Document jgpZLG8bY346O13y6aEyGd1np

ifp* ^ -> v *>..-> A-.. -v; . V,' ; nJSa**!**' C U 11 R K N T S T A T U S O 1' i T O X I- C 0 L 0 C I C A L 15 !' F K CTS OF IV C It s .s i Albert C. Kolbye, Jr., M.D. Deputy Director ' Bureau of Foods September 1, 1971 ' DSW 162561 F STLCOPCB4041131 . The.PCBs are manufactured in the USA as Arochlors and arc also im ported from other countries of manufacture in a variety of unknown pro , duets.. . . it is likely that l'CUs have been getting into environmental cireu- lation for a period of years, although such contamination on an environ mental -ncalc has only been recognized recently in the .past few years. Residues have been found in a variety of foods as a result of either direct contact with materials containing PCBs or as a result of biolo gical uptake of PCBs 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 LD"^ 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 been 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 livei cells indicating fibrotic changes. Re flecting alteration of liver metabolism, changes in hexabarbital sleep ing .time and other enzymatic related detoxification steps were noted, - ' ' . . ** ` . DSW 162562 -. . . >..* STLCOPCB4041132 /Inrgo-'iy related to Induction oi: hepatic hydroxy lulling e.nzyi.ioo. . in bird;: pericardial edema haa been noted and may possibly in part be related to. the .contaminating presence of chlorinated dibenzofurans in PCBs of for eign manufacture. . At levels around 100 ppm in the diet, adverse reproductive effects hwith decreased litter size and survival have been noted in-rats with in- .' creases noted in liver and thyroid weights.- Obviously PCBs affect ine- .Cabolism -by.inducing certain enzyme systems and undoubtedly inhibiting -others. It is likely that such changes adversely affect the metabolism of hormones and pesticides, not to mention the relatively unexplored area of interactions with therapeutic drugs. We know that PCB residues have been found in human fat and millc at levels of 60 ppb. However, little is known about the metabolism of the PCBs' themselves in animals and humans. ' Human intoxication with Kanachlor 400, a PCli manufactured in Japan with 43% chlorine, but unknown chemical characteristics as to the purity, was noted when a heat exchanger leaked into rice oil which was consumed by Japanese families in 1968. About 600 people were eventually affected. Exposure levels to the oil were calculated to approximate 15 gm/day. Tue oil. itself was apparently contaminated at levels estimated to range from 200 to 2,300 ppm PCBs, but the origin of the lower figure is not given, in the particular Japanese publication,and is currently under FDA investigation. The higher figure is (derived from the known organic chlorine content, of rice oil related to the known organic chlorine con tent of Kanachlor 400. . . / DSW 162563 STLCOPCB4041133 . The clinical problems associated with Japanese Yuslio incident in cluded- chlordcno, blindness, systemic gastro intestinal symptoms with jaundice, edema, and abdominal pain. Birth abnormalities wore noted in th.at a few babies were born with decreased birth weights and skin dis- -a ' \. . '. ' ' colcx*ation which later regressed. Nothing is known as to whether or not these children-have experienced permanent liver damage or alterations in liver- function or metabolic detoxification of hormones, etc. Nothing was described in relation to thyroid function which you will remember was noted apparently to be affected in animals. Transplacental transmission of PCBs were 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 d 1,500 gm human dietary food intake, the ADI would permi t a 100-fold margin of safety if set at 150 /Ogms l'CUs per day. I'rom 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 avbrage doses to these Japanese may have been higher. Using a tenfold safety margin, we could roughly estimate that 300 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. 300yogms/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 to emphasize that' we know very little about the potential metabolic con sequences to long-term PCB exposures even at these low levels. r DSW 162564 STLCOPCB4041134 -4- . In further consideration of low-level exposures, we can predict . - . that since 2 gins wau reported to be the total dose necessary to cause an effect in the Japiine.se, then 200 mg would be an estimated total safe in gestion over an extended period of time. I emphasize that I am now talk- ' i. . ' -. - ing total accumulated exposure and not a daily exposure. Our previous lowest estimate of a safe dose was 150 ^g/day based on animal data or 300/^gin/day based on human data. With a total allowable ingestion of 200 mg..we could estimate a safe period of intake of 44 months based on the 150/ygm/day animal exposure data or 22 months at the 300/c^grn/day level based on human data. : If . we can a.ssume new regulatory approaches will bring the problem under better control within 6 months, this would permit 1.1 mg/day of - .' '' ; " *: PCB in the dietary intake for the next six-month period only as a tern-. porary measure.- ... At a level of5 ppm this allows total Intake of 200 grams food. At a level of4 ppm this allows total intake of 250 grains food. At a level of.3 ppm this allows total intake of 330 grams food. At a level of2 ppm this allows total intake of 500 grams food. At a level of 1 ppm this allows total intake of 1 kilogram food. 4 DSW 162565 STLCOPCB4041135