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A pril 18, 1975
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Dear George:
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Very truly yours,
JCC:AR
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BIO-TEST J2aM&atc*iu , 2*c.
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REVIEW OF PCB MEETING
. . The central issue in question is whether the PCB's are
carcinogens or not. The long term studies conducted at BIO-TEST
indicate that the answ er is no. D rs. Ward Richter and Donovan
Gordon are of this opinion which is shared by M. L. Keplinger and
J. C. Calandra.
On the other hand, a study conducted by Dr. Renata Kimbrough
presents evidence that in female rats of the Sherman strain, liver
carcinom as were found. This is the only study in which this finding
is reported in rats. BIO-TEST has no basis for refuting the findings
of Kimbrough except to take exception td the design of the experiment
that used only fem ale rats and to point out that to our knowledge no one
else has reported sim ilar results in rats. It should be noted that the
earlier allegation by Kimbrough that bladder cancers developed in
female rats fed PCB was successfully counteracted by BIO-TEST and
Monsanto personnel.
Kimura* worked with Kanechlor-400, a com m ercial brand
of PCB and in a rat study of 400 days' duration concluded that "PCB's
induced a benign neoplastic change, though it seem ed to be still short
of m alignancy, and that the change appeared exclusively in the females. "
The author expressed concern that the benign nodules in the liver may
progress to carcinom as if "specific or non-specific stimuli are
introduced into the anim al. "
204 100731
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B I O TEST
Sne.
and
w ell-*Id*toif2fecroenndtiuactteedd
& study in mice and found "hyperplastic nodules hepatocellular carcinom as" at a dose level of
500 ppm of Kanechlor 500. H epatocellular carcinom as w ere not in
duced by Kanechlor 300 and Kanechlor 400.
The evidence to date indicates' that male rats are more resistant
than fem ales to the formation of nodular hyperplasia as well as hepato
cellular carcinom a. Rats also are m ore resistant to the induction of
these lesions than mice.
To return to the BIO-TEST studies on PCB, it should be noted
that the liver sections which were read by the pathologists and reported
in IBT No. 641-06672 and dated March 24, 1975, were not the same
slides or sections as those reported on originally. The preserved
livers were reprocessed by taking 4 "cuts" from different areas to
obtain as large a representative sample as possible. It is not surprising
that under these circum stances a different tabulation of the various
prim ary liver lesions was found. Studies on thyroid hyperplasia and
by R ichter's associate. Dr. Stanley Vesselinovitch, have shown that
this procedure generally results in a different qualitative and quantitative
line-up of lesions that are reported by the same pathologist.
Ideally one would like to be able to reaffirm the original
findings by this procedure, but this is not always possible because of
the additional variables introduced. Serial sections of the liver would
205 1007
SfJtutA ial B1O TEST iStiwa/ixH $mc.
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elim inate tome of the covariant*. The im portant point in the mo*t recent study of the sections is the fact that no hepatocellular carcinomas w ere fo*und which is in agreem ent with the e a rlie r findings. It must be emphasized that the diagnosis of "hepatoma" by Cordon and Richter connotes a benign process and m ust not be confused with the classical definition of the term by "human" pathologists.
F urther, Dr. Squires reviewed a number of the same slides on A roclor 1260 with D rs. Cordon, Levin ska s, Kimbrough and Richter and agreed with the BIO-TEST pathologists that liver carcinomas were not present in the slides. In addition, the original slides have been in the possession of FDA since June, 1973 and to date we have not been informed of any disagreem ent with BIO-TEST findings.
Dr, Squires has stated in a letter to Dr. Kimbrough dated November 12, 1974, that "I define 'd iscrete nodules' and 'trabecular (basophilic) hyperplasia' as precancerous lesions and thus indicative of carcinogenic response." This reflects a viewpoint which is not shared by all pathologists and there is nothing that BIO-TEST can do to change this definition except for its pathologists to accept or reject the view. D rs. Richter and Gordon do not accept Dr. Squire's definition*
W orkers in the field have published extensively on the pathogenesis of hepatocellular carcinom a in recent years and the concepts have undergone considerable changes since the preparation
206 1007H;j
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of the final BIO-TEST report on chronic oral toxicity studies. One m ust note that Popper^ in his studies on A ram ite in i960 postulated that hyperplastic nodules were transform ed into hepatocellular cancer; however, this concept was not generally accepted by the scientific community.
An excellent paper which describes ''the highlights of some new er developments in our understanding of liver carcinogenesis" has been published by E arber. 4 If the concepts presented in this paper as well as those of Squires, Saffiotti and others are accepted, a number of substances would have to be reclassified as liver carcinogens. C arried to extrem e, we could argue that any substance that results in stimulation of liver m icrosom al enzymes or possesses hepatocytoxic properties to any degree is a potential liver carcinogen.
BIO-TEST is unwilling to accept these concepts. The lesions seen in the liv ers of the ra ts in its PCB studies for Monsanto do not show vascular invasion, m etasteses or anaplasia - all classical features of carcinom a. We continue to view the lesions seen to be benign.
Several additional things need to be done by BIO-TEST and these include:
(a) Re-exam ine the original liver slides. (b) bCluotckneswansdecrteioadnssalitdedsif.ferent levels from original paraffin (c) Tabulate liv er findings separately in female and male ra ts. (d) lIifvpeorscsihbalneg, eds.evelop inform ation on the reversibility of the
207 10073
iiual B IO - T E S T
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It is im portant to point out the .following: 1 The BIO-TEST position was and rem ains that the PCB's w ere not shown to be liv er carcinogens in its studies. This conclusion is the opinion of its resident pathologists as well as its independent consultant. 2. The BIO-TEST results show that a no-effect level for the development of hyperplastic nodules was found in each of its studies. 3. BIO-TEST has no means at its disposal to dispute the findings of Kimbrough that A roclor 1260 in fem ale Sherman rats is a liver carcinogen except on the basis of experim ental design. 4. BIO-TEST is not in agreem ent with the classification by Squires et al. that considers hyperplastic liver nodules to be precancerous. 5. BIO-TEST studies on PCB's m eet the scientific standards of Toxicology and Pathology and we are prepared to assist Monsanto in any adversary situation in or out of government.
J. C. Calandra
A pril 18, 1975
References
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COO N. liA tfltrg* C o u lm 'd S t. lw'S. M itto v n 63160 N oai:i3U: 614*1000
July 18, 1975
Dr. J.C. Calandra Industrial BIO-TEST Laboratories 1810 Frontage Rd. Northbrook, 111. 60062
re: AROCLOR 2-year Rat Feeding Studies
Dear Joe:
The attached table summarizes a comparison of the 3 revised AROCLOR reports (12U2, 125^, 1250).
In 2 Instances, the previous conclusion of "slightly tumorigenic" as changed to "does not appear to be carcinogenic'. The latter phrase is preferable. May we request that the AROCLOR 125^ report be amended to say "does net appear to be carcinogenic".
The number of hepatomas reported for AROCLORS 1260 and 12^2 have been interchanged. This appears to have arisen from con fusion regarding the numbering of the animals. The original
reports show tumors in animals with numbers in the 100-300 range
for AROCLOR 1260 and in the 500 to 800 range for AROCLOR 12U2. This leads me to conclude that the numbering scheme shown in the second set of reports is correct. With AROCLOR 125^ confusion is compounded. The original report showed tumors in animals with numbers in the units to teens, but the revised report shows
animal numbers ranging from ^0 to 1000. Can this be straightened
out?
I was unable to reconcile the differences in the animal numbers between the first supplemental report and the original reports, I had inquired as to the changes in the numbers. As I recall, I was told that the sections had been renumoered when the new slides were made and that a key relating to the sets of numbers
100737
received
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DJru.lyJ.1C8., 1C9a7l5andra
Page - 2 would be supplied. This has not been done. It may not be necessary for AROCLORS 1260 and 1242, but AROCLOR 1254 remains unresolved. Insofar as I can see, the remainder of the reports appear acceptable. Kindest personal regards,
Sincerely,
George J. Levinskas, PhD Mgr., Environmental Assessment
and Toxicology /bkp att. cc: Dr. George Roush, Jr., M.D.
210 100738
cc
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Product
Supplemental Report
#1 (mailed)
AROCLOR 1260
conclusion
slightly tuaorlgenic
hepatomas
3
range of
p. p.
109
test
animal
nos:
6100000tos8e0r0ies
p. 11
pP..
12 13
p. 14
57000
to to
160000
60700 0tos7e0r0ies
S#u2pple( mJCeCntadleliRveeproerdt
does not appear carcinogenic
7
100 to 300
81000
to to
900 4o
22080000
to to to
200 300 300
AROCLOR 1254
conclusion
(
hepatomas
slightly tumorigenic
6
slightly tumorigenic
6
AROCLOR 1242
conclusion
slightly tumorigenic
does not appear carcinogenic
hepatomas range of test animal nos.
73
as In report #2 as in report #1 for AROCLOR 1260 AROCLOR 1260
211 100 ( oO\il\
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August 4, 1975
J*r'! . SM8DE0trn,o0*vnLiNsrGaooonusnrotitmsorhgeCLtnMoitJnmai.dlspsbALaoeneusrysvgreihinsssB6mk3oa1ues6nl,e6tvMaarnidduTgtorxicology Dear George: Pe: Aroclor - 2 Year Rat Studies dated Julyla1r8e,ga1r9d75t,o ptheertacoinminmgetnotsthaenadbqouvees,tipolnesasceovneorteedthlae fyoolulorwlientgte:r bpeagcea1r2.coinfWotgheeenwAiiclr"loacinmloerpnlad1c2e5o4uorfres"ptsaoltiregtmhtteolnyrtetuIanmd,tohre"idgloaeenssticpn"oaatrasagprrpeaeqpauhreosttnoed. wIannedrthe1e22r.o6e0rviIegrnrienspreaeodlgr.artsre,dpotthroetsyth, aetrhaeencAimorraorlcenlcoutrmintbiteolreussr iffnoinrtahltehreAesvreoisctewldoorrme1pa24ote2rrt.ials aresptohr3ot.sseoiTnnheoevuaarlnuoiamrtiiagolinnidaoelfnratedipfdiocitraitto.inoanTl hnlieuvmearnbiemsresactlasipowpnesearareirnengotthineretsnhaeummebered. " - aognodnfruadm1Api2tb4hri5oeo.i4crnc.asalolWliPrneleeri1vtrrch2ehoae5rarn4prn.soeseonpcttHothpfiroiioanstwgnsdeeiss(vao1dentrarwhyi,tegehdidiibnincsaahMctlsrh,iraeseerprfceoareh-fenreprcy2voeyo4ardu,ltIurnt1oaoc9nato7iAnon5rinrem,fuo-,etacshvfilloioeaninrrldaue.el1anw2trti6eiaof0vsinciiseanoitostfitnyoepn)aod you for yoIuhropaesstihsatat nthciss awnidllcsoeorpveerattoiofnu.rther clarify the situation. Thank Sincerely yours,
JP.reCs.ldCsaatlandre
212 a 0Z113080714