Document a4Z3wo3o2drRdLgQ8zZK6NwBR

J jL L C u o l O i ' !ti\ o in. . TOX ICOW^/V-'bfe feicr K b C O M 5T ION' PRODUCTS. C H E M I O L ^ T R , .Ofc* :> -d er W a l t e r W p v j p -d--- PC3s or polychlorinated biphenyls are still widely used in the electric utility industry. They are very heat stable resist oxidation, are excellent dielectric fluids, are fire resistant anc of low volatility. There are a number of factors that have focused public concern cr. PCBs as a potential hazard for human health and for the environ ment. 'Twenty years age, PCBs came to the attention of researchers as the chemical that interfered with the analysis of environmental samples for DDT. PCBs had in common with DDT the fact that they also are found all through the environment, that they are very persistent and that they are chlorinated. Around the same time, a new disease erupted in Japan, which was linked to the consumption of rice oil contaminated with PCBs. As we will see later, it was more than just PCBs in the oil. As a result of these and other factors, PCBs have the curious distinction cf being the only chemical cited by name in the Toxic Seestances Control A rt in the 70s. ' Mere recently, there has been increased pool nee1th risks c f sever al cf the PCS combustic cs_sed by the finding of PCDFs tpo Ivor, lor ina and also ?CDD (polych lor inated cibenzod iox in fire in transformers containing PCBs. ?C=s have been found in blood samples of most members of t.ne general public, i.e., "non-exposec" persons. Typical background levels a r e "about 10-20 ppb or less. Levels in "exposed person" such as utility workers are very similar, although higner levels are occasionally found. NEV 036909 -1- The toxicology of PCBs is quite complex. Commercial PCbs are complex mixtures of isomers, containing from one to eight clorinc atoms. Toxic potency is related to degree of cr.lor ina t ion, and varies widely. A great number of combustion products is theoretically possible and several have been isolated. In discussing the toxicology of PCBs and their combustion products, I will deal only with those that have a significant potential as toxicants, i.e. PCDFs and PCDDs. Their toxic potency of these compounds depends or. the degree of chlorination and the position of the chlorines. For PCBs, PCDFs and PCDDs, it has been found that the 2,3,7,8 - substituted isomers are orders of magnitude more toxic than the other isomers. The toxic effects observed following administration of these chemicals are quite similar, but there are substantial differ ences in severity. T C D D is 10-100 times as toxic as TCD F which in turn is 10-100 mor toxic than ?C3s. In evaluating the toxicity data for ?C3s, the furans and dioxins ore r.us z keep in mind that we are dealing with complex mixtures of isomers, which contain additives {trichlorobenzene is routinely added and can be a significant source of dioxins), impurities and degradation products formed curing the operation of the equipment. In addition, the circumstances of human exposures are often poorly defined, so that dcse is usually not known. ?C3s PCBs are readily absorbed through the skin or, following inges tion, from the gastrointestinal tract. If vaporized, such as in case cf a fire, they can be inhaled. They are fat soluble and -2- * NEV 036910 -o for that reason tend to concentrate in fatty tissues, liver and skin. Metabolism is slow and depends on the decree of chlori nation, The higher the chlorination, the slower the metabo lism, Great differences have been observed in the metabolic rates between animal species which may account for the species differences in toxicity. Non-human primates, for instance, are more sensitive than ra t s . ?CBs are generally classified as "not very toxic" to "slightly toxic" according to the internationally accepted convention for classification of toxic substances. This means it takes coses of grams per kg body weight to cause toxic symptoms. At high enough doses, PCBs cause loss of appetite, progressive loss of weight, and death, Ir. addition, liver damage, skin changes like chloracne, and symptoms of central nervous system toxicity have been observed. Chronic low-level administration of PCBs in primates also causes edema, loss of hair, depression of the bone marrow and the immune system, and endocrine d i s t u r b a n c e s , PCBs administered to pregnant animals cause death of the fetus, but r.o malformations or terata have seen observed. caused liv n s ;ut not all es ts were conducted. Tr.e significan ce of this observation for the c = rc ino genicity cf ?C=s in humans is un k n o w n . Chlorinated c o m p o u n d s , administered to rodents in ce ne ra 1 , especially at levels where they cause liver tox ici t y , cause a spectrum of her. icr. and malignant turners, nocules, etc. Also, the dose levels at which these tumors were observed is much higher than the levels of human exposures. -3 - NEV 36911 t 1 29 PCHs are not mutagenic in bacterial s y s t e m s , nut in vitro cell systems were positive for sister chromatid exchange and chromosome a b n o r m a l i t i e s . Based on these ccservations (i.e. positive in two mammalian assays), OSHA classifies PCB as a careinocen, Category I. Human St es Yusho is the a canese term for a case of mass PCS poisoning that occurec in Jape n in 1563. It was caused by the ingestion of cooking oil cor.taminatec wi th PC5 s , About 1TM00 people became i l l . objective symptoms in the affected people included skin changes such as chioracne, neuromuscular involvement and perhaps liver pathology . Host patients have since recovered, no unusual patterns of mor tality or cancer rates have been observed thus far but the number of people is rather small. Yusho is usually cited as a typical example of ?C3 toxicity. We now know that the cil these victims ingested contained signifi cant amounts cf diosrzofursns and other related c h e m i c a l s . Since TCDF is considerably more toxic than ?CBs, it is now believed tha: the toxicity reserved in these people was p r e d o m i n a n t l y , if not totally, caused tv furar.s. ------ C ?" s e smal- c cups Cl vorxe rs vrc where exposed to ?Csa in t he workplace . 7 e resul ts cf these studies are remarcarle for the absence of ill ,eal tr.. Orgective symptoms in these repula t ions , exposed to high levels of ?C3s compared to the general p u n ic , include cnlcra re and other skin c h a n g e s , and oranges in hepat io enzymes . In c a r*v- cz w o r k e r s , some decrement in res piratory functic was seer.. A follow-up study of. some 2500 workers exposed to PCS while working in a capacitcr plant did not find abnormal mortality patterns or increased risk of cancer. The study is, however, not very powerful and includes only a-email number of deaths. Conse- NEV 036912 130 quer.tly, th* results of tnis study have to be interpreted with caution until more definitive data become available. In summary# acute transitory symptoms of PCB toxicity in man have been observed. At this time, no evidence for the carcinogenicity of PCBs in man exists, but more definitive information needs to be developed. Dioxins and Furans Toxicity information on dioxins in animals and man is not very extensive compared to PCBs and even less is known about the toxicity of diser.zofurans. Most of the toxicity studies on dioxins were conducted with 2,3,7,8 - tetrachlorodibenzodioxin, the most toxic isomer. Information on other isomers is scarce. From these studies, it is quite obvious that there are substantial differences in toxicity among the i s o m e r s , and that there are great differences in the sensitivity of the different species tested. The acute toxicity (1D50) for 2,3,7,8-TCDD in guinea pics is 0.5 microcram per kg oocyweight (males are more sensitive than females'. In hamsters, or. the other hand, the LD50 is 5000 mi crocrams. The LD50 of most other soecies tested is between iOQ u, and SOD micrograms per kg. an example of intraspecies difference, inbred C=A mice are 10 times more sensitive tnan mice cr the C5 " strain. As for the effects or cn a c r ina t ion on toxicity, it was found tnat 2,6 dichlrro and hexachlorc cicxins, at levels of 1 microcrams caused nc observable toxic effects. In this context, it is important to keep in mind that the combustion products of commercial PCBs mixed with trichloro benzene contain a whole spectrum of dioxins. Reporting the mere presence of dioxins or furans is not very helpful in evaluating NEV 036913 -5- 131 toxicity. Of real importance is the level of furar.s and dioxins of significance relative to toxicity or risk. As an example, soot from the transformer fire in Binghamton contained about L" ^ 2200 parts per million d i b e n z o f u r a n s , but the level of the ^ U f^t y f 2,3,7,8 dibenzofuran (T C D F ) was 10 ppm. In the sar.e soot, about , 20 ppm of 2 , 3,7,8 dioxin (TCDD) was found. ^ " /[/l ) Tne acute toxicity in laboratory animals expresses itself as loss of appetite and progressive weight loss until death in weeks or months. Depending on the species tested, other symptoms are pancytopenia, skin changes including chloracne, edema, liver pathology. The mechanism of the toxic action is not well understood. Chronic toxicity studies of TCDD in rodents, at levels that cause some liverpathology, causes liver cancer. Again, the signifi cance of these liver neoplasms for the carcinogenic potential of dioxins in m an is not known. There is considerable difference in the carcinogenic potency between the various isomers. The 2,7 cichloro isomer is not carcinogenic. The minimal effective dose of the 2,3,7,6 isomer is about 0,01 rr.icrograms per kg. The MED of one hexa-isomer is 0,36 rr.icrograms per kg. r, r ,3,7 ,- TCDD is r.ct act :ve C -5 muta ici t v . li tcxic to the fetus. m ne svstert. 1* tn oa no tes, erial or mammalian in vitro teratogenic but is highly t is a potent suppressor of There are several sources cf information on human toxicity of dioxins. One source are the reports of medical fellow-up of persons occupationally exposed, mostly in chemical industries involved in the manufacturing of chlorinated chemicals. This population consists of about 1000 workers involved in some 20 separate incidents. The other-source of information comes from the medical follow-up of people exposed in a major accident in Seveso, Italy, in 1976. The data on workers are not very helpful -6- 036914 132 because they are mostly sm.sll croups, with unknown levels c:` exposure, and alr.est certain exposures to other toxic chemical? before and during the accident. The studies in Sevesc concern? exposure to dioxins only. A naicr problem, is that the population is poorly characterized and the exposure levels are unknown. Symptoms of dioxin toxicity in both peculations are cuite s i m i l a r . Objective symptoms that could be consistent!'.' linked to dioxins are chlcracne and other skin chances, miId liver involvement, disturbances in the porphyrin metabolism., and neurouscular involvement. A study cf limited size die net observe impairment of the immune system.. Also, no increase in spontaneous abortions, still-births, or malformations were sear.. Again, it should be kept in mine that the power of these studies is limited, and that a continued follow-up is required before definitive information is available. In summary, severe irreversible acute and long-term texi; effects following exposure to PCBs and related chemicals ha; been observed in animals. Acute toxicity in humans has been observed but it is limited to skin abnormalities i r. humans in the case of ?CHs. Mere severs but reversible symptoms cf toxicity caused by TCD7 and TTT- have alsc been observed. L o n g-term follow-up cf persens exposed to these chemicals hnet been able tc demonstrate at "his time an increased m.rrt; from cancer. The results cf these studies should be interpr; with caution since the cover cf these studies is limited a: additional fcllew-up is required before mere definitive res. are available* NEV 036915