Document bay3mBKY47Ed8y3YYxn9RjB61

! V/ \ A SUMMARY OF TOXICOLOGICAL DATA OF THli PHENOXY HERBICIDES William McBride, M.D. SUBJECT TO PROTECTIVE ORDER. C24720 2,4 .5-Trichl prophonoxyacct It: a c i d .. Registered in 194^ - phenoxy herbicides - are synthetic plant growth regulators. The phenoxy compounds mimic the properties of a naturally occurring plant growth regulator, indoleacetic acid. The military furthered investigation by studying : ph e n ox y herbicide used as a vegetation control weapon in 1 9 4 4 - 1 9 4 5 . Phenoxy herbicides presently in use today in the U.S. include 2,4,D, 2 , 4 , 5-T, MCPA, silvex, 24-DB, MCPB, dichlorprop, mecoprop, 2,4-Dep and dichlorprop-methyl. In 1 9 7 5 'the U.S.A. used 59 m i l l i o n pounds of 2,4-D, 6.7 million pounds of 2,4,5-!' and two million pounds of silvex Stanford Research Institute, Chemical Economics handbook Stanford Research Institute - Menlo Park, California - 1976. In 1969, 11,626,000 pounds of 2,4,5-!' acid esters and salts were produced in the United States alone. In 1070 the quantity rose to 12,335,000 pounds. Between 1971 and 1974 73^,907 pounds of 2,4,5-!' were imported into the U.S. averaging a total of 148,000 pounds per year -- E.P.A. - Herbicide report, Document EPA-SAB-74-D01 US EPA, Washington D.C., 1974. The phenoxy herbicide enters the plant in an imperfect and uncontrolled way. It interferes with the regulation of growth processes normally governed by the plants own naturally occurring gr owt h hormo nes (Ashton, F . M . , Craft, A.S. Mod<; of act ion of Herbie.1d e s , Wiley I nt er sci en ce publishers. N.Y. 1973 . O U1 US V" The phenoxy herbicides interfere with cell division (mitosis) and cell enlargmont, food u t i l i z a t i o n anti v a r i o u s -other processes necessary to stabilize life. C24 Scientists do not know the p r e c i s e .mode of action ( of either synthetic or natural plant growth regulators. They know that phenoxy herbicides ar e far m o r e t o x i c to' gr e en p l a n t s than to animals. Plant g ro wt h r e g u l a t i n g c o m p o u n d s act on plant, cell compounds such as ce ll u lo s e and l i g n o c e l l u l o s e which arc not present in animals. 2 ,4,5-T C h e m i s t r y : 2,4, 5_Tr:i.chJ o r o p h e n o x y a c eti c acid has a chemical formula, CgH^Cl^O^ The pure form occurs as white crystals and its molecular weight is 2^5.49 g r ams per mole. 2, 4, 5-T melts, at t e m p e r a t u r e s of lSf' - 1 5 8 C. It is stable at its melting point. 2 , 4 , S-T has a solubility in water of 278 parts per mi ll i on (-ppm) at 25 C. Further s o l u b i l i t y occ ur s when this herbicide is mixed with acetone, ether, and ethanol. Technical g r a d e 2,4, S-T m a n u f a c t u r e d for igri cul tur al application generally contains 90 to 92# of the herbicide and 8-10% impurities. - detailed composition of tho h o r b i c i d e tfiver. by-, onu protlucrr: 0 1.0 - J .0% 2,4,5 Tr.iehlorophonoxy a co tic acid . O.S - 0.1 % 2 , 4 , 5 - T r i c h l o r o a n i s o l o 2.0 - 0.$>% 5,niethoxy 2, 4 - d i c b l o r o p h e n o x y a c e t i c a c i d . 2.0 - 0 5 2 ,methoxy, 4-5 d i c h l o r o p h o n o x y a c o t i c acid CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. onn \<1 * + ^ ^>vi .- .i C2472 Kis hcr, J. K. letter, TOT 12.. In Final EIS, Vol 1. ..lion management wi th herb ic id e s , U.S. department F A,"n c i i H i m t , Forest Service 1977, - repor te d t h a t the average level ol <1ioxi u in 2 , 4 ,U.S. production of 5-1' app ea rs to be about- n."l p p m - This was supported by In 1orna I,ional Agency for Kesea rch on Cancer 1977 - Chlorinated Dihen /.o-d.i ox ins, vol 15 World Health Organi/ation and McQueen et al ? j 4 ; S - ' f and Huinan Birth Defects, Division nl Public Health, -Department of Health, Now Zealand, 1977* Thermal stabi lity - 2,4,5-T is stable at least, to .its'molting; point ( 1^6- 1SPC ) B jocheni.i ca I degradation - 2,4*5-T degrades slowly in soil containing organic matter under warm moist conditions. Half li fe for the herbicide- under' these; optimal conditions approaches several weeks, Metabolic degradation is caused by two concurrent processes. Binding of the herbicide nioiecule to other compounds, nui.inly glucose to form a non-toxic complex and actual degradation of the molecule. Three months is generally, accepted as the; time span for tile herbicide to disappear compi('t(`ly from the s o i l . Disappearance rate is independent of the amount' ot herbicide present. t o CC c Kven in the presence of sunlight 2 ,4 *S-T remains re Iative1y unreactive. F * uj > ri b W g Resi dues / A residue is an accumuJ at ion o f a prode:!. for '.a period * following initial apfi.1ration. Reside vs occur when the iniial product is not total ly degraded. The p . : r \ s i s t < `l i r e o f a residue can # cause; problems. II use* ol a known toxin Iraves sii I I ieiont rosidues in active lorm, (die extend and du ra ti on of that toxicity must' In* recognised and appropriate cautions 'Followed. 024723  *- 4' - ii oC flu* particular chCmlca I. Soil residues Scientific studies demonstrate that phrnoxy herhicidcs break clown in soils - Andos , L.J. M i.< roe io Iog i<a I breakdown of Herbicides in Soils. In Ib-rbi c ides and tire Soi I E.K. Woodford et Sugar (cds), Blackwell Sc.i Tub. Ox lord England. 2,4,5-T and 24-b form carbon dioxide,- Inorganic chloride and wafer as final degradation products. Cl assi Iied as slightly persistent 2,4,5-T takes anywhere from two to six weeks for a fifty percent d isa p|)<;aranee rat*. The co-np('r;vU vc studies by Stork e t a 1 Soil incorporaH on llindegraf ion o I*Hcrh ir ido Orange Microbial and Baseline ecological sl.udy ol* the U.S. 'ii rforxc Logistics command test range Hill AMI Utah timcl report, Tecorn project No 5Co-213-00-01 S U .S . Army Dugway proving ground - D u g w a y III <il J97.S, Arnold et al. 'three years ol* f:io Jd studies on tin* soil persistence and movement ol* 2,4 ,- 1), 2,4,5-T and TCDD - .Weed ' Science Soc Am. Meet.- Abst, 197^ - demonstrated the ippl ical. ions of 2,4,5-T anc* 2,4-0 at massive rates not only did not sterilise the soil but indeed stimulated the growth ol certain inic ro I1ora , and that" this stimulation may have cord, r iluited to the degradation ol IIre herb jcido. N o r r i s , L. A. e t a l , "The P e r s i s Mmici* ol 2 , 4 , S-T in t h e Piic.il j.c Nortliwes 1 l*orest, W eed Sc (nee, 2 ry(ry) 417, in 77 - examined I o 1 iag o , forest Iloo r 'and soil lor* 2,4 ,S-- I1 res i(Ii k *, The conclusions, summarised in the Journal oI Weed Sci once were lhal within six \ months of application., herbicide residues declined no percent, within one year less than six p e r c e n t o f flu*, horhic.idc remained. They found l ittle leeching <>f 2 , 4 , ^-T from the forest floor CONFIDENTIALto flu* soi J and no residues were found deeper than 15cm. C24724 If s IlcU in,-. ct a l ."Chlorodioxins in pesi icidcs, soi ls and ni a n i : " .1 . l-'.nv . Qua I . , .2 ; 1 7 1 - 1 7 , 1 9 7 3 , I ouiul I li.U. - , 4 , S-T rei atively mobile in soils. However', that movement decreases as organic coni ent. increase's. 2,4,S-T there Cor* becomes moderai e Iy moli iI<- in (lay soils and only slightly mobile in mulch. W`it <T res ichu.s : ?.,4,<)-T acids and ester s are sol ub le in wat-rr. In addition 2 , 4 , 5-T rapidly d i ss i p a t e s in streams by dilu imi and p ho t nd e gr ad n ti on in waLer - see: Cro sb y & Wong'Vliotoducompos i-M mi of 2 , 4 , S-T in water." J . Agr . Fo o d C h e m ., 2 1(6 ) 1 0 5 2 - 5 0 5 4 , 1070. Rese arc h reports involving s t re a m contami nat ion icom land spray in g in Oregon d e mo n s t r a t e d that peak co nc en t ra t i o n ol phenoxy he rb ic i de s s e l d o m exceed 0.1 ppm. These residues rarely last for mo re than a few hour's in almost, all 'the streams, see (Norris, L.A. et al. The persi stance of 2 , 4 , 5-T in a Pacific Northwest F o r e s t \ We ed Sc i o n c e , 2 5( 5 ) 417- 1977 ). The report of the Advisory C o mmittee on 2 , 4 , 5-T to the Ad mi n is tr ati on of the F.P.A. stated that all available data . indicated that a/small amount of 2 , 4 , 5-T is presemi hut does <1gS not persist long bec a u s e clay or the biota absorb the herbicide ` LU w ith in a m at t e r of da ys (F.P.A. H e rb i c i d e Document HI'A-SAIf 1 J /pt 7 4 - O b 1-US FPA - W a s h i n g t o n iW Q Animal res iduos : D.C., 19 74 ). O ) 3iij CO --- Animal r es id ue s would accumu 1aI.e because ol he r bi c id e build-up elsewhere;. An im a l s rap id ly e l im i n a t e about o 5e o f .ingest -d 2 , . J , 5- T unchanged i n t h e urine - s e e ( S a u . - i h . . I ( , M.W. i>l. al. "ihe d os e -d ep e iclent p h a r m a e o k i Mel ic p r o f i l e of 2 , 4 , 5- T following intravenous a d m i n i s t r a t i o n in rats." T o x . App. Pharm., .lb; 491-501 , 19 - 6- 1iI>i,* et a I ."Metabolism of' ?,4,5-T in Rats." Health Aspects Pesticities, h (5) : 272 , 1973. Piper noted a si g ni f i ca n t difference, in the .plasma h a l f life of ?, 4 , 'i-T tMu.itiu ng in the dog as compared to the amount seen in the rat. This d e la ye d ex cre ti o n time for 2,4,'5-T' e x p e r i e n c e d by', the dog is po s tu la te d as the cause for g r e a t o r .t o xi c i t y of the h e r b i c i d e to does tha n to rats. Hook et al . "The renal ha n d l in g of "2,4, S-T in the / --- D o g , " Fd & Cos T.ox, 14: IP-23, 1 9 7 b ) -suggest, a tight bi nding of the h e r b i c i d e to tho anim.il s plasma p r o t o i n o p er at es as t he m e d i a n ism for d e l a y e d urin e clearance in the dog. A study by Celiring e t al . "The f a t e o f 2,4,'5-T ` fol low in g oral admin js< rati on to man'.' fox . App I. 1`harin. , 20 : 1 5 2 - 3 9 1 ^ 1973, s ug ge sts that human ur.i lie clear unci' m o r e closely p a r a l l e l s th e rate of ex err ti on in the rat than the dog, sec K o ci b a e( al. "Results of 2 years chronic toxicity study and oncogenic study of r a t s ::-ingest i rg diets c on t ai nin g 2,4,5-T'.\ Id. Cnsiii. T o x . 1 7 : 205-221, 1979 who su pp o rt Gehr j ng et al ts work. Residues do not remain indefinitely. Their loss from the" en vi ro n me nt can be pr ed ic t e d th ro u g h the c h e m i c a l 's half Life. in var io us me di a in the environment- and a kn ow le d g e of the Jkic h e m i c a l s physical ch ara cteristics. .Q Jte? oc: pT Pol yc hl o r i n a t e d Di oxins Recognised in 1957 as an impurity io the manufacture o FT g. of h e r b i c i d e 2 , 4 , 5 ~ T TCDD is one of the m o s t potent small m o l e c u l e 87 I CO (I/D) to xin s known to man. Small am o un t s of the chemical car c aus e en or mo us c h a n t s in animal ,, c e l l s . C u r r e n t l y t,ectmica.1 iira>lr 2 ,4 > 5-T .024728'in tho U S . nml, i m `ly roumains I'd)!) luvols al or helnw H. I ppm. 7 Chemistry 2 , 3 , 8-to trachlorodibenao-p-dioxin exists as a white crystalline solid having a molecular weight of .)22 grams per mole. It melts at temperatures between 3u3, and 30o^C. and decomposes, at temperatures ^between 980 - 1000 C . About 99.5'/i. ot the* dioxin decomposes at temperatures of 80o C . 2 ,3*,7,8-TCDD irises >. during the hydrolysis of tetrachlorobenzene to form 2,4.5- Trichlorophenol, the industrial precursor of 2,4 ,5-Trichlorophenoxyaee' acid (2,4,5-T")'. T-.C.D.D. has a low water solubility and a hi.r;h lai solubility. Dioxin can accumulate in the environment under some conditions. TCDD however is read iJy decomposed by -u ltru-v.io Iel light which helps' to diminish potential accumulation of (.lie chemical. Crosby and Won^ (1977) - "Environmental Dgradation of 2,3,7,8-TCDD". Science, 195: 1337-1338 - found that herbicide formulations with TCDD cpntaminard lose most or all their TCDD within a single day when the leaves, soil or grass of U n treated foliage receive natural sunlight. Photochemical dechlorination causes this degradation of TCDD. While.the stability of pure TCDD as a persi stent residue in the env irnnmont is accepted, & U is not stable in the presence of its herbicide -vehicle-' Appearing g on the foliage in a thin herbicide film, the eontaminent >. diminishes as it is exposed to sunlight. Crosby and Wong established y three requ irement s For significant dioxin breakdown in the onvironmont They are (3) dissolution in a li^ht transmitting film. (E) 'flu o- O presence of an organic* hydrogen-donor - siu:h as a solvent or pesticide H <j and (3) ultraviolet light. They propose that all three' conditions Ul*S* are normally met in applications of 2,4,5-T. Tlicn-I'orc iln-y leol (A -- - that these data suggest l.lurt en vi ro n me n t a l residues, of T C D D often will be considerably less than previously expected. 24727 t 8 Residue ex per i m en t s ha ve m o n i t o r e d (In- TCDD levels, in land, water and.' various species of animals. lor the most part. TCDD residue levels directly c o m p a r e to the amount o! initial it |)|) app lic at io n and are not .defect.ah Ie in m a n y instances. KccuiiUy the Dow chemical company of Midland Michigan, .I released a report (lenionsl.ral ing t hr p r o d u c t i o n ol TCDD as a hyr.prnduct of normal combustion pro e s s e s . A n a l y z i n g sa mp l e s from ; number of com b u s ti on product-s such as refuse iiicinuration emissions, automobil; exhausts, firep Iace s o o t , .charcoal' grills,, c i ga r e t t e smoke and parti cul at e .ein iss ion from chemical plant p o w e r h o u s e s - researchers q u a n ti ti ve l y measured the a mo unt of TCDD present. -( D ow ch.;m.ieal comp any - Midland, Michigan, 1979.)' ' IT environmental presence oT dioxins from combustion can b<; further established and supported,' th en it will becorn; invreusing Jy difficult if not impossible t o link environmental residu<;s equ ivocally and solely to herbicide spraying. CONFIDE*mL SUBJECT TO PROTECTIVE ORDER, death in 50% of the test animals. An L D ^ value can differ due to such variables as iii,rr or sex of test animals, n u t r i t i o n a l state, lonnu la tio n of toxicant, timer of day, route of adni Lni strut ion and temperature Mode' of entrance and chemical form of the s u b s t a n c e can also alter* the u observa bl e adverse of I'rils .# Animals su IT e r "fox ic .effects from 2 ,4 ,S-l in dosages d ranging It'om 10 mi I Igr ains per k i l o g r a m olv body weigh! per d a y u.u'tdw <! !<.<s ul 2 , 4 ) ^ - 1 t o x i c i t y . V.iri.il oris arc expect `tl hy (IiI'lVn m < will.... s i x ^ c i o s - a 1l e r n . i t . e m od es of' c h e m i c a l ent * ml. Mi. '...Hv .ml v a i i a h l o I <-n^( ls o f l i i n c Tor t il e d u r a t i o n ol (.lie -pxer.i m.-Mi . II.i>. i s iii.nlain<Mit a I t o a ny l ox i eo I of^i c a l i n v c s t i f i . i l i n n . A I .1,.. .I cli<-in i c a I t o x i n w i l l p r o l ' o u n d J y a f f e c t an a n i m a l m - 11<>i-1 i m<. I wm s t u d i e s <ui it* l o x i c i t y ol * TCDD a r e p . i r t u i r l . p i \ n o t e w o r t h y - ( l ) 1 t w o \ e a i d u d v d e l . a i l i n g t l u* r l i n i i m \ p u -*u. o f TCDD i n S 1 1 1 D.nv I r y 11! h > K< >r 1 I)il e l i1 l . ( J i a 11 i *on 1 . stai d y d e s t r i h i 1 1;; I o 1te - t < n. 1 n \ 1 e l l o r t. s o l TC 1) 1) i n KI u -a i >> hi ai k * *-, h \ A I Iell and Van M i l l e r . ^ All n and Van M. I Ie r ( l ' ) 7 7 ) "Mor pi u >Io/l; i e. a I eiiuu;.. i n m o n k e y s < onsi.im i 11", a d i e d 1 <ai l a i 11 i n; low I.eve* 1s ok ? , 4 , r> 1 ei 1 1 c h Io r o d i l ) e t i / o - p - d i ox i 1 1 I nod (,'osm. T o \ M I S : 4 111- 4 I11 . Tin \ Inmsed I(\adult Rhesus monkeys eaeli we 1 h .n*' in an environment sinmlatinv, their natural habitat durin. the mahii m /l; season. lor six months, invest, i^at ors morri tnrrcj nenrr. } .health and heiruito Io/n ic; values and estab Ii shed control parameters Tor the study. At the end ol* t i n t s time they divided the numki \.- into two groups ol ei^ht animals each. One j^roup was pJa-ced on a diet LU J C jo= lu H* o E a ce 0- < y containing *500 ppt TCDD. T h e other mroup at e an ident i< a I d n * without TCDD. Food intake was quant itated lor each ^rmip o u t a nine month period ol < me. Al'ler six months on tin- e xpe r 1 m< id a I diet, the I'emalers were mated w.i Mi mah^s liom (hr Control -raip. A l t e r n i n e m o n t h s t h e exper* i m en t il a n i m a l s < a^etl cat i niz t h e 1(1)1) c ol d am i h a t e d client and invested a c o n t r o l d i id I'o r an add i t lo ii al t h r e e m o n t h s . R e s e a r c h e r s e s t i m a t e d t o t a l TCDD l e v e l s ?o r ll i c s r aiiMiial.s at ^ . S 1 n.Mji* a l t e r t h r e e m o n t h s , I I . 4 l . ' i * six mmd lis and I 7 . d - 2 . Op/* In I lowin'.', n i n e m o n t h s on l In di - ; . r. 9 - 4 7 9 . 3 t* # Alter three months on the diet, monkeys developed pe r*i orb i t a J edema, loss ol Lacial ha ir and eye Lashes , aene, a c c e n tu a te d hair -to H i d e s and dry scaly skin. After six mont hs these! c l au s es became prominent in six o f the eight animals concerned. A< llie six m o n t h a n a l y s i s m o n k e y s also experienced a decreased--'' h a e m o g l o b i n and 1aeiiiatocr i t (an de cr eas e in red cells). . These lo w er ed h a e m a t u l u ^ i al pa ra me t e r s became especially ! 'e x a g g e r a t e d in si x ol' the s ev en m o n k e y s that survived the nine 'mouths -on experimental' treatment . Ani ma ls in the experijuental g r o u p lost weight d e s p i t e 'no ch an g e in feeding* habits. Alter seven months, one monkey became severely | p.m < y ( o p m ic . Trior to dou tli 11 u: ani ma I bad virtually no p lat ele ts or immaturi! red or white! blood cells. In the following four mo n t h s four add 1 t ional m o n k o y s e x p e r i e n c e d similar* clinical changes and died. Of tile ani mal s that s u r v i v e d -the regime all displayed .significant hair loss and periorbital edema. During the twelfth I and final month of the study, one monkey developed a reduction in lu( h pi ate Lets and white h Iood cells. Au topsy findings re ve a l ed "several areas of damage Ir<*in ft 1)1) ex posu r e . local areas ol hae mo rrh ag e appeared in the ^k iii, .heart, lung and stomach, intestine, adrenals, skeletal Fj o r 8" w ft u U ro oc CL mu.se u .1 a tu r e , bruin and bone marrow. 1`inger nai Is and toe nails grew ir regul arly, often accompani ed by gaugreoUs necrosis (i.e. death til cel is su rro un d ed by living tissue;). They also suffered from asc.i tes (an abnormal -collection o f . s e r o u s fluid in the peritoneal c av ity , ii is seen iu case's of carcinoma, 3UJ tub erc u 1 osi s and othe r c h r o n i c i n f diminutions of the peritoneum) D and su bc u t a n e o u s - e d e m a H y p e r t r o p h y , ' d i l a t i o n ,edema, and hydropi c (/) degeiier.il ion of the m y o c a r d i u m o c c u r r ed in all the animals. The hi Iary .duels showed m a r k e d d i l a t i o n without associated ja undice K.. 1 epith.el i(ini of the .urinary Tract anti uex-fcs ui uu: pai.penrui conjunct.i va<i (tlu! conjunctiva of the eyelids). They coiic Jtided that the primary target area for TCDD i n non-humuu p r i m a t e s (iimn kr ys I i s I he hae me t.o po e t i c ( 1)1 ood producing) s y s t em' * As e x p o s u r e I.c n/ i ' t hci i s' cellular degeneration involving the lymphoid sy stem, i t s puns ih Ie lor the formation of white blood cells (Jeuko< y 1e.s ) and bone marrow responsible for red blood cells (erythrocyte) format ion, increases in s(`Vrrity. In additional atrophy o! (In* th vinus sp !eon and lymph nodes also occur. Allen and Van Mil h `i` a ss ert Ihat there is consid er abl e d iI Ieponces in_._t.he level ot !'t`I)I) -necessary to produce iuioxicat ion. The LD^ ran^i' o I St 71)11 body weight roilmvf; ' 'death in ol the test animals in an acute space of time, a co ns iderably .lower dose ut .Ipff TCDD per l</^ body weight wi 1 J a Isn yield the same results when adniini ste red c o nt i nu ou sly over a nine month period. Al len and Van M i ll e r also demonstrat e lhat tlu* pathological cha ng es Caused' by the two (lose Ieve Is remained- quite similar. T he ref or e Iliev he Iieve their data indicate that, exposure' to. 'ext-reiue ly low c oncenf rat. ioils ol TCDD 01 produce widespread del.etar i.ous effects 1n pr imat e s . ' 11 Koc i1>a, K ..J . << al . Results f' a ?. year chronic toxici (y and oiu-oien ix< study <> '>.' 7 8-T*L rach J-oi*o<l i1><;h/.o-- p--'tliox:i.n in rats. Tox. ami A|>[>! . iMiarin. .)h ; 2 7*0 - 1 <).1 , Id 78. C24731 SU BJFfT tn DD^Tr/*+M ri-- 'llVcy placed male and fc'inule Spraune- Dawley rats a/^ed six to seven weeks into suspen de d wire hot lorn < af;es. I .ed and water were', available to Uie animals ad .libitum.' Gr.oups of l<"> iat s (SO males, 50 females) invested a diet that contained 0. I , 0 . 0 1 , :O/OOlUfiTroD/Ki'/day for up to two years. The. diet of the emit m l firou)) (P6 males, P6 females) .172 rats contained only tin- -carrier, no TCDD. The TCDD was provided by Dow chemical (vompany and had 1 purity exceeding 99 perernt a s d e t e r m i n e d by (dvcl t'oii capturr gas chromatography. body weight and food co ns um p t i on niild m al es aiid In females at each treatment level worn routinely recorded for each week of .the first three m o nt h s of the study and monthly intervals .tlierea It e r . Eight, rats per sex gro up provided blood sampler for- hiiemafo] og Leal investigation at three, twelve and twenty three mo n t h s of treatment. Urine s am ple s were col 1ected from seven to eight rats per sex per group at these same t i m e levels to det er m in e -specific- gravity, pH, sugar prut; -in, ketones, hi Jfirubiu, ad oCru.lt blood. At terminal necropsy, investigators collected, serum samples .from all survivors or - m a x i m u m of 10 rats per sex gr oup for determ inat. ion . A H rats dying or killed during the course of the study underwent gross p a th ol ogi c investi git ion and represent at i v< .s portions of major organs and any lesion suggestive of a significant pathologic pr ocess or tumour formation -were preserved- ift I 0% formal in . SUBJECT TO PROTECTIVE ORDER. G24732 t 13 Terminal necropsy e x a m i n a t i o n took place at klir end of two years of treatment. The w e i g h t s of the liver, l.idney, brain, heart, thymus, spleen, testes and ovaries/uterus were recorded for a ma xim um of 10 rats per sex per group. hone mar row smea rs from most rats were also prepared. They ilso fro/.e p o r t i o n s of fat, liver and kidney from a -maximum of five rats per sox jvr group for possible* TCDD analysis. All rats from the control and the high dose love I regardless of whether they died, dur ing tin* c ou rse of tin* study or were killed upon its completion, un de rw e n t h i s t o l o g i c invest igat ion of an extensive "list of ti s s u es int(Mulcil tn include a m a j o r i t y of those tissues ^listed above and those col lected at tin* time of terminal n e c r o p s y . All rats from the lower dose; l ev els were subjected to histological examination of those selected, tissues identified as possible target area organs in addition to gross lesions suggestive of tumor formation. They found at the c o n c l u s i o n of the study (l ) conii nuous ingest ion of di (its. cont ai ni ng approx imate? Jy 2200 ppt, T C D D (0 . lug/kg./da'y) for* two -years' caused m u l t i p l e toxic effects, including increased mortality, de cr ea s e d body we ig h t gain, slight, depression of certain haenuitological parameters, increased urinary Of ^excretion of porphyrins and A-amino levulinic acid. Increased ca serum ictivi ties ol Ap, GGT, and SGPT ind m o r p h o l o g i c a l changes LU > , ; p;pr;imari l.y ol the hrpat ic: lymphoid respiratory and vascular tissue <J H<>f t he hodv. T h is h igh d o se -le v e l seem ed to re d u c e th e i nr i d eu ce Os CC a,and severity ol chronic renal''disease in aged male r ats. IVmale rats gi ven this high dose -for two ye a rs had 24,ono ppt T(l)l) 2Lj present' in the liver. Thi s' .compares with 34,600' ppt. T C D D present 3 i n Mio liver ol Iema Ie rat s g.iven t h i s dos o l'r 1 liiiloon week.-,, IIiiis .jml ic:iting aitai runeiit ol s1.r:ady state c o n c e n t r a t i o n in (.lie early t4 14 - Jripest ion o I (1 * ini rrnirdialc dose IcV(`l ni o V_> .u.nrji Tcnn/kii/tlay {approximate Iy IMO ppt. in cheti :aus<-(l a lesser decree ol' toxicity. Iloro rvsiMi't li found: 1. increased urinary e x a c t i<n <>l propliy ri ns (toma Ics) 2. '1 Ivor ,toxicity, i.nclud im /A* an j u c r e a s e d iih idtMico o I* hepatocellular nodules 3 . incniasoil i nei de ne e od' Focal a l v e o l a r h y p e r p l a s i a in the luii^s. Terminal liver and lai c o n t e n t ol* TCDD av eraged 5 1 00 and I700 ppt , resper I ive Iy . This c o m p a r e s with 3 ?()(> ppt present in the I iver alter thir te en weeks at tills dose level . L ilet imi' Lii/'estion at a doso of 0.00 JPg/kg/day approx. 22 ppt in the diet.) caused no eTFects considered to be ol toxi col og:i ca 1 s ig n iI ic a m e . The I iver and fat -each contained 540 ppt of TCDD at. the end ol I ilet me ingestion at this low level. Koc i ha et al demons lrate d a dost; re Jatod tpx ic response to TCD1). At the low(`sl levels ol' T C D D tested, 0 . oof ug /k g /d ay tlie authors could find no toxic: r e s p o n se attributable* to the* i nc l u s i o n of TC DD in daily diet v v i m i to rats over a t w o year period-of time. CONFIDENTIAL ', luxici 1y Summary ; SUBJECT TO PROTECTIVE ORDER. TCDD inevitably c o n t a m i n a t e s 2 , 4 , S-T, no cons iderat ion ol toxicity ol idle herbi cide w i tho ut p r op e r att (*nt ion to the toxicity ol Idle contaminate 'I'CDD can be cons idered complete. 2 , 4 ,I Toxic response. ;to S--T and TGDI)S vary among and 1 . 50 wit hi n speci es. Id) values For 2 , 4 , 5~T rang e From a single <Mimg/kg j alose in tile (lor (acid Form) fo 5<)0 in the rat (arid Iorni ). In the ora ! mixed butyl csl.-r lorin ol ?*,4,'5'-T,- t h e m o u s e oxhi h it s an I of 1 4`)0nifi/kfi-,siu/n I doso. C84734 |.0 f TCDI) tIk - i'of the. g u i n e a p iiA is 0 . <Mi/ ' l r .. Tlx; mou.si Ii.'im a M)^*- Do s ,,,,w,`Vnl' show no .-II.m I a I d o s e s a s li i mil a s 1unjin-'ku. 1 0 ^ l o r dotfs -is .?*<<>M / I nit i.iV tuxii r e s p o n se <o 2 ,4 ,5 -'I ap pe a r s at dns.i^ vs of I0mg./kg in the (log and escal ales to i4#()mg/kg .in the mouse. W(` i ght. Io s s , mu s o Ie w e a k n e s s and a c c o m p a n y i n g 1 i s s u c c h a n g e s rep.i/osemt t h e most r rumhi e l I ect..s o I 2 , 4 , 1" I t o x i c i t y . In a (lii'uii i c two year st udy d e t a i l i n g U n i r l T c e l s ol 7 , 4 , S-T <>ii S p r a m i i c - D a w l e y r a t s , k n e i h a e l a l . ( l D 7 lH a s c e r t a i n e d a l e v e l (.lm g/k g) where t h e an.i m a ts exit i l u t e d no t o x i c e f f e c t s from c h r o n i c e x p o s u r e t o 7 , 4 , S- T H o w e v e r t.lie* h e r h i e i d e u s e d in t h i s p r o j e c t was p u r i f i e d 2 , 4 , *>-1 e e m t a i u i n g O. } ppl> It 1)1). r.emiii^rr i a I samp I e s o f t he * eh e*mi 4a I r o u t i n e l y e o 11( a i n O . I p | mi T(! 1)1) The thymus and to a lossfr degree, the Lymphoid t issue and bone marrow ( including hematological dyscrasias derived from damage there) are the primary areas which exhibit a toxic response to TCDI). Mice arc least s en si ti ve to T C D D ^ s toxic effects.. Guinea pigs and chicks .suffer the great est a d ver se effects. Initial toxic response appears after single, (loses of jpg/kg' in the gu inea pi and up to a (lose of lOOpg/kg in the rat.' Exposure of Rhesus monkery to ppt TCDI) in t.he diet reported by Allen and Van M i l l e r ( 1 0 7 7 ). The autho rs deta ile d toxic: changcs Icadi rig to death in fi ve of the* eight m o n k e y s studied, after what they d et er mi ne d to be d a i l y do se s of 2 - 1 pg/kg -TCDI) for* a chronic period of time*. Allen and Van M i l l e r .sugge.sled that, (lie el Ieels no! ed in tlie ir experi merit para I I<led the changes e?pxer ienced alt er a single* a d m i n i s t r a t i o n of an acute* I.C dese* of <)n-70pg A g . CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C24735 I# 16 Kocili.i d .al ( I`>7H } c o n c i l i c i cd a two y e a r l i r n i c l o x i r i l on S ora tn u -Dawl oy r a t s . Tliosr r-xp.-r i mriiLs doso (0..001 UK/k ) can sod no o fleet's of loxicoloeic.il si^ni licaucc. Tor toni'ii ic i1y : (Ma! i n r m a l ion.; in t h e Ol I' spr iup . The d i sc: i p I i no o-I 1 orat,c> Io o y oncomp.iNSos litro- categories..; Causes, meclian isms and m a n i f es t a t io n s . A causiis an exte rna l element capable ol o I.ic ll :iug a doli-iincut a I * lian.rp(t o r a t o g m i e ago.ni ). Those* agents act in spccil ir ways (nirrli.mi m m > i . on devoloping c o l l s . M e c h a n i s m s all interact at Ilio r a d i o s i st a y s of development involving many cellular iirocosses and on v i ronmonl a I c o n d i t i o n s . Up t o Day 17 a I't o r r o n e r p t i o n tri humans tlioro o c c u r s a "r ot ra ct ory pori od". Fruiti day 1^ to day |0 tlio cinlM-yu liccomcs very su scc pt i bl o to ou ts i d o inter ferenc.o. At Lli is stage th oarly statfos of tassili! a n d or#an d i f f o r o n t ia f ion t a l c o p I an* ( from castro 1at iun to or/L^an di I fononi. ial iori ) . Tlioroa I(c o 1 ho -rnI>ry o sliows an inricas in^- ros ist aito.o to fo oa (0^011 io l'oroos a.s orttano/_p*no.sis advanoos In rompi r U un in rlays ^^ t- (i in man In mi day <l **11<*<*jI imi J ii all s p ec ie s tin* p e r i o d ol or'^ario^rnosi s rrm,i ins riiosl f r a g i 11* l o mil siili t c r a t o ^ r n i r i n l l u r r i r n s . Upon c n u i p l o l i o n ol or^aiKi^ciicsi s , o u t s id e in f lu e n c e s can general* an ad verse change, h u t those* a r o u s u a l ly in t h o form o f g r o w t h or* l u m i i nda I a l l i b r a i i o n s SUBJECT TO PROTECTIVE ORDER. - 17 - Wi Isoli, . ) . ( ! . l'.nv ii'iiiiiikmi Ia I and liir*f11 Di'IVi I s, A< adoni j < I V o s s , NoW Yoi U .imi I.orni..11, W i l s o n I j s t .s <> i i o r u T a l i s a l i o n s ni tonai- I'ha i< s u s o p l .ibi l.i.ty . I. s u s c c p l . i bi I i t.y la* ( ni a l n i 'v i i c s i s d o p o n d s n UVc gcno-t.yp<^ ol' t l u : c o n c o p t u s a n d Mi o i n . i i m n r i n w l i i c h t h i s ;i n t e i ac t s w i t . l i a d v t r s c eh v ju'onmenl a I ! urs. ? . s u s c ej>t. i b i I i t y l o I d T . i l i < v i i i ' s i s vai* i c s w i t h t h d c v r J o p n u i n t a l ni I n n Is i a ^ r ai ( lc I ime e x |><imi r e dii a d v i T . s r i l i k m h e . 3 . t ci'al <mvn i <: ascili s a d i n .^|>e< i l i < ways ( mcchaii i s i i i s ) 011 (lc.V('Jopj ii cVclls and l i s s v i e s 1n ini ti al e . ^ c q u e n r e s oi' ahiiuniia I devel.opmental e v e n i s ( pai h o / ^ e n r s is I . 4 . I In* a c c c s s <>! a'd v e r s e ini* I n e r i r e I n d e ve I<>p i nv I i s s i h v s d e p e n d s on l III* naturi* o! t h i ni l u e n e e ( a / p %nl. I ^. t h I ni r inaili T o s t a i .i oiis ni ahnnrirtal de ve Io|>m< n I . i r e d e a l ma I Id nn a i i o i v s , /^rowtli rei. a r d a ! i mi and l i u u l i olia I d e l i il . h. mani T e s t a t i o n & oT abnormal eie ve 1opmeni in e rea>.e- in Tre<|uenry and de/"ree as -.(Insalo inereases l'rom th no e l l ei I leve! in th tota 1J y letlial I eve.l A l i n o s i a n y e h e m i e a l s o l i s i a n c e p o s s r s M ' . s a I e i .i l " i-n i < p n l e n l i a l wlien adm i 11 i s I <*r e d i n r x c e s s a m o u n l s d u i i n;> a -a i j I i I . I < o l d e v e I npruent . A b i ' o a d s p e o t r u m n i r n i i i p n i i i i d s a r e r r s | ) ( n s i I l e or a m y ria d o l b io ln / ;i( al and eh em ieal e l T e e t s . CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. r is - Somo types of Drugs and other chemicals that have been shown to-be tera to gcn ic in one or more species of laboratory a n i m a l . Drug typo salicylates certain alkaloids tranquilizers antihistamines antibiotics hypoglycemics steroid hormones alkylating agents antimalerials anesthetics int imetabol i ties .solvents pest icidco industrial effeluent mi sc el 1 aneou s Lxanipl es aspr.in, oil of wintergreen ca ffeino , nicotine , colchicine nieproh mate, chlorproina/J ne, reserpine hue Ii/ ine , mccli/ine , cyclizine eh Ioi ampheii ieo I, streptmye in tponri IIui, tot raeycl c a r h u l a m i d e , toihut a m i d e , hypoglye ins tri amcj noinruj, cortisone, te st os t er o ne busu 1 fan, chlorambucil, eye]ophosphemide chloroqu ine , qiiinacrine , pyriinet.hami ne halothane, urethane, nitrous oxide, pentobarbi folic acid^ purine, ind pyrimidine a n a l o g s benzene, di m e th y l s u l foxide, pr op yle ne g l y c o l . 2 , 4 , S-T, carharyl , captan, folpet some c o m p o u n d s of Hg, Pb, As, Li, Cd. trypan blue, tryparariol, d i:i;uox T er at o g e n i c effects we r e u s u a l l y seen only at. d o s e s well above t h e r a p e u t i c levels for t h e drugs, above or likely exposure levels for the environmental chemicals. Source Wilson, J .Cm Handbook ol' terato lo gy Vo , I . General p ri nci ple s and et i o I o g y , Jani(*s W i l s o n , Clarke I'rascr (eds),v Plenum Press, Now York and London, 1077. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. e 19 Wilson in his bo ok liivironiin-til ;md U i H h D< l. ls ( IU7.1I .igcnt in man. or association of defects ?. co in c id en c e of this i n c r e a s e w i th a kn o wn on v iroiuuoiil .<I eh.mgo-, i.o. wi clos p re ad use; of a n o w d r u g 3. known e xp os u r e t o tin; environmental, elianto early in prognaiu io'. yielding characteristically defective infants 4. absence of other factors c o m m o n to all pregnancies y i e ld in g infants with the characteristic defect Since c he mi ca l r e s p o n s e v a ri e s with dosage route ol a d m i n i s t ra ti o n end p a r t i c u l a r agent, 'Wilson ( 1977 ) opcit. has ' Y .established criteria, and c a t e g o r i e s for c l a s s i f y i n g chemical., accordi nr to tJu'i r (Mnlvryotox ic ( c a u s i n g damage- in ea rl y pregnancy ') potent jal f (assu ming (`X p o s u n * to t h e r a p e u t i c or h i g h e r dosi* duri oil; 1 st trimester) in man, I. establ ished as being e m b r y o t o x i o (a V 11n<pirsi, i<>nai> Iy p r o d u c e s a liigher percepii age n drvrl opulenta I UJ a O lii 2. .det ect s or i n t r a u t e r i n e deiith in infants of exposed women t h a n otherwi sc simi.lar noru'xposed womrii. suspected of b e i ng embryotoxic SUBJECT TO PROTECTIV! (a) apparent increase a b o v e b a c k g r o u n d level of developmental d e f e c t s or* i i\t r a n t e r i n e d e a t h a m o n g i n f a n t s <>l r x p o s r d w o m e n , based on large nu m b e rs 4)1* ac c um ula ted case reports, (b) retrosper I ive '.surveys indicate sign tfj ant iiirren.se <ii delects or death among infants of e x p o s e d women, but "memory bi.is" ol m o t h e r s i ut r od io e s uin e r l a i nt,y G2 4 7 3 9 ( c ) p r o s p e c t i v e s u r v e y s i ud i <--ate s i g n i f i c a n t iiu l e a s e <11114llg - ?1 - Numerous studies have; been conducted, lutai ling the Lefatogenic embryotoxic and fetotoxic e f fects generated by 2,4,S-T and its contaminant dioxin. Researchers, experimented with a va ri e ty of species and ha ve d e m o n s t r a t e d both r.o effect and lethal levels in many cases. The prime target areas for teratogenic response from 2,4,5--T and dioxin arc cleft palate and kidney anomalies. Mutagenicity The ability of a s u b s t a n c e to induce genet ic u Iter.it ions . Because of the si mi la r it i e s of basic: m o l e c u l a r me c ha n i s ms by which chemical mutagens; and'most chemical carcinogens appear to induce genetic effects (i.e. molecular lateral ization of DNA) researchers l. postulate that mutagenic effects can be predictive of carcinogencity - - Scientists rely on short term tests to indicate the mutagenic potential, a chemical possesses. These tests include: 1. tests for mu t a ti on in b a c t e r i a and e u ka ry oti c m i cr o o r g a n i s m s 2. tests for m ut a t i o n s in somatic m a m m a l i a n cells 3. tests on chromosomal effects' in h ig her eukaryot es incluidng nuimmals. 4. ev a lu at i on of DNA re pair synthe si s. All of the 2 , 4 , 5-T m u t a g e n i c i t y studies have drawn either negative or inconclusive results in tests covering primary DNA damage, gene mutations and chromosome effects. The scientific dispute resolution conference on 2 , 4 , 5-T, 1979 August, stated that \ reasonably adequate experimental data has been generated regarding 2 , 4 , S^T and that these data are not suggestive of 2,4,5-T induced mutagenic activity. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER CS474 *v 72 The s ci ent ifi c dispute* re so lution coitfcrcnc.e uiv : 2,4, S-T 9 7 9 'also felt t hat results from several microbial si iKlic.-, have de t er mi n ed that T C D D i n cr e a s e s the frequency of gone nuta ions. M i c r o b i a l data suggests that DNA repair processes ar e involved in lhe ''mechanism ol action since no m u ta g e n i c effects can be elicited m s tud i(;s u s i n g repair do! t*ck.l vc hue tori al st rains . Iho bael -'a <lal a s u g g e s t s that TCDD acts as a direc t initiator ol' ma lignant transformation since most mutagenic carcinogens afe of the initiator class. Few promoters or cocarcinogens show mutagenic activity. Carcinogenicity Animal model studies- have long been used l'or pi*edict.ing c a r c i n o g e n i c potential in man. The species of animals used in these studies must bo as carefully considered as the data resulting from th e experiment. R o d e n t s 'm e e t c e r t a i n s p ec i f i c a t i o n s that ma ke them t. highly desirable for carcinogenicity experiments. Their lifespan is short - which allows the dullest expression of a positive c a r c i n o g e n i c response. Roden ts are small, relatively inexpen si ve, easily bred, all of which encourage largo study samples and .confirmation of test results by other investigators. Yet res ult s obtained u s i n g rats or mice caiiiiot be U n e q u i v o c a l l y adapted to m an .because of ce rt a i n h io Iog iea I <Ji ITereneo.s.. Se con d the S p r a g u e - D n w Ioy rat and several m o u s e stra.i 11?; noted for* thoi i* high rale of s p o n t a n e o u s lumai' in ci d e nc e are -often used in "those ex per im e nt s so care must he taken to di s cr i m i na t e hoi ween sp o n t a n e o u s tumors and those ca used by c a rc in oR cn ic mechanisms. Also .1 c a r c i n o g e n i c responsi* ca n become apparent long al ter -the- original c an ce r c a us i ng stimu lus has boon removed. Maini festal i011s of cellular alt 'rations can taka ye ar s to d e v e l o p -- By th e tim a care iriogen ic i ' 25 % l)(!tuuso Lila L woul d not i iL with the cl as sic cart, iriogon ic. mechanism. All these factors must ho c o n s i d e r e d when ana 1y/i ng a chemical for its possible; c a rc i no ge nic properties. Research conducted on animal models lor potential carcinogenic effects of 2 ,4 ,5-T have failed to yield positive results The E.P.A. C ar c i n o g e n Assessment group, re port in February l`>79 ack no wl ed g ed these conclusions. "On th e ba s is ol the c o mp let ed mice and rat studies there is no significant evidence of c a r c in o ge ni c it y for 2 , 4 , 5-`f" They added however, that t e st i ng had not been done s u f f i c i e n ( 1y in mice." TCPD is an extrmely potent inducer of hepatic aryl h y d r o c a r b o n -(AIIH) activity in the rat -(see Poland & G l o v e r "Compa ri so n of 2 , 3 , 7 , B-tetrachloroben/.o-p'-dioxin - a po tent indu cer ol aryl hydrocarbon hydroxylase with 3-meLhyJeholcuthreno," M o l e c . P h a r m a c o l .. 1 0 ; 349-359, 1974). This enzym e s y st e m is propo se d as the promoter of carcinogenic- activity. Fur th er ,. in the prese nc e o<v known c ar ci no ge n DM SO,- TC DD is weak tumor initiator in the two stage system of mouse* sk in t u m o r g e n e s is . OTECTIVE ORDER. Investigations of the carcinogenic potential of TCDD 'have produ ced d ose -d epe nd en t results. At r e l a t i v e l y h i g h , long te rm doses, a diet containing TCDD has been found to cause increased i nc id en c e -of liver and lung tumor as well as nasal turbi nat . Ct palate tumors in ce rtain rat. species. e Two animal studies'-arc* important, in l.lie anal ys is I-- [jj of care inogenes is potential of TCDD. 03 --3 I a two y;ar chronic st udy by Kocib a et al, 1 9 7 8 . Tox. and Appl. Pliarm., 4 6 , 279-303, i7,1 2. A 78 we<*k inv<;.sl igat imi conducted by Van Miller e.t al. II Increas`d incide nce <if neoplasms in rats expos1! L<> Iw I-v<;I - 24 - ]n both studies Sprague-Dawl ey rat s won* used. At slie 111 ghes l d o s a g e tested Choir (xporiiiumls yi.ldr.l im . la, i v .m i I(... At highly toxic levels ot 2200 p p t and 5<l(' |>|* . re-spec li v*l y lI.. .< reports documented an increase in Uu; inejd.nce .I 1i vee and lung. 'tumors in Sprague-Dawley r a t s . At the tower dose levels .their results dithered.* Kocibas group considered 'the-lower dose ranges negative, lor ca r ci nog en ic effect citing the a p p e a r a n c e of hepatic Itypeep last it mod ul e s from a medium dose as l.lie only c e l l u l a r change observed. - Van Miller reported significant carcinogenic potential at doses well belo w the 500 ppt dose. Tumors, lie claimed, app eared wit h TCDD levels of 1000 ppt, 500 ppt, 50 ppt and 5 p p t . Only at 1 ppt did Van Mi H e r acknowledge no chemical related effects. There have been- sev er al c r i t i c i s m s of Van Mil ler* irivcst igat iin. Tin; carc in oge n as s es s m e nt g r o u p au di ted the study and found that, it had maj o r s h o r t c o m i n g s in d e s i g n and conduct, that limited the re liability of da ta d e ve l o p e d at dose l e ve l s lower than 100 ppt (KPA 1977). Therefore its carcinogenic effects could ui D only be verified at the two highest dose levels. In additi on the ("* uj z _3L-, > ld w OEZ0 *115O- Vr \ w " in ve st ig ato rs in the study reported no t um ors in the control animal a highly .-unlikely phenomenon, when u s i n g S p r a g u e - D a w Iey rats" (HP A, 1979). This st.rain of rats is p a r t i c u l a r l y s u sc e p t i b l e to spontaneous tumor induction and lack of tumors in controls is hi g hl y suspect. Also the areas of t u m o r i n d u c t i o n at lower dost.* ranges of TCDD did not correlate with the epxectied target organs de t e r m i n e d from the higher* dose s - i.e. lung and liver. Also tlve exp eri me nt only involved 10 a n i m a l s per test, group. Thi s small nu mbe r is below, the mi ni mu m number r e c o m m e n d e d .by (lie Nat iotial Cancer Institute. C2'jt74a 2s - The Kociba sl-mly lias also been triti sod. k o o i b a o( >t| ilound b y p o r piastir aJ ti-rat imis r. tbo Jivor at (bo 2 IO pp( d o s o and cons id ere d ibis a nomati vo fimii iitf. In an audit 0 t tin- Kociba study by the C a r e i n o e o n .isstissmont firi'Upj.-a. coni l i t i ol t. Lass i I i cat i on of hyp er pl ast ic nodules became evident. The CAG f^roup re -- ovai uated the study and concluded that the co m b i ne d i n c i d e n c e oi Itcpcbocel luiar hyperplastic nodules and the hepatocellular carcinomas is s t a t i s t icai ly sigili licant for both the 22 0 0 ppt and 2 10 ppt levoL. Studies by llirota and W i l l i a m s 1979 - Persi sto nee and Growth of Rat Liver Neoplastic; Nodules Following Cessai ion of Care in og e n Ex posure .M J . NC I 6.1 ( ^ ), 1257-1 2 6 5 j 1979 - Tli.y 1nvestig ate d the persistence and gr o wt h oi* rat .neoplasms and concluded-, that these 'nodules 'represent a d i f f e r e n t type ol '--neoplasm than, ca r ci no m a possibly a benign neoplasm. They assert that these neoplastic nodules are not obligatory., precursors of cure.inuma and may in fact he; at a stagi* in ne o pl a s t ic d e v e l o p m e n t that is Iess au to no m ou s than carcinoma. tilt*ir i nterpret ati on oi* nodu le t h e r e i n ' is an end stage, benign ne oplasm that is c a p a b l e of c o n t i n u e d growl'll hut is not. invasivi or m e t as t a t ic and may only :inl requent Iy aujuire these [roper I ie s . In tliej r sl.mly, Hie aii( liot-s d e t e c t e d no transition of nodules to carcinomas. At i n t e rv a l s .after cessai ion ol* carcinogen exposure, .nodules displayed changes suggestive of phenotype reversion or degenerati on that were not present in carcinomas. 'Those who support the K o c i b a c o n c l u s i o n i'avour this i nt er pr e ta t io n ol hyperp IaM,.i c .nodul es as n o n - p r o o f of carcinogenicity'.' ,, Further support, lor such ra ti ona le lies in the -lack of c a rc i n o g e n i c c h a r o! nodules to tumors within the two year test period ol t h e kneiha et al s t u d y . C24744 o b j e c t to p r o tec t iv e o r d e r 26 - The EPA, FI FRA Scienti lie Advis or y Pane] , 'Review ol* Vi fr aScclion 6 (6 ) 2 A ct io n on 2 , 4 , 5-T and Silvcx, Srpl ember 27, Also has reservations as to w h e t h e r hy pe rpl as tic nodules are precursors , per se ol hepatocel lutai cui c.i)ionia HUMAN l-XPF.U IKNC I- 'WITH 2,4 > 5-T and TCDD 1. Dow chemical pLant wor kers. .The study e x a m i n e s the m o r t al i t y ol 204 persons exposed to 2 , 4 , 5-T during its manul'acturr from 195^ to 1971 at the Dow chemical, pl ant, in M id l a n d M ichigan. The h e al t h status of 2 , 4 , 5-T wo rkers exposed for a period-of over 'one year. In ve s t ig a t o rs c o nc e n t r a t e d on the cr ew directly involved in the 2 ,4 , 5-T m a n u fa c t u re 'process. In general, at exposure c o n c e n t r t ion of 2 , 4 , 5-T (c o n t a i ning less than 1 ppm T C D D ) 'experienced by the wo rk m e n in-the study, no ad-verso mortality effects have been o b se r v e d al tri Imtub'J < to (lie work e n v i r o n m e n t . M ort al ity c o m p a r e d well with that of all U.S. whit.- males arid also comp are s well with the b a ck gr ou nd m o r t a l i t y e x p er i en ce in the geo g ra p hi ca l area see Ott et, a l . "A M o rt a l i t y analysis of e m pl oy ees engaged in the m a n uf ac t ur e of 2 ,4 , 5- Tr ich lb ro p h e no x y a co t i c acid ." . H .J i t M e d . 12 ( I ) 47-SHj 1*1^0. T h e sing]* o b se rv ed r an cor deat h oeeurrod as a re};; ll of respi I'atory ma l ig n a n cy d is< o vot-ed in a (\.\ year old retiree who had boon e x p o s e d to 2 , 4 , r)-T lor eight, years. The employee also had a past history of smoking up.to two packs of cigarettes per day. 2. Monsant o plant accident , Nitro, West. Virginia A st udy 'ol the c h r o n i c heaLth <;|'lV(i ,s of ex p o su re to IDD as rel lee.t-ed in tI<* mortal it.y ex p er i e n eo of a gro up ol moiisanlo C24'/,4workers who de vc Ioped symptoms of ehloracne loi lowing a c) t.r ieh Iorophenol process a c c id en t in Nitro, V/ost Virginia, |`>4 9 . SUBJECT TO PROTECTIVE ORDER. 0-' <t 27 ('hlotucnu is a skin di sease characl cii.MHl hy e< >m<d. .n>, , cysts, pu.slulcs and abscesses. Ac co m p an y i n g j.hi.s may be h< pali< d y s f u n c t i o n ( impa iimnnt of function of tin- Ii.vci V per iplu-ia I n e u r i l U (paralysis (il tin- Iac ia I imrvo) disorders' of fa I me ta bolism and pti rpli.vr ia< n fa m -a l.ucl.i, a chronic skin lesion (.-inlilion < nosed by (lie (Iisi urbane <-s in pro pb y r in metabolism. Cbloraciu is pr imari ly assoei ifrd wit h expo su re to TCDD. In March- 1949 * a reaction accident .-occurred al llie plant d i s c h a r g i n g TC1)1) -into U `Ye at mosphere and interior ol the Inn Idiu Krnpl oyees involve d in i lie p r e l i m i n a r y c l e a n u p (Ii'VrInpcd immediate symptoms - iin hiding eye and iv s p i.rato i v t i a< l iiriLa* ion, headache, di //ness and nausea and severe irril.ml react ion ol* e xp os ed skin. Alter these symp to ms subsided c hl ora cne symptoms appeared. A four, year follow up revealed I. acne from lesions,. 2. severe pains in muscl es o f `upper and lower e xt rein iL ies , should ers and thorax on rxert-inn 3. Iil i^uo ,norvoiisnrss and irrj (.ability 4. decrease ol Ijb.ido ^ . dyspnoea, (>. vi?ri i;;o and intolerance to cold. One year alter the a c c i d e n t ,four of the six workers ex*'iminoci bad liver enlargement. Also found were liver impai rment i n d i ca te d by h e p a t o m e g a 1y ( J iver enlargementV, tenderness in the right u pp er quadrant and ep i^as(-ri um and a delayed pro tb mini) in t ime . examined. 1953* tour of the six original workers were again v Investigators observed a general regression of. both cutaneous and non cutaneous symptoms. All workers exhibited, a marked improvement in their skin lesions.' C247 IS CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. m* 2K - f 11h * Journal of O c c u p a t i o n a l Med.it in c r(*|Mi t in J a n u a r y , 1980, carried out a 29 year fp-llow-up >1 121 me mbers ,,r the or ig ina l study cohort - 89 m e m b e r s were veril'icil . e living .a nd .12 were v er if i ed deceased by death erf iH rate.- The m i l l s ..I st an dar d ised m o rt a li ty r a ti o . f or all d ea ths was 0 .1*0 with 12 deaths- observed, and 40.41 d eat hs expected. The .report by the A m e r ic an C o u n c i l on Science and He a l t h 1 9 8 b - Ielf this was the only s t a t i s t i c a l l y s ign if ica nt value dot ermi n o d . -There were nine mu Iitenant ne o pl a s m with P .04 expected.. - No deaths resulted from stomach or- liver cancer. Five."lung c a nce r d e a t h s occurred versus .1.1*1! expected. One skin c a n c e r (a fibrous h i st i o c y t o m a ) proved fa ta l. Fxcood ilie,Iy rai the ex pe c t e d i n c i d e n c e of its a p p ea r a n ce is 0.1 <5. Three- d eat hs from Lym pha ti c and hcniatopoet ie neoplasms rnsulto'd with 0.88 expected. The r e were 17 de aths from di s e a se s of f ho circu Iafory svs* <111 with 2 5 .OI expected. Because the study c oh ort was small and only .12 dea th s wer e o bs er v ed the results from this study cannot- he consi de red con clusive. Nevertheless, this is the best long term study ol' TCDD eff ec ts to date / Tlu: an a ly s i s of m o r t a l i t y e x per ie nce s -of personnel at- this point indicate no 'apparent e x ces se s of total m o r t a l i t y or of deaths- due to m a l i g n a n t neoplasms, or cj m i Iatory diseases, C2474 7.1. Arkansas cjrff palate study. , A study to d e fo r m ipe what.., if .any , .human -efleets were e xp er i e n c e d alter exposure; to 2,4,5-T. A rot.rpspeef ivis- study V . on .the inc ide nc e oi c 1 e ft. palate in areas sprayed, wi tli 12,4 , S-T- Kcscarcluirs analyzed iac: i1 1 cleft rates and concurrent use of 2,4* 5-T in Arka nsa s diirin/M h)4 ,V- |n 7.4 . list,jma t ed levels el exposure -to I lie h e r b i c i d e was t a( r/'iirisrd as high, me d iu m o r low exposure 011 the bcisis of rice a c r o a m * d u ri n g 6 - 7 year intervals inn i SUBJECT TO PROTECTIVE ORDER. SUBJECT TO PROTECTIVE ORDER. i t s d e v e l o p m e n t a l t o x i c i t y u n d e r , c o n d i i? o n s o f r c ^ i i 1 a t e d u s o to -- 7Z < 3 k --; f 3 -5 3 2 3 rs --. 3 3 n --j hi 3 H /* T 3 O >"S -7 -- --. < -- Z. --- s c. --; u-'. < 2 h- h-* 3 *7 3 ** U- :r 3 -- : r-- 3 >- 3 V. - 3 *> -- .A .3 3 -- 7 cr. v 3 r* -- - 3 --_ 3* 3 CL 3 -* * X t .3 3 3 X CL rU* *3 hJ. 3; r*\ 33 3 V 3 . 33 cr. C "3 *-r A ft* V UI. "3 3T 0 3 3 X v* >-- vC <! 1 k. nC IO .3 *. 7 -- "* 33 / O CO rfs* .- 2 r~. H-U 3 -TZ 3 --. 3 __ -- ;; * --* 3 -- a' <; 33 ** - w . 3 - 3 .- "7 X. -- 3 ". 3 /. r -c 7 jt --; 3 -- /* --- 3 3 a3 < 2 L 3 -- yZ 3 < V * 3 --, 3" 3 a si' 3 -- .-- 3 C 3 c~ < < r.. h* .-r - - J 3P -- 22 3 ' r*" 3 3 3 r- C/. 3 C 3 #* T 3 3 " -- *T 3 V* 3 H* 3 bJ. 33 3. -- 3 3^ 3 r-- ^ = 3 ~ 3 3 j- 3 " 3 3 -- -n cr 3 - 3 3 33 3 2 .3 j- n-3 3* 3 a 3 3" / cr 3 *3 3 < c cr C+L_. `Ti 3 h-. 3 .3 . 3 '*3-- 3 X *-. 3 C. 3 . 3- X ! - 3: O .-- 3 '3 cr w IT. O 3 X V 3" C 3 3" HO M C. cr -3 "3 -wt 3 3 C 3 * 0 '. 3 3 *3 r" t-. 4^ 0 'N -- 2a k-. 3 a 73 C h"3 3 3 .in: w 3' Jt -- O 'r** 0 CL\ O J5 h-- - r c 3-- H -- 3 5 3- H- . ** cr Ui. b <3 33 0 3 < 3 cr <t HTi t: 3* *- . u> 3 T. 3. r. -- , ---3 c3 3 -- 3 3_ .3 33 *< >-- 3 r 3 X n *. *-- --j -- 3 0 3 3 Ui. r 3 t *-1 X X. a 7 7. X 3 3. "3 /* 3 " .3 3 -- * .. 03 -- .3' 2j . -- L-. r- ***** t3 - / 33 *3 ' 3 3 .-- . 3 33 * -- - 3 . -- /-s = tL -- .'' Nelson nt al . Ret respect ive study oT the rei ali otislii p study does not iijdicate any overt causa l r e l a ti o ns hi p between 30 O *) c c+ C; ZT M H- Cfl H* 3 0) O3 T0 O3 3 CJ cn H* Vi H 33" 5C 33 u.. y 3r*. - 7-- ft 3: 33- -3 3 33_ "3 y or r r- --37i* ft w. *3 z . t 3 << r, Cl fl; G y. ft 3*3*"- d t- r-*` 33 ft y yft y .**33 3 r334-* y 3 r- *-> 3r* r) *1 3 .r 3-5" d 3* C 7" T ---3 d33" X. --. z3- ty c 3 ---. -- 3 33 T ft c. .a d o 0 ct C a H"!- 3. 33 Vi -3 . 3_' 3 3 -- y 3 X n 3 3 <~ -33 --"" 3 X -"d" v> 3j c. y c . -3 *3 -" cO H* n n 0 c "O n t. 3. 33 3 V-* O h-* O d * "3 ti u- f3 ' r-- y Vf !: -* y y X* - -. n T *t 33 r c H* D > T 7? CJ 3, y iy- > 3 11 --3 ' z. i1 I_ T -3 *t .3 3j t; Tkj. O c h-' d C j O --i c y ft y -- 3 .. r" : n . < 33 3_*3t_ . Vi j V* -3 - V f- * Vf 1i ---- 1 - = y*t NX' ^"3 .-- ' 3Zr-3-\'. z c "T '^J i; . 1 --y ^c . U) d (d 3- r4* u--*.t h3-- 33 r --* XC1*--Jt1. M '--V*. r . "" CL V# -- vC "z3 uL -y* ChJ-1. d: r0 .33 r f3 y3 4 ) 1ill ``IV ii`ws wil liaffected m o t h e r s in Or 1enas I<..r ci.it es and ((Mail* of p i T ^ n a m y urnhlcms. Wi (hin the study period, 7 pic^nanr ics nccuriTd. 01 fbest , eight , 9'/. .tindiid in s p o n t a n e o u s abort ion, one* ( 1 pore ent j j n IVI-ai death (placenta previa) and t he rema in iii/la 7^ in live- births. - Rood, D. California d e pa r t m e n t of H o a J t h S e r v i c es m e m o r a n d u m , further inyesfi gat ioiis into re ports ol' abnoriua 1 ou Icome ol pre ignanc jes i n Humboldt and trinity counties, April 27, 1979. " 01* the l.i vo births, six {7.7%) chi Jdren were h o r n with birth cle Tec ts' (two hypospadias, two with i n c o m p l e t e hip socket-- formation, one cleft lip and palate, one mild talipes oquinovarus) one sudden infant death syndrome at age sev en months. Phenoxy herbicide* sprayiniL luis been ca rried out in the fall of the year* since 196.1 wit h the* excepti on of 1062, 1972, and 1973. Spraying cea se d in N o v e m b e r 1976. T h e r e f o r e spraying consistency cannot be e s t a b l i s h e d in this case, When ..the 16 abnormal p r e g n a n c i e s were c o m p a r ed to the total pregnancy outcome* for that region, the -picul.re came into perspect ive 1 I.The spontaneous abortion rale* of 9# is Iess l.ban (he o x p o c t e d rate of 1 $%. / 72 1 M a j o r c o n g e n i t a l ma l i o r m a t i o i i s o c c u r at t h e r a t o o f % o f live births, while inclusion of minor d e f e c t s brings t h e percentage up to 1 5# The Orlenas rate of o c c u r r e n c e is 7 . 7/f> - so the figure's were within the e x p e c t e d hotiridar ie s . V ... 3) One total death and one s u d d e n infant d e a t h also reflect .1,1k * CONFIDENTIALpattern's est ah Iished lor the statu*. SUBJECT TO PROTECTIVE ORDER. C24749 .# . \ Reed concluded that " i t appears uni i k e l y that t h e r e ha^ h e r n an unusually high rate of p r e g n a n c y w a s t a g e in Orleans". 5. St. Louis Missouri, H o r s e arena. Beale et a l . 1977. Long-term e T e c t s - o f dioxin exposure'.. Letter to editor, Lanc/et, I(R(> 14 1: 74^. August 1972, the M i sso ur i Divi si on of Health and the Center for' Disease Control r e po r t e d an i n v e s t i g a t i o n of a horse arena in Eastrn Missouri where 54 o f 57 h o r s e s ex po sed to the arena had died of an illness c h a r a c t e r i s e d by skin lesions, -severe weight loss, and hepatotoxicity. Birds, dogs, cats, insects and rodents were also found dead in and ar ound t h e arena. A six year old g-irl who frequented the arena as a playgroun d, d e v e l o p e d epistaxis, a gastrointestinal complaint and severe hemorrhagic cystitis characterised by hematuria. Bacterial and viral urine cultures yielded negative results. '-T h r e e o t h e r p e r s o n s s u f f e r e d from milder illnesses with symptoms of headaches and nausea. They also visited the arena though for shorter periods than the young girl. Subsequent soil analysis showed that both TCP (trichlorophenol) and TCDD wore the probable toxic substances causing the adverse health effects. 1 t was found that the arena soil contained- a. TCDD level of 3 J .H .to 3 3 pg/ g( ppm ) of soil. The contamination was traced back to waste oil used in the area to control dust. 24750 On reexami nat ion of the young girl alter n live year \ (. interval since exposure, the patient had grown n u r m a U y . Both height and weight exceeded the 75th percentile,. Detailed physical, neurological and chemical examinations revealed no abnormalties. The sana. studies were cond uc te d on the p a t i e n t s 1 s i s t e r ' and m o t h e r - e x p o s e d simultaneously though less extensively to TCDD and the results were * 32 - Beale et al c o n c l u d e d "Our e x p e r i e n c e dcmonsl I'al.r.s that people exposed to d i o x i n can r e c o v e r c o m p l e t e l y with no apparent sequela li-om the toxin. It r e m a i n s to he seen: -whether 1 In exposure to dioxin in 'these c h i l d r e n wi ll result i . abnoi.na I pregnancies or affect their ol 1 spring. S e v e s o , Italy: ------- --- !-- f Tire lemesa ( I n d u s t r i e C h i m i e h e M e d a Societa A m mima) chemical plant did not produce herbicide 2 , 4 , 5-T hut made hexachloroplietic, an anti bacterial agent. The herbicide and hex ach lo r op he n e share a c o m m o n d e n o m i n a t o r , 2 , 4 , S - t r i c h 1orophenol In their manufacturing process. . The Icmcsa factory explosion -occurred in a reactor that produced 2 ,4 >S - t r i c h l o r o p h e i m L by c o m b i n i n g tet ra ch Ioroben/.ene with sodium hydrox ide in. an e t h y l e n e g l y c o l solvent. The explo sio n propelled forth a toxic white cloud which when cooled, descended slowly over the surrounding area. A m o n g the Chemicals that con tam ina te d the area d u r i n g c o o l d o w n was the chemi ca l di oxin ( T C D D ). based on determi na tio ns m a d e by p r o d u c t i o n offi cials, an estimated 4 ,0-00 to 5, 00 0 kg of r e a c t i o n product was lost in to th e atmosph ere (di Domenico, 1977). Estimates of the TCDD dispersion ranged from 6 50 gra ms to 1,700 g r a m s - K e ar n e y , P.C. et a l . (TCDD in tilt; environment, sources, fate and d e c o n t a m i n a t i o n . Envi ronmeiita I Health Perspective, 5, 273-277, 1973)- A s a m p l e of the product taken from tho reactor head for analysis rcvrlacd * - \ the presence of 3.5% 35,000 ppm TC1)D. C24751 M Reggiani - T h e e s t i m a t i o n ol' t h e TC DD tox it potenti al in the light ol the seveso fecidont. P a p e r 'preseiile-tl. a( the 2<>(.h Congress o the European S o c i e t y of T o x i c o l o g y , her Iin (West) June 25-2P, 1 9 7 H. - Reggiani r e p o r t e d that birds, rabbits and CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. 33 of TCDD p o i s o n i n g or wcrp s e l e c t i v e l y killed to wand off furl her contamination. By t he following Mo nd ay, 'loaves, from p l a n t s . a n d trees turned b ro w n and fell off trees in an area m e a s u r i n g 1 ,<"><> to l.iidii in a tii angle with a b a s e of 4 "'v "" 'ters and a -vertex of around IOO meters c en ter ed aronitd l-he lacl-ory. M e a s u r e m e n t s ol 1 ( 1)'.) residue on vegetation in this area ranged from 1 to 65 ppm, with one re ad i ng as high as S(l ppm Children and adult s exposed to the 'descending dust Jco m pl ai ne d of n aus ea and ticve 1 oped skin lesions ac co mp a n i ed by redness and swelling. .Some experienced- the burns and blisters common in exposure to caustic material. II . 11 G a r a t t i n i - J9 77. TCDD p o is on ing at yovosoj H iomed ic.i n e , 26: 28-29. re ported the lushest TCDD content was determ innd in .the h e r b i v o r o u s animals. People c o m p l a i n e d ol' nervous sympt oms, moo d ch anges and above all a serious rash-like skin lesion - later diagnosed as chloracne. The Sevcso area being divided into two /ones - C iov an a rd i , A. ( D e c o n t a m i n a t i o n p r o g r e s s for- tin* d i o x i n eon Iam j nu t ed areas ol Se ve so ..-and M(`di a, C r u h l a KcsjonaJ o D e 11 a L o m b a r d i a , Mini stero Della Sanita, Milan, Ttaly, August .1-8 , 1976 min. p . 1 7 ). described the Ii rst zone 11A n as a t r ia ng ul ar area co vering ap p ro xi m at e ly 100 he cta res (ha 1 . Zone -A. included Land, located south, -southeast oi the lemesa factory and d o w n w i n d at the time ol the accident. Keggiani ( 1 9 7 ^ opcit) d e t e r m i n e d that spi L levels r e gi s t e r e d TC DD levels a p p r o x i m a t e l y IO )|J) s. The i nh ab it ant s of this area were ev acu at ed in throe .-stages - on Ju ly 26, J u ly 2K and August. 2, 19 76. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C24752 I 34 - Zone B had detectabl e soil levels ol TCDD. Reggiani ( 1978 opcit) lator dost: ri l>;d this area as h a v i n g ru.sidi! le vel s b e t w e e n 0.1 and 10 pphs lor TCDD. This area c o v e r e d ap pro xi ma t e I> 250 ha and was divided between a large urban center and un extensive rural area with some small residential aggregates. The p o p u l a t i o n of 4,900 was not. evacuated. R e c o m m e n d a t i o n s wo re m a d e for th e wo me n and children in order to re duce the possibi lit.y of exposure A third Zone, Zone R, covered a total of about. 1,43b lui. Occassional residue concentrations, all less than 0.1 ppls TCDD in soil, y\ characterised this zone. This population of Zone R approximated 40,000 people. An extensive health surveillence system was sot up to d e t e r m i n e t h e m i d - t e r m and l o n g - t c n n range eff ec ts .of- TCDD exposure. Medical surveillence included laboratory tests, medical examinations, m o n i t o r i n g of pregn anc ie s and a b or ti ons f o r .any abnormal outcomes, rate of stil lbi r t h s , population m o rb i d i t y and mortal it.y, and cancer registry. The medical surveillence program was extended, to 11 D i s t ri ct s w t.ii a population of 2l6,()no. Reggiani, G. (The es ti ma t i o n ol* the T C DD toxic po te nt ia l in the light of the Sev es o accident, Paper present eel at the 20th Congress of the European Society of Toxicology, B e r l i n ( We s t! J u n e 2^-2?, 197$). He co n c l ud e d "The 'Seveso acc ident has not re v e al ed up to now, toxic effec ts in h u m a n s which have- not bee n o bs e rv e d in -other episodes. ChJoraene, '.the. Oypical skin lesion, has occurred in chiIdren with the tendency to spontaiuious and rapid healing. T h e peripheral nervous system lias p e rh a p s been aft no keel and reacted- with suhclinical signs of impairment. Signs of C247o3 in v ol v e m e n t of the liver without ap pa r e nt functional cliorders' * CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. f ( and l o s s , no g r o s s mal fo rm a t i on : , no H'rnwt h it l a r rial ion at t e r m ami - no c y t o g e n e t i c hnroma 11 t i ns . Tin-, filin' m i c a p n b i I- *i y ol Un* p o p u l a t i o n n o t o v e n o f the- c iu i e r o n wit h ch.l..rac.ue , h a s m . r h^; ,, attained, 2 , 4 , r, fA t t h e d J s p u l e r e - olu t *\>r eon; r e n e mi T i u fojv) D oct or L. San< hi pni. and II. k e l i d o r p r e s e n t e d ' da ta 'on abort ion e x p e r i e n c e s follo wi ng U n e x p ' :-. on: O Twenty- eig ht of tin* .}> * iduc.ed abort iuiiS we r e r e p r e s e n t e d by produc ts of concept ion ;l\a< vvere .partially- fragm en ted Jur imj cu rr et t ag e and incoiiipJ.(`lr ini mo rp hologic ..valnat ion No morphologic. ma.J formations., were noted in any of these; tei.ua.-, 2) A slight -increase in the incidmicr of s p o n t a n eo u s abort t> was determined in the B Zone. These increases might have he*n due to improved regj strati on '.some ui` t in- abort Lons als< ma\ b.vb been .s<:11 lnchn ed V. Fourteen Ml the. ->7 cases ot -pont ;ircous \u< .* and peri natal mortal ity examined w ere in.i1 fornicd structurally (24#h^). This incidence was within the range that mix.* no expec te d generally, hut could iml. he* c o m p a r e d to the. rat e in M s particular- area prior to tile accident as no (lata are av.i <ahle, The types of mal Iormat ioiov -ccn were consistent w n n those which would be expected spontaneously. All the report ed m a 1iormations were in the K and RT Zones; whore the soil cone ont rat ioils ol dioxin were below d e tec t ah Je 1 im its SUBJECT TO PROTECTIVE ORDER. \ C2475 and loss, no gross r.ial format t on- , no growl ii 1< 1 ai-<U< t on at < m and no cy togonrti c I'nroma |1 1 i>:.s. flu: ii.u-i* o..<ap.iii i Iiy ol 'In- population not oven of tin.- aluldron with < U.l .ra< u, , lias no* 1***1_ attained. At t he d i s p u t e r i - o i u t \.jr- c o n ; i T a c r on 2 , 4 , r T i n | p 70 D o c t o r L. S a m Ivi oni, and II. Re nde r p r c s ^ . i t c d d a < a on a!x>rt 1 <ni experiences following the e\p4:>.orv. 1 V Twenty-eight of the i i *-uluced abort :iu'/is wc*ro rTpruMMitcii by products of c.onc<i|)l ion *hat wort, .partially fractnented durrii'. cur rettage and incomplete 1 01 unrpho lijgic .valnai ion No morphologic maJ formations wer (% noted in a n v o f these `etu, ,^ 24 1 A slight Increase in the incidence ol" sp onlaiK'niih abort nn.% was de termined in the I) Zone. `These in creases might have b e e n due to improved registration ..some of tin* abort ions al s< rnu\ h.-vt* been .*>< 11 1 ndiM ed ). Fourteen 411 \ho >/ CuS(iS of >pont ;ircou s -aho r \u.-< and perinatal mortal it.y ex amined were. m a l f o r m e d st rue 1u r.illy (24.6^). This incidence was w i t h i n i;lir range that m u hi be < xpoctnd g e ne r a Il y , but c o ul d not. he < o m p a r e d to the rate in il'is particular area prior to the accident as no data are available. The types ol ina lformat ion's -.mn were cons! stent w e n those which would be expected .spontaneously. All `the reported ma lfo rm at ion s wore in the R and RT Zones; where the soil concent-rat i011s of. dioxin were b e l o w 'dehorfabJe limits. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. s C2.47-55 * Al s e a .I . . The study deals with a limited number of woiixm residing in the Alsca .Basin Area of Oregon. A n u mb e r of women living in this 2 , 4 , 5-T treated forest area experienced miscarriages, which they said were c o r r e l at e d w i t h th e s p r a y i n g season. Ini fia]ly 10 miscarriages were r ep o r t e d by eight- women.- S u b s e q u e n t 1y 11 mistarri.. were reported from nine women. T w e l v e of the 1 .] mi scarrj ages occurred within the first 2.0 weeks of ge st at i o n . When this data w a s compared to the live birth rate in Alsea (86 in the six year period studied) a miscarriage rate of 12-13 lies well within the limits of an expected one miscarriage for every seven live births. The report noted a seasonal variation in miscarriage incidence when the Alsea values were compared with those from nearby C o r v e l l i s ,Oregon. However, insufficient evidence precluded any establishment of proof or non-proof for a relation between miscarriages and 2,4 , j-T. Mantel, N. (An e v a l u a t i o n of th e s t a t i s t i c a l m e t h o d s 'used in EPAS report of as s e ss m e nt of" a f i e l d i n v e s t i g a t i o n of six years spontaneous abortion rates in three Oregon areas in relation to forest 2,4,5-T spray practices. (Alsea 11 report) George Washington University, March 26, 1979) - c o m m e n t e d that "the possibility thus arises that at least some of these m i s c a r r i a g e s wer e expe rienced by mis ca rr i ag e- p ro ne women. He also felt the " p u b l i c i t y about. 2 , 4 > 5-T spraying and s p o n t a n e o u s a b o r t i o n could h ave caused more previou. spontaneous abortion to be recalled and reported". Al sea 1 1 024*756 A continuation of the Alsea study, this epidemiologic ~ investigation further analyzed the possible relation between spraying' of herbicide 2, 4, 5-T and :r`e p r o d u c t i o n events. The' results of this I. study provided the basis: tor th e EPA. s u s p e n s i o n or de r in Tobruary 2 8 , CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. 37 Tin* A lstia '12 .investigators co lluci <m I da fu. from .tliroo areas of Oregon. 'The study area, w h i c h included .m a r o a <.l approximately l60u s q u a r e miles of Oregon c o a s t and c o a s t a l mountain range. The "urban" area which is c o n t i g u o u s with llic slui!> area and, included the' inland t o w n s of Co rv a l li s and Albany, and tht; rural "control" area which is in s p ars el y p o p u l a t e d -eastern. Oregon on the Idaho border. The in formal ion g a t h e r e d in th e study earner' from hospital records anci i n c l u d e d co d ed diagn os es, age o!` patient, spontaneous abortion data, gestation period and zip code of patients residence. The investigators limited themselves to spontaneous abortions of less than 20 weeks gestation. Treated in hospitals in a six year period from 1972-1977. These data were then compared to live births for the respective areas. Conclusions revealed v b y the EPA study are summarised as follows. 1 ) the spontaneous abortions index (hospitalised miscarriages per 1000 births) for the Alsca study area where 2 , 4 , 5-T was used significantly greater than the index for the urban and control areas, where there was no known use of 2 , 4 , 5-T. 21 There was a dramatic in c r e as e in th e s p o n t a n e o u s abortion index ior the study area relative to the urban and control areas in the month ol June and July. This i n c r e a s e fo ll o w ed by a p pr o xim at ely two months a period *x\ M a r c h and A pr il when 2,4,.5-T was used to control vegetation in the study, area. R e l a t i v e to the' urban and control areas in the mon t h of J u n e and JulV* T h i s i n c r e a s e r followed by -approx imat e Iy two m o n t h s a pe r io d in March and April ^ when 2,4,5"T was used to control Vegetation in the study area. CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER. C24757 $* 38 - f 3^ Statistical analysis of these data indicate that there was a sibili fica nt co rre l at io n ho t w e e n tire am ou n ts o I ^ j4 j ^ 1 used in "The Ageway 's s y s te m a t ic s u rve y of-.the occu ra nc e of spo ntaneous a bor ti ons in an area of ? ,'4 > 5-T- use, indicates that there was an unusually high number of spontaneous -abortions in-the area, and that the incidence of spontaneous abortions may reasonably be related to the us e of 2 , 4 , 5~T in that area. Tire data further indicates that the miscarriage experiences which.the eight Alsea women re p o rt e d to the* A g e n c y w e r e r e pr e s e n t a t i v e of the experi en ces of the larg e p o p u l a t i o n of wo m en livin g in the study area". Numerous cri ti cs of t h e A'lsea II study l V M a n t a l , N. An ev a l ua t i o n of the s t a t i s t i c a l m e t h o d s used in EPA report of Assessment of a field investigation of six year spontaneous abortion rates in the three Oregon areas in relation to forest 2,4,5-T spray pesticides (the Alsou II report) George Was h i n g t o n Universit y, M a r c h 26, 1979. O and report, Environmental Health Sciences Cente (J University, Corveilis, Oregon, O c t o b e r '25, 1979 7 r /~\ ID O These* 'oriti siiis^ ha ve r e v e a l e d f r a g m e n t s t a ti st i ca l and epidemiological flaws that the majority of the scientific community has accorded little if any weight to the EPA conclusions ?)<} - * 1 V Spoilt a n r n u s a b o r t i o n s , o r mi s c-tr r i a g e s t t <`(|Ut`ii( l \ o c c u r i n t h e r i r*>it t h r e e m o n t h s o f p r i g n a i u y . St -.tl'i1 n *. c i t t : a. spoi l' a n e o u s ni.i s c a r r i a g e i n c i d e n c e <>l I 2 i< : v / . V\ a \$% r a t e most commonly r e f e r r e d t o in 11 f e r a l u r c . In the U.S.A. hospitalization rate lor spontaneous abortion approaches $% or ^2 per 1 (K)0 niaterni ty adini ssi ons Whethe r a spont ane ou s abortion will be h o s p i t a l i s e d depends on: 1 . whether the -women .recognized the event as a mi scared ago. ?. how anxious the woman is about ab or t i on and the social support, system her life style provides her 3 . whether the wonuin is financially able to secure? treatment. 4 . whether the troiit-ing physician is a specialist who denis regularly with s p o n t a n e o u s 1--abortion cases. 5 . the availability of treatment in an out-patient clinic. 6 . the standard of health care in the communi ty 7 . the gesta L ioiiai age of the conc ep fus and flic*..comp Ie tcncs.s of the abortion (Lamm, 1979 ) Alsea II, considered only h o s p i t a l ised s p o n t a n e o u s abortions. Attended abortions in clinics.* .unattended a b o r t i o n s , and those events 1 hat took place at .aroa' h o s p i t a l s not included in the study area were not considered* The study numbers, t h u s d o n 11 accurately reflect the miscarriage incidence in either the control or study group. The Alsea II study stat ed that o b s t e t r i c i a n s in the area hospitalised only 10 percent of persons experiencing spontaneous abortion, while general- practitioners faced with the same problem CONFIDENTIALhospitalised approximately 70'X of these women. SUBJECT TO PROTECTIVE ORDER. 024759 4u - % Tlir study v(*rsus control areas {s a lurlhrr romp I1 111 I .. lipmod 1 cal effect l>o ing mcasuiMM! is c o m m o n 'to U 10 g e n e r a I popit Iat ion . M l variab les must bo c o n s i d e r e d . . Alsca JL did not (al` into account : 1 . level of medical practice ' ? a/go. of mothe r .1. n u t r i t i o n a l state, diet, a v a ri et y of infecf.i o ils JUt'iils, anatomic or genetic abnormalities,' medicine and other drugs, Co n s u m p t i o n o f aicohoJ or- tobacco, s o c i o ec on om i c status etc. .Th u s live ef fects of the stress agent, 2,4, S-T coni d not be adequately asessed. Also the towns involved in the study Alsca (study) and Corvellis (control) do not maitain constant populations. Alsea a co astal r(;sort t o w n lias an i nt l u x of fjc:opJ c- du r i n g the summer months. CorveJ lis a c o l l e g e town, ox'por iernes a summe r exodu s at the end of* the school, year. "The hPA cited Ma d r a m a t i c i n c r e a s e in m i s c a r r i a g e s which' hav e c o n s ist ent ly occurred at an a l a r m i n g rate. to the s pr ay i n g of herbicide 2 ,4 , 5-T. This they attribute Yet* critics say on .closer e x a m i n a t i o n of the dal a 'I'lie dramatic 'June! peak was apparent in only one of the six yeais-sl.mlh* / There! was co nsi s te nc y to the abortion p a t t e r n and tliox-c was no sol id establishment, of background m i s c a r r i a g e e v en t s 'to 'clarify a st r e s s related 'occurrence. In ad di t i on there was 110 incr ea se' in the nu mbe r ol s po nt a ne ou s abortions in til.e latter y ea rs of -(.lie? .study, even \ (bough there- was a significant increase in Hie amount of 2,4* ri-T s p r a y e d ill the test area. Of her [leaks and t r o u g h s a p p e a r i n g on \ .v the Alsea graphs randomly occur fhoughout the year and could not CONFIDENT! AL C obe attributed to sprayj ng - a strictly soasona I r visit . 2476 SUBJECT TO PROTECTIVE ORDER. Wagner stated when I In* data was cniTcr' ed Io a common hospj t.i lisa t jon rate .'t-ii<l the (<>(al number ol' h o s p i t a l i s e d spontaiieous abortions arc rxprrs.srd as a jKTccnl ,i^' ol I ivc -births tho values are : study area - 11.4$ urban control- 1 4 .<]% control, area - {) . \\% At best the Alsea 13 study coul d only represent 'the in hospit al spontaneous abort ion index: lor its test area. The study has been d is cr edi te d to such an extent that it. is no longer considered a useful study for analysis of the alleged problem, that is the effects oi h e rb i c i d e 7-,4,5-T on huma n r(!product ion. / SUBJECT TO PROTECTIVE ORDER. 024761 Scientific Studies The first reports linking possible adverse lira IIh effects to Agent Orange appeared in Vietnamese n< w. | ` -1 h.d w m i June 26, lyoy and July $, 1969 (Advisory Comni iI (,-e <.n 2,4,',. I ). 'The- public response.to these reports p r om pt ed the r e t i o s p n I ive studies of Vietnamese hospital records c o n d uc t e d 'independent Iy by Cutting (1970) and Meselson (1971)- The President's Advisory Committee on 2 , 4 , S-T (iu7l) (evaluated these studies and c on clu de d t he Id Ilowing: "Summari /.ing th e Vi etnam dal a on human embryo! ox 11 1 (y , it can be said that (l) the s a mpl e of births s u rv e y e d was from year to year a variable but us u al l y very small fraction of tin- total number. (2 ) it was qui te u n r e p r e s e n l a l i v e of 'the ge o gr a ph i c and ethnic d i s t r i b u t i o n s ( 3 ) the he av i l y ..sprayed' and olherw.isr exposed areas were greatly under- represented, and (4 ) the Inrth records were riot trust wor thy and, there' l o r e , the rates of stillbirth, and especially of congenital malformation, derived from them were equally unrealizable. For example, the overall congenital malformation rate found in South Vietnam, 4 . 91 per 1000 livebirlhs, ls about half of what was reported in other studies In various parts of Asia, and possibly a quarter of' what might a c tua ll y exist, at term. A surther indication that the newborn children were not curefnLJy examined is the absence of Down' s sy n d r om e in the list, of specific m a l f o rm at i on s comp ile d by the Army s u rv e y (Cutting, el a I. ) (197<> ) despite the fact hat some Oriental p o p u l a t i o n s liVvo been 1C.<-<1 to have an i nci de nce of this c o nd i t i o n not u n li k e that, in Western CONFIDENTIALpopulations. SUBJECT TO PROTECTIVE ORDER, C24762 t* /^ VJ SUBJECT TO PROTECTIVE ORDER. finally there. is, ami can lie, no p r o i.sr knowledge ot roaaonablc a p p r o x i m a t i o n of the expo s u r e (a, 2 ,4 , S T (ami hem--, K U h I experienced by pregnant Vietnamese women, including what amount.-, they ingested or abs orb ed and when this may. haVe o c c u r r e d d u r i n g pregnancy. Thus, any attempt to r e lat e birth d-leets or st i III, ii-lli-, to her b i ci de exposure is .p r e d e s t i n e d to failure-. It can only laconcluded that the birth records that have been surveyed, and ' probably any that will be surveyed in the future, for South Vietnam for the perio d 19 0 0 - 1 9 7 ^ canno t a ns wer po s it i v e ly flu- *jo-sf ion.-, about possible ad verse p renatal et le ets following human -xposure t.<, 2 ,4 ,5 ~T* It mu st bi. empha si ze d, however, t h a t the s e ar c h e s 'that have b ee n m a d e almost c e r t a i n l y w o u l d h a v e r e v e a l e d any m a r k e d j i k t v .i m * in the incidence of birth defects or the introduction' of a .striking defect such as that produced' by thalidomide. In spite of considerable effort, no such occurrences were found". A further study on birth de le cts in South Vi-(mam was pe r f o r m e d by Dr. Ton That Tung, et a J . ( 1V 71 ) They r e por te d that out of 903 South Vietnamese seeking shelter in the North, in h os pi ta ls and lodgings in Hanoi, 19 adult women, includ in g lour mothers and 70 chil dre n be tw e en the ages of 6 and 14 had e x p e r i e n c e d ''dir;cl ex po su re to h e r bi ci d e s p ray s wh i le li ving in the .South. Of flu- lour mothers, two had given birth to children with Downs syndrom-. Amo n g the 70 children, nu m e r o u s casu s ot d e f o r m a t i o n s (ocular lesions, lumps on forehead, valgus leet (feet that extended o u t w a r d ) and chromosomal aberrations became .evident. Tung concluded: v (translation in Young, et a l ., 1 9 7 8 ) "Though still limited in number, our clinical -observations1 donlirm the results obtained on ahimal-s -by American- researchers. Th e ma s s i ve C24783 and prolongtid utilization of deformants besides Sc i <mt i 11 ( S t u d i o s Tlio lir&L rcpurl/h linking p<>ssil>l<- .iilvcV.sr Ih .iM I i effects to 'Agent.Orange appeared. in Viclu.um-se n. w..( | i -. between June 26, 1909 and July 5, 1969 (Axlvi soi y Cumm iItee m i 2,4,', I ). The public response to these re po r t s prompted the retrospect ivc studies of Vietnamese hospi ta l records conducted independent Iy by Cutting (1970) and Meselson (1971). The President's Advisory Committee on 2 , 4 , S-T (l97l) e v al ua t ed these studies and c o n c l u d e d (.he following: "Suiumari zing th e Vi et n a m data on human eiiihry.pt <>\ 1 t 1 (y , it can be said that (l) the s a m p l e of b i r t h s surveyed was from year to year a v ar ia ble -but u s u a l l y very small fraet 1011 of Untotal number, (2 ) it was quit e u n r e p r e s e n t a t i v e of tin; g e o gr ap h ic -and ethnic distributions, (3 ) the heavily sprayed and otherwise exp os ed areas were gr ea t l y u n d e r -r e p r es e n t ed, and (4 ) the .In rt It records were not t trustworthy and, there l'ure, .the rai.es of stillbirth,-- and e s p e c i a l l y ol co n g en it a l mal 1 ormation, derived from them were equally unrealizable. For example, the overall congenital malformation 4 . 9 1 1U00rate found in South Vietnam, per livebirths, ls about half of what was r ep or ted in othe r s t u d i e s in various parts ol Asia, and po s si bl y a quarter of what migh t actually exist, at term. A surthter i n d ica tio n that the ncwluirn c h il dr en were not carefuLJy- e xa min ed is th e absence of D o w n 's synd ro me in the Iist, of s p e c i lie m a l f o r m a t i o n s c om pi led by the Ar my survey (Cutting, el. a I. ) (197) de sp it e the fact that some Oriental po pulations hvave been reported to have an incidence, ql this c o n d i t i o n not unlike: that in West e r n ' CONFIDENTIALpopulations. ; SUBJECT TO PROTECTIVE ORDER. b<54 0 4 >4 Finally, there is, and can hr, im |rrr'i.sr k n<.w Indg< ,I reasonable, a p p r o x i m a t i o n oi' the -a i m .-sure to 2,4 ,'y T (.ml It...<<, n || ) ex p er ie nc e d by pregnant- Viubnaiuosu womun, including wli.it <im>unt the y i n g e s t e d or a b s o r b e d and w h e n th is may h a V e o cc ur r e d tli.i*i pr eg na nc y. Thus, any a t t e m p t to r e l a t e birth' d e t e e t s or s( iLhirl h s to h er b ic i de exposure is [Predestined to tailure. It cau o n ly hi* concluded that the birth records that.haVo been surveyed, am i ` probably any that will be surveyed in the luture, lor South Vietnam lor the p er i o d 1 9 0 0 - 1 9 7 0 ca nnot answer positively Un* 'unst imi.? ab ou t p o s s i b l e a d ve r se p r e n a t a l e f f e c t s following hum a n e x p o s u r e t.o 2 , 4 , 5-T* It must be em ph asized, however, that the searches t hat have been made almost certainly would have revealed any marked . i n c r e a s e in the incidence of birth defects or the introduction of a striking defect such as that pi'pduced by thalidomide* in spite of c o n s i d e r a b l e effort, no such occurrences, w o r e f o u n d " . A furt he r s t ud y on birth de le c ts jii South V i e t n a m w a s p e r f or me d by Dr. Ton That Tung, ct a i . .(1971) They reported that < gSi O H >IU n go Us E esa, 0 --1 CQ ID CO out of 903 South Vietnamese seeking shelter in the North, in h o s p i t a l s and lo dgings in Hanoi, 19 adult women, including four* mothers and 70 children between the ages of 6 and 14 had experienced direct exp os ur e to h e r b i c i d e spr a ys while' living- in the .South. 01'H u * lour mothers, two had given birth to children with Downs syndrome. Among the 70 children, numerous cases of deformations (ocular lesions, lumps on lorehead, valgus feet (feet that extended outward) and chromosomal aberrations became .evident. (translation in Young, et a l . , 1 9 7 8 ) Tung concluded: V 024*765 "Though still limited in number, our clinical observations Confirm the results obtained un animals by American researchers. The massive and prolonged utilization of deformants besides 1 44 to ancestral soil and Chest; alterations ran provoke anion their progeny conguii ital nial I'uniuit ions the importance of which remains to bo determined. In the abominable history ol\ war.s , have wo ever seen such an.`inhuman fate reserved `for the survivors except i n .the case ol` atomic war?" A study similar to'that of Dr. Tuny was performed by Rose and Rose (1972). The authors reported monstrous births, spontaneous abortions and death among man and animals following exposure to the defoliants. The linkage of Down's Syndrome and exposure to 2,4,5-T suggested by Tung has been supported by Grumner (-- in a report by Honoroff (1973))* Grumner1$ comments after inspection of i both North and South Vietnam were: v '"provided that it be understood that this '.estimate, cannot be anything but a cautious one, it may be assumed that there are at least 2 5 , 0 0 0 children with hereditary defects in Suuili V ietuam. This does not include all the unborn babies whose mothers were sprayed during.the missions that were fl6wn in recent months. It does not include those who were stillborn, or died soon after birth, on account of their serious chromosomalic delects. Even after the war, it will probably he possible to arrive at only an approximation of the e.nt ire scale of this crime since one will only be able to examine ' CONFIDENTIALthe survivors when the time conies". SUBJECT TO PROTECTIVE ORDER. C24766  Tungj'.et a l., also reported on another .uJvrihr Ik m Ii h effect'.he attributed to defoliant exposure. lit J97.1, Tung' repor te d an increase in the number of p e r s o n s d i ag n o s e d wit.li primary liver cancers in proportion to all c a n c e r .p a t jouts, admitted to Hanoi hospitals during the peri od 1962- 19hH. He compared the 79U -liver eases out ol 7,911 total c a m or c ases ( 1 0 /), with those documented in ear li er p r e - s p r a y i n g ycai s, 1955-1961 . --- 1^59 liver cases out of t o t u l c a nc e r in cidence of 5,492 (2.9*). In a 1977 International Agency lor Research on Cancrr (1ARC`) monograph-, (19 77), tjio- Tung study was. critic iv-ed lor its limitations in reporting which they cun^idcred iv^ulUid in in j tinadequate assessment between herbicide spray ing and vor cancer frequency. v ( Ford! et a l .j ( 19 7#) % offered a luiilior factor worthy of consideration, the consumption of al'latoxin>coutaiuinated food in parts of the East . Aflatoxin occurs n a t u r a l l y as a coul.im iriant in cereal grains and has been suggested as an e x p l a n a t i o n lor the increase in liver cancel1 incidence. War c o n d i t i o n s would bo exp ect ed to increase aflatoxin risks in avail able l o o d g r a i n s . In 1974, the National A c a d e m y of* S c ie n c e (NASI announced result s of its study of Vietnam during 197--1973 The' NAS cou ld l'ind n< co ncl usi ve evidence o f associ at ion b e t w e e n expose re to herbicides and birth detects in humans. An analysis of hospital records.-or three Vietnamese hospitals showed no co ns is t e n t pa tt e r n of assoc i.it ion \ l>etween malformations and annual amounts of herbicides dissminai ed . To date th(;re is still a gr e at d e b a t e about lIn- h ar m ful e fects resu.L ting from human e x p o s u r e to Agent. Orange- in c o n f i d e n t i a l 2 4767Vietnam. Studxes per formed by Tung have general ly been met sr.Rirr* t ~ '5R0TF''T!VF o r h f r Tung, <!. .1 1., also r e po r t e d on anoUici: .idv< i>><- .11*.tt h effect he attributed to defoliant e xp osu re . in 1 9 7 V, I'une repor te d an increase in the number of p e r s o n s diagnosed' with- primary liver cancers in proportion to all cancer .patients a d m i t t e d to .Hanoi '-hospitals dur ing t he p e r i o d i y 6 2 - 1 9 <iH . He compared the 7 9 0 .liver cases out of 7,911 totaJ cancer cases (10%), with -those documented in ea rl i e r p r e - s p r a y i n g yeais, 19 5 5 - 1 9 6 1 . > - - 1^9 liver cases out of total cuncur incidence of 5,492 (2.9%). In a 1977 International Agency for Research on Cancer (1 ARC) monograph, ( 1 9 7 7 ), the lung st u dy was critici/.ed tor'its limitations in reporting which they c o n s i d e r e d resulted in an inadequate assessment between herbicide spraying and 1 1 ver <ancer frequency. s Ford, et a l ., ( 1 9 7 H), o f f e r e d a further factor worthy u consideration, the consumption of aliat ox i 11-cun tain m a t e d food in parts of the East. Aflatoxin occurs natui*aily as a contaminant in cereal grains and has been suggested as .in e x p l a n a t i o n for the increase in liver cancer incidence. /War c o n d i t i o n s won Id he e xp ect ed to increase aflatoxin ri sk s .in a v a i l a b l e food grains. In 1974, the National Academy o fSci euce (NAS) ann results of its study of Vietnam during 19711-1973. The NAS m u I co ncl usi ve evidence of association b e t w e e n e x p o s u r e to.herb ir ir birth defects in humans. An analysis of hospital rcturds oi t Vietnamese hospi tals showed no co ns is t e n t p a tt e r n of assoc i.i( \ b e t w e e n m a i 1 ormations and annual amounts of h e r b i c i d e s d j ss To date there, is still a g r e a t debate, about t h a r m f u l etle ct s r esul ti ng from human e x p o s u r e to Agent O r a n g e in CONFIDENTIALVietnam. Studies performed by Tung h a v e g e n e r a l l y been met 'SUBJFC7 T'' ^ O T E C T J V E OR D E R . C24767 nto MOWINAMAW( LOCATION ^MONt I Dept, of Medicine & Environmental Health - G . J . L e v i n s k a s , G2WF ( -880$ March 8, 1982 Agent Orange Litigation :R.T. Berendt, E2ND , H.S. Scott, E2ND / ` o* MMHfMCI.Memo 3/2/82, TMB/GJL TO T.M. Bistline, E2NJ ' . l L.v The document "A Summary of Toxicological Data of the Phenoxy Herbicides" by Dr. William McBride contained 45 pages. Since the last page ended in the middle of a sentence, I am not sure how much of that document I did not see. Nevertheless, the part that I read was well written. It is a good, objective review of the subject. It is a balanced presentation with which I have no quarrel. On page 27, I noted a question mark that you had put alongside the phrase "four of the six original workers were examined" in 1953. I do not know if that is correct or incorrect. While the statement can be checked, it is unlikely that we can get an answer back to you before the scheduled March 19 submission to the Australian Parliament. One difficulty in checking out that statement is the absence of a specific reference to it. As I noted earlier, the document appears to be incomplete. Certainly, no bibliography was attached. I suggest that Dr. McBride's review be given to Charlie Love who is defending Monsanto in the Nitro litigation. _ alw CONFIDENTIAL SUBJECT TO PROTECTIVE ORDER* IN-10M (REV. 2/78) C24768