu11) Mt'n Abardaan. 5.0. S7c. 03-U3-S323 116 S lilh S l i t u Rapid C il/. S.D. S iic i *0S-JrS51 *00 South C i.il S fo u i F il l * . S O. 5MC3 603-334-9416 439 Cannon Building W ashington, O.C. K S iS 1-SW-424 SG3 or 202-225-1301 DOW AND DIOXIN: A STUDY S ta te m e n t by C ongressm an Dasfchle June 2 , 1983 P a u l O r e f f i c e , p r e s i d e n t o f Dow C h e m i c a l , r e c e n t l y t o l d a n a t i o n a l t e l e v i s i o n a u d ie n c e : "T here i s a b s o lu te ly no e v id e n ce o f d io x in doing any damage to humans e x c e p t fo r som ething c a lle d c h lo ra c n e ." T he s t u d y I am r e l e a s i n g , a s t u d y o f w h ic h Dow w as c l e a r l y a w a r e , i n d i c a t e s M r. O re f f ic e h a s e i t h e r d e li b e r a t e l y m is le d th e p u b lic o r i s t o t a l l y ig n o r a n t o f s tu d ie s p o ssessed by h is company. T h is s tu d y , c o n d u cted by D r. M ilfo rd W ard o f th e D epartm ent o f Im m unology, R o yal H a lla n s h ir e H o s p it a l, S h e f f i e l d , E n g la n d , do cu m en ts a lo n g - te r m immune s y s te m breakdow n in humans exposed to d io x in some te n y e a rs p r i o r to t h e i r e x a m in a tio n . The stu d y c o rro b o ra te s s e v e ra l s im ila r s tu d ie s on anim als and hum ans. O n ly y e s t e r d a y , Dow i n v i t e d j o u r n a l i s t s fro m a c r o s s t h e c o u n t r y t o i t s M id lan d , M ich ig an , h e a d q u a rte rs to h e a r a b o u t new s tu d ie s and re c e iv e th e company a p p r o v e d l i n e o n t h e s a f e t y o f d i o x i n . I t i s my u n d e r s t a n d i n g t h a t t h e s e j o u r n a l i s t : w e re t o l d t h a t Dow p l a n s t o s p e n d m o re t h a n $ 3 m i l l i o n t o s t u d y d i o x i n d am ag e i n th e M idland a re a . Z c a n n o t h e l p b u t w o n d e r w h e t h e r Dow t o l d th e m o f t h i s s t u d y b y D r. W ard , o r , i f - Dow e x p l a i n e d t h e dam age t h i s s t u d y d o e s t o t h e c o m p a n y 's r e p e a t e d c l a i m s a b o u t d io x in . I t i s n o t s u r p r i s i n g Dow h a s m a i n t a i n e d s i l e n c e a b o u t t h i s s t u d y d e s p i t e i t s obvious s ig n ific a n c e to th e A gent Orange is s u e . Nor i s i t s u rp ris in g th e a u th o r o f th is stu d y has d escrib ed i t as " c o n fid e n tia l," and "never p u b lish ed in th e s c ie n tific p re ss." These th in g s have happened, and th ey a re b u t th e tip o f th e ice b erg o f e f fo r ts to suppress the fa c ts and m islead th e p u b lic about d io x in . Y et j u s t t h is t i p o f tlie ic e b e r g , in th e form o f D r. W ard 's s tu d y , c a s ts th e g r a v e s t d o u b t o n t h e c la i m s o f Dow a n d t h e U n i t e d S t a t e s g o v e r n m e n t c o n c e r n i n g A gent Orange and i t s d ead ly c o n ta m in a n t, d io x in . ...m o re ... A ccom panying C ongressm an D a sc h le i n t o d a y 's News C o n fe re n c e i s D r. J o s e p h K. P r in c e , a r e s p e c te d im m u n o to x ic o lo g is t who i s a R e se arc h A s s o c ia te w ith th e U n iv e r s ity o f I l l i n o i s M edical C e n te r and a T o x ic o lo g is t w ith th e E n v iro n m en tal P ro te c tie r. Agency in C hicago (R egion V ). Statement by Congressman Daschle -- . Page 2 C o n firm a tio n o f lo n g - te r m immune s y s te m c o ll a p s e a s a r e s u l t o f d i o x in e x p o s u re w ould re v o lu tio n iz e o u r th in k in g a b o u t th is e n tir e is s u e . I t w ould e x p la in th e w id e-ran g in g m aladies re p o rte d fo r y e a rs by v e te ra n s exposed to A gent O range. I t w o u ld o p e n Dow a n d t h e g o v e rn m e n t t o b o t h m i l i t a r y a n d c i v i l i a n c l a i m s f o r l e g a l " and l e g i s l a ti v e rem edy on a p o te n tia lly m assive s c a le . And th e Ward s tu d y r a i s e s a h o s t o f im p o r ta n t q u e s t io n s f o r fo llo w -u p -- q u estio n s lik e : Why w a s t h e s t u d y k e p t c o n f i d e n t i a l , t h u s p r e v e n t i n g i n d e p e n d e n t e v a lu a tio n by th e s c i e n t i f i c com m unity? What i s th e h e a lth s t a tu s o f th e ex p o sed v ic tim s today7 Were fo llo w -u p s t u d i e s made? I f th e y w ere n o t , why n o t? I f th e y w ere, w hat d id th e y show and why have th ey rem ain ed s e c r e t? And f i n a l l y , d o e s Dow h a v e f u r t h e r s t u d i e s r e l a t i n g t o d i o x i n w h ic h i t i s w ithholding? And th e r e a re q u e s tio n s f o r th e E n v iro n m e n ta l " P r o te c tio n A gency and o t h e r governm ent agencies as w e ll: ' How d i d E .P .A . o b t a i n t h i s s t u d y a n d why h a s s o l i t t l e b e e n s a i d a b o u t i t Was t h e W ard s t u d y show n t o t h e V e t e r a n s A d m i n i s t r a t i o n , t o t h e D e p a r t n e r o f D efense, o r to o th e rs concerned w ith th e A gent Orange m a tter? I f n o t, why n o t? And i f t h e V.A. w as show n t h e s t u d y , why h a v e n 't t e s t s f o r immune s y s te m breakdow n been in c lu d e d in th e f r e e h e a lth exams g iv en th o u sa n d s o f V ietnam v e ts S im ila r ly , why h a s n 't th e V .A . aw arded a s i n g l e r e s e a r c h p r o p o s a l t o s tu d y th e e f f e c t o f d io x in on th e immune sy ste m ? L eaving th e A gent Orange m a tte r e n ti r e l y a s id e , was p ro p e r a c c o u n t o f th e Ward f in d in g s ta k e n i n c o n s id e r in g c i v i l i a n u se o f d io x in c o n ta m in a te d d e f o l i a n t u se w hich c o n tin u e s to th is day? T hese a re b u t a few o f th e q u e s tio n s r a is e d by D r. W ard 's s tu d y . T h a t th e s e q u e s tio n s rem ain unansw ered f u lly 20 y e a rs a f t e r th e sp ra y in g o f A gent Orange in V ietn and f iv e y e a r s a f t e r th e ' Ward s tu d y was c o m p le te d s ta n d s a s an in d ic tm e n t o f a l l in volved in th is m a tte r. I r e l e a s e t h i s s t u d y , a n d c o n t i n u e my i n v e s t i g a t i o n i n t o o t h e r m a t e r i a l s w h ic h may have b een s u p p r e s s e d , in th e hope C o n g re ss and o u r g o v ern m en t w i l l a t lo n g l a s t ta k e th e a c tio n s re q u ire d to com pensate th o se a f fe c te d by d io x in and p r o te c t th o se a s y e t u n a f fe c te d . I t i s s u r e ly th e 'v e r y l e a s t we can d o . Page A:1 LETTER FROM DR. A. MILFORD WARD Th i s l e t t e r c o n f i r m s t h a t *h i s s t u d y -- "w r i t t e n f o r an INDUSTRIAL COMPANY" -- WAS CONFIDENTIAL AND NEVER PUB LISHED IN THE SCIENTIFIC PRESS. Pages A:2-4 PORTION OF TRANSCRIPT FROM E.P.A. CANCELLATION HEARINGS ON 2,4,5,-T AND SILVEX (NOV. 14, 1980) This t r a n s c r i p t confirms t h a t .Dow was a w a r e o f the Ward s t u d y . Pages A:5-13 IMMUNE STUDY BY DR. A. MILFORD WARD Th is s t u d y r e v e a l s t h e p r e s e n c e of l o n g -t e r m i m m u n e b r e a k d o w n s IN; ADULT MALES EXPOSED TO DIOXIN. A-l LETTER'FROM DR, A. MILFORD WARD Th i s l e t t e r c o n f i r m s t h a t h i s s t u d y -- "w r i t t e n f o r an INDUSTRIAL COMPANY" -- WAS CONFIDENTIAL AND NEVER PUB LISHED IN THE SCIENTIFIC PRESS. CH 357 Tl: Shelllrid (0743) 36484 EM. 3837 T el*. 54348 U iihcl. G. Di**ciot; Di. A. Milloid Wid AMW/JA e r r T~^ Supra regional Protein Reference Unit Department of Immunology, Royal Hallamshire Hospital. Sheffield. S10 2JF 6 A p ril 1983 Dear O T h an k y o u f o r y o u r l e t t e r o f t h e 2 8 t h M arch r e g a r d i n g my p a p e r o n " I n v e s t i g a t i o n o f th e Immune c a p a b i l i t y o f W o rk ers p r e v io u s ly e x p o s e d t o 2 3 , 7 , 8 TCDD". I w ould b e m o st i n t e r e s t e d t o know how t h i s p a p e r came i n t o y o u r p o s s e s s io n , I t was w ritte n fo r an i n d u s tr ia l company in 1978 and was n ev er p u b lis h e d in th e s c i e n t i f i c p r e s s . As su ch i t was a c o n f id e n tia l docum ent and was n o t w ritte n in a form at fo r w ider d is tr ib u tio n . W h ils t t h i s w ork w as d o n e som e y e a r s a g o , my i n t e r e s t i n t h e s u b j e c t i s s t i J c u r r e n t an d I w ould be i n t e r e s t e d t o h e a r y o u r com m ents an d e x p e r ie n c e . May 1 a l s o a s k y o u r i n t e r e s t o r in v o lv e m e n t i n th e p ro b le m a r e a . I n o te re fe re n c e to A gent Orange in y o u r l e t t e r h ead and I can o n ly assum e t h a t i t i s in th is connection th a t your in te r e s t l i e s . K ith b e s t reg ard s Y ours s in c e re ly A MILFORD WARD A-2 PORTION OF TRANSCRIPT FROM E.P.A. CANCELLATION HEARINGS ON 2 A 5 - T AND SILVEX (NOV. 14, 1980). Th i s t r a n s c r i p t c o n f i r m s t h a t Dr . Wa r d 's s t u d y w a s d o n e for Dow. 17220 to push i t any h ig h er than th a t. Q So, you r e a l l y d o n 't know a t w hat s ta g e i n th e chem ical p ro cess th e ex p lo sio n o ccu rred in th e C o a lite in c id e n t, do you? A P erhaps I could p u t i t d if f e r e n tly . What I d o n 't knovz i s t h a t D e r b y s h ir e an d A m sterdam h a d th e sam e a m o u n ts o f TCDD fo rm e d ; o f c o u r s e , I d o n ' t , I a g r e e . .MM. HOZOr: X t h i n k we c a n t a k e a b r e a k r i g h t now. JUDGE riU C iI; L e t ' s com e h a c k a t f i v e m i n u t e s o f 4:00. 12 (W h e re u p o n , a s h o r t r e c e s s w as t a k e n . ) JUDCE r iiJ C 1!: H a d ; on t h e r e c o r d . MR. JIOZOF: exam ination e x h ib it. I 'd lik e to hand you a c ro ss- I" "" Th is docum ent i s e n t i t l e d " I n v e s ti g a t i o n o f th e Immune C a p a b i l i t y o f W orkers P r e v io u s ly e x p o s e d t o ? , 3 , 7 , 3 - T o t r a c h l o r o d i b e n z o - i ) a r a - d i o : : i n , TCDD, } y D r. A.' ! 1 ilf o rd W ord. -3 T h is d o c u m e n t s a y s 1C t r i c t l v C o n f id e n t but t h a t i s n o t b ow 's stam p o f c o n f i d e n t i a l i t y , i t i s n o t -- ,,-- e l n i r e d b " Dow to bo c o n f i d e n t i a l , and a l l t h e nam es o f th e p a tie n ts involved have been b lo tte d o u t. JUDGE F i l i a l : L o t ' s m a rk t h i s 14 8 0 . (3031 334.4433 (W hereupon, th e docum ent was m arked C ro ss-E x a m in a tio n E x h ib it Ho. 1400 fo r id e n tif ic a tio n .) NEAL R. GROSS COURT MPORTIRS ANOTRANSCIIIKS 1330 V1IMOHT AVtHUt, NW WASHINGTON, D.C 30003 A-3 A -4 17222 1 A T hat n en n t no c h lo ra c n e . I t m eant th a t they 2 wore round ab o u t th e p la c e and co u ld co n c e iv a b ly have 3 c o n e i n c o n t a c t w i t h TCDD o r n o t , - n o b o d y k new ; t h e y w e re 4 an in term ed iate group. 5 ;> -A nd t h e t h i r d g r o u p , C ro u p A , w e re t h e u n e r a s e d 6 co n tro ls? r------------------ 7 7 T h a t 's r i g h t , who './e re a p p a r e n t l y s a i d to bo 8 c e r t a i n n o t to have come i n to c o n ta c t w ith i t . 9 bow, th e o n ly num bering on th i s page is th e 10 n * irJ jc r' i n t h e r i g h t - h a n d c o r n e r o f t h e s e p a g e s , a n d I 11 t h i n k i t ' s p a g e MC708 t h a t I w o u ld l i k e t o d raw y o u r 12 a t t e n t i o n t o . 13 A I ' v e g o t t h a t . T h e r e 's a l o t o f u n d e r l i n i n g o n 14 p h a t p a n e . \) Acta in f we r e c e i v e d t h e d o c u m e n t xn t h i s f o r m , I11!TIIIIIIIII <iw ijm w i ro w Dow. ilov;, t h e s e c o n d p a r a g r a p h s t a t e s t h a t '"T est . |< C ro u p C show s a `i i g n i f i c a n t i n c r e a s e i n t h e -~.ro.lo r ti- a n o i l : ;iow, t h i s s u g g e s t s t h a t t h e r e was some immuno s u p p r e s s i o n o f t h e - ^ r o u > t h a t w as e x p o s e d t o TCDD a n d 23 e x h i b i t e d c h l o r a c n e , d o u s n 't i t ? NEAL R. GROSS COURT REPORTERS a n d TRANSCRIBERS 1330 VI8M O HT AVENUE. NW W a s h in g t o n , d c . aoo os or?00T>n A-5 IMMUNE STUDY BY DR, A. MILFORD WARD Th i s s t u d y r e v e a l s t h e p r e s e n c e o f l o n g -t e r m i m m u n e BREAKDOWNS IN ADULT MALES EXPOSED TO DIOXIN, INVESTIGATION OF THE IMMUNE CAPABILITY-OF WORKERS PREVIOUSLY EXPOSED TO 2 , * 3 ,7 , 8 , TETRACHLQR0DI3ENZ0 p a r a - DIOXIN (TCDD). Dr.A.M ILFORD WARD SUPRAREGIONAL S P E C IF IC PROTEIN REFERENCE UNIT a n d DEPARTMENT O f IMMUNOLOGY, HALLAMSHIRE HOSPITAL, SHEFFIELD . >;rf -- -- xlud w as i n i t i a l j ' l j a s a r e s u l t o f th e p o p u la tio n and in view o f th e a v a ila b le e x p e rim e n ta l ev id en c S tu d ie s in ex p erim en tal an im als, b o th ro d e n t and prim ati have shown t h a t thym ic a tro p h y and lym phopenia a re c o n s is te n t * a n d s e n s i t i v e i n d i c a t o r s o f TCDD e x p o s u r e o r t o x i c i t y (Vos 1 9 7 8 ) P re lim in a ry s t u d i e s i n man h a v e , h o w e v er, f a i l e d to docum ent a s im ila r a b n o rm a lity . The s tu d ie s co nducted on c h ild re n exposed a t S eveso (F ara 1977) have shown no d iffe re n t in serum im m u n o g lo b u lin s, com plem ent, o r lym phocyte fu n c tio n betw een exposed and nonexposed c o n tro l c h ild re n . T he p r e s e n t s tu d y s e t s o u t t o ex am in e th e i n v i t r o immune c a p a b ility o f th re e groups o f a d u lt m ales 1 ) e x p o s e d t o t o x i c l e v e l s o f TCDD m o re t h a n 10 y e a r s p re v io u s ly and show ing c l i n i c a l evidence, o f t o x i c i ty in th e form o f ch le ra c n e i i ) e x p o s e d t o TCDD b u t n o t s h o w in g e v i d e n c e o f d e r m a t o l o g i c fI to x ic ity . \ ' i . i i i ) unexposed c o n tro ls- & .. \ RESULTS Ic su n o g lo b u lln s. Strictly-Confidential XgGl T here v u no s ig n if ic a n t d iff ra n e e betw een the C n f th re e groups o r betw een th e t u t groups and t h e _ f la b o ra to ry rafe ra n ca rang a f te r due ag* c o rre c tio n . X gX i' T hara v as no s ig n if ic a n t d iffe re n c e betw een th e th re e groups o r betw een th e t e s t groupd and th e lab o rato ry referen ce range a f te r due age co rre c tio n . S i o f t h e p o p u l a t i o n a r e d e f i c i e n t i n s e r u s IgA. a n d th is p ro p o rtio n vas ra fle c ta d in aach o f the te a t groups. . Xgtli T here vas no s ig n if ic a n t d iffe re n c e betw een t e s t groups X end S and th a lab o ra to ry referen ce ran g e. T e s t group C sh av ed a n o n a l a e d la n v a lu e f o r IgM" and an observed range v h ich was In d ia tin g u lc h a b le fre a th e o th e r groups b u t th e re vas a s ig n ific a n t ^ ----------------------------------- ( pi0.05J in crease in tha p ro p o rtio n o f oases v h ich g a v e XgK v a l u e s b e lo w t h e 5 t h c e n t i l a f o r th e lab o rato ry reference range. Xg3t The d is trib u tio n o f th is irau n o g l a b u lia In the n o en a l p o p u l a t i o n i s t r i n o d a l w i t h 10 h a v in g ' u ndetactable serua le v e ls. There vas no s ig n ific a n t d iffe re n c e In th is su b set o f th e population fo r the th ree t e s t groups. 2 3 .SI o f Croup B and 211 o f Croup C had v a lu e s o f ZgO b e l e v t h e 5 th c e n t l l e . T h is r e p r e s e n t e d a S ig n ific a n t d ifference iro n tha la b o rato ry reference p o p u l a t i o n [p<0 .0 0 5) b u t t h e r e w as no s i g n i f i c a n t d iffe re n c e betw een t e s t groups 3 and C. loC ^of th e norm al po p u latio r;V ;av e very h ig h scrum le v e ls o f IgS and th e se re p re s e n t th e pool o f a to p ic in d iv id u a ls . T here was no s ig n if ic a n t d iffe re n c e betw een th e th re e groups and betw een th e t e s t groups end th e la b o ra to ry re fe re n c e range b o th w ith re s p e c t to m edian v a lu e s and to th e p ro p o rtio n o f a to p ic in d iv id u a ls. *. ..ft T a ti3n I X nutiuncK | l o l ) n H n T>>- n I<jG A 31 9 /1 B 56 C 3B . IgjT ' 3 /1 A B C 31 56 38 ' IgM 3/1* A B C 31 56 3fi m edian 1 0 .0 9 .7 1 0 .2* 1-9 2 .0 t 1.5 ** 0 .B \ O.B 0 .7 ` o b se rv e d ' ra n g e 6 .5 - 14.0 6 .5 - 1 5 .B 5 .6 - 13.1 i 0 .6 - 4 .8 0 .4 - 4.1 0.4 - 4 .0 No(%) b e lo w 5 th c o n t i l e o f . re fere n ce range. a o (-) o (-) 1 (2 .6 ) N .S. 1 (3 .2 ) *1. (1 .8 ) 1 (2 .6 ) \ N .S . 0 ,4 - 1 .4 0 ,2 - 2.4 0 .2 - 1.4 o (-) 2 (3 .6 ) 7 (IB .4) p< 0.05 Strictly Confidential ;5>- , . i & i r .il.Ia I IContJ ig o lV/ml k 0 c n* 2B S3 34 T Madian* 2 1 .5 1C.0 13.0 . t . J --: *. , *. * * f obaorvad rango* H o(t)bolow Stli c a n tilo * N o(t) n ot d atoctcd 8.5 - as 1 .0 - 88 2 .0 - 121 1 (3.2) 13 (23.6) 8 (21.0) . |X *0.005 3 (9.7) 4 (7.2 4 (10.5) tf.B J *i N o(l)below tha 10th c a n tilo o f rotarono* rango Ho(I)ab ove 90th c a n tila o f r a farane range. j ig s JU/ml X 31 D SC c 38 10 44 37 <S - 980 <5 - >1000 <5 - , >1000 Caaea In w h ich orua JgO n ot, d * t* o t* 4 a ra a x a l tid ed . 4 (12.9) fi (1 0 .9 ) 3 (7.9) . H .8. 3 (9.7) (14.3) : 2 ( S *J * H .S. | ** 1 Strictly Confidential  A-1Q .L y m p h o c y t e s , l y m p f / ^ z y t e - s u b p o a u l a t i o n s a n d f / IH l t o g e n t r a n s f o r r e a t l c T here was no s ig n if ic a n t d iffe re n c e betw een th e th re e grouns o r betw een th e t e s t groups and th e la b o ra to ry re fe re n c e ran g e fo i t o t a l lym phocyte co u n t, T - c e lls , o r B - c e lls . T here w as, how ever, an in c re a se d p ro p o rtio n o f ca ses in t e s t g ro u p C (p < 0 .1 0 ) i n whom t h e ly m p h o c y te t r a n s f o r m a t i o n i n re s p o n s to p h y to h aem ag g lu tin was red u ced - Strictiy Confidential `i i * 7 < ii l / A-11 T a b iu 1 J liyninluic y toB nnd In v i t r o n lto n o n tr a n s fo r m a t io n T obai Lym phocytea x 109/1 c e ,l,l o X 109/1 n A 29 B 56 C 38 A 29 a B 56 C 38 1 0 th c a n tile . 1 .6 - 1 .6 1 .6 . 1 .0 0 .7 1 .0 B - c e llo X 109/1 VbmJ t r a n s f o r m a t i o n d e p re sse d A 29 0 .2 B 56 C 38 0 .2 0 .2 A 2/29 6 .6 B 2/56 3.5 C 5/3 8 13.0 , m edian 2 .3 2 .2 2 .5 1 .3 1.4 1 .5 0 .4 0 .3 0 .4 90th c o n tile ' 4 .3 .. 3 .6 4 .0 M.J 2 .7 . 2<1 . 2*5 0 .9 0 .6 0 .9 N .i N . p < 0 1C Strictly Confidential. A-12 U4b7U t CONCLUSIONS ** / f. j J 'I T est group X I t in d istin g u ish a b le fra a the w z u l p o p u latio n v i t h r u j t c : to c a m in a u n o g lo b u lin s IgC* IgA , IgM, IgD and IS* and w ith re s p e c t ta p e rip h e ra l b lood lym phocytes and th e ir B ltogen tra n s fo rs a tio n . % T ac t .group C chows a s i g n i f ic a n t in c re a s e in th e p ro p o rtio n o f e a s a s w ith re d u c e d l e v e l s o f IgD and I g h .^ X h i s g ro u p shew s an l a c r e a s e d p r o p o r t i o n o f c a t e s w i t h d e p r e s s e d PEA. r e a c t i v i t y . -- *-- 1 T act group B f a l l s in te rm e d ia te betw een groups X and C w ith i n c r e a s e d p r o p o r t i o n o f c a s e s w ith IgD l e v e l s o n l y , ZgM l e v e l s s a d PEA r e a c t i v i t y b e i n g nor t a l . IgM i s th e a n tib o d y c l a s s a s s o c ia te d w it h th a i n i t i a t i o n o f th e iSsuna response and w ith t o n resto r.se to v ir a l and p a rtic u la ttt a n t i g e n . XgO I s t h o u g h t t o b e a s s o c i a t e d w ith , t h a t r a n s f e r o f lra u s a c a p a b ili t y fr e n th a T -c e ll to th a B -c e ll and w ith, s h o r t ta m issu n o lo g ical seaory. " These r s s u it s w ould le a n to su g g e st t h a t T est group C i s r e la tiv e ly d e fic ie n t in p rla ary I r a n i c a p a b ility and in T -ceiL -- a c a l l c o - o p e r a t i o n , d a re d u c e d PEA t r a n s f o r m a t i o n r e s p o n s e l a th is group is lik e ly to be the r e s u lt o f v ir a l Induced T -c e ll d e p r e s s io n a s a s e c o n d a ry f e a t u r e o f th e re d u c e d , h u m o ral Immune c ap a b ility ra th e r than a p rleery T -ca ll d e fec t. T h is w ould f u r t h e r s u g g e s t t h a t t o x i c e x p o s u re t o TC2D i n d u c e s i l a s t i n g a f f e c t on B - c e l l u n a r y end immune c a p a b i l i t y , th a in te rm ed iate p o sitio n of t e s t group B b eing c o n s is te n t w ith p r e v io u s e x p o s u re t o TCDD b u t a t n o n t o x ic l e v e l s . Strictly Confidential c n /.o tO * C o m p ariso n o f t h i a d a t a w i t h t h e . p u b li s h e d l i t e r a t u r a on tcdd exposure In nan is d if f ic u lt in th a t com parative d a ta has n ot y e t b e a n p u b lis h e d , t h e s tu d i e s by Voe a t a l i a a r a c o n fin a d t o e x p e rim e n ta l anm ala w h ils t th e s tu d ie s on th e Seveso In c id e n t re p o rte d by F are a re confined to c h ild ren w ithout e x p lo ra tio n o f ^ the* I c e l l - S c e l l c o -o p e ra tio n a x is and th e p o s s ib le envolvem ent o f t h e c y to t r o p h i c a n tib o d y XgD. S u p e r f ic ia lly t h is data, would sa a a to c o n f lic t w ith th e fin d in g s 'i fro m S e v e s o , b u t t h i s may s im p ly b V o n t h e m eth o d o f a p p ro a c h t o th e problem . She p o s s ib ility th a t th is ap p aren t d iffe re n c e i s so re fundam ental and a s so c ia te d w ith dsgrea o f exposure in an a d u lt r a th e r , th an p a e d ia tric population* r u s t a ls o bo con sid ered . 1 ' T he c o n c e p t t h a t TChO e x p o s u re c a n in d u c e a l a s t i n g e f f e c t o n B c e l l B e a ty and lzaune c a p a b ility could be te s te d by exam ination o f th e .. w ork a t t e n d a n t '`r e c o r d s o f s u b j e c t s o f t h i s s t u d y . W h il s t t h e r e n a y be no o v e rt in c re a s e i n m ajor in f e c tiv e i ll n e s s e s am ongst Croup C, * i t w ould b e i n t e r e s t i n g t o know w h e th er th e i nd iv id u a ls r e l a t i v e l y d e f i c i e n t i n X gh a n d Xg9 o r sh o w in g a l t e r e d ly m p h o c y te s u b p o p u la tlc r .^ dem onstrated an in c re a s e d frequency o f m inor in fla n s a to ry d is o rd e rs . The exposed en d contam inated groups e ra sm all, and the s ig n ific a n c e o th e s e fin d in g s w ould be im proved i f th e s e group could^ b e in c re a s e d . I t w ould be an advantage to stu d y f a r th e r c a se s r e fe r a b le to th e se two groups if- th e y c o u ld be obt a in e d , even i f I t means draw ing th a n from an a lte rn a tiv e in d u s tr ia l S e rv ic e . r a il i n g th is i t would be in ta r s s tin g to stu d y w orkers exposed to * o r c o n ta m in a te d b y c h e m ic a ls r e l a t e d , t o "TCBD, p a r t i c u l a r l y i f t h a t contam ination was a sso c ia te d w ith th e developm ent o f ch lo racn e as e to x ie m an ifestatio n - B-l ENVIRONMENTAL TOXICOLOGY Principles and Policies Ediud fy SATU M. SOMANI, Ph.D. AiudaU Profittar of Pharmatolcp and Tfixitolegp Dtpartmtnl bJ Pharmctvlofy Seutfum Itlinoa Unsttrnlj * &A00 e j Mtditint Sprinffuid, lUinoil ftd FINIS L. CAVENDER. Ph.D. DitttUr, Inhalation Tiauelegy TenCtnitt Drtstkt, Hinca CHARLES C THOMAS PUBLISHER Sprinffuid fllinmt U.S.A. 7Z aisitMawa*/ TunoJafr related in div-asv stales. T his author feels lhai a inn Irm nl inhumation lias hern dcw lupcd hi- immunological inves tigators tu indiralc lhal the immune sysiem organs ami tissue (thymus, spleen. bone marrow. lymphocytes. niiiiion i n | may provide a ferule wiil Cur such investigation* that allitnpl In provide valiv ihienion of ca|vicity (nr t brook di-casc by environmental iliemirals. Immune rtiiciciicy or modulation ul ihc immune response has been kitciwn for mans* w ars. Irradiation. malnutrition, thymectomy anil certain aniirancer drugs currently in use arr proven to r n n r change in th e,im m u n e system. Although the immune system t complex anil not cumplctclv understood. auflicieni infnrmailnn i asailable tn indicale that various elements in ihr immune lystrin jpjHJr quite w n tilitr in chemical*. It is well tr*(abli*hcil thai ariivc tells a ir the n ii-l sensi tive 10 chemicals. A p w d deal nl iniurnialiun has Seen developed on ihc n 1uf anticanccr age nis and (heir capa bility to induce secondary anti tertiary canters in utiem s undergo'up anliraiieer irratineni. Som e u[ ihe change* associated with v.irh trvainirni al die ceih ib r li ve! arc also seen in isis>ami in emu and n( tin in c raise* :ltv ipii'snnn of whether this activity can lie Jl work during esjwisuu- In environ mental client irals' This author lecls ihjt (here arc some relationship* lhat make the ties I decade in immnnohMientiigical research possibly the muM exciting and mten* (ally the must im|turlAn. Ininxluciion During the Iasi tit e rears, nuns* u have heard llu 'latenu nl that "a laigv iittudier uf Camels mav hate iheir rli"lui;y in die cns'ii oilmen 1." I his staleineul hrl]w d tn propel an all rails' ener getic national ih-*ire in r l i j i i k I u i m s ami tin * ' Mdunigh there are many dillerrnt upnnnns a* in the a iliu l nnmliers nl earner cases coutrihul'd hv ihe t ions eiivimiunrtitul tact"is. n ha* le ru grill' alls* agreed upon. among hii-mviliiallv tuiviilixl research saieiilisls, that rnsiioiim rnlal ta ll imigviivsi* is a real entity.' In an ellurt in seek a tills' m in bsgui a [m veniitui (m e Chapter 3 IMMUNOTOXICOLOGY AND CHEMICAL CARCINOGENESIS Josicn K. Pi i m i ABSTRACT T he inlluence ol environ menu I chemicals mi mamma. lian sysiem* has been given much aticntinn over ihe last several years. Biuas*ays of a chronic dura imu as si el I as short-term genetic a**av* have been d evelop'd s>uh an eye toward the early recognition of ihe occur tent c* of a lesion in some larger organ, nivsiotogrial and Im . lo-miiat changes are targeted fur analtsis and siiTVcdlans r in an Hlorl In develop a screen lhal Hill signal ihe pn>im ti:t nl Hie cvcurrt'iice nr chronic disease. Allhough ihe liter and kidney have hts o mnsi mi. nsivelv investigated, other sysirins hate been u*ed m this elhirl in establish an early teaming tvsteni. The majornv of the studies earned mil have nut taken m ln -i count die jaissihility that the immune Stsiem mav be the* nieal v eh u ie lor such bioavsayt. for whatever reasons, insv'itgjinr* have underestimated the inijvsrtaucc o l the immune sssient as * Th" I4tk wt*A*s itiSfnl u* I* I * H %l \ | U . n , l ) I h M M m j i W 1 J w w u i u . , ; , r 4tn\ Ih ib lh lM ^ ai t li M a iM l^ ^ 1^I M.tsMt U ti: *.1t llr^ di ^1\Ub.il Vfl I h # M h Afw* ht I(w s rtk hi Ip f'tl i k s m l a - <> n M r* Ib lA te ||t |q L iw I f l It|wni i i i l n h i 'H ^ o l'U lv il* n*q-s |- 1 W i i n in-* -m1 *1**% ^^^, tN i M ftV hs **'. Melli'|ia *> mt* h*dr lfv mV* <4li f* mj* i*n4<Bttim.it 71 / . . ( o i u t i ^ c i and C itn u a l Cann (( TM 7.1 grain, ihe ens imnmviilal ch em iu ls lhal p m - n l a (artiiurgeiiti ruk In humans, are an ideal largel lor investigation.1 In nrrh-r to establish some messi ite nl risk, pn-dir live in stnilecv ha* had lnii*e ihe various avail able tinti*: epidviiiiitrv. sialism j I eatrajiolatinns nt pharmacnlogical dose rfspwise stiulii'*, the nmitiple sjiecic end target organ bin assays, mirnibi il. bincliem:i at studies, and chemical sin ictiur relationships. **'* 'I hese tools. i-.s: caiilKtuily, have served us very well. Howeser. Ihe fact lhal human siala is lacking in majority of the cases has Iteen a source ut conclrrnaiion. Recent development* in th area ul immunulngv have provided a nucleus o data and of cuncvpls that may help resolve some m these pnihlemv associami with e.stra|>oljtions to in m u ns, AJllmogii im m une mechanism* and die svstetn has imi !htii delim-d abso lutely, research lala has hcc-u de\elo]>ed that sh.n.s that ininiom* system cells (small lymphocytes. '1 anil li cells, mail''tillages Iji,0 products such as Ivinphokiues plav a ssrv im|Mii lam n .ie i:i .tie body's immuni rearrum lo |Mi--iliIe patfmlngs troni mil lutila! infection, grail rejettiun. ami lumino prosliuiitin. T h e Tan that these cells are readily accessdde and are human til*lie present in ralensin- amuuiils in |iei iplietal b ln i.l ami tu se ptiiemial (nr rapid prettieratinn m ates them an ideal svilirle for the itudv of [wtlemijl Ins icily. Immune Celi .\n ih -et (Ine .tea d ui lus noi lus-u wvll imesiigals d Imi ih --i se* allenti!'i, b llie human immune *i*:rm. Vii*1* as w*-ll as .Si)Lwi>iih ami L*ntH'.': ha fouiid rs nielli e lh.il siip|Hiils il:.-. oi i epi "'..il e: 11 n nin en ia! ihem itats ran p n .liu **mmbiii altiius m die a*li* il le* ut lite tii.nillie sislrm tells. A iilitii.lv mediateli tr-i-ljiin - t eli ini -!i a ln i ivsistju ie. a* wvll as mi llu-isI lis e l- o l iTn-ilahi thie l,< lowrissi iisisU lii e li* lurli'l iJI itileilions t u ie hv.-n rv]wirii*l ir divo itvirws. B-2 Immune Deficiency and M ilip u in y One ul the must significant advances in cancer information it |h e finding that inirminoiieiick-nl 'lairs arc associated with an increasi-ll incidence oi malignancy, Keripv*1has shown that pal ems who have tiahirally I'ccurring stales of immunodeficiency such as Wiskott-Aldrich disease, Ataxia telangiectasia, or agaminaglobitlinem ia have an unusually high incidence of malignant disease. Numerous experimental hinassays are cilcd in his review, show ing that immune suppression facilitates transplants ni malignant cells, increases a normally low incidence o( viral or chemically induced cancers and accelerate* gn--vth of melastasc'. Immunosuppressive therapy has been used for some twenty odd years ami has had a significant impact in producing secondary and tertiary cancels in patterns who were under such treatment. Penn* has been maintaining a tumour registry of patients who were on immunosuppressive therapy and classified them into fis-c groups with the billowing results. A tin ill nrith Transplanted C sn d u Si*tv-one patients who had rrteis-ed organ transplants from donors who wpre ncuplustic or within several month' snbsi-ijucni to donation drvrlu|ied eiidi-tur of malignancy showed that twenty-one patients or 31 percent had evidence of transmitted cancers. Cessa tion of immunosuppressive therapy and removal of the graft re sulted in the complete disapjtearumen! the disseminated neoplasms. Traiu^Inf Palimlr infA De-neie ilfufiriundn In a long-term follow up of the University of Culurado scries of renal humcgralts, 32 of 56-1 patients developed cancer, an inci Ni UnnnwMrataf Viuts(tr Sim Tramplanl / 'afimi Tirateli irith Immuwoiupprenti f.4h/iinfiam ma futy thn ap itf Data has bevn cnllecietl that iudita ti-s tlu t u( sevi-oiy patienls wlui Ila*e liern ..... . juliinnatimialory iherjpy. srvcuty-lwn ranrrt-s develo)ied tluritig Irvatini-ut witli varimi* agvnls. />Vcv Psoriasis ,Vn Cares Thtnpy 24 Mrthniresale Aminopierin Other .Vo. 35*. (B O Canter Type Cam 23 Lymphoma 1 1 Ij-ulamii 1 H Skin 3 Mise. 16 Urtai Disease 13 Arathoprine 7 Skin Cyrtnphm[ihimidc 7 Lymphoma oihcT 10 Mbe. 5 2 6 Ithcumaiuid AnhritU It) (iyctuphosphamidc 6 Other 8 Lymphoma Leukemia Lymphoma Mbc. 5 3 2 4 Svsirmir latpui Eryltivmalinus 7 Cyclnphenpbi mide 3 Amihroprine 6 Other 6 Kaposi'* Sareuma 1 Other Inflamatney Disease* -. r ' " ` e--. 16 Agent* I'sed 31 (a* above. atone or as combines^) t Cancer* 16 (Lymphomas. Leu- Lrmia*. Hodgkins. and cancer of skin, blackler. colon, bronchus.) i . U t p ia tir D iletteti Pmtimii mihoaS Tmnrpimntl III uoulians|daul palit-nls with neoplasms n* rising unmiitmuppres'ive cancer tln-rapy, Penn" anil M-cm-v" showed that secnml and esco lisird tumours have ar'rn sluriug tn-atment with theniolliera|ieiilies. U l |8*i p.ilivnls with luiiumrs treated with eitlu-r Melphalan. cyclnpliosplianude, buso 1lati, t>-invicupo >pui me. Imwiun,struttali'fy end Chemtetl C jm iupiinii dence- of 5.7 percent. The Denver Transplant Tumor Registry ha data on 4*11 if* non, cancer* that have occurred in 174 patients whi have receives! Irrlncys. The average age of the patients were tliim* nine years old (range eight to ses-entv years| and the neoplasm occurred from one month to one hundred fiftv four months (1 : 154) after the transplant (average 32 months). Alter the in n s plants, the following immunosuppressive procedures were nsec Prednisone. Aaulhloprine. anli-ltm phocyle glolmlin (Al.(r), A m nomyrin. cytlnphnsphnmidr. Radiation. splenic iiimv, ills m i- tone, and thoracic duct lislula procedures were also in use In conjunc lion with ALC treatment, b-mcrcapmpurinv. mellmi resale, am. leaserine were also used. T he patients receiving irradiation, splcncctomv. thymectom-.or thoracic duct drainage tnatm enl accounieil [or 217 <U tm;. cancers, while the patients on pharmacologic theiapy accotmtul for the remaining Ifi-J cancers. The development ol malignancy could not he related to the use of any our agent, but appeared to hr an effect of the general immunosuppression. A significant finding was that the incidence rate of solid lymphomas among the organ transplant patients was (-.proportionally higher than the genet a! population. One variety. Reticulum Cell Sarcoma, was calculated to be 350 times more common. H ie lymphoma patients were slightly ynungcr than the olhrr cancer patients (36.j versus -ft years old), and the tumours appeared earlier than the other cancer patients llwcnty-ihrcc versus thirty-five months). '1 he solid lvmphomas occurred in ninety-five patients with the following break.down: Rrticuluin celi sarcoma* . . (One palicnt also had a Ka|x>si's sarcoma.) Kapi>si'* sa rco m a ............... fW )| Lymphoma.............................................................. .. .............. (Including 1 plasm aceli lymphoma). Lymphosarcoma.............................................................................. Lymphorelicular maliguancv....................................................... lludgkins Dsease ......................................................................... 8 5 2 ) Il istiocyt ic Reticu loss (?).............................................................. 1 tati l'hertimtl Carith.-e-s>'ti eli lori lapiiaritu-, tliliiramliuid. |]iii>ic|>a. nielliMiii-sate. ami piti nisoue, aI*-tie or ili loiidiinjlinn. I"l new malignai,, u-s il,.seln)* Various leukemias ai lo, intis Lfor eightv.iwoo] iln-tnw m alignam i,' thirty-five lymphomas, iwemv blaikter caie inuma*. two caw ram rr of the servi*, and mu- llialgkiiis iliv js r m it im il. li: remantler id the law s were salimi* ami niisci-llanenu* turni' malignancy ami tondini lihv-five. Acute leukemia occurled in lliirly-niur cases where the palli ni originally hart m ultiple myeloma. Twenty-seven solid lymplii-iua developed in cases whi-te the patient's original neoplasm wa chronic granulocytic leukemia. T hese unusual >(iirrm t es w .o l lend to dispel any idea* that these cancels were transit inn fui m s , the existing malignancy. Thus, one can caul music rstrajwdati- th data and identify a significant associatimi between the devil,,] meni of malignancy of lym phoid elements and the use of cheim cals that have the capability of suppressing i-leineiiis in r!i im m unc/hosl defense system. (C hlornaplu/ine is the our am-n capable of directly causing cancer in man since it meta Indues t befanajihlhylamine. It has causetl bladtler cancer m aniline dv workers.) Leukemias and Chemical Immune Modulation Of the four major tyjN-s of tytulogiral leukemia, myeloid am lymphatic constitute the greatest tn-rcvoijge. M selotd case* pea' out at about nil percent o l all leukemi.is at age till ns to torts-, the! declines thereafter. T h e lymphatic type has the highest presa lence in children pcaLing at about '<0 percent ami then ileiline till age thirty to forty It then rises tuisljH-rcent ]h j * between ag>- eightv to ninelv. On the wav up to its peak, the lymphatic t\p< passes mvetoid type leiiLeinu .it s.-st-tilv seats ,,1 agr.,: An cp idem ulogival study of solvent vs |Hisirre a nil leukemia wa conducted among rubber workers hv McMirhael el al.** imlitatm, that au associatimi In-twes-tt Ic.ilviiua and jobs that involved usui; solvents esistisi llrioi to tins nut,-, hessh-r atul I ii]ti'iilrtil i X*--- a* well a* Vigltaui ami Sai la" hall pirpat, ,1 |,a|H-is uulu am ig tin , thought that the cm reni evident e 'Uppm teil lieu ielle, piteli v 1 bularnnr. ami rhlui aniphentrul as living luckcntirgrtis, huwi-sir they hail klllllil h llle epld. .illulugti al evuielitt- to sup|iMt ll> KH Fali'iuinrukJ liumii/r |im liirr. M cM irlurl t l aI,*" hail analyzed some IW<) fn-worlicn (nialeruldwr wotkers) who were ww King during (he yean INi-t to 1972. but hail an employment duration of twenty-five yejrs. They were followed for nine yean with a I pert cm lim . Matched con troli ere also analysed, with -tanihrrl innrlaiiiy ratios and pro portional mortality ratios calculated. Oi the various relationships that wvrcanalyrrd. tin- a"* iatinn of death from lymphatic leukemia with a history n( having win kill in in lirtil n ju in ire eiivimnnn-iil Mood out. It it id ime rot that the tvmphaiir h-nkeinia stands nut a ia iu ic h to U iili vdvenl o.|*n'uir join. T itle leukemia (n id i in lie lh f myelnhlasir or the Mem cell tvpe. MrMichael had indicated that the lenkeiungeiiir effects may have been the result of curicnmilant ex jvesuri- to other vilvctm that were used in the rubber industry. However. Infante el al.'n studied a population of worker* who were occupationally exposed to only bettrene during fiMU to 1949 and who were followed until 1975. Comparisons with two control groups show a significant excess o i olcrvcd leukemia |p less than U.lkti), A five fnhl excess risk ill all leukemias anil a ten fold exress risk-of death from myeloid and monocytic leukemias combined were demonstrated in the comparison between populations. T he environments of those workers were ana Ivied, and records have sltown that tin* benzene levels were generally lower than the recommended limits at the time they were measured. Tin- observations are in agicemen I with Vigliani and. Saila.*' whereby a sp.-i.ilk type of leukemia is asvK.iated with the exjmsnre to hett/ene. The myelogenous nr mottoes lie letikemia has been shown to rnrrcljlc very welt wiili the i-X]K>snre and inniirms the MisptVitm that lien/eue is a powerful Imoic marrow jioiinu.'i Goldstein'1has written an excellent review nl the toxic hcm ojxviiic effect nf Ix-it/cm* ecf him ire. T hese r fleets, although somewhat complicated by concomitant exposure in some cases, are fairly Well demo its!ratciL T he mechanism by which this toxicity occurs is nut known; however, the alteration of item cef/ ftinctinn is apparent,'1*'*7 ""1 Ocrupatiiinally exposetl persons as well as laboratory animal stud ies have shown chruiuosomal ahnotm alines, and correlates well with the known clinical picture of (wnieue toxicity.''*"*" Goldstein Jmmwmotoxirolnga nnfCirmtufhtirtwiconn X9 has w ported ibal in mice chronically exjmsed to Id) pjun of benzene, lenknjienia,dm* primarily to Ivniphixytojiruia. wasclearlv demonstrated. T hese manilcslaiimtv o l pam ylopenia n uv repre sent a dcstrunion nf the stem cells, failure of the cells to mature, or prevention o f differentiation at some critical stage. Other ageius known to produce pancytopenia art in this fashion through mod ification of nuclear m aterul. T hey iurlmle ionizing radiation chhirnmytvltn, vinblastine, mitomycin. purnmvi in. rob hu me and cytochalasjo B. Many of thru* taller com]minis have been useil in clilihul treatment of malignancy. Fund cl al.'1 carriixl out cylogonc studies and have conlirm ed chromosomal aberrations occurring in jieripheral blood lym pho cytes, due to benzene exposure. If one examines the ontogeny of lymphoevtes, it is readily apparent that hone marrow stem tells devi-lop im n twit ikllrieiit line* o l cells*.The one line produces hemopoietic prertrrwirs, and the second line produces the lymphoid cells. Logically, inierlercore al the item cell level is bound to affeci both the blood eleinenls-as well as the immune svsirm elements, ladmrainrv investigation! have observed pancytopenias such as monocytic, and m yelogenous leukemias due in I x im w ex)wisurc a ls o show stem cells that h a w produced abnormal mature rrythmryttx. which further supjwirls stem cell nuclear linn lion iiireriervitcv- \VnlmanH hat inilirated that ample evidence is present to s h o w that chm m ovim al alvrrjiunis can tie iudunvl itm iugli esjiosure to benzene. G a p s and jiiiitliinl bleaks base Ix-eti nhv-rveil in cultured human cells (leukocytes and 1lel.a tells tal 1.1 or 2.2 - 111- 1 M. Iw-ii/ene. Higher doses cau-i-tl inhibited DMA synthesis. 1`et iphs*ral lymphocyb-ssiimutaitvlIn* phviolietuagUitiiini(I'llA i r\]>uv-d In tienn ne for seventy-two hours retejltvl Imih toniierual ami stn iilu rjl alterations. Aiieuploitlv anil ihrotuosoinr lueakagc occurred .seven and eight times mure freipietuly in treated tells. /n m x iu rA m ir d i and Cancer Advances in pharmacological llierjpv has pn-duud jirublems as well as rends-ions in the treatment id tli-ej-e -Ijies Palieiits who have been irraisvl with anlilis |w-rteu-iie. am uri vllimtr agents at well as aotubercolar or aiiittuuvtilsjte agents have shown to Ik* 'll AtttSMHKSlrl IklMtaifCr 'tiweplible tu a sylldiome related to the immuni* iliwase ia lin i sysieinii lupus ei stheinjlnsiis (M.K).r-'" ' In M.K. the pa lieu I ilevehi[is auliluidirs stimulated hy the patieol's own lellu tar material. es|w-t u lly the mu tear eleinenls. Il allei Is vai unis tissues, and lias a lalal form. One id the major findings in diagnosis fias b i n llw pu-v-me ol nn I.K tell fjwilvniorplmmutear Inum iti*-- I'M N 'l that (oiitaiiis phagm yii/td mu li a r o i j [i*m I. Ibis eli is lu m in i as -acon v s pienii* ni reati ion Imwi-en ail aiildnidr privimi that /a n lumi tclltilar inn leuproteins, fren i inalile the mechanr-m itim iviv lltr lymphocytic our lei that reacts with the antrliodv. l.yinpluHvies 1x1111111* saturatisi on tlir-sr aitivi- -ill's, atid l*MN evils come to coglili the swollen lymphocytes. Digesting away (phagocytosis) the remainder of the lympiurtvie, the I'MN jiarkages the iiuthsijimtein material as a residual body called Lf,, Although this disease is usually viratly induced. thenijieiitic agents suth asdipheiulbyiLtiiinii, i.wmiazitl, htibala/iiie. anilpoxaioaiiinlr have indili n l the syndrome that generally* disappears ujinn with drawal of the ibug. T h r v mechanisms that induce the M.K s n drome ate nut yet well nndeistood: huwvwr. chemical iniluence on the immune system has produced antibodies dial incluilc antiDNA. antinurleopnuein. atm histones, antinocleuljr RNA. and antibodies io ftnui** or particulaie nitcivopmirius. I he mjmrlanceot thew dala rellect thjt exogenous client it aU. width mnilifv or iniluence binlngital sysicnn, have unusual d iesis that are nut always readily apparent. Ilow this important defense ntecnamsm has been modulativi bv intel play wiih chemicals n unknuw n. but nv real rapacity In ehret nortear material creates grrjler puvsibilitics n | biological ihston/inm . Zarrab cl al.'; stilli m l (our groups til humans under Irea imeni fee lom e two am) one-half yean, with chlnrpromaiine ami varimi other anti|jsychulic drugs. T he main ohservalion was the preva lerne nf innuiinologii anil thrnmhnplastic coagulative disorders, lit patients on lung term thlorpium jtuii-. the authors luuinl dial patients hart increased levels nf wrtun IgM. -lUi Yi (m <tdnrprnmarini* irealeil patients), whereas io n i rots bail 1 *7 t 2 I. anil nor mal isiom u leiivl lo tange ln<m u>tu"J'(i panelli' who it e gis en combined ihrrajo*. rhlorprnnrjzmr p in i aioilh ir ilrug, for the same length ill time showed lew isiti scrum IgM at I'll a YtJIher /nMXW4ilb,airvWttlf(klMSlt I/o*loie*l(l*-l- **t a n lijis y ilu tili itvvf wer<* lliiu iiili/iiie . Im IIiio | i, i jin o * . ih o * ih isi io*. |iei|ilieiiariiie. h aloperikil. lidi nini, am i jo u li i . l.iio 1 h i- g io o p a to n e d iti n o i p ro s u le a n i sn^iuJu j m iM!i i >*oi i-le u *x n |... i satu s w e r r in aile Ix -lw n ii d ie g in u p s - tm lin k A lv i o o t u l was au iktiviv- ili In ig lli o t j u il ia l ih io m ls ip ljiiu i limi-, li lw.il> m iIj i i i i s . M g stllitatti t o i i e l j l i o u lielwi-eu u n n a v i l h*sels ..I J*-M in - . 1 n m a h x ig wrtdi lliio tiilx .jila -liu itin e wen* noi n i m ,-Ij i i . . ii lo liov* a n d do rat ion ni theiajiy. lindi grnups liad a pisiiivi* aiiiiuiu b a r aniihtwly t r - t (ti'l'A), l o t h h ai) n m l in jiio ie in j i i IiU mIk-- |V s 'i ). a m i bolli g ro u p - had anlilm ihes lo native DN A l IH). Il is in le riv im g tu note llie auiho is' r otti lu -io ii. " ili.- IgM was di.* m agu lalion intiibitor."'and was iilc-nl (i li ihrouglt im m une isolila al* izatimi and iinm ium gltibulin iv ila lin n ttv h n iip iis , A pruduti ni th im m u n o lo g ita i analyses was die lin d in g that d ie jw ire n u g e nl [Ivm phocyies wvri* helow normal in d u ritv n uni o fi iris -mu* p .n e u is trcalvd w ith ( `.hlo rp ru m a/ne and tw eiilv im i ot N>rtv-i*n patienis under single o r com binivi treatment developetl splemmiegaty. Recently. Doctor I. Fidler" al die Detrieh Mare lami (Ijikit Research Center, working wjth m acrophage- frinii m unse jieritoncum, ftmiul that h>r some twlil rra-rni th niactnph.iges Itegan lusitig their tunionriiLI attiviti* during in i-ifr stiules Orilinanly,such nucniphagfs in th wTitntieuiii aretini tvti*tosit tu imnmir cvlls m nini. lii*it*r, a lymphoLnie relea-.-il liv art jitisa ln l lymphocs te. relerred in js maemphage actis^rtng iaccor l MA i I has thealiility tu iti muale th niai mpli.ige lo Insume timioru ibi. Such pcntoiieal ex tuLite mjrrnphage- | l'KMt tan al- he stmiulalrd tu hernme rvlolusir bv h.irteii.il pnnlm ls Ili|w.[w.1sm i lu r id e--l.l'S). eiuiiiinsots, pvran ri-|n >l<mei s. ilnulde Mrai'ded KN,\. or during chlim ir iiifeitmn wnh o ld igiie Uailena. Ilo* in iiin> siudtes wvre s|np|v*d amL in certa in tav-s, tlu* uinnlnn* mmlilred becau v tlu* l 'I.Ms wete tuiind tn bave lost th es-ustnsir enpduluv, A t j n fol e\Joiiniui ol tlu* iv i iirrenie o | lo-| n i n n i m *tned In u n telale wjlh a minor thange in lite diiiikm g water u w i (or die m ouse enlomes. Uali-T bvl tu lite noi.* lu d a chini m e I n r i of a la .u t Iw elve tu si s ti v o |ia t t s |w r n id h o u tjip o it. I l o . logli l e s t i is i i i i i - - j r v tu re th ic e th ra te o l c a rie i h j i h svitili.im<- m llu* |i< |im v d u e lo fV*tiikwii,uiat tr.U v Io n i s o ., e tilt- l u n e l u d In v i h l h .i l l i iiia sh a le sl B-4 92 finimmmtHUl Taiiii'im 'f IIn- in an lum nijlly high ini idem ul n u li ejrls deaili syndn m u ', the (lih.ruu- level k j i raised to 2*. in .til ppm. ami ihc experimental 'Indies 'e r e carrii-d mi as usual. At ih c Mari ul the os|>erimi-iii ami jnsi bclon- treatment, the mean number ul i'KMs |n-r mimic was 21 -1 Hr-. One week taler llu- level uf I'M \ in Ilio m ne ret riving hi`|x-rrldnnnaird water had decreased in Ul st 2 * Iff per munse. fj.utri.lv were yielding 2.9 * .1 HI* per nw ine. On coristi ulivo weeks, 1*KM yield imroaxil Irrnn ihe unii ml mire, bin u nirm i hvjirr. hluniiaied water hail retlnrnl I'hMv ur remained Inner than (murids, Miro dial were rei riving tap waier yielileil nut (..ullages dial when limu b lu I were tiinjnrdiLd in i-tlm Id Ulh meljnunia celli nr to V \ ` 112 librusarinma when ji livaieil by Cnmanavalin A-MAK ai measured hy release of railin.itlivily. T h e mire ilrinking hy|K-flld.>ri.i3ied waier exhibited htwerod (ovoli ol cyh'lt.xii altilily (nr Ilio lin i I n i " i l l s . anil. hv Iho d ill nf iho third week id in-aim.-iu. Ihe colli, although stimulated by Con A-MAF. wore not lumnritidal. T h e v Indies \litiw lhat hypr-rchlnrinaird waior produrre proEound alterations in the tm m W ii ami lumtiriiidal capacity nf PKMv. Lower levrli ( 10*19 ppm) may* altn cxcrl such influence although over a hinder period ul lime. Supporting theve effects wav a report hy Miller lhat ihtiwed that pallenti oil lung-li-riti lirniMlialivii dcvr]u|Mil anno hemolytic anemia when irealed with water ihai. although (ilu n il hy reverie mtnrniv, hai 2 In I ppm clitnriiie. (Thimine nrmpnnds brought about a (L-uaiuialum ni lite ticiitogliiliin hi iliriii oxidation and aim hy irifuhitinii of III) i!iih I uviiLitive pai1.ua> 11l.-io'i- niinmjihiiipliate dinntl id red hhmd celti iKIK'.sj. The damage tn Klitis h ai Inumi'il iH-cuinulalivc over M irnil ] i itali id ili.ilvm . Al Ihunch Ihe mechanism lor tliiv depieiiinii ul tiiam iphjge Iuntiincida I activity iv uuliunwn. Hiller suggests leverai |mindillitie, lilt - vacuoles nf the macrophage system are piohahly invidved iu the cytotoxic inei lu n i'in , T h ii tu> heeu 'lu>"ii by 1lildn and Weinberg'" wlierehy inhibit i<m id the Ivnimmal ens vines id Iho macrophages tit tu n by addition nl trepan blue, anil Mjliilwauttn o f Ihe lysosomal menib u r n occurs with the addition <d liyitrucortbone. and the cyhduxic atlivjty is suppressed. /etitiirJtt.l*.1*1Ii/i.cr mtl Chrmuet rd itutiflinil ITI Mairupl.agcs thal hai** lui-n j t l i u l n l hi Iwuplinkiix-s lin e i-nham iil hjtlrn itil.il ailiviiv. ami rueljladitalii a ie dim iti tu havoa (olir tu righi lu m i tucrr-jse in th DpiaLe ni ginn e and ili oxiilaltui ai i (impani! In iniurtil'. Nini e lite i l.lm ino Iri.injunirirtsl iuhihilv th IIMI'.S ju lln u v * libai ii Mie major palli lur g lu tin e fixiibtinn in lite Kllti li. Mirre ii a [mssiljdilv lliat hlnritie ami.-tir ili tuniprtuiuls may m llii rrrilly inhiljil gtiunw iiiiiu in u i tu th pttiul whctohv mai ruidiagti thal (uve n i lutivi limi, .tu u u b i .ip.it-ity will allttw a lieiu iit te li' In i uulm iif ginwiug aul ir-lutali/ing1 (amcurreiilly. indire l paltinlugv alm tu turi* f hhnirie I.w ls alili I crylhmtyirx* ghirosi* meialwiliiu). aliti lai g ainniiiit' *.l fi.uit.g'rbin flegraiLliuli prtMlui li aud/nr larg- uiiiiiIhI' .il tlaiiiagul KIKa cau lupprew mai mphage tiiiiuuuliial ai tiviiv. Rugari 11(IV tif Mie niethauiini hy whit li Ilio ihlnt ii.jletl u .ilti or chlurno tuni[a.LiiiiU may rvcil llti ii udliii'iite Mie iiiijmiii.nil lai I rema inv Miai niat ruphage acliviiv il toni pi uni li-li. bini - il t ai i i n a major mio in limi tleFemo agallili ueuptailie diw-aie, ilie | i i. bilily CIMV ihal a hmt whu 1 exjMixil In 'itili tniu|iiiiiiitli niav in Taci boto nle imniiuiia uiuprumixit. Si Ilia. caragtiuau ami lrv|u n blue are'iib'taiKO ' Miai aImi bave ilio a ld in e In n ip p le mal riephagcV in lab vlm liti bave beeii repuried In t l.ir r j'r hmt revtMance agallivi trauiplaniaide lumuiirv. * barutlViT et al.1leteu llv re|irtod llteir M u d iti uf ilio eliti li nf poMiciiUmn ihe im m unen.ipon'o lIjm 'ler'(t.JK i.I AK) Inetti righi wvcLv uhi alui weighiiig alvini IH' grami werr g ii en a ('e ni jw itiutle t-tiual tu t.ne-huU ihe l.t) " ili*dvnl in 1 mi *>t m tu nil. Atta hii.r b ,Jl. Dinmeb. I'jr,.l!iItili, u'iiiaililuit.niri. In ii/ftu-, pijw-ri.iivl hninvidr. nn\i-d pvit'Miiini* and i'Miiitbtui w're adtnirii'toieil utli.rgj'li itally. Ih'- .iiiuii.iU itrtr rianim i ' !*i all end | hlini <<l "It ib u n ami iw elliug *\ iiilhiinmali v te'|u*u-e| ami thange in teiu|wiature tif Ibi- l.>l p.ul'. ai i r l i a i hiM uIi.git.il exam. aller :m aiiiigeiiic t liath-ug>*. Setuiil aiitiUnlv Miei, b itu liu g aftniiv. and h iie iu g n ieily weu- ih'lertiliueil hy III......-Meni |xilni ilatiuii mi j'iiri ineiit'. T he animati wete lin i gin-n ali iiijn limi ul lliiMtewi-in Ij Ih-Ih I ti-jlbiiniin. alh.ueil i.ulv water ad W. fin i"t*tiiy-(uut .......... and thvn givrn a Imlm u( h*l wiili ibi- pc-ih ile bv inliaga-nit l. i ding lubc tweniy-li.ur him n aller th luuuiitii/aiiun. I he iitt.'t Wt (imniiiihriial 7*..*/<<cr Mriking lea Inre re| wuled hy Ilie aiillitin alter iiiuiiiiuaiiatyvii nidita ln l in jiL .il Iinuunal and tellular inuuiiiimii|.]i>eimi In single t k m ul I)iitm-li ami I'arallm.u. anti a inarL.il 'ilunil at mu ul ihe n-llular nijw .m e hy rrsmrlhrm. T he nihrr jm n ciilii showed filth-nr uti rflert under Mn.se ifiithtii.iis. til Jiu.lli.r simlv*1 using Ihe |H i|niites Amelrvm*. Carliarvl, (3 littime form. 1)1)1*. Malatlli.m, Mirex. anil )>atatlui.it. a single tktse ul ]w-sli< iilc was given ..rally at the M )'*1nr Ihe 0.1 1.1)*"' live days he(tire, two ih iv l*v(ure. nr I n . (lavs, aller imtmmi/alutii m ill diti*|i rTvthmryrn. Assavs were th.-ii rt.titliu led using aiililaxlv |dat|iu- burning (ells l.mr .ta il lali-r, (I'la.jtn- kirming tells -- antibody- pindm mg cells thal ran lorn, a heinnlytiv plaque in lluprx-senre ul mmph-mrnl anil t-rylhnuyles.) A ll animals rn eivin g the higher l i r e cvliibiUil ugnilkanl dcpriisttuis in splenic pljque kntiling toll nunilieiv, l.uw ilnso animals rerriviug (he ibix- (ur either eight or twcniyi-ighi days prinr io immutiitalit.ii exluhiuvl nn signiliranl riilnrttim in ihc anlilvitlv plaque (turning Cell num bers. T he ainhnr indicates lhai a lack nl infiirmatiiui prevcmi a ci.nrlu'iim as in Mu- ellu aiy ul llu-'e (unqwmmls nn miMlulaiiug the im mi me system. .Siiicr (he mclluxiuhigy on li ii'i-v one tt-'l fur the oryihrtw ite m e pinr. link- can be com Iiiih i I. This is why m ultiple juranicter assays are necessary. faith and Luvici^ havr perinrmi-d exiensive invosiigaiinnv on Ihe |i i i - and)wntnatal ethclsidTelrachhimdibentndi.iMii I'l ClHJ) nit the tnnume ssiicm and have h.iiini lhat 1(11)1) apiwirs a relatively e w ll e n t imnuuuiM ippriisiie in die liseller.Lli'lar rat strains. H ie Kixber Strain is repulnl In l v less id a ni|wiiiilcr Mian its H xhcr/^ ' l'lar rnusm. Jiowesrr. timing ol nursing ft-malu has shown that ihe TCDO has ihe ca)ulnliiv o l cauiing imnuimisupprxi'Miu in lilternulcv. T he olh-clv hast* fj-itil as lung as 270 Mass. Irum throe iln m to the nu.tlu-r at tUvs rot, -even, and h un u en . applied at live rmtrngramt |er kilogram lug/kg) btwlv weight. At th y i eighteen and ihirtv-kve. both h.-male and male liliermalos skwrwevlih-preswsl buds' weight as well as ilep m w ii ihvmic weight', "nieve iU-pies*ed w ines wen- evident at ilay 12.' |knlduiing. th e weight uf ihe >pleein were also Innml in be allu led, KfliTtvuf*1(11)1) isjs.'u n - >mthe liutmng paiteinsiil lymphiwvtos wore aIwt siuibis Iin these same rai Mraini. Splenic cells taken hum fmmta..ci-^yr aw./iSi'i'.i. ,11 I.,;. ! TI 7; > / ilio T (!l)l) l .q a is il rais bere iu jiil.il iulu ruuiesp.isiil u ls . and Mie Ihytiius was (uiiiid lo sigt.jlh anils mi mms.- Me- iq .ia le i.l su. !i irlts, lliv iilil le 11' I j l.ii h.mi tuiiiesjH.'.il u ls s*fn- in p ile d un.*1(1111) evjHncd rais, and il was (tonni Miai il.eie was ib i irao-d hum iugabilitv In llit-ll.uu m . I In-antimi ' ;.t.i|a.'*il Miai a <liiu.g.u cellnlar iurta Ihdisiti . u n ir m i JIteli rtg Ilo- (e li ninni ira..-, m Miai insertimi I.| lite KIUlJ min th m. iubum - ausili su ila .r altoraltuns. and iliis ihange in lln- .r ii niudilinl iis lu.iuial htuiitg |ultcrns. Vati..iis uisi-siigalnrs hase slu.wu su. li alti-ralmus in immune finn liuti dm- I n i (11)1) i-s| Moliri-.*.",*' I). igjwn*1 has siiti ii Miai snlw Iil. h al ihnei >d I(Il M) l.j.l iImabilily lo alleil In.'l ie'|.n x-. wlu-n M il.'tip ie t.i t-S|w.si.rr tu .salm ontlk infoi limi ri-mifu i in reilined rime tu m urulilv. llm s far. cvposnrc lo PCI)]) has lai n sliuwn 111 (ansi- ali iiu t.-j'e in Mie vuscoptibility In batti-rial inleciiuns iM ippie'sii.n ut im m une r o ) vinse) as eli as siipp ressimi ul unii .gei i ros|H.idiietu-'s. supprpssinn ni th kin grali rejn timi, and depressimi ul Mie Mt-laved hy|>crscnvitivjty r.-'|winw. (Siqq.ressi..n I Mie lu c ll ih-jH-iulent immune lim c tiu iis ap|M-ars In iwcur ai jn miaIni ro|w .m e.| Summiry T h e in il urn cc u l cnviroiim enial ch e n ikals upon lite puliltc hcatlh h or cuii'iilerabk- ini|xirtanti-. Determ ini Mg how mii h t hemi n l i may cause adeene elfrcis iip m hintiaiis i\ a cnnlim nng prubtvm lliat jn.-rple\es a ll pliases til s t ir n id ii iu pnrv. t t u r ile ehrtm ic to x irly am i dose respnn'es are eiefi lieti Irnm a nim ai btoasvays am i m u m liijl U N A sim lies Iu r human use. am i c o ii'tituie a m ajor source of tu iiiro versy anione pi (-elidivi* loxiculngists. A m ajn r strp [tirstari! in n u d e in g M ie ti p roli Irm s rim iti h r at la i ned itti ihe use o f lium an iyin p h tiiti te ils , h it li are reai li iy available [rum ili e per iph crai rircutatiu g blood. `U h* lym phnd c e lli of ih e im im in c System a ie an n ieg ra l p a li n i th (Ir felice mechanism known at um iline su rvcilla tu e and are vere im po r tane in ih e re cu ^ i il im i am i rem oval o f a h lie ra iil o r n ia lig ita iii c r ii* . I l is Ib is retaiiuuship tlial may1bc d is im b ill tjy e n film im e lital etii-mica Is am i al Itosi (a rcu o .g enesi' [u prixi-ed in suscepiilde in d iv id u a li. T l i e un* ut in iiiiu n ii'tip p o -ssivi' llii-rap v ha stum ii lln-re i an hit re g io 1Ireip init y ol s a n im i t v jm ul ma litu a n i lineasi- a sm ia liti it h ctm lim ied m e ul s itili agi-ili'. S i- tim tL iy as e li as t r in a r e C a i t r i have In v i pnxhui-d liV llie r.ip e u lii 'O ppressim i ul d ir im m une sileni. (Im ieu netilly, im rsligatnrs base a ln i 'lu m i ihat oonuTvncc- d inai guani lineasi- is atso Inum i in im liv id iu ls idi genette im im in iw lrfii rut i l i at a liig lir r b op tencv lliau in hiim m it' n o rm al hiistx. So il l m tu tu me a p p a ien l Miai tiijlig iia n l re sp inse in a g seri busi mas* in la ti be v e iy n - rin u ily itepentieni iip m an im m une s p le n i Miai h a i In v i saime lu i t iim p iu iiiiw d . lt*l / atiWatatratil h I'lliu am i I'in i sliulies uviiity jx itiiid e s , im lallit n ig a u d s ami ta iim ts plianfiJi illogical ugi-nls, bait- sliuwn llial certain at livilies ol lym phoid tells an- mmliilaleti by till- p resentt-ul many lit lim e Omi |uni nils. I.ytiijiltiK-ytrs base Ikvh eillier sopjiinx-it o f stimulated. ami eillirr tomliiiou may In- affeclmg iniimme rtip m se. I lie lihxxl mom Kites. Iiitli |itaf a vital tide in die II-t e li/ l- t ell inleiacItous. ate slurxii to be vrrvscverclvdisiurlirxlbv excessive amounts o f chlorine nr hctnuglohin degradation proabit is. So, direet or in d irm effivts tan modulate lire iniim iue m|HiiiM*. 'Iiusiin; the M-nsitivily o l llie lymphoid jM.pidali.m to i-iivinuimt-iiiat 111)11rrar. T h e cells ilieniselves mav Im nine deiiviive Through Hint I action, o r llte lissoe in h u b dies* nialurr and diilt-rt nliaie may be motiirieiL producing an itiipiti-ni n-ll. T h e cell may tie alletted at die sin late, within lilt- rvlupljsm where* antigenic dclerminanls arc synlUnirctL or within the mir tear protein anil/nr chnimnsonia1levels. Tim s there exists a cell lor all K a sim s; mnrpludugist*. bios hem ills, immunologists, pure chi-muls. pure biologists. all -ill [ml an abnmlancc 11I.suitable material to investigate. The most rewarding ponton of our work may ell be that -c `ill be closer la effective extrapoladnn for human exposure. Conclusion T he mes liauixim when-bv chemicals influence the itmium 0I1igical surveillance system are nol under* nid- In fasl. there ale ntjuv h o h a w asked qursiinni Ibal mav dull die esciiem enl over the immunoMirveillance lhenry. However, thev tiave mu been solficirntly substantiated. What has been elucidatrd in diis pii'i-nialion is that e cannot deny llu- itiflm -m si esiernal chemicals have on the cells and prixhui o( tissue from the Ivmphnul-inimimc tyxlem. The role of chemically induced malignancy m (he immune rnpptessed [laticnts receiving ihrrjpv nr the excess orrtirrrnt n id malignant disease in mimmixleficieni individuals is significant anti taniiul be igum rd t he com plesilv o l die iitimum- sisient, detail' of mechanisms, in fact, whether rclls air pmtlucts may be influencing this lysiem is in must cases nol known. Ilneser. it can be staled that many of the substance mentioned here tualas- faiiaH **a^r aaJ f 'krm*af laiua.r*a'Wt till are in tin* i-us iiiumii-iit and lin y ilo li.ivi* iimiimioiiuliil.iim^ rllects, 1low litui Ibis mb- id itiiiiiimoiMtHliilaiiuii jllea 1 inli pi (alimi id pn-viims su o liti dial sliwrl msl Ilia! a iinoi** i.it. emu* .1 pig. nr sunti- ollur Ijh animal lias or lias not iti|>iitn-d 1. idi malignauiy to a 1 aninugriiit ilu irinjl* Ilae llu.se minhdaiiiig rlierts has-n la Lao into at 1 mini in rail Indirti dial satini- ilti-imt.il is tie is not a can 1migro.' (dearly sm li tpinium s tan in aliiish a compromised position h en making tone Iliso ms as in lii-itu-r any chemical shimlil In* allowed ill tile human a-nvmiiinirnl. Mit e, rats, hamsters, and guinea pigs have variable *V'ltiiis. (las lluChem leal lu tisi 1 ansasi a leprin i on ail lite ss stem dial jlhaea! som e'virus lo intinti- a tam er.' Ur has d ie jntittal p e t haps a depressaci ininnine sysn-m. due to ri-pi essimi of gnu-tii es | n u sti in due 10 inbreeding that no aliens a neoplastic response to m i m* Immunnlm iridi.gy is ilia- ne Villon the Idm k and is able In jsI> some verv diibridi questions. Questions for salitili e-havr tint all the answers. In the area of prrdictive toxicology. however. I would suggest the following. Because imiti unntos it uiugy mav tiring alti ml an additional dimension in estrapolai ion. I m ild suggest dial lim ile Minlies bi* dirrcusl Inward cvanuiuug these inumine im i. m vie*, menti and lui- they rii|uid to imitagi-iur urearcmngt-nit agents. Not only in the lab animat spetu-s. but bv using the j*ei Iplu-ral blood elements from hnnuiis. Kstabbslimg a lisina*culture proaelUitv with buina 11 Is inpliiK vies ambor nurrupbagn. even (lioogli (X niru. s*imtd allow- fimi lion ami sui lai e ideili 1lira rum studies as well as biochemical 111 litigations to ptiict-U` and p -ilu p s pruroutegrvaii-r ronliiicnn-hen |Hissildy iili-nliltuig m su r t'| n w TOhumans. OlluT luiman cells base been t nil unsi, 'm b as libroblasts anti the 1lei.a celts, suretv the same um ld be him- (ix tin- mommisystem cells. Il nubi go far in irii|iJitMg the program ol pulilic health fur which we arc all rcs|*mtblr Kefetcnces t k liv b ltt. | | I '1 C iftIW ^ ih i'M s tin U ilisI lit l r i ' I tm ljm tb itd x tn b il r t j !wtiXew U L Smith, M.: (AiTiiiwnt tmrt uh1tx t ; > 1k Y- T* Q BACKGROUND INFORMATION The a t t a c h e d r e p r i n t s f r o m p e r i o d i c a l s a n d t h e Co n g r e s s i o n a l Re c o r d a r e i n t e n d e d t o p r o v i d e BACKGROUND INFORMATION REGARDING AGENT ORANGE, DIOXIN, DOW, AND RELATED TOPICS. The LAST PAGE IN THIS GROUP IS A COPY OF THE Ag e n t Or a n g e b i l l i n t r o d u c e d b y Co n g r e s s m a n Da s c h l e (H.R. 1961), a n d h i s r e m a r k s a t th e TIME OF INTRODUCTION. W A SH IN G T O N , TUESDAY. APRIL 19, 1983 DOW CHEMICAL CO., AND DIOXIN public because the situation m ight "ex plode" and generate a new wave of govern HON. THOMAS A. DASCHLE ment regulation for the chemical Industry. Another scientist noted th at Dow oill dais OF SOUTH DAKOTA IN THE HOUSE OF REPRESENTATIVES had disclosed a t the m eeting a study which showed th a t dioxin caused "severe" liver damage in rabbits. . Tuesday, April 19, 1983 Dioxin, which has also been linked to birth defects and disorders in labora O Mr. DASCHLE. Mr. Speaker, in tory animals. Is believed to be th e deadliest today's New. York Times, April 19, chemical made by m?m, h u t its effects on 1983, a front page article appeared re hum ans have been difficult to prove conclu vealing what many of us' have been saying for some time; that the Dow Chemical Co. was aware of the health hazards and toxicity of dioxin, th contaminant found in agent orange sively. Since th e Midland session, various studies have yielded conflicting'evidence on whether dioxin Increases th e'risk of cancer In humans. Although it has been known for many years th a t Dow held th e 1255 m eeting w ith and other herbicides, before extensive its competitors, excerpts from corporate use of agent orange and these other herbicides occurred both in Southeast Asia and in the United States. Dow of course, made no effort to notify the USDA, DOD, or any other major gov ernmental purchaser of dioxin con taminated herbicides of their con 'memorandums about the session are-only now beginning to emerge as a result of a lawsuit filed in 1973 against Dow and sever al o ther chemical companies. T h e m em oran dums raise the possibility th a t Dow scien tists have been saying one thing in private about dioxin while th e com pany's m anage m ent has said something else in public. cerns. "T here Is absolutely no evidence of dioxin Dow's track record on dioxin has doing any damage to hum ans except for been far from exemplary and the in formation revealed in the Times arti cle today further damages the claims of Dow, the Veterans' Administration and others that dioxin Is relatively safe and that veterans in Vietnam are something called chloracne," Paul F. Oreffice. the president of Dow, said last m onth on NSC's "Today" sh o w .'"it's a ra sh .'' Dow has performed medical tests on individuals suffering from chloracne i'or " over 20 years." he added, "and. th ere is no evidence of;any damage other than this rash which unlikely to be suffering unusual went away soon after." health effects as a result of their ex Dow's critics* challenge th e accuracy of posure to dioxin contaminated chemi cals. I submit this article for the R ecord and; hope that all Members and staff will take the time .to read It. Mr. Oreffice's fla t assertion th a t th e re is no evidence th a t dioxin causes hum an damage other than chloracne and also charge th a t Dow has failed to publish all th e inform a tion it has collected in its own dioxin' re The article follows: [From th e New York Times, Apr. 19,19831 1965 M emos S how D ow's Ahxtety oh * D ioxxh search. Furtherm ore, they say; Dow has sys tematically resisted Federal and state ef forts to learn about and regulate dioxin. According'to a pretrial m otion filed by Yannacone <fc Associates, th e legal organiza (By David Burnham ) tion created to represent th e Vietnam Veter W ashington, April 18--Almost 20 years ans in th e A gent O range case, th e 1865 ago. scientists from four rival chemical com meeting on dioxin was attended by eight of panies attended a closed m eeting a t th e Dow's senior scientists and six oiiiciala of Dow Chemical Company's headquarters. Hooker Chemical: the Diamond a Com T h e subject was th e h e a lth hazards of pany, which la ter became p a rt of D iam ond dioxon. a toxic contam inant found in .a Shamrock, and the Hercules Powder Com- widely used herbicide th a t-th e companies .pany. A representative of the M onsanto m anufactured. Chemical Company was invited but did not Shortly after the meeting in Midland. attend. Mich., on M arch 24. 1965. one of those a t Donald R. F rayer, a spokesm an fo r Dow, tending wrote in a m em orandum th a t Dow confirmed in an Interview A pril th a t th e did not want Its findings about dioxin m ade giant chemical com pany had called the (Over) m eeting to discuss th e herJth hazards of Daniel Bishop, a M onsanto spokesma dioxin. "We feel th e mc.eUr.g T5tji p re tty said in ^an interview th a t his com par d arn straightforw ard and proper."* he said. " didn't do any testing, period, n o t then ar "I th in k on th e balance th a t th e record n o t now." He said th a t a fair reading of D shows we discovered a problem, sought out Prawley's full statem ent would make it cle: ou r com petitors and tried to Rive th em in th a t h e had n o t received the toxicity info form ation and & means to control th e prob m ation from Monsanto, but was not able i lem ." v : i i.-. identify the information's source becaui INVITATION TO MEETING T he pretrial motion filed by Yannacone & Associates quoted a number of documents. V. K . Rowe, then director of Dow's Bio chemical Research Laboratory, said in his th e m aterial in the Agent Orange case ha been sealed by the Judge. The document were sealed at the chemical companies' ri quest, GROUP o r 75 COMPOUNDS. Invitation to the*, meeting th a t Dow had D ioxin Is th e nam e given to any of , been researching "toxicological problems fam ily of 75 compounds, called clibenze caused by the presence of certain highly para-dioxins, composed of benzene mole toxic impurities in certain samples" of the cules and oxygen atoms. The compounds ar herbicide 2.4,5-T and wished to share its a n unw anted byproduct of several chemica findings. T he Dow laboratory was and is rec processes, including th e m anufacture c ognized as one of the world's finest private 2,4^5-T under certain circumstances; 2,4,5-'] ly owned toxicology labs. is one of the two m ajor com ponents o Two days afte r th e meeting, C. L. Dunn, a. A gent Orange. chem ist who was manager for regulatory af Proving the specific effects of toxic chemi fairs for Hercules, summarized in writing cals' o n humans la; extremely difficult w hat he had been told. "Dow says th a t their examination of their own and com petitors' 2,4,5-T products con ta in w h at th ey call `surprisingly hig h ' pmnnnts of the toxic impurities," he wrote. "In addition to the skin effect," he wrote, describing th e results oi tests on rabbits, "liver damage is severe, and a no-eifect level based on liver response has not yet been es tablished. Even vigorous washing of the skin 15 m in u tes' afte r application will n ot pre hum an experiments are generally prohibit ed by medical ethics. Animal tests, which are universally accepted by scientists as pro viding essential guidance on appropriate ex posure levels for humans, are not a perfect guide because various species react differ ently. - In laboratory rats, concentrations as small as five parts per 1,000 million have caused statistically significant increases of cancer in rats. v en t damage and may possibly enhance the Two studies, conducted on a group of. for absorption of th e m aterial. There is some estry workers In northern Sweden and on a evidence It is systemic." group of agriculture workers in southern FEAR ON SITUATION . Dr. Jo h n Prawley, the chief toxicologist for Hercules, who had also attended the M arch meeting, got a follow-up telephone rail four months later from Earl Fam um , a Dow executive. -Dr. Prawley immediately wrote a confidential memorandum to the file. Sweden, point to a possible association be tween exposure to-herbicides contaminated w ith dioxin and an` increased risk of softtissue cancers. Other studies, however, in cluding one in New Zealand, show no higher risk of cancers for a group of farm ers, for esters and fisherman exposed to dioxin than in m en in other occupations. Mr. Fam um , he wrote, said he was calling WARNING ON DIOXIN STUDIES on behalf of a Dow vice president, Donald Dr. Sam uel S. Epstein, a-physician who is Baldwin, and "stated th a t Dow was ex professor of occupational and environm en trem ely frightened th at this situation might tal medicine at the University of Illinois explode." "They are aware th at their competitors are m arketing 2,4,5-T which contains 'alarm ing am ounts' of acnegen," Dr. Fraw- Medical Center in Chicago, cites the Swed ish studies and other research on such ques tions as reproductive abnormalities to chal lenge the statem ent of Dow's president th a t ley continued, referring to dioxin, "and if th e Government ieam s about this the whole industry will suffer. They are particularly fearful of a Congressional investigation and th ere is no evidence th a t dioxin causes any more damage than a skin rash; "For Mr. Oreffice to make th a t statem ent is absurd," he said in a recent interview. excessive restrictive legislation on the m an ufacture of pesticides which might result." A second memorandum w ritten . by Dr. Prawley, and quoted in part by lawyers for . On M arch 23, Dr. Perry J. Gehrig, Dow's vice president for agricultural research and development and director oi heaith and en vironm ental science, cautioned the House th e veterans, said he had Just received new Subcommittee on Natural Resources, Agri inform ation about health effects of dioxin culture Research and Environment against from M onsanto, which did not sent a repre "overinterpreting" the Swedish studies. The sentative to th e meeting. "From th e data reports, he argued, "are too incomplete, provided, a sample which contained 5 parts both individually and in ugb*'c-gate, to cur per million would be acutely. toxic," he rently formulate a clear picture of the possi wrote. "W hether this refers to death or ble associations between 1CDD and soft- liver dam age is h o t clear." tissue sarcomas." TCDD is a form of dioxin. Mo r e ! In 1982, Dow scientists published a report SUITS AGAINST COtn,ANIE3 of a company survey on the occurrence of spontaneous abortions, stillbirths. Infant Billions of dollars are a t stake in th e answer to the question of what th e chemical deaths and several categories of birth de fects among the wives of Dow workers who had been directly exposed to dioxin. The stu d y concluded there were few differences companies knew and When they knew it. In addition to the tens of thousands of veter ans who have sued the chemical companies because of their exposure to Agent Orange In the.num ber and kind of birth abnormali ties found In these women compared with in Vietnam, thousands of other Americans living near toxic dumps, such as the one in th e wives of Dow workers not exposed to th e Love Canal area, of N iagara Fails, N.Y.. dioxin, and the report has been used fre are seeking damages on the grounds th a t qu en tly to support th e theory th a t dioxin is dioxin and chemical poisons le ft th e re have n o t as'dangerous as generally believed. shortened th e ir lives and caused cancer, B u t Dr. Marvin S. Legator, professor and b irth defects and genetic damage. director of environmental toxicology at th e In Jan u ary 1379, a croup of veterans University of Texas in Galveston, questions brought a Federal suit in Kew York, charg th e study. . ing th a t th e dioxin contained in th e 2.4^5-T "Initially,M Dr. Legator went on, "Dow sprayed in Vietnam was a cause of cancer planned on comparing the birth defects and other diseases among tneir members am ong th e wives of Dow dioxin workers and had resulted in genetic dam age-and th e w ith two controls. First, a group of wives of b irth of severeiy deformed children. Dow workers in Midland who had not been Victor John Yannacocn, Jr., a principal 'directly exposed to dioxin, and second, some organizer of the association of lawyers h an wives of workmen who lived outside the dling th e class-action suit, raid in a recent Midland area. This second control group interview th at the group row represents was im portant because th e Midland area Is 20,000 Vietnam veterans, widows and ch il quite poUuted and the general population dren of veterans who are seeking damages h a s a relatively high level of congenital ab against th e chemical ccm nanics t e s t pro normalities. But when they published the stu d y th e second control group was n ot in cluded." vided the Government with Agent Orange. The suit against Dow and the other m ajor m anufacturers of 2,4.5-T is scheduled to go to trial in the Uniondale, LX. court of Fed A " sampling problem " eral D istrict Judge CJeorge C. P r a tt J r. in M r. Frayer, the Dow spokesman, said the second group had been deleted because of "sampling problems." "T he w om en could n o t be com pared with th o se in th e first two g ro u p s, a n d th e y w ere Q u e stio n e d in a d iffe re n t way," Mr. F rayer said. June. Lq an annual report filed with th e S ecuri ties and Exchange Commission in W ashing ton called a 10-K, Dow said i t was odc of ah; chemical companies who were defendants in th e su it, " Dow believes it h as n o t been sci entifically demonstrated that the injuries claimed by th e plaintiffs were caused or Inform ation compiled by D r. Alvin Young, could have been caused by exposure Lo an expert a t the Veterans A dm inistration, Agent Orange." th e report said. indicates th a t from 1961 to 69 American T h e L o w . rep o rt also n o ted th a t th e com panies made & to tal o f 154.5 million chem ical company was on posing a move by pounds of 2,4,5-T. ' - ^ - th e Environmental Protection Agency initi Of th a t total. 44 million pounds were ap ated during the Carter Administration th a t plied to th e jungles of Vietnam, 3.4 m illion would to tally ban t o e use of 2,4^5-T-in th e pounds were exported to o th e r countries U nited S tates. T h e h em ih d e th e re fo re is and 78.1 million pounds w ere used domesti- still being used oh ric e fielna, on ran g e lands cs^ly. T h e hain n r^ lo m illion pounds, was and in industrial a r e a s such a s refineries, lo destroyed by the G overnm ent after it was control weeds. decided to h alt the Vietnam defoliation pro T he company's repeated public state gram. m ents about the comparative safety, of D r. Young estimates th a t L7C0 pounds of dioxin, including testim ony to Congression- dioxin a year were produced in the United al committees, press releases and scientific S tates from the mid-lSO`s to ab o u t 1975, papers, have been accompanied by efforts when steps were taken to limit it through on its part, particularly in the Reagan A d changing the man mac luring process. m inistration. to block th e G overnm ent iron-, T h ere is broad agreem ent th a t a su b stan collecting inform ation ab o u t th e contam i tial portion of dioxin-contaminated wastes nant. . are buried in thousands of dumps around Evidence of the repeated contacts between th e country. T he EmLronmenxai P rotection Dow and E_P_A. officials in W ashington. L Agency recently said th e re were" 12.000 of n o t of th e subject of th e meetings, is con th ese dumps. O ther experts have estim ated tnined in the calendars and travel records c, th e num ber may be closer to 53,060, these officials th a t have been ootam ed c. the House subcommittees Investigating th: agency. (Over) Dow re!eass a&('if*i*i '.i. j t.*7* v(TJ*V* ^jC ji^i*O> Vbf^TTH* ^*71 f* EPA- New studies by the Environmental Pro tection Agency (EPA) show that the Dow Chemical Co. is releasing dioxin and at least 40 other toxic substances into waters downstream from its Midland, Mich., plant site, agency officials have reported. Catfish placed in cages in the Tit tabawassee River just downstream from the Dow plant for lour weeks w ere found to have become contaminated with con centrations of the most potent form of dioxin of 110 pans per trillion. That level is nearly 14 times the con centration found m fish tested in a similar manner just upstream from the Dow plant, indicating that site as the likely source of the contaminant. The downstream concentrations are more than twice as high as the 50 parts per trillion level labeled by the Food and Drug Administration (FDA) as the "level of concern" for human consumption. Officials pointed out, however, that comparisons may be inappropriate, since the EPA tested dionn levels in the whoie fish, while the FDA standard refers only to edible portions, which may not be comparable. Regional EPA officials in Chicago long had charged that the Dow plant was a significant source of toxir - o - ..mmation in downstream waters, inuuU.ng the Tittabaw assee and Saginaw Rivers and Saginaw Bay-- where catfish and carp are harvested commercially. Earlier evidence had been ambiguous, however, and was dispuled by Dow. EPA officials said. The new study "confirms for us th e problem is th ere ," said EPA Regional Administrator Valdus Adamkus. "N ow we've got very good and clear evidence that dioxin and other toxicants are being released from the plant. The levels are of concern to us. It has to be controlled." Dow officials said the new Mudips were not consistent with pievious djta. some of which had been provided bv Dow, and that contamination levels were small. The newly reported study also found traces of more than 40 toxic compounds in water samples taken downriver from the Dow plant, including methylene chloride, chloroform, various pesticides, PCBs, and herbicides such as Silvex. The dioxin found was in the form of 2,3,7,8-T, or TCDO, considered by many experts to be the most potent toxic chemical known. The levels detected were extremely small -- 50 parts per quadrillion of TCDD in water downstream from the plant -- but the EPA analysis extrapolated from its findings the estim ate that some 35 pounds of toxic chemicals were released from the Dow plane every day. The plant discharges more than 61 million gallons of waste water daily. The water level study was conducted in 1931, Adamkus said, but results were delayed so long because of ihe.difficulty of analyzing such small concentrations An earlier report by the EPA regional office led to the forced resignation of Acting EPA Administrator John W Her nandez last month. Adamkus, in congres sional hearings, had said that Hernandez had ordered the altering of the earlier report to eliminate conclusions that Dow was the source of contaminants in the downstrea rivivers. / AMERICAN MEDICAL ASSOCIATICI NEWS A p ril 15, 1983 L U T E S T O C O V E R iT M E N T Anne McGill Burford, for example, made a t least two trips to Midland, Mich., in her 22 m onths as th e head of th e Environm en tal Protection Agency. R ita M. Lavelle, the form er head of the Government program to clean up toxic waste dumps, m et a t least 14 tim es w ith Dow officials in th e 11 m onths she held office. -M rs. Burford, Miss Lavelle and 11 other political appointees'1recently resigned or were dismissed amid Congressional inquiries on al1?gat ions th a t th e agency's toxic waste (C ontinued from p re v io u s paqe) program had been mishandled. F y According to th e public testimony of some officials of the agency, Dow used its connec tions w ith th e top echelon of th e agency's W ashington officials to get its way on sever al im portant m atters relating to the regula tion of dioxin. Three weeks ago, for example, agency of ficials In Chicago told th e Investigations Subcommittee of the House Committee on Energy arid Commerce th a t their superiors in W ashington ordered them to change an inportant report on dioxin to comply with th e wishes oi Dow. The key deletion from the report was the following central conclusion about Dow's Midland plant: "Dow's discharge represent ed the m ajor source, Lf not th e only source, of TCDD contam ination found in th e Tittabawasse and Saginaw Rivers and Saginaw- Bay in M ichtghan." % v i f ; *\*'*' J li ti* V j ^*1 Gw3 ii ^ i 5ij SCmb J jJ gats us day in court When the first phase of the long-await Kimmtg, the program's director, to help ed Agent Orange trial begins in U. S. seek the cause of the outbreak. Federal District Court (Uniondale, By 1957, the collaborative effort was -N.Y.) neat month, it will focus on the bringing results. Schulz's research iden "government contractor" defense, tified dioxin as a by-product in the pro . Chemical makers who supplied the duction of both 2,4,5-T and its precur Dept, of Defense with Agent Orange sor, trichloropnenol (TCP). Skin tests on and other herbicides that contain 2,4,5,- his own body and on animals indicated a IVicholorophenoxyacetic acid (2,4,5-T) direct link between dioxin and chlor will argue that at the start of the Viet acne. Monitoring of employees who had nam war, data concerning the potential contracted chloracne showed a possible human health effects of 2,3,7,&-totnich- link between dioxin and liver disease. toridibenzo-p-dioxin ]2,3,7,8-TCDD), a At the same time George 5orge, a Boehringer chemist, was seeking ways to cut dioxin levels in fin ished products. "He be lieved that temperature was the key to dioxin control," Schulz says. Sorge subsequently de veloped a low-tempera ture TCP production process whose end- product showed nesra* tive results in Schulz's animal tests, Lhref damage. Schulz's findings were published in four German medical publications in 1957. They became widely available in the U.S. contaminant of 2,4,5-T commonly known when one of the Schulz articles ap as dioxin, were equally accessible to peared in the Dec. 10, 1958 issue of both government and industry. And Chemical Abstracts. The article clearly they will argue that what data existed points to the presence of liver damage were scanty at best. found in several Boehringer workers. But a closer look at some trial docu The chemical makers want to prove ments--sealed in the courtroom but that the government knew cf Schulz's publicly available elsewhere--indicates work. About a year ago, two Dow law that a great deal more waa known yers met with Schulz and asked him about potential health troubles associat whether he had been contacted by Air ed with dioxin than most companies Force personnel or by Friedrich W. have allowed. In fact, data were emerg Hoi7tr.an, who in 1959 was chief of the ing in Germany as far back as the late research branch of the U. S. Army 1950a that suggested that dioxin was a Chemical Warfare Laboratories and potentially hazardous substance. was charged with scouting Europe for Outbreak. The early warnings about potential chemical warfare agents. dioxin came from Karl Schulz, a young Schulz says he told them that he "had German physician who. in 1955, was never been contacted by either Hoff treating a Boehringer Ingel'neim factory man or anyone from the Air Force." worker for chloracne. The worker, says But Dow asserts that a report by Hoff Schulz, told of similar cases among oth man noting Schulz's article was circulat er 2,4,5,-T workers in Boehringer's ed widely throughout the military. Hamburg plant Boehringer stopped Dow Chemical apparently was con producing 2,4,5-T and asked Schulz, ducting its own research in the 1950s. It then t member of Hamburg Universi had asked Joseph V. Kiauder, a Phila ty's dermatological program, and Josef delphia dermatologist, to conduct a se ties of human experiments to gauge the potential health eifecta of herbicides baaed on 2,4,5-lriclilorophenol. Kiauder, according to publicly available doeu. menta, noted that some of the materials he was working with were "highly aller genic." The documents are specific about some substances. For example, on' internal Dow report on Klaudcr's findings indicates that a herhicirial com position containing 557* Silvex (2,4,5-TP) proposed for "control of acquatic weeds" is irritating only in concentra tions exceeding 5A AVarriiivja. It is not known whether Kiauder, who died in 1562. carried out any experiments using 2.4.5-T. But Boehringer dearly did. In 1955 the com pany wrote to all manufacturers of TCP and 2,4,5-T worldwide, warning them of problems inherent in 2.4.5.-T production and apprising them of its safer produc tion process. While confirming the let ter's existence, Boehringer declined to release a copy to Chemical Week. Insight into its contents can be gleaned from "Early Dow History of the Chloracne Problem--Bicchem's [Dow's Biochemical P.esearch Laborato ry's] Contribution," an internal report A !-.:t rrsro v/ya knov-n bobit dioxin's hBriioi k-azarcs tnan many c o m p o rts wcuid admit prepared by Dow just 13 dav3 before its controversial Mar. 24. 1565 meeting with representatives of other TCP man ufacturers, including Hercuies. Dia mond Alkali (now Diamond Shamrock) and Hooker Chemical (now Occidental), The report says that the Boehringer letter, which it dates to 1957, contained the "results of research on chloracne.'' including a description of "danger points" in the production process. Tb report s'nlea Unit firwhnnger called for a rroci-ss U-fniy-ra'iiro unit of t./) G lc~ "avr-in nr*inuring In** acne ex'v7r''~in TCP a-P 2.4.5,-T. ''he Uow aocumi-n: is annexed as an -exhibit to the records of Lie 1979 Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) hearings to cancel the registrations of 2,4.5-T and of Silvex. Both materials contain dioxin. Slow to move. The Biocnem report notes a 1955 letter from Boehringer to the Swiss firm Givaudan, in which Boehringer sought safely information. Givaudan referred the letter to Dow, which, according to the document, sent its own letter to Boehringer describing "hazards and precautions for safe han dling of 2,4,5-lrichlorophenol." Despite its interest in the Boehringer a s Ownical W w l/M n 1 1963 technology, Dow did not license it im mediately. In early 1904. the company Switched to a production tecnninm? tr.ai required plant process temne rain res ol 215 C. Measured in December it-o-i. TCP waste streams cur.mined dioxin IcveiS ranging from G.fXXHiMXxj parts per mil lion, according to material introduced by Dow during its recent motion for summary judgment. The Bioehem re- fort indicates that it was, indeed, the igh process tomiwrmtur thsl general* ed the high dioxin levels, and led to a major outbreak of chloracne si Dow. Although Dow toM the Mici'iran Dept, of Public Health about that problem, it did not mention it to the DcpL of De fense until 1967. Dow has contended in court that "knowiedge of the precise occupational hazard'' that occurred in 1964 is "irrelevant" to the government contractor defense because it "promptly remedied" the problem. Neither the dioxin levels in finished product during this period, nor the amount of Dow's output that went into domestic or military use is known. But &n Air Force sampling of Agent Or ange's predecessor, Agent Purple, which was used between 1962 and li-65, showed dioxin levels as high as 45 ppm. Both Dow and Monsanto supplied 2.4.5>'' T to the military during this time. Cit ing the penning Litigation, Monsanto has reserved comment. Dow's rights. In March 1965--the same month as its meeting with other TCP mrike-s--Dow purchased licensing ngnts to Boehringer's low-tempers,lure TCP manufacturing process. From then on, Dow contends, its 2,4,5-T never con tained more than 1 ppm of u>ox:n. Tr.e company has recently stated that 2,4.5-T c o r . ! . * . 1 ppm or less presents no human health hazards. Still, Dow seeks to prove that govern ment officials were alerted to t'oter.ual problems with dioxin well before 1964. In pre-tnal documents, Dow notes "a 1962 article in the Journal of Investiga tive Dermatology that ; .nn- i 2,3,7,5-TCDD as a potent aringeii i'i.e article was based on res-.uren min the physiology of acne, conducted at the University of Chicago Medical Center and commissioned by the Army. Helen Krizer, a university chemist who worked on the project, recalls get ting the idea to use Tt'DD as a standard to m.nsure the strcr.rths of cibt-r m is* peeled uetiegens from cRuiz's ;ir'_. ,e in Chemical Abstracts. Knzer cannot re call whether she mentioned Scr.ulz's work in her own am,.--I report* to the Am y prior to 1962. But she does say that "it's possible." livers were severely dam aged As one par D iotn P u is D o w on ih s S p o t ticip an t in the 1965 m eeting la te r wrote, the Dow scientists reported that "even M emos o f 1965 meeting hint at company's fears vigoroui w ashing or the Irabbit'sl skin 15 m inutes after application lof dioxin) will not prevent damage and m av possibly en- On a chilly m orning in M arch 1965, a ing the prelim inary legal m aneuvering in h a nee the absorption of the m a te ria l." : highly unusual gathering took place at a class-actinn lawsuit that has been Now, 18 years after the private parley .D o w C h em ical Co.'s h e a d q u a n e n in M id brought on b e h alf o f 20.000 Viet N am vet 1 o f scientists, the M idland a rea is still la n d , M ich. W ithout a ny co rp o rate ian- j erans. them widows and children against w restling with dioxin. It continues to fare, Dow scientists m et with colleagues j Dow and eth er producers of Agent Or show up in tainted w ater from Dow s from th ree rival firm ;. H ooker C hem ical, ? ange. Scheduled for in a l on Long Island M idland plant, has been found in fish in D iam o n d A lkali and H ercules Powocr, j next m onth before U.S. D istrict C ourt ten M ichigan rivers a nd is the source o f : O n theagenda that day w asa discussion of | Judge George C. Pratt, the suit charges I considerable anxiety am ong local resi- r the effects on hum an health of a family of ; that the dioxin contained in Agent O r j dents'Says Diane H erbert, a young m oth- . chem icals known as dioxin. The cnemi- i ange caused cancer and other ailm ents I er o f two children; "Almost everyone * cals, including A gent O range, la te r used j am ong m e soldiers a nd genetic defects in I seem s to have thyroid proolems.' a nd i by th e U.S. to defoliate the jungles o f Viet i their children. Dow has resolutely denied I_there are a lot of skin tum ors a nd allergies i IN am . a re an unw anted byproduct in the i the charges In a television interview . in pels." To assess those fears. M ichigan's m aking o f herbicides. A t the tim e, most j Dow President Paul F. Orefificc said. stale health departm ent is seeking slate or , ch em ists w ere only vaguely aw are of i "T here is absolutely no evidence o f dioxin federal m oney for a m ajor study o f diox- 1 in's effects on residents. } W hatever the pnvate concerns o f the | D ow scientists at the 1965 m eeting, they i did not lead to public action. As a com pa- ! ny spokesm an said last week, "W e found : we had a problem. We corrected u. We re- i ported it to the appropriate authorities, i We called in our competitors, urged them j to adopt our practice. This was really an j attem pt by industry to police itself." T he i Viet N am veterans' lawyer. Victor Yan- ! nacone, has a harsher view. He calls the backstage parleying nothing less than "a ; conspiracy of silence." ; TIME MAGAZINE May 2, 1983 S ittin g along the T ltta b aw assee River, Dow's sprawling m i Lalu ll on in Midland, Mich, Ghostsfro m w hat seem ed h k e a corporate gesture o f good wtii to competitors. dioxin, or its problems. But Dow had just doing any dam age to hum ans, except experienced an outbreak of dioxin poison something called chioracnc. It's a rash." in g am ong w orkers in M idland. It w anted Many scientists do not take the chem i to sound a private alert to prevent similar cal so lightly. They say m at even concen incidents at oth er chem ical plants, includ trations as low as 5 parts per trillion can ing those o f its com petitors. cause birth defects, cancer and ctner seri L ast week this seem ingly generous ous illness in laboratory anim als Last g estu re o f good will cam e back to haunt week the C enters for Disease C ontrol in D ow . A ccording to a re p o rt in the New A tlanta reported th a t 112 c-f 130 residents York Tim es, m em orandum s from partici tested in Im penai, M o , near dioxin- pants in that almost forgotten session in contam inated Times Beach, showed ab dicate that Dow s objective m ay not have normalities in b'ood. liver orikidnev func- j been corporate benevolence. R ath er, the dons. Says D r. Irving SeUkoff. director of j docu m en ts show, the m eeting ap p ea rs to the environm ental-science lab at M ount I have been part of an effort to keep discov Sinai Medical C enter in M anhattan: "N o | eries about dioxin's perils from exploding question a o oul it, diox<n is harm ful to in to a public scandal, w hich could have ( hum ans. It is m an-m ade. A s a result, the brought a new outcry for governm ental j hum an body doesn't know how to break regulation o f the chem ical industry. it down. We store it m c u r bodies and W rote a p articip an t from H ercules Fow- I `accum ulate it." ; d e r " T hey (Dow) arc p a rticularly fearful j In 1964. after 64 w orkers at its M id- j o f *. congressional investigation a nd ex- j land plant developed cnloracne following j cassive restrictive legislation on the m an- j exposure to dioxin, Dow began a full- i ufacture of pesticides." j seals investigation of its effects. W hen T h e docum ents were unearthed dur- . dioxin was adm inistered to rabbits, them R e p rin te d f o r Your In fo rm a tio n from th e NEW DISCLOSURES* REGARDING AGENT ORANGE liver disorders, nervous system effects and severe depression. None of these m aladies were diagnosed th ro u g h testa th e m en had In th e VA's Agent O range screening program . D avti was told by VA d o cto n he needed surgery on nerves In bis w rist and should undergo psy --A low ered level of liv er fu n ctio n s and a w hite blood cell count p a tte rn th a t u sim i la r to one In a perso n x h iu c Im m une system Is depressed. --N orm al kid n ey fu n ctio n s, b u t a n in crease In uric arid level th a t could lead to kidney damage and bouti with gnut or HON. THOMAS A. DASCHLE chological counseling. O rouio-rskl. who h as ao u tty a rth ritis. Davis has h id a tm e is of su ffered fro m seizures since 1972. said VA g o u t lin ce 19J8. o ne y ear a f te r h e re tu rn e d o r BOOTH DAKOTA docto rs w ere u n ab le to id e n tify th e ir cau se. from hi* V ietnam service. IK IHE HOUSE or REFRZSHrrATlvrS T h e th ird v e teran In th e gro u p . M edal of --A -'variety of nervous sy stem d y sfu n c H o n o r recip ien t J o h n B aca of S p rin g field . tions. T h e raelda nerve In b is n g h t h a n d ts Tvetday. May 24. 1983 M o,, will req u ire f u r th e r ex a m in atio n befo re Inflam ed and In te rfe res w ith sen so ry con C Mr.' DASCHLE. Mr. Speaker, a recent news story In the Robinson, 111., Daily News, present striking evidence of the link between the dioxin In agent orange, to which many servicemen a diagnosis can be m ade. Wells said. Both Davis and Gromowkkl v e n t thro u g n th e VA'i A gent O ran g e screen in g a t th e VA H ospital a t Wood. Wise., a M ilw aukee suburb. A t th e conclusion of tests there, they were sent letters alined by Dr. M ichael duction. a condition often a'.soc-.ated w ith degenerative process. He also suffer! from petty m ill seizures, which make him n au seous. dizzy and blur his vision. -A bficnm liU ci la bis reproductive system which, alth o u g h it U (till possible were exposed In Vietnam, and the Ill O . O 'G rady, th e s ta ll environm ental p h y s i fur him to fa th e r children, produce sperm I i ness that many of those servicemen have suffered. I commend the writer, Tony Gordon, for hli extensive researen, and 1 rec ommend h is article to my colleagues for their understanding of this signifi cant Issue; [F rom th e R o b in so n (111.) D ally N ev a, May 8. 1G33] Afo caltpsi I aatxtT " O ramcz-H ot'* CoxraovEMT cian. th a t said the results of th e n initial te sts w ere "eat is facto ry ." T he Daily News attem p ted to co ntact O 'C rad y on W ednesday, b u t was bold h e couid n o t speak to th e press and was re ferred to puouc relations *toucim an Y. C. P arish. A woman In P arish's office said be w ould rio t re tu r n u> w o rt u n til M onday. I t Is th e p re s e n t policy of th e V ete ra n s A dm inistration to deny any disability claim s based on dioxin's effects. T h e VA provides free.physical exam inations to vets who fr-1 they may have su ffer'd adterae li-a.lh ef forma th a t are n o t norm al In th e ir ability to Im pregnate or are m utated. --An o rganically-based ever* depression po in tin g to a n Im balance of n o u rish m e n t in some of th e ceils la bis tra in . Davis said Carr.ow toid him he has not suffered brain damage, b u t some of th e cells are dam aged to m e point w here they are unable to absorb oxygen. --H is to d y also h a s d ifficu lty In th e proc ess of energy production and transfer, which brings on occurrences of extrem e w -iijie s s D a.is said m e t'-.ts in d n a trd th e (By Tony Gordon) A medical specialist In Chicago h u diag nosed a n u m b e r of physical a ilm e n ts In W est York resident Samm y Dsvta and an o th e r V ietnam v eteran as being related to the defoliant Agent Orange. T h e diagnosis la believed to be th e first tim e a physician has draw n a connection be tw een Illness and th e exposure of U.S. servIcemen in V ietnam to th e dangers of dioxin, an Ingredient of Agent Oranxe. Davie, who was aw arded th e M edal of H onor for service In V ietm an. was one of th e first three Vietnam veterans to be ex am ined for possible dioxin-related Illnesses by Dr. B ertram Car-now. president and senior sd rn tlst for Camow. Conibear and Associates. Ltd. C am ow lx th e d irector o f o ccu p atio n al and fects from exposure to Agent Orange. T h e VA said V reilnesciy 3.00J V ietnam vets have gone to VA h o s p ita l co m plaining of illnesses they [nought could be related to A gent O range in th e Iasi y ear an d 9.40o ol th e m were 111 en o u g h to be h o sp ita lised , n o n e fo r an y i l i u m th e VA say s is cau sed by Agent Orange. Vem Roger*, a spokesm an for th e VA Office of Public ana C onsum er A ffairs in Chicago, la s t v k i aald th e agency u " pro viding medical sureem ng lo r any veterans who think they may nsve a problem and we a r e doing so w ith o u t an y oi'C ioal p ro o f In the entire world th a t a link betw een A gent O range and medical problem s exists. T here is no piece of paper oy any doctor an y in ere th a t u y s a s y l h n g a t all is cau&cd by A g en t O range. body produtrs an en /.m e to ;,i:m the d ioxin c o n tam in atio n v ;i i;h sw-.-ils th e n u cleus of a is and re ta rd s th e flow of en erg y through h u body, Grou-.ov.vki said C arrrjw to id him a likely cause of his (cizures U dam age to his brain caused by m alfo rm ed cells, tits Liver and central nervous system are damaged, there Is a blockage in h is lungs and ab n o rm alities Ln b is blood. "Dc. Cam ow told me th e diseases I have are all a result of exposure tn th e dioxin in Agent O range." Grom ew rki sard. T he disguntis of G ruriow ski may be espe cially significant because wt.de Davis was av.rgned to a com c a l unit Li areas of Viet nam epm yn) * ;;n A r-n t 'range. Grom u ' i was not. He u : ai.-ivri'd as a cock in D a Nwr.g S x e rju n p for n x m o n in s. an d w-as never sunt In to a s p ra i r<t area . environm ental m edicw r a t m e University of R esu lts from G am o w 'a te stin g an d ex a m i 'T n e fl.ig r.ik u of Ju tu ) p u ts us in m e po Illinois School of Fubhc H ealth, an atten d ing physician a t th re e Chicago hospitals and nations may prov.de th a t piece of paper. Although Cim ow ta:d " I have no mleo- r t i o n to rv ih tn x th e in r i j e n u of ex p o su re to Included areas of South Vietnam previ th e a u th o r of m ore th a n SO article* and U cn of becom ing involved La th e pc h u e s o f ously unsuspected ol posing a th r e a t." W ells publications on th e effects of. th e environ th is L-isue." h e said Ins diagnosis of D avis *u said. m ent on hum an health. a m a ile r of in te rp re tTM n o n of sUKue* of C am ow said h is tesla'c n th e th r e e v e te r An advisor to th e th ree veterans. Irv people who have th e tam e things." ans involved " a stu d y of th e pvti>-ni' h is to W ells, Is ch a irm en of th e V ietnam V eterans " It comes down to a Question of w hether ry. a cumci-rte physiral r ia .ii and laboratory C onfederation of M ilwaukee and a licensed you believe som ething lh a i looks like a tests to m easure tn e funrunna of various surgical p h y sician 's assistan t. He arran g ed d u e l, walks tike a d u es an d UUXj l.xe a duck o n ran system s; th e Uver, c e n tra : and p e rip h to have th e th re e m en see C am ow fo r a n e l is a a u d t. T h e re m ay be o th e r an im als w ith eral nervous system s. cardlo-.s^g;uiir an d re im ination. fe a th e rs t h a t sp en d tim e Ln th e w ater, b u t a p roductive system*. 'A t a:;o do a serie s of "W e w anted to h a v e o u r guys exam ined d uck Is one specific an im al an d people blood te sts to d eterm in e blood co u n ts in th e by*the finest ex p ert in .m e country and a should be able to determ ine th a t from inves liver and kidneys." review of th e research c oioxia led us to tigation." Cam ow said in assessing th e link He said n il firm employs "Lhe state of the i D r. C am ow . H e's p u re p n y u c iu i. a r.on-po- betw een d ioxin an d th e h e a lth o l th e tw o a r t tn clinical m edicine." b u t h e h a s no 11tical anim al, and was wlihrig to look to r v eteran s. equipm ent or procedures n o t available to th e reason these m en are r'ck." w eiis said. In an interview restricted to th e results of the VA C am ow perfo rm e d a iv-hc-ur sene* of th e Davis ex am in atio n and g en e ra l In fo rm a " T h e Veterwna A d m in istratio n h a s th e ca tests and physical e Lamination on th e three tion about bis procedures. Cam ow told th e pability to do anything v e m but not v eteran s in M arch. Cam ow ' lin d tz c i are D aily N ew s "M r. Davis displays Lhe sam e having th e resu lts of M r. D avis' te sts th e re. m arkedly, d iffe re n t from in fo rm atio n th e sym ptom s tra d itio n ally fo u n d in people v n o I d o n 't know w h at ty p e of e x a m in atio n th e y m en received follow ing ex am in atio n s by h av e been exposed to d icxin. an d th e r e l r cun du ct. T h e VA h a s a tw o-volum e oook on V eterans Administration docto'-- ab so lu tely n o th in g else in h is b ack g ro u n d to Lhe researc h in to d io n n . th e y know w h a t is T h e results of C arnow 's u id e p e n a e n l tests su g g est an y o th e r ex p o su re to dioxin th a n being done. T h ey h av e th e to nolo gists, bio- show Davis and fellow v eteran J o h n Cro- the A gent O range in V ietnam ." sutislieiana and laboratory physicians capa m oaaki of M ilwaukee suffer from abnor According to both th e doctor and p atient. ble of dome these same testa. I t becomes a m alities In th e ir blood and vascular ayuem . C am ow s exam ination of Davis detected th e question of w h e th e rtir n o t they agree w ith following:. tne." Camow said. --H igh c h o lestero l, h ig h trig ly cerid es an d O ne g reu p of people believed to have a large concentration of fatty ceils m h u agired wVh Cam ow and his t U for ad blood, a condition norm ally found tn people verse h ealin effects caused by dioxin expo m u c h o ld e r th a n Davis. T h e se facto rs. su re a re th e 12 m em b ers o l a M adtvun C am o w said, poof " a very h ig h risk of b ea n , C o u n ty Jury v n o tn A uritat S van g ra n tin g disease." Judgm ents of betw een 11 m i-uun an d 11.i m lflton to each of 17 r .i.r o a J w o r s e n in volved In an expoiure re it ted suit. T ile workers charged In th e m il th e y had xuffered central nervous system damage and cancers because the N oiinu an J W estern Railway h a j failed to p rc i-c i them when th e y were Invoiied Li a dM xln e ira n u p o p era tio n a f te r a rail accid en t in 1979. Cam ow testified on behalf of the workers And described th e m edical problem* he has d etecte d in th e m th ro u g h h it tesla. A fter 10 d a n of h i: :> :iv :v ihvi.ird th r w orkers h id been a! ire ted and began m aking th e fu ian cial awwnix. ln his Interview w ith tn e D uly News. Camow iv.J he is , : a,, vi:y o u i 'r d o cto n of negligence even Lhuugh th e re su lts oT h is te sts o n P a . u o i l (rcm .iw ski C o n g ressio n a l Record Show d iflrrc ill n - v i.'s it .- n ! h r V.1, ir I.v "1 do n o t th in k an y o n e Is fa k ir* th e te sts, K ay.24, 1903 but they may not be d.-tn; all of them and m ay n o t be viewing th e results th e lam e way W e have citiy rw ii.itird th ree pcnp.e an d w hen and if we do 30 or m ore, w r wul Vr-.\ i- i 1*L^t- v Mr. DASCHLE. Mr. Speaker. Mr. Paxetta as vice chairman ot the Viet nam veterans In Congress, and myself as chairman, are introducing legisla tion th at ill to an extent provide fi nancial relief for a limned group of Vietnam veterans suffering from the effect): of toxic chemical exposure from their service In Vietnam: 111 or my colleagues from both sides of the aisle have Joined with me in this : effort. I believe this legislation Is even more compelling after the administration's decision to compensate the residents Of Times Beach. Mo. Though the extent of Federal Government culpa bility a t Times Beach is soli somewhat unclear, the decision to purchase the property in the community Implies an acknowledgment that dioxin, the same contalnant in the herbicide agent orange. Is dangerous enough to pay for the evacuation of an entire community of 2,500 people. If IhU Government is willing to accept this responsibility for Times Beach, It hA3 even more of a re sponsibility to provide compensatory relief to individuals It was directly re sponsible for cxoojing to the very same chemical In Vietnam. My colleagues may be Interested to learn that dioxin levels at Times Beach, averaging ICO parts per billion, re approximately 20 tunes less than the mean level of dioxin In agent orange, 2 parts per million. Dioxin levels In agent purple averaged 32 parts per million and in agents green and pink they averaged 65 parts per million. Herbicides pink, purple, and green used primarily before 16G5, thus had dioxin levels hundreds of times higher than levels discovered at Times Beach and Lho<isands of times above the EPA danger level of 1 part per bil lion for domestic use of herbicides con taining the contaminant. We thus believe it especially appro priate to introduce legislation which would compensate certain Vietnam veterans for Illnesses and disabilities which may be related to their service In Vietnam. Current law allows for the establishment of presumptions, and the payment of compensation, when there Is doubt as to whether a specific illness originated during a veteran's service or not. This legislation would establish three new presumptions for compensation purposes in section 312 of title 38, United Elates Code. The new presumptions are for soft tissue sarcomas, a liver condition known as porphyria cutanea tarda, and a sain affliction called chioracne. Scientific studies presently show a strong corre lation between these illnesses and dloxtn exposure. There would be no presumptive period applicable to these illnesses, but in recognition of the largest end probably most costly epl- - demlologlcal study ever undertaken, there Is a sunset provision which would terminate benefits within 1 year of the first report from the Centers for Disease Control epidemiology study unless the results of the study Indicate that there continues to be a significant correlation between service In Vietnam and certain ncaitn effects. Since the CDC study is expected to have Initial findings by 1537. the --'sunset provision would likely become effective sometime in 1633- A few h m -lnd veterans suffering from soft tissue cancers and purpiiyr;* Cutanea tarda dll benefit from this legislation as would some 2,500 veter ans with chloracne or chloracne form lesions should Veterans' Administra tion extrapolations of current chloracne cases prove accurate. Tills k-gh.Ixtlon b expected to cost only *3 to dt ' mtltlon year. The following chart provided by the Velrram' Administra tion lists the number of agent orante Totaled compensation claims filed with { h e a v eil pa hn-akrlow n o f AGENTRANGECLAIMS Prsd AlM -- g ora_______________ C*t >4 CC X ) ids*!__________________ 1 QwmwA Anj ifiiAarf Horn! b n ta n OH*;at a a fi___ 1LSU ut1 OK Lfl *u;i IXti *11 a* hi mi Ki ni ar*mt&wrx*ciirfif oft M mj wp4 *r u1J*0U7 naMrfto)cijnloiNf t n a m ijfb*dm*vi fc unL tf jifeM U , MPTa^im B a f iW m t t f U l PCM hi*} ntrbnrci>cm n. *** 9m m M at* fcwMw-*omm (km, mAlitjj 1" iaoLa flora_ Q AK p r a t m w M tCpf ip v m t --i-- . !L<iurcts i BAMka, m o m . w m , jcq p * i * fc*-kl3 K U t o t f j J ELmtf4i*** * mrtyem >rrahM -- *37 *1%*1 5bI J&S 4H7`siI3 1*4 As my colleagues can see, veterans have filed claims for a number of ad verse health effects from agent orange exposure. Virtually all ot these condi tions have been described In scientific literature on phenexy herbicides and dioxins. For reference purposes, J would refer my colleagues to chapter S of the Review of Literature on Herbi cides, Including Fhenoxy Herbicides and Associated Dioxins, ordered by Congress In Public Law 95-151, and completed In September 1981. An up dated review should be available In several months. This document, as well as a bibliography with over 1,118 references on the Bubjtrct is available from the Government Printing Olfice. Certainly, there is ho shortage of In formation on this subject. Despite the large number of adverse effects no ticed in exposed populations to dioxin. I felt that at thfs Lime the legislation should be limited to those Illnesses which are most Indisputable. The efforts of the Army Agent Orange Task Force will also enable us to verify in most cases whether or not a veteran waa actually exposed to her bicides. The task force, which has been busy Identifying cohort groups of veterans who `ere exposed, not ex posed. as well as those who aid not serve in Vietnam for the two Centers for Disease Control epidemiology stud ies on the Vietnam experience and ef fects of agent orange exposure, is a most capable and credible source to tmnduct this research and Is complete ly willing to assist the Congress and Veterans' Administration with this particular effort. Mr. Speaker. Lhe alleged scientific uncertainty surrounding ail the defini tive effects of agent orange exposure In my opinion will continue to be ex pressed for some time. After all. if we have been unable to find conclusive evidence after publication of over 1.100 studies and reports on the chemical spanning decades of work, what can we expect those studies now underway to add to the current knowl edge that has not already been re vealed, 1 personally believe that deci sions can and must be made on the evi dence which is already available and there is sufficient evidence to do so. The social policy Implications of agent orange poisoning have been ignored too long. Regardless of whether agent orange can be definitely linked to on Illness or is merely correlative, there are over 16.500 Vietnam veterans with severe illnexM-s they believe are caused by their exposure to agent orange. To hold their fate In the balance while Congress, the VA. and the r-nenufic community deliberate the conclusive ness of Lhe science is a mockery of their service to this Nation and to their suffering. The legislation 1 ocr now Introducing U a tightly crafted bill whi'** "* diseases to compensatory relief cur rently not available. If compensation con be provided to residents of Times Beach, and I think It should, it defi nitely should be provided certain Viet nam veterans as well. Following ts .the text of the legislation: XLR. 1M1 A bill to am end title 38, U nited E la te s Code, to provide a presum ption of service con nection for th e occurrence of cerium dis eases related to exposure to he role.lifts or oth er entireom ental hazards or condition* bi veterans who served In S o u th east Asia during th e Vietnam era B e If enacted by the Senate a n d H ouse of Aep ream tali te r of the b a ile d St atit o f A m erica tn C o n g r tit a-nem ced. T l u t Lhix A ct m ay be cited as Lhe "V ietn am V eteran* A gent Orange Relief Act". Esc. 2. T h e C ongress find* th a t-- (1) certain adverse health effect* occur rin g am ong person* who served In Lhe A rm ed Forced In S o u th e a s t Asia d u rin g Lhe Vietnam e r a and o ertaji b irth defects oc curring among the children of such persons, may be the result of the exposure of such person* during *vcn aervlre to p hrnoxy her bicides liu 'lu d in g the herbicide know n os Agent Orange! and the class of rhrm irnis kncViU * th e dioxins p ro d u ced d u n n g th e m anufacture of such herbicides or to o th e r factors Involved la such service Including ex posure to o th er herbicides, chem icals, medl- cat-ons, o r environm ental hazards o r condi tions: and (2 j a com prehensive review and scientific ahalyxia of th e lite ra tu re co v ering m u d tea relating to w hether there may be long-terra adverse h e a lth effects In h u m an s from ex posure to any of m e cLlis of che m ica ls know n as th e dioxin* p ro d u ced d u rin g Lhe m anufacture of the various phenoxy h e rb i cide* Ld.eli.ihng th e herbicide know n u A g rn t O range!, a* req u ired by section i i l i a h l A B ) of P u t lx Law id -1 5 1 , h a s te e n com pleted and ruem itted to th e V eterans' A dm inistration. E n a I. EecUum 311 o f title 38. U n ited S ta te s Code, u am ended by ad d in g a t Lhe and th e toilsalng new auowction: f o x il i'o r th e purpc*>i-x of sectio n 310 of th is title and su b je c t Lo th e p rovisions of section 313 of th is title, in th e esse o f * vet eran who served In Southeast Asia during th e Victr.'-m era and who a fte r such service suffers from a disease described In parx- grapn i3XA) of th is subarction. such disease shall be considered to have been incurred in or aggravated by such service, n o tw ith stan d ing th a t th e re la no record o f ev id en ce of su ch disease d u rin g Lhe period of service. "tyxA l T he diseases referred to Li para graph (1) of this subsection a re th e follow ing: " 111 Soft-tissue sarcom a*. "til) P rc p h y n * cu tan ea Lard*. "(UP Active and residual cldoracne an d chloraeseforra lesions. "(1v) A disease listed In a re g u la tio n p re scribed by th e A dm inistrator under ubpara- g rap h (13) of th is p arag ra p h . "(B) The A dm inistrator m ay determ ine, and presepbe by regulation, diseases (in ad dition to those listed In su b p arag rap h (A) ol this paragraph! th a t medical m e a re n has shown may be due to exposure to hertu- cidea, chemicals, medications, o r environ m ental hazards or conditions. T h e Adminla- -traio r ir.il) Include In such re g u la tio n s . a ipcdJicatioa of th e standards used by the A dm inistrator In m iking such determ ina tion. Paragraph (1) of th ii subsection shall te rm in a te on th e ILrai d ay of th e l i n t m onth beginning alter th e end of th e cue- y ear r e n o d beginning on th e a-*ie th e Ad- fninisL-alur lu u m it* Ij th e a r o r e p r ia ie Comnutvcea oi Conereis th e first r--poit re. quired by section JOTtaxJ) of th e Veteran* H fiiih fhogram s i j tension and Im prurr- ta e o l A ct Dt 197 (PuhUe Law 88-151; 93 S lot. 10931".4 ' MARCH 8, 1983 D io x i n 1rt1/iacis nr *u m a O f T o 7 r a c x r n1 T .-/'-I L i _: i ^*S V"\j w 3i J a a "**>C *v. / n .. C7 < ?`- ir vo ru *a r n o v # kteJtC iit Tribune Report Fkon: the reckoning of St. Joseph's " 1 saw some chemiluminescence stud Hospital's I3r. Gedney, a loam of Mis- ies lie did with neutrophils," commented souri doctors spent a total of about S-JtO. Luui:* U .'s Dr. Slavin. luidid he incu hours examining the Times Beach test bate lymphocyte, with mitogens?" ' population of 120. Dr. Cumow said each Yes*. Dr. Prince averred, he did -- with . of the 47 railroad trackmen spent a total of phytohemagglutinin. pokeweed mitogen 16 or 18 hours seeing his team of 12 spe and concanuvulin-A. Moreover, he found cialists. The group were examined starting the generation of superoxide radicals was 10 months after the accident, and reexa affected. He said the changes indicate a mined at intervals until last No'-ember. change in hone marrow at the 'ii;!:i cel! `"The stuff, which included phenol and level. 1le speculates chat w itn the iymph'j- orthochlorphenoi, affected every major proliferative ability of the body impaired, organ system and numerous enzyme sys the freshly transformed neoplastic cells tem s," according to this specialist. His may no longer be swept away in time. colleague in these studies-was his associ Dr. Camow added that in animals, ate, Dr. Shirley A. Conibear. # - the dioxin is a cocarcinogen beyond be-, " Many of the workers-had diabetes. lief. For example, 3-n;ethylcho!ar.threne Four had Pevronie's disease. A number on its own is known to stimulate produc had complete urinary obstruction. Five, or tion of zr. ihydraxyhyrfroxylase and the re - about 10 percent. Je- j j - I~'~- by, tumor growtn. veloped skimn cancer., i : . - * j i But when dioxin is One had a 1.-44000 tri- I11! ( . : r . \ ^ `,-' ^ ' ` '*7- ' 'i.'j added, the carcino glyteride. Eighteen !! 5P " ' i L - ' V.* ' / genic process is en had abnormma.allllyv low- j' i- ov^.. hanced thousands of testosterone . usually | ; L ~ - _ jI with a marked de- 1 \ -'x--^ - f' . '* - 1 crease in K b U o . l a ! many, ' prLe*rripnhkej ri*anlI i1 ............... > - . h I. * - / t_`j neuropathy, a numb- !' ness and tingling, be Y came deeply painful at nighrf causing in OR. PRINCE.' -- --7" : 7 *a . DR. SLAVIN times. Such inferential risks aside, to fully assess the individual risks in the Times Beach population, professional inter viewers las: January somnia. There were changes in muscle reached bOO or 'X) residents with ques metabolism, an ATPase and CPK abnor tionnaires eliciting data on lifestyle and mality.' ' "-* ......... *v ;'" " possible exposure of all types from all dif " Another major problem was a com ferent sources. From the answers, investi y. plex o f extensive neurobehavnir.il abnor gators-drew the test group uf 120. malities. often cluiacterized by a severe A leading environmental specialist, the depression. It was nonpsvchogcmc and in Palo A!m (Calif ) Medical Clinic's Dr. some cases amounted to what the Russians David Disc her, made thr; plea: "W e very call a neu rove genitive statu. There were much need CDC's expertise here, to Jo the severe personal u\ disorders, marked t:v a longitudinal cp.Jem. tologic fallow up '.hut to 0,1 ^ handle.." needed, and with its experience follow In c0 of the -17 **'c:i, almost two ve.us imt g pom:Lirions that to dispersing ireni* after the dioxin spii, UmvetMiyoi lim.ois selves .liiuiuJ the Ration. vJtiee-u study ininuinoioxieoloeist Joseph Pruice. that ever,body e.m live with. We should I'll.I)., Ii utiv i;-.:;-.ni meut :;i neiitruputl pul oui tu: *( m CDC iu V.,l tl.IS, and lv :'\pl,iv.v te lei'-tion wueu ceuip.iicd with that in age-nutehed normals 'I lu* Dying irotn d :oxint n hnrr.?> on nn Imperi pi nue nu wots nl host ic-.ivt.ince no ioimei al. M*t. I.irm (h o iin uvolu in nearby :.ml had full rec *-"i:tum ol the enemy. w e r e 3?,tHi ppb. a t.l.ilowutu tmjti. '4VNcy?5; % 'V riCl''Crvui Ti.h'jn-?. Sunoay. M 'ON 27, i Keactions to dioxin ca VH!1 *. e *'j . u .4 y i ' j .i j T jL. 71 r * t:t ( A i j ;> O. L). rs . .in 1III : i n \ 111n N "II-: N T Al . 1'!>tfi. (lull A i l M. \ 1i f i l to Me. fin town of T . - I*. li M "OC.U e it Iris heeii s :i*..o n:i . mi oy ; .tent ..di v l'..i/ni IllllS il '*CN ol I: '!., or. 1 >et.rcs i ithel sites M i a I II n. : i"n .1.01 . . f 111. m in Mis S'- r i. ii: . e. a* 1 Mi. hip ai 1li.Ve also I* t o t \| <! !o tl < contini.. r- ml homi c ..! t* e : i: uni; i* .hale >\ l 11It* i !.'.i.i ' *Si;'! !\ :.. pe Mi f,|* i .nv 1ir .id.it d ,i lieu ;. i>\ i 1.ii.e ri s.\n i l. i sh.." nip ' ' !11 to \. i y. simili a nielli.i' of Mil Ce 1 i. .1* a iH'i -en's ;.lnhl( In v . ' oi l I . c.< n v !)<i t e d h y . h e e j . ' i P i i r i e o . r t i :; :.. .? ,. - t o ' e e ' r .1 a t l i t e P n i \ i s p y i t l a . a -, n ' t : i :' s h o w s u b t l y d ill c a n e !:. t i . 11 n a n h <lv . . n i l I I I . t v ri p i e* ;>! <<n ` e . , i . w a r * , a a ; s\ ' l e u . ' f o r ! -.a. 1- M i l . i l . i ' s i - . m s c d I t v t h e t o x i c c n , a! vr r i \vi Mi-ii anjlhu.,: this Invio," hi* .*i 1 1`IIIN l 1 S s | l '|>Y# uiir ni (In* Irw r! ,i.. ; a iP..sa: expo- u; a in hum ans, f- : d . . . ' ... ,. J !*.(' t .' ll to d i.\m ; it . 1 ell . 1.1. i.l 1 ch.-lull el spill1 in U i'h ;.' 1. .n. . tiir e v ai s ap.o The :i vs. . i ' 1*A 1 to m ii,Pi amount .. of 1 Mil 1* r 1 1 li Is rni'pm ; fiom a few d.: S' to l*a to 11! v. r.S. ' ]Pi im c : ar. 1 a h i. . main ie.s in the . Into M - 1 cell a< !lVlt> of l.io tini Us oi the r a n Amo '*1 : 1:01n was u reduction m the normal fund ion of nenli'iph'ls. "Pncn ia n '-ly p r <-11:; lli.it s c u iiy about III' Imdy " iMlini; ' hai lu n a and f o lc ic i do* hris. Also found was a (In lease in Ihe mini U r of eosinophils, te lls timi p iai .i role in roi (rolling allerp.ic leaelion s. and a i*nduelioti in the concentration of oxypencaiiyinj Iit-i iit>f',,I->hin in the red blood cells. Al'limiph v idcly n 'cup.ni/ed a.*: a toxin, Ilie exact extent of dancer posed h\ diox m in the environment i, <t ni.ittei of niro.'ei: y amom' Mieliti is. 'J ill ! Will I P lileixl ells f`i iuee k ( i i i ! h i! Mm mally will desi m y e.int ions <ells that rei'.nlarly occur in the human hody a> well as haelena and othei loi<*ip,n mat' r i als II the cells fail lo leenpni/.o and liistro y ni di/'.Man! cells, a p c i-oil's risk of d. velopim; cancer i\ii! increase. Changes in normal him turn of Mood cells m ay also indicate b.*` a* ch.ane.es in the Imne mai row where Mood c e ll; are m anu l.itlured. Prince said Such hanp.es could mean a p.rcnter ' ; i.*A of dcvelopm/j leukemia, a can or of (he Mood. The i haiipes l `linee lountl in Illim is w oil.iucn are renisi'.lent with si tidies don* in mi *. he said In mice spose I to l.u pe amounts of lii>m, the natural inimunc system shuts down. When line- are expo?-.ed l<> liny a mounts if the jm .m.u, t!i**ir while hloml cell production actually is stimili di I, hul function of those Ci Its is altered. " T II K liMMUNK b)slem is a dell idcly halanerd n ,r;ulalor\ .pelatimi,'' l 'rincc said. " WIhmi voli j;'l too man-. of onc liin.l f celi and not enoiiph ot . aimther, il co m p ie!'ly up.sels Ino no: mal n*'.penso A rompi orni si itmuiaie System p, incapaMe ol lu.titinp, oli eliali' n jf s in a normal fa .l id i " T h is i>. a verv stillilo and coinplex r ..timi " Pnm .v s;iil his sludy ic su lls are consis ti ni wilh llmse dune tri f. eden ubere mcn wmkinp in a lorr.sf spr.iyi-d wilh a hi rhuade sint.iininit dio.viu xporicnced I;. .iplioma';. Iunior , o! .`.oli tiv*, al a raie si\ timi s /realer jl mi noi mal IP.-l.ai tl Wilson, cliaii inali <f !!:( phy sii , ilcpai Iin* ni al ll.u i.a I t m versiiy wl.o lia.s studs-d diesili ami has w rilleii a numher ot hooks e- *imat n:;* l'V*ls of ch.iii'ers a:.MiM.itel wilh (osnis. ai! 111.* siodn . loti>* in hum :ns, in l:i.!:n* tk.e S i ede li s!ldv . Iteli hy I T iIm:. il,IVO lailed tu estahlisli (hai ehi unir explisiiro (o si tulli ainount:; >l lu xm eausiv cancer. ` SOM! : STI'D IM S sup.ee-.t chronir lovi* city is cai ciici'.enic |eaiicer-eiMisinf| and olhers su/'i'esl il is ;>i.i i careinop.cnie." Wilson said "Sludie*; bave shnivu it oan pie.luce eanr in raP: al hirli i.ises and Iemise b u lli d- fe'lM a hi,li lo-,-*,. It is Uasly al hlp.h (loses, bll', so a li: lots of tlnnes." Wik.on said that use of A i'.en ` Jranjie in Vietnam hy U.S. m ilitaiy hiices lo clear vepelation w as clor.e wtihoul norm aI s.d cp u an ls fer human e>;postire and wilh coniam inani Icvcks of dioxin thut were si.m ifirenfIv In *1.: U.a !, those y e t re IX)rt- ed in 11. l l i l t e d . ' a t ' as "Ixven under t1.ose 1.;.* f*!! c, <r..M- linns, w haven' See .1 C :. ''l Si 1 i %; li'iie* o: <f !*.! -. l tv Ml r. a .' .t* e x ;* -. . h- s a i d , it In atm tl. a. the dafV-'i s n. .V he sm all A si lid V r e j H . i t e i l !: f 1*1.*jeU is * Vl:ari'n*p#, ! fa if .,t s th.l i V That :.lucl;/. nn :*. r ! ! e|tl hi tf;*k Vii-* r. .III . ere.me ut. r n - if 1,; v. ho-e lei -Imi. !. r ' f ' 1, s. *, durmp, tl w a r i ;1*! C ol has in,: t i e i l i e I V - v 'r a .r i.s ; ^ 1 cle ! d l e|> V. ith ,v , :: t f -.an v.::: *.n V. i l o . e l i : r h.mds m av ! I II i*u e.\:<O' **J to A .eut irar.iu!" i'i tl.* ll i *i u \ ( i: N.M1 > ihe V i- '. ii.iin finii,:i. -!s are ` e.r,.., t e t l t '..ith t! 'iii:ml .'..*1 1 would c .m :<cl i* 'ji'h.s ( a!! h.< c *... hilities noriimi ol inter:. ac!W ill.". i'n*#; s a! 1 k . r . d 5 Ani.lli.-r Pmvr : silv 0f n:. Ii*`I ti \j: !c>- nisi, J(.hn iJede'i-..I, h X ` ' i;-; i *P fe l:* <\{ a !in> '*1 '.!. 1 . *. * i P H .1/ *Jc si raved r. r id ir,' / .ri t ; i r .1 V. .<or. .:n f a irnl.imi rnoix* tf an a .J le a .si A c la s s ic i. f . l o m , * oC l . i f l ' d m , dioxin exr .MS'l" C i * a .v'-M chlor.ie r. l.u* It. .!} a lr :;:h . C. r, *: ; d ohi l o . l s s\ mph.iv. 1-.-. i t r i r , a. i ,ief. "Kcwr r ifiar, .V/ j- n c*. of a :-n exf/i'wsl lo iJoa;:; w.il sr/.v a r.. least \t*ry soen." IP-'I.-m:: '.. id "p. p ; a skin can cer in ih-.* .se-.''- ' hat it r-, taka years after exposuie U fore i- ap pears." 5. i