Document 5bJxkDanG9V1vOyxYq0rr5rqV
GENERAL
ELECTRIC
GENERAL ELECTRIC COMPANY
FAIWriCUO. CONNECTICUT0*3I
KM
mmm G
S TE P H E N B HAM ILTO N. JR.
*
MAMAOca - c n v i h o n m c n t a l ocer a m o k c x m o i o o t
January 12, 1987
Dr. Ruth Arisman Rt. 1, Box 21 Burkvilie, AL 36725
Dear Ruth:
Here are the two items on inhibition of dioxin toxicity by PCBs. I think they are pretty exciting. I am also enclosing an abstract of a paper given by Steve Safe last October in Montreal. The bottom line conclusions on PCB health effects are very similar to those drawn by Seymour Friess back in 1982-83.
Safe, as you may recall, has been one of EPA's main consultants on PCB toxicity, and what he says on the subject should be very influential.
I will plan on taking you up on your offer to see the Burkville plant sometime when I'm traveling to the South.
Very truly yours
SBH:cas Enclosures
783736
GENP 010925
0971
SOCIETY OF TO XICO LO G Y
A B S T R A C T F O R M F O R T H E 1987 A N N U A L M E E T IN G
Anycorrespondence regarding yourabstract
must reference the above number.
FoOow (o m u l forheading. Leavedouble space between heading and abstract.Text of abstraclm uifbeeirigie spaced. There will be a charge of torarty ebstract that must
baretyped.Lun nomargins--typomustbawithinrectangle.SInglaspaca,atitatype,exceptfordoublaspaeabetweenbodyoftaxiandauthors.DeadlineforracalptIn ExecutiveSecretary'sofiles IsOctober24,1988. FollowInstructions accompanyingthis form.Submitoriginal andona copy only. Originalmust baon thisform. Proof carefully. -
TERATOGENICITY OF 2,3,7,8-TETRACHLORODIBENZO-
p-DIOXIN: ANTAGONISM BY AROCLOR 1254: J.M. Haake, F. Mayura, T. P h i l l i p s and S. S a fe ,
Departments of V e terin ary Physiology and Pharmacology and V e te rin a ry Public H ealth,
Texas A&M U n iv e rsity , C ollege S ta tio n , TX.
1. Name and address of presenting auth o r Nam M s, J .M . H a a k e O iqm izatioit T e x a a ^ U n i v e r s i t y ___________
Address: G oH S f V e te rin a ry Medicine
The d o se -resp o n se te r a to g e n ic e f f e c t s o f
2 ,3 ,7 ,8 - t e t r a c h lo r o d i b e n z o - p - d i o x in (TCDD) were d ete rm in e d in th e C57BL/6J mouse. Ad
m in istra tio n o f a s in g le dose o f 2,3,7,8-TCDD (20 ug/kg) in corn o i l to th e pregnant fem ale on day 10 r e s u l t e d in 70% c l e f t p a l a t e and 85% h y d ro n e p h ro s is in th e f e t u s e s . In con tr a s t, adm inistration o f the commercial poly c h lo r in a te d b ip h e n y l, A ro c lo r 1254 (750
<nol/kg), to th e pregnant mice d id not r e s u l t any c l e f t p a la te or hydronephrosis in the
.e tu s e s . C otreatm ent o f th e pregnant C57BL/6J mice with A roclor 1254 (750 umol/kg) and 2,37,8-TCDD (20 ug/kg) r e s u lte d in o n ly 8% f e t a l c l e f t p a la te and was s ig n i f ic a n t l y lo w er th a n th e 70% f e t a l c l e f t p a l a t e ob s e rv e d u sin g 2 ,3 F7,8-TCDD a lo n e . T hese r e s u lts are comparable to other stu d ies in our la b o ra to ry which dem onstrate th a t A roclor 1254 antagonizes recep to r-m ed iate d re s p o n s e s
to 2,37j8-TCDD. (S p o n so red by N.I.H. ES03554.)
College S tatio n
TX 77843
City Slate Zip Code
U.S.A._______
Country
*09 , 845-9181_______________
y 1 wAMmteert*nmmcbbigMenrtWesrhHrmi1p steaSgOtuTMsnt:a_rg_i_n__aSOATarmofteemtpbomerond'feftmmbtr.dNsopann-amnee,mBabeTr
Dr. S. Safe
Signature of SOT member sponsor Typed name of SOT member sponsor
Undergraduate and graduate students and postdoctoral fellows are also requested to check one of the spaces below:
_____U ndergraduate
^ G raduate _____Postdoctoral
3. The Program Committee reserves the right to assign papers to either a platform or poster session. Please indicate your preference below and w hether you wish to withdraw your p aper it your choice cannot be m et
Sfattami X
p o ste r_______
E ith e r _______
W ithdraw_______ Ifchoice cennot be met
l. Select from the list below the session topic that best suits your paper. Specify your first and second choice or specify another possible session topic area under "other."
Specify only two choices.
I
SESSION TO PICS
1. General/Methods 2. Aquatic/Environmental 3. Molecular/Cellular
4. Biotransformation/Disposition 5. Reactive Intermediates 6. Genotox/Mutagenesis 7. Oncogenesis 8. Reproductive/Teratology 9. Cardiovascular/enl
10. Inhalation 11. Hematologic 12. Dermaj/Ocular 13. Hepatic/Gt system
Nervous system: 14. Neurochemistry 15. Neuropathology 16. Electrophysioiogy 17. Behavior
18. Immune system 19. Endocrine system 2 a Metals 21. Pesticides 22. Solvents 23. Hatogenated hydrocarbons 24. Food/Drugs 25. Communicating Concepts 2& OTHER:_________________
(one topic onfy)
ReturnthisformbyOctober24,1988,toeProgramCommittee,ctoExecutiveSecretary,SOT,1133FifteenthStreet,N.W.,Suite820,Washington,D.C.20003(202/2S&&25).
PCBs may counteract dioxin, chemist says '
If you (she c both In PCIIs,
vpii might notice some effect* Maybe a little acne-typO-akin trouble which will go away.
JACK MILLEn
. Then again you may see noth
ing. Any exposure less extreme limn that probably won'l do any*1
Science
tiling to you at ell, soy idenHsIp
expert In these things. * *;
There, now -~ `do'we have, Four more of those 75 cliloro-
your allenlloit?
dloxlns are somewhat toxic, and
Jt*a taken years for the gener the oilier 65 seem to have no bad al public to become convinced effects whatever on humans. `
has concluded'that many of be dumped Into Ihe-cnvlron- even llllle harm"
those relatively' harmless 'PCIIs ment.
. <Thcn he switched lo the sub
oclually can work as s proles- Hut If (here's an accidental*, ject of chiorodloxlnsi and drop^
lion, If not an outright antidote, exposure, like that spill of PCIIs ped his bombshell. *"
against the bad chiorodloxlns. - flroin a truck on the Trans-Cana '. **lnour studies of Ihe effects ot
" And, yes, this doea work da Highway In Ontario some the few toxic forms of these
against 2378-TCDD, the worst of lime ago/ U'i nothing lo worry chemicals, we felt there must lx
the bunch.
about.
- some anli-dloxins at work In Ihi
hast week the Ontario envl-> People driving their cars body. And we found lhal Then
ronmonl ministry sieged a through Ihe alufr were not In were.
forum In Metro on dioxins In Ihe* any danger, Tlie near-panic lhal "We have now developed t
environment lo a full house, and followed- that spill, which wound number of compounds that give
.some of. whal Ihe crowd heard up with long stretch of pave this effect on laboratory test anl
seemed lo surprise..many of. ment' being dug up and carted mals. When administered alon*
that polychlorinated biphenyls That w o n t chlorodloxln of them;
are deadly poisons, >o II prob them all jjworal for humans, that ably will lake Just as many more li) carries the cumbersome
Government advisor
sway, was rldlculouk and pure with Ihe worst of Ihe chlorodlox'
hysteria, Safe said.
Ins, they have cut the Incidence
` Several years ago. there were of harm by 80 per cent."
years to convince the public that chemical till* of. 2378-TCUU, Safe was brought un from bad m an poisonings, one.In . One of Inose magic anll-dloilr. this has all been blind, uimues- which Is short *for* 2376* Texas to be keynotespeaker. Ills Japan and another In Korea, of' compounds Is Arodor 1351.
Honing,* gross misinformation, lelrechlorodlhento-para-dloxln credentials are good, lie's % people who consumed rice oil What's Arodor 1251? "It's a
Ihese people say.*
(the name alone la enough Id lleilevlfle native who studied at contaminated with-chemicals mixture of l*CB>. It's well
Ilut If lliat'a what the Job calls scare you off).
Queen's University and Ilian Ox There were PCIIs In Ihe clieml known. H'a been avallahlejcom-
for, lei's alart.
None of this Information; up ford on his wiydo becoming an caIs, and the outcome was lhal merclally for years." Safa tald."
Uh, and while we're at It -- till now, Is new. It has been advisor*on these Subjects tor all PCIIs (there are several) were Any more bulletins) Well, II
you've heard of dioxins? Or to generally missed by the media liolli Ihe U& pnt| Canadian gov labelled deadly.
may turn out that you can also
use the more common term,* end the public, faui lots of Ion ernments.
In fad, Sale seld. some or the light dioxin wllh dioxin. Some of
"deadly dioxins?"
:C.l.i.e..m..l.s..t.a....h...a..v..e....known It all FCDs, he laid , are almost other components In the chemi Ihose 65 non-toxic chiorodloxlns
S i x polsonnus
along.
totally harmless to people. They cals must have done the damage, seem lo offer Ihe same.sort of
Uui here's something that Is may he damaging lo some plants because he has studied PCIIs protection from 2378-TCUU as
Well, llin proper term In Hits new, Iter;rareIt under. chem_i_st or oilier life lorms in Ihe food exposure cases for years and. Ihe PCUs do. '
rase Is chlorinated dlhxlns, al- - Stephen Safe at Texas A and M chain,' and- they do not break found you practically have lo Stay tuned to. the good-newi
though It's etpinlly correct .le University, sqon to bp published, down readily, so they should not drown a human In Ihe Muff lo do channel,'
call lliem chlnrudloxlns.
We make the distinction be-,
dause there are thousands of
1`other dioxins lliat are not In*.
vnlved with chlorine, which
means they are not port of this
family of chemicals lliai people -'
'worry so much ahoul, even though lliey can all properly, be
THE TORONTO >R rtfE
called dioxins.
Well, there are 73 known
10/ 27/86
`chiorodloxlns. And yes, of those
75, six are considered harmful
' though to people lo he called polf '
sons, and one or those six Is ruled as the third most poison*
783738
Nfwr substance hi the world fm;
1 (turnons (b form or bolnllsin Is
. *fIre Number f poison, but Uml's aiinlher story).
E N P 010927
V w' 86 i 5/07 14:43
314- 694-6898
MONSANTO STLO UIS
@002
,, - -- - o . Confrence tur fes SPC ft If fluid d f remplawmont #29 m tsm b ra -If f obre1986 IEEE MONTECH186 onf@renca on PC3 *nd replacement fluid September 29 - October 1,1986
HEALTH EFFECTS CF PCS AND RELATED SUBSTANCES
Stephan H. Safe, Kathy Faorra i l , Roy Bannister Michael Kelley, 3talvio Bandiera m Grmt Mason
Veterinary Riyslology and Pharmacology Texas A&MUnivarsity, College Station, Tx T7S43
Polychlorinated biphenyls (PCBs), dlbenzo-pd lo x in s (PCOOs) and dibenzofurans (PCDPs) are halogenated aromatic chemicals which hive been used as I n d u s tr ia l compounds <PC8s); o r hava been Id en tified as by-products In the production of organic compounds or their combustion (PCBs, PCTOs and PCCFs) (1,2). These chemicals are characterized by their chemical stab ility , resistance to chemical and bio lo g ical breakdown and high llp o p h ilio lty . These ohemical properties contribute to the adverse environmental e ffe c ts of the c lass o f compounds which have been widely Id e n tifie d In the global ecosystem and preferentially bioconcentrate in fish, w ild life and humana(3). Since the commercial PCBs are complex mixtures of isomers and congeners, i t is not suprising that the PCS composition of extracts from environmental samples and occupationally exposed humans is also complex. Moreover .it Is also apparent that the re la tiv e composition of the individual PCB compounds which have been Identified In various m atrices are highly v ariab le and do not resemble the distribution patterns observed fbr the commercial PCB praduots (4). I t is apparent from several studies th a t the environmental persistence end bloeccufflulatlCR of individual PCBs are dependent on se v e ra l fa c to rs in c lu d in g t h e i r degree o f c h lo r in a tio n , l l p b p h l l l c l t y , v o l a t i l i t y , and biodegradab i l lty . Hazard assessment of commercial and environmental PCB mixtures req u ires a n a ly tic a l data on the composition of these m ixtures and .the toxicology of Individual PCS Isomers and congeners and their interactive effects.
PCBs and Related Halogenated Aryl Hydrocarbons -
Toxicology and S tructure - A ctiv ity Relationships
(SARs).
"
Toxicology
Although the acute LDcn values fbr commercial PCS mixtures are re la tiv e ly high, I t Is apparent from subacute end chronic exposures stu d ies th a t much lower dose levels of some PCB mixtures e lic it diverse biologic and toxic e ffe c ts which include (2 ):
1. the development of skin lesio n s (which resemble human chloracne) In several laboratory mitmal species vid turnons;
2. icmunotoxic effects; 3. a wasting syndrome; 4. reproductive and fetal toxlelty; 5. earoinegenesls (In itiatio n and promotion) 6. ' porphyria and hepatotoxioity; 7. the Induction of diverse drug-metabolizing enzymes Including aryl hydrocarbon hydroxylase (AHH), a cytochrome P-450-dependent nenooxygenaae enzyme. It was also evident that the spectrum of toxic effects elicited by PCBs quantitatively were sim ilar to those observed a fte r treatm ent with several related classes of halogenated aryl hydrocarbons which in clu d e the dlbenzofurana (PCDFs)(2f5). Several studies with individual PCBs indicated that
3,3*4,4*- t e t r i - , 3 ,3 ',4 , U ^ S -p e n te , and 3|3*| 4(4^3,SMiexachlorobtphenyl a r t minor to tra c e components o f the commercial PCS formulations and are unlikely to be the sole contributors to the toxicity of these mixtures (2,4) Our research has focused on the identification of the toxic PCBs, the determination of th e ir presenoe o r 1absence is commercial and environmental PCB m ixtures end the us* of th is data to develop risk-assessment of W j .
PCBs - SARa The observed c o rre la tio n between the toxiciEy and the AHH induction potencies for the boxle halogenated sry l hydrocarbons suggests th a t the induction assay can be used as In d icato r o f p o te n tia l PCS to x ic ity . Our research i n i t i a l l y focused on the a c tiv ity o f PCBs as Inducers of AHH in immature male Ulster re ts, and ra t hepatoma H-4n E cells In culture. A comprehensive study of a ll 209 PCBs was not feasible. However, several reports indicated th a t tha most potent AHH inducers are su b stitu ted a t both para and two or more meta positions. In itia l studies confirmed th a t only 4 of these compounds (3 ,3 ',4 ,4 '-te tra -, 3 ,4 ,4 ',5 -te tra -, S ^ '^ ll^ S - p e n ta - and 33*, 4,4r,5 ,5 '-h e x a c h lo ro biphanyl) Induoed Alfil and Its associated cytochrome P-450 isozyme and l i c i t a d th e : to x ic e f f e c t s associated with halogenated aryl hydrocarbons. In subsequent research we synthesized and reported the biologic and toxic e ffe c ts of a l l the monoortho chloro-substitutad analogs of the 4 highly toxic eo p lan ar PCBs (See Figure 1). The r e s u l t s demonstrated th a t th is group of 8 PCB congeners e lic ite d a spectrum o f biologic and toxic e ffe c ts comparable to these observed for the coplanar PCBs although I t was apparent th a t the introduction of the ortho-ohloro substituent su b sta n tia lly reduced th e a c t i v i t y o f th e se compounds (2 ,6 ). The oonoortho oopianar PCBs have been identified in the commercial PCBs and environmental e x tra c ts and appear to fa* th* major toxic components o f these mixturas (4).
783739
m u
u m 'j
iAs;,<e .mM&r
. ' 8S 10/07 14:44
314- 694-6898 *
` PCSs - Human Toxicology Human populations have
Mefl.'eip b a e i to PCBs and PBBs v ia th re e major aathwaya, i.e ., en v iro n m en tal, o c o u p a tio n a l, and
idental. The e ffe c ts of PCBs and PBBs on humans . been determined by studying the occupationally
accidentally exposed in d iv id u a ls , sin c e i t has
acknowledged th a t th ese two groups have been
posed to th e h ig h e s t le v e ls o f PCSa. The major ffe c ts and symptoms observed during th e Yusho xisoning in Ja p and Taiwan include chlorecne and several rela te d dermal changes, ooular damage,
increased serum tr ig ly c e r id e s , re p ro d u c tiv e
problem s, a lte ra tio n s in s te ro id metabolism, increased serum (and adipose tissu e) le v e ls of PCBs,
md immunologic e f f e c ts (7). In c o n tr a s t, only a few o f th ese symptoms have been n o ted , in the Occupationally exposed workers. I t is not oleer vhy ;h is l e t t e r group does not p re s e n t more severe symptoms of PCS poisoning since the serum levels of
workers exposed to PCSa a re com parable and o fte n ligher than the lev e ls observed in viotim s of
xzcldental poisonings. The to x ic Yusho o i l co n tain ed a m ixture o f
;o L /c h lo rin a te d b ip h e n y ls (PCBs) w hich were :on tam in ated by o th e r h a lo g e n a te d a ro m a tic s .Deluding th e hig h ly to x ic PCDFs. I t has been
sported (7,8J Chat Che PCBs and PCCFs vtoich p e rsist n the liv e r of victim s s t i l l su fferin g from Yusho olsoning Include the fo llo w in g compounds; ?.3,,tt,`t ,,5 - p e n ta - l 2,2*. 4,4,5,5'-, 2 ,2 * ,3 \ M \ 5 -
nd 2 , 3 , 3 '^. 4 ',5 - h e x a , 2,2 ,3 , 4 , 4 \ 5 , 5 1- and . 'rB ^ '.^ U ^ S - h a p ta c h lo r o b ip h e n y ls and th e , 3 , 7 , 8 - t e t r a - , 1 , 2 , 4 , 7 , 8 - , 1 ,2 ,3 ,7 ,8 - and ,3 ,4 ,7 ,8-pen ta - and 1,2,3,4,7,8-hexaohlorodibenzourans. A ll v f th ese PC8s and PCDFs have been ynthealzed in my la b o ra to ry and r e c o n s titu te d to
oximate th eir composition in hum liv e r (8)* A
;arison of the dose-response e ffe c ts of the ^ c o n stitu te d PCS and PCD? m ix tu re s In causing e ig h t lo s s , thymic atrophy and th e in d u c tio n o f
ytochrome p-4U8-dependent oonooxygenases Indicated
n at the PCBF m ixture was a t l e a s t 700 tim e s more
ctive than the PCBs. Since the r a tio of PCBs/PCBFs e r s i s ti n g in Yusho p a ti e n ts ' blood and l iv e r was ess than 600: 1 and 5*1 r e s p e c tiv e ly , th e r e s u l t s
Jggest th at the PCCFs are the major e tio lo g ic agent
i Yusho poisoning. Comparable s tu d ie s on the ?xicity of the PCB and PCCF fra c tio n s iso la ta d from uaho o i l confirm th a t th e PCDFs were by f a r th e
oat toxic fraction present and must make the major
antribution to the to x ic ity o f the contam inated ice o il (9). These r e s u lts explain the toxic >sponse differences in the Ytisho and occupationally
1posed hums. YLsho o il oontained re la tiv e ly high
vela o f toxic PCCFs whereas most commerci a l PCSa antain lower lav els of these toxin im p u rities, sad on th e s e r e s u l t s , r i s k a sse ssm e n t o f
^vironm ental PCB exposure should be e x tra p o la te d
pld#al lc g ic evaluation o f occupationally 2Lnc* wor* rs exposed to high
is of PCBS exhibit r e la tiv e ly few adverse health
i v t t V l h l3 woul<1
that the potential
wiiro^n^mJ eVntia?l*e"xphoesuarlet hto PCBesQatrae rveersyu llot iwn. g from
MONSANTO STLOUIS
@003
REFERENCES
Cl 3 0. H u tz in g e r, . Chemistry . of Press, rH,
C2) 3. Safe, "Polychlorinated biphenyls (PCBs) and polybrcminated biphenyls (PBBs); biochemistry, toxicology and mechanism of action," CRC Crlt. Rev. Toxicol., Vol. 13, PP-319-391*, 19SC
C3J S. Safe, "Halogenated hydrocarbons and aryl hydrocarbons Identified in human tissu e s,"J. Toxicol. Environ. Chem. Rev.,. Vol. 5, p p .lb i165, 19tf2-
[4] S . S a f e , L. S a f e an d M. H u l l l n .
"Polychlorinated b ip h en y ls (PCBs) - congener-*
sp ecific a ly s i s o f a commercial m ixture and s human m ilk e x tr a c t" - J. A grlo. Food Chem.,
Vol. 23, pp.2*-29, 1935.
C5] 3. Safe, "Comparative toxlcolcgy and mechanism of aotlon of polychlorinated dibenzo-p-dioxlns and d ib a n z o f u r a n s " , Ann. Rev. P h arm aco l. T oxicol.. Voi. 26, pp 371^37$,"15815
C6] 3. Safe, 3. B andiara, T. Sawyer, L. Robertson, A. P arkinson, P.E. Thomas, D. Ryan, L.M. Reik.
W. Levin, M. A. Denomme, and T. F u j it a , "PCBs: S tructure-function rela tio n sh ip s d mechanism o f a c tio n ," Environ. H ealth P e rso e o t., Vol. ao, p p .tr^ o rW B ----------------------------
C7) M. fCuracsune and R.E. Shapiro (E ditors), PCB Poisoning in Japan and Taiwan, New York."tTan n n 5 u n i i a : f i M .----------
C8] S. S andlera, 1C. F a r r e l l , C. Mason, M. K elley,
M, R o okta, R. B a n n i s t e r , and S. S a fe ,
"Comparative to x io ltle s of the polychlorinated
diban aofur an (PCDF) and biphenyl (PCB) mixtures
which p e rs is t in ttisho victim s", Cheaoephere.
Vol. 13. pp. 507-512, 1984.
--------- c------7
C93 H. K u n ita , T. Kmah i a a t o , H. M ly a to , S.
PUkushlma, 1 Kori end H. Cbena, "Causal agents
o f YUsho", Amer. J . In d . Med.. Vol. 1. nn.
58, 1 9 8 4 . ------------------- *------ 7
7^
783740
