Document nkL7agZR1wyNEb0jQgg51DL6w

C II R U ): N T S T A T U s O 1* T O X I C OIi 0 C T C A L )i F K V. C T S 0 V V C 15 n i Albert C. Kolbye, Jr., H. D. Deputy Director Bureau of Foods September 1, 1971 NEV 036293 TIk* PCIte arc manufactured in the USA as Arochlors ami arc also im ported I'rom other countries oi manufacture in a variety of unknown pro- due is. It is likely that PCBs have been getting into environmental circu lation for a period of years, although such contamination on an environ mental scale has only been recognized recently in the pact few years. Residues have been found in a variety of foods as a result of either direct contact with materials containing PCBs or os a result of biolo gical uptake of I'Clis circulating in the environment. What is the toxicological significance of PCBs? I would like to briefly summarize data derived from animal experiments and from human intoxications. % While the oral LDJ^ in mammals varies from about 2 to 10 gms/kg, sub stantially smaller doses adversely affect egg production in birds. Chick embryo studies indicate that lethal effects decrease with increases in the chlorine content of the PCBs, and that a variety of birth defects can result from PCBs tested in this sensitive system. Rats experience growth depression and increase in liver size when dosed with 1,000 ppm in the diet; however, induction of certain enzymes has boon noted at levels as low as 25 ppm in the diet. Generally, enzyme induction increases with increases in chlorination of PCB. Pathologi cally, monkeys given 1.4 to 16 mg/day PCBs in their diet showed liver cell enlargement, fatty degeneration, and an increase in the smooth en- doplasmic reticulum of the liver cells indicating fibrotic changes. Re flecting alteration of liver metabolism, changes in hexabarbital sleep ing time and other enzymatic related dotoxiflcatl 0n stePs were noted I largely related Lo induction of hejxitic hydroxylating enzyui tcvl e.ardiaL edema lina been noted and may por.:;ibly in part b the contaminating presence o chlorinated dibenzofurans in eij;n manufacture. At levels around 100 ppm in the diet, adverse reproduc with decreased litter size and survival have been noted in ereases noted in liver and thyroid weights.- Obviously PCJJs tabolism by inducing certain enzyme systems and undoubtedly others. It is likely that such changes adversely affect th of hormones and pesticides, not to mention the relatively u of interactions with therapeutic drugs. We know that PC15 residues have been found in human fat levels ol 00 ppb. However, little is known about the me tab PClls themselves in animals and humans. Human intoxication with Kannchlor 400, a PC15 inanufaetu with 487- chlorine, but unknown chemical characteristics as was noted when a heat exchanger leaked into rice oil which 1 by Japanese families in 1968. About 600 people were eventu exposure levels to the oil wore calculated to approximate 1. The oil itself was apparently contaminated at levels estima from 200 to 2,300 ppm PC15s, but the origin of the lower figi given in the particular Japanese publication and is current. investigation. The higher figure is derived from the known chlorine content of rice oil related to the kr.owr. organic cl tent of Kannchlor 400. j tc; u l ; an irea it xe m .ty, :d :ed. ;e iA 95 3- TIk * clinical problems associated with Japanese Yusho incident juchuK'd chloraono, blindness, systemic gas tiro intestinal symptom:: wj Hi Jaundice, edema, and abdominal pain, birth abnormalities were noted in that a lew babies were born with decreased birth weights and shin dis coloration which later repressed. Nothing is known as to whclher or not these children have experienced permanent liver damage or alterations in liver function or metabolic detoxification of hormones, etc. Nothin?; was described in relation to thyroid function which you will remember was noted apparently to be affected in animals. Transplacental transmission of l'OJs wore noted by the presence of residues in fetal tissue. To summarize what is presently known, the no-effect level in test mammals may approximate 10 ppm in the diet. based on this animal data with allowance for a 1,500 gm human dietary food intake, the ADT. would permit a 100-fol.d margin of safety if set at 150 /CV.nis l'Clls per day. From the observations available to us concerning Yusho, the lowest reported figures estimate a minimal positive effect level at 3 mg per day even though the average doses to these Japanese may have been higher. Using a tenfold safety margin, we could roughly estimate that 300 yogms would be without overt effect although possibly subtle changes in liver function may still occur. Thus animal and human data both point to 150 to 300 /gms/day as being in the range of consideration for establishing an acceptable daily intake for the period of time that we as a society are forced to tolerate the presence of these chemicals in our food supply, but I would like Lo emphasize that we know very little about the potential metabolic con sequences to long-term PCB exposures even at these la., levels. 036Z96 NfcV !' ; i : / 4- - ln further consideration of low-level exposures, we e/wi pi.vdiui: ' time since 2 gms was reported to be Lbe total dose necessary to cause an effect In tbe Japanese, then 200 mg would be an estimated total safe jngo.:;Lion over an extended period of time, I emphasize that I am now t a l k ing total accumulated exposure and not a daily exposure. Our previous lowest estimate of a safe dose was 150/ j'& fday based on animal data or 300y*/gm/day based on human data. With a total allowable invest ion of 200 mg we could estimate a safe period of intake of 44 month:; based on the 150//gm/day animal exposure data or 22 months at the 300 ^ m / d a y level based on human data. if we can assume new regulatory approaches will bring the problem under better control within 6 months, this would permit 1.1 mg/day of VCH in the dietary intake for the next six-month period only as a tem porary measure. At u level of 5 ppm this allows total intake of 200 grams food. At a level of 4 ppm tills allows total Intake of 230 grama food. At a level of 3 ppm this allows total intake of 330 grams food. At a level of 2 ppm this allows total Intake of 500 grams food. At a level of 1 ppm this allows total intake of 1 kilogram food. NEV 036297 voonhtstituut veterihaire farhacologie bit toxicologie seek r .u . Biltstraat 172 Utrecht* Beelnemegslltet PCB oonferentle 20 sent, 1972* Ur* J. Bonnema Kouringsd* van Varan, Et. Janastra&t 4 Ir. H.W.L. Bruckman Xeuringsd.'van Haren, Florjnruwe 111 Drs.Cirkel Sigma Coatings OT, Oostzydo 39 hr. H*R* Collet Monsanto Europe SA (Monsanto, J. v. Hassaustr* 53, Ban Haag) Br. T* Boorgeeat Verfinstitut TSO, Postbus 203 Dr. C. Engel Cantraal Inst. Voedlngsondarzoek Utraahtaaveg 4S Dre. C.J* van Each Bijks Inst* voor da Yolksgezondheld, Lab* voor Toxloologle, Postbus 1 lieJ.Dr* C. Kikelenboom Schdikundiga bIJ Kouringsdienst van Waren, Prinsegracht 50 - G.. Feskens I.E.O. Transformatorenfabriak 2T7 Poethus 206 Hr* Fowler f J 4 % \K G+tetr f i i f ICI Holland H7. Postbus 551 (ifond Division) C-Kfn yr^*' Prof. . van Genderen Inst* Tat. Farmacologle an Toxicologie, Biltstraat 172 Dr. P.A. Greva Rijks Inst* voor da Yolksgezondheld Postbus 1 ^ Dr* xT.J.A. Groan Hoofdinsp. van do Yolksgezondheld voor da Hygibne v/h Ililisu Dr. Rayerastraat 8 A.Th. Groot Waaseld5jk Philips Hedisohe Dienst art* G.P.A* Buising Mobil Chemie . Postbox 130 C SLU * ~ Prof.Dr. J.H. Eoaman Landbouvhogeeobool I Be Breyen 11 '''st/lMimr* A. Stare S5jpest*yn Organisch Chem. Institut Croasastraat 79 .B. Boome ICI Holland BT Postbus 551 Bra* F.B.J* Koope Bema HV Utraohtaavag 310 Br* M*E* Xronenberg Studie- an Inform,osntrum THO voor OnCorzoek tan dianata van hat Hilleubehetr, Postbus 186 Groningen Maastricht Zaandaa Brussel Belft Zalst Bllthovan Bsn Haag Breda Rotterdam Utreoht Bllthovan Leidschendaa Eindhoven Balft Vagenlngen - ^ Utrecht Rotterdam Arnhem Balft 036298 - 2- Drs.' A. Kruysse .Hoofdinspeotie van de Volksgezondheid op het gebied van levensmlddelen en de lceuring van Waren, DrReyorsstraat 10 Leidsohendam liej. II.B. van Lennep Centrale Orgenisatie TNO, Fostbus 297 Ben Haag F.E. Looejes Hoofdinspoctie van de Volksgezond- Wageningen heid voor de Hygiene v/h lliliou Geertjeaweg 15 , Br Ir. A. Oho Technisch Bureau Brandschade preventie, Eemnesserweg 56 Baaxn Br J.C Overeen Organisch Chera. Instituut TNO Croesestraat 79 Utreoht F.L. Pelt Landbouwhogeschool Vageningen P.JA MaTslw Ifoneanto Europa SA (Honanto HV, J.v.ITassauatr. 55 Ben Haag) Brussel Br8 L.S Schuddeboom Br R Sijdoriuo Ir GE. Standhardt Hoofdinspectie van de Volksge zondheid voor de Levensmiddelen, Br Heyersstraat 10 Kema UV, Utreohtaewog 310 tfobil Chemie, Poatbox 130 Leidsehendaa Arnhem Belft Br. H. van der Velden Keuringsdlenst van Waren, ITieuue Gracht 3 Haarlem Br H.G. Verschnren Rfjk Inst, voor de Volkagesondheid Bilthovan Postbus 1 -- -^Br J.G. Vo* Ir R.n. de Vos Fac. der Biergeneeskunde Pathologisch Instituut Biltetraat 172 Utrecht Centroal Inst, voor Voedingsonderzoek Zeist Utreohtseweg 48 NV 036299