Document X8yGLO3NqZ3Jn5zgMGywamLv4
Two Year Oral (Diet)Toxicitv/ Carcino.eeniciSttvudv of FluorochemicalFM-3924 in Rats Riker Experiment No. 0281 CRO01 2
Review bv Dr WilliamH Butler At therecuestof 3M CorporateToxicoloev.I have reviewed the above studv with specific regardto the evidenceof carcinogenicitoyf FM-3924. I have reviewed the studyreport includingthe individualhistot)athololidciaalgnosesof Dr R Geil.studvDatholop-isIth.ave not reviewed theindividualpathologicalslidesof the studv,
Concern has been expressedover the findingsof het)atocellu]aadtenomas and carcinomas in female ratsreceiving100 ;);)mFM-3924.
R 0az.111tiz..
There aresignificandtose dependentreductionsof bodv weightsof 20.8% high dose.]5.3% mid-dose and 3.5% low dose group female rats.There isno effectut)onmortalitvA.t I vear thereisa significanitncreaseof liverweights inthe high dose grout).
Of the maior non-neot)lastifcindinlyrseDortecLhet)atocvtmeelalocvtosis hvl)ertrovhvwas reportedin 88% of high dose ratsand 0% in the controls.T4vr)emlastincodules were observed in I controland 9 hilyhdose female rats.In males. meealocvtosiswas recordedin the treated.groupasnd hv;)emlasfincodulesin both the high dose.grout()10%) and mid dose grout()2%).
Of theneot)lastifcindingsh.et)atocellulcaarrcinomas were recordedin allmale groups with
no evidence of an increaseassociatedwith treatment.No adenomas were seen in anv male
group.In females het)atocellulaadrenomas and carcinomas were onlv observed in the high
dose LITOUD.
Control
High 100 t)vm
Adenoma
n
4
CarCinnmsa
0
The excessivreeductioonfbodv wellyhLtyaisneeninbothmaleand femalehllyhdloserats1.1;
an indicatiotnhattheNM had been exceeded in both sexes.The melyalocytosiosr
hypertrot)hovf hepatocytesis evidenceof metabolicinductionH.enatocyte bypertrot)hv.
follovanainductioIn,iswell
reco-gniseda.-a;proliferativsetimulusfor
henatocytes.A
A
I
long
term seauelaof thishvl)ertronhyisreco2nisedas henatcvtedelenerationret)orteidn thisstudv
a--e.Ivstoidde-lenerationF.urtherevidence
of
ber)atocvtedamale
A
I
isthe r)resenceof
hypemla-,ticnodules.Hyperpla.-;tniocdules are a reparativeproliferativreesponse to chronic
liverinjury.From thisstudy itcan be seenthatatdoses in excessof the NM. thereis
chronichenatocyteinjuryleadingto a proliferativreesponse.
in additionto the evidenceof chronicliverikiurydiscussedabove.in the female hilh dose
group both hepaticadenoma.-,and carcinoma.-w;ere observed.When consideredindividually
neitherachievesienificanceI.tis,however, necessaryto considerthe combined incidenceof
adenoma.-.and carcinoma.-&,-,ithas been suLy2estedthatthe two lesionsmay representa
continuum- a suLLye.%fiwohnich in mv oninion isnot justifiedT.n the absense of L'enotoxicitv.
I
A
itisnow clearlyrecoenisedthata chronichepatocyteprofilerafisvfeimulus,as evidencedby
continuedhepatocyteinjury,may be a.-.sociatweidth the development of a neopl&-,tircesponse.
In the absenseof chronichepaticinjuryno neoplasficresponseisseen;the observationof this
study.
In my opinionthe marginal increaseof the combined incidencehepaticadenomas and carcinomasobserved in thisstudyissecondary to the chronichepaticeffectsof FM-3924 at doses in excessof the MTD.
Dr WilliamH Butler MB. BS., F.R.C.Patb.A,TS Glebe Cottage Big Common Lane Bletchingley SurreyRHI 4QE U.K.
12 November. 1998.
Tel 44 (0)1883743 289 Fax.44 (0)1883744 355